Pediatric Surgery: 2-Volume Set (Grosfeld, Pediatric Surgery) 6th ed

Molecular Clinical Genetics and Gene Therapy Alan W. Flake

The topics of this chapter are broad in scope and outside the realm of a classic core education in pediatric surgery. However, both molecular genetics and gene therapy will be of increasing clinical importance in all medical specialties, including pediatric surgery, in the near future. A few conservative predictions include improvements in the diagnostic accuracy and prediction of phenotype, the development of new therapeutic options for many disorders, and the optimization of pharmacotherapy based on patient genotype, but there are many other possible uses. The goal here is to provide an overview of recent developments that are relevant or potentially relevant to pediatric surgery.

MOLECULAR CLINICAL GENETICS Although hereditary disease has been recognized for centuries, only relatively recently has heredity become the prevailing explanation for numerous human diseases. Before the 1970s, physicians considered genetic diseases to be relatively rare and irrelevant to clinical care. With the advent of rapid advances in molecular genetics, we currently recognize that genes are critical factors in virtually all human diseases. Although an incomplete indicator, McKusick's Mendelian Inheritance in Man has grown from about 1500 entries in 1965 to 10,000 in 2000, documenting the acceleration of knowledge in human genetics. 44 Even disorders that were once considered to be purely acquired, such as infectious diseases, are now recognized to be influenced by genetic mechanisms of inherent vulnerability and genetically driven immune system responses. Despite this phenomenal increase in genetic information and the associated insight into human disease, there remains a wide gap between the identification of genotypic abnormalities that are linked to phenotypic manifestations in humans and any practical application to patient treatment. With the notable exceptions of genetic counseling and prenatal diagnosis, molecular genetics presently has little impact on the daily practice

of medicine or, more specifically, on the practice of pediatric surgery. The promise of molecular genetics cannot be denied, however. IdentifYing the fundamental basis of human disorders and of individual responses to environmental, pharmacologic, and disease-induced perturbations is the first step toward understanding the downstream pathways that may have a profound impact on clinical therapy. The ultimate application of genetics would be the correction of germline defects for affected individuals and their progeny. Although germline correction remains a future fantasy fraught with ethical controversy,56 there is no question that molecular genetics will begin to impact clinical practice in myriad ways within the next decade. A comprehensive discussion of the field of molecular genetics is beyond the scope of this chapter, and there are many sources of information on the clinical genetics of pediatric surgical disorders.

Human Molecular Genetics and Pediatric Surgical Disease The rapid identification of genes associated with human disease has revolutionized the field of medical genetics, providing more accurate diagnostic, prognostic, and potentially therapeutic tools. However, increased knowledge is always associated with increased complexity. Whereas the classic model assumed that the spread of certain traits in families is associated with the transmission of a single molecular defect-with individual alleles segregating into families according to Mendel's lawstoday's model recognizes that very few phenotypes can be satisfactorily explained by a mutation at a single gene locus. The phenotypic diversity recognized in disorders that were once considered monogenic has led to a reconceptualization of genetic disease. Although mendelian models are useful for identifying the primary cause of familial disorders, they appear to be incomplete as models of the true physiologic and cellular nature of defects. 15 .66 ,71 Numerous disorders that were initially

Ability to predict phenotype from genotype • Higher •

Multifactorial

<

.

~

Polygenic

Lower

m ::l

::l

3

CD ::l

[ Oligogenic

a

cCD

::l

"oCD ::l

"C

:::r

CD ::l

~

"C

Number of genetic loci influencing phenotype

CD

WlIIii#§1 Conceptual continuum of modern molecular genetics. The genetic characterization of a disorder depends on (1) whether a major locus makes a dominant contribution to the phenotype, (2) the number of loci that influence the phenotype, and (3) the presence and extent of environmental influence on phenotype. The farther toward the right a disorder lies, the greater the complexity of the genetic analysis and the less predictive genotype is of phenotype.

characterized as monogenic are proving to be either caused or modulated by the action of a small number of loci. These disorders are described as oligogenic disorders, an evolving concept that encompasses a large spectrum of phenotypes that are neither monogenic nor polygenic. In contrast to polygenic or complex traits-which are thought to result from poorly understood interactions between many genes and the environment-oligogenic disorders are primarily genetic in etiology but require the synergistic action of mutant alleles at a small number of loci. One can look at modern molecular genetics as a conceptual continuum between classic mendelian and complex traits (Fig. 2-1). The position of any given disorder along this continuum depends on three main variables: (1) whether a major locus makes a dominant contribution to the phenotype, (2) the number of loci that influence the phenotype, and (3) the presence and extent of environmental influence on phenotype.

cohorts indicated that this assumption was an oversimplification of the true genetic nature of this phenotype, particularly with respect to the substantial phenotypic variability observed in some CF patients. For instance, although CFTR mutations show a degree of correlation with the severity of pancreatic disease, the severity of the pulmonary phenotype-which is the main cause of mortality-is difficult to predict. 1,16,45 Realization of the limitations of a pure monogenic model prompted an evaluation of more complex inheritance schemes. This led to the mapping of a modifier locus for the intestinal component ofCF in both human and mouse. 63 ,73 Further phenotypic analysis led to the discovery of several other loci linked to phenotype, including (1) the association of low-expressing mannose-binding lectin (MBL; also known as MBL2) alleles, human leukocyte antigen (HLA) class II polymorphisms, and variants in tumor necrosis factor-a (TNFa) and transforming growth factor-I3-1 (TGF{3I) with pulmonary aspects of the disease5,6,21,30; (2) the correlation of intronic nitric oxide synthase 1 (NOSI) polymorphisms with variability in the frequency and severity of microbial infections 22 ; and (3) the contribution of mucin 1 (Muc1) to the gastrointestinal aspects of the CF phenotype in mice (Fig. 2-2).55 Recently, further layers of complexity have been discovered for both CFTR and its associated phenotype. First, heterozygous CF mutations have been associated with susceptibility to rhinosinusitis, an established polygenic trait.69 Second, and perhaps more surprising, a recent study reported that some patients with a milder CF phenotype do not have any mutations in CfTR. This indicates that the hypothesis that CFlR gene dysfunction is requisite for the development of CF might not be true. 23

TNFa TGF~1

MBL2

~I

ICFTR . . . .

Disease-Specific Examples of Changing Concepts in Molecular Genetics Monogenic Disorders Cystic fibrosis (CF) is an example of a disorder close to the monogenic end of the continuum, but it also illustrates the complexity of the genetics of some disorders, even when a mutation of a major locus is the primary determinant of phenotype. On the basis of the observed autosomal recessive inheritance in families, the gene CFTR (cystic fibrosis transmembrane conductance regulator) was first mapped in humans to chromosome 7q31.2. 68 Once the CfTR gene was cloned,62 it was widely anticipated that mutation analyses might be sufficient to predict the clinical outcome of patients. However, analyses of CFTR mutations in large and ethnically diverse

Severity of pulmonary phenotype

HLAII

Cystic Fibrosis

~

Microbial infections

I

~1'

Pancrealic/GI phenotype

1

CFMl

I Meconium ileus I

WlII"#§J Complexity in monogenic diseases. Mutations in the cystic fibrosis transmembrane conductance regulator (CFIR) almost always cause the cystic fibrosis (CF) phenotype. Owing to modification effects by other genetic factors, the presence and nature of mutations at the CFrR locus cannot predict the phenotypic manifestation of the disease. Therefore, although CF is considered a mendelian recessive disease, the phenotype in each patient depends on a discrete number of alleles at different loci. aMI, cystic fibrosis modifier 1; GI, gastrointestinal; HLAII, major histocompatibility complex class II antigen; MBL2, mannose-binding lectin (protein C) 2; Mucl, mucin 1; NOSI, nitric oxide synthase 1; TGF{3I, transforming growth factor-~-I; TNFa, tumor necrosis factor-a encoding gene.

Oligogenic Disorders Recent developments in defining the molecular genetics of Hirschsprung's disease (HD) exemplifY a relatively new concept in genetics-the oligogenic disorder. Although mathematical analyses of oligogenicity are beyond the scope of this discussion,18,47 it is important to recognize that modifications of traditional linkage approaches are useful tools for the study of oligogenic diseases, especially if a major locus that contributes greatly to the phenotype is known. In the case ofHD, two main phenotypic groups can be distinguished on the basis of the extent of aganglionosis: short-segment HD (S-HD) and the more severe long-segment HD (L-HD). Autosomal dominant inheritance with incomplete penetrance has been proposed for L-HD, whereas complex inheritance that involves an autosomal recessive trait has been observed in S-HD. Oligogenicity has been established in both HD variants by virtue of several factors: a recurrence risk that varies from 3% to 25%, depending on the length of aganglionosis and the sex of the patient; heritability values close to 100%, which indicates an exclusively genetic basis; significant clinical variability and reduced penetrance; and nonrandom association of hypomorphic changes in the endothelin receptor type B (EDNRB), with rearranged during transfection (RET) polymorphisms and HD.54,57 So far, a combination of linkage, positional cloning studies, and functional candidate gene analyses has identified eight HD genes (Table 2-1), 2 of which the proto-oncogene RET is thought to be the main predisposing locus,4.39 particularly in families with a high incidence ofL-HD.2o The nonmendelian transmission of HD has hindered the identification of predisposing modifier loci by

conventional linkage approaches. When these approaches (parametric and nonparametric linkage studies) were carried out on a group of 12 L-HD families, very weak linkage was observed on 9q31. However, based on the hypothesis that only milder RET mutations could be associated with another locus, families were categorized according to the RET mutational data. Significant linkage on 9q31 was detected when families with potentially weak RET mutations were analyzed independently,39 indicating that mild RET alleles, in conjunction with alleles at an unknown gene on chromosome 9, might be required for pathogenesis. The mode of inheritance in S-HD has proved to be more complex than in L-HD, requiring further adjustments to the linkage strategies. Recently, the application of model-free linkage, without assumptions about the number and inheritance mode of segregating factors, showed that a three-locus segregation was both necessary and sufficient to manifest S-HD, with RET being the main locus, and that the transmission of susceptibility alleles was additive. 2o The inheritance patterns observed in disorders such as HD illustrate the power of both expanded models of disease inheritance that account for reduced penetrance and phenotypic variability and the ability of these models to genetically map loci involved in oligogenic diseases-a first step toward identifYing their underlying genes. More important, the establishment of nonmendelian models caused a change of perception in human genetics, which in turn accelerated the discovery of oligogenic traits.

Polygenic or Complex Disorders Polygenic or complex disorders are thought to result from poorly understood interactions between many genes and the environment. An example of a polygenic

~ TABLE 2-1 Genes Associated with Hirschsprung's Disease and Relationship to Associated Anomalies Population

Associated Anomalies

Incidence in

CCHS MEN2A MEN2B

1.8-1.9 2.5-5.0 Unknown

AD

17-38 (S-HD) 70-80 (L-HD) 50 (familial) 15-35 (sporadic) <1*

CCHS

1.8-1.9

AD

<1*

Unknown

Unknown AD/AR

3-7

Ligand for EDNRB

AD/AR

5

EDN3 processing gene Transcription factor

AD AD

<1 <1

Gene

Gene Locus

Gene Product

Inheritance

RET

10ql1.2

Coreceptor for GDNF

AD

GDNF

5p12-13.1

NTN

19p13.3

GFRa-l EDNRB

10q26 13q22

Ligand for RET and GFRa-l Ligand for RET and GFRa-2 Coreceptor for GDNF Receptor for EDN3

EDN3

20q13.2-13.3

ECE-l

lp36.1 22q13.1

SOX10

Unknown Waardenburg's syndrome CCHS Waardenburg's syndrome Unknown Waardenburg's syndrome type 4

HD

Unknown 1.8-1.9 Unknown

Unknown

*Limited data available. No mutations detected thus far in humans, but associated with HD in mice. AD, autosomal dominant; AR, autosomal recessive; CCHS, congenital central hypoventilation syndrome (Ondine's curse); ECE-l, endothelin-converting enzyme-l; EDNRB, endothelin receptor B; EDN3, endothelin-3; GDNF, glial cellline-derived neurotrophic factor; GFRa-l, GDNF family receptor a-l; HD, Hirschsprung's disease; L-HD, long-segment HD; MEN, multiple endocrine neoplasia; NTN, neurturin; RET, rearranged during transfection; S-HD, short-segment HD; SOX, Sry-Iike HMG bOX. t

disorder relevant to pediatric surgery is hypertrophic pyloric stenosis (HPS). The genetic cause of HPS has long been recognized, with frequent familial aggregation, a concordance rate of 25% to 40% in monogenetic twins, a recurrence rate of 10% for males and 2% for females born after an affected child, and a ratio of risk of IS for first-degree relatives compared with the general population. 46 However, this risk is considerably less than would be predicted based on mendelian patterns of inheritance.1O In addition, HPS has been reported as an associated feature in multiple defined genetic syndromes,9,35,36,59,67 chromosomal abnormalities, 12,27,29,60,70 and anecdotally with many other defects,24,31,37,42,72 suggesting a polygenic basis, Although the molecular genetic basis of HPS remains poorly defined, a likely common final pathway causing the disorder is altered expression of neural nitric oxide synthase (nNOS) within the pyloric muscle,51 A detailed analysis of the molecular mechanisms of this alteration has been published, describing a reduction of messenger RNA (mRNA) expression ofnNOS exon lc, with a compensatory up-regulation of nNOS exon If variant mRNA in HPS.5! DNA samples of 16 HPS patients and SI controls were analyzed for nNOS exon lc promoter mutations and single nucleotide polymorphism (SNP). Sequencing of the 5'-flanking region of exon lc revealed mutations in 3 of 16 HPS tissues, whereas SI controls showed the wild-type sequence exclusively. Carriers of the A allele of a previously uncharacterized nNOS exon lc promoter SNP (-S4G/ A SNP) had an increased risk of developing HPS (odds ratio, S.O; 95% confidence interval, 2.5 to 25.6), which could indicate that the -S4G/ A promoter SNP alters expression of nNOS exon lc or is in linkage dysequilibrium with a functionally important sequence variant elsewhere in the nNOS transcription unit and therefore may serve as an informative marker for a functionally important genetic alteration. The observed correlation of the -S4G/ A SNP with an increased risk for the development of HPS is consistent with a report showing a strong correlation of a microsatellite polymorphism in the nNOS gene with a familial form of HPS,13 However, the -S4G/ A SNP does not account for all HPS cases; therefore, other components of the nitric oxide-dependent signal transduction pathway or additional mechanisms and genes may be involved in the pathogenesis of HPS. This is in accordance with other observations suggesting a multifactorial cause of HPS,46 In summary, genetic alterations in the nNOS exon lc regulatory region influence expression of the nNOS gene and may contribute to the pathogenesis of HPS, but there are likely numerous other genes that contribute to the development of HPS as well as predispose to environmental influences in this disorder. These examples provide insight into the complexity of current models of molecular genetics and illustrate the inadequacy of current methods of analysis to fully define genetic causes of disease, particularly polygenic disorders. The majority of pediatric surgical disorders currently fall into the category of undefined multifactorial inheritance, which is even less well understood than the genetic categories described. In these disorders, no causative, predisposing, or influencing gene loci have been identified. Isolated regional malformations are presumed

to result from interactions between the environment and the actions of multiple genes. Multifactorial inheritance is characterized by the presence of a greater number of risk genes within a family. The presumption of a genetic basis of the anomalies is based on recurrence risk. The recurrence risks in multifactorial inheritance disorders, although generally low, are higher than in the general population; they are increased further if more than one family member is affected, if there are more severe malformations in the proband, or if the parents are closely related, Beyond these generalizations, genetics can provide little specific information about this category of disorder,

Utility of Molecular Genetics in Clinical Pediatric Surgery Genetic Counseling and Prenatal Diagnosis As mentioned earlier, there is still a gap between genotypic understanding of a disorder and direct application to clinical treatment. The exceptions are in the areas of genetic counseling and prenatal diagnosis. Pediatric surgeons are likely to require some knowledge of molecular genetics as their role in prenatal counseling of parents continues to increase. Molecular genetics can supply specific information about an affected fetus by providing genotypic confirmation of a phenotypic abnormality, a phenotypic correlate for a confirmed genotype, and, in many instances, the recurrence risk for subsequent pregnancies and the need for concern (or lack thereof) about other family members. Once again, HD is an example of how molecular genetics can be valuable in genetic counseling. 8 ,64 The generalized risk to siblings is 4% and increases as the length of involved segment increases. In HD associated with known syndromes, genetic counseling may focus more on prognosis related to the syndrome than on recurrence risk. In isolated HD, a more precise risk table can be created. Risk of recurrence of the disease is greater in relatives of an affected female than of an affected male. Risk of recurrence is also greater in relatives of an individual with longsegment compared with short-segment disease. For example, the recurrence risk in a sibling of a female with aganglionosis beginning proximal to the splenic flexure is approximately 23% for a male and IS% for a female, whereas the recurrence risk in a sibling of a male with aganglionosis beginning proximal to the splenic flexure is approximately 11 % for a male and S% for a female. These risks fall to 6% and lower for siblings of an individual with short-segment disease. Prenatal diagnosis is possible if the mutation within the family is known. However, because the penetrance of single gene mutations is low (except for SOXIO mutations in Waardenburg's syndrome), the clinical usefulness of prenatal diagnosis is limited. More commonly, a general knowledge of genetics can allow accurate counseling of recurrence risk and reassurance for parents of an affected fetus diagnosed with a multifactorial inheritance defect, the most common circumstance involving prenatal consultation with a

pediatric surgeon. Pediatric surgeons should also be aware of the value of genetic evaluation of abortus tissue in cases of multiple anomalies when, after counseling, the parents choose to terminate the pregnancy. It is a disservice to the family not to send the fetus to an appropriate center for a detailed gross examination and a state-of-the-art molecular genetic assessment when appropriate. As molecular genetics increasingly characterizes the genes responsible for specific disorders, their predisposing and modifier loci, and other genetic interactions, a better ability to predict the presence and severity of specific phenotypes will inevitably follow. This will allow prenatal counseling to be tailored to the specific fetus and lead to improved prognostic accuracy, giving parents the opportunity to make more informed prenatal choices.

Postnatal Treatment In the future, molecular genetics will allow specific therapies to be optimized for individual patients. This may range from specific pharmacologic treatments for individual patients based on genotype and predicted pharmacologic response to anticipation of propensities for specific postoperative complications, such as infection or postoperative stress response. Of course, the ultimate treatment for an affected individual and their progeny would be to correct the germline genetic alteration responsible for a specific phenotype. Although there are many scientific and ethical obstacles to overcome before considering such therapy, it is conceivable that a combination of molecular genetics and gene transfer technologies could correct a germline mutation, replacing an abnormal gene by the integration of a normal gene and providing the ultimate preventive therapy. Although the state of gene transfer technology is far from this level of sophistication, progress in the past 3 decades can only be described as astounding. The next section provides an overview of the current state of gene transfer and its potential application for therapy.

GENE THERAPY Gene therapy continues to be embroiled in controversy, its seemingly unlimited potential obscured by repeated disappointments and, more recently, adverse events. The year 2000 brought the first clinical gene therapy success-treatment of X-linked severe combined immune deficiency (XSCID) II-only to have this dramatic achievement undermined by the occurrence ofleukemia in two patients. This and other adverse events threaten to overshadow the substantial progress made in gene transfer technology in recent years. Slowly but surely, methods for gene transfer are being developed that will have greater safety, specificity, and efficacy than ever before. Although complex issues remain to be solved, it is likely that successful gene therapy strategies will be developed and proved within the next few years. The technology of gene transfer can be divided into viral vector-based gene transfer and nonviral gene transfer. Because of the

limited scope of this chapter and the limited efficiency of nonviral-based gene transfer thus far, only the current state of viral-based gene transfer is reviewed.

Viral Vectors for Gene Transfer Viruses are highly evolved biologic machines that efficiently penetrate hostile host cells and exploit the host's cellular machinery to facilitate their replication. Ideally, viral vectors harness the viral infection pathway but avoid the subsequent replicative expression of viral genes that causes toxicity. This is traditionally achieved by deleting some or all of the coding regions from the viral genome but leaving intact those sequences that are needed for the vector function, such as elements required for the packaging of viral DNA into virus capsid or the integration of vector DNA into host chromatin. The chosen expression cassette is then cloned into the viral backbone in place of those sequences that were deleted. The deleted genes encoding proteins involved in replication or capsid or envelope proteins are included in a separate packaging construct. The vector genome and packaging construct are then cotransfected into packaging cells to produce recombinant vector particles (Fig. 2-3). Given the diversity of therapeutic strategies and disease targets involving gene transfer, it is not surprising that a large number of vector systems have been devised. Although there is no single vector suitable for all applications, certain characteristics are desirable for all vectors if they are to be clinically useful: (l) the ability to be reproducibly and stably propagated, (2) the ability to be purified to high titers, (3) the ability to mediate targeted delivery (i.e., to avoid widespread vector dissemination), and (4) the ability to achieve gene delivery and expression without harmful side effects. There are presently five main classes of vectors that, at least under specific circumstances, satisfY these requirements: oncoretroviruses, lentiviruses, adeno-associated viruses (AAVs) , adenoviruses, and herpesviruses. Table 2-2 compares the general characteristics of these vectors. Oncoretroviruses and lentiviruses are "integrating," that is, they insert their genomes into the host cellular chromatin. Thus, they share the advantage of persistent gene expression. Nonintegrating viruses can achieve persistent gene expression in nondividing cells, but integrating vectors are the tools of choice if stable genetic alteration needs to be maintained in dividing cells. It is important to note, however, that stable transcription is not guaranteed by integration and that transgene expression from integrated viral genomes can be silenced over time. 53 Oncoretroviruses and lentiviruses differ in their ability to penetrate an intact nuclear membrane. Whereas retroviruses can transduce only dividing cells, lentiviruses can naturally penetrate nuclear membranes and can transduce nondividing cells, making them particularly useful for stem cell targeting applications. 19 ,74 Because of this difference, lentivirus vectors are superseding retrovirus vectors for most applications. Both types of vector, because of their ability to integrate, share the potential hazard of alteration of the host cell genome.

Parental virus

Inverted repeats Structural protein genes

I I I

Genes required for DNA replication

I]

Poly (A)

Pathogenicity genes

Genes encoding envelope proteins

Promoter

A

Transgene

Vector genome

C B

Packaging construct

Viral vector

Structural proteins

mllh••'

Requirements for the creation of a generic viral vector. A. The basic machinery of a chosen parental virus is used, including genes encoding specific structural protein genes, envelope proteins, and proteins required for DNA replication, but not genes encoding proteins conferring pathogenicity. B, The vector is assembled in a packaging cell. A packaging (helper) construct, containing genes derived from the parental virus, can be delivered as a plasmid or helper virus or stably integrated into the chromatin of the packaging cell. Pathogenicity functions and sequences required for encapsidation are eliminated from the helper construct so that it cannot be packaged into a viral particle. In contrast, the vector genome contains the transgenic expression cassette flanked by inverted terminal repeats and cis-acting sequences that are required for genome encapsidation. Viral structural proteins and proteins required for replication of the vector DNA are expressed from the packaging construct, and the replicated vector genomes are packaged into the virus particles. C, The viral vector particles are released from the packaging cell and contain only the vector genome. (See color plate.)

This could lead to the undesirable complications of human germ line alteration or insertional mutagenesis, particularly important considerations for pediatric or fetal gene therapy.56 Nevertheless, these vectors have proved most efficient for long-term gene transfer into cells in rapidly proliferative tissues and for stem cell-directed gene transfer. Nonintegrating vectors include adenovirus, AAV, and herpesvirus vectors. Adenovirus vectors have the advantages of broad tropism, moderate packaging capacity, and high efficiency, but they carry the usually undesirable properties of high immunogenicity and consequent short duration of gene expression. Modifications of adenovirus vectors to reduce immunogenicity and further increase the transgene capacity have consisted primarily of deletion of "early" (EI-E4) viral genes that encode immunogenic viral proteins responsible for the cytotoxic immune response. 3 ,38 The most important advance,

however, has been the development of helper-dependent adenoviruses (HD-Ads) that are deleted of all viral genes, thus eliminating the immune response to adenoviralassociated proteins. 48 These vectors may ultimately be most valuable for long-term gene transfer in tissues with very low rates of cell division, such as muscle or brain. AAV is a helper-dependent parvovirus that, in the presence of adenovirus or herpesvirus infection, undergoes a productive replication cycle. AAV vectors are single-strand DNA vectors and represent one of the most promising vector systems for safe long-term gene transfer and expression in nonproliferating tissues. AAV is the only vector system for which the wild-type virus has no known human pathogenicity, adding to its safety profile. In addition, the small size and simplicity of the vector particle make systemic administration of high doses of vector possible without eliciting an acute inflammatory response or other toxicity. Although the majority of the

~

TABLE 2-2 Five Main Viral Vector Groups

Vector Type

Coding Material

Retrovirus

RNA

Lentivirus

RNA

HSV-l

dsDNA

AAV

ssDNA

Adenovirus

dsDNA

Tissue Tropism

Vector Genome

8

Only dividing cells

Integrated

8

Broad, including stem cells

Integrated

40

Neural

Episomal

<5

Broad

8

Broad

Episomal (90%) Integrated (<10%) Episomal

Packaging Capacity (kb)

30*

Advantages

Disadvantages

Persistent gene transfer in dividing cells Integrates into nondividing cells; perSistent gene transfer Inflammatory response; limited tropism Noninflammatory; nonpathogenic Extremely efficient gene transfer in most tissues

Requires cell division; may induce oncogenesis Potentia I for oncogenesis

Large packaging capacity; strong tropism for neurons Small packaging capacity Capsid-mediated potent immune response; transient expression in dividing cells

• Helper dependent. AAV, adeno-associated vector; ds, double-strand; HSV-l; herpes simplex virus-l; ss, single-strand.

AAV vector genome after transduction remains episomal, an approximately 10% rate of integration has been observed. 50 There are two primary limitations of AAV vectors. The first is the need to convert a single-strand DNA genome into a double strand, limiting the efficiency of transduction. Recently this obstacle has been overcome by the development of double-strand vectors that exploit a hairpin intermediate of the AAV replication cycle. 43 Although these vectors can mediate a 10- to 100-fold increase in transgene expression in vitro and in vivo, they can package only 2.4 kb of double-strand DNA, limiting their therapeutic usefulness. This relates to the second primary limitation of AAV vectors, which is limited packaging capacity (4.8 kb of single-strand DNA). One approach to address this limitation is to split the expression cassette across two vectors, exploiting the in vivo concatemerization of rAAV genomes. This results in reconstitution of a functional cassette after concatemerization in the cell nucleus. 17 ,49 Finally, an approach that has become common for enhancing or redirecting the tissue tropism of AAV vectors is to pseudo type the vectors with capsid proteins from alternative serotypes of AAy'58 Although most rAAV vectors have been derived from AAV2, eight distinct AAV serotypes have been identified thus far, all of which differ in efficiency for transduction of specific cell types. AAV vectors have proved particularly useful for muscle, liver, and central nervous system directed gene transfer. Herpes simplex virus (HSV-l) vectors are the largest and most complex of all currently used vector systems. Their primary advantages are a very large packaging capacity (up to 40 kb) and their strong neurotropism, allowing lifelong expression in sensory neurons. This has made neuropathologic disorders a primary target for HSV-1-mediated gene transfer.

Clinically Relevant Challenges in Gene Transfer Recent adverse events demonstrate the potential for disaster when using vector-based gene transfer. Major initiatives must be undertaken to delineate the potential complications of gene transfer with specific vectors to convince physicians and the public of their safety for future clinical trials. Nevertheless, because of the potential benefit, continued efforts to develop safe and efficacious strategies for clinical gene transfer are warranted. One of the primary obstacles to successful gene therapy continues to be the host immune response. The intact immune system is highly capable of activation against viral vectors using the same defense systems that combat wild-type infections. Viral products or new transgene encoded proteins are recognized as foreign and are capable of activating an immune response of variable intensity. Adenovirus vectors are the most immunogenic of all the viral vector types and induce multiple components of the immune response, including cytotoxic T-Iymphocyte responses, humoral virus-neutralizing responses, and potent cytokine-mediated inflammatory responses. 7 Great progress has been made in reducing T-cell responses against adenoviral antigens by the development of HD-Ad vectors that are deleted of all adenoviral genes. These vectors have demonstrated reduced immunogenicity with long-term phenotypic correction of mouse models and negligible toxicity.14.34 However, even HD-Ad vectors or less immunogenic vector systems such as AAV or lentivirus vectors can induce an immunologic response to capsid proteins or to novel transgene encoded proteins, a potentially limiting problem in a large number of human protein deficiency disorders caused by a null mutation. Thus, the application of gene transfer technology to many human disorders may

require the development of effective and nontoxic strategies for tolerance induction. Another major area of interest that may improve the safety profile of future viral vector-based gene transfer is specific targeting to affected tissues or organs. Whereas wild-type virus infections are generally restricted to those tissues that are accessible through the route of transmission, recombinant vectors are not subject to the same physical limitations. The promiscuity of viral vectors is a significant liability, because systemic or even local administration of a vector may lead to unwanted vector uptake by many different cell types in multiple organs. For instance, lack of adenovirus vector specificity was directly linked to the induction of a massive systemic immune response that resulted in a gene therapy-related death in 1999. 7 Because many of the toxic effects of viral vectorbased gene transfer are directly related to dose, increasing the efficiency with which viral vectors infect specific cell populations should reduce viral load and improve safety. There are a variety of promising methods to achieve the targeting of viral vectors for specific organs or cell types. Perhaps the simplest approach is vector pseudotyping, which has been performed for retrovirus, lentivirus, and AAV vectors. By changing the capsid envelope proteins to alternative viral types or serotypes, a portfolio of vectors with different tropisms can be generated. 40 Another approach is the conjugation of capsid proteins to molecular adapters such as bispecific antibodies with specific receptor binding properties. 33 ,61 A third approach is to genetically engineer the capsid proteins themselves to alter their receptor binding (i.e., to abolish their normal receptor binding) or to encode a small peptide ligand for an alternative receptor. 28 These and other approaches, when combined with the appropriate use of tissue-specific promoters, may significantly reduce the likelihood of toxicity from viral-based gene therapy. Another important obstacle to human gene therapyparticularly fetal gene therapy-is the potential for insertional mutagenesis when using integrating vectors. Until recently, this risk was considered extremely low to negligible, based on the assumption that oncogenesis requires multiple genetic lesions and the fact that induced cancer had not been observed in any of the hundreds of patients treated with retrovirus vectors in the many gene therapy trials. However, recently 2 of 11 patients treated in an otherwise successful trial ll ,25 of retroviral gene therapy for XSCID developed a leukemia disorder.26 Evidence suggests that this was caused by retroviral genome insertion in or near the oncogene LM02. These concerns have been further heightened by evidence that retroviral genes are not randomly inserted, as previously believed; rather, they preferentially integrate into transcriptionally active genes. 65 Although such events may be more likely to occur under the unique selective influences of XSCID, it is clear that the risk of insertional mutagenesis can no longer be ignored. Approaches designed to neutralize cells expressing transgene if and when an adverse event occurs, such as engineering suicide genes into the vector, are one option, but this would also neutralize any therapeutic effect. More exciting approaches are based on site-specific integration-for

instance, taking advantage of site-integration machinery of bacteriophage <j>X3l.5 2 This is undoubtedly only one of many approaches that will use site-specific integration in the future and should, if successful, negate the risk of insertional mutagenesis. Finally, a critical issue for in vivo gene transfer with integrating vectors in individuals of reproductive age is the potential for germline transmission, with alteration of the human genome. The risk of this event is poorly defined at present and is most likely extremely low, although in some circumstances (e.g., fetal gene transfer), it could be increased. 56 Although still not technically possible, the intentional site-specific correction of defects in the germline would be the ultimate in gene therapy. However, even if the technology becomes available, the intentional alteration of the human genome raises profound ethical and societal questions that will need to be thoroughly addressed before its application. The considerations are similar to those for insertional mutagenesis, so many of the approaches mentioned earlier for gene targeting and reduction of the potential for insertional mutagenesis are applicable here as well.

Overview of the Current Status of Gene Transfer At present it is clear that viral vectors are the best available vehicle for efficient gene transfer into most tissues. Several gene therapy applications have shown promise in early-phase clinical trials. Although the adverse events noted in the XSCID trial have dampened enthusiasm, this still represents the first successful treatment of a disease by gene therapy. The treatment of hemophilia B using rAAV is also promising. 32 ,41 The next few years are likely to bring advances in the treatment of certain types of cancer using conditionally replicating oncolytic viruses and in the treatment of vascular and coronary artery disease using viral vectors that express angiogenic factors. In the future, new disease targets are likely to become approachable through the fusion of viral vectormediated gene transfer with other technologies such as RNA interference, a powerful tool to achieve gene silencing, Such vectors could be useful in developing therapy for a range of diseases, such as dominantly inherited genetic disorders, infectious diseases, and cancer, Advances in the understanding of viral vector technology and DNA entry into cells and nuclei will likely lead to the development of more efficient nonviral vector systems that may rival viral vectors in efficiency and have superior safety, Gene vector systems of the future may be very different from those in use today and will ultimately provide efficient delivery of target-specific, regulated, transgene expression for an appropriate length of time.

REFERENCES 1. Acton JD, Wilmott RW: Phenotype of CF and the effects of possible modifier genes. Paediatr Respir Rev 2001;2: 332-339. 2, Arnie! J, Lyonnet S: Hirschsprung disease, associated syndromes, and genetics: A review,J Med Genet 2001;38:729-739,

Ethical Considerations Donna A. Caniano and Carolyn Ells

In his classic text The Surgeon and the Child, Potts noted that "the satisfaction of correcting a deformity in a newborn infant lies in the fact that all his life lies before him. Parents hope for miracles, but are grateful for the best that can be given by a mere human being."lg This profound statement underscores the essence of pediatric surgery, whether repairing a major congenital anomaly, treating a devastating traumatic injury, or resecting a malignancy. Each endeavor offers the pediatric surgeon the joy of providing a child with relief of suffering and the potential for a full and productive life. The ethical challenges faced by pediatric surgeons encompass the basic moral principles of medical practice, issues that are distinctive to the profession of surgery, and other factors that are unique to the care of infants and children. In this chapter we review some of the basic ethical concepts and responsibilities pertinent to pediatric surgical ethics. We also address some new areas of ethical and surgical controversy, including the operative management of children with morbid obesity and sex assignment surgery in infants with intersex conditions.

PEDIATRIC SURGICAL mHICS What is distinctive about surgical ethics flows first from what is distinctive about the relationship between surgeons and their patients. Little" has identified five pillars that mark the moral domain of the surgeon-patient relationship: rescue, proximity, ordeal, aftermath, and presence. These factors may be present in other therapeutic relationships as well, but they have a special intensity in surgery. The term rescueacknowledges the elements of surrender and dependency that patients and their families experience when surgery is pursued. To be rescued from a serious threat, patients open themselves up to invasive and traumatic surgcal remedies over which they have little control. Surgeons and patients and their families (parents in most pediatric surgical encounters) need to work together to confront and negotiate the patient's surrender and dependency within the context of the surgeon's power. Proximity refers to surgeons' acknowledgment of the close, intimate interactions they have with their patients. Remarkably, surgeons explore the inner bodies of their

patients, an aspect of the encounter that differs from other medical interactions. Surgeons see and touch, and incise and suture, parts of patients that the patients themselves can barely imagine. Proximity privileges surgeons with knowledge and an understanding of suffering that patients cannot reciprocate. Patients cannot know their surgeons in this intimate way, nor can they know themselves in the way that their surgeons come to know them. Surgeons must realize that surgery is an ordeal for patients; it is an extreme experience that must be endured. Little" has emphasized that surgical patients forgo their autonomy, acknowledge dependency, place trust, face risk, confront embodiment and mortality, lose control over time and space, and experience alienation, pain, fear, discomfort, suffering, and boredom. Depending on the surgical procedure, the patient's sense of personal identity may be irrevocably challenged or changed. In the aftmath of surgery, surgeons must recognize that some patients may have difficulties long after their immediate recovery. Physical and emotional scars, discomfort, risks, and other types of suffering can be reminders of a past illness or injury and signs of vulnerability to future illness or injury. Understanding the aftermath of surgery can help surgeons understand threats to their patients' existential experiences, as well as to their own. In pediatric surgery, aftermath takes on a unique aspect in its dual nature, affecting the child-patient and the parents, both of whom experience the consequences of the surgical encounter. Presence is both a virtue and a duty for surgeons. They must be a visible and engaged presence throughout the entire surgical experience. In pediatric surgery, this professional obligation extends to the long-term follow-up of their patients, often into young adulthood. For example, pediatric surgeons may be the only specialistswho understand the potential long-term complications and functional difficulties that may arise from major neonatal reconstructive operations in the gastrointestinal and hepatobiliary systems. Meeting this duty requires a patient-centered approach to care in which each patient, and his or her particular situation and experience, guides the surgeon in nurturing the surgical relationship and promoting the patient's interests.

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Surgeons bring to the surgical relationship the values and ethical principles of their profession, which give priority to the interests and well-being of their patients. 111 Surg-icnl ethic^, McCullough et a1.'2 present patients' rights related to the surgical encounter, each of which implies a key professional value. They remind us that patients have the right "not to be killed intentionally or negligently by the surgeon, not to be harmed by intent or negligence of the surgeon ... not to be deceived by the surgeon ... to be adequately informed about the risks and benefits of surgery, to be treated by a knowledgeable, competent practitio~ler,to have his or her health and well-being more highly valued than the surgeon's ow11econornic inierest, and to decide whether to accept treatlneilt under the conditions described."" In pediatric surgery, the professional commitment to fi~llyirlform patients, to enable them to choose treatment or nontreatrnent, and to not deceive them typically requires third parties (in most cases, their parents) to speak, understand, and consent on behalf of infants, children, arid adolescents. Although parents are usually the surrogate decision makers for their children, courtappointed guardians or other spokespersons may fulfill this role, depending on relevant laws. In somejurisdictions, and in certain specific circumstances, adolescent patients may be granted authority to make their own decisions about the health care they receive. This situation is particularly applicable to adolescents with chronic illnesses, such as sickle cell disease, cystic fibrosis, and advanced malignancies. However, when an adolescent's consent to or refusal of surgery is in direct opposition to parental wishes, the assistance of social services and legal counsel may be required. Including the family or surrogate decision makers in the surgical relationship is necessary notjust to authorize (or refuse) surgery on behalf of patients. Providing patient-centered care requires an understanding that the patient lives in a family context, which defines, in part, who he or she is as an individual. It also requires acknowledging the greater vulnerability of minor patients who have less of a voice-or often no voice-in treatment decisions and little or no understanding of the surgical process. These patients must be provided with the support they need to optimize their care and the protection they need in light of their vulnerability. Extending the surgical relationship to others helps the surgeon understand the patient and make recommendations that are in the patient's best interests, and it allows others to share in providing the support that these young patients require. One ethical challenge routinely faced by pediatric surgeons (and surrogate decision makers) is determining the interests of patients whose moral characters and values are not yet substantially (much less fully) formed. The character traits, goals, values, and preferences of minor patients should be factored into plans for their care, but judgment is needed to determine what weight to give them. Pediatric surgeons should have in their armamentarium various approaches to ethical decision making and problem solving. Baylis and Canianol advocate a team approach to difficult ethical problems encountered in the surgical treatment of infants and children. This approach acknowledges that contemporary health care in tertiary pediatric

hospitals relies on several teams: the patient-parent unit, the nursing and allied health care members, and the surgical-medical professionals. The health care team for any given patient must unite around a common moral language and an understanding of the ethical issues relative to the particular situation. For example, the caregivers and decision makers for an extremely premature neonate with multiple congenital anomalies must have practical and cognitive knowledge about the pertinent ethical issues. The team or team leaders must have the capacity to elucidate the values and goals that are important to the parents and other involved family mernbers. The values of the parents and Family assume particular relevance when their cultural or religious background differs from that of the health care team in substantive ways. For instance, certain cultural practices may dictate that the authority for medical decision making resides with individuals other than the parents, such as grandparents or community elders. Finally, the team must decide on a specific decision-making method. Several maxims apply to difficult ethical problems in pediatric surgery: (1) good ethics begin with good facts; (2) rational people may hold opposing and irreconcilable views; (3) generally, the best decisions are those developed by consensus; (4) most decisions do not need to be made in haste; and (5) in cases of severe neonatal and pediatric illness, most decisions are painful, and many do not have happy solutions. Most ethical dilemmas arise when there is a dispute or disagreement between the surgical-medical professionals and the patient-parents. These disagreements usually center on what constitutes the best interests of the patient (e.g., continued life with the burdens of severe disability) and what describes an acceptable quality of life for the patient. Glover and %aniano7have outlined a process for ethical decision making that involves several components, including identifying the decision makers, gathering all the medical-surgical facts with the best available prognostic indications, clarifying the relevant values from the "stakeholders" (usually the parents or close family members, in the case of infants), defining all available treatment and nontreatment options, evaluating all options and making recommendations (usually the responsibility of the pediatric surgeon), and achieving a consensus resolution (an ethics consultant or mediator may be useful in cases of significant dispute). Some of these approaches are addressed later in this chapter, when we discuss some of the newer ethical challenges faced by pediatric surgeons.

INNOVATION AND RESEARCH Most citizens of progressive societies place great value on innovation in all areas, including medicine. To achieve advances and technical improvements in pediatric surgery, the profession has relied on the individual and collective innovation of its members. Society expects surgeons to pursue innovation and to develop new therapies and treatment techniques. Patients gravitate toward new operations that offer a presumed benefit, as witnessed by the rapid conversion from open to laparoscopic

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cholecystectomy 2 decades ago. Patients also give great latitude to their surgeons in allowing, or even expecting, them to modify or refine traditional surgical techniques as necessary to complete an operation. McKneallyls observed that individual surgeons are usually acknowledged for their original thinking and technical accomplishments by having operations named in their honor. Numerous operations in pediatric surgery carry the names of those surgeons who first described them, including Ladd's procedure for midgut volvulus and the Duhamel pullthrough for Hirschsprung's disease. In contrast to other areas of medicine, in which randomized clinical trials precede the introduction of new drugs and treatments, the field of surgery has been free to develop new operations without stringent legal and professional regulations.Ulthough some notable procedures, such as pneumatic reduction of intussusception and the Swenson pull-through for Hirschsprung's disease, were tested in animal models, most operations in pediatric surgery are piloted and perfected on patients. New operations are typically introduced by means of a presentation at a professional meeting of pediatric surgeons and subsequent publication in a peer-reviewed journal. The pediatric surgeon who developed the operation usually reports on his or her experience, in terms of complications and outcomes, in patients treated at a single institution with a variable period of follow-up. Reasons given for adopting operations in humans without rigorous scrutiny include the following: (1) suitable animal models may be lacking for the particular anatomic condition; (2) the new operation represents an extension of standard, accepted techniques applied in a novel manner; (3) the new operation is meant to benefit an individual patient rather than to learn something; (4) professional standards are lacking for the introduction of new operations; (5) it is often unclear when an operation should undergo clinical trials; and (6) the current system has worked reasonably well for patients in terms of safety and presumed benefit. In fact, numerous operations have been abandoned either because they did not achieve the desired outcome (e.g., sympathectomy for Hirschsprung's disease) or because they had unacceptably high morbidity and mortality rates (e.g.,jejunoileal bypass for morbid obesity). Research is considered to be a systematic investigation designed to develop or contribute generalizable knowledge. In pediatric surgery, an operation may be performed in a novel way to treat a single patient; thus, in a strict sense, such an operation is not research. But, as is often the case, subsequent operations are performed on additional patients, data are collected, and the novel procedure is presented and published. What began as a treatment for a single patient has crossed over into clinical research, making it subject to the ethical standards for human investigation. In 1966 Beecher published a seminal article in the Nnu England Journal of Mdicine detailing several examples of medical and surgical treatments that had been published in respected journals yet violated the ethical norms of informed consent and safety.* Although the Nuremberg trials following World War I1 had unveiled the horrors of unethical human experimentation,

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mainstream medical research in the United States was largely unregulated, and examples of unethical research practices were problematic. Beecher's report galvanized the public to demand, and the federal government to reqiire, institutional review to ensure the-ethical acceptability of all research (medical, behavioral, and surgical) on human subjects. Through the National Research Act of 197'4, the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research convened a group of respected clinical scientists, physicians, and experts in ethics, religion, and law to review the basic principles that should characterize the conduct of research involving human subjects and to develop guidelines to ensure the conduct of ethical research. The commission issued its summary statement, the Belmont Report," in 1979. The report identified the principles of respect for persons (which it divided into respect for autonomy and protection of the vulnerable), beneficence, and.justice as particularly relevant to research ethics. These principles have subsequently become important in clinical practice as well, although their application differs. Within the Belmont Report were two features of critical importance to pediatric surgeons: the role of informed consent for research subjects, and the protection that must be accorded when research is performed on vulnerable subjects, such as children. Parents and society expect that pediatric surgeons will be conservative guardians in surgical innovation, relying on a long tradition of generally safe operations and of progress in ameliorating the effects of congenital anomalies. Levinel0 has described some newly introduced procedures as nonvalidated, a term that acknowledges the ethical and medical hazards of novel o~erations.which may be obscured by the terminology of innovation. For both pediatric surgeons and parents, the concept of a nonvalidated operation is more transparent and honest; it embodies the fact that the proposed operation has not been subjected to rigorous clinical investigation. The presumption that a given novel operation is superior to its traditional counterpart is, in reality, a presumption only if it lacks an empirical basis. Clinical trials of a nonvalidated operation may reveal that it is superior to, equal to, or worse than conventional procedures. For example, the recent National 1nstit;tes of Healthfunded clinical trial of fetal endoscopic tracheal occlusion for congenital diaphragmatic hernia was stopped after the enrollment of 24 patients because survival was unexpectedly higher for the infants who received standard care (planned delivery and postnatal care at a tertiary center) compared with those undergoing the fetal intervention." Lacking rigorous scrutiny, the current system of surgical innovation may hinder the determination of an optimal surgical therapy for a given condition. A compelling argument can be made that pediatric surgeons have an ethical obligation to participate in well-designed prospective, multi-institutional clinical trials that seek to establish the best operations or treatments for their patients.Vatients and their families have a right to expect pediatric surgeons to practice competent surgical care that includes the best proven surgical treatments

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and operations. When pediatric surgeons perform nonvalidated operations on their patients, no matter how well intentioned, they may be providing treatments that are not optimal, because they have not been rigorously tested.

BARlATRlC SURGERY Obesity among children and adolescents is recognized as a major public health concern in many developed countries. In the United States, obesity affects about 16% of children, one third of whom are considered morbidly obese. Although the causes of this trend are not fully apparent, the decline in physical activity and the high-calorie diets of American children are likely contributing factors. Obesity in children and adolescents has significant ramifications for the individual and for public health. Because obesity is associated with serious conditions such as hyperlipidemia, hypertension, and type 2 diabetes, the financial and social costs are high. The adverse psychological factors associated with obesity in children and adolescents have not been well studied, but these may have considerable social and financial costs as well. Health care professionals and the broader social community share concerns about the effects of obesity on children and adolescents, in part because of the serious ramifications for their physical and mental health and long-term well-being. Treatment for morbid obesity includes medical and surgical approaches. The range of success with these approaches varies, and research is needed to better assess them, particularly in a pediatric population. Medical therapy that includes a comprehensive program of exercise and diet has not been successful in adults over the long term. Few children's hospitals have developed comprehensive medical obesity programs; thus, there is scant evidence in the pediatric literature about the outcomes of such programs. For adults with morbid obesity, surgical therapy is quite popular because it has been successful in achieving weight reduction with acceptable morbidity and mortality rates. Based on the good results in the adult population, it is not surprising that pediatric surgeons are being asked by the public-in particular, eager patients and their parents-to provide bariatric surgery for children and adolescents with morbid obesity (see Chapter 78). Roux-en-Y gastric bypass and gastric banding, both performed laparoscopically, are the two bariatric operations performed most frequently in adults in North America and Europe. Although both achieve weight loss, gastric banding does not alter the anatomy and is reversible; gastric bypass alters the anatomy in an essentially irreversible manner. Gastric bypass is very effective in achieving weight loss not only because it reduces the size of the stomach but also because it causes malabsorption. Long-term studies in adults indicate that gastric banding is somewhat less effective in achieving major weight loss but is successful in reducing the comorbid conditions of hypertension and diabetes.

There are some ethical concerns about bariatric surgery that pediatric surgeons should consider.9 Both operations are currently nonvalidated therapies for pediatric patients, and neither safety nor efficacy has been proved by multi-institutional clinical trials in this population. Patients and their surrogate decision makers should understand the nonvalidated nature of these operations before they make an informed choice to have a bariatric operation. Moreover, pediatric surgeons performing these operations should participate, whenever possible, in well-designed clinical studies that seek to define the safety, efficacy, and long-term outcomes of these surgeries in pediatric patients with morbid obesity. As with other nonvalidated treatments, research evaluating the safety and efficacy of bariatric procedures should be designed in a way that does not interfere with the therapeutic objectives of patients. Because of insufficient research and the relatively recent history of bariatric surgery (isolated case reports in adolescents), the risks and potential benefits of these operations are difficult to assess. Although early results have shown these operations to be safe for adolescents, the long-term outcomes are unknown. The gastric bypass operation raises concerns about chronic nutritional issues, such as vitamin deficiencies, and possible adverse effects over a lifetime. An additional concern is that patients must comply with prescribed dietary restrictions and undergo medical surveillance indefinitely. It is generally well recognized that patients tend to forgo regular checkups over the long term, particularly if they have no physical complaints. Because the long-term risks of these operations for adolescents are unknown, subtle aberrations in physiology that would be detected by close medical supervision might go unnoticed and undiagnosed until they cause serious consequences. Risks alone do not render a therapy unethical. The ethical assessment of risks involves taking into account the gravity of the risks, the probability that they will occur, and the potential benefits that patients may experience. The potential benefits should be assessed in light of the available evidence and the particular patient's situation. Where there are gaps in research, pediatric surgeons should draw on evidence from the adult population and extrapolate to adolescent patients, as their experience and expertise deem appropriate. In the informed choice process, pediatric surgeons should be honest with patients and their surrogate decision makers about what is known, what is unknown, and the reasoning behind their recommendations regarding a bariatric operation for a particular patient. For children or adolescents with morbid obesity, bariatric surgery may be viewed as a quick and easy "fix" compared with nonsurgical means of achieving weight loss. Quick and easy solutions are certainly desirable, but if nonsurgical means or less invasive procedures are (or prove to be) safer or more effective, or if they protect important options for children and adolescents (e.g., the ability to make important decisions about their health, bodies, and lives in the future), pediatric surgeons should be wary about agreeing to perform bariatric surgery. Pediatric surgeons, in their role as child advocates, have

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a professional responsibility to encourage a more balanced reflection and assessment of the therapeutic options for morbid obesity. In general, surgeons should be hesitant to operate on patients who are not capable of making their own informed decisions when the surgery can be safely delayed until they are capable of making such decisions. This is especially true when the surgery has irreversible effects and the safety and efficacy of the surgery are unknown. Pediatric surgeons must consider not only whether bariatric surgery is a potential therapeutic option for a particular patient but also whether it is the best option for a particular patient. Although the choice to have or forgo surgery is ultimately up to the patient and his or her surrogate decision makers, the surgeon's recommendations are usually an important factor. For some patients, this may mean recommending a less effective but reversible surgical technique or delaying a decision about surgery until the patient is older and pursuing medical therapy in the meantime.

SEX ASSIGNMENT SURGERY A variety of conditions in infancy, including ambiguous genitalia, cloacal exstrophy, and penile agenesis: may lead pediatric surgeons to consider sex assignment surgery. During the past decade, the traditional medical and surgical management of newborns with genital ambiguity has become controversial, with individuals who were "reconstructed" in infancy challenging the appropriateness of their treatment and questioning the success of their outcomes. Through advocacy organizations such as the Intersex Society of North America and the Androgen Insensitivity Support Group, adults with intersexuality (most of whom had sex assignment surgery in infancy and childhood) have publicly voiced their extreme dissatisfaction with several aspects of their medical and surgical care. Intersex is the term now used bv medical wrofessionals and the public to refer to congenital conditions that result in nonstandard male or female genital anatomy. A primary assumption underlying sex assignment surgery is that having nonstandard genitalia will cause psychological harm and that this harm can be avoided or reduced by performing surgery to normalize the appearance of the genitals, so that the child can be raised in the gender tha
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behavior and maternal feelings, but that the postnatal environment is the primary determinant of gender identity. In essence, Money's theory implied that for humans, behaviors that are denoted male or female are sociocultural constructs rather than biologic imperatives. For infants with intersexuality, Money's theories had significant implications for decisions about the sex of rearing. First, because the postnatal environment would be critical in determining the infant's gender identity, successful treatment would involve giving unequivocal and clear messages about that gender identity. Second, because gender identity does not depend on the cause of the genital ambiguity, sex and gender assignment should be based on anatomic considerations (and the potential for surgical reconstruction), reproductive potential, and capacity for intercourse. Thus, the individual was assigned a sex and a gender that were medically determined and, in most cases, reinforced by surgical reconstruction in infancy. Advocates from the intersex organizations, social scientists, and others cite several concerns about early sex assignment surgery. They have identified a paucity of objective, long-term, multi-institutional data on outcome in terms of sexual function, sexual pleasure, and psychosexual identity.14 Single-institution series involving small numbers of patients who had feminizing surgery in infancy have reported acceptable anatomic, functional, and psychosexual outcomes.18Other more recent reports (in which the evaluators were not part of the original pediatric surgical team) indicate that the long-term results of feminizing surgery are not optimal, with funcW study of tional problems and poor c o ~ m e s i s . ~ Jrecent 14 genetic males with cloacal exstrophy who had female sex assignment surgery in the newborn period found discordant sexual identity in 8 individuals, who reassigned themselves as male.*()Because there are so few reports on comprehensive outcomes for the various intersex conditions, it is not clear whether the dissatisfaction voiced by those opposed to early sex assignment surgery represents a vocal minority of patients or is reflective of less than optimal results in the majority of patients. A major ethical concern about the traditional approach involves the paternalistic decision making of medical and surgical professionals. Parents were frequently not given the entire truth about the diagnosis, and if they were, they were told to withhold certain aspects of the condition from the child to lessen gender identity conflicts. Thus, for most individuals with intersexuality, their diagnosis was not revealed to them by their parents or physicians. As adults or adolescents, if they experienced gender identity problems or sexual difficulties and eventually discovered the truth, they expressed tremendous anger and resentment about their treatment as infants and children. In addition to causing disrespect and distrust toward parents and physicians, lying to patients about their intersexuality and withholding their medical histories denies them the opportunity to come to terms with who they are and what has happened to them, to receive psychological counseling, and to seek support from others who have had the same or similar experiences. The ethical duty of informed consent

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requires that parents of infants with intersexuality be given all relevant information about the diagnosis, treatment options (including no early sex assignment surgery), expected outcomes (including the paucity of comprehensive data on long-term results), and the availability of advocacy organizations and counseling. In most cases, early sex assignment surgery is not necessary for the infant's physical health. In fact, advocates from the intersex organizations argue that it is not necessary for the child's psychological health either and that it sometimes causes harm. Daaboul and Fraders argue that a "middle way" approach should be adopted when making decisions about infants with severely intersexed genitalia and complete discordance with the assigned gender.Vhey note that delaying surgical reconstruction in these infants may cause considerable psychosocial difficulty in the school-age and adolescent years. Further, there are no reliable data on the outcomes of intersex children in developed countries whose genitalia are significantly discordant with their assigned gender. Parents of these severely affected infants should be allowed to make decisions regarding early sex assignment surgery, as long as they have been given full disclosure of the current state of knowledge (or lack thereof) about functional and sexual outcomes. Adherence to the ethical obligation of full and honest disclosure to the parents of infants with intersexuality should include a willingness by pediatric endocrinologists and pediatric surgeons to honor parental choices, including the rejection of early sex assignment surgery. As long as deferral of surgery carries no risk of physical harm (infection, malignancy in dysgenetic gonads), parents of these infants should be accorded the same authority for decision making that they are given in all other areas of medical treatment. REFERENCES 1. Baylis F, CanianoDA. Medical ethics and the pediatric surgeon. In Oldham KT, Colombani PM, Foglia RP (eds): Surgery of Infants and Children: Scientific Principles and Practice. I'hiladelphia, Lippincott-Raven, 1997, p 382. 2. Beecher H: Ethics and clinical research. N Engl J Med 1966;274:1354. 3. Caniano DA: Ethical issues in the management of neonatal surgical anonlalies. Semin Perinatol 2004;28:240.

4. Creighton SM, Minto CL, Steele SJ: Objective cosmetic and anatomical outcomes at adolescence of feminizing surgery for ambiguous genitalia done in childhood. Lancet 2001; 358:124. 5. Daaboul J, Frader J : Ethics and the management of the patient with intersex: A middle way. J Pediatr Endocrinol Metab 2001;14:1575. 6. Frader.1, Caniano DA: Research and innovation in surgery. In McCullough LB, Jones JW, Brody BA (eds): Surgical Ethics. New York, Oxford University Press, 1998. 7. GloverJ, Caniano DA: Ethical considerations in newborn surgery. In Puri P (ed): Newborn Surgery. Oxford, Butterworth-Heinemann, 2003. 8. Harrison MR, Keller R1, Hawgood SB, et al: A randomized trial of fetal endoscopic occlusion for severe fetal congenital diaphragmatic hernia. N Engl .J Med 2003;349: 1916. 9. Inge TH, Krebs NF, Garcia VF, et al: Bariatric surgery for severely overweight adolescents: Conccrns and recommendations. Pediatrics 2003;114:217. 10. Levine RJ: Ethics and Regulation of Clinical Research, 2nd ed. New Haven, Corm, Yale University Press, 1988. 11. Little M: Invited commentary: Is there a distinctively surgical ethics? Surgery 2001;129:668. 12. McCullough LB, Jones JW, Brody BA: Principles and practice of surgical ethics. In McCullough I,B, .Jones JW, Brody BA (eds): Surgical Ethics. New York, Oxford University Press, 1998. 13. McKneally MF: Ethical problems in surgery: Innovation leading to unforeseen complications. World J Surg 1999;23:786. 14. Meyer-Bahlburg HF: Gender assignment and reassignment in 46,XY pseudohermaphroditism and related conditions. J Clin Endocrinol Metab 1999;84:3455. 15. Minto CL, Liao LM, Woodhouse CRJ, et al: The effect of clitoral surgery on sexual outcome in individuals who have intersex conditions with ambiguous genitalia: A crosssectional study. Lancet 2003;361: 1252. 16. Money.1: Gender: History, theory and usage of the term in sexology and its relationship to nature/nurture. .J Sex Marital Ther 1985;11:71. 17. National Commission for the Protection of' Human Subjects of Biomedical and Behavioral Research: The Belmont Report. OPPR Reports. Washington, DC, US Government Printing Office, 1979. 18. Newman K, Randolph J, Parson S: Functional results in young women having clitoral reconstruction as infants. J Pediatr Surg 1992;27:180. 19. Potts WJ: The Surgeon and the Child. Philadelphia, WB Saunders, 1959, p 3. 20. Reiner WG, Gearhart JP: Discordant sexual identity in some genetic males with cloaca1 exstrophy assigned to female sex at birth. N Engl J Med 2004;350:333.

Accident Victims and Their Emergencv Management Jeffrey R. Lukish and Martin R. Eichelberger

EPIDEMIOLOGY OF CHILDHOOD INJURY Preventable injuries take an enormous financial and emotional toll on injured children and their families, but also on society as a whole. Unintentional injury is the leading cause of death among children aged 14 and younger in the United States, claiming more than 5600 lives annually or, an average, 15 children each day.2 In addition, there were nearlv 11.8 million medical visits for unintentional injury among American children aged 14 and younger in 2000, or one injury visit for every five children. More than 16% of all hospitalizations for unintentional injuries among children result in permanent di~ability.~ The death rate from unintentional injuries among children aged 14 and younger declined 39% from 198'7 to 2000; it declined 42% for children between 1 and 14 years. Nevertheless, unintentional injury continues to be the leading cause of death among children in this age group in the United States. In 2000 the leading cause of fatal unintentional injury among children was motor vehicle occupant injury (28%), followed by drowning (16%) and airway obstruction injury (14%). Falls were the leading cause (36%) of nonfatal injuries seen in hospital emergency rooms in 2001.2O Leading causes of unintentional injury-related death vary according to child's age and are dependent on the child's developmental abilities and exposure to potential hazards, in addition to parental perceptions of their child's abilities and injury risk. The smallest decline in the injury death rate occurred among infants younger than 1 year; the decline in that age group was only 1096, compared with 42% in those aged 1 to 4 years, 42% in those 5 to 9 years, and 40% in those 10 to 14 years. Children younger than 1 year have the highest rate of unintentional injury-related death-more than twice that of all children. Airway obstruction is the leading killer in this age group. In children aged 1 to 4 years, drowning accounts for 27% of unintentional injury deaths and is the leading cause of injury-related death. The lowest rate of unintentional death is in the 5- to 9-year age group; the most common cause of death in

this age group and in those aged 10 to 14 years is motor vehicle occupant injury (Fig. 15-1).2" In all age groups, male children are at higher risk for unintentional injury than are females. This may be due to greater exposure to activities that result in injury, risk taking, and rough play in male children. Race and ethnicity are also important risk factors for unintentional injury in children. American Indian and Alaskan native children have the highest unintentional injury death rate, and African American children have the second highest. These racial and ethnic disparities likely have more to do with living in impoverished communities, a primary predictor of injury, than with biologic differences.17.2" Intentional injury and death may result from homicide, child abuse, or suicide. Recognition of this intent requires referral to child protective services for assessment. The resuscitation of these children is frequently a challenge because abuse may be chronic, which results in a child with a limited physiologic reserve (refer to Chapter 24 on child abuse).

RESUSCITATION AND IMPACT ON OUTCOME Resuscitation of an injured child includes the actions necessary to reverse and control the sudden alterations in physiologic homeostasis that occur as a result of injury. Children are remarkably resilient; however, the initial period of stability has been shown to be significantly shorter as age decreases.lq Therefore, resuscitation is not complete until injuries have been definitively treated and the child displays physiologic stability without continued intervention. Differences between children and adults with respect to patterns of injury, physiologic presentation, and management are important, particularly in children younger than 2 years. Physicians who treat injured children must recognize and understand these important distinctions so that the resuscitation process addresses the special needs of the child. The principle of a trimodal pattern of trauma-related mortality and morbidity in adults must be modified

266

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Leading Causes of Fatal Unintentional Injury Children 14 and under, 2000

.

Leading Causes of Nonfatal Unintentional Injury Children 14 and under, 2001

C I I I ; I ~ C01'

fitt:~l ; I I I ~ ~i l li e( ~s I I ~ I c I I . ~ I I

agc3c1 1 4 ).(.;IIS : ~ n t ly o u n g c l i l l t l l c l ' i i i t c . t l SI:IICS, 2 0 0 0 - 2 0 0 1 . ( F Y O ~ I I N i l ~ i o n ; ~( l; ~ I I I C Y f i ) ~ l. l c : d t 1 1 S t ; ~ t i s t i c . s ,( : ~ I I I ~ I 101. . S I)isc;~sc ( : O I I I I ~ O I: I I I ( ~ I ' I ~ ( ~ V C I I I ~ O N;iiio11;11 II: F.lc(~t~~o~~ic I I + I I . ~ S I I I Y ( ~ ~ I I ; I I I S( ~~CS I CAI lIl I111j11i.y

Motor vehicle Occupant Bicycle 4% 4%

Other

I'CIX

I I O I I ~ ~ I I ;I II~I I ~ I I I ~ I I I ~ i~ ~I !I ~j ~I ~~

2%

Falls

36% owning

Firearm 2%

Against

1%

for children. In the trirnodal model, the first mortality peak ;\inong i11j1u.ed children occurs within seconds or minutes afier injury, due to damage to the central or peripheral nervous system and the central vasculature. Survival call be improved in this group only through pi-evention efforts. The second mortality peak occurs minutes to houi-s aftel- injury and is due to mass lesions in the central Iler\rotrs system (CNS), usually subdural and cpid111.;11 hernatoril;~s;solid organ injury; or collections oi' fluid in the pleural and pericardial spaces. These inj~lriesrequire r;ipid identification and treatment because resuscitation is shorter in chilthe time limit f i ~effective dren than in adults by as much as 50%; the Advanced Tra~umalA'r S11ppo1-tprotocol focuses on such injuries. Although initial physiologic compensation may have been sufficie~~t to achieve some temporary accommodation, progi-cssive dysfi~nctionand exhausted reserves bring about a cl-itical impairment of oxygen delivery and the child's eve~itualdemise. Advances in the aggressive and systci~~;~tic delivci~yof' emergency medical services f i x children h;~vchad a salutary effect on preventable death in children. The third mortality peak occurs days to weeks fie^- the initial injury and is the result of complications of' i i j u ~ ysuch as sepsis and systemic inflarnrnato~yresponse syndrome, leading to multiple organ failiu-e syndrome.lVhis late peak in traumarelated mortality is less frequent in younger children.

PRINCIPLES OF RESUSCITATION

Dog bite 2%

twice that of adults in thc out-of~hosl>ital ~)hascoi'~.c.s~iscitation. Similarly, tllc s~~rvival rate f0r ()lit-of-hospital cardiac arrest in children is only half' that of' adlllts.1' Although part of this discrepancy results fi-on1 the diilkl-ent causes of cardiac arrest in children and adults, ~mfamiliarity and inadequate training with childr-en also (,ontributes to poor outcome. The fhi1ur.e rate fiw resl~scitationinterventions in the field is twice as high in cllildrcn as in adults; the failure rate {Or prehospit;il cndolr;~c.llcal intubation in children is close to 5O'%.li Unt:nrnili;~rity with pediatric resuscitation skills is undcrstandahlc; although trauma is the most common indication fiw pediatric ambulance transport, it accounts fi)r lcss than 10'%1of'total paramedic patient volume in most metropolitan areas. The most important objectives for emergency pcrsonnel in the field are:

1. Recognition and treatment of' immediate lift-threatening dysfu~lction. 2. Assessment of the mechanism of trauma and extent of injuries. 3. Documentation of pertinent medical d;~t;i. 4. Triage to an appropriate-level pediatric trii1111l;ifi~cility. Added to these are the challenges of comfi)rting a tei-rified and hurt child as well as the distraught pa~.cnts. Thus, the paramedic's task can be forniidahle. Consequently, prehospital personnel fi~nctionbest by adopting strict protocols to treat in-jured children. The priorities and techniques associated with pediatric field resuscitation are similar to those for emergency department care described later.

Prehospital Care Systematic management is essential to an injured child's sulvi11al. The resuscitation process begins when emergency transport personnel first encounter the child in the field. The fate of any child can turn o n the decisions and interventions that ti-anspil-e during these first crucial moments. The inj~u-y-acijusteddeath rate for children is

Primary Survey and Treatment of Life-Threatening Injuries When an injured child encounters medical personnel, whether in the field o r in the emergency room, events should transpire in a rapid sequence designed to

CHAPTER

15

recognize and treat acute injuries. This systematic approach allows the standardization of diagnostic and treatment decisions so that individual variations in patterns of injury do not prevent caregivers from recognizing and treating subtle injuries that can have a profound impact on outcome. This systematic framework comprises a primary survey, a resuscitation phase, and a definitive secondary survey. The primary survey is the initial process of identifying and temporizing injuries that are potentially life threatening and follows the ABCDE sequence: airway, breathing, circulation, disability, and exposure. The system relies on simple observations to assess physiologic derangement and immediate intervention to prevent death.

Airway and Cervical Spine Control Provision of airway control is perhaps the least controversial of all priorities in pediatric trauma management. The inability to establish and maintain a child's airway, leading to hypoxia and inadequate ventilation, continues to be a common cause of cardiorespiratory arrest and death. Significant clinical hypoxia is suspected when oxygen saturation is less than 95%. Assessment of the airway includes inspection of the oral cavity; manual removal of debris, loose teeth, and soft tissue fragments; and aspiration of blood and secretions with mechanical suction. If a child is neurologically intact, phonates normally, and is ventilating without stridor or distress, invasive airway management is unnecessary. Airway patency can be improved in a spontaneouslybreathing child by the use ofjaw-thrust or chin-lift maneuvers. An airway that is unsecured because of coma, combativeness, shock, or direct airway trauma requires endotracheal intubation. A nasopharyngeal or oropharyngeal airway can improve management during bag-mask ventilation, but this is a temporizing measure until definitive control is established. In most cases, orotracheal intubation with in-line cervical spine stabilization is the preferred approach to airway control. Although nasotracheal intubation is recommended in nonapneic adults with potential cervical spine injuries, this approach is not indicated and is poorly tolerated in children. Pediatric ainvay anatomy is unique and affects management technique. The child's larynx is anatonlically higher and more anterior than in the adult, necessitating an upward angulation of the laryngoscope to place the endotracheal tube properly. Removing the anterior half of the rigid cervical collar allows access to the neck for gentle cricoid pressure. The pediatric epiglottis is shorter, less flexible, and tilted posteriorly over the glottic inlet. Because of this, direct control of the epiglottis with a straight blade is usually necessary for proper visualization of the vocal cords. The vocal cords themselves are fragile and easily damaged. The narrowest point in the pediatric ainvay is the subglottic trachea at the cricoid ring, as opposed to the glottis in adult patients. Therefore, passage of the endotracheal tube through the vocal cords does not guarantee safe advancement into the trachea or avoidance of subglottic injury. Appropriate endotracheal tube selection is an important part of pediatric resuscitation. The internal diameter can range from 3.0 to 3.5 mm in newborns to 4.5 mm at 1 to 2 years of age. After 2 years of age, the internal diameter can

Accident Victims a n d T h e i r Emergency Management

267

be estimated by the following formula: Internal diameter = Age/4 + 4. Approximating the diameter of the patient's little finger is also useful. Because of the narrow subglottic trachea, an uncuffed endotracheal tube is indicated in children 8 years of age or younger (Fig. 15-2).1 1-13 The technique of intubation depends on the urgency of establishing an airway. In a hypotensive, hypoxemic, comatose child, orotracheal intubation is accomplished without delay as an integral part of the resuscitation. In a more elective situation, more attention is given to adequate preoxygenation by bag-mask ventilation with 100% oxygen and premedication. Thoracic trauma can preclude intubation or make attainment of adequate oxygen saturation impossible. Inducing hypocarbia (carbon dioxide partial pressure [Pac:02]30 to 35 mm Hg) by hyperventilation is advantageous. Following preoxygenation using mask ventilation, children should receive atropine sulfate (0.01 to 0.02 mg/kg) to ensure that the heart rate remains high during intubation. It is important to maintain an adequate heart rate because this is directly proportional to cardiac output; stroke volume does not change much in children. Also, children should be premedicated with intravenous sedatives and muscle relaxants. Appropriate sedatives include short-acting barbiturates such as thiopental sodium (5.0 mg/kg) if volume status is normal or a benzodiazepine such as midazolam (0.1 mg/kg) if hypovolemia is suspected. Muscle relaxation is achieved with short-acting nondepolarizing agents (vecuronium bromide 0.1 mg/kg) or shorter-acting depolarizing agents (succinylcholine chloride 1.0 mg/kg) . The presence of burns and devitalized tissue precludes the use of succinylcholine because of the risk of hyperkalemia. Continuous monitoring of an intubated child with end-tidal Co, and pulse oximetry is essential. In the rare case when tracheal intubation is not possible as a consequence of oral or maxillof'acial trauma or congenital anomaly, a surgical airway is indicated. A surgical cricothyrotomy is the preferred approach in children older than 10 years. The cricothyroid membrane is easily exposed through a transverse skin incision to accommodate placement of a small, uncuffed endotracheal tube. Morbidity is lower than with an emergency tracheostonly because of the superficial location of the cricothyroid membrane. The cricothyrotomy should be converted to a formal tracheostomy when the child is stabilized, to avoid subglottic stenosis. In small children, the cricoid cartilage is a delicate structure and provides the rnajority of support to the trachea. Injury of this membrane during emergency cricothyrotomy can lead to significant morbidity and lifelong laryngotracheomalacia. To avoid this complication, children younger than 10 years should undergo needle cricothyrotomy andjet insu!Tlation of the trachea. A 16- to 18gauge intraverious catheter is used to access the tracheal lumen through the cricothyroid ine~nbraneand is connected to a 100% oxygen source at a high flow rate of 10 to 12 L,/miiiute. Needle-jet ventilation is limited ill children by the hypercarbia that occurs ill approximately 30 minutes; therefore, this method is effective fi)r only a short time. Following stabilization of' the child, endotracheal intubation or formal tracheostorny is necessary.1"

268

PART

I1

TRAUMA

. .. .,.y -

i

.

F -

End

nx and supraglottic space are anterior and angled cephalad compared with the

position in adults. A posterior neck roll optimizes visualization of the vocal cords in children. B, The tongue is large relative to the space in a child's oral cavity. The tongue should be moved to one side of the oral cavity to facilitate exposure of the posterior pharynx and supraglottic area. C,The laryngoscope blade is inserted from the right side of the mouth and slides back along the vallecula. 0, With the blade in the proper position and the child's neck slightly extended in the sniffing position, lifting the handle (positions 1, 2, 3) raises the epiglottis and brings the vocal cords into direct vision. E, In all except newborns, the straight blade should be placed over the epiglottis to lift it, along with the base of the tongue, to expose the larynx. A stylet with the tip curved within the endotracheal tube facilitates successful intubation. The endotracheal tube is held in place while the laryngoscope is removed and secured after verification of bilateral breath sounds. (From Eichelberger MR: Pediatric Trauma, Prevention, Acute Care, Rehabilitation. St. Louis, Mosby, 1993.)

Breathing Compromised breathing and ventilation in an injured child are usually the result of either head injury (impaired spontaneous ventilatory drive) or thoracic injury (impaired lung expansion). Recognition of a head injury is usually obvious, but recognition of a thoracic

injury that impairs lung expansion requires a detailed survey. The potential seriousness of these injuries is underscored by the fact that mortality rates for thoracic trauma in children approach 25%.14 Following thoracic trauma, air, fluid, or viscera can compromise the pleural space. Compression of the pulmonary parenchyma can result in impaired gas exchange sufficient

CHAPTER

15

to produce respiratory distress. In the case of traumatic rupture of the diaphragm, loss of muscular integrity also has a direct effect on lung expansion. The child's mediastinum is extremely mobile; as pressure increases in the pleural space, the mediastinum is displaced to the opposite side, causing compression of the contralatera1 lung. The distortion of mediastinal vascular structures, along with elevated intrathoracic pressure, can result in a critical reduction in venous return. Loss of chest wall integrity from flail chest impairs ventilation and oxygenation. Consequently, paradoxical chest wall movement occurs during inspiration, preventing complete lung expansion; assisted positive-pressure breathing is the best treatment. Because of the flexible nature of a child's chest, the force required to fracture multiple ribs is enormous and is transmitted to the underlying lung parenchyma, resulting in a pulmonary contusion. Regions of parenchymal hemorrhage and edema impair ventilationperfusion matching, and the decrease in pulmonary compliance can dramatically increase the work of breathing; both can precipitate ventilatory failure. Recognition of ventilatory compromise is usually not difficult, especially with a high index of suspicion. The sound of air movement at the mouth and nares is assessed, as are the rate, depth, and effort of respirations. On inspection, asymmetrical excursion of the chest wall suggests a ventilatory abnormality. Percussion elicits dullness or hyperresonance, depending on the presence of fluid or air in the pleural space, and breath sounds are decreased. With tension hemopneumothorax, mediastinal shift can be detected by tracheal deviation, displacement of the point of maximal cardiac impulse, and distended neck veins caused by impaired venous return. Mechanical ventilatory failure is life threatening and requires immediate treatment during the primary survey. All children require supplemental oxygen by nasal cannula, mask, or endotracheal tube. Endotracheal intubation and assisted ventilation are sufficient to treat hypoventilation due to head injury, pain from rib fractures, flail chest, and pulmonary contusions. Simple hemopneumothorax may be well tolerated with supplemental oxygen until tube thoracostomy can be performed after the primary survey (Fig. 15-3). In cases of hemopneumothorax that results in compromised ventilation or hypotension, tube thoracostomy is required, often combined with endotracheal intubation and intravenous access for rapid fluid infusion. If tension is present, the hemodynamic derangements can be minimized by needle thoracostomy in the second intercostal space at the midclavicular line, followed by thoracostomy tube placement. A chest tube of adequate caliber to evacuate blood and air should be inserted into the pleural cavity. The narrow intercostal space of a small child usually limits the size of the tube, but the largest-caliber tube that can be placed should be used. The tube is placed in the midaxillary line at the nipple level (fourth or fifth intercostal space) to avoid intra-abdominal placement through an elevated diaphragm. The tube is directed posterior and cephalad, to evacuate both blood and air, and is connected to a Pleurovac closed-suction drainage system set at -15 cm H 2 0 (see Fig. 15-3).Persistent hemorrhage

Accident Victims and Their Emergency Management

269

from a thoracostomy tube is uncommon in children; however, drainage of 1 to 2 mL/kg per hour is a sign of significant ongoing bleeding from a vascular or mediastinal injury that may require thoracotomy to identify and control the source. When endotracheal intubation has been performed, the child's fraction of oxygen in inspired air should be loo%, with a tidal volume of 10 to 12 cc/kg at a rate of 15 to 20 cycles/minute. Oxygenation and ventilation should be manipulated to maintain an arterial oxygen ~ tension (PO?) greater than 80 mm Hg and a P C Oof 30 to 35 mm Hg, with a positive end-expiratory pressure not to exceed 5 cm H 2 0 . The goal is to prevent secondary brain injury by optimizing oxygenation and cerebral perfusion by minimizing intracranial pressure (ICP). Children with head trauma are best managed by moderate hyperventilation and hypocarbia (Pco, 30 to 35 mm Hg) to reduce ICP.6,13,18

Circulation and Vascular Access The third priority in the primary survey is the rapid assessment of circulation and the establishment of venous access. Seriously injured children often have normal vital signs, even with significantly decreased circulating volume; their cardiovascular reserve delays the early hemodynamic signs of hypovolemia until relatively late in the resuscitation phase. A high index of suspicion based on the mechanism of injury and continuous careful scrutiny of physiologic parameters and clinical signs are necessary to minimize morbidity. A reliable sign of adequate perfusion is normal mental status. As the child is resuscitated, clinical signs of the efficacy of resuscitation should be monitored. Improvement in the following parameters is consistent with hemodynamic stability and success of resuscitation:

1. 2. 3. 4. 5.

Slowing of the heart rate (20 mm Hg). Return of normal skin color and peripheral perfusion. Increased warmth of extremities. Clearing of the sensorium (improving Glasgow Coma Scale score). 6. Increased systolic blood pressure (>80 mm Hg). 7. Urinary output of 1 to 2 mL/kg per hour in infants and 1 mL/kg per hour in adolescents.

After establishment of an adequate airway, provision of venous access in a hypovolemic child is often a challenge. Two functioning catheters are best in all cases of significant injury. Optimally, venous access should be achieved above and below the diaphragm, given the potential for extravasation of resuscitation fluids from occult intra-abdominal venous injuries. Nevertheless, in children, any peripheral venous access is useful. Two attempts should be made to place large-bore peripheral lines in the upper extremities. If percutaneous placement is unsuccessful, insertion of an intraosseous line is useful in a child younger than 6 years (see later). In children older than 6 years, a venous cutdown performed at the ankle is best. The greater saphenous vein is easily exposed through short transverse incisions 0.5 to 1 cm proximal and anterior to the medial malleolus.

270

PART

I1

TRAUMA

, Thoracostomy tube insertion. A, An incision is made in the midaxillary line just below the nipple in a male or inframammary fold in a female (fourth intercostal space). B, The dissection is carried out in a cephalad direction subcutaneously over two ribs. A long subcutaneous track is preferable in a child to minimize air leak around the tube. C, The fourth intercostal space is the ideal place for thoracostomy tube placement. 17, The entrance into the pleural space should be made just over and superior to the rib to avoid injury to intercostal vessels. E, Lateral view of the technique. (From Eichelberger MR: Pediatric Trauma, Prevention, Acute Care, Rehabilitation. St. lmuis, Mosby, 1993.)

T h e exposed vein is suspended over a silk ligature, and t h e largest appropriate i~ltravenouscatheter is introduced r vision. Transection o r i n t o t h e vessel lume11 ~ u l d e direct ligation o f t h e vein is n o t necessary (Fig. 15-4). Central vexlous catheterization can result i n significant complications, s u c h as laceration o f t h e subclavian o r femoral artery, rnakirlg it a less useful technique. T h e femoral r o u t e is preferred because o f ease o f access. I f subclavian v e n o u s access is necessary, t h e child should b e placed i n t h e T r e n d e l e n b u r g position with t h e head maintained i n a neutral position without t h e placement o f a posterior shoulder roll. T h i s positio~i provides

optimal cross-sectional area o f t h e subclavian vein i n b o t h children a n d adults.12 An intraosseous line is a simple, reliable, and safe route for t h e administration o f fluids, blood products, a n d medications. T h e t e c h n i q u e is applicable i n children 6 years o f age and younger because t h e marrow is well perfused i n early childhood. T h e preferred site for intraosseous i n s e r t i o n is t h r o u g h t h e flat a n t e r o m e dial surface o f t h e tibia, about 2 t o 3 c m below t h e tibia1 plateau. T h e needle is angled 60 degrees f r o m horizontal a n d pointed toward t h e foot. T h e cortex is penetrated, and t h e marrow cavity is detected b y aspirating

CHArTeu

15

blood arid particulate material. Alternative sites include the midline distal femur, 3 cm above the condyles directed cephalad i r i sinall children, arid the distal tibia above the 111edi;llrnalleolus or the proximal humerus in adolescents, although the need for an intraosseous line is I :ti e in this age group. Specially designed intraosseous needles shot~ldhe available in the pediatric resuscitation roo111to facilitate this maneuver; however, a 1 4 to lcgauge needle can be used. The coinplication rate is low, but potential coniplications include osteomyelitis, cellulitis, fi-actwe,growth plate injury, fat embolism, and compartment syndrome. As soon as vascnlar access is established, fluid resuscitation with ;I bolus of fluid is begun. Generally, isotonic cryst;~lloidsolution, such as lactated Ringer's solution, is ;~dniinistei-cd in 20 mI,/kg increments. If evidence of

Accident Victims arid T h e i r Emergency M a ~ ~ a g e ~ l ~ r ~271 lt

hypovolemia persists after 40 mI,/kg has been given, tl-ansfi~sionof ABO-matched packed red blood cells is initiated in a bolt~sof' 10 1n1Jkg. Packed red blood cells have the advantages of raising colloid oncotic pressure and effecting a AOI-crapid and sustained intravascula~expansion than ciystalloid. In addition, the red blood cell provides hemoglobin to increase oxygcn carrying capacity. All fluids (crystalloid, colloid, and blood) should be warmed during iiifi~sion.This is accolnl)lishcd by microwaving crystalloid solutions oi- using a warrning device. It is important to reassess the child's I-csponsct o I-csnscitation contirlually. to characterile the nati11-cand extent of the injuries, and to avoid the coniplic;jtions of cxccssive fluid resuscitation. As pel-fi~sionis restored, the rate of fluid infusion is gradually reduced to avoid unnecessary fluid administra6on. Puliiionary c d e ~ n ararely occurs i n

a

-

(;rc;~tcrs;lplw~io~isv\'c.i~i c.;~nnulatiotl

A, <:011sistentemergency \.enous ;tc.crss is ;~chicvc*d

Medial malleolus

at the ankle, atltcrior to the 111rdi;d~ t i i ~ l l e ovia l ~ ~illc s saphrno~tsvein. R, A i~.ansvc~-sc incisio~iis tilade anterioi- to thc 1nedi;ll m;rlleol~~s ( 1 ( I I I ; I I I ~ ~ I . ;111d ~ ~ I 1 cm cephalad). Perl,ct~dicula~d i s s r c t i o ~in~ tlic. incision exposes the sal~licnousveiii. (,', TIic vcin is disscctcd cii.curntcrc~~ii;lIly. I), A S I I ~ I Ilig;~tui.c I-c is passed around the vessel. I(;ltid 1; (;c1111ct ~ ; l c t i o ~ ~ o n thc sut~u-c ficilit;%lcs c n i l ~ c t c ~ ~ . i l ; ~ofi i ot11c ~i (From Eic11elhe1-gct-MU: I'rdi;~ti.icl't.;~u~na. Prevention, Ac~tte(:arc, Reli;lhilit;~tion.St. I.ouis, Mosby, 1993.)

272

PART

I1

TRAUMA

normal lungs, but considerable morbidity results from fluid sequestration in a region of pulmonary or cerebral contusion. If hemodynamic stabilization does not occur with crystalloid and blood resuscitation, hemorrhage is likely from an intra-abdominal or pelvic source, cardiac dysfunction due to tamponade or contusion, tension hemopneumothorax, cerebrospinal injury such as atlantooccipital dissociation, or profound h y p ~ t h e r m i a . ~ , ~ "

Disability A rapid neurologic evaluation is included in the primary survey to identifjiserious injuries that may have immediate consequences for airway management. A rapid method for describing gross cerebral function is the AWU mnemonic: alert, voice responsive, pain responsive, or unresponsive. An assessment of pupillary responsiveness and symmetry is also useful. Transtentorial herniation secondary to an expanding intracranial hematoma causes ipsilateral pupillary dilation and loss of light reflex. Direct trauma to the eye is an equally common cause of unilateral anisocoria, but this is usually obvious. Characterization of extremity posturing as decorticate or decerebrate indicates the loss of cortical or global brain function, respectively. In a comatose child with a unilateral fixed and dilated pupil, measures to reduce ICP are imperative. These include early controlled endotracheal intubation to keep the Pco,, regulated (30 to 35 mm Hg) with moderate hyperventilation, which causes cerebral vasoconstriction and decreases cerebral blood flow. This lowers brain volume and ICP, with a resulting increase in cerebral perfusion pressure (CPP). The reverse Trendelenburg position, in which the head is elevated 30 degrees, can also reduce intracranial hypertension but should be used only in children with normal cardiac function.

Exposure Complete exposure of the child is essential to facilitate a thorough examination and identification of injury. A conscious child does not understand the need for such action, so exposure must be done carefully. A thorough primary survey on a stable child with a normal Glasgow Coma Scale score can be performed without removing all items of clothing simultaneously. Children are particularly apprehensive about pain when exposing an injury that was previously covered, so attention to these special sensitivitiesfrequently results in a more efficient evaluation. In a child, hypothermia affects physiologic parameters, such as cognitive function, cardiac activity, and coagulation. It is important to maintain core temperature above 35°C to 36OC. A warm resuscitation room preserves core body temperature and minimizes heat loss. Similarly, resuscitation fluid and inhaled gases should be warmed and humidified. Overhead and bed warmers are essential, but a radiant warmer is best for an injured infant.

Resuscitation Phase The cornerstone of resuscitation is continuous reappraisal of the child's response to therapeutic intervention. Deterioration at any point requires repetition of the

primary survey. After the ABCDEs are complete and life-threatening injuries are stable, a gastric tube and urinary catheter should be placed, followed by the drawing of blood for analysis and placement of a cardiac monitor. In children, acute gastric dilatation can cause both respiratory compromise and vagus-mediated bradycardia. Gastric decompression to evacuate the stomach and reduce the risk of vomiting and aspiration is important in all injured children, especially those with a decreased level of consciousness. Assessment for a stable midface and for the presence of cerebrospinal fluid rhinorrhea is important before the placement of a nasogastric tube for decompression. If the assessment is abnormal, oral gastric tube placement is in order. A urinary catheter is also placed following a thorough perineal assessment, including a rectal examination. In instances of a high-riding prostate, meatal bleeding, perineal or scrota1 ecchymosis, or unstable anterior pelvic fracture, a retrograde urethrogram is indicated before insertion of the catheter. An electrocardiogram is essential to monitor cardiac rhythm, which is rarely abnormal. Secondary abnormalities are occasionally seen and include sinus bradycardia due to advanced shock; electromechanical dissociation from hypovolemia, tension pneumothorax, or pericardial tamponade; and ventricular fibrillation due to hypothermia or acidosis. Ventricular ectopy, low voltages, and signs of ischemia can accompany myocardial contusion. Beyond evaluating the actual rhythm, diffuse low voltage may be the first indication of hemopericardium. After vascular access is obtained, blood and urine are obtained for laboratory analyses, including complete blood count and metabolic studies, urinalysis, and arterial blood gas analysis. Blood alcohol level and a toxicology screen are not routine in children but reasonable in adolescents. Blood should also be drawn for type and cro~smatch.~,~

Neuroresuscitation Brain injury is the most common cause of acquired disability and mortality during childhood. It is estimated that each year, 1 in 500 children in the United States sustains a brain injury, 7000 children die from head injuries, and 28,000 children become permanently disabled.IJ0Largely as a result of prevention strategies and regional trauma systems, the overall mortality from severe traumatic brain injury has decreased from approximately 50% in the 1970s to 36% today. In children, the current overall mortality from injury is 3%; the primary cause of death in 70% of cases is central nervous system injury. Overall, the outcome for children older than 3 years is better than for adults with comparable injuries; however, outcome in children younger than 3 years is often p ~ o r . ~ , l " l ~ Traumatic brain injury can be defined as either primary or secondary. Primary brain injury is the structural derangement of cerebral architecture that occurs from direct mechanical impact, resulting in cellular and vascular disruption, infarction, or tissue loss. The child's brain is susceptible to injury of the deep white matter, shear, punctate hemorrhage, brain swelling, and linear nondepressed skull fracture, rather than mass lesions such as subdural

CHAPTER

15

and intracerebral hematomas and depressed skull fractures, which are more frequently encountered in adults. Children, however, have a higher incidence of epidural hematoma, perhaps because the thinner, less rigid skull is more apt to fracture and lacerate the meningeal artery. The proportionately larger size of the cranium in children, along with a less muscular and more flexible ligamentous cervical spine, may account for the increased incidence of diffuse axonal injury in injured children. Primary brain injury responds only to preventive efforts, whereas secondary brain injury is the target of clinical neuroresuscitation. Secondary brain injury occurs as a result of decreased cerebral perfusion following the traumatic event. Both diffuse and regional brain swelling impairs oxygen and substrate delivery largely as a result of increasing ICP and its effect on CPP. CPP, ICP, and mean arterial pressure (MAP) are related by the following equation: CPP = MAP - ICP. Resuscitation should optimize CPP by controlling ICP and maintaining MAP. When ICP exceeds venous outflow pressure (as a result of brain swelling), it acts as a Starling resistor and determines the pressure gradient for cerebral blood flow. Normal CPP values and the ideal range of ICP in children with severe brain injury are not clear.*Favorable outcomes in children are possible by maintaining the ICP less than 20 mm Hg in all ages and a CPP greater than 45 mm Hg in children younger than 8 years and 70 to 80 mm Hg in older ~ h i l d e n . ~ Efforts to reduce secondary brain injury focus on maintaining a therapeutic ICP and CPP and normalizing the MAP. The most expeditious method is intubation and controlled hyperventilation, initially reducing PCO? to 30 to 35 mm Hg, Po2 to greater than 100 mm Hg, and pH to 7.40 + 0.05. Hypocarbia and alkalosis promote cerebral vasoconstriction, limiting cerebral blood volume and lowering ICP. The effect is rapid but can be limited in duration by re-equilibration of cerebrospinal fluid pH balance. The maximal duration of the effect is unknown but may range from several hours to several days. Current therapy maintains PCO*in the 30 to 35 mm Hg range. This regimen avoids excessive hyperventilation, which may be deleterious in patients with severe brain injury by converting borderline regions of cerebral . ~ ventriculostomy is usually ischemia into i n f a r c t i ~ nA placed, allowing cerebrospinal fluid to drain to further optimize CPP. A repeat head computed tomography scan is indicated 24 to 48 hours after injury to assess the extent of brain edema, identify new infarcts, or demonstrate the development of a new hematoma or large contusion that may require evacuation. The status of ventilation and fluid hydration should be reassessed and optimized frequently in the first 48 hours. If these measures fail to control ICP, osmotherapy is undertaken with a rapid bolus intravenous infusion of 20% mannitol at a dose of 0.25 to 0.5 g/kg - every 4 to 6 hours. Mannitol is withheld if the serum sodium concentration is greater than 145 mEq/L, serum osmolarity is greater than 310 mOsm, urine output is less than 0.5 mL/kg per hour, or blood pressure is low. Mannitol exerts a therapeutic effect by creating a hyperosmolar environment in the cerebral microcirculation; this improves brain oxygen delivery by exerting a diuresis of free water from the cerebral interstitium, which improves blood flow.*

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273

The induction of mild to moderate hypertension may reverse abnormal ICP and raise CPP by improving brainstem microvascular perfusion.16 Therapy is begun with an intravenous infusion of dopamine at a dose of 5 to 20 pg/kg per minute. Hyperthermia and seizures are common after traumatic brain injury and can adversely affect efforts to normalize ICP and CPP. Both fever and seizures promote further secondary brain injury by increasing the metabolic demands of the already compromised brain. Therefore, core temperature should be maintained in the normal range (35" C to 36' C) with acetaminophen 10 mg/kg every 4 to 6 hours. Cooling blankets may be necessary for recalcitrant fever. A single seizure in a child following head injury and a subsequent normal neurologic assessment does not require treatment. Seizures that occur within 1 week after injury are treated with phenobarbital in children younger than l year and with phenytoin in those older than 1 year. Either drug is administered in a one-time intravenous dose of 10 to 20 mg/kg, followed by daily dosage of 5 mg/kg. Treatment is discontinued after 7 days. Children who develop late seizures require long-term anticonvulsant medication. Whether a comatose child who has not demonstrated seizure activity requires anticonvulsant prophylaxis during the resuscitation process is controversial.

Coagulopathy Dysfunctional coagulation related to injury occurs in several circumstances: extreme hypothermia, massive transfusion, and severe brain injury. Hypothermia causes excessive bleeding by reducing the efficiency of enzymatic processes that promote coagulation. Massive transfusion, defined as the acute administration of blood products equal to or greater than one blood volume (65 to 80 mL/kg), also causes coagulopathy. Another mechanism results from the storage of blood in anticoagulants containing ethylenediaminetetraacetic acid or citrate (citrate-phosphate-dextrose), both of which chelate calcium and inhibit the calcium-dependent steps of the coagulation cascade. Acute hypocalcemia is another consequence of massive transfusion. The most common mechanism by which massive transfusion causes coagulopathy is dilutional thrombocytopenia. Coagulopathy due to dilution of other clotting factors is much less common because of a much greater functional reserve of these components. As continued hemorrhage depletes circulating platelets and blood is replaced with red blood cells, a progressive reduction in the platelet count ensues. With acute injury, a reduction in the platelet count to 50,000 can produce surgical bleeding. Platelet levels below 100,000 signify impending coagulopathy, and levels of 50,000 or less require platelet transfusion. Administration of ABO-matched platelets at an initial dose of 0.1 U of concentrate/kg or 4 U/m2 of body surface area raises the platelet level by about 40,000. Severe head injury is also associated with coagulopathy unrelated to platelet dilution. Presumably, large amounts of procoagulant tissue thromboplastin are released from injured areas of the brain, initiating disseminated intravascular coagulation and a consumptive coagulopathy

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in which all clotting factors and fibrinogen are depleted, as well as platelets. <:oagulopathy after head illjury is a grim prognostic sign. Treatment requires administration of matched ti-esh frozen plasma at a dose of 15 to 30 mL/kg. amounts of fibrinogen, (:ryoprecipitate c o n t a i ~ ~large s factoi- VIII, factor XIII, and von Willebrand's factor and can be given at a dose of 0.1 U/kg in addition to fresh fi-oxcn pl;isma. Admi~~istration of fresh frozen plasma, cryoprccipikltc, o r both may also he required in the setcoag~ilopathiessuch as hemophilia, ting of' ~m~existiiig von M'illcl,r;lnd's disease, alitl advanced liver disease.'"

PAIN MANAGEMENT The primary goals of acute pain management are to rcd~icethe sti-css on the injured child and to improve ontcoine. Acute pain s r ~ - \ ~as c s a i~oxiousstimulus that Ic;lds to activation of'the physiologic stress response. The 1.cs11ltis ;lcti\.a~ionof'thc ne~~rocndocrine response, which has a 1~1-ofi)undiind deleterious rffect o n metabolism, thermoi-cgt~latioi~, wound healing, and immunity. T h r fi~llowingare critical elements in the management of' pa it^ in inj~u-cdchildren: 1. An cxprrienced ii1terdisciplina1-yteam, led by a clinician devoted to pail1 management. 2. A cori~niitrncntto ensure the least possible pain. 3. Recognition that rffective pain managcrnent requires const;tnt adjustri~cnt. 4. Recognition that anxiety needs to he considered and ti-ciitcd bec;it~seit may altei- the effectiveness of pail1 trcatlnellt. 5. ?'he ability ;1nd knowledge to effectively use all pain thcrapy in I-eal-tirne coordination with the rest of the child's supportive care and treatment plan. A team-oriented, protocol-based algorithm that attempt? to control pain i11 this environment will enhance the overall success of' the emergency management of these children."

CONCLUSION A systematic approach to injured children can save lives. Nevertheless, prevention of injury is essential. T h c unintentional injury death rate among children has declined nearly 40% during the past 16 years."' The most notable progress in prevention has beer1 a 72% decline in childhood deaths from unintentional firearm i~lj~lrics and a 60% decline in deaths from bicycle-related i~ljtuies.The death rate from fire and burn injuries declined 56%, while that from pedestrian injuries dropped 51 %. Unfortunately, the motor vehicle occupant death rate, particularly among children aged 5 to 9, has been slow to decline, and the death rate from airway obstn~ctioninjury among infants remains unchanged. Many Factors have contributed to the overall dramatic decline in the unintentional childhood injury death rate. It is clear that the highest priority should be on injury prevention, with a particular emphasis on minimizing the injury risk to minorities, younger children, and inotor vehicle occupants. Once injury occurs, however, proper resuscitation can save lives.

REFERENCES 1. Centers for Disease Co11tr-ol:(:l~iltlhood iniuries in the United States. Am.] l)is i:hild 1990;144:(i'L7-(i4(i. 2. Centers f < ~Disease r (:oritrol and 1'rc.vcntion: Wcl1-hascd Injury Statistics Qnery and Reporting Systc>ni(W'ISQAKS). Fatal Injury Reports 1999-2000. National (:cntcr fi)l-Irljul~ Prevention and Control, (:cntc3rsfix I)isc;~sc(:ontrol and Prevention. Available at www.cdc.go\~/nci~,c/wisqa~~s. 3. Chambers IR, Trr,adwell I., Mrndclow AI): I)ctcr~nination of threshold levels of cerebral pcrfi~sion pressure and intracranial pressure in ~e\~c.rcIicad injr11.y 1,y using receiver-operating characteristic cit~.vcs:An o1,servational study in 291 patients.J Nc~~rostlrg 2001 ;!14:4 12-4l (i. 4. <:l-iildren's Safety Nctwork, Economics and Insr~rance Resonrce Center: Special run: Hoslti talizc,d 11ninten tional injury among children 15 and r~ndcr.1;eh 2003. 5. Chn UB, Clevenger FW, Ilnani ER, ct ;+I:'l'hc in11);lc.tof' selective laboratory evaluation o n ~~tilization of' laboratory resollrces and patient call in :I Icvcl 1 tralllrla ccntcr. Aln J Surg 1996;172:558-562. 6. <:ornmittee on Quality Inlprovc~ncnt,Amc~.ic.anAcademy of Pediatrics, and Commission o n i:linici~lI'olicies and Research, American Academy o f ' Family 1'hysici;ins: The management of niinor closed head it!jltt.y i l l chiltlren. Pediatrics 1999;104:1407-1415. 7. <:ommittee on Trauma of the Alnc~.ican <;allege of St~rgeons:Advanced Trauma I.ili. Su\)l)ort instructor Manual. Chicago, American (:ollcgc 01 S~~r.geons, 1997. 8. Faillace WJ: Management of cliiltlllood ncl11.otlatllna. Su1.g Clin North Am 2002;82:349-363. 9. Golianu B, Krane EJ, Galloway KS, Yastcr M: Acute pain in children: Pediatric acute pain managclncllt. I'cdiatr i:lin North Am 2000;47:1-24. 10. I(ra11s.JRRoltk A, Heniyaris P: Brain illjury among infants, Aln ,j Dis i:hild children, adolescents, and young ad~~lts. 1990;144:684691. 11. 1,osek JD, Bonadio WA, Walsh-Kelly <:,ct al: I'rehospital pediatric endotracheal intubation pcrfit~.mance review. Pediatr Emerg Care 1989;5:1. 12. 1,nkish J , Valladares E, Bulas 11, et al: i:lassic;tI positioning decreases subclavian vein cross sectional area i l l children. J Tr-anma 2002;53:272-275. 13. Magnnson DK, Eichelberger MR: Apprt~achto the pediatric trauma patient. In Surgery of Infants and i:hiltlren. Philadelphia, 1,ippincott-Raven, 1997, pp 391-414. 14. I'eclet MH, Ncwman KD, Eichelberger MR, ct al: Thoracic traltna in children: An indicator of increaseti ~nortality. J Pediatr Surg 1990;2.5:961. 15. RarnenoE5ky MI,, 1,uterman A, Q~~intilen E, et al: Maximum survival in pediatric trauma: The ideal system. J Trauma 1984;24:818. 16. Rosner MJ: Pathophysiology and management of increased intracranial pressllre. In Andrcws BT (ed): Nelrros~~rgical Intensive <:are. New York, MrGraw-Iiill, 1993, pp 57-1 12. 17. Scheidt PC, et al: The epidemiology of nonfatal irljr~ries among US children and youth. Am J Public Health 199.5; 85:932-938. 18. Stafford PW, Blineman TA, Nance MI,: Practical points in evaluation and resuscitation of the injured child. Surg Clin North Am 2002;82:273-302. 19. Taylor GA, Ei~helherg~r MR: Abdominal <:T in children with neurological impairment following blunt trauma. Ann Surg 1989;210:229-233. 20. Wallace AI,, Cody BE, Mickalide AD: Report to the Nation: Trends in Unintentional i:hildhood 1nj11ry Mortality, 1987-2000.Washington, D(:, National Safe Kids Campaign, May 2003.

Thoracic Injuries --

David E. Wesson

EPIDEMIOLOGY AND PREVENTION

The most common thoracic injuries are lung contusion, pneumothorax, hemothorax, and fracture of the ribs, Injuries to the chest wall, diaphragm, lungs, and medisternum, or scapula. Injuries to the heart, aorta, trachea, astinal structures occur in about 25% of children treated bronchi, and diaphragm are much less common but in level I pediatric trauma centers, usually after highenergy potentially more dangerous. The most common immediately blunt or penetrating trauma. Low-energy mechanisms, life-threatening injuries to the chest are airway obstrucsuch as simple falls from playground equipment, seldom tion, tension pneumothorax, massive hemothorax, and cause chest injury. Thoracic injuries range in severity cardiac tamponade. Open pneumothorax and massive from minor to rapidly fatal, but virtually all chest injuries flail chest are rare. The most common potentially lifecan be treated successfully if they are promptly diagnosed. threatening injuries of the chest are myocardial contusion, Although chest injuries are less common than injuries to aortic disruption, ruptured diaphragm, tracheobronchial the abdomen, soft tissues, and extra-axial skeleton, they disruption, and esophageal rupture. are more lethal. Because of the impact required to cause The relative incidence of blunt and penetrating thoracic such injuries, patients have a significant risk of mortality. trauma varies widely, depending on the amount of violence In fact, thoracic injuries account for a high proportion of in the community. Peterson et a1." reported a large series all trauma deaths not caused by central nervous system (CNS) injury. As with most types of pediatric trauma, the male-tofemale ratio is between 2:l and 3:l. Thoracic injuries can be classified by anatomic site (e.g., rib fracture, pulmonary contusion, bronchial laceration), mechanism (blunt or penetrating), or threat to life (immediate or potential). Although most serious blunt injuries to the chest are Blunt Penetrating Total (%) *motor vehicle related in all age groups, the proportion of children injured as pedestrians is much higher than Pneumothorax/hemothorax in adults. The causes of penetrating thoracic injuries in Pneumothorax teenagers mimic those in adults-mostly knife and gunHemopneumothorax Hemothorax shot wounds. BBs or pellets fired from air guns, although Lung often considered relatively innocuous, may also cause Contusion life-threatening injury." The causes of penetrating Laceration injuries in preadolescent children include a number of Heart other unusual mechanisms, such as impalement by shards Contusion of broken glass or metal rods.64 Laceration The most common thoracic injuries seen clinically Diaphragm are listed in Table 16-1." Autopsy series, which include Rib fractures prehospital and emergency department deaths, reveal Aorta a higher proportion of rapidly fatal major vascular and Bronchus Esophagus In adults, rib fractures are by far the cardiac inj~ries.:~ most common type of blunt trauma to the chest. In chil~ dren, pulmonary contusions are the most f r e q ~ e n t . ~ 2 , . ~ *Percentage of the total cases with each type of injury. Overall, 83% of injuries were Tracheobronchial lacerations are more common in chilblunt, 15%were penetrating, and 2% were caused by other mechanisms. dren than in adults, whereas the opposite is true for From Cooper A, Barlow B, DiScala C, String D: Mortality and truncal injury: The pediatric perspective.J Pediatr Surg 1994;29:33. traumatic rupture of the aorta.*l

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of adults and children with thoracic trauma. Blunt injuries constituted 81% of thoracic injuries in children 12 years of age or younger; penetrating injuries accounted for 58% of chest injuries in adolescents. In Nakayama and Ramenofsky's series,j8 97% of thoracic injuries in children up to 17 years of age were blunt. Meller et al.sQeported a series in which nearly all wounded teenagers had penetrating injuries. The National Pediatric Trauma Registry (NPTR) reflects the combined experience of many pediatric trauma centers across North America. From 1985 to 1991, more than 25,000 cases were reported to the NPTR, including 1553 cases of thoracic injury.l2 Eighty-six percent of injuries were blunt (mostly motor vehicle related). The remaining 14% were penetrating (mostly stab or gunshot wounds). The overall mortality rates for blunt and penetrating cases were almost identical, at 15% and 1496, respectively.l2 Mortality increases with the number of associated injuries. Most of the deaths in the group that had blunt trauma were caused by associated head injuries, whereas most of the deaths in the group with peneirating injuries resulted from the chest injuries themselves. Overall, thoracic injuries were second only to CNS injuries as the cause of death in the NPTR. Most deaths from chest injuries occur at the scene of the accident or in transit to the hospital and result from fatal injuries to vital organs. Patients with thoracic injuries who reach the hospital alive are potentially salvageable. Although the ratio of blunt to penetrating injuries varies in adults and children, the spectrum of chest injuries and the basic principles of diagnosis and treatment are the same for all ages. The most common injuries-pulmonary contusion, rib fracture, pneumothorax, and hemothorax-can be treated with simple measures such as tube thoracostomy, oxygen, and analgesia. Approximately 20% of patients with these injuries also require endotracheal intubation and mechanical ventilation, often for the management of associated head iniuries. ., Several thoracic injuries virtually always require operation: major airway lacerations, aortic injuries, structural cardiac and pericardial injuries, and esophageal perforations. One of the greatest challenges in thoracic trauma is to recognize as soon as possible the rare cases that need surgery. In Nakayama's series,58 2 of 3 patients with penetrating injuries and only 3 of 83 patients with blunt injuries had chest operations. In Peterson's report,64 15% of the children with blunt injuries required thoracotomy (about the same as in adult series), and 40% of those with penetrating injuries required surgery (much higher than in adult series). Although clinicians are naturally concerned about the treatment of patients, no discussion of chest injuries in children woild be complete without mentioning prevention. Motor vehicle accidents and gunshot wounds cause the vast majority of severe pediatric thoracic injuries. These injuries are all preventable. Increasing the use of seat belts and child restraints would substantially reduce the risk of injury to motor vehicle occupants. Reducing the illegal use of firearms would also have major benefits, especially for teenagers. Chest protectors may be effective in reducing the incidence of chest injuries, including commotio cordis, in young a t h l e t e ~ . " , ~ V ncombination, these measures would L,

substantially reduce the incidence and severity of pediatric thoracic trauma and the death and disability that result from it.

CLINICAL PRESENTATION The pathophysiology of thoracic trauma and the anatomy and physiology on which management strategies are based differ significantly between children and adults. The most important anatomic factors in children are the relatively narrow airway, which is prone to obstruction; the anterior and superior of the glottis, which makes nasotracheal intubation difficult and therefore inappropriate in an emergency; and the short trachea. which increases the risk of endobronchial intubation. The increased oxygen consumption and low functional residual capacity of children predispose them to hypoxia. Because young children rely largely on the diaphragm to breathe, any increase in intra-abdominal pressure compounds the problem by restricting diaphragmatic excursion. Children with significant thoracic injuries may present with minimal signs and symptoms. A large adult series from the Maryland Institute of Emergency Medical Services Systems (MIEMSS) found that two thirds of patients with thoracic injuries arrived with stable vital signs.79 This same finding was reported in ~hildren.~%bout 25% of the patients with significant intrathoracic injuries in the MIEMSS series did not have a rib fracture. These "occult" injuries included pneumothorax, hemothorax, myocardial contusion, cardiac rupture, tracheobronchial injury, pulmonary laceration, ruptured diaphragm, and ruptured aorta. The ribs of a child are more liable than those of an adult. Consequently, rib fractures are much less common in children. However, it is important to note that because of the elasticity of the chest wall in childhood. severe thoracic injuries may occur without external signs of injury. In Nakayama's series,s8less than half the children with significant thoracic injuries had rib fractures. The flexibility and compressibility of the chest wall may also explain why traumatic asphyxia is almost unique to children and why major airway trauma is so much more common in children-than in adults. The mediastinal structures are more mobile in children than in adults. Therefore, tension pneumothorax is more likely to shift the mediastinum, compromising ventilation of the contralateral lung and impairing return of venous blood to the heart.

DIAGNOSIS AND INITIAL RESUSCITATION Diagnosis and initial treatment of patients with traumatic chest injury must occur simulta~eously.Although the manifestations of thoracic injury may be immediate or delayed by hours or days, the initial goal is to rule out injuries that are immediately life threatening, such as airway obstruction, tension vneumothorax~ massive hemothorax, and cardiac tamponade. All injury victims should be managed according to the principles of the Advanced Trauma Life Support (ATLS)

CHAPTER

program of the American College of Surgeons.' The overall plan is as follows:

1. 2. 3. 4.

Primary survey. Resuscitation of vital functions. Detailed secondary survey. Definitive care.

All children with thoracic trauma must have supplemental oxygen, two large-bore intravenous lines, and a nasogastric tube to prevent gastric distention. A nasogastric tube may also reveal an abnormal position of the esophagus or stomach, indicating aortic injury or a ruptured diaphragm. Children with thoracic trauma should be observed closely. Vital signs and oxygen saturation in arterial blood (Sao,) should be contiriuously monitored. If the child is intubated, end-tidal carbon dioxide should be monitored continuously or checked frequently. Blood should be available for transfusion. The equipment and skilled personnel needed to address breathing problems and to manage the airway with suction, oral airways, endotracheal tubes, laryngoscopes, and a bag-valve-mask apparatus must always be on hand, especially during transport and diagnostic procedures. Life-threatening injuries should be identified and treated during the initial resuscitation phase of the ATLS protocol. The first priority is to clear and secure the airway. Endotracheal intubation may be required. After intubation, the position of the endotracheal tube must be checked by observing chest excursion, listening for bilateral air entry, monitoring end-tidal carbon dioxide, and obtaining a chest radiograph. A colorimetric carbon dioxide detector may be used to verify endotracheal tube position, especially in the prehospital setting." The second priority is to ensure adequate ventilation. Tension pneumothorax, if present, should be treated before a radiograph is obtained. Occasionally, open pneumothorax or massive flail chest requires intubation and assisted ventilation during the initial resuscitation. Persistent shock despite adequate fluid administration usually indicates ongoing blood loss (most likely abdominal). However, if no obvious cause of hypovolemia can be found, the possibility of acute pericardial tamponade should be considered; this condition can be relieved, at least temporarily, by pericardiocentesis. The indications for urgent thoracotomy may become obvious at any stage (Table 16-2). The most common indications are massive bleeding, massive air leak, and

Penetrating wound of the heart or great vessels Massive or continuous intrathoracic bleeding Open pneumothorax with major chest wall defect Aortogram indicating injury to the aorta or major branch Massive or continuing air leak, indicating injury to a major airway Cardiac tamponade Esophageal perforation Diaphragmatic rupture Impalpable pulse with sardiac massage

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cardiac tamponade. Emergency room (ER) or resuscitative thoracotomy is a controversial technique that does not seem to have clear indications or contraindications. In the report from MIEMSS,79 none of 39 adult patients who presented without vital signs in the ER survived after emergency thoracotomy. However, emergency thoracotomy may be lifesaving in children, especially those with penetrating cardiac injuries. Powell et a1.W reported a 26% survival rate in a series of children and adolescents who had ER thoracotomy. These authors recommend thoracotomy in the ER for post-traumatic arrest, or near arrest, in three situations:

1. All cases of penetrating thoracic trauma. 2. Blunt trauma with acute deterioration but signs of life in the ER. 3. Blunt trauma with signs of life at the scene when the scene is in proximity to the hospital. The incision for emergency thoracotomy should be on the left anterolateral chest wall in the fifth interspace. A rib spreader should be used. If evidence of pericardial tamponade exists, the pericardium should be opened longitudinally, anterior to the phrenic nerve. Cardiac wounds should be controlled by direct pressure and simple suture unless coronary artery damage has occurred, in which case repair may be required. If cardiac tamponade is not present, the aorta should be cross-clamped. If the patient has massive lung injury, the hilum should be clamped or twisted off (see Treatment). Patients who respond to these measures should then have definitive repair performed in the operating room. In most cases of thoracic trauma, the child is physiologically stable. After initial resuscitation, the next step is the detailed secondary survey. To avoid missing a significant injury, a complete and careful assessment is essential. In nearly all cases, a history that suggests significant impact to the chest can be elicited. Therefore, it is crucial to obtain as much information as possible regarding the details of the accident. Children involved in motor vehicle accidents, occupants and pedestrians alike, require an especially careful assessment. A history of difficulty breathing also indicates significant thoracic injury. A systematic physical examination of the chest by inspection, percussion, palpation, and auscultation is the next step of the secondary survey. Tachypnea and tenderness and abrasions of the chest wall are predictive of e look for cyanosis, intrathoracic i n j ~ r y . ~ , 2 W nshould dyspnea, noisy breathing, tracheal deviation, hoarseness or stridor, subcutaneous emphysema, open or sucking chest wounds, reduced or absent breath sounds, venous engorgement, pulsus paradoxus, and hypotension. Dyspnea and cyanosis suggest inadequate oxygenation. Noisy breathing may result from an injury to the airway or the presence of foreign material, such as blood, mucus, or vomitus. Tracheal deviation implies tension pneumothorax or massive hemothorax. Hoarseness, stridor, or other difficulty with phonation suggests direct laryngeal or tracheal injury. Surgical emphysema suggests a tracheal or bronchial laceration or, on rare occasions, an esophageal perforation. Jugular venous engorgement, hypotension, and pulsus paradoxus greater than 10 mm Hg imply cardiac tamponade. The patient should also be checked for signs of acute aortic

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coarctation, which can be caused by injury to the thoracic aorta. The most sensitive sign of a significant cardiac injury is hypotension or a large fluid requirement that is not explained by bleeding. A cardiac injury may also cause a loud systolic murmur. Acute congestive heart failure may result from valvular injury or a traumatic ventricular septa1 defect. Holmes et a1.v developed a set of clinical predictors for the presence of chest injuries in a group of children younger than 16 years with blunt torso trauma. The strongest predictors were hypotension, increased respiratory rate, abnormal physical examination of the thorax, associated femur fracture, and a Glasgow Coma Scale score less than 15. Ninety-eight percent of proven cases had at least one of these predictors. Inspection and palpation were the most sensitive, but abnormalities detected on auscultation had the highest positive predictive value. This confirms the importance of clinical assessment in children with blunt trauma. The most common injuries were lung contusion, pneumothorax, and rib fracture, in that order. In recent years, bedside surgeon-performed ultrasonography (US) has proved helpful in assessing abdominal trauma, and US is now a routine part of the clinical S has a role assessment of all major trauma c a ~ e s . ~ Walso in chest trauma. It is sufficiently accurate to be clinically useful in diagnosing pneumothorax, hemothorax, and . ~ ~ recent ," report documents pericardial e f f u ~ i o n . ~ ~One that surgeon-performed US in the ER is an accurate screening test for the presence of a p n e u m ~ t h o r a x . ~ ~ Because it lacks sensitivity and specificity, clinical assessment is routinely supplemented by diagnostic imaging, which is usually the key step in identifying those children who need an operation.Z7 Plain chest radiographs are routine, although some authors suggest that they are not necessary in blunt trauma cases when the chest physical examination is completely norma1.7.47 A standard posteroanterior and lateral examination is best, but a supine anteroposterior film will suffice. The chest radiograph should be repeated on arrival at the trauma center, even if the patient has been transferred from another hospital. The inlportant signs of chest injury on plain chest radiographs include subcutaneous emphysema, fi-actures of the rib or other bony structures, hemothorax, n other parenchymal lesion pneumothorax, c o n t ~ ~ s i oor (e.g., aspiration pneumonia), mediastinal shift or widening, and diaphragmatic rupture. Computed tomography (CT) provides greater detail than plain radiographs and is more sensitive in the diagnosis of pneuinothorax, rib fracture, and pulmonary contusion. It may also help i11 the diagnosis of ruptured diaphragm. Because chest films are not 100% sensitive, some groups recommend that CT be used to screen all patients suspected of having a chest injury. The most common injuries identified by CT are pulmonary contuMany pneumothoraces revealed sions and laceratio~ls.~~) by <:T are either not evident or underestimated on plain films. Mansol1 et al.?" concluded that plain radiographs, especially those obtained in the trauma resuscitation roonl, are only "a gross screening examination" for thoracic injury and recorrln~endeddynamically enhanced CT in all cases of significant thoracic trauma diagnosed

clinically or by plain radiograph. In such cases, CT provides better definition of the injuries already recognized and may reveal occult injuries not visible on plain radiographs. Exadaktylos et al.'O support this view. In their experience, CT revealed potentially life-threatening aortic injuries even when the plain chest radiographs were normal. They recommend routine chest CT in all patients with major chest trauma. Renton et al.70 studied the question of whether CT should replace routine chest radiographs as the initial diagnostic imaging test and concluded that it should not, mainly because the increased cost was not justified by the relatively few changes in management that resulted from the use of CT scans. They estimated that 200 CT scans would have to be done for each clinically significant change in management. In summary, CT should be used liberally in cases of suspected chest injury. Occasionally, other diagnostic tests, including US, transthoracic or transesophageal echocardiography, bronchoscopy, radionuclide bone scan, angiography, and even video-assisted thoracic surgery are helpful. US is more sensitive than supine anteroposterior chest radiographs and equally sensitive as CT in the diagnosis of traumatic pneumothorax.72 Recent case reports document the use of video-assisted thoracic surgery to diagnose pericardial rupture and herniation of the heart.65 In cases of suspected child abuse, a radionuclide bone scan helps detect recent and long-standing rib fractures. Although impractical in most emergencies, magnetic resonance imaging is helpful in defining injuries to the thoracic spine, especially when spinal cord involvement is suspected. It may also help identify diaphragmatic injuries in equivocal ca~es.5~ For many years, angiography has been the gold standard for the diagnosis of injuries to the aorta and its main branches. However, there is a clear trend to use helical CT as the initial test for suspected aortic injury, reserving aortography for proven cases to guide the repair or, in some cases, eliminating aortography entirely. Transthoracic echocardiography is a useful way to diagnose all types of structural heart injury and ventricular dysfunction caused by contusion. It may reveal intracardiac injuries or pericardial tamponade. Transesophageal echocardiography (TEE) is a useful screening test for traumatic rupture of the aorta. It can identify the cause of mediastinal hematomas seen on plain radiographs or CT scans.46 Pericardiocentesis may be used for diagnosis when cardiac tamponade is suspected and echocardiography is unavailable. All patients with thoracic trauma shoi~ldhave continuous electrocardiographic monitoring during assessment in the ER. A full 12-lead electrocardiograin should be obtained in cases of suspected cardiac contusion to rule out an arrhythmia. Bronchoscopy should be done in the operating room under general anesthesia in cases of suspected major airway traun~a.

TREATMENT The treatment of thoracic injuries varies fro111supportive (oxygen, analgesia) to simple intel-ve~ltions(entiotrxheal intubation, ventilation, tube thoracostorny) to operation

of' rib fi-actures inclndes rest and analgesia. Oral or (niinimally invasive, open thoracotomy with 01-without intravenous narcotics are usually sufficient for pain cardiopnl~nona~y bypass), depending on the specific st111ccontl-01. Intercostal nerve blocks may also be helpful. t~u-esinjtu-cd and the scverity of the injuries. However; (:hiidsen rarely expel ience l)ulmonary atelectasis most patients d o not I-cqnirc an operation and can be from splinting of the chcst wall. Kib fi.;ictnrcs usually managed with supportive measures, with or without tube heal spontaneously witllin (5 weeks. The overall morthoracostonly. '2 tality rate for children with rib fi-actul-cs in the NPTK When ;III operation is indicated, the ideal location was 10%.'2 for the incision varies, depending on the preoperative Rib fi-actures in infants a n d toddlers younger than diagnosis. An ;interolatcral incision in the fifth interspace, 3 years old al-e ofien c;tuscd I)y child a l ) t ~ s c . ~ "The l . ~likewhich can Ilc cxtcndcd across the midline, is best in an emergency. A trapdoor incision may be best for vascl~lar liiood of nonaccidcntal injul'y in children with one or more sib f~.actnl-esdecreases with increasing age.*' injlu-ies in the t~l)pcr rncdiastinum. For esophageal In cases of' t hild abuse, the typical site of fi-actwe is injul-ics,a right postcl-olatcral thoracotomy gives adeqnate exposure, except for tlic most distal thol-acic csophag~~s, the neck of'thc rib near the costotransvcrse process al-ticnlation. Kleininan ct al.4" described f'ractures of'the head \vliich is best viewed fi-om thc Icfi. Median stcrnotonly is of' the rib in allused infants; these ir1jt11-icsare nst~ally best for cardiac i~ljnries.<:a~-diopnlmonasy bypass is only undetectable on radiographs l)ecar~sctile l ~ e ; ~isd c.artiI-arely needed e~nergentlyfor injuries such as coronary laginous. Cystic lesions of' the I-ills that arc located artery laceration and I;~ccration of' the thoracic aorta. uoste~io~-lv are another inclic ation of cl~ilda l ) ~ s e ,as' ~are 11itracardi;ic injul-ics to thc atrioventricl~la~valves or the ~nultiplerib f r a c t ~ ~ r at e svarying st;~gesof'11e;tliilg. scptac do require bypass, but they atrial or ventric~~lar can 1)e repail-ed sc~nielec.ti\~ely. The conccpt of' damage control, which is now well Flail Chest established fhr intra-abdominal trauma, can also bc Flail chest is relatively uncommon in children. It occ111-s ;ipplied in selected c;tscs of' intrathol-acic injury. when a segment of the chest wall is desta1)ilized by Nonanatomic resection of' the lung to control bleeding the fracture of sevel-a1 acijacent ribs. The injured chest and massive air leak, pulmona~ytractotomy with a (;IA wall moves paradoxically-in dlu-ing inspiration and stapler for throt1gh-a1ld-tl11-o11g11 wotlnds of the l l ~ n gen , out during expisation. Ventilation is inefficient l)ecat~se masse pneumonectomy, and hil;ir twistxxmay he lifesa\ing. The last has been reported in cases of uncont~-ollable of the pal-adoxical movement. Flail (,hest is usually assobleeding or air leak from the lung. The infClior p ~ ~ l m o n a ~ yciated kith a lung contusion. <:hest wall splinting and ineffective coughing of'tcn compound the 111i m a ~ yinjury. ligament is divided, and the lower lobe is twisted antel-iThis leads to consolidation and collapse of the affected orly over the upper lobe. This controls the situation lung, which in turn s c s ~ ~ lin t s \.entilation-l,e~.fi~sio~~ rnisso that the patient can be taken back to the intensive match and hypoxia. care unit (IGU) for stabilization and returned to the Initial treatment of flail chest i n t l ~ ~ d s~~pplemental es operating room later for definitive control, usually by oxygen, pain relief (intercostal nerve I~locks,or-al or pneurnonectomy. intravenous narcotics, or an epidural blockade given as a continuous infusion), and physiotherapy. Fluid therapy must bc carefully monitored to avoid pt~l~nonary Blunt Injuries edema, and ICU monitoring is advisable. (:hiidsen with isolated flail chest and no othel- significant injuries seldom Chest Wall require ventilation. If respiratory fai1tu-c develops, endotracheal intubation and positive-pressm-c ventilation Soft Tissue with positive end-expiratoly may be I-equired for several days. Tracheotomy is rarely nccessar-y. In the Although seldom clinically important, injuries to the soft NPTR, the overall mortality rate fhr patients with flail tissue of the chest wall suggest the possibility of more chest was 40%.12 serious intrathoracic injuries. Soft tissue injuries to the chest wall should be managed according to accepted principles of wound care. Sternal Fracture <,

pressure

Rib Fracture In childhood, the ribs are strong and pliable. Therefore, rib fractures are less common in children than in adults, and flail chest is quite rare. Because rib fractures require a great deal of force, they are an indication of severe injury. FI-actl~rc of' the first rib suggests the possibility of a major vascular injury, especially to the subclavian artery.2g First rib fractures may also be complicated by Horner's syndrome and thoracic outlet syndrome. The goal of treatment is to prevent atelectasis and pneumonia while optimizing patient comfort. The treatment

Sternal fractures are less common in young children than in adults because the sternum is cartilaginous.

Pleural Space

Pneumothorax Pneumothorax can result from an injury to the chest wall, lung parenchyma, tracheobronchial trcc, or esophagus. High energy is required to produce a pneumothorax, so it must be considered a marker for other occult injuries.

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Open Pneumothorax: Open pneumothorax is rare in children. In cases of open pneumothorax, the intrapleural pressure is equal to that of the atmosphere. As a result, the lung collapses and alveolar ventilation decreases. Sucking wounds should be recognized clinically. They can be treated by inserting a Heimlich valve or applying an occlusive dressing to the wound-taping the dressing on only three sides so that it can act as a flutter valveand inserting a chest tube in the usual location.

Simple Pneumothorax: Simple pneumothorax may cause chest pain, respiratory distress, tachypnea, decreased air entry on the affected side, and oxygen desaturation. Careful examination may reveal an abrasion of the chest wall, crepitus, or tracheal shift. However, many patients show no clinical signs or symptoms. This underscores the importance of routine chest radiographs for all trauma cases. The radiographic signs include unilateral or asymmetrical lucency, a sharp outline of the mediastinum, mediastinal shift, and a visible visceral pleural border away from the chest wall. The diagnosis of simple pneumothorax should be confirmed by chest radiograph before treatment. Simple pneumothoraces should be treated by intercostal chest tube drainage (Fig. 16-1). The best location for chest tube insertion is the fourth or fifth intercostal space (nipple level) in the anterior axillary line. The recommended chest tube sizes are as follows: newborns, 12 to 16 French; infants, 16 to 18 French; school-age children, 18 to 24 French; and adolescents, 28 to 32 French. The chest tube should be connected to an underwater seal on gentle suction and removed when the air leak stops. For most cases, this is the only treatment necessary. A continued or massive air leak suggests injury to the tracheobronchial tree. A small, asymptomatic pneumothorax may be observed in carefully selected cases. If the patient is to be transferred to another hospital or intubated and ventilated for any reason, or if the pneumothorax exceeds 15%,it should be drained. When in doubt, a chest tube should be inserted.

A

Tension Pneumothorax: Tension pneumothorax may develop when a one-way valve effect occurs, allowing air to enter the pleural space but not to escape (Fig. 16-2). The underlying cause is usually a pulmonary laceration or injury to the trachea or a large bronchus. The intrapleural air pressure exceeds that of the atmosphere, collapses the ipsilateral lung, pushes the mediastinum to the opposite side, flattens the diaphragm, impairs ventilation of the opposite lung, and reduces the return of venous blood to the heart. The pulse and respiratory rate increase, and the patient develops severe distress. The trachea is usually deviated away from the involved side, and the neck veins may become engorged. The ipsilateral side of the chest is hyperresonant to percussion, with diminished breath sounds. Frank cyanosis is a late sign. The most important differential diagnosis is pericardial tamponade. However, this disorder can be distinguished from tension pneumothorax because the trachea is not displaced and the chest is normal to percussion. Tension pneumothorax should be considered when an injured patient, especially one on a

B

A, Left hemopneumothorax; note the nasogastric tube in situ. B, The same patient after insertion of an intercostal drain; no other treatment was required. (From Wesson DE: Trauma of the chest in children. Chest Clin North Am 1994;3:&3.)

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of blood loss. It is wise to establish two large-bore intravenous catheters; begin treatment for shock, if present; and obtain blood for transfusion before draining a massive hemothorax, because it may precipitate further bleeding. However, drainage and re-expansion of the lung usually stop the bleeding. In most cases, intercostal drainage is the only treatment needed. However, thoracotomy may be indicated for the following reasons:

1. Initial drainage exceeds 20% to 25% of estimated blood volume. 2. Continued bleeding exceeds 2 to 4 mL/kg per hour. 3. Bleeding is increasing. 4. The pleural space cannot be drained of blood and clots. Hoth et a1.35 reported an increased likelihood of nontherapeutic exploration when thoracotomy is performed for increased chest tube output in cases of blunt trauma. Autotransfusion may be helpful during surgery for massive intrathoracic bleeding.

Lung Left tension pneumothorax. This photograph demonstrates the classic findings with tension pneumothorax, including mediastinal shift, depression and inversion of the diaphragm, and widening of the interspaces on the involved side. This child had hypotension in addition to respiratory distress because of caval torsion, which was relieved following tube thoracostomy drainage.

mechanical ventilator, suddenly deteriorates for no h gaskc dilatation and right apparent reason. ~ 0 t acute mainstem intubation may result in diminished breath sounds on the left and should not be confused with a tension pneumothorax. The treatment for tension pneumothorax is immediate needle catheter drainage (without waiting for chest radiographs) through either the second intercostal space in the midclavicular line or the fourth or fifth interspace in the axilla, followed by insertion of a chest tube.

Hemothorax When enough blood is lost into the thorax to cause shock, the term massive hemothorax is used. Massive hemothorax is more common after penetrating than blunt trauma. Hemothorax may result from laceration of an intercostal or internal mammary artery, a lung, or a mediastinal blood vessel. Free bleeding into the pleural space from a major vessel, such as the aorta or one of the pulmonary hilar vessels, is usually rapidly fatal. Most bleeding from the lung stops spontaneously because of the low pressure in the pulmonary circulation. Bleeding from a systemic vessel, such as an intercostal artery, is more likely to cause massive hemothorax, producing signs of hypovolemia, mediastinal shift, diminished breath sounds, and dullness to percussion on the affected side. Hemothorax is often associated with pneumothorax (see Fig. 16-1). The treatment is intercostal drainage to prevent a clotted hemothorax and to monitor the rate and total volume

Hematoma and Contusion Pulmonary contusion is the most common type of blunt injury to the chest in children. Direct force to the lung causes disruption of the parenchyma, bleeding, and edema in a nonanatomic distribution, often without obvious injury to the chest wall. Specific clinical signs or symptoms are seldom evident at presentation, although rib fractures and abrasions over the chest may be present. Because of the lack of specific physical features, routine chest radiographs are the key to the diagnosis of hematoma and contusion. Pulmonary contusions are usually obvious on plain radiographs taken at admission (Fig. 16-3) and are even more striking on CT, which has shown that they usually lie posteriorly or po~teromedially.~~ However, there is no need for CT when a contusion is obvious on plain films. Pulmonary contusions may be progressive, especially when compounded by edema and atelectasis. Children with pulmonary contusions seldom require mechanical ventilation and almost never develop adult respiratory distress syndrome. The differential diagnosis includes aspiration pneumonia, which can result from aspiration at the scene, during transportation, during intubation, or with vomiting after admission. It affects the right lower lobe most frequently. Patients with extensive lung hematomas or contusions should be monitored carefully with continuous Sao, measurements, preferably in an ICU. The treatment for these disorders is supportive, with analgesia, physiotherapy, supplemental oxygen, and fluid restriction. Endotracheal intubation and mechanical ventilation are less likely to be needed for children than for adults. Deterioration after admission is unusua1.H It is important to guard against overhydration and aspiration of gastric contents. The most common complication is infection of the lung. Most pulmonary hematomas and contusions clear within 10 days unless the lung becomes infected.

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Pulmonary contusion. A, Crush injury with pulmonary contusion; note the multiple rib fractures. B, The same patient 2 days later; note the progression of the lesion. C, Gunshot wound with pulmonary contusion and subcutanet011s emphysema. (From Wesson DE: Trauma of the chest in children. Chest Clin North Am 1993;3:423.)

Pulmonary contusions may be complicated by pneumothorax, hemothorax, or pleural effusion, all of which may require intercostal drainage. These secondary phenomena are much more common in the presence of concomitant fractures of the bones of the chest wall and may be delayed as long as 48 hours. Therefore, serial chest radiographs should be obtained in cases of pulmonary contusion (see Fig. 16-3). Occasionally, a post-traumatic pneumatocele forms when the injured lung cavitates during healing. Because pneumatoceles usually resolve spontaneously in a few months, treatment is seldom necessary.

Laceration Pulmonary lacerations are most often seen after penetrating injuries and usually result in a pneumothorax or hemothorax. They may also be caused by rib fractures. Air embolus is the most serious complication of pulmonary laceration. This diagnosis should be

suspected in all children with thoracic trauma who suddenly deteriorate, especially while receiving positive-pressure ventilation in the absence of a pneumothorax. Air embolus may cause focal neurologic deficits. Frothy blood aspirated from an arterial cannula is a telltale sign. Emergency thoracotomy, clamping of the pulmonary hilum, and aspiration of air from the heart or right ventricular outflow tract may be l i f e s a ~ i n g . ~ ~

Trachea and Bronchi Injuries to the major airways are uncommon in children. Nearly all are caused by blunt trauma.12 The most common specific lesions are partial or complete transections of one of the main bronchi and tears of the membranous trachea. Airway injuries usually occur within 2 to 3 cm of the carina and may be rapidly fatal if not recognized and treated promptly. Injuries to distal lobar bronchi are also common.

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Some patients with major airway injuries die from respiratory failure before reaching the hospital or shortly thereafter. Most present with dyspnea, which is often caused by tension pneumothorax. Other characteristics of patients with major airway injuries are voice disturbance, cyanosis, hemoptysis, massive subcutaneous and mediastinal emphysema, and failure of the lung to expand or continuing large-volume air leak despite properly functioning chest tubes. A lung that fails to expand or a continuous massive air leak after intercostal drainage strongly suggests a major airway injury (Fig. 16-4). Although not common, "dropped lung," in which the lung actually falls to the lower half of the pleural cavity below the level of the injured bronchus, is virtually diagnostic of a major airway injury. Finally, some patients present late with chronic collapse and infection of the involved lung from bronchial obstruction. Initial management in the trauma room depends on the clinical situation. The initial treatment of airway injuries is to control the airway and breathing according to the ATLS protocol. This may require endotracheal intubation and intercostal drainage. If the patient has a good airway and is well oxygenated, it is prudent not to manipulate the airway by attempting intubation before taking the patient to the operating room. Flexible bronchoscopy may facilitate endotracheal intubation beyond the site of the injury or selective intubation of the uninjured bronchus. High-frequency ventilation with low mean airway pressure may be more effective than conventional

methods in the presence of a massive air leak and may help stabilize the patient for surgical repair.69 Helical CT may be a good initial test in stable patients with suspected major airway injuries, but bronchoscopy is more reliable. Bronchoscopy is indicated whenever the lung fails to expand or a massive air leak continues after intercostal drainage. It should be performed in the operating room under general anesthesia using a rigid, ventilating bronchoscope. If possible, the patient should be allowed to breathe spontaneously during induction of anesthesia and passage of the bronchoscope. Staff and equipment for thoracotomy must be at hand. In unstable patients or those with possible or confirmed cervical spine injuries, flexible bronchoscopy with the patient awake or through an endotracheal tube may also demonstrate the lesion. At bronchoscopy, a defect in the wall of the airway may be visible. Other bronchoscopic signs of injury include mucosal disruption or exposed cartilage. Bronchography may be needed for distal bronchial injury. Spontaneous healing is the rule for small lacerations in the membranous trachea and some partial bronchial tears involving up to one third of the circumference. These may be treated nonoperatively. For larger lacerations of the trachea or bronchi, primary surgical repair through a posterolateral thoracotomy is the best way to ensure good long-term results. Distal injuries to a lobar or segmental bronchus may be sealed with fibrin glue or treated by lung resection rather than direct repair. The right side of the chest allows the best exposure of the trachea, carina, and right main bronchus; the left side gives better exposure for injuries to the distal left main bronchus. In the presence of a massive air leak, it may be necessary to clamp the hilum before attempting to repair the airway. Advancing the endotracheal tube or passing a sterile tube across the surgical field into the distal airway may also be helpful during the repair. Simple, interrupted sutures after debridement of the margins work best. Although lobectomy or pulmonary segmentectomy may be necessary, pulmonary resection is done only as a last resort in unstable patients or when the lung is extensively damaged. The late functional results of pulmonary resection or bronchial repair are usually excellent.59 Bronchial injuries that are missed initially may seal spontaneously, but there is a risk of stenosis. After months or years, children with spontaneously sealed bronchial injuries may have persistent atelectasis, often with pneumonia or frank bronchiectasis in the involved lung, caused by a bronchial stricture. The diagnosis can be confirmed by bronchography or bronchoscopy. This type of stricture can be dilated in some cases, but open repair or even resection of the involved lung is usually necessary. One report illustrates that late repair of a completely transected mainstem bronchus with preservation of the lung is possible.78

This patient had a sustained air leak associated with blunt thoracic injury despite adequate chest tube drainage. Blood was noted in the right upper lobe bronchus, and contrast injection demot~stratedthe location and extent of the leak, whic was contl.ollcd by the injection of fihrin glue and chest tube drainage. Opvrative closure or resection is sometimes required.

Esophagus The most common causes of esophageal injury are ingestion of caustic liquids and penetrating trauma, which includes iatrogenic instrumentation. Forceful vomiting and retching rarely cause esophageal tears in childhood.

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with other severe injuries. They may be asymptomatic or cause abdominal, thoracic, or ipsilateral shoulder tip pain. Physical examination is rarely helpful in the diagnosis of diaphragmatic injuries. The diagnosis is usually based on the plain chest radiograph, which is the most important diagnostic test (Fig. 16-5). Table 16-3 summarizes the radiographic signs of diaphragmatic injury. Basically, any abnormality of the diaphragm or near the diaphragm on plain chest radiographs should arouse suspicion. Chest radiographs are initially normal in 30% to 50% of cases.Vherefore, repeat radiographs should be obtained if a diaphragmatic injury is suspected. Because other injuries often dominate the clinical picture, delayed diagnosis of a diaphragmatic injury is common. At first, herniation of abdominal viscera into the chest may not have occurred, especially in patients receiving mechanical ventilation. However, the negative intrathoracic pressure of normal breathing may gradually draw the stomach and bowel up into the chest. This can be recognized on plain radiographs, especially if the stomach herniates with a nasogastric tube in place. In the absence of a nasogastric tube, acute dilatation of the herniated stomach may develop, leading to severe respiratory distress. The diagnosis can be confirmed, if necessary, by upper or lower intestinal radiographic contrast studies. However, these studies may not be possible in patients with multiple acute injuries. Here, CT with multiplanar reconstruction may be helpful. The signs of diaphragmatic injury on CT include discontinuity of the diaphragm, herniation

External blunt trauma rarely causes esophageal injury. The mechanism of esophageal injury from blunt trauma is believed to be a sudden increase in intraesophageal pressure caused by expulsion of gas from the stomach through the gastroesophageal junction. Esophageal perforations cause fever, chest pain, and tachycardia. Occasionally, subcutaneous emphysema develops in the neck. Mediastinal or intrapleural air may be visible on routine chest radiographs or CT. If esophageal injury is suspected, a water-soluble contrast swallow, endoscopy, or both should be done. When diagnosed within the first 12 hours, esophageal injuries are best treated by primary closure and drainage. When diagnosed later, they may require salivary diversion by means of a cervical esophagostomy and gastrostomy, in addition to thoracic drainage.

Diaphragm Although rare in children, diaphragmatic injuries can be caused by a forceful impact to the abdomen or by a penetrating missile. It is important to recognize these injuries, because the stomach and bowel may herniate through the defect and strangulate. Ninety percent of diaphragmatic injuries occur on the left side. In blunt trauma, tears are usually in or near the central tendon and oriented radially. Diaphragmatic injuries are easily missed at initial presentation, especially because they are often associated

A

B Ruptured diaphragm. A, Plain chest radiograph. B, Herniated bowel on gastrointestinal contrast study.

CHAPTER

Obscured hemidiaphragm Elevated hemidiaphragm Herniated viscera causing abnormal gas pattern above the diaphragm Tip of nasogastric tube curled up into the chest Atypical pneumothorax Platelike atelectasis adjacent to the diaphragm

of intra-abdominal viscera into the chest, and constriction of the stomach as it passes through the defect.89 In stable patients, magnetic resonance imaging may also help establish the diagnosis. Some patients present with obstruction or strangulation of the herniated gut late in the course of the disorder. This causes severe abdominal or chest pain (or both), nausea, and vomiting. Primary repair through an abdominal incision is indicated. The usual repair is via open laparotomy, but several recent reports of laparoscopic repair demonstrate the feasibility of this approach.52.67 Thoracotomy may be required for patients presenting late, because of adhesions in the chest.

Heart and Pericardium Blunt trauma to the heart can produce several types of injury: concussion, contusion, or frank rupture of myocardium, valve, or septum.57Although rare, disruption or thrombosis of a coronary artery may also occur. A tear of the pericardium may allow herniation of the heart into the pleural space, thereby impairing cardiac function and causing a low output state. Occasionally, blunt trauma to the chest produces occult structural cardiac injuries without gross impairment of cardiac function, bleeding, or cardiac tamponade.18 These injuries include atrial or ventricular septal defects, mitral or tricuspid insufficiency, and ventricular aneurysm formation. Often, the only sign is a new murmur or a change in the electrocardiogram. The diagnosis can be confirmed by echocardiographyor cardiac catheterization.These injuries may be repaired electively once the patient is stable.18 Follow-up echocardiography should be arranged in all cases of known or suspected injury to the heart. Several case reports have appeared documenting sudden cardiac arrest in children after a direct blow to the chest. The term commotio cordis has been applied to this entity.51,8Wommotio cordis occurs most often during organized sporting events such as baseball. No contusion or other sign of injury can be found at autopsy, and death is usually attributed to ventricular fibrillation. When performing emergency surgery for cardiac trauma, the surgeon should bear in mind a few simple rules:

1. Prepare and drape the entire chest.

2. Place the incision in the left fourth or fifth interspace in an anterolateral direction (except for stable patients undergoing elective repair of known cardiac injuries, which should be repaired through a median sternotomy).

3. 4. 5. 6.

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Avoid the phrenic nerve when opening the pericardium. Apply direct pressure to control the bleeding. Suture the heart using pledgets as required. Leave the pericardium open.

Some authors have reported the use of skin staples to control cardiac wounds, but direct suture is preferable. A Foley catheter may be introduced through the defect to control the bleeding during repair. Although most cardiac injuries can be repaired without cardiopulmonary bypass, this option should be available. During the operation, the surgeon should always check for a thrill, which might indicate a ruptured valve or traumatic ventricular septal defect. It is also important to check for intracardiac lesions by listening for new murmurs and performing echocardiography in the postoperative period. Follow-up echocardiography should also be done after discharge.

Myocardial Contusion Myocardial contusion is the most common type of blunt cardiac injury. It produces focal damage to the heart that can be identified histologically. It can cause lifethreatening arrhythmias and cardiac failure. Treatment is aimed primarily at these complications. Contusion can be distinguished from concussion and commotio cordis because the latter does not produce any structural change, even at the microscopic level. Contusions are usually, but not always, associated with an injury to the chest wall. Myocardial contusions may be completely silent or cause an arrhythmia (supraventricular tachycardia or ventricular fibrillation) or hypotension secondary to reduced cardiac output. Unfortunately, although many tests have been proposed, including electrocardiography, echocardiography, myocardial enzyme determinations (CKMB, cardiac troponin I and troponin T ) , and radionuclide scans, there is no definitive diagnostic test for cardiac c o n t u s i ~ n . ~ ~ ~ This makes it difficult to define the indications for any of the currently available diagnostic tests and even more difficult to decide on treatment. Tellez et al.84concluded that a "comprehensive diagnostic evaluation of the heart in all children sustaining multiple injuries from blunt trauma cannot be justified." The simplest test is a 12-leadelectrocardiogram, which may reveal reversible changes to ST segments and T waves. Echocardiography may show reduced ejection fraction, localized systolic wall motion abnormality, or an area of increased enddiastolic wall thickness and echogenicity. Swaanenburg et a1.80 found that cardiac troponin I and T levels were more accurate and reliable than any of the other diagnostic tests in selecting patients for ICU monitoring. They also recommended a repeat analysis after admission for patients suspected of having myocardial contusion but with normal values at admission. A prospective study of 41 children with blunt thoracic trauma using a battery of tests, including serum enzyme levels, electrocardiography, echocardiography, and pyrophosphate myocardial scanning, revealed a high incidence of abnormal tests. However, there was little correlation between any of the test results and the

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clinical course."? The authors concluded that myocardial contusion is rarely clinically significant in pediatric thoracic trauma. For practical purposes, significant myocardial contusion can be ruled out when findings on the 12-lead electrocardiogram and echocardiography are normal. Treatment of myocardial contusion includes inotropic support as indicated, with electrocardiographic monitoring for 12 to 24 hours and frequent blood pressure determinations. Complications tend to occur early in the disorder or not at all.'Vellez et a1." recommended cardiac monitoring in the ER and ICU to identify arrhythmias and, in patients with arrhythmias and obvious thoracic injuries, serial electrocardiograms and cardiac enzyme tests.

Myocardial Rupture Rupture of the heart is usually rapidly fatal. In fact, myocardial rupture is the most common cause of death from thoracic injury. In a population-based autopsy series, Bergman et al.Vound that two thirds of these patients died at the scene of the accident and one third died in the emergency room. Most cases of cardiac rupture result from high-energy impacts, such as those sustained in motor vehicle accidents or falls from great heights. The atria tend to rupture when impact occurs during late systole; ventricles rupture from impact during late diastole. The right ventricle is the most commonly ruptured site. Children with myocardial rupture usually present with pericardial tamponade (see later). Myocardial necrosis, aneurysm formation, and delayed rupture may also occur.54 Those with a traumatic atrial septal defect or ventricular septal defect may present with a new murmur without obvious cardiac failure. All patients with chest trauma should be checked carefully for a new murmur before discharge. Any new murmur is an indication for echocardiography. Occasionally, with early diagnosis and repair, patients can survive myocardial rupture.

Valve lnjury Valve injuries are rare but well recognized after blunt tra~~ma.~.~Qtrioventricular valves are most commonly injured, causing incompetence by damage to the annulus or rupture of the chordae tendinae or papillary muscle (Fig. 16-6). This is one type of blunt cardiac injury that can be repaired semielectively.

Pericardial Tamponade Pericardial tamponade can result from an accumulation of blood in the pericardial sac after blunt trauma. The full spectrum of pericardial tamponade-pulsus paradoxus and Beck's triad (elevated jugular venous pressure, systemic hypotension, and muffled heart sounds)-rarely develops in patients with acute trauma. Pericardial tamponade is usually associated with tachycardia, peripheral vasoconstriction, jugular venous distention, and persistent hypotension despite aggressive fluid resuscitation.

Cardiomegaly and pulmonary edema 2 days after blunt chest trauma; note the Swan-Ganz catheter. A tom mitral valve annulus and chordae tendinae were successfully repaired. (From Wesson DE: Trauma of the chest in children. (:hcst Clin North Am 1995;3:423.)

In fact, pericardial tamponade should be suspected in all cases of unexplained hypotension, especially when it is associated with elevated jugular venous pressure. The best way to confirm the diagnosis is by transthoracic echocardiography, which can be performed by the surgeon at the bedside in conjunction with the focused abdominal sonography for trauma (FAST) -examination. 10.62 Treatment of suspected pericardial tamponade begins with control of the airway and breathing plus restoration and expansion of the circulating blood volume. The diagnosis should be confirmed b y echocardiography, which is the single best diagnostic tool. However, if the patient is in severe shock, needle catheter drainage of the pericardial space may be lifesaving (Fig. 16-7). Therefore, in emergency situations or when echocardiography is not available, immediate pericardiocentesis is indicated. The needle should be inserted by the subxiphoid approach at a 45-degree angle upward and toward the left shoulder. A successful tap is confirmed by aspiration of nonclotting blood. A catheter should be inserted and left for repeated aspirations, if necessary, pending definitive treatment. Pericardiocentesis may be complicated by bleeding or damage to the left anterior descending coronary artery. If pericardiocentesis does not stabilize the patient, immediate thoracotomy should be performed to relieve the tamponade a n d control the bleeding.

Pericardial Laceration The pericardium may be torn by blunt trauma. The most common site is on the left, anterior to the phrenic nerve. The heart may herniate through the defect and undergo

CHAPTER

A

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287

B

Pericardial tanlponade from blunt chest trauma. The patient was a backseat passenger in a high-speed frontal collision. There was a seat-belt nark over the lower sternum. Shock was unresponsive to fluid, and pericardial effusion was demonstrated on transihoracic echorardiography. A, Normal heart on plain chest radiograph, with evidence of pulmonary contusion. B, Chest radiograph after catheter drainage of bloody pericardial effusion. No further treatment was required. (From Wesson DE: Trauma of the chest in children. Chest Clin North Am 1993;3:423.)

torsion, impairing its function and reducing cardiac output. This type of injury may be recognized on CT or by video-assisted thoracic s ~ r g e r y . ~ ~ , ~ ~ , ~ ~

Aorta Traumatic rupture of the aorta and its major branches is uncommon in children.' Eddy et al.17 reported that aortic injuries caused 2.1% of all traumatic deaths in children in King County, Washington. Traumatic rupture of the aorta causes a higher proportion of traumatic deaths in adults (approximately 10%) than in children, probably because adult aortas are more brittle and easily torn. Predictors of aortic injury include hypotension, head injury, unrestrained motor vehicle occupant, pelvic fracture, extremity fracture, and other chest injury. However, it is not clear whether mechanism is a reliable predictor. Dyer et al.lVound it to be "imperfect" and "subjective." Horton et al." found that velocity of 20 miles per hour or greater and near-side passenger compartment intrusion of 15 inches or greater correlated strongly with aortic injury. Traumatic rupture of the aorta occurs with rapid deceleration, which applies shear stress to the wall of the aorta. The most common sites of injury are near the ligamentum arteriosum, the root of the aorta, or one of the other main branch points, such as the takeoff of the innominate, vertebral, or carotid artery. Tears of the distal arch are usually located on the anteromedial aspect of the aorta and oriented horizontally. Children with Marfan's syndrome are at risk for aortic dissection following blunt trauma to the torso. Although it is usually rapidly fatal, in some cases, the adventitia and pleura contain the blood and

prevent exsanguination. The natural history of patients who do not exsanguinate immediately is unknown, but imminent rupture in these patients is unlikely. Therefore. it is unhecessarv to rush them to the o ~ e r a t ing room before stabi~izatibn,a full diagnostic wdrkup, and treatment of other injuries. This may require laparotomy, craniotomy, or both before repair of the aorta. he management of aortic injuriks in children is ~ ~ , ~ ~ is difficult essentially the same as in a d ~ l t s .Diagnosis because there may be no clinical evidence of thoracic injury. Acute coarctation syndrome-upper limb hypertension, a difference in blood pressure between the upper and lower limbs, and a loud murmur over the precordium or back-is rare. DelRossi et al.I3 reported series of 27 cases of aortic injury without a singie case of coarctation syndrome. The diagnosis is most often suggested by plain chest radiographs, which are sensitive (false-negative 2% to 7%) but not specific (false-positive 80%). The radiographic signs of traumatic rupture of the aorta are the same as described for adults (Table 16-4, Fig. 16-8).

a

Widened mediastinum (mediastinum-chest ratio >0.25) Loss or abnormal contour of aortic knob Depression of left main bronchus (>40 degrees below horizontal) Deviation of trachea (left margin to right of T4 spinous process) Deviation of esophagus (nasogastric tube to right of T4 spinous process) Left pleural cap Left hemothorax

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D Traumatic rupture of the aorta and branches. A, Widened mediastinum with deviation of the endotracheal and nasogastric tube the right. B, In the same patient as in A, aortic injury is confirmed by aortogram. C, Widened mediastinum in a different patient who sustainc Int trauma to the chest. D,In the same patient as in C, there is an innominate artery laceration at its origin (amow). (From Wesson DE: Traum the chest in children. Chest Clin North Am 1993;3:423.)

Nearly all reported cases demonstrate widening of the mediastinum (mediastinurn-chest ratio >0.25) and an abnormal aortic contour. Until recently, most authors considered aortography the gold standard diagnostic test. Many now believe that contrast-enhanced multislice helical CT, which is equally sensitive to aortography, is the definitive test for diagnosing aortic injury (Fig. 16-9).l6,2554,61

If the helical CT scan is normal, an aortogram is unnecessary. This has substantially reduced the number of negative aortograms done for patients with blunt chest trauma and suspicious plain radiographs. The techniques of helical CT and CT-angiography have been reviewed by Melton e t a1." and Rubin.73 Timing of the contrast injection, as well as the volume and rate of infusion, must be carefully controlled to

CHAPTER

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Thoracic Injuries

B Helical computed tomography scan reconstruction showing traumatic rupture of the aorta in a 14year-old boy. A, Transaxial view. Note the periaortic hematoma at the isthmus. B, Three-dimensional reconstruction. Note the interruption of flow at the isthmus.

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yield optimal results. Helical CT costs about half as much as a o r t ~ g r a p h y . ~ ~ There is still a role for aortography in equivocal cases or to provide more anatomic detail before repair in proven cases. However, many authorities now argue that helical CT alone is sufficient for the management of aortic injuries.54 Transesophageal echocardiography also has a role in the diagnosis of injuries to the descending thoracic aorta, especially for unstable patients in the ICU who are unable to go to the radiology department. It is not useful for injuries of the ascending aorta or its branches. Unfortunately, TEE is operator dependent and not universally available. Le Bret et al.46noted three signs on TEE that are sensitive enough to screen patients for aortic injury: increased distance (>3 mm) between the probe and the aorta, double contour of the aortic wall, and US signal between the aorta and the visceral pleura. The sensitivity for diagnosing traumatic rupture of the aorta by TEE was 100% in this report; the specificity was 75%. The authors proposed that TEE be done in all cases of severe chest trauma. TEE is also useful in cases with equivocal findings on CT or aortography to avoid an unnecessary thora~otomy.~~ Once the diagnosis is proved, treatment options include open repair, endovascular stent-graft, or even nonoperative observation in some cases. Aortic surgery carries a significant risk of complications, including intracranial hypertension, which may exacerbate bleeding; left ventricular strain; renal failure; and spinal cord ischemia. Heparin may increase the likelihood of bleeding at remote sites of injury. A small intimal flap may heal spontaneously, but surgical repair through a left posterolateral thoracotomy is the treatment of choice, after the patient has been stabilized (the bleeding at other locations should be repaired first). Surgery can be safely delayed pending repair or control of associated severe injuries to the CNS, extensive burns, septic or contaminated wounds, solid organ injuries likely to bleed with heparinization, and respiratory failure." In such cases, beta blockade to control mean arterial blood pressure and ICU monitoring are essential until repair can be safely accomplished. Esmolol is the preferred beta blocker. Cardiopulmonary bypass (usually left heart bypass) should always be available during repair in case the injury extends to the aortic root. The left lung should be collapsed and retracted. Care is required when dissecting the aorta for cross-clamping to avoid injury to the branches that supply the spinal cord and injury to the vagus nerve and its recurrent branch. Some partial tears can be repaired primarily; however, repair usually requires placement of a woven Dacron graft, especially when the tear is circumferential. There are three basic ways to perform the operation: 1. Clamp and sew. 2. Intraoperative shunt. 3. Mechanical circulatory support. The simplest is to clamp and sew without a shunt or cardiopulmonary bypass. This is the fastest method

and requires the shortest cross-clamp time; it is adequate if the injury is not too extensive. Razzouk et a1.68 reported that the clamp-and-sew technique is feasible in the majority of patients without increased mortality or spinal cord injury. Kwon et a1.43concur that the clamp technique does not increase mortality or morbidity. However, others strongly disagree. Hochheiser et al." reported a lower incidence of postoperative paraplegia after repair with mechanical circulatory support. Another option is intraoperative shunting with a heparin-bonded shunt. This may reduce the risk of ischemic damage to the spinal cord without the risks of systemic heparinization; however, there are no controlled studies to prove this. The third method is to use mechanical circulatory support during the repair. The most common choice is cardiopulmonary bypass from the left superior pulmonary vein or left atrium to the femoral artery.56 Femoralfemoral bypass with direct perfusion of the distal descending thoracic aorta has also been used. Some authorities believe that cardiopulmonary bypass reduces the risk of paraplegia, but it requires systemic heparinization, which can increase the incidence of intracranial hemorrhage.44 The rate of paraplegia after repair of traumatic rupture of the aorta is about 5% to 10%. Individual variations in spinal cord blood supply, crossclamp time, and intraoperative hypotension are important determinants of spinal cord injury. There have been several recent reports of transfemoral stent insertion (endovascular stent-grafts) for injuries to the thoracic aorta in adults. Early results indicate that the outcome may be better than with standard open repair. Three case series have had remarkably low incidences Endovascular stent-grafts have been of paraplegia.15,39,60 reported in a small series of children, but there are no reports of long-term results.38 Only 1 of 13 patients in Eddy's report,17a populationbased study that included prehospital deaths, survived traumatic rupture of the aorta. In contrast, DelRossi et al.13 reported a '75% survival rate in a clinical series. Three of the 21 survivors in DelRossi's series were paraplegic after repair, but two later recovered. DelRossi found no evidence to support one technique of repair over the others. However, Fabian et a1.Z1 reported that the clamp-andsew technique is more likely than repair with bypass to result in paraplegia, especially if the cross-clamp time is longer than 30 minutes. As is true for many types of injury, outcome also depends on associated injuries.44 Hormuth et a1.33reported excellent overall results in a series of 11 children with thoracic aortic injuries. They repaired isthmus injuries with left heart bypass and direct perfusion of the distal thoracic aorta, and arch injuries were repaired with hypothermic arrest.

Chylothorax Injury to the thoracic duct, though rare, causes chylothorax. Most cases resolve spontaneously with nutritional support (total parenteral nutrition or elemental diet with medium-chain triglycerides). Occasionally, ligation of the thoracic duct is necessary.

CHAPTER

Traumatic Asphyxia Traumatic asphyxia, a clinical syndrome that is unique to children, occurs with sudden compression of the abdomen or chest (or both) against a closed glottis.76 This event causes a rapid rise in intrathoracic pressure, which is transmitted to all the veins that drain into the valveless superior vena cava. Extravasation of blood occurs into the skin of the upper half of the body, the sclerae, and possibly the brain. The brain may also be damaged by hypoxia during and after the injury. The clinical features of this disorder include seizures, disorientation, petechiae in the upper half of the body and conjunctivae, and respiratory failure (Fig. 16-10). Treatment is supportive, and most patients recover uneventfully.

Penetrating Injuries The initial management of penetrating injuries is the same as for blunt trauma: clear the airway, give oxygen and intravenous fluids, carefully assess the patient, and obtain a plain chest radiograph in every case. An attempt should be made to determine the path of the injury by marking the entry and exit wounds on the plain films. Endotracheal intubation and chest tube insertion should be done as needed during the initial resuscitation. It is important to consider the possibility of a concomitant abdominal injury with any wound below the nipple line. Bronchoscopy is indicated for suspected injury to the major airways; esophagoscopy and water-soluble contrast studies are indicated for suspected

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esophageal wounds. Echocardiography can be used in stable patients to diagnose suspected heart injuries. Treatment is also the same as described for blunt trauma. Most patients do not require thoracotomy. The most common indications for surgery are massive bleeding, massive air leak, and pericardial tamponade. Penetrating injuries are more likely to involve the heart, especially with anterior wounds medial to the midclavicular line. These injuries may cause pericardial tamwonade or, if the wericardium has a defect. exsanguinating hemorrhage into the chest. Shock is a clear indication for urgent thoracotomy in cases of penetrat, management of ing wounds to the chest. ~ o w e v e i the patients with wounds near the heart who present with normal physiologic parameters is problematic. The most conservative and safest approach is to take all such patients to the operating room for a subxiphoid pericardial window, followed by thoracotomy through a median sternotomy, if necessary. Recent reports suggest that early echocardiography may be a sensitive test for occult cardiac injuries and that this technique can be used to select patients who require a pericardial window, thereby In minimizing unnecessary invasive proced~res.~0.~7,62 one report, only patients with pericardial effusions on echocardiography underwent subxiphoid pericardial window; if blood was found, a median sternotomy followed. Patients with normal echocardiographs were observed clinically. Harris et a1.Z8 reported a large experience with penetrating cardiac injuries and recommended cardiac US to diagnose these injuries in stable patients. When an operation is required for a penetrating cardiac injury, a Foley catheter through the defect may control the bleeding temporarily to facilitate suture of the defect. Median sternotomy is best for known cardiac injuries.

COMPLICATIONS There is little information in the literature on the morbidity of chest injuries or the complications after surgical management of thoracic injuries in children. The two most common postoperative complications are pulmonary atelectasis and pneumonia. The most serious is paraplegia, which occurs in 5% to 10% of cases of injury to the thoracic aorta.

OUTCOME

Traumatic asphyxia. This child, injured in an auto accident, was restrained but still suffered a severe compression injury of the chest. In addition to petechial hemorrhages over his upper torso, he had 48 hours of mental confusion, indicating that his brain suffered hemorrhage as w l l .

The risk for death from thoracic injury varies with the type of injury and the number and severity of associated injuries, particularly to the CNS. Roux and Fisher71 reported a series of 100 consecutive children with motor vehicle-related chest trauma in South Africa. Ninety-one pedestrians constituted the largest subgroup. The eight patients who died had a mean injury severity score of 34, compared with a score of 25 among the survivors. Seven of the eight children who died had fatal head injuries. Thus, in children with blunt injuries to the chest, the severity of injury and the presence of concomitant head injuries are the main determinants

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of survival. In children, death from thoracic injury tends to occur in the first few days after the injury, usually from other injuries and not from respiratory failure or sepsis, as is the case in adults. The overall mortality for chest injuries was 15% in the NPTR-virtually identical to most adult series.l2 Mortality increases with each individual chest injury: 30% for a ruptured diaphragm, 40% for cardiac injury; and 50% for injury to a major vessel. The morbidity among survivors is remarkably low. DiScala'4 reported that 90% of survivors in the NPTR had no impairment at the time of discharge.

12. 13. 14. 15. 16.

SUMMARY The following points summarize the management of thoracic injuries in children:

1. Most thoracic injuries can be diagnosed by a combination of clinical assessment and plain chest radiographs. 2. Most heal with supportive treatment and tube thoracostomy drainage. 3. Life-threatening thoracic injuries are relatively uncommon. 4. A few thoracic injuries require surgery, but even the most severe can be managed successfully if they are recognized and treated expeditiously.

REFERENCES

17. 18. 19. 20.

21.

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82. Taskinen SO, Salo,JA, Halttunen PE, et al: Tracheobronchial rupture due to blunt chest trauma: A follow-up study. Ann Thorac Surg 1989;48:846. 83. Tatou E, Steinmetz E, Jazayeri S, et al: Surgical outcome of traumatic rupture of the thoracic aorta. Ann Thorac Surg 2000;69:70. 84. Tellez DW, Hardin WD Jr, Takahashi M, et al: Blunt cardiac injury in children. J Pediatr Surg 1987;22:1123. 85. Thomas P, Saux P, Lonjon T, et al: Diagnosis by video-assisted thoracoscopy of traumatic pericardial rupture with delayed luxation of the heart: Case report. J Trauma 1995;38:967.

86. Wang JN, Tsai YC, Chen SL, et al: Dangerous impactcommotio cordis. Cardiology 2000;93:124. 87. Williams RL, Connolloy PT: In children undergoing chest radiography what is the specificity of rib fractures for non-accidental injury? Arch Dis Child 2004;89:490. 88. Wilson A, Wall MJ Jr, Maxson R, et al: The pulmonary hilum twist as a thoracic damage control procedure. Am J Surg 2003;186:49. 89. Worthy S, Kang EY, Hartman TE, et al: Diaphragmatic rupture: CT &dings in 11 patients. ~adidlogy-1995; 194:885.

Abdominal Trauma Steven Stylianos and Richard H. Pearl

Who could have imagned the influence of Simpson's 1968 publication on the successful nonoperative treatment of select children presumed to have splenic injury?142Initially suggested in the early 1950s by Warnsborough, then chief of general surgery at the Hospital for Sick Children in Toronto, the era of nonoperative management of splenic injury began with the report of 12 children treated between 1956 and 1965. The diagnosis of splenic injury in this select group was made by clinical findings, along with routine laboratory and plain radiographic findings. Keep in mind that this report predated ultrasonography (US), computed tomography (CT), or isotope imaging. Subsequent confirmation of splenic injury was made in one child who required laparotomy years later for an unrelated condition, when it was found that the spleen had healed in two separate pieces. Nearly 4 decades later, the standard treatment of hemodynamically stable children with splenic injury is nonoperative, and this concept has been successfully applied to most blunt injuries of the liver, kidney, and pancreas as well. Surgical restraint is now the norm. based on an increased awareness of the anatomic patterns and physiologic responses of injured children. Our colleagues in adult trauma care have slowly acknowledged this success and are applying many of the principles learned in pediatric trauma to their patients.7g A recent review of the National Pediatric Trauma Registry (NPTR) indicates that 8% to 12% of children suffering blunt trauma have an abdominal injury.z8 Fortunately, more than 90% of them survive. Although abdominal injuries are 30% more common than thoracic injuries, they are 40% less likely to be fatal. The infrequent need for laparotomy in children with blunt abdominal injury has created a debate regarding the role of pediatric trauma surgeons in their treatment. Recent analyses of the NPTR and the National Trauma Data ~ a n emphasize k the overall "surgical" nature of pediatric trauma patients, with more than 25% of injured children requiring operative intervention.l.141 Clearly, a qualified pediatric trauma surgeon would be the ideal coordinator bf such care. Few surgeons have extensive experience with massive abdominal solid organ injuries requiring immediate surgery. It is imperative that surgeons familiarize themselves with current treatment algorithms for life-threatening

abdominal trauma. Important contributions have been made in the diagnosis and treatment of children with abdominal injury by radiologists and endoscopists. The resolution and speed of CT, the screening capabilities of focused abdominal sonography for trauma (FAST), and the percutaneous, angiographic, and endoscopic interventions of nonsurgeon members of the pediatric trauma team have all enhanced patient care and improved outcomes. This chapter focuses on the more common blunt injuries and unique aspects of care in children. Renal and genitourinary injuries are covered separately in Chapter 18.

DIAGNOSTIC MODALITIES The initial evaluation of an acutely injured child is similar to that of an adult. Plain radiographs of the cervical spine, chest, and pelvis are obtained after the initial survey and evaluation of the ABCs (airway, breathing, and circulation). Other plain abdominal films add little to the acute evaluation of pediatric trauma patients. As imaging modalities have improved, treatment algorithms have changed significantly in children with suspected intra-abdominal injuries. Prompt identification of potentially life-threatening injuries is now possible in the vast majority of children.

Computed Tomography CT has become the imaging study of choice for the evaluation of injured children owing to several advantages. CT is now readily accessible in most health care facilities; it is a noninvasive, accurate method of identifying and qualifying the extent of abdominal injury; and it has reduced the incidence of nontherapeutic exploratory laparotomy. Use of intravenous contrast is essential, and "dynamic" methods of scanning have optimized vascular and parenchymal enhancement. The importance of a contrast "blush" in children with blunt spleen and liver injury continues to be debated and is discussed later (Fig. 17-1).3Wead CT, if indicated, should be performed first without contrast, to avoid concealing a hemorrhagic

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A ,

B

A, Abdominal computed tomography scan demonstrating a significant injury to the right hepatic lobe with intravenous contrast "blush." This patient had successful angiographic embolization and avoided operation. B, Abdominal computed tomography scan demonstrating a significant injury to the spleen with intravenous contrast "blush" (arrow). The patient remained hemodynamically stable and avoided operation.

brain injury. Enteral contrast for enhancement of the gastrointestinal (GI) tract is generally not required in the acute trauma setting and can lead to aspiration. Not all children with potential abdominal injuries are candidates for CT evaluation. Obvious penetrating injury often necessitates immediate operative intervention. A hemodynamically unstable child should not be taken out of an appropriate resuscitation room for the performance of CT. These children may benefit from an alternative diagnostic study, such as peritoneal lavage or FAST, or urgent operative intervention. The greatest limitation of abdominal CT in trauma is the inability to reliably identify intestinal rupture.flJ5 Findings suggestive but not diagnostic of intestinal perforation are pneumoperitoneum, bowel wall thickening, free intraperitoneal fluid, bowel wall enhancement, and dilated A high index of suspicion should exist for the presence of bowel injury in a child with intraperitoneal fluid and no identifiable solid organ injury on CT.lZ7The diagnosis and treatment of bowel injury are reviewed in detail later.

Focused Abdominal Sonography for Trauma Clinician-performed sonography for the early evaluation of an injured child is currently being evaluated to determine its optimal use. Examination of Morrison's pouch; the pouch of Douglas; the left flank, including the perisplenic anatomy; and a subxiphoid view to visualize the pericardium is the standard four-view FAST examination (Fig. 17-2). This bedside examination may be a good rapid screening study, particularly in patients too unstable to undergo an abdominal CT scan. Early reports have found FAST to be a helpful screening tool in children, with a high specificity (95%)but low sensitivity (33%) in

.

Schematic of a focused abdominal sonography for trauma (FAST) examination, with emphasis on views of the subxiphoid, right upper quadrant and Morrison's pouch, left upper quadrant and left paracolic region, and pelvic region and pouch of Douglas. (Original illustration by Mark Mazziotti, MD.)

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identifying intestinal injury,lObnda lack of identifiable free fluid does not exclude a significant injury. FAST may be useful in decreasing the number of CT scans performed for "low-likelihood" injuries. Repetition of the study may be necessary, depending on clinical correlation, and the finding of free fluid in itself is not an indication for surgical intervention. Recently, a simple scoring system for quantifylng the amount of hernoperitoneum has been shown to be predictive of the need for laparotomy in a small series of children after blunt abdominal trauma.lo1Prospective validation of such a FAST score is necessary.

Diagnostic Peritoneal Lavage and Laparoscopy Diagnostic peritoneal lavage (DPL) has been a mainstay in trauma evaluation for more than 3 decades. However, its utility in pediatric trauma is limited. Because up to 90% of solid organ injuries do not require surgical intervention, the finding of free blood in the abdomen by DPL has limited clinical significance. Hemodynamic instability and the need for ongoing blood replacement are the determinants for operation in patients with solid organ injury in the absence of blood in the abdominal cavity. Additionally, the speed and accuracy of CT have further decreased the'indications for DPL in pediatric trauma. The sensitivity of CT in diagnosing solid organ injuries and more subtle injuries to the duodenum, pancreas, and intestines continues to improve. This has relegated DPL to the evaluation of patients with clinical findings suggestive of bowel injury and no definitive diagnosis on CT. In this setting, the presence of bile, food particles, or other evidence of GI tract perforation is diagnostic. Recent literature has suggested that laparoscopy can both diagnose and, in some cases, allow definitive surgical management without laparotomy, further limiting the usefulness of DPL. In a study from Dundee, Scotland, comparing DPL and laparoscopy, both tests were highly sensitive (loo%), but laparoscopy had a higher specificity (94% versus 83%).Z9 Large prospective trials using laparoscopy in adults have demonstrated increased diagnostic accuracy, decreased nontherapeutic laparotomy rates, and a significant decrease in hospital length of stay, with an attendant reduction in costs. For example, in a report from the University of Tennessee, 55% of patients with abdominal trauma avoided laparotomy after laparoscopic e~aluation.3~ Similar work from Jacobi Medical Center in New York City revealed a direct relationship between a reduction in negative laparotomies and increased use of laparoscopy for diagnosis and rnanagement.l26 Multiple adult studies have shown the utility of laparoscopy not only in trauma evaluation but also in the definitive management of related injuries. Repairs of gastric and intestinal perforation, bladder rupture, liver laceration, diaphragmatic injury, and splenic injury have all been reported.21J28J40The extent of feasible operations is directly related to the surgeon's skill with advanced laparoscopic techniques and the patient's overall stability. At the Children's Hospital of Illinois, our two most recent handlebar injuries causing bowel perforation were successfully treated laparoscopically.As with elective abdominal surgery, the role of laparoscopy in trauma will increase substantially as trauma centers redirect their training of

17

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297

residents to this modalitv and as more ~ediatriccenters report outcome studies for laparoscopic trauma management in ~hildren.2O>~~,Q

SOLID ORGAN INJURIES Spleen and Liver The spleen and liver are the organs most commonly injured in blunt abdominal trauma, with each accounting for one third of the injuries. Nonoperative treatment of isolated splenic and hepatic injuries in stable children has been universally successful and is now standard practice. However, there is great variation in the management algorithms used by individual pediatric surgeons. Review of the NPTR and recent surveys of the American Pediatric Surgical Association (APsA) membership confirm the wide disparity in practice.",'" Controversy also exists regarding the utility of CT grading and the finding of contrast blush as a predictor of outcome in liver and spleen injury.49,82,89,106Several recent studies reported contrast blush in 7% to 12% of children with blunt spleen injury (see Fig. 17-1).2"76,wThe rate of operation in the "blush" group approached or exceeded 20%. The authors emphasized that CT blush was worrisome but that most patients could still be managed successfully without operation. The role of angiographic embolization in pediatric spleen injury has yet to be determined. Recently the APSA Trauma Committee analyzed a contemporary multi-institution database of 832 children treated nonoperatively at 32 centers in North America from 1995 to 1997 (Table 17-1). 135 Consensus guidelines

Grade I

Grade II

Grade Ill Grade lV

(n = 116) (n = 341) (n = 275) (n =ZOO) Admitted to ICU (%) No. hospital days (mean) No. hospital days (range) Transfused (%) Laparotomy (%) Follow-up imaging (%) Activity.restriction (mean wk) Activity restriction (range wk)

55.0

54.3

72.3

85.4

4.3

5.3

7.1

7.6

1-7

2-9

3-9

410

1.8 0 34.4

5.2 1.0 46.3

10.1* 2.77 54.1

26.6* 12.67 51.8

5.1

6.2

7.5

9.2

2-6

2-8

4-12

6-12

*Grade Ill vs grade IV, p < 0.014. tGrade Ill vs grade IV, p < 0.0001. CT, computed tomography; ICU, intensive care unit. From Stylianos S, APSATrauma Committee: Evidence-based guidelines for resource utilization in children with isolated spleen or liver injury. J Pediatr Surg 2000;35:164-169.

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Grade l Grade I1 Grade Ill Grade lV ICU days Hospital stay (days) Predischarge imaging Postdischarge imaging Activity restriction (wk)*

0 2 None None 3

0 3 None None 4

0 4 None None 5

1 5 None None

6

CT, computed tomography; ICU, intensive care unit. *Return to full-contact, competitive sports (e.g., football, wrestling, hockey, lacrosse, mountain climbing) should be at the discretion of the individual pediatric trauma surgeon. The proposed guidelines for return to unrestricted activity include "normal" age-appropriateactivities. From Stylianos S, APSA Trauma Committee: Evidence-basedguidelines for resource utilization in children with isolated spleen or liver injury. J Pediatr Surg2000; 35: 164-169.

on intensive care unit (ICU) stay, length of hospital stay, use of follow-up imaging, and physicai activity restriction for clinically stable children with isolated spleen or liver injuries (CT grades I to IV) were defined based on this analysis (Table 17-2). The guidelines were then applied prospectively in 312 children with liver or spleen injuries treated nonoperatively at 16 centers from 1998 to 2000.l36 Patients with other minor injuries such as nondisplaced, were noncomminuted fractures or soft tissue injuries ., included as long as the associated injuries did not influence the variables in the study. The patients were grouped by severity of injury defined by CT grade. Compliance with the proposed -guidelines was analyzed for -age, organ injured, and injury grade. All patients were followed for 4 months after injury. It is imperative to emphasize that these proposed bidelines askme hemodynakic stability. The extremely low rates of transfusion and operation document the stability of the study patients. Specific guideline compliance was 81% for ICU stay, 82% for length of hospital stay, 87% for follow-up imaging, and 78% for activity restriction. There was a significant improvement in compliance from year 1 to year 2 for ICU stay (77% versus 88%, P < 0.02) and activity restriction (73% versus 87%, P < 0.01). There were no differences in compliance by age, gender, or organ injured. Deviation from the guidelines was the surgeon's choice in 90% of cases and patient-related in 10%. Six patients (1.9%) were readmitted, although none required operation. Compared with the previously studied 832 patients, the 312 patients managed prospectively by the proposed guidelines had a significant reduction in ICU stay (P< 0.0001), hospital stay (P < 0.0006), follow-up imaging ( P < 0.0001), and interval of physical activity restriction ( P < 0.04) within each grade of injury. From these data it was concluded that prospective application of specific treatment guidelines based on injury severity resulted in conformity in patient management, improved utilization of resources, and validation of guideline safety. Significant reductions in ICU stay,

hospital stay, follow-up imaging, and activity restriction were achieved without adverse sequelae when compared with the retrospective database. The attending surgeon's decision to operate for spleen or liver injury is best based on evidence of continued blood loss, such as low blood pressure, tachycardia, decreased urine output, and falling hematocrit unresponsive to crystalloid and blood transfusion. The rates of successful nonoperative treatment of isolated blunt splenic and hepatic injury now exceed 90% in most pediatric trauma centers and in adult trauma centers with a strong pediatric commitment (H. N. Loworn, personal communication) .87,135.'3" A study of more than 100 patients from the NPTR indicated that nonoperative treatment of spleen or liver injury is indicated even in the presence of associated head injury if the patient is hemodynamically stable.63 Rates of operative intervention for blunt spleen or liver injury were similar with and without an associated closed head injury. Not surprisingly, adult trauma services have reported excellent survival rates for pediatric trauma patients; however, an analysis of treatment for spleen and liver injuries reveals alarmingly high rates of operative treatThis discrepancy in operative rates ment.42,64,87,113 emphasizes the importance of disseminating effective guidelines, because the majority of seriously injured children are treated outside of dedicated pediatric trauma centers. Mooney and Forbess8reviewed the New England Pediatric Trauma Database in the 1990s and identified 2500 children with spleen injuries. Two thirds were treated by nonpediatric trauma surgeons, and two thirds were treated in nontrauma centers. After allowing for multiple patient- and hospital-related variables, the authors found that the risk of operation was reduced by half when a surgeon with pediatric training provided care to children with spleen injuries. In a similar review using the KIDS 2000 administrative data set, Rothstein et al.lI4 found that despite adjustment for hospital- and patient-specific variables, children treated at an adult general hospital had a 2.8 greater chance ( P < 0.003), and those treated at a general hospital with a pediatric unit had a 2.6 greater chance ( P < 0.013), of undergoing splenectomy than those cared for at a freestanding pediatric hospital. Adult trauma surgeons caring for injured children must consider the anatomic, immunologic, and physiologic differences between pediatric and adult trauma patients and incorporate these differences into their treatment protocols. The major concerns are related to the potential risks of increased transfusion requirements, missed associated injuries, and increased length of hospital stay. Each of these concerns has been shown to be without merit.78,86,90,95,104,118,133

Associated Abdominal Injuries Advocates of surgical intervention for splenic trauma cite their concern about missing associated abdominal injuries if no operation is performed. Morse and Garciago reported successful nonoperative treatment in 110 of 120 children (91%) with blunt splenic trauma, of whom 22 (18%) had associated abdominal injuries. Only 3 of

CHAPTER

A

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B

A, Splenic pseudoaneurysm after (arrows) nonoperative treatment of blunt splenic injury. B, Successful angiographic embolization (arrozus show occlusion of ruptured vessels). a

these 120 patients (2.5%) had GI injuries, and each was discovered at early celiotomy done for a specific indication. There was no morbidity from missed injuries or delayed surgery. Similarly, a review of the NPTR from 1988 to 1998 revealed 2977 patients with solid abdominal visceral injuries; only 96 (3.2%) had an associated hollow visceral injury.95 Higher rates of hollow visceral injury were observed in assaulted patients and in those with multiple solid visceral injuries or pancreatic injuries. Differences in mechanism of injury may account for the much lower incidence of associated abdominal injuries in children with splenic trauma. There is no justification for an exploratory celiotomy solely to avoid missing potential associated injuries in children.

Complications of Nonoperative Treatment

liver injury.l3,40 These rare occurrences lead to caution when determining a minimum safe interval before the resumption of unrestricted activities. Routine follow-up imaging studies have identified pseudocysts and pseudoaneurysms following splenic injury (H. N. Loworn, personal c o m m u n i ~ a t i o n ) .Splenic ~~~~~ pseudoaneurysms often cause no symptoms and appear to resolve with time. The true incidence of self-limited, posttraumatic splenic pseudoaneurysms is unknown because routine follow-up imaging after successful nonoperative treatment has been largely abandoned. Once identified, the actual risk of s ~ l e n Gdseudoaneurvsm nmture is also unclear. Angiographic embolization techniques can successfully treat these lesions, obviating the need for open surgery and loss of splenic parenchyma (Fig. 17-3).Splenic pse~d6cystscan achieve enormous size, leading to and GI disturbance (Fig. 17-4). Simple percutaneous aspiration leads to a high recurrence rate. Laparoscopic excision and marsupialization are highly effective (Fig. 17-5).

Nonoperative treatment protocols have been the standard for most children with blunt liver and spleen injuries for the past 2 decades. This cumulative experience has allowed us ;o evaluate both the benefits and the risks of the non-operative approach. Fundamental to the success of a nonoperative strategy is the early, spontaneous cessation of hemorrhage. Transfusion rates for children with isolated spleen or liver injuries have fallen below lo%, confirming the lack of continued blood loss in the majority of patients.7".8'.87.13".'"6 Despite many favorable observations, isolated reports of significant delayed hemorrhage with adverse outcomes continue to appear.13,40,46J23 Shilyansky et a1.lz3 reported two children with delayed hemorrhage 10 days after blunt liver injury. Both children had persistent right upper quadrant and right shoulder pain despite normal vital signs and stable hematocrits. The authors recommended continued inhouse observation until symptoms resolve. Other reports a Computed tomography scan of post-traumatic have described patients with significant bleeding 38days after grade I1 spleen injury and 24 days after grade IV splenic pseudocyst.

CHAPTER

A

.

17

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299

B

-

A, Splenic pseudoaneurysm after ( a m s )nonoperative treatment of blunt splenic injury. B, Successful angiographic embolization (arrou~s show occlusion of ruptured vessels).

these 120 patients (2.5%) had GI injuries, and each was discovered at early celiotomy done for a specific indication. There was no morbidity from missed injuries or delayed surgery. Similarly, a review of the NPTR from 1988 to 1998 revealed 2977 patients with solid abdominal visceral injuries; only 96 (3.2%) had an associated hollow visceral injury.95 Higher rates of hollow visceral injury were observed in assaulted patients and in those with multiple solid visceral injuries or pancreatic injuries. Differences in mechanism of injury may account for the much lower incidence of associated abdominal injuries in children with splenic trauma. There is no justification for an exploratory celiotomy solely to avoid missing potential associated injuries in children.

Complications of Nonoperative Treatment

liver injury.lS4O These rare occurrences lead to caution when determining a minimum safe interval before the resumption of unrestricted activities. Routine follow-up imaging studies have identified pseudocysts and pseudoaneurysms following splenic injury (H. N. Loworn, personal communication).41.g* Splenic pseudoaneurysms often cause no symptoms and appear to resolve with time. The true incidence of self-limited, posttraumatic splenic pseudoaneurysms is unknown because routine follow-up imaging after successful nonoperative treatment has been largely abandoned. Once identified, the actual risk of splenic pseudoaneurysm rupture is also unclear. Angiographic embolization techniques can successfully treat these lesions, obviating the need for open surgery and loss of splenic parenchyma (Fig. 17-3).Splenic pseudocysts can achieve enormous size, leading to pain and GI disturbance (Fig. 174). Simple percutaneous aspiration leads to a high recurrence rate. Laparoscopic excision and marsupialization are highly effective (Fig. 17-5).

Nonoperative treatment protocols have been the standard for most children with blunt liver and spleen injuries for the past 2 decades. This cumulative experience has allowed us io evaluate both the benefits and the risks of the non-operative approach. Fundamental to the success of a nonoperative strategy is the early, spontaneous cessation of hemorrhage. Transfusion rates for children with isolated spleen or liver injuries have fallen below lo%, confirming the lack of continued blood loss in the majority of patient~.7"."2.87.~35,~36 Deswite many favorable observations, isolated reports of significant delayed hemorrhage with adverse outcomes continue to appear.13,40,46,123 Shilyansky et al.123 reported two children with delayed hemorrhage 10 days after blunt liver injury. Both children had persistent right upper quadrant and right shoulder pain despite normal vital signs and stable hematocrits. The authors recommended continued inhouse observation until symptoms resolve. Other reports Computed tomography scan of post-traumatic have described patients with significant bleeding 38days after grade I1 spleen injury and 24 days after grade IV splenic pseudocyst.

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A , -

B

A, Laparoscopic view of splenic pseudocyst capsule. B, Appearance of cyst wall after laparoscopic aspiration and before marsupialization.

Sequelae of Damage-Control Strategies Even the most severe solid organ injuries can be treated without surgery if there is a prompt response to resuscitation.lo8 In contrast, emergency laparotomy, embolization, or both are indicated in patients who are hemodynamically unstable despite fluid and red blood cell transfusion. Most spleen and liver injuries requiring operation are amenable to simple methods of hemostasis using a combination of manual compression, direct suture, topical In young chilhemostatic agents, and mesh ~rapping.l~2~2 dren with significant hepatic injury, the sternum can be divided rapidly to expose the suprahepatic or intrapericardial inferior vena cava, allowing for total hepatic vascular isolation (Fig. 17-6).150 Children can tolerate periods of vascular isolation for 30 minutes or longer as long as their blood volume is replenished. With this exposure, the liver and major perihepatic veins can be isolated and the bleeding controlled, permitting direct suture repair or ligation of the offending vessel. Although the cumbersome and dangerous technique of atriocaval shunting has been largely abandoned, newer endovascular balloon catheters can be useful for temporary vascular occlusion to allow access to the juxtahepatic vena ~ a v a . ~ The early morbidity and mortality of severe hepatic injuries are related to the effects of massive blood loss and replacement with large volumes of cold blood products. The consequences of prolonged operations with massive blood product replacement include hypothermia, coagulopathy, and acidosis. Although the surgical team may keep pace with blood loss, life-threatening physiologic and metabolic consequences are inevitable, and many of these critically ill patients are unlikely to survive once their physiologic reserves have been exhausted. A multiinstitutional review identified exsanguination as the cause of intraoperative death in 82% of 537 patients at eight academic trauma centers.57 The mean pH was 7.18 and the mean core temperature was 32°C before death.

Moulton et al.Y3reported survival in only 5 of 12 (42%) consecutive operative cases of retrohepatic vascular or severe parenchymal liver injury in children. Maintenance of physiologic stability during the struggle for surgical control of severe bleeding is a formidable challenge even for the most experienced surgical team, particularly when hypothermia, coagulopathy, and acidosis occur. This triad creates a vicious circle in which each derangement exacerbates the others, and the

.

Total hepatic vascular isolation with occlusion of the porta-, supra-, and infrahepatic inferior vena cava and supraceliac aorta (optional). (Original illustration by Mark Mazziotti, MD.)

CHAPTER

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Abdominal Trauma

301

physiologic and metabolic consequences often preclude completion of the procedure. Lethal coagulopathy from dilution, hypothermia, and acidosis can rapidly occur.145 Experimental studies have defined the alterations in proPhase 1 Abbreviated laparotomy for exploration and anticoagulant enzyme processes, platelet activation, Control of hemorrhage and contamination and platelet adhesion defects with varying degrees of Packing and temporary abdominal wall closure hypothermia.14' The infusion of activated recombinant Aggressive ICU resuscitation Phase 2 Core rewarming factor VII in patients with massive hemorrhage has been Optlmizatlon of volume and oxygen delivery promising in several case reports.68 Correction of coagulopathy Increased emphasis on physiologic and metabolic Planned reoperation(s) for packing change Phase 3 stability in emergency abdominal operations has led to Definitive repair of injuries the development of staged, multidisciplinary treatment Abdominal wall closure plans, including abbreviated laparotomy, perihepatic packing, temporary abdominal closure, angiographic embolization, and endoscopic biliary stenting.5,32a45.69J4g ICU, intensive care unit. Asensio et aL6 reported on 103 patients with mostly penetrating grade IV or V hepatic injuries treated between have been proposed beyond the conventional vital signs 1991 and 1999. Mean blood loss was estimated at 9.4 L, and urine output, including serum lactate, base deficit, and mean volume infusion in the operating room was mixed venous oxygen saturation, and gastric mucosal 15 L. Packing of the hepatic injuries was used in 50% of pH. Once a patient is rewarmed, coagulation factors are patients at the first operation. Forty percent of patients Eeplaced, and oxygen delivery is optimized, he or she can who survived the initial operative control of hemorrhage be returned to the operating room for pack removal and had postoperative angiographic embolization (Fig. 17-7). definitive repair of injuries. A review of nearly 700 adult Survival was 63% in grade IV patients and 24% in grade V patients, emphasizing the lethality of such injuries patients treated by abdominal packing from several instidespite a well-choreographed, staged, multidisciplinary tutions demonstrated hemostasis in 80%, survival of 32% to 73%, and abdominal abscess rates of 10% to 40%.26,53 approach. Trauma surgeons treating critically injured Although abdominal packing with planned reoperation children must familiarize themselves with these lifesaving has been used with increasing frequency in adults during techniaues. Abbreviated laparotomy with packing for hemostasis, the past 2 decades, there is little published experience in children.30,36,5"80~115,13'L~134.'38Nevertheless, we believe allowing resuscitation before planned reoperation, is an that this technique has a place in the management of chilalternative in unstable patients in whom further blood dren with massive intra-abdominal bleeding, especially loss would be untenable. This "damage-control" philosoafter blunt trauma. phy is a systematic, phased approach to the management The ~ J ~three 3 We reported a 3-year-old child who required abdomiof exsanguinating trauma p a t i e n t ~ . ~ , ~ phases of damage control are detailed in Table 17-3. nal packing for a severe liver injury, making closure of the &though controversial, several resuscitative end points abdomen impossible.138A Silastic "silo" was constructed

A

.

B

-

A, Hepatic artery angiogram in a patient with persistent hemorrhage after initial damage-control laparotomy. The bleeding vessel is identified (curved arrow). B, Successful embolization was performed.

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to accommodate the bowel until the packing could be removed. The patient made a complete recovery. The combined technique of packing and a silo allowed time for correction of the hypothermia, acidosis, and coagulopathy, without compromise of respiratory mechanics. One review reported 22 infants and children (age 6 days to 20 years) with refractory hemorrhage who were treated with abdominal packing.134The anatomic site of hemorrhage was the liver or hepatic veins in 14, retroperitoneum or pelvis in 7, and pancreatic bed in 1. Primary fascia1 closure was accomplished in 12 patients (55%), and temporary skin closure or prosthetic material was used in the other 10. Packing controlled hemorrhage in 21 of 22 patients (95%). Removal of the packing was possible within 72 hours in 18 patients (82%). No patient rebled after the packing was removed; however, 2 patients died with the packing in place. Seven patients (32%) developed an abdominal or pelvic abscess, and all were successfully drained by laparotomy (6 patients) or percutaneously (1 patient); 6 of the 7 patients with abdominal sepsis survived. Overall, 18 patients (82%) survived. Two deaths were due to multisystem organ failure, one to cardiac failure from complex cardiac anomalies, and one to exsanguination after blunt traumatic liver injury. There were no differences in the volume of intraoperative blood product transfusion, time to initiate packing, physiologic status, or type of abdominal closure between survivors and nonsurvivors. Although the success of abdominal packing is encouraging, it may contribute to significant morbidity, such as intra-abdominal sepsis, organ failure, and increased intra-abdominal pressure. Intra-abdominal packs are contaminated by skin and gut flora, but these organisms are not those implicated in subsequent patient sepsis.48 Adams et a1.2 evaluated fluid samples from 28 patients with abdominal packing and found peritoneal endotoxin and mediator accumulation even when cultures were sterile. The authors concluded that laparotomy pad fluid accumulating after damage-control laparotomy can contribute to neutrophil dysfunction by enhancing neutrophil respiratory burst and inhibiting neutrophil responses to specific chemotactic mediators needed to fight infection. Thus, the known propensity of such patients to both intraabdominal and systemic infection may be related to changes in neutrophil receptor status and effector function related to the accumulation of inflammatory mediators in the abdomen. Early washout, repetitive packing, and other efforts to minimize mediator accumulation deserve consideration. It is essential to emphasize that the success of the abbreviated laparotomy and planned reoperation depends on an early decision to employ this strategy before irreversible shock occurs. When employed as a desperate, lastditch resort after prolonged attempts at hemostasis have failed, abdominal packing has been uniformly unsuccessful. Physiologic and anatomic criteria have been identified as indications for abdominal packing. Most of these focus on intraoperative parameters, including pH (-7.2), core temperature (<35OC), and coagulation values (prothrombin time >16 seconds), in a patient with profuse hemorrhage requiring large volumes of blood product transfusion.

The optimal time for re-exploration is controversial, because neither the physiologic end points of resuscitation nor the increased risk of infection with prolonged packing are well defined. The obvious benefits of hemostasis provided by packing are also balanced against the potential deleterious effects of increased intra-abdominal pressure on ventilation, cardiac output, renal function, mesenteric circulation, and intracranial pressure. Timely alleviation of the secondary abdominal compartment syndrome may be a critical salvage maneuver for patients. Temporary abdominal wall closure at the time of packing can prevent the abdominal compartment syndrome. We recommend temporary abdominal wall expansion in all patients requiring packing until hemostasis is obtained and visceral edema subsides. A staged operative strategy for unstable trauma patients represents advanced surgical care and requires sound judgment and technical expertise. Intra-abdominal packing for control of exsanguinating hemorrhage is a lifesaving maneuver in highly selected patients in whom coagulopathy, hypothermia, and acidosis render further surgical procedures unduly hazardous. Early identification of patients likely to benefit from abbreviated laparotomy techniques is crucial for success.

Abdominal Compartment Syndrome The abdominal compartment syndrome is a term used to describe the deleterious effects of increased intra-abdominal pressure.l16 The syndrome includes respiratory insufficiency from worsening ventilation-perfusion mismatch, hemodynamic compromise from preload reduction due to inferior vena cava compression, impaired renal function from renal vein compression, decreased cardiac output, intracranial hypertension from increased ventilator pressures, splanchnic hypoperfusion, and abdominal wall overdistention. The causes of intra-abdominal hypertension in trauma patients include hernoperitoneum, retroperitoneal or bowel edema, and use of abdominal or pelvic packing. The combination of tissue injury and hemodynamic shock creates a cascade of events, including capillary leak, ischemia-reperfusion,and release of vasoactive mediators and free radicals, which combine to increase extracellular volume and tissue edema. Experimental evidence indicates that there are significant alterations in cytokine levels in the presence of sustained intra-abdominal pressure elevation.100J12 Once the combined effects of tissue edema and intra-abdominal fluid exceed a certain level, abdominal decompression must be considered. The adverse effects of abdominal compartment syndrome have been acknowledged for decades; however, abdominal compartment syndrome has only recently been recognized as a life-threatening but potentially treatable The incidence of this complication has increased markedly in recent years due to -high-volume resuscitation protocols. Measurement of intra-abdominal pressure can be useful in determining the contribution of abdominal compartment syndrome to altered physiologic Intra-abdominal presand metabolic parameter~.~g,fl.s4 sure can be determined by measuring bladder pressure. This involves instilling 1 mL/kg of saline into the Foley

CHAPTER

catheter and connecting it to a pressure transducer or manometer via a three-way stopcock. The symphysis pubis is used as the zero reference point, and the pressure is measured in centimeters of water or millimeters of mercury. Intra-abdominal pressures in the range of 20 to 35 cm H 2 0 or 15 to 25 mm Hg have been identified as an indication to decompress the abdomen. Many prefer to intervene according to alterations in other physiologic and metabolic parameters rather than a specific pressure measurement. Chang et al.19 reported 11 adult trauma patients with abdominal compartment syndrome in whom abdominal decompression using pulmonary artery catheters and gastric tonometry improved preload, pulmonary function, and visceral perfusion. Anecdotally, decompressive laparotomy has been used successfully to reduce refractory intracranial hypertension in patients with isolated brain injury without overt signs of abdominal compartment ~ y n d r o m e . ~ j Experience with abdominal decompression for abdominal compartment syndrome in children is limited.31,34,97,122.134,138 Nonspecific abdominal CT findings in children with abdominal compartment syndrome include narrowing of the inferior vena cava, direct renal compression or displacement, bowel wall thickening with enhancement, and a rounded appearance of the a b d ~ m e n .Neville ~~ et al?7 reported the use of patch abdominoplasty in 23 infants and children, only 3 of whom were trauma patients. These authors found that patch abdominoplasty for abdominal compartment syndrome effectively decreased airway pressures and oxygen requirements. Failure to respond with a decrease in airway pressures or fraction of inspired oxygen was an ominous sign in their series. Several authors have found that abdominal decompression resulted in decreased airway pressures, increased oxygen tension, and increased urine output in children with abdominal compartment syndrome.31,97J22 Many materials have been suggested for use in temporary patch abdominoplasty, including Silastic sheeting, Gore-Tex sheeting, intravenous bags, cystoscopy bags, ostomy appliances, and various mesh materials (Fig. 17-8). The vacuum-pack technique, used successfully in adults, seems pr0mising.~,~~J39

A I

17

Abdominal Trauma

303

Bile Duct Injury Nonoperative management of pediatric blunt liver injury is highly successful but is complicated by a 4% risk of persistent bile leakage.lOJ17 Radionuclide scanning is recommended when biliary tree injury is suspected.120 Delayed views may show a bile leak even if early views are normal. Several reports have highlighted the benefits of endoscopic retrograde cholangiopancreatography (ERCP) with placement of transampullary biliary stents for biliary duct injury following blunt hepatic trauma. Although ERCP is invasive and requires conscious sedation, it can pinpoint the site of injury and allow treatment of the injured ducts without open surgery (Fig. 17-9).Endoscopic transampullary biliary decompression is a recent addition to the treatment options for patients with persistent bile leakage. The addition of sphincterotomy during ERCP for persistent bile leakage following blunt liver injury has been advocated to decrease intrabiliary pressure and encourage internal decompre~sion.2',9"12~It is important to note that endoscopic biliary stents may migrate or become obstructed and require specific treatment.

INJURIES TO THE DUODENUM AND PANCREAS In contrast to the liver and spleen, injuries to the duodenum and pancreas are much less frequent, accounting for less than 10% of intra-abdominal injuries in children sustaining blunt trauma. Isolated duodenal and pancreatic injuries occur in approximately two thirds of cases, with combined injuries to both organs occurring in the remainder. The severity of the duodenal or pancreatic injury and associated injuries determines the necessity for operative versus nonoperative management. The "protected" retroperitoneum both limits the chance of injury and increases the difficulty of early diagnosis. Added to this diagnostic dilemma is the frequency of associated intra-abdominal or multisystem injuries, which can mask subtle physical and radiographic diagnostic signs of injury to the duodenum and pancreas.

B A, Abdominal wall expansion with Silastic sheeting. B, Abdominal wall expansion with a Gore-Tex patch.

304

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A

B

, A, Endoscopic retrograde cholangiopancreatography demonstrating several bile leaks after blunt liver injury. B, Endoscopic view of transarnpullary biliary stent.

Duodenum In a report on blunt duodenal rupture, Ballard et reviewed a &year statewide (Pennsylvania) experience. Of 103,864 patients registered from 28 trauma centers, blunt injury to the duodenum occurred in 206 (0.2%),of whom only 30 (14%) had full-thickness rupture. The mechanism of iniury was car crash in 70%, which included both adults

number were interpreted as ndrma~.~ o r t a l i 6was <3% and was not affected by a delay in diagnosis or treatment. This study emphasizes the difficulty of analyzing this injury owing to the low numbers reported by individual centers (and surgeons). Additionally, the investigators reviewed the range of repairs performed-from duodenal closure to the Whipple procedure-but commented that no definitive recommendations could be made because of the small number of patients and the many centers reporting. In contrast, a group from Toronto reported a singlecenter experience in a series of 27 children (mean age, 7 years) sustaining blunt duodenal injuries and treated over a 10-year period (1986 to 1996).124 Thirteen children had duodenal perforations (mean age, 9 years), and 14 sustained duodenal hematomas (mean age, 5 years). Associated injuries were seen in 19 patients (10 pancreas, 5 spleen, 4 liver, 2 long bone fracture, 1 central nervous system, 1 renal contusion, 1jejunal perforation, and 1 gastric rupture). Seventeen patients were transferred from other facilities, with a 4hour median time to transfer. The median interval from injury to surgery in those sustaining perforation was 6 hours. A comparison of the clinical

presentation, laboratory evaluation, and radiographic findings in those with duodenal hematoma versus perforation is presented in Table 174. Most patients had abdominal CT scans performed with oral and intravenous contrast (Figs. 17-10 and 17-11). A comparison of CT findings in these patient groups is presented in Table 17-5. These data

I

1

Patient Characteristic -- - ..--

--

Duodenal - --Hematoma -

Duodenal Perforation -

1

Number Age (YO ISS score Seat belt worn: no. (%) Presentation Pain or tenderness: no. (%) Bruising: no. (%) GCS score Associated injuries Pancreatic: no. (%) Lumbar spine: no. (%) Total: no. (%) Laboratory evaluation Hgb: mg %/Hct Amylase: units (%)

*Statistically significant difference. GCS, Glasgow Coma Scale; Hct, hematocrit; Hgb, hemoglobin; ISS, Injury Severity Scale. From Shilyansky J, Pearl RH, Kroutouro M, et al: Diagnosis and management of duodenal injuries in children.J Pediatr Surg 1997:32:880-886.

CHAPTER

24 days after her injury.

A

B

portions of the duodenum was

A

B

17

Abdominal Trauma

305

306

PART

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TRAUMA

Finding

Duodenal Hematoma ( n = 10) No. (%)

Duodenal Perforation ( n = 9) No. (%)

Free air Free fluid Retroperitoneal fluid Bowel wall and peritoneal enhancement Duodenal caliber change Thickened duodenum Mural hematoma Retroperitoneal air Retroperitoneal contrast7 Retroperitoneal air or contrast

*The child had an associatedjejunal perforation. tEnteral contrast was not administered in two children. From Shilyansky J, Pearl RH, Kroutouro M, et al: Diagnosis and management of duodenal injuries in children. J Pediatr Surg 1997:32:880-886.

demonstrate that the clinical presentation is strikingly similar in both groups, with only age and injury severity score achieving statistical significance (but of little clinical relevance in individual patients). However, extravasation of air or enteral contrast into the retroperitoneal, periduodenal, or prerenal space was found in every child with a duodenal perforation (9 of 9) but in none ofthe 10who had duodenal hematoma. The authors noted that few previous reports in the literature described these specific CT findings with duodenal injuries in general, and in particular, no previous series of pediatric patients had been reported. This experience and a 1986report from the same center146summarize a total of 24 patients with duodenal hematoma, all treated nonoperatively. The CT scans (or upper GI contrast studies in equivocal cases) showing duodenal narrowing, corkscrewing, or obstruction without extravasation were diagnostic in all cases. In the current series of 14 patients treated nonoperatively, the duration of nasogastric decompression was 12 days (mean),and the length of total parenteral nutrition administration was 18 days (mean). Symptoms resolved in 13 of 14 patients an average of 16 days after injury. The remaining child developed a chronic fibrous stricture requiring operative duodenoplasty 49 days after injury. This child also had a pancreatic contusion. Desai et a1.33 from St. Louis Children's Hospital reviewed their experience with 24 duodenal injuries from blunt abdominal trauma.33 There were 19 duodenal hematomas (15 diagnosed by CT, and 4 by upper GI studies), 17 of which were treated nonoperatively. In those with perforation, 4 of 5 were amenable to simple suture repair. The experiences from Salt Lake City and Pittsburgh emphasize an alarming finding that a common cause of duodenal trauma is child abuse, especially in younger patient~.'~,~"herefore, isolated duodenal injures should

raise suspicion if the history or mechanism of injury described is inconsistent with the actual injury. In all these series, patients sustaining duodenal perforation were treated operatively in a variety of ways, depending on the injury severity and the surgeon's preference. We recommend primary closure of a duodenal perforation (whenever possible). Primary closure can be combined with duodenal drainage and either pyloric exclusion with gastrojejunostomy (Fig. 17-12) or gastric drainage with feedingjejunostomy. These surgical options decrease the incidence of duodenal fistula, reduce the time to GI tract alimentation, and shorten hospital stay. When faced with complicated duodenal trauma, an effective combination is the three-tube technique: duodenal closure (primary repair, serosal patch, or anastomosis) with duodenal drainage tube for decompression (tube 1), pyloric exclusion with an absorbable suture via gastrotomy and gastric tube placement (tube 2), and feeding jejunostomy (tube 3). Several closed suction drains are placed adjacent to the repair. When the duodenum is excluded (via an absorbable suture for temporary closure of the pylorus), complete healing of the injury routinely occurs before the spontaneous reopening of the pyloric channel (Fig. 17-13). However, no matter what repair the surgeon selects, a summary of the literature demonstrates that protecting the duodenal closure

-

Lateral duodenal injury treated by primary duodenal

repair and pyloric exclusion consisting of closing the pylorus with an absorbable suture and gastrojejunostomy. Closed suction drainage of the repair is not depicted. (Original illustration by Mark Mazziotti, MD.)

CHAPTER

, -

17

Abdominal Trauma

307

Upper gastroin-

testinal study of a 7-year-old girl with duodenal perforation resulting from a motor vehicle accident. Primary repair, pyloric exclusion, retrograde tube duodenostomy, gastrojejunostomy, and feeding gastrostomy were performed. The child tolerated jejunal feeds 6 days after the injury and oral feeds 12 days after the injury. A, Six weeks postinjury, an upper gastrointestinal study demonstrated spontaneous closure of the gastre jejunostomy (arrow).B, A patent pyloms is evident (arrow).

A

(drain and exclusion) and a route for enteral feeding (gastrojejunostomy or feeding jejunostomy) reduces morbidity and hospital length of stay.39,70 The surgical options are listed in Table 17-6 and illustrated in Figures 17-12 and 17-14. Of note, pancreatic o d ~ o d e n e c t o(the ~ ~ Whipple procedure)-is rarely required. Although occasionally reported in the literature, pancreaticoduodenectomy should be reserved for the host severe iniuries to the duodenum and Dancreas in ,. which the common blood supply is destroyed and reconstruction is impossible.

B

The mechanism of injury was car or bike crashes. Sixteen of the 18 patients had CT scans on admission. Of these, 11 suggested injury; in 5, the injury was missed. Distal pancreatectomy was performed in 8 patients (44%).In 5 of 6 patients with either proximal duct injuries or injuries missed on the initial CT scan, pseudocysts developed;

Pancreas Injuries to the pancreas are slightly more frequent than duodenal injuries, with estimated ranges from 3% to 12% in children sustaining blunt abdominal trauma.'l As with duodenal injuries, individual centers frequently have small patient numbers and thus are unable to evaluate their results critically. Recently, two centers (Toronto and San Diego) reported their experience with divergent methods of managing blunt traumatic pancreatic Here, we cominjuries in a series of report~.16,17,61,75,125~~~* pare these papers and excerpt other authors' experience to make management recommendations. Canty and Weinman (San Diego)l7 reported 18 patients with major pancreatic injuries over a 14year period.

Repair of the duodenum Diversion of the gastrointestinal tract (pyloric exclusion or duodenal diverticularization) Gastric decompression (gastric tube insertion or gastrojejunostomy) Gastrointestinal tract access for feeding (jejunostomy tube or gastrojejunal anastomosis) Decompression of the duodenum (duodenostomy tube) Biliary tube drainage Wide drainage of the repaired area (lateral duodenal drains)

, -

Duodenal diverticularization for combined proxi-

mal duodenal and pancreatic injury. Resection and closure of the duodenal stump, tube duodenostomy, tube cholecystostomy, gastrojejunostomy, and multiple closed suction drains are depicted. A feeding jejunostomy should be strongly considered (not depicted). (Original illustration by Mark Mazziotti, MD.)

308

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pseudocysts also occurred in 2 other children who had minimal initial symptoms and no admission CT scans. Of these 7 pseudocysts, 2 resolved and 5 were treated TWO patients, treated more recently, by cystogast~ostomy. received ERCP with duct stenting and experienced resolution of symptoms and complete healing. The authors concluded that distal injuries should be treated with distal pancreatectomy, proximal injuries with observation, and pseudocysts with observation or cystogastrostomy. They also concluded that acute ERCP management with stent placement is safe and effective, and that CT is suggestive but not always diagnostic for the type and location of pancreatic i n j u r i e ~ . l 6 , l ~ ~ ~ ~ The experience summarized in three reports from The extensive CT Toronto is markedly different.i5,125J44 findings suggestive of pancreatic injury are detailed in Table 17-7. In the first brief report, 2 patients with documented duct disruption (by ERCP or catheter-gram) had complete duct healing without operative intervention.75 This was followed by a summary report of 35 consecutive children treated over 10 years (1987 to 1996).l2"wentythree had early diagnosis. (<24 hours), whereas diagnosis was delayed (2 to 14 days) in 12 patients. Twenty-eight children were treated nonoperatively, and the other 7 had operations for other injuries. In the 28 cases treated nonoperatively, CT was diagnostic, revealing five patterns of injury: contusion, stellate fragmentation, partial fracture, complete transection, and pseudocyst (Fig. 17-15). The patients were placed in three clinical groups based on

1 Associated Finding

No. of Children

lntraperitoneal fluid Lesser sac fluid Focal peripancreatic fluid Retroperitoneal fluid Right anterior pararenal fluid Left anterior pararenal fluid Thickened Gerota's fascia (right and left) Mesenteric fluid or hematoma Left posterior pararenal fluid Fluid separating SV and pancreas Fluid surrounding SMV and PV Fluid separating pancreas and duodenum CT, computed tomography; PV, portal vein; SMV, superior mesenteric vein; SV, splenic vein. Data from references 75, 125, 144.

CT grade (Table 17-8). In these 28 patients, pseudocysts occurred in 10 (2 of 14 in group 1 , 5 of 11 in group 2, and 3 of 3 in group 3). No patients in group 1 required drainage, whereas 4 in group 2 and all 3 in group 3 required intervention. These drainage procedures occurred 10 to 14 days after injury. Average time for the

CHAPTER

Group (Clinical) 1 2 3

17

Abdominal Trauma

309

No. of Children

Grade (CT)

Pancreatic Injury

Description

I II Ill IV V

Contusion Stellate fragmentation Partial fracture Complete transection Pseudocyst

Diffuse or focal swelling of the pancreas Fluid or blood dissecting within pancreatic parenchyma Incomplete separation of two portions of the pancreas Complete separation of two portions of the pancreas Persistent peripancreatic fluid collection

14 2 1 8 3

I

I

Data from references 75, 125, 144.

San Diego (OR = 40%)17

initiation of oral feeding was 15 days (11 days for group 1, 15 days for group 2, and 23 days for group 3). Mean hospital stay for all patients treated nonoperatively was 21 days. A comparison of the San Diego and Toronto protocols is depicted in Figure 17-16. The striking differences in these series are the 100% diagnostic sensitivity of CT in Toronto versus 69% in San Diego and the 44% operative rate in San Diego versus 0% in Toronto. A subsequent study from Toronto reviewed the follow-up on 10 patients Four of these children (40%) with duct tran~ecti0ns.l~~ developed pseudocysts, three of which were drained percutaneously (Fig. 17-17). The mean hospital stay was 24 days, and all recovered. Follow-up CT in eight of nine patients revealed atrophy of the distal pancreas in six and completely normal glands in two. There was no exocrine or endocrine dysfunction in a mean of 47 months of follow-up. The authors concluded that following nonoperative management of pancreatic blunt trauma, atrophy (distal) or recanalization occurs in all cases with no longterm morbidity. Reports from Dallas and Seattle favor early distal pancreatictomy for transection to the left of t'he spine to shorten hospital stay.81p83However, long-term seq;elae of adhesive intestinal obstruction and endocrine and exocrine dysfunction were not assessed. Other reports document the efficacy of magnetic resonance pancreatography as a diagnostic tool, early ERCP intervention for diagnosis and treatment with ductal stenting, and the use of somatostatin to decrease pancreatic secretions and proOf note, a large singlecenter mote healing.12,51~65~111,130 series from Japan reported nonoperative management in 19 of 20 children with documented pancreatic injury (9 contusions, 6 lacerations, and 5 main duct disruptions).67 In all cases, recovery was complete witho;t surgery. That center's experience with pseudocyst formation and treatment and overall outcome virtually mirrors that of the Toronto report. These reports from major pediatric trauma centers are clearly in conflict. Some favor and document the efficacy and safety of observational care for virtually all pancreatic injuries, including duct disruption; others advocate aggressive surgical management with debridement or resection. Because proponents supply compelling data for each of these treatments, algorithms reflecting individual hospital or surgeon preference will probably determine which treatment plan is selected. However, it is clear that with simple transection of the pancreas at or to the left of the spine, spleen-sparing distal pancreatectomy

N=18*

-1

CT scan

Positive = 11 : Negative = 5

I

J.

ERCP with stent = 2

Distal pancreatectomy = 8

Pseudocyst = 7

Cystogastrostomy = 5

Resolved = 2

A

* 1 death. unrelated Toronto (OR = 0%)126

Contusion= 14

Transection = 11

Pseudocyst = 3

4

Pseudocyst = 10

B

$.

Resolved = 4

$.

Drained = 5; Aspiration = 1

a Comparison of protocols in the management of blunt pancreas injury in children. A, San Diego. B, Toronto. CT, computed tomography; ERCP, endoscopic retrograde cholangiopancreatography; OR, operating room. (A, from Canty TG Sr, Weinman D: Management of major pancreatic duct injuries in children.J Trauma 2001;50:1001-1007.B, from ShilyanskyJ, Sen LM, Kreller M, et al: Nonoperative management of pancreatic injuries in children. J Pediatr Surg 1998;33:343-345.)

310

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INJURIES OFTHE STOMACH, SMALL INTESTINE, AND COLON

, -

Contrast study through a percutaneous drain

placed into a pancreatic pseudocyst (arrowhead) after blunt trauma in a child. Communication with the main pancreatic duct (arrow) is demonstrated. The pseudocyst resolved without fistula formation or operative intervention.

can provide definitive care for this isolated injury, with short hospitalization and acceptable morbidity (Fig. 17-18). With this controversy in mind, we favor conservative therapy whenever possible, including the following:

1. Early spiral CT with oral and intravenous contrast in all patients who, by history, physical examination, or mechanism of injury, may have blunt trauma to the pancreas. 2. Documentation of injuries and early ERCP to provide duct stenting in selected cases. 3. Nonoperative management with total parenteral nutrition. 4. Expectant management of pseudocyst formation. 5. Percutaneous drainage for symptomatic, infected, or enlarging pseudocyst.

.

-

Spleen-sparing distal pancreatectomy. (Original

illustration by Mark Mazziotti, MD.)

Injuries to the stomach, small intestine, and colon are easier to diagnose and manage than those previously discussed. In blunt trauma there are three different mechanisms that cause distinct patterns of injury to these organs. First is a crush injury that occurs as the stomach, jejunum, ileum, or transverse colon is compressed violently against the spine. Hematomas, lacerations, or partial or complete transections can occur, with instantaneous or delayed perforation or obstruction. Second, burst injury occurs when rapid compressive forces are applied to a filled and distended hollow viscus, without direct mechanical compression. Shoulder- and seat-belt injuries to the GI tract can occur in this fashion. Third is shear injury caused by rapid acceleration-deceleration of an organ that is tethered at one end, such as the ligament of Treitz, ileocecal region, or rectosigmoidjunction. With deceleration, the injury is caused by the tearing of tissue at the point of fixation. Regardless of the mechanism of injury, a perforated viscus causes rapid contamination of the abdominal cavity. On the initial trauma assessment, virtually all neurologically intact patients have some symptoms (pain) and physical findings (tenderness, guarding, rebound). In fact, many reports have documented that the initial and serial physical examinations have a higher degree of diagIn nostic specificity than US or CT for these injuries.2"~O~gl a series from New Mexico reporting 48 patients with small bowel injury, all conscious patients had abnormal physical findings either on presentation or after serial physical examinations.91 Other diagnostic tests (US, CT, DPL, lab tests) were of comparatively less value. These findings were confirmed by a similar series from North Carolina involving 32 children with intestinal injury confirmed at laparotomy; 94% had physical findings suggestive of intestinal injury on admission, with 84% having diffuse abdominal tenderness (peritoneal signs) .60 Prompt diagnosis of these injuries is possible when free air and GI contrast extravasates into the abdominal cavity at the time of the initial injury. However, when partial-thickness lacerations, hematomas, or avulsed mesenteric blood vessels occur, progression to full-thickness defects with leakage can be delayed over hours to days (Fig. 17-19). A high index of suspicion is indicated, along with the liberal use of serial physical examinations. Injuries to the stomach and small intestine are straightforward to repair. A full stomach usually ruptures at the greater curvature with a blowout or stellate configuration. Debridement with direct repair is virtually always sufficient. Small intestinal injuries run the gamut from simple laceration to transection to complete avulsion with larger segments of compromised bowel. However, unless the contamination is massive (or other injuries require extensive repair), debridement or resection with anastomosis is usually sufficient. In colon injures, particularly if there is a delay in diagnosis and significant fecal contamination, colostomy with a defunctionalized distal mucous fistula or Hartmann's pouch is in order. If isolated colon injuries occur and are repaired

CHAPTER

.

-

Small bowel mesentery avulsion with ischemic bowel.

early, on-table bowel irrigation, bowel anastomosis, and perioperative antibiotic coverage are safe and effective and avoid the complications caused by stomas and reoperation. The critical factors with injuries to the intraperitoneal GI tract are early recognition of the injury; prompt resuscitation; expeditious surgery, with complete removal of contaminated and devitalized tissue; reconstruction or diversion of the GI tract, as clinically indicated; and broad-spectrum antibiotics, with the duration of therapy dependent on the degree of contamination and postoperative clinical course (e.g., normalization of white blood cell count, absence of fever, return of GI tract function).

17

Abdominal Trauma

31 1

Multiple studies have documented increased abdominal injuries to both solid and hollow organs with this finding.18,131,148 An interesting triad of injuries has been noted: abdominal wall contusions or herniation, Chance fractures of the lumbar spine, and isolated jejunal or ileal perforations. One report reviewed 95 patients admitted with abdominal trauma, all of whom were wearing seat belts at the time of injury; in 60 of 95 there was a seat-belt sign.148Nine of the 60 patients with the seat-belt sign had intestinal injuries, compared with none of the 35 without the seat-belt sign. The more common injuries described earlier can distract both the patient and the trauma team, causing delay in the diagnosis of serious vascular injuries involving the aorta and iliac vessels.94J07 In recent reports from Philadelphia, a database created by the State Farm Insurance Company was used to review 147,985 children who were passengers in motor ~ , ~series, ~ 1967 children (1.33%) vehicle c r a ~ h e s .In~ that had abdominal bruising from seat-belt restraints. Although abdominal wall bruising was infrequent, those with this finding were 232 times more likely to have a significant intra-abdominal injury than were those without a bruise. These data further revealed that 1 of 9 children with an abdominal seat-belt sign had a significant intraabdominal injury. Therefore, although the seat-belt sign is rare, CT scanning (admission and serial) is mandated when it is present. Optimal (n = 881) and suboptimal (n = 1086) use of seat-belt restraints was noted. After adjusting for age and seating position, optimally restrained children were more than three times less likely (odds ratio 3.51) than suboptimally restrained children to suffer an abdominal injury.

Imaging for Gastrointestinal Injury Seat-Belt Sign Frequent physical examinations and vigilance are required for the subset of injuries caused by lap-belt restraints when children are passengers in high-speed automobile crashes.2Vhese children present with visible seat-belt signs on physical examination of the abdomen (Fig. 17-20).

.

Seat-belt sign across the lower abdomen

Imaging of the GI tract has evolved over the past decade, with spiral CT or FAST examinations done by surgeons in the emergency department directly impacting diagnostic accuracy and decision making. Some of the strengths and weaknesses of CT diagnosis have already been discussed. However, the ability to diagnose and treat blunt abdominal trauma in children has clearly been enhanced by this modality. Two studies from Toronto examined these issues. The first, in 1992, reviewed 12 patients with blunt abdominal trauma evaluated by CT." It found that bowel wall enhancement was a sign of either global GI tract ischemia associated with fatal central nervous system injury or, when seen with bowel wall thickening and free peritoneal fluid, bowel perforation. A follow-up study in 1996 reviewed 43 patients evaluated over 10 years with surgically confirmed GI tract perforaair was seen in 47%, with one t i ~ n Extraluminal . ~ ~ false-positive. Five CT findings were found to be suggestive but not diagnostic of GI tract perforation: extraluminal air, free intraperitoneal fluid, bowel wall thickening, bowel wall enhancement, and bowel dilatation. In every patient who had all five of these findings, bowel perforation was confirmed. However, this occurred in only 18% of the study population. All patients had at least one of these five specific CT findings. There were no false-negative studies.

312

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As mentioned previously, although CT scanning is a reliConversely, injuries sustained by sexual abuse are comable modality for assessing GI tract perforations, it monly rectal or vaginal penetrations from violent, should not replace and does not improve on diligent nonconsensual acts or the purposeful insertion of serial clinical evaluations. A similar study from Calgary objects into these orifices. Therefore, when examining a reviewed 145 children with blunt abdominal t r a ~ m a . ~ 7 child with injuries to the perineum, isolated rectal or CT scans were interpreted as positive for GI tract injury vaginal trauma should always be considered child abuse in 20 and negative in 152 (several children had more until proved otherwise; conversely, polytrauma to the than one study). The sensitivity of abdominal CT scan perineum with genital, perineal, and anal involvement is was determined to be 0.93 for mesenteric or intestinal typically accidenta1.62JlO Diagnosis of the extent of perineal injury frequently injuries requiring surgery, with a negative predictive requires examination under anesthesia by means of procvalue of 0.99 in this study population. Therefore, CT toscopy, sigmoidoscopy, and retrograde urethrogram. rarely misses significant mesenteric or intestinal injuries. The significance of isolated free intraperitoneal fluid After assessing the degree of injury, surgical strategies include repair of urethral injuries (directly or via stentin the absence of solid organ injury has frequently been heralded as a sign of intestinal trauma. Hulka et al.58 ing), urinary diversion with a suprapubic cystostomy, reported a series of 259 CT scans (all with oral and intrarepair of rectal tears, rectal irrigation, placement of drains venous contrast) and found only 24 patients (9%) with when required, and, in more complex injuries, fecal isolated free intraperitoneal fluid. Among the 16 patients diversion by colostomy. After recovery, detailed radiologic with only a "small amount" of isolated fluid, only 2 confirmation of complete healing (e.g., by intravenous pyelogram, cystogram, urethrogram, contrast enemas) required laparotomy. However, 4 of 8 patients (50%) with fluid in more than one location had a bowel injury must be performed before reconstruction of fecal contirequiring exploration. These authors also noted that nuity or removal of urinary stents or urinary undiversion. enteral contrast is rarely present to aid in the diagnosis of Although rare, pediatric fatalities have been reported bowel injury. Similar findings were reported by Holmes with rectal impalement from abuse.102 Neonatal rectoet a1.,55 with small quantities of intraperitoneal fluid vaginal injuries have also been reported as an infrequent having little clinical significance. In their report, only but life-threatening complication of traumatic delivery.74 However, more commonly, rectal insertion of thermome8% of abdominal CT scans were positive for isolated ters, Hegar dilators, or enema tubes can cause significant intraperitoneal fluid, and in only 17% of these cases was there an identifiable injury. This represented only 7 of rectal injuries in newborns, requiring surgical repair. the 542 children (1.3%) studied. We recently treated a 3-day-old infant with perforation of Finally, FAST was found to be useful as a screening the rectosigmoidjunction from frequent enemas required tool, with high specificity (95%) but low sensitivity (33%) for the treatment of obstipation from cystic fibrosis; in evaluating intestinal injury.lO3 In that study of 89 FASTlaparotomy and colostomy were required. Therefore, in negative children, only 20 went on to have CT scans newborns, apparently innocuous rectal manipulation can performed, all at the surgeon's request. Without this cause severe injuries requiring surgical evaluation and finding, they all might have had abdominal CT scans. intervention. Clearly, FAST can decrease the number of unnecessary CT scans performed, but it cannot detect the specific abdominal organs injured. FAST is therefore of limited DIAPHRAGMATIC INJURIES value in assessing these injuries. Finally, to come full Traumatic injury to the diaphragm is infrequently circle, in a large study from Pittsburgh, 350 children with observed, even at the largest pediatric trauma centers. abdominal trauma were reviewed, with 30 requiring At Children's Hospital of Illinois, only two traumatic laparotomy (8.5%).3There were five false-negative CT diaphragmatic injuries were treated from 1998 to 2002 scans (26%) in 19 patients who underwent delayed laparotomy (3.5 hours or longer after injury). Those out of more than 800 admissions requiring level I pediatric trauma evaluation. At the Hospital for Sick authors concluded that serial physical examination, not CT scanning, is the gold standard for diagnosing GI tract Children in Toronto, only 15 children with this injury perforations in children. We concur. were seen from 1977 to 1998.66J09In a similar report covering 1992 to 2002 at Denver Children's Hospital, 1397 children were admitted and observed for blunt abdominal trauma, 387 had intra-abdominal injuries, but there INJURIES TO THE PERINEUM, ANUS, were only 6 diaphragmatic ruptures (0.5%).9The injury AND GENITALIA is caused by massive compressive forces to the abdominal Children present with injuries to the perineum, anus, cavity, creating acceleration of abdominal contents cephaand external genitalia primarily from two mechanisms: lad, rupturing the diaphragmatic muscle. Occasionally, accidental falls and sexual abuse. Accidental injuries are penetrating trauma causes this injury; however, in these sustained by falling onto blunt or sharp objects in a stradcases, the injury is often found incidentally at explodled fashion. These injuries are characterized by bruising, ration for other injuries. In the series reported from contusion, laceration, or penetration, depending on the Toronto, 13 of 15 patients had diaphragmatic rupture object struck and the height of the fall. Accidental from blunt trauma; the mean age was 7.5 years, with the injuries frequently involve the external genitalia, urethra, right and left diaphragm equally involved.lO9 The diagnoperineal body, and anus but rarely involve the rectum. sis was made with only a chest radiograph in more than

CHAPTER

half the patients. T h r e e injuries were missed a t t h e initial evaluation. Owing to t h e force required t o cause this injury, multiple associated injuries should b e expected. In this report, 81% of patients h a d multiple injuries, including liver laceration (47%),pelvic fracture (47%), major vascular injury (40%),bowel perfusion (33%),long bone fracture (20%),renal laceration (20%),splenic laceration (13%),a n d closed head injury (13%).As expected, ive a n d a mean there were many ~ o m ~ l i c a t i o n s ~ fdeaths, hospital stay of 20 days. Emergent surgery i n children with this constellation of associated injuries should include palpation of both diaphragms as routine part of the abdominal exploration. Direct suture repair is usually possible after debridement of any devitalized tissue. Pledgeted sutures can b e used to buttress the repair a n d prevent tearing of t h e muscle, making the closure m o r e secure. If sufficient diaphragm tissue is destroyed, a tension-free closure with a 2-mm Gore-Tex patch can b e used, similar to t h e repair of congenital diaphragmatic hernias i n newborns. Reports of laparoscopic o r thoracoscopic repair of this injury include delayed repairs on stable patients without associated i n j u r i e ~ . ~Delayed ~J~~ diagnosis of this injury in infants has b e e n reported; as has renal avulsion into t h e chest through a traumatically ruptured diaphragm.27,129,137Owing to the infrequent presentation of this injury, o n e must have a high index of suspicion when the mechanism of injury a n d t h e degree a n d location of o t h e r injuries support t h e possibility of diaphragmatic injury.

a

SUMMARY Recent advances i n the treatment of trauma a n d the provision of critical care i n children have resulted i n improved outcomes following major injuries. It is imperative that pediatric surgeons familiarize themselves with c u r r e n t t r e a t m e n t algorithms f o r life-threatening abdominal trauma. Important contributions have been made in the diagnosis a n d treatment of children with abdominal injury by radiologists a n d endoscopists. Clinical experience a n d published reports addressing specific concerns about t h e nonoperative treatment of children with solid organ injuries a n d recent radiologic a n d endoscovic contributions have m a d e vediatric trauma care increasingly nonoperative. Although the trend is i n this direction, t h e pediatric surgeon should remain the physician of record i n the m u l ~ d i ~ c i ~ l i n a r y care of critically injured children. T h e decision n o t t o operate is always a surgical decision.

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25. Cloutier DR, Baird TB, Gormley P, et al: Pediatric splenic injuries with a contrast blush: Successful nonoperative management without angiography and embolization. J Pediatr Surg 2004;39:969-971. 26. Cogbill TH, Moore EE, Jurkovich GJ: Severe hepatic trauma: A multicenter experience with 1335 liver injuries. J Trauma 1988;28:1433-1438. 27. Cohen Z, Gabriel A, Izrachi S, et al: Traumatic avulsion of kidney into the chest through a ruptured diaphragm in a boy. Pediatr Emerg Care 2000;3:180-181. 28. Cooper A, Barlow B, DiScala C, et al: Mortality and truncal injury: The pediatric perspective. J ~ e d i a t rSurg 1994; 29:33-38. 29. Cuschieri A, Hennessy TP, Stephens RB, et al: Diagnosis of si~nificant abdominal trauma after road traffic accidents: " Preliminary results of a multicentre clinical trial comparing mini-laparoscopy with peritoneal lavage. Ann R Coll Surg Engl 1988;70:153-155. 30. Davies MRQ: Iatrogenic hepatic rupture in the newborn and its management by pack tamponade. J Pediatr Surg 1997;32:14141419. 31. DeCou JM, Abrams RS, Miller RS, et al: Abdominal compartment syndrome in children: Experience with three cases. J Pediatr Surg 2000;35:840-842. 32. Denton .JR, Moore EE, Codwell DM: Multimodality treatment for grade V hepatic injuries: Perihepatic packing, arterial embolization, and venous stenting. J Trauma 1997;42:964968. 33. Desai KM, Dorward IG, Minkes RK, et al: Blunt duodenal injuries in children. J Trauma 2003;54:640-646. 34. Epelman M, Soudack M, Engel A, et al: Abdominal compartment syndrome in children: CT findings. Pediatr Radio1 2002;32:319-322. 35. Eubanks JW, Meier DE, Hicks BA, et al: Significance of "blush" on computed tomography scan in children with liver injury. J Pediatr Surg 2003;38:363-366. 36. Evans S, Jackson RJ, Smith SD: Successful repair of major retrohepatic vascular injuries without the use of shunt or sternotomy. J Pediatr Surg 1993;28:317-320. 37. Fabian TC, Croce MA, Stewart RM, et al: A prospective analysis of diagnostic laparoscopy in trauma.- Ann Surg 1993;217:557-565. 38. Fallat ME, Casale AJ: Practice patterns of pediatric surgeons caring for stable patients with traumatic solid organ injury. J Trauma 1997;43:820-824. 39. Fang JF, Chen RJ, Ling BC: Controlled reopen suture technique for pyloric exclusion. J Trauma 1998;45:593-596. 40. Fisher JC, Moulton SL: Nonoperative management and delayed hemorrhage following pediatric liver injury. J Pediatr Surg 2004;39:619-622. 41. Frumiento C, Sartorelli K, Vane DW: Complications of splenic injuries: Expansion of the nonoperative theorem. J Pediatr Surg 2000;35:788-791. 42. Frumiento C, Vane DW: Changing patterns of treatment for blunt splenic injuries: An 11-year experience in a rural state. J Pediatr Surg 2000;35:985-989. 43. Gaines BA, Shultz BS, Morrison K, et al: Duodenal injuries in children: Beware of child abuse. J Pediatr Surg 2004;39:600-602. 44. Gandhi RR, Stringel G: Laparoscopy in pediatric abdominal trauma. JSLS 1997;1:349-351. 45. Ginzburg E, Klein Y, Sutherland M, et al: Prolonged clamping of the liver parenchyma: A salvage maneuver in exsanguinating liver injury. J Trauma 2004;56: 922-923. 46. Goettler CE, Stallion A, Grisoni ER, et al: Delayed hemorrhage after blunt hepatic trauma. J Trauma 2002;52: 556-559.

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Genitourinary Tract Trauma Rebeccah L. Brown and Victor F. Garcia

EPIDEMIOLOGY Injury is the leading cause of death in children and young adults in the United States, with injury to the kidney from either blunt or penetrating trauma being the most common genitourinary tract injury.2l,l22Almost 50% of genitourinary tract injuries involve the kidney.lZ1 Blunt abdominal trauma is responsible for 90% of pediatric genitourinary tract injuries," with the kidney being injured in 10% to 20% of all blunt trauma cases.121J22 The kidney is the most commonly injured solid organ, injured more frequently than the liver, spleen, Serious renal injuries are most often or pan~reas.2~8~3J30 associated with injuries to other organs, with multiple organ involvement occurring in 80% of those with penetrating trauma and 75% of those sustaining blunt trauma.'% The majority of associated injuries are closedhead injuries a n d extremity fractures.7~43J45Associated abdominal injuries occur in 42% to 74% of patients, primarily involving the spleen and liver in blunt trauma The and the bowel in penetrating trauma.102,104,122,179,182 majority of isolated renal injuries can be classified as relatively minor injuries.40 Mortality is rare due to isolated renal trauma and is more often attributed to the combined effects of major multisystem trauma.

however, violent deceleration with severe flexion-extension as seen with seatbelts is a well-recognized mechanism of renal injury associated with a higher risk of renal pedicle avulsion and ureteropelvic junction (UPJ) injury. Interestingly, bicycle crashes are the most common sports-related cause of renal injury in children and are associated with a significant risk of high-grade renal injury.75Although there is a perception among pediatric surgeons and urologists that contact sports such as football, hockey, and martial arts incur the greatest risk for renal injury in children,l75 a review by McAleer and c0lleaguesl2~ demonstrated that bicycle crashes accounted for 24% of injuries compared with only 5% for contact sports. This may have some impact on the type of counseling that should be provided regarding activity for children after severe renal injury and for those with solitary kidneys. Penetrating genitourinary tract injuries are becoming more common and should be suspected with any penetrating injuries to the chest, ~~ abdomen, flank, and lumbar r e g i 0 n s . 2 ~Iatrogenic injuries are uncommon and generally readily diagnosed. A significant risk of trauma occurs with needle puncture of the kidney for biopsy or endourologic access; endoscopic access of the urethra, bladder, or ureter; and procedures done on viscera adjacent to the genitourinary system. The most common iatrogenic injury is to the ureter during gynecologic and oncologic procedures.

MECHANISMS OF INJURY Most blunt renal injuries are due to sudden deceleration forces. Confined within Gerota's fascia, the kidney may be crushed against the ribs or the vertebral column, resulting in laceration or contusion. Direct injury to the renal parenchyma and collecting system may also occur from penetration of sharp, bony fragments of adjacent fractured ribs. Rawid deceleration mav cause arterial or venous injury from stretching of the fixed renal vascular pedicle.Z1 Because the intima of the renal artery is less elastic than that of the media and adventitia, it is predisposed to laceration, which may lead to subintimal dissection and arterial thrombosis.69 Mechanisms of blunt renal injury include pedestrian/motor vehicle crashes (60%),falls (22.5%),sports injuries (lo%),assault (3.5%), and other causes (4%).17jMost children who sustain renal injury in motor "chicle accidents are unrestrained122;

ANATOMIC CONSIDERATIONS Children are considered to be at increased risk for genitourinary tract trauma owing to unique anatomic differences between children and In children, the kidneys are larger relative to the size of the child's body and positioned lower in the abdomen, making them more exposed and vulnerable to injury. They are also less protected because of decreased perirenal fat, weaker abdominal wall musculature, and a poorly ossified thoracic rib cage. Because many pediatric kidneys retain their fetal lobulations, the risk for renal parenchymal disruption and lower pole amputation is increased. Furthermore, the renal capsule and Gerota's fascia are less developed than in adults, creating a greater potential for laceration, nonconfined bleeding,

r

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and urinary extravasation. Because of the relative mobility of a child's kidney, rapid deceleration is more likely to result in renal pedicle injury and UPJ disruption. In a comparative series of children and adults who sustained blunt renal trauma, Brown and colleagues21 concluded that although the likelihood of major renal injury was significantly higher in the pediatric population, the severity of trauma was significantly lower. For similar reasons, preexisting renal disease or congenital renal anomalies may predispose children to an increased risk of genitourinary tract injury from blunt trauma. The reported incidence of preexisting renal disease or congenital genitourinary anomalies in children sustaining renal trauma varies from 1% to 23%.19,"345,67,1*1,122,1352146 Underlying congenital anomalies associated with hydronephrosis (UPJ obstruction), abnormal kidney position (horseshoe kidneys, crossed fused renal ectopia), or abnormal kidney consistency (polycystic kidney disease, urinary reflux) may predispose the kidney to significant injury despite relatively minor f o r c e ~ . ~ W r o shematuria s associated with an ostensibly minor trauma should alert the physician to the possibility of an underlying pathologic lesion of the urinary tract and should prompt further radiologic imaging. Although underlying congenital genitourinary anomalies may have an increased risk of injury in children, they do not appear to be associated with any increased morbidity or long-term disability.lZ3

and disruption of the UPJ have both been described in the absence of hematuria. 14.3"38.43,131 ,I 58,166,'79 Whereas fractures of the lower ribs and lumbar spine mav be associated with renal trauma. fractures of the may be associated with bladder and urethral injuries. Eight percent of patients with a pelvic fracture have associated lower urinary tract injuries. The comparative incidence of lower urinary tract injury with various types of pelvic fractures is 27% in patients with symphysiolysis, 17% in patients with pelvic fracture, and 2% in uatients with a fracture of the uubis.196 In a study by Aihara and associate^,^ certain types of pelvic fractures were found to be associated with increased risk for rectal, bladder, or urethral injuries. Rectal injury was associated with widening of the symphysis p6bis. Bladder injuries were most commonly associated with widening of the sacroiliacjoint, symphysis pubis, and fractures of the sacrum, with widening of the symphysis pubis being the strongest predictor of bladder injury. Urethral injuries were most commonly associated with widening of the symphysis pubis and fractures of the inferior pubic ramus. Fractures involving these locations should heighten suspicion of associated rectal and lower urinary tract injuries and prompt directed diagnostic studies. Gross hematuria in the presence of a pelvic fracture strongly suggests a bladde; perforation. kny degree of hematuria in the presence of a pelvic fracture is an indication for cystography. Ninety-five percent of patients with bladder injuries have gross hematuria, and the remaining patients have microscopic hematuria.

CLINICAL FEATURES The evaluation of possible injury to the genitourinary tract is a part of the systematic and expeditious assessment required in all seriously injured patients. The mechanism of injury is important to know in order to assess the risk of injury. Direct blows to the abdomen or flank and significant deceleration forces as may occur in motor vehicle accidents and falls should alert the physician to the possibility of renal injury. Penetrating injuries to the abdomen, flank, back, chest, and pelvis should also raise suspicion for injury to the genitourinary tract. Although the presence of abdominal or flank tenderness and flank ecchymosis or mass suggests renal injury, up to 25% of patients with severe renal injury have unremarkable abdominal examinations. Indeed, only 55% of children with significant renal injuries present with tenderness over the injured kidney. Conversely, only about half of children with renal tenderness on examination have a condition more serious than minor renal trauma.lG7 Perineal ecchymosis, swelling, laceration, and bleeding are highly suggestive of genitourinary trauma. The presence of blood at the urinary meatus or a boggy mass or upward displacement of the prostate on digital rectal examination in boys requires formal urethrography to evaluate for possible injury to the urethra before any attempts at urethral catheterization. Gross hematuria is indicative of genitourinary trauma and mandates further radiologic imaging. Conversely, the absence of hematuria, either gross or microscopic, does not exclude the possibility of significant genitourinary trauma. In fact, complete avulsion of the renal vascular pedicle

DIAGNOSTIC EVALUATION A urine sample should be obtained in all trauma patients to assess for potential injury to the genitourinary tract. Gross hematuria is highly indicative of trauma to the genitourinary tract, a1t.hough it does not necessarily correlate with severity of injury. In the absence of gross hematuria, the urine dipstick is a safe and reliable method to screen for the presence of hematuria. The false-positive rate is 4.3%.58Dipstick results that are negative for hematuria do not need the added expense of microscopic analysis. However, if hematuria is revealed by dipstick evaluation, the suecimen should be examined microscopically for more accurate quantification.44.58It should be noted that microscopic hematuria can be associated with such procedures as atraumatic passage of a urethral catheter. However, in this instance, the degree of hematuria is minimal, and more than 5 red blood cells (RBCs) per high-powered field (HPF) should be considered abn0rmal.~~J78 A critical issue in the management of suspected genitourinary tract injury is the need for and extent of radiographic evaluation. Although most would agree that gross hematuria is an indication for formal diagnostic evaluation, much controversy exists as to whether microscopic hematuria as an isolated finding on urinalysis in pediatric trauma patients warrants further radiologic imaging." It remains unclear what degree of microscopic hematuria, if any, warrants radiographic evaluation in children. *See references 7,8,22,30,71,90,91, 102,112,114,121,133,140, 145, 167,170, 174, 182, and 183.

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18

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319

CT has replaced the intravenous pyelogram (IVP) Several studies have a t t e m ~ t e dto answer the cluestion as in the hemodynamically stable patient. However, a oneto whether the adult criteria for imaging of renal trauma, shot IVP still remains useful in the hemodynamically including findings of gross hematuria, shock, major unstable patient before emergent surgical exploration associated injuries, and significant deceleration injury, to determine the presence of two functional kidneys, can be applied to children. &though degrees of microhematuria ranging from any degree of rnicrohematurial12Js3 the presence and extent of urinary extravasation, and to 20 RBCs per HPFS1 to 50 RBCs per HPF14j have been the presence of renal pedicle injury. In children, 2 to reported assignificant in the literature, a careful analy3 mL/kg of nonionic contrast is injected intravenously, sis of published reports on 382 children with renal followed by an abdominal radiograph immediately injuries reveals that the application of adult criteria for and 10 minutes later.133It should be recognized that the IVP provides only very basic information and is not imaging would have identified 98% to 100% of all renal ini~ries.l7~ useful in staging of renal injuries. In fact, some studies ., It is generally accepted that abdominal trauma assohave shown that as many as 20% of patients with significant renal injuries will have a normal IW.Likewise, ciated with shock warrants radiographic evaluation of nonvisualization of the kidney on IVP does not necessarily the genitourinary system. several- a;thors have found correlate with arterial occlusion or injury. Other factors, that young adults with a history of blunt trauma and microscopic hematuria without shock, associated major including renal contusion with vascular spasm, overhydraintra-abdominal injuries, or a history of rapid deceleration tion, and hypotension or hypoperfusion, may produce similar findings in up to half of patients.48 can be managed safely without renal imaging.29,128,138,152 However, up to 25% of patients with any degree of Arteriography has been largely supplanted by CT hematuria and shock have significant renal and CT angiography for the diagnosis and staging of One of the pitfalls in applying adult criteria for the renal injury. More invasive than CT, arteriography imaging of renal trauma to children, especially with requires the expertise of an experienced interventional regard to the presence or absence of shock, is that chilradiologist and may be associated with a formidable dren are unique in their ability to maintain normal risk for arterial injury in small children whose vessels blood pressure in the face of significant hypovolemia may be prohibitively small, fragile, and difficult to access and blood loss. In fact, only 5% of children with major or cannulate. The current role of arteriography is in Therefore, renal injury have clinical signs of sho~k.lOl,l6~ the diagnosis of delayed or ongoing renal hemorrhage, hypotension itself is not a reliable indicator of the renovascular injury, or delayed arteriovenous fistula or seierity of renal injury in the pediatric p ~ p u l a t i o n . l ~ ~ ,pseudoaneurysm l~~ formation where interventional techor niques such as selective embolization61,64,93,116,137,184 Tachycardia typically precedes hypotension as an early endovascular stenting23J1IJ" may be therapeutic. indicator of shock in children and may be a worrisome Ultrasound, although utilized extensively in Europe sign. Accordingly, the decision on imaging in children, for the assessment of acute renal trauma, has not found as in adults, should be based not on isolated findincs u but rather on the whole clinical picture, including widespread acceptance in the United States. In the mechanism of injury (direct blow, major deceleration, United States, ultrasonography in the trauma patient or flexion-extension injury), vital signs (tachycardia or is mostly limited to the Focused Assessment with Sonography for Trauma (FAST) examination, which is hypotension), physical examination findings (abdominal/ performed primarily to detect the presence of free flank tenderness or contusion), urinalysis (microhemaintraperitoneal fluid. The FAST examination has not turia or gross hematuria), and associated injuries. In most cases, microhematuria is not an isolatedVfinding. Most been particularly useful in children except perhaps in children with microhematuria will have some other paramthe hemodynamically unstable patient with an associated eter, such as mechanism of injury, physical findings, or closed-head injury to rapidly exclude the presence of intraabdominal hemorrhage. In the hemodynamically stable other associated injuries, that would warrant further imagchild, CT provides more useful information. Ultrasound ing, therefore decreasing the likelihood of missed injury. Abdominal computed tomography (CT) is the stanis not particularly sensitive for detecting parenchymal dard for radiographic evaluation of abdominal trauma in injuries, except in the most experienced hands, and only with close color and pulsed Doppler interrogation can a children and is the most accurate imaging and staging CT is modality for evaluation of renal inj~ry.ls,l02,~2~,20~ vascular injury be diagnosed. Therefore, its utility in the highly sensitive and specific for detection of parenchymal acute setting at present remains quite limited. contusions/lacerations, perinephric/retroperitoneal It is critical to remember that CT and IVP are not hematoma, urinary extravasation, and segmental or major sensitive for bladder laceration unless the bladder is arterial injuries; delineation of nonviable, nonperfused fully distended. Haas and coworkerss6 compared the accuracy of routine helical CT versus conventional tissue or segmental infarction; and demonstration of cystography in 15 patients with suspected bladder injury. other associated intra-abdominal injuries. With the advent Cystography accurately diagnosed and classified the of the newer, faster helical CT scanners, it is essential injury in all 15 patients, whereas CT was only about to obtain delayed images during the nephrogram 60% accurate. Consequently, cystography is the imaging phase (>80 seconds) to detect renal parenchymal and venous injury as well as during the excretory phase modality of choice when bladder injury is suspected. (2 to 10 minutes) to avoid missing urine or blood For conventional cystography, after a scout film is extravasation. Extravasated urine accumulates, whereas obtained, a small amount of contrast medium is infused, extravasated arterial contrast dilutes out after the bolus followed by a second radiograph to check for gross of contrast agent is stopped.l"J76 extravasation. If gross extravasation is seen, a Foley

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catheter is inserted and placed to drainage. If extravasation is not seen, then the remainder of the contrast medium is instilled and radiographs are obtained in the anteroposterior, oblique, and lateral projections. It is essential for the bladder to be fully distended to avoid missing small-to-moderate tears of the bladder wall. The bladder of adolescents should be filled with 300 to 400 mL of contrast medium. The bladder of smaller children should be filled by gravity infusion until the patient becomes uncomfortable or the bladder capacity is reached. In children younger than 2 years of age, the bladder capacity is 7 mL x weight (kg). In children 2 to 11 years of age, the bladder capacity is age in years plus 2 x 30 mL.68,106 As part of the cystogram, all the contrast medium is drained from the bladder and a wostevacuation radiograph is taken. Up to 15% of extraperitoneal bladder ruptures are identified only on the radiograph taken after evacuation. The extent of extravasation seen with extra~eritoneal bladder rupture may be limited to the pelvic area or be quite dramatic, extending into a pelvic hematoma or coursing along the lateral pelvic wall. Extravasation from an intraperitoneal bladder rupture flows into the peritoneum, outlining the bowel with contrast agent. More recently, CT cystography has been found to be faster and equally accurate for defining and staging bladder injuries provided that the basic principles for conventional cystography, including complete distention of the bladder and imaging both before and after evacuation, are followed. ~ i k p i yclamping a Foley catheter after intravenous contrast agent administration for CT is not adequate and will result in an unacceptably high rate of missed inj~ries.fl3J5~ Retrograde pyelography plays a role in the assessment of ureteral and renal pelvic integrity when UPJ injury is suspected. Failure of opacification of the distal ureter on CT should raise suspicion for a ureteral injury187; and if insufficient detail is provided by CT, then retrograde pyelography is indicated. Retrograde urethography is indicated when urethral injury is suspected. A Foley catheter with a minimally inflated balloon is inserted into the fossa navicularis of the distal urethra, and approximately 30 mL of vision. contrast medium is instilled under fluorosco~ic I A normal retrograde urethrogram should demonstrate complete filling of the intact urethra with passage of contrast medium into the bladder. The presence of filling defects or extravasation of the contrast agent indicates urethral disruption. In the presence of hematuria, a cystogram should follow the retrograde urethrogram, even if the retrograde urethrogram is normal, because 10% to 15% of watients with urethral disruption from a pelvic fracture will have a concomitant bladder injury.48

INJURY GRADING AND SCORING SYSTEMS FOR GENITOURINARY INJURIES In 1989, the American Association for the Surgery of Trauma (AAST) Injury Scaling Committee devised and published a classification or grading system for

genitourinary tract injuries (Table 18-1) to standardize injury descriptions for research and data collection purposes. Figure 18-1 is an illustrative depiction of this grading system. Injuries are graded on scale from I to V ranging from the most minor injury (grade I) to the most complex (grade V). For the kidney, this grading system has proved highly applicable, and a study by Santucci and associates173 of 2467 renal trauma patients validated its usefulness as a measure of the seriousness of renal injury and as a predictor of the need for surgery. For example, patients with a grade I injury require observation only, whereas those with a grade V injury are more likely to require nephrectomy. Those with intermediate injuries (grades I1 to IV) require individualized therapy, with a trend toward more invasive therapy as injury grade increases. It should be noted, however, that this study was composed primarily of adult patients. Thus, extrapolation of results from this series may not be entirely applicable to children. Furthermore, the AAST system has been criticized for grouping complex parenchymal injury with major renovascular injury in the grade IV and V categories, because management may be quite different for the same grades of injury. Modifications addressing this issue have been proposed for future iterations of the scaling system. The AAST scaling systems for ureteral, bladder, and urethral injury (see Table 18-1) have not gained as widespread acceptance and have been used less consistently.

MANAGEMENT OF SPECIFIC INJURIES Kidney Blunt Injuries As with traumatic injuries to the spleen and liver, the majority of blunt renal trauma in children can be safely managed nonoperatively.' Almost 85% of pediatric renal injuries are considered relatively minor, with grade I and I1 contusions and minor parenchymal lacerations predominating. These lower grade renal injuries will invariably heal without further sequelae. Major parenchymal injuries occur in 10% to 15%, whereas major disruption of the renal pedicle occurs in the remaining 5% of ~hildren.~8J79 Children with microscopic hematuria and a minor renal injury diagnosed and graded by CT may require brief hospitalization for observation or may be discharged home with clear follow-up instructions. Children with higher-grade renal injury by CT and/or gross hematuria are hospitalized and placed at bed rest with close monitoring of vital signs and serial physical examinations and blood cell counts. Traditionally, ambulation is begun once the patient is fully resusci;ated and hemodynimically stable, blood cell counts have stabilized, and gross hematuria has resolved. It is not unusual for patients with gross hematuria to occlude their bladder outlet or ~olefcatheterwith clot. Decreased urine output, bladder distention, or bladder spasms should alert the clinician *See references 2, 7, 8, 43, 88, 109, 112, 118, 120, 168, 171, 179, and 197

CHAPTER

18

Genitourinary Tract Trauma

Grade*

lnjury Description?

Renal lnjury Scale l Contusion Hematoma II Hematoma Laceration Ill Laceration IV Laceration Vascular V Laceration Vascular

Microscopic or gross hematuria; urologic studies normal Subcapsular, nonexpanding without parenchymal laceration Nonexpanding perirenal hematoma confined to the renal retroperitoneum <1 cm parenchymal depth of renal cortex without urinary extravasation >1 cm parenchymal depth of renal cortex without collection system rupture or urinary extravasation Parenchymal laceration extending through the renal cortex, medulla, and collecting system Main renal artery or vein injury with contained hemorrhage Completely shattered kidney Avulsion of renal hilum that devascularizes kidney

Ureter lnjury Scale l Hematoma II Laceration Ill Laceration IV Laceration V Laceration

Contusion of hematoma without devascularization 150% transection >50% transection Complete transection with 2 cm devascularization Avulsion of renal hilum that devascularizes kidney

Bladder lnjury Scale I Hematoma Laceration II Laceration Ill Laceration IV Laceration V Laceration

Contusion, intramural hematoma Partial thickness Extraperitoneal bladder wall laceration 1 2 cm Extraperitoneal (>2 cm) or intraperitoneal (12 cm) bladder wall lacerations lntraperitoneal bladder wall laceration >2 cm Intra- or extraperitoneal bladder wall laceration extending into the bladder neck or ureteral orifice (trigone)

Urethral lnjury Scale l Contusion II Stretch injury Ill Partial disruption IV Complete disruption V Complete disruption

321

Blood at urethral meatus; urethrography normal Elongation of urethra without extravasation on urethrography Extravasation of urethrographic contrast medium at injury site, with contrast visualized in the bladder Extravasation of urethrographic contrast medium at injury site without visualization in the bladder; <2 cm of urethral separation Complete transection with >2 cm urethral separation, or extension into the prostate or vagina

--

*Advance one grade for multiple injuriesto the same organ. tBased on most accurate assessment at autopsy, laparotomy, or radiologic study. From Moore EE, Shackford SR, Pachter HL, et al: Organ injury scaling: Spleen, liver, and kidney. J Trauma 1989;29:1664

Grade

.

- Artist's rendition of the American Association for the Surgery of Trauma grading system for genitourinary tract trauma. (Reproduced with permission from Coburn M: Genitourinary trauma. In Moore E, Feliciano DV, Mattox KL [eds]: Trauma, 5th ed. New York, McGraw-Hill, 2004.)

to this possibility. Placement of a Foley catheter or irrigation or replacement of an existing Foley catheter should remediate the problem. Although it is generally suggested that patients maintain a decreased level of activity until the microscopic or gross hematuria resolves, there are no evidence-based guidelines in the literature addressing appropriate length or type of activity restrictions for renal trauma. The period of time at which healing is adequate to allow return to full activity without risk has not yet been defined. Prospective studies are warranted. Although there is little controversy regarding management of the lower grade, less complex renal injuries in hemodynamically stable patients or the management of high grade, complex renal injuries in hemodynamically unstable patients, the management of those with intermediate injuries remains less well defined. Although the AAST grading scale appears to have some predictive value on the need for surgery, indications for surgery are based more on hemodynamic stability of the patient and associated injuries, rather than on grade of renal injury based on imaging criteria. The only absolute indication for surgery is hemodynamic instability with ongoing bleeding and transfusion requirements. Radiographic signs of

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ongoing renal bleeding include an expanding or unconwith major renal lacerations with a devitalized fragment tained retroperitoneal hematoma or complete avulsion after blunt abdominal trauma, Husmann and associof the mai; renal artery or vein with extravasation as ate@ found that renal exploration and surgical repair significantly improves the prognosis only in those demonstrated by CT or arteriography.g4 Although significant renal injury with urinary patients with concomitant intraperitoneal injuries. extravasation has in the past been considered a relative, Therefore, operative exploration of the kidney should be considered in children-with major blunt renal injuries if not absolute. indication for renal exdoration, more with a devascularized segment in association with intesrecent studies would suggest that most of these types tinal perforation or complex pancreatic injury to reduce of injuries can be successfully managed nonoperatively in the hemodynamically stable patient.120~148,161~171the incidence of serious infectious com~lications. Nonoperative management of hemodynamically Matthews and associates120reported spontaneous resolution of urinary extravasation in 27 of 31 patients (87%), stable children with complex higher grade blunt renal injury has become the standard of care in most centers. while the remaining 4 patients required ureteral stents ~ o s t . ~ e d i a t rand i c adult series report successful nonopdue to ~ersistentextravasation. Similarly, ,. Russell and erative management of even the most complex injuries, coworkers171 reported management of 15 pediatric including shattered but perfused kidneys and complex patients with grade IV renal injuries with urinary lacerations with extensive verinewhric hematoma and extravasation-9 patients (60%) required observation urinary extravasation.6J71 Proponents of nonoperative only; 1 required emergent partial n&phrectomy due to management of these patients note that in the absence hypotension and ongoing bleeding; and 5 developed of prospective studies comparing immediate explourinomas, 2 of whom were treated with percutaneous ration versus expectant management, no reliable data drainage and 3 of whom required ureteral stents. are available to suggest that surgery done early in the ~ l t h o u g hcomplications can occur with nonoperative course of injury reduces the long- or short-term complimanagement, most complications associated with urinary cations. The risk for nephrectomy associated with extravasation are easily treated by percutaneous drainage171 immediate exploration is avoided, and delayed surgery or endoscopic stent pla~ement,120,161,1~~ thereby achieving higher rates of renal salvage. is only necessary in 0% to 13% of With recent advances in interventional radiology techPatients with major renal trauma associated with niques and equipment, the need for delayed open enteric or pancreatic injury may be at increased risk for surgery has diminished significantly.78 An algorithm serious infectious complications, such as perinephric for the management of renal injuries in children is abscess and infected urinoma. In a study comparing presented in Figure 18-2. nonoperative versus surgical management of patients

* PK-1

Kidney all grades injury

i"l

Observation

Exploration

Persistent gross hematuria Persistent transfusion requirement Expanding abdominallflank mass Persistent fever

I

Repeat CT scan I

;4 Nephrectomy

Enlarging urinoma

Enlarging hematoma

Angiography Selective emb~lizations~~ C4, 93,184

Percutaneous drainage171 Cysto~copy/stenting'20.~6~~ In Exploration if unresponsive to above

-

-

Algorithm for the management of renal injuries in children.

CHAPTER

Collective review of 10 retrospective pediatric series of blunt renal trauma published over the past 13 years (1991-2004)* consists of 668 patients with the following grades of injury: grade I (342); grade I1 (46); grade I11 (64); grade IV (85); grade V (24); grades IV and V (16); grades I and I1 (50); grades I to 111 (18); and grades I1 and 111 (23). Operative intervention for renal injury was required in 45 patients (6.7%),including 31 nephrectomies (4.6%), 11 partial nephrectomies (1.6%), 1 renorrhaphy, and 2 nephrostomies. All patients with grades I and I1 renal injuries were successfully managed nonoperatively. Only 2 patients with grade I11 renal injuries required operative intervention: 1with nephrectomy and 1 with a partial nephrectomy. Forty-one of 125 (33%) children with grade IV and V renal injuries required operative intervention, including 30 nephrectomies (13 grade IV, 15 grade V, 2 grades IV and V); 10 partial nephrectomies (8 grade lV, 1 grade V, and 1 grades IV and V), 1 renorrhaphy (grades IV and V), and 2 nephrostomies (grades IV and V). The indication for operative intervention in almost all cases was hemodynamic instability with ongoing bleeding, with most requiring emergent operations within 24 hours of admission. The percentage of patients requiring operative intervention for renal injury ranged from 1.7%"2 to 12.7%,118 with the vast majority being those with highgrade (IV to V) complex injuries. Nonoperative management was successful in 93% of all patients with blunt renal trauma, 97% of those with grade 111 renal injuries, 75% of those with grade IV renal injuries, and 33% of those with grade V renal injuries.

Penetrating Injuries Penetrating renal injuries are rare in children. Although most gunshot wounds to the abdomen will require abdominal exploration, retroperitoneal dissection and exploration isindicated only if preoperative or intraoperative assessment suggests a major renal injury with extravasation outside of Gerota's fascia, there is suspicion for significant nonurologic retroperitoneal injury -(great vessels, duodenum, pancreas, colon), and/or inspection reveals an expanding or pulsatile retroperitoneal hematoma.lgl McAninch and c0workersl2~ classified gunshot wounds involving the kidney into five categories: (1) contusions (18.4%), (2) minor lacerations (13.8%), (3) major lacerations (50.5%), (4) vascular injuries (6.9%), and (5) lacerations combined with vascular injury (10.3%). The majority of patients had multiple injuries, with 95% requiring associated procedures. The nephrectomy rate was 13.8%. Although many of the kidneys rembved were potentially salva&able, most were removed because of the patient's precarious hemodynamic status. For renal-proximity stab wounds, nonoperative treatment is appropriate in hemodynamically stable patients without associated injuries who have been staged approHowever, a high index priately by triple-contrast CT.68,198 of suspicion for missed ureteral and other associated injuries must be maintained if a nonoperative pathway is chosen. *See references 7,8, 21, 43, 112, 118, 158, 171, 174, and 179.

18

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323

In a retrospective review by McAninch and coworkers,l27 55% of renal stab wounds and 24% of renal gunshot wounds were successfully managed nonoperatively with an acceptable complication rate. In the hemodynamically unstable patient with penetrating trauma or those with a retroperitoneal hematoma at laparotomy, a oneshot IVP may be useful to identify renal injury and confirm the presence and function of two renal units to further guide management.

Renovascular Injuries

Major renovascular injuries are rare in children. Carroll and c0lleagues3~and Turner and associates1g0reported penetrating trauma as a cause of renovascular injiries in 64% and 68% of their patients, respectively. Conversely, Cass and coworkers39 identified blunt external trauma as the cause of renovascular injury in 76% of patients. Regardless of the mechanism, these patients tend to have high injury severity scores, large transfusion requirements, and associated life-threatening multisystem injury,31,39J79the management of which supersedes that of renal injury. Knudson and colleagues105 reported that factors associated with a poor outcome after renovascular injuries include blunt trauma, grade V injury, and attempted arterial repair. Grade V injuries are frequently associated with severe major parenchymal injuries, which contribute to poor function of the revascularized kidney. Patients with grade V injuries with severe parenchymal disruption may be better served by immediate nephrectomy, provided that a functional contralateral kidney is present. Bruce and associatesZ3 compared 12 patients with blunt renal artery injuries who underwent operative intervention (9 nephrectomies; 3 revascularizations) with 16 patients who were managed nonoperatively, 1 of whom underwent endovascular stent placement. They concluded that nonoperative management of unilateral blunt renal artery injuries is safe and often successful, with a 6% risk of developing post-traumatic renovascular hypertension. . The pathogenesis of renovascular injuries due to blunt trauma is thought to be caused by rapid deceleration, which results in stretching of the renal vasculature, disru~tionof the arterial intimar and arterial thr0mbosis.3~ Blunt arterial injury occurs more commonly on the left side than on the right side31,33,34,190because the right renal artery is longer than the left and may be better able to withstand the stretching " caused bv d e ~ e l e r a t i o n . ~ ~ Although hematuria may be absent or microscopic in 13% to 56% of patients with renovascular injuries,3l,39,65,128,179 most hatients have other symptoms or signs that raise suspicion for a major renal injury and prompt further diagnostic imaging.31J7g Renovascular injury is suggested on CT by (1) lack of renal enhancement or excretion, often in the Dresence of normal renal contour; (2) vein enhancement; (3) central hematoma; (4) abrupt cutoff of an enhanced renal artery; and (5) nonopacification of the pelvicaliceal ~vstem.31,~79 The approach to this type of injury depends on the time to diagnosis, the type and extent of the vascular injury, and the extent of the associated i n j ~ r i e s . ~ ~ J O ~ J ~ ~

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artery injury or solitary kidney~.~~,~6J60 Repair of the right renal vein may be difficult owing to its An algorithm for short length and proximity to the inferior vena cava. the management of renovascular injuries is presented in Nonetheless, injuries to the main renal vein can be Figure 18-3. r e ~ a i r e din mosi cases.31Laceration of the left renal vein at its origin can be managed by ligation because collatComplications eral circulation supplied by gonadal and adrenal veins Although most renal injuries in children can be managed usually allows for adequate venous drainage.31~83 Segmental arteries are difficult to repair and may best nonoperatively, nonoperative management is not withbe managed by ligation with accompanying partial out complications. If a nonoperative course is chosen, nephrectomy if the area of infarction encompasses more the patient must be carefully monitored. Falling blood than 15% of the kidney.g0However, others suggest that counts, ongoing transfusion requirements, and persistent nonoperative management should be considered in any gross hematuria may be indicative of ongoing bleeding. patient with segmental artery occlusion that is not associA repeat CT scan or arteriogram is warranted. An arteriogram may be especially useful since some injuries ated with uncontrolled retroperitoneal hemorrhage, with ongoing bleeding may be amenable to selective extensive urinary extravasation,o r other intra-abdominal embolization to control the bleeding. Indeed, the sucindications for $urgev. This management strategy has been associated with an acceptably low incidence of cess of nonoperative management may be enhanced by com~lications.~~3~ angiographic embolization in select patients.G4 However, Arterial repair is most appropriate and most sucprofuse bleeding not amenable to embolization requires cessful for renovascular injuries caused by penetrating emergent operative exploration. trauma. Notwithstanding occasional reports of successful Prolonged ileus, fevers, and expanding abdominal/ revascularization in patients 19 hours after injury,82the flank mass or discomfort may be indicative of persistent urinary extravasation or urinoma, which is the most success of the procedure greatly diminishes after 8 hours ~ ~ ~ , ~ ~and ~ coworkersg9 common complication after renal trauma. Russell and of renal i s ~ h e m i a . 3 1 , 6 9 , 8 2 ,Ivatury associates171reported that about two thirds of all urinoreviewed 40 penetrating renovascular injuries and mas in children will spontaneously resolve. Accordingly, concluded that salvage of a kidney with a renovascular small, noninfected, stable collections require no treatinjury is determined primarily by the nature and extent ment other than observation, whereas larger, expanding of associated injuries. Furthermore, they reported that collections may be managed by percutaneous drainage171 while attempts at renal artery repair are often futile, or endoscopic placement of ureteral ~tents.~20J61J~~ renal vein injuries are more amenable to repair and Broad-spectrum antibiotics are also administered intrahave a better prognosis. Nephrectomy, however, remains the procedure of choice in the hemodynamically unstavenously. Delayed renal bleeding is unusual and most commonly ble patient with multiple trauma. occurs within 2 weeks of injury. However, Teigen and Blunt injuries to the main renal artery are associated with ,l~~ reported two children who developed maslowest success rate for complete renal p r e ~ e r v a t i o n . 3 ~ J ~ ~coworkers184 Haas and associates85 reviewed the management of sive life-threatening hemorrhage several weeks after the initial injury diagnosed by arteriography and successfully 12 patients with complete renal artery occlusibn secondary to blunt trauma. Renal artery revascularization was treated by percutaneous transcatheter embolization. Perinephric abscesses may be associated with ileus, attempted in 5 patients with a median warm ischemia time of 5 hours (range: 4.5 to 36 hours). Although four high fevers, and sepsis. CT is diagnostic. Most of these of five revascularizationswere deemed technically successabscesses are successfully treated with intravenous broad-spectrum antibiotics and percutaneous drainage. ful at the time of operation, 3 patients demonstrated no function and 1 showed minimal function on postoperaMultiloculated abscesses not amenable to percutaneous tive renal function scans. Two patients required delayed drainage may require operative drainage. nephrectomy due to complications, and of the 7 patients Late complications may include hydronephrosis, who underwent nonoperative management, 3 patients arteriovenous fistula, pseudoaneurysm, pyelonephritis, developed significant hypertension requiring nephreccalculus formation, and delayed renal hypertension. Posttraumatic arteriovenous fistula and pseudoaneurysm may tomy for blood pressure control. Based on these results, be successfully managed by percutaneous endovascular the authors are unable to advocate emergency revascularization for unilateral renal artery occlusion in the embolization.ll6Jfl The incidence of renal hypertension Dresence of a normal functional conhalateral kidney after trauma is quite low, occurring in fewer than 5% of patient~.85,141~142~~9~ The incidence is thought to be even unless the patient is hemodynamically stable and warm lower in children. Although hypertension usually occurs ischemia time is less than 5 hours. Patients with unianywhere from 2 weeks to several months after lateral injury, complete arterial thrombosis, extensive i n j ~ r y , ~ ~long-term , ~ ~ 2 , ~follow-up ~~ is essential because associated injuries, and a prohibitively long period of onset may be delayed up to 10 to 15 years after injury.IG0 renal ischemia may be managed either by primary nephrectomy or expectant nonoperative management depending on the hemodynamic stability of the patient. Follow-UplOutcomes There are reports of successful endovascular stenting Evidence-based guidelines for follow-up of children for traumatic renal artery dissection and thrombosis after renal injury are conspicuously lacking in the literain both children134 and adults.23~flIAn attempt should be made to revascularize all patients with bilateral renal ture. In a retrospective study, Abdalati and associates1

I

CHAPTER

18

Fienovascular injury

I

Genitourinary Tract Trauma

325

4 Unstable

f5 Exploration

Observation Consider angiographyl endovascular stentZ4.I l l s 134

25 Nephrectomy

I

Kidney appears salvageable

Kidney appears unsalvageable

I

I

I

Attempt revascularization

-

25 Nephrectomy

.

Algorithm for the management of renovascular trauma in children.

correlated initial CT grading of renal injury with frequency of complications and time course of healing in 35 patients. From this study, they concluded that grades I and I1 injuries healed completely and required clinical but not radiologic follow-up. Grade I11 injuries were associated with the highest risk of complications (30%),with healing taking up to 4 months to complete. Thus, it was recommended that grade I11 injuries be followed by sequential imaging with CT, scintigraphy, and/or ultrasound for 3 to 4 months until complete healing was documented. Grade IV injuries were often associated with some degree of renal loss and required radiologic follow-up to assess complications and residual renal function. Although CT provides important information regarding healing and the presence of complications, quantitative dimercaptosuccinic acid (DMSA) scintigraphy is a more useful tool to assess residual renal function after injury.143A study by Keller and coworkers103evaluated the functional outcome of nonoperatively managed renal injuries in 17 children as measured by blood urea nitrogen (BUN), creatinine, blood pressure, and DMSA renal scan after radiographic evidence of complete healing. Similar to the findings of Abdalati and associates,l complete healing was documented radiographically within 3 months in all cases. They concluded that functional outcome correlates with injury grade, with grades I1 to IV injuries retaining near normal function and grade V injuries demonstrating significant loss of renal function due to scarring

and parenchymal volume loss. Despite diminished function on DMSA renal scans, all children were asymptomatic, normotensive, and had normal BUN and creatinine levels. Larger prospective clinical and radiologic outcome studies are warranted to further assess time to healing, incidence of complications, residual function, and longterm outcomes after renal trauma to provide the physician with a more evidence-based approach to appropriate follow-up and counseling for the injured child. At present, it is generally recommended that children with more severe renal injuries be followed with serial blood pressure monitoring and CT and DMSA at 3 to 6 months postinjury. Further imaging is also indicated for onset of any urologic symptoms or development of hypertension.

Operative Management of Renal Trauma Although most cases of renal trauma in children may be successfully managed nonoperatively, the surgeon should be familiar with techniques of operative management as well. As discussed previously, operative management of renal trauma is generally reserved for hemodynamically unstable patients or those patients with severe associated injuries. The patient is usually explored through a generous midline abdominal incision. Although traditionally it has been taught that the surgeon should first gain proximal control of the renal artery and vein before entering Gerota's fascia or the hematoma in order to reduce blood loss and decrease the nephrectomy rate,""

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this approach has recently been challenged. In both , ~ ~ a prospective, randomized retrospective s t ~ d i e s 4and clinical trials1 it was concluded that vascular control of the renal hilum before opening Gerota's fascia has no effect on the nephrectomy rate, transfusion requirements, or blood loss but does significantly prolong operative times by up to an hour or more. The nephrectomy rate appears to depend more on the degree of injury rather than on the type of renal vascular contr01.~ No matter what the approach, the kidney is exposed and vascular control is obtained at the hilum. With exsanguinating hemorrhage, rapid mobilization of the kidney with digital control of the hilum may be necessary. The left renal vein can be ligated because collateral drainage is provided by the left adrenal and gonadal veins. However, trauma to the right renal vein requires repair. Segmental arteries may be ligated and partial nephrectomy performed if the area of infarction encompasses more than 15% of the kidney.g0If the patient is hemodynamically stable, the kidney itself is salvageable, and the period of warm ischemia after injury is acceptable, renal artery repair and revascularization may be attempted. Otherwise, a nephrectomy should be performed. If it appears salvageable, the damaged kidney is debrided to viable tissue and intrarenal hematomas are evacuated. Hemostasis should be obtained with absorbable sutures placed in a figure-of-eight pattern. The open collecting system should be closed with fine, absorbable, monofilament sutures, because woven sutures may cut through renal tissue.1z6 Internal stents may be required if the ureter or renal pelvis has been injured. The renal capsule should be closed to approximate the renal margins. If the capsule is destroyed, the lacerated margins should be covered with omental pedicle grafts, retroperitoneal fat, or polyglycolic acid mesh.gOJ26 Approximation and covering of renal tissue aids in hemostasis and wound healing and prevents delayed bleeding and extravasation of urine.lZ6

Ureter Ureteral injury is uncommon and assumes secondary importance in children with potentially life-threatening injuries. Nonetheless, delays in diagnosis and treatment are associated with major morbidity and a significant risk for life-threatening urosepsis later during the course , 2 ~ , ~and ~ , ~colleague^^^ ~ reported the of i n j ~ r y . ~ ~Boone risk for urologic complications to be 13% when blunt UPJ disruption was diagnosed within 24 hours compared with 54% with delayed diagnosis. The risk for renal loss was 4.5% to 9% with early diagnosis compared with 32% to 33% with delayed diagnosis.'4,96 Ureteral trauma is classified by the anatomic location of the injury and by the extent of mural damage (see Blunt ureteral injuries are rare, occurring Table 18-1).144 in less than 1% of patients with blunt abdominal trauma. Direct injuries may result from crush injuries or severe hyperextension or flexion injuries. Direct compression against a transverse process or vertebral body has been described,'gg and an association with traumatic paraplegia has been noted.loOPatients with congenital ureteral

obstruction are also predisposed to injury of the collecting system.89 Surgical repair is unlikely to be successful if the underlying obstruction is not recognized and treated. Indirect mechanisms of ureteral injury in children include falls or rapid deceleration. As noted by Boone and colleagues,l4 the UPJ is particularly prone to disruption secondary to these mechanisms. Howerton and associates96 reviewed 54 cases of ureteral avulsion within 4 cm of the UPJ and found that this type of injury was three times more common in children than in adults. Similarly, the right kidney was injured three times more often than the left. Penetrating trauma involving the ureter occurs in approximately 4% of patients and is most often caused by a stab or gunshot wound. Although this type of injury is most commonly seen in adults, it occurs in a significant percentage of children as we11.l8I In the largest series to date, PerepBrayfield and coworkers1" reviewed 118 patients with gunshot wounds to the ureter managed by a variety of surgical procedures, depending on the location and severity of the defect. They reported a 20% incidence of comvlications and concluded that a high index of suspicion is necessary to avoid missing these injuries. Iatrogenic injuries to the ureter in children occur most cokmonlfduring ureteroscopic and percutaneous endourologic procedures. Open surgical procedures, such as those involving resection of an abdominal or pelvic tumor or colectomv. ,, mav, also be associated with ureteral trauma. Radiation injury is also occasionally encountered. The paucity of early signs and symptoms makes the nonoperative diagnosis of ureteral injuries difficult. Boone and colleagues14 encountered gross hematuria in 27% of patients with UPJ disruption, whereas an additional 26% of patients had microscopic hematuria with shock. Absence of hematuria was noted in about one third of patients. As reviewed by Brandes and coworkers,l6 23% to 37% of ureteral injuries reported in the literature have conspicuous absence of significant hematuria. Flank tenderness. ecchvmosis. and mass effect are encountered in only approximately 7% of patients with proximal ureteral injury.14 Patients occasionally present with anuria if the injury is bilateral or involves a solitarv kidnev. Imaging modalities for diagnosis of ureteral trauma include CT and IVP. Up to 75% of ureteral injuries are missed by IVP.'69'65 Ureteral injuries may be difficult to diagnose by CT as well. With the faster helical CT scanners currently in use, it is critical to obtain delayed images during the excretory phase (2 to 10 minutes) so that ureteral extravasation is not missed. Failure of opacification of the ureter should also raise suspicion for ureteral injury.187 Retrograde pyelography is quite sensitive and should be performed in hemodynamically stable patients suspected to have a ureteral injury. Delayed diagnosis of ureteral injury occurs in approximately half of patients owing to the subtle nature of the clinical findings, frequent absence of hematuria, lack of sensitivity of radiolbgic imaging techniques, and high incidence of multisystem injury with concomitant patient instability.14J6Wreteralinjuries may be heralded

CHAPTER

by sepsis, vascular collapse, or drainage of urine from surgical wounds. Periureteral fibrosis, phlegmon, and abscess are common. Other complications include obstruction from stenosis and renal failure. In contrast to management of renal injuries, nonoperative management has limited application for ureteral injuries. Minor ureteral injuries with limited extravasation may be managed nonoperatively with a retrograde stent. However, most patients with ureteral injuries fare better with early operative repair. If the diagnosis is delayed significantly, temporary stenting or percutaneous nephrostomy diversion followed by interval operative reconstruction may be indicated, owing to the increased inflammation, friability, and complications associated with attempts at repair more than 3 to 5 days after injury. The treatment of ureteral injuries is dictated primarily by the location and mechanism of injury, amount of tissue loss, and the condition of the local tissues. Ureteral injury associated with a severely damaged or shattered kidney is best managed by nephrectomy. In the absence of or with limited renal injury, attempts at primary ureteral repair should be attempted. Disruption of the UPJ is generally manageable by dismembered pyeloplasty. If damage to the renal pelvis is extensive, it should be surgically debrided and closed and ureteral continuity should be restored by ureterocalicostomy. Midureteral injuries are repaired by limited debridement to viable tissue and a spatulated end-to-end anastomosis using fine absorbable suture. Injuries to the pelvic ureter are often amenable to a simple ureteral reimplantation. Occasionally, a psoas hitch or Boari flap is required for ~ stents are used a tension-free a n a s t o m o ~ i s .Ureteral routinely. Patients with ureteral trauma from a bullet wound require that the ureter be debrided until the edges bleed freely. Intravenous fluorescein and a Wood's lamp are occasionally useful to predict viability. Peristalsis is not a reliable sign of viability. A spatulated end-to-end anastomosis is performed, and stenting is mandatory. Unstable patients with multiple injuries are best managed by exteriorization of the transected ureter as an intubated ureterostomy or by simple ureteral ligation with intraoperative or postoperative percutaneous nephrostomy. Simple ureteral ligation is also an excellent form of management for unstable patients in whom the length of the ureteral defect precludes primary repair. Definitive reconstruction of a long ureteral defect is done on an elective basis once the patient is stable.12J65J81 Options include renal mobilization (which can yield 3 to 5 cm) ,Is1 the Boari flap or psoas hitch,l5 and autotransplantation.12.193 Additionally, transureteroureterostomy and ileal interposition can be done.ls1 Delayed diagnosis associated with significant adjacent visceral injury (i.e., duodenal or pancreatic injury) may be particularly problematic. Such injuries are marginally amenable to reconstruction. Percutaneous antegrade ureteral stenting with later, elective surgical correction of stenosis or fistula, if encountered, is the preferred method of management.ls6 This may also be the best approach to management of ureteral injury associated with infected urinoma, abscess, delayed diagnosis, or ureteral contusions complicated by urinary extravasation.

18

Genitourinary Tract Trauma

327

Bladder Anatomy Although the bladder in children is located in the extraperitoneal space of Retzius, it is considered an the bony pelvis grows, the intra-abdominal organ.5" bladder assumes a pelvic position and is increasingly protected from injury. The anatomic attachments of the bladder influence the pattern of injury seen after some forms of trauma. The bladder is bound laterally by the internal obturator muscles and the umbilical ligaments.53At its base the bladder is attached to the urogenital diaphragm. Denonvillier's or the rectovesical fascia binds it posteriorly. Unlike the rest of the bladder, the dome is mobile and di~tensib1e.l~~

Causes

The bladder may be injured by blunt or penetrating trauma. Although penetrating injury to the bladder can be caused by any injury to the lower abdomen, the most common cause of unintentional injury is i a t r o g e n i ~ . ~ ~ ~ ~ 2 Migration or erosion of drains, ventriculoperitoneal shunts, intrauterine devices, and Foley catheters are rare causes of unintentional injury to the bladder.25,50,53,202 Intentional penetrating injuries are most commonly caused by gunshot wounds, which are usually associated with other intra-abdominal injuries. Blunt trauma accounts for 80% of injuries to the bladder. The susceptibility of the bladder to injury is somewhat dependent on the amount of urine contained at the time of injury.154 Motor vehicle crashes are the most common cause of blunt trauma to the bladder.53 Pelvic fractures with sharp bony fragments may lacerate the bladder (usually near the bladder neck), and shearing forces can tear the bladder at its mooring~.~3J~l A forceful, direct blow to the abdomen may rupture the dome of the bladder, even without an associated pelvic fracture.53JsO Because of its relatively protected position within the pelvis, considerable blunt force is required to cause bladder injury. Not surprisingly, serious injuries to other intra-abdominal organs are seen in almost half of patients with bladder injuries.70While 75% to 95% of bladder injuries are associated with pelvic fractures,27,70,151,180only 4% to 20% of patients with pelvic fractures have concomitant bladder i n j ~ r i e s . l ~ , 2 ~ , ~ 2 , l ~ ~

Classification and Definitions Bladder injuries due to blunt trauma may be further classified as contusions, and extraperitoneal and intraperitoneal ruptures. Extraperitoneal bladder ruptures occur in 60% to 65% of cases; intraperitoneal ruptures occur in 25% of cases; and a combination of the two occurs in 10% to 15% of cases.95 The AAST grading scale for bladder injuries is shown in Table 18-1. Contusions are disruptions in the bladder muscularis without loss of continuity of the bladder wall, whereas ruptures are complete disruptions of the bladder Contusions typically resolve without intervention.

328

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TRAUMA

Extraperitoneal bladder ruptures are usually assodeliberate evaluation of the patient. The weakest and Nineteen percent of ciated with pelvic fracture~.~2.~22~~ most mobile part of the bladder, the dome, is the most patients (mostly male) with extraperitoneal bladder common site of intraperitoneal rupture. This type of ruptures have a concomitant urethral injury, and 8% injury occurs more commonly in children."J2' have an associated intraperitoneal i n j ~ r y . ~ 3 , ~ ~ Intraperitoneal bladder ruptures are best managed by In contrast to extraperitoneal ruptures, intraperitoneal early operative repair. Protracted extravasation of urine ruptures are infrequently associated with pelvic fractures into the peritoneal cavity can lead to life-threatening (Fig. 18-4). These injuries are often caused by compresmetabolic, septic, and mechanical derangements.27.",92 Patients presenting more than 24 hours after intraperision (burst-type injury) from a suprapubic blow to a toneal rupture of the bladder may have elevated BUN, distended bladder or sudden, forceful de~eleration.~2~",l~~ creatinine, and potassium levels; a decreased serum Intraperitoneal ruptures most commonly occur at the sodium concentration; and a laboratory profile similar dome of the bladder, whereas extraperitoneal rupto that of patients with acute renal f a i l ~ r e . ~ z tures are usually caused by bony perforation or shearing f o r c e ~ . ~ ~infants ~ ~ V nand young children, the bladder The bladder should be approached through a lower midline abdominal incision to avoid lateral contained is an intraperitoneal organ, and if it is ruptured it will often cause intraperitoneal extravasation of urine.122 hematoma. If necessary, the rent in the dome of the Occasionally, bladder ruptures may result from an extenbladder can be widened to facilitate a thorough examsive hematoma of the bladder wall or, in neonates, ination of the inner aspect of the bladder. Associated from manipulation of an umbilical artery catheter.20Jj0 extraperitoneal tears can be closed from within by a single running layer of absorbable suture; however, the surgeon must ensure that the patency of the ureteral Management orifices is preserved. An intravenous injection of indigo carmine may help verify the location and Bladder Contusions integrity of the ureteral orifices. The dye should be seen effluxing from the ureteral orifices within 10 minutes. Most bladder contusions heal spontaneously without intervention. If the sacral innervation of the bladder is Lacerations extending into the bladder neck should be carefully repaired to reconstruct the sphincteric compointact, patients with bladder contusions have excellent nents and reduce the likelihood of later urinary outcomes. Patients with a large pelvic hematoma that causes considerable bladder distortion may have difficulty incontinence. Intraperitoneal bladder injuries are voiding and may benefit from Foley catheter drainage. repaired with absorbable suture in two layers. After the bladder is repaired, a closed-suction drain is placed and brought out through a separate stab incision. Intraperitoneal Rupture Although in the past most surgeons would insert a largeIntraperitoneal ruptures are frequently associated with bore suprapubic cystostomy tube instead of or in addition to a transurethral catheter for urinary drainage other significant injuries, necessitating a thorough and after repair of an intraperitoneal bladder rupture, more recent literature would suggest that transurethral catheter drainage is not only adequate, but preferable. For any degree of bladder injury, transurethral catheters are equally effective, are associated with fewer complications, and may be removed sooner than suprapubic catheters.Y5,18.i,192 Urinary drainage is generally maintained for 5 to 10 days. Most surgeons will obtain a cystogram before removal of the urinary drainage catheter to evaluate the integrity of the repair. If no extravasation is documented, then the urinary catheter and closed-suction drain can be removed.

Extraperitoneal Rupture

Voiding cystourethrography demonstrating intraperitoneal rupture of the bladder. The patient also had bilateral fractures of the superior ischial and inferior pubic rami.

The preferred management of extraperitoneal rupture is transurethral catheter drainage alone. This approach is safe and effective and obviates the need for bladder exploration, manipulation of the extraperitoneal hematoma, and converting a closed pelvic fracture into an open one. At times, the degree of extravasation of contrast medium may be alarming. However, because it is dependent not only on the size of the tear but also on the amount of contrast medium instilled,"g,55the degree of extravasation alone may not indicate the severity or extent of the tear in the bladder.'7.3"-"7," In most

CHAPTER

instances, the tear heals completely and transurethral catheter drainage is successful even with extensive Almost 90% of extraperiurinary extravasation.41~42~55 toneal bladder ruptures heal within 10 days and the remainder within 3 weeks.55 Operative intervention is rarely required.

Penetrating Injuries Because of the high likelihood of associated injuries, which often take priority in management, patients with penetrating injuries to the bladder generally require exploratory laparotomy. The peritoneal cavity is opened in the midline, and injuries to the intra-abdominal viscera and major vasculature are addressed first. Attention is then directed to the bladder, and the extent of injury is determined. All devitalized bladder tissue and debris from clothing or bony spicules are removed.27 The integrity of the ureters can be confirmed with intravenous injection of indigo carmine. A diligent search should be made for extravasation, and, if necessary, the ureters should be intubated. Bladder mobilization is unnecessary and invites precipitous bleeding. Large, nonexpanding hematomas should be left undisturbed. The bladder should be entered through the dome. Extraperitoneal defects should be closed intravesically with a single layer of running absorbable suture. A watertight closure is ideal but not essential. With adequate bladder drainage, even a tenuous closure can heal satisfactorily. Intraperitoneal defects should be closed in two layers with absorbable suture. Closed-suction drains are placed as previously described, and transurethral catheter drainage is maintained for 5 to 10 days.

Urethra Although urethral trauma is a secondary consideration in children with potential life-threatening trauma, such injuries account for a disproportionate degree of long-term morbidity. It remains unclear whether delayed or immediate repair is superior, and there are no prospective, randomized studies addressing the issue. The majority of the available data are based on retrospective series in adults. The only available pediatric series are limited by small numbers of patients. Data from adult studies may not be applicable to children owing to anatomic differences. For example, in contrast to adults, the posterior urethra is not protected by the prostate in children and may be injured at any level. Blunt trauma with disruption of the bony pelvis accounts for most posterior urethral injuries in children. About 5% of males with a fractured pelvis will also have an injury to the posterior urethra.153Of these cases, 10% to 20% will have an associated bladder rupture.55 Motor vehicle accidents account for 90% of urethral injuries, and the remaining 10% result from falls, crush injuries, or sporting injuries. A lateral pelvic force without pelvic fracture rarely results in urethral disruption. Penetrating injuries involving the posterior urethra including stab wounds, gunshot wounds, and iatrogenic causes are rare.

18

Genitourinary Tract Trauma

329

Anterior urethral injuries are often encountered after straddle injuries, such as a fall astride a fence, kicks, or bicycle injuries. Penetrating trauma to the anterior urethra is rare but may be seen with gunshot or stab wounds. Urethral instrumentation, penile surgery, and injuries from sexual intercourse and masturbation may also result in anterior urethral trauma. The diagnosis of urethral trauma is relatively straightforward. Symptoms of urethral injury may include the inability to void or the sensation of voiding without passing urine. Blood at the urinary meatus or gross hematuria after trauma strongly suggests urethral injury. Physical examination of the penis, scrotum, and perineum may reveal swelling and ecchymosis. The integrity of and boundaries of Buck's, Colles', and Scarpa's fascias indicate the region injured. Digital rectal examination may reveal upward displacement of the prostate or a boggy mass. This, however, may be difficult to assess in young children, so urethral imaging is required to confirm the diagnosis. If there is suspicion of a urethral injury, blind passage of a transurethral urinary catheter should not be attempted because there is a risk of creating a false passage with the catheter and converting a partial disruption into a complete one. Retrograde urethrography is the imaging modality of choice for diagnosis of urethral trauma. Findings of elongation, filling defect, or extravasation indicate urethral injury. If urethral integrity is demonstrated by retrograde urethrography, the catheter is then advanced and a cystogram is performed to exclude concomitant bladder injury. Table 18-1 outlines the classification of urethral injuries that includes contusions, stretch injuries, partial disruptions, and complete disruptions. A filling defect caused by contusion and hematoma or an elongated urethra without extravasation on retrograde urethrography indicates grade I or I1 injury. Urethral extravasation with bladder continuity indicates partial disruption (grade 111).Urethral extravasation with no admission of contrast agent into the proximal urethra or bladder suggests complete disruption (grade IV). Spasm of the periurethral musculature can mimic complete disruption. Figure 18-5 provides an example of injury to the bulbous urethra.

, - . Extravasation of contrast from the bulbous urethra due to penoscrotal urethral disruption. The posterior membranous and prostatic urethra is intact.

330

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The long-term sequelae of urethral trauma can be devastating and may include impotence, retrograde ejaculation, incontinence, and urethral strictures. Some of these complications may be a direct consequence of the trauma itself or may be related to surgical attempts at repair. ~ - d i a ~ n o sof i s anterior urethral injury is suggested if the retrograde urethrogram reveals only minimal extravasation with good urethral continuity and if the patient is able to void. Grade I or I1 injuries to the anterior urethra usually heal spontanedusly without insertion of any indwelling urinary catheters, as long as the patient is able to void. Intermediary grade anterior urethral injuries may be managed by an indwelling transurethral Foley catheter, whereas more complex injuries are best managed in the initial stages by placement of a suprapubic catheter. Delayed urethral strictures occur~commonly,and most are. amenable to urethroplasty. Penetrating injuries to the anterior urethra may be managed by exploration and primary repair or suprapubic urinary diversion. Husmann and colleaguesg7 reviewed management of 17 patients with partial transection of the anterior urethra due to low-velocity gunshot wounds and concluded that patients were best managed by aggressive wound debridement, corporeal repair, primary suture repair of the urethra, and placement of a suprapubic catheter. Strictures developed much less frequently with this approach (1 of 8) compared with suprapubic diversion and transurethral catheter stenting (7 of 9). In Ehildren, the majority of posterior urethral injuries may be managed nonoperatively. Grade I or I1 injuries, which may allow spontaneous voiding, are managed without surgery and without an indwelling urinary catheter. Patients who are unable to void are managed by insertion of a small, transurethral Foley catheter. Grade I11 injuries with minimal extravasation may also be managed by passing a small, transurethral Foley catheter under fluoroscopic guidance immediately after the retrograde urethrogram. If the catheter does not pass easily, however, a suprapubic tube should be placed. Options for repair of more complex posterior urethral injuries include primary surgical repair with anastomosis of the disrupted urethral ends, delayed primary surgical repair, primary surgical catheter realignment, primary endoscopic and radiologic realignment, or suprapubic cystostomy with delayed urethroplasty. Primary surgical repair involves evacuation of the pelvic hematoma, mobilization of the prostate and urethra, and direct end-to-end anastomosis between the prostatic and membranous urethra. Problems with this approach include increased risk of uncontrolled bleedin;" d u e to exploration of the injury site with release of the tamponade effect of the hematoma; increased risk of impotence due to dissection of the periprostatic and periurethral tissues; and increased risk of incontinence due to damage to the intrinsic urethral sphincter mechanism by dissection, mobilization, and debridement of torn urethral ends.51,53,56,57~108~1g5 TO minimize these complications, Mundy150 advocated delaying primary surgical repair

until 7 to 10 days after injury once the patient was more stable, the operative view was less obscured by bleeding, and before the onset of fibrosis. Primary surgical catheter realignment was first introduced by Ormond and Cothran in 1934 with multiple variations in technique over the ensuing y e a r ~ . ~ ~ ~ ~ ~ 7 " 1 0 7 Despite not requiring direct suturing of the disrupted urethral ends, this technique still requires an open procedure with entry into and evacuation of pelvic hematoma with all of the attendant risks of primary surgical repair. More recently, innovative combined transurethral and transvesical endoscovic and interventional radiologic techniques have been introduced to achieve primary alignment without the risk of explor,~~,~~~-~~2,~~ ing the disrupted ~ r e t h r a . ~ 7 , 4 9 , ~ ~Furthermore, because there is no manipulation of periprostatic tissues and no additional trauma to the cavernous nerves, there should be no additional risk of erectile dysfunction other than that caused by the injury itself. These minimally invasive techniques have produced encouraging results so far, but clinical experience is limited to small series. Postoperative outcomes of these small series indicate that 88% to 100% of patients are continent, 14% to 39% of patients have some degree of erectile dysfunction, and about half require subsequent internal urethrotomies. Concerns about the impact of primary open surgical repair or catheter realignment on potency and urinary continence led to the introduction of an alternative treatment approach, namely suprapubic cystostomy with delayed urethroplasty. First advocated by Johanson of Sweden in 1953, no attempt is made to explore the urethra but rather the urinary stream is simply diverted via a suprapubic cystostomy tube. A stricture is considered inevitable and is repaired several months later. This approach has gained widespread acceptance and is considered a standard approach to the management of complex posterior urethral disruptions. Advantages of this approach include avoiding entry into a fresh pelvic hematoma with risk of blood loss and infection, speed and simplicity of suprapubic tube insertion, and decreased incidence of i m ~ o t e n c eand incontinence due to avoidance of dissection of the prostate and urethra.73 Disadvantages include prolonged need for a suprapubic tube with risk of infection and stone formation as well as the nearly 100% risk for urethral strictures, which may be quite complex and difficult to repair even in the delayed setting.Io7 Tunc and colleagueslsg reviewed 77 cases of delayed repair of traumatic posterior urethral injuries and demonstrated adequate urethral continuity in 9596, postoperative incontinence in 9%, and postoperative erectile dysfunction in 16%. They concluded that delayed posterior urethroplasty is a successful treatment option with acceptable morbidity. After extensive literature review regarding different approaches to management of complex hosterGr urethral injuries, Holevar and associates" concluded that these injuries may be treated with either primary endoscopic realignment or suprapubic cystostomy with delayed urethroplasty with similar results. Urethral trauma in females is rare."J" The usual mechanism of injury involves pelvic fracture incurred

CHAPTER

during a motor vehicle accident. Straddle injury occasionally results in damage to the urethra. Female urethral injuries may be distal avulsion from the perineal attachment or proximal disruptions and lacerations. The latter type of injury is characteristically associated with other pelvic injuries, including vaginal and bladder neck lacerations. Perry and colleagues159 reviewed the evaluation of urethral injuries in females with pelvic fractures. Blood at the vaginal introitus mandates a meticulous vaginal examination. The urinary meatus must also be carefully examined and its patency confirmed by passage of a catheter. However, it is important to note that catheters can often be passed into the bladder even in the presence of a significant urethral injury. Development of vulva1 edema after removal of the catheter warrants prompt investigation. Because urethrography in young girls is difficult and unreliable, urethroscopy is the preferred diagnostic modality. Delays in diagnosis of urethral injury in girls occur frequently and have devastating consequences.159Such injury is misdiagnosed in about 50% of cases and can result in life-threatening sepsis and necrotizing fasciitis. Therefore, one should have a low threshold for performing urethroscopy when urethral injury is suspected in a young girl. Treatment is dictated by the extent and location of injury. Urethral injuries that extend into the bladder neck require meticulous repair with reapproximation of the bladder outlet and urethra. Such injuries are encountered about two thirds of the time.121,122,126,129 Associated vaginal injuries are repaired primarily. Urethral crush injuries that do not involve the bladder neck are managed by extended transurethral Foley catheterization (6 to 8 weeks) or, if necessary, suprapubic catheter drainage. Significant long-term complications associated with pediatric female urethral trauma are common and include urethral stenosis, urethrovaginal fistula, incontinence, and vaginal s t e n ~ s i s . ~ ~ Clearly every effort must be made to promptly detect and aggressively manage this uncommon injury.

External Genitalia Girls Blunt genital trauma in girls is fairly common. The presenting symptoms are usually the presence of blood in the underpants or on the perineum shortly after injury.l17 Blunt genital trauma most commonly results from straddle injury. The most common types of injury, in decreasing order of frequency, are lacerations or contusions of the perineal body, vagina, labia, urethra, and rectum. Due to the extreme difficulty of performing a thorough genitourinary examination in an awake, uncomfortable, anxious, and embarrassed child, the majority of patients are best evaluated in the operating room under general anesthesia. Indeed, as many as 76% of patients will have more extensive injuries than can be appreciated in the emergency department.l17 Management of female genital trauma is dictated by the type and extent of injury. Necrotic, contused tissue

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should be debrided. Lacerations are primarily repaired after hemostasis is achieved. Absorbable sutures are used to preclude the need for removal. Urethroscopy and proctoscopy may be necessary to more thoroughly evaluate the injury.

Boys The most common injury to the penis is iatrogenic injury during circumcision.80 Complications of circumcision include penile amputation, urethral fistulization, laceration of the glans penis, and inaccurate removal of the foreskin resulting in phimosis degloving injury. Most of these injuries are avoidable with use of proper technique. Penile injury resulting from blunt or penetrating trauma is rare in children. Urethral lacerations should be managed as described in the previous section. The findings of an expanding hematoma, palpable corporal defect, and excessive bleeding suggest cavernosal injuries. When possible, these injuries should be repaired primarily.17Urinary diversion with a suprapubic tube is occasionally necessary.79 The preferred method of management of gunshot wounds with a limited extent of injury is debridement of superficial wounds, repair of the cavernosal defects, and primary repair of the urethral injury.87 Penile erectile dysfunction (impotence) can occur after blunt pelvic and perineal trauma.149The dysfunction results from shearing of the penile blood vessels in the pelvis. Penile revascularization may restore potency.119 Priapism may also occur after blunt trauma. For this disorder, selective angiography is helpful to diagnose the injury and to embolize the arteriovenous fistula causing the priapism. Doppler ultrasonography is also useful to characterize and localize the lesion.lS8 Injury resulting from zipper entrapment of the penis can be addressed, in many cases, in the emergency department but may require a general anesthetic for release of the penis.20° Penile strangulation injuries due to constricting bands are managed by removal of the constricting band in as atraumatic a manner as possible. In children, hair tourniquets are common sources of constriction and may be quite difficult to remove. Severe strangulation injuries may result in necrosis of the distal penile skin, glans, cavernosum, or urethra. Conservative debridement and urinary diversion may be required.48 Scrota1 injuries may result from penetrating trauma, blunt trauma, or both. High-resolution ultrasonography is very useful in the evaluation of these injuries.1° Ultrasonography of penetrating injuries can identify testicular rupture and extratesticular soft tissue abnormalities as well as the presence and location of foreign bodies.110 This technique is also useful in distinguishing less serious injuries, such as scrota1 hematomas, hydroceles, and hematoceles, from surgical emergencies, such as testicular rupture and infarction. It should be noted that epididymal rupture is not as easily identified on ultrasonography.l55 Patients with hematoceles should be considered for exploration to evacuate the blood from the tunica vaginalis testis because this approach reduces morbidity and hastens recovery. Testicular disruption is managed by debridement and primary c l ~ s u r e . ~

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149. Munarriz RM, Yan OR, Znehra A, et al: Blunt trauma: The pathophysiology of the hemodynamic injury. J Urol 1995;153:1831. 150. Mundy AR: The role of delayed primary repair in the acute management of pelvic fracture injuries of the urethra. Br J Urol 1991;68:273. 151. Murphy JP: Genitourinary trauma. In Ashcraft KW (ed): Pediatric Urology. Philadelphia, WB Saunders, 1990. 152. Nicolaisen GS, McAninch JW, Marshall GA, et al: Renal trauma: Re-evaluation of the indications for radiographic assessment.J Urol 1985;133:183. 153. Noe HN, Jerkins GR: Genitourinary trauma. In Kelalis PP, Kemp LR, Belman AB (eds): Clinical Pediatric Urology. Philadelphia, WB Saunders, 1992. 154. OliverJA, TaguchiY Rupture of the full bladder. BrJ Urol 1964;36:524. 155. Patil MG, Onuora VC: The value of ultrasound in the evaluation of patients with blunt scrota1 trauma. Injury 1994;25:177. 156. Peng MY, Parisky YR, Cornwell EE, et al: CT cystography versus conventional cystography in evaluation of bladder injury. AJR Am J Roentgenol 1999;173:1269. 157. Perez-Brayfield MR: Gunshot wounds to the ureter: A 40 year experience at Grady Memorial Hospital. J Urol 2001;166:119. 158. Perez-Brayfield MR, Gatti JM, Smith EA, et al: Blunt traumatic hematuria in children: Is a simplified algorithm justified? J Urol 2002;167:2543. 159. Perry MO, Husmann DA: Urethral injuries in female subjects following pelvic fractures. J Urol 1992;147:139. 160. Peterson NE: Review article: Traumatic bilateral renal infarction. J Trauma 1989;29:158. 161. Philpott JM, Nance ML, Carr MC, et al: Ureteral stenting in the management of urinoma after severe blunt renal trauma in children. J Pediatr Surg 2003;38:1096. 162. Pode D, Shapiro A: Traumatic avulsion of the female urethra: Case report. J Trauma 1990;30:235. 163. Poole GV, Ward EF, Griswold JA, et al: Complications of pelvic fractures from blunt trauma. Ann Surg 1992;58:225. 164. Porter JR, Takayama TK, Defalco AJ: Traumatic posterior urethral injury and early realignment using magnetic urethral catheters. J Urol 1997;158:425. 165. Presti JC, Carroll PR, McAninch JW: Ureteral and pelvic injuries from external trauma: Diagnosis and management. J Trauma 1989;29:370. 166. Pumberger W, Stoll E, Metz S: Ureteropelvic junction disruption following blunt abdominal trauma. Pediatr Emerg Care 2002;18:364. 167. Quinlan DM, Gearhart JP: Blunt renal trauma in childhood. Features indicating severe injury. Br J Urol 1990; 66:526. 168. Radmayr C, Oswald J, Muller E, et al: Blunt renal trauma in children: 26 years clinical experience in an alpine region. Eur Urol 2002;42:297. 169. Rehman J, Samadi D, Ricciardi R Jr, et al: Early endoscopic realignment as primary therapy for complete posterior urethral disruptions. J Endourol 1998;12:283. 170. Rober PE, Smith JB, Pierce JM: Gunshot injuries of the ureter. J Trauma 1990;30:83. 171. Russell TS, Gomelsky A, McMahon DR, et al: Management of grade IV renal injury in children. J Urol 2001;66:1049. 172. Sagalowsky AI, McConnell JD, Peters PC: Renal trauma requiring surgery: An analysis of 185 cases. J Trauma 23:128, 1983. 173. Santucci RA, McAninch JW, Safir M, et al: Validation of the American Association for the Surgery of Trauma

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organ injury severity scale for the kidney. J Trauma 2001; 50:195. 174. Santucci RA, Langenburg SE, Zachareas MJ: Traumatic hematuria in children can be evaluated as in adults. J Urol 2004;171:822. 175. Sharp DS, Ross JH, Kay R: Attitudes of pediatric urologists regarding sports participation in children with a solitary kidney. J Urol 2002;168:1811. 176. Shuman WP: CT of blunt abdominal trauma in adults. Radiology 1997;205:297. 177. Skinner D: Traumatic renal artery thrombosis: A successful thrombectomy and revascularization. Ann Surg 1973; 172:264. 178. Sklar DP, Diven B, Jones J: Incidence and magnitude of catheter-induced hematuria. Am J Emerg Med 1986; 4:14. 179. Smith EM, ElderJS, SpirnakJP: Major blunt renal trauma in the pediatric population: Is a nonoperative approach indicated? J Urol 1993;149:546. 180. Snyder H, Caldamone AA: Genitourinary injuries. In Welch KJ, Randolph JG, Ravitch MM (eds): Pediatric Surgery, 4th ed. Chicago, Mosby Year Book, 1986. 181. Spirnak JP, Persky L, Resnick MI: The management of civilian ureteral gunshot wounds: A review of 18 patients. J Urol 1985;134:733. 182. Stalker HP, Kaufman RA, Stedje K: The significance of hematuria in children after blunt abdominal trauma. AJR Am J Roentgenol 1990;154:569. 183. Stein JP, Kaji DM, Eastham J, et al: Blunt renal trauma in the pediatric population: Indications for radiographic evaluation. Urology 1994;44:406. 184. Teigen CL, Venbrux AC, Quinlan DM,Jeffs RD: Late massive hematuria as a complication of conservative management of blunt renal trauma in children. J Urol 1992;147:1333. 185. Thomae KR, Kilambi NK, Poole GV: Method of urinary diversion in nonurethral traumatic bladder injuries. Retrospective analysis of 70 cases. Am Surg 1998;64:77-80. 186. Toporoff B, Sclafani S, Scalea T, et al: Percutaneous antegrade ureteral stenting as an adjunct for treatment of complicated ureteral injuries. J Trauma 1992;32:534. 187. Townsend M, DeFalco AJ: Absence of ureteral opacification below ureteral disruption: A sentinel CT finding. AJR Am J Roentgenol 1995;164:253. 188. Tso EL, Beaver BL, Haller JJ Jr: Abdominal injuries in the restrained pediatric passenger. J Pediatr Surg 1993; 28:915. 189. Tunc HM, Tefekli AH, Kaplancan T, et al: Delayed repair of post-traumatic posterior urethral distraction injuries: Long-term results. Urology 2000;55:837. 190. Turner WW Jr, Snyder WH 111, Fry WJ: Mortality and renal salvage after renovascular trauma: A review of 94 patients treated in a 20 year period. Am J Surg 1983;146:848. 191. Velmahos GC, Degiannis E: The management of urinary tract injuries after gunshot wounds of the anterior and posterior abdomen. Injury 1997;28:535. 192. Volpe MA, Pachter EM, Scalea TM, et al: Is there a difference in outcome when treating traumatic intraperitoneal bladder rupture with or without a suprapubic tube?J Urol 1999;161:1103. 193. Wazzan W, Azoury B, Heinady K, et al: Missile injuries of the upper ureter treated by delayed renal autotransplantation and ureteropyelostomy. Urology 1993;42:725. 194. Weaver FA, Kuehne JP, Papanicolau G: A recent institutional experience with renovascular hypertension. Am Surg 1996;62:241. 195. Weems WL: Management of genitourinary injuries in patients with pelvic fractures. Ann Surg 1979;189:717.

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196. Werkman HA, Jansen C, Klein JP, e t al: Urinary tract injuries in multiply-injured patients: A rational guideline for the initial assessment. Injury 22:471, 1991. 197. Wessel LM, Scholz S,Jester I, et al: Management of kidney injuries in children with blunt abdominal trauma. J Pediatr Surg 2000;35:1326. 198. Wessells H, McAninchJW, Meyer A, et al: Criteria for nonoperative treatment of significant penetrating renal lacerations. J Urol 157:24, 1997.

199. Whitesides E, Kozlowdki DL: Ureteral injury from blunt abdominal trauma: Case report. J Trauma 1994;36:745. 200. Wyatt JB, Scobie WG: The management of penile zipper entrapment in children. Injury 1994;25:59. 201. Yale-Loehr AJ, Kramer SS, Quinlan DM, et al: CT of severe renal trauma in children: Evaluation and course of healing with conservative therapy. AJR Am J Roentgen01 1989; 152:109. 202. Zakin D: Perforation of the bladder by the intrauterine device. Obstet Gynecol Surv 1984;39:59.

Musculoskeletal Trauma Richard S. Davidson and Michelle S. Caird

Musculoskeletal trauma is the most common medical emergency in children. The number of cases continues to increase in association with the popularity of motor vehicles, all-terrain vehicles, and power lawn mowers. In a child with multiple injuries, optimal treatment requires a cooperating team of medical professionals with diverse specialties who understand the priorities of each team member. As in all other pediatric specialties, it is important to remember that children are not "little adults." Priority management need not compromise complete patient management. This chapter reviews the important differences between the musculoskeletal systems of children and adults, and it highlights the principles of evaluation and management in children with musculoskeletal injuries. The treatment of high-priority musculoskeletal injuries is specifically discussed, including open fractures, compartment syndrome, femoral neck fractures, mangled extremities, spine trauma, and suspected child abuse. For details on the management of specific musculoskeletal fractures and injuries of childhood, readers should refer to textbooks on children's f r a c t ~ r e s . l ~ , 2 ~ 2 ~

MUSCULOSKELETAL SYSTEMS OF CHILDREN AND ADULTS Differences in the musculoskeletal anatomy and biomechanics of children and adults determine the unique patterns of musculoskeletal injury seen in childhood. Injuries to growing bones are a double-edged sword: they can have a remarkable capacity for healing and remodeling, but they are also subject to the problems of overgrowth and growth disturbance, which can have lifelong consequences.

Anatomy The major anatomic distinctions of skeletally immature bones are the physis and the periosteum. Each long bone in a child contains the epiphysis, physis, metaphysis, and diaphysis (Fig. 19-1). The epiphysis is the area beyond the physis, or primary growth plate, which contains the

articular cartilage. The secondary center of ossification arises within the epiphysis and progressively enlarges as the cartilage ossifies during skeletal maturation. The physis provides longitudinal growth and converts the newly formed cartilage into bone in the metaphysis. The diaphysis, or shaft, is surrounded by periosteum, which generates new bone and provides circumferential bone growth. By adulthood, the growth plate closes, and there is limited potential for remodeling.

Biomechanics Skeletally immature bones are porous, less brittle, and better able to tolerate deformation than are mature bones. Pores stop the progression of a fracture line but weaken the bone under a compressive force. As a result, a greater variety of fractures is seen in children than in adults. A child's bone can bend without fracture (Fig. 19-2); it can buckle under compression;it can fracture like a "green stick," with an incomplete crack on the tension side and a bend on the compression side; and it can fracture completely. The thick periosteum that surrounds the diaphysis of the bone can minimize or prevent displacement of diaphyseal fractures. The periosteum tears on the tension side of a fracture but often remains intact on the compression side. The intact periosteum can then function as a hinge or a spring, increasing deformity. Depending on the injury, the periosteum may simplify or complicate reduction of a fracture (Fig. 19-3). In the complex of bone, ligaments, and cartilage in a child, the physis is the weakest part and therefore is the most likely site of failure. An angular force to a joint in a young child is most likely to cause a fracture along the growth plate, whereas in an adolescent or an adult, a ligamentous injury or dislocation would occur. Frankel and Nordin15 provide extensive information on the biomechanics of bone. In a fall on an outstretched hand, a young child is unlikely to sprain a wrist; more commonly, a child sustains a fracture with a displaced distal radius growth plate. Similarly, instead of spraining an ankle, a child is more likely to sustain a physeal fracture of the distal fibula. Under low-energy forces, these injuries are unlikely to lead to growth disturbance.

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. - .

Anatomy of the child's bone.

Articular cartilage Epiphysis Ossification center Growth plate

Physis

Primary and secondary spongiosa

Metaphysis

Cancellous bone Diaphysis Compact bone

The Salter-Harris classification system of fractures involving the physis can guide proper management (Fig. 194).28 Type 1 fractures extend along the entire physis. Type 2 fractures involve part of the growth plate and part of the metaphysis; these fractures are seldom associated with growth arrest except when they occur in the distal femur

i

d

........ ............ ...... ....... ....... ...............

Bend

Buckle

Greenstick

,

- -

Fracture types in children. (From Rang M: Children's

Fractures. Philadelphia, JB Lippincott, 1974.)

and proximal tibia. Type 3 fractures involve part of the physis and pass across the epiphysis into the joint. Because of the possibility of incongruity of the joint, type 3 fractures often require open reduction and fixation. Type 4 fractures occur longitudinally, crossing the physis from the metaphysis into the epiphysis. This type of fracture is commonly associated with subsequent formation of a bony bar across the physis, which causes partial growth arrest with subsequent angulation. Open reduction and internal fixation are usually required for type 4 fractures, because joint incongruity and fusion across the physis are common. Type 5 fractures are diagnosed retrospectively, when all or part of the physis fails to grow. It is hypothesized that injury to the physis results from direct compression or local vascular insult. Growth disturbance may result in loss of longitudinal growth or angular deformities. Damage to the physis in high-energy injuries can lead to asymmetrical growth in any of the fracture types.

The physiologic differences between the musculoskeletal systems of children and adults are found in healing and remodeling. Growing bones are also at risk for the unique problems of overgrowth and growth disturbance. Healing in children is rapid and age dependent. A newborn may achieve clinically stable union of a fracture in 1 week, whereas a similar fracture in an adolescent may take 6 weeks to heal. In children, the rapid healing process partially results from the thick periosteum, which may form its own bone bridge. Except for displaced

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= closed hinge

-

.

A, In children, the intact periosteum of a fracture prevents reduction by traction. B, By retracing the path of injury, the fracture can be reduced. C, Closing the hinge. D, A cast with three-point molding holds the hinge closed and keeps the fracture reduced. (From Rang M: Children's Fractures. Philadelphia, JB Lippincott, 1974.)

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intra-articular fractures or fractures with gross soft tissue interposition, nonunion of fractures is rare in children. The bones of children have great potential for remodeling, but the limitations must be understood. Remodeling potential is better in younger patients, in deformities closer to the physes, and where angulation is in the plane of motion of the nearestjoint. Remodeling does not effectively correct angulation perpendicular to joint motion or rotation. These deformities should be reduced before healing begins (Fig. 19-5). Growth stimulation may follow fractures of long bones. This can be especially apparent in the lower extremity. The inequality in leg length that results from such stimulation is less important in children younger than 2 years and in adolescents. For children of other ages, an average l c m increase can be expected in femur fractures.11,29,3* Although discrepancies in leg length are unpredictable, it is often possible to reduce the ultimate inequality by allowing the fracture to heal with a 1-cm overlap in an otherwise anatomic alignment. Most of the growth stimulation occurs within the first year after injury, so follow-up visits for 1 year are recommended, even after uneventful healing. Damage to the physis can produce severe shortening, angular deformity, or both. Although this may be caused by the initial trauma, it can also result from failure to obtain anatomic reduction of a physeal fracture or from repeated or overzealous attempts at reduction (Fig. 19-6). When major (>2 cm) limb length discrepancies in the lower extremities are evident, treatment depends on the amount of remaining skeletal growth and the projected difference in limb lengths. Treatment may involve timed ablation of the growth plate on the normal limb, shortening osteotomy of the normal limb, or lengthening of the short limb. Angular deformities can also be addressed, taking into consideration the patient's skeletal age and the severity of the deformity.

EVALUATION OF MUSCULOSKELETAL INJURIES Clinical Assessment The initial assessment of children with multiple injuries may be difficult. Details of the incident may be missing, and the patient's history may be incomplete. The Advanced Trauma Life Support (ATLS) system of assessment involves a primary evaluation to identify and immediately address life-threatening injuries, followed by a secondary

Salter-Harris classification of epiphyseal fractures. Type 1 involves the entire physis. Type 2 involves part of the growth plate and part of the metaphysis. Type 3 involves part of the physis and passes across the epiphysis into the joint. Type 4 is longitudinal, crossing the physis from the metaphysis into the epiphysis. Type 5 is diagnosed retrospectively when the physis fails to grow. See text for clinical implications of each fracture type.

7

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TRAUM Slwen2year m with eigh~degrees of re'moq :

a forearm fracture over a 9period. A to C, An teroplOStC plane. D t o E Late ral plane

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Anteroposterior radiograph of the knees in a 13-year-old boy shows growth disturbance of the left distal femoral growth plate after a fracture (on right in photo).

children, cannot provide a history,judicial use of special diagnostic studies can be critical.

evaluation to find and treat other significant injuries. The injuries identified in the secondary evaluation must also be treated in a timely manner to prevent devastating lifelong consequences. Postponing the management of serious musculoskeletal injury for an extended period can be associated with a poor prognosis for return to normal function. The musculoskeletal examination begins with observation of the patient for sites of deformity, swelling, contusions, abnormal color, and open fractures. If a fracture is suspected, confirmatory diagnostic studies may be integrated into the complete physical examination. If such studies cannot be done, it must be assumed that a fracture exists, and the suspected site must be splinted until the fracture is confirmed or ruled out. Splinting may also reduce discomfort and limit further damage to soft tissue. A complete neurovascular examination is essential in any case of suspected limb or spine injury. When an uncooperative patient will not allow an adequate physical examination or, in the case of comatose patients or preverbal

A

-

.

Radiographic Assessment Plain radiography is the first and most widely used test to identify skeletal injury in children, but it can also be a major source of misdiagnosis in this age group. Cartilage, which makes up a large percentage of the child's skeleton, is radiolucent but can fracture. Ossification centers appear at different ages in different locations. The timing of their appearance a i d their location vary greatly and can suggest fractures. Confusion most frequently occurs in the elbow, knee, and cervical spine. Comparison of the injured and uninjured limbs can be useful. Plain radiographic soft tissue signs, such as the posterior fat pad-sign in elbow injuries, are associated with a high likelihood of underlying fracture (Fig. 19-7).30

B

Lateral elbow radiographs of a 2-year-old boy with a mildly displaced supracondylar humerus fracture and posterior fat pad sign (A) and a normal age-matched elbow (B).

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A number of imaging studies are available for the assessment of pediatric musculoskeletal injuries and are injury and age specific. Radiographs may confirm fractures. Ultrasonography is a readily available, noninvasive imaging test that can be used to evaluate the unossified epiphysis, especially in injuries about the elbow.8 Magnetic resonance imaging (MRI) may also be helpful, especially in evaluating the injured spine, but it may require general anesthesia in a young or uncooperative patient. Computed tomography (CT) scanning is useful in periarticular fractures in children approaching skeletal maturity. For exarnple, ankle physeal fractures in children with partially closed physes are best delineated with CT scan.22 Arteriography may be required to assess vascular injury associated with a fracture. Rarely, proximal tibia1 physeal fractures and distal humerus fractures through the supracondylar region can be associated with disruption of the blood supply to the distal limb. These injuries require emergent treatment, and an intraoperative arteriogram may also be needed. Joint aspiration can identify blood and fat, which indicate an intra-articular fracture that would not be identified on radiographs. Finally, arthrography and arthroscopy may define intra-articular injury to the cartilage and ligaments.

MANAGEMENT OF MUSCULOSKELETAL INJURIES Immediate Treatment Priority treatment cannot interfere with complete treatment of an injured child. Proper timing and coordination of management with other disciplines are imperative. Traction or splinting often adequately stabilizes the musculoskeletal injury until other tests and treatments have been completed. Immobilization may also reduce the need for pain medications, which can mask the symptoms of other disorders, such as intra-abdominal injuries, and inhibit diagnosis. Although there are many types of splints, ranging from plaster to traction bows, the basic principles of fracture management remain the same. The injured part should be splinted as it is found, and the joints above and below the injury should be immobilized without compromising the circulation of the soft tissues. Portable traction splints or custom-molded, well-padded plaster or fiberglass splints can be used in the initial management of fractures. Failure to immobilize the fracture can cause further soft tissue damage from sharp bone ends, crushing of entrapped neurovascular elements, or reopening of clotted vessels.

The choice of fixation method depends on the child's age, the location of the fracture, the presence and extent of soft tissue injury, and the presence of multitrauma. Metaphyseal undisplaced or impacted fractures are likely to heal faster than diaphyseal or displaced fractures. Fractures with devitalized bone or soft tissues take longer to heal. Radiographic evaluation in conjunction with clinical judgment and experience is needed when determining the healing time of fractures in children. Fragments of bone must be held together until they are sufficiently strong to withstand the forces specific to the bone. A satisfactory position must be obtained, without harming adjacent tissue, before the fracture becomes fixed. Fractures in newborns and infants begin to heal within a few days, but fractures in adolescents can be moved freely for 10 to 14 days. Excessive cast padding, resolution of swelling, or a poorly applied cast may permit progressive malposition within the cast. Fractures should be followed with frequent radiographs until union is secure, to avoid displacement. Unstable fractures should be imaged before consolidation to evaluate for loss of alignment. This allows for easy repeat reduction. In children, the thick periosteum tears on the tension side of a fracture but often remains intact on the compression side. The intact periosteum can then function as a hinge, increasing the success of closed reduction of displaced fractures by three-point molding (see Fig. 19-3). Reduction must be performed gently. Forceful and repeated manipulation of physeal fractures can produce iatrogenic damage and growth disturbances. Entrapment of soft tissue occasionally prevents reduction of an otherwise stable fracture (Fig. 19-8) and requires open reduction and immobilization in a cast. In some cases, internal fixation with crossed pins, plates and screws, intramedullary nails, or external fixation with pins in metal outriggers or rods may be useful (Fig. 19-9). The benefits of each of these devices must be weighed against the future need for operative removal and the possible disturbance to the growth plate. Specific indications for internal and external fixation may include fractures with significant soft tissue injury, fractures in

Radial nerve

Definitive Fracture Management Adequate stabilization of fracture fragments prevents further soft tissue injury, frequently decreases pain, and facilitates wound care and patient mobilization. Techniques of definitive stabilization in children include splinting, casting, skeletal traction, external fixation, pinning, flexible intramedullary nailing, and plating.

, .

. - Supracondylar elbow fracture. Soft tissue may become

entrapped between bone fragments in these types of fractures.

CHAPTER

,

.

..

Anteroposterior radiographs of right femur

fractures fixed with a variety of fixation methods. A, SalterHarris type 2 fracture with crossed pins in a 9-year-old girl. B, Intertrochanteric fracture with screws and side plate in a 7-year-old boy. C,Transverse shaft fracture with elastic intramedullary nails in a 13-year-old boy. D, Subtrochanteric fracture with external fixator in an 8-year-old boy.

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children with closed head injury, those associated with neurovascular injury, and fractures that fail nonoperative treatment. Comminuted and oblique fractures and those with complete tears of the periosteum may be too unstable for cast immobilization. In cases of intra-articular fractures, such as Salter-Harris types 3 and 4, open reduction and internal fixation are frequently necessary to avoid incongruity of the joint or growth disturbances. Fractures associated with neurovascular injury requiring repair should be stabilized first.

HIGH-PRIORITY MUSCULOSKELETAL INJURIES Although many musculoskeletal injuries in children can be treated on an urgent rather than an emergent basis, the discussion of some high-priority musculoskeletal injuries in children is warranted. Even in nonurgent cases, it is important to remember that injuries to growing bones can have lifelong consequences.

Open Fractures and Traumatic Arthrotomies Open fractures are true orthopedic emergencies because a delay in treatment can lessen the chance of saving the limb. These injuries frequently result from high-energy trauma. The fractures communicate with the outside environment and are at increased risk for infection. The cornerstones of management include recognition, administration of appropriate antibiotics, stabilization of the fracture, and prompt irrigation and adequate debridement of wounds. Open fractures may require multiple surgical procedures to achieve adequate soft tissue coverage and fracture healing. When a laceration or abrasion is noted in proximity to a fracture, an open fracture must be suspected. Radiographic evidence of air shadows around the fracture may confirm the diagnosis. A sharp fragment of bone can tear through the skin, and the elastic properties of a child's bone can readily straighten the fracture fragments after the force is discontinued. The protruding point of bone can then draw back under the skin, taking debris and bacteria with it into the deep tissues. Minimal signs of injury do not necessarily mean a minimal chance of infection. Wounds should not be probed in the emergency department, where the risk of iatrogenic contamination is high and the likelihood of adequate debridement is low; if necessary, such procedures should be done in the operating room. The Gustilo system classifies open fractures according to the size and extent of soft tissue damage." Type I is an open fracture with a clean wound smaller than 1 cm. Type I1 is an open fracture with a laceration longer than 1 cm without extensive soft tissue damage, flaps, or avulsion~.Type I11 is an open fracture with extensive soft tissue injury and is further divided into three subtypes; type IIIA has adequate soft tissue coverage of a fractured bone despite extensive laceration of soft tissue, type IIIB involves extensive soft tissue injury with periosteal stripping that requires grafting or a flap for coverage, and type IIIC is an open fracture associated with arterial

injury that requires repair. The risk of infection is related to the severity of the injury: 2% in type I open fractures, 2% to 10% in type I1 open fractures, and up to 50% in type I11 open fractures.'7 Wounds should initially be dressed with sterile gauze soaked with antiseptic. Hemorrhage should be controlled by direct pressure. Patients should receive tetanus prophylaxis and antibiotics at recognition of the injury. Firstgeneration cephalosporins cover the gram-positive organisms found in type I and type I1 injuries. An aminoglycoside is added for type I11 injuries, and ampicillin or penicillin is added for farm injuries to fight potential anaerobic infection. Each wound must be adequately debrided and copiously irrigated with the patient under general anesthesia. Wounds may need to be re-evaluated after 2 or more days for additional debridement. Primary closure or delayed primary closure may be appropriate for some open fractures, whereas grafting or flap coverage is needed for larger soft tissue defects. The goal of debridement is removal of devitalized tissue to avoid the catastrophic consequences of an infection, which may include limb loss or chronic osteomyelitis. Adequate immobilization is necessary for soft tissue healing. For small lacerations, immobilization in a cast that has been windowed for wound inspection may suffice. For larger lacerations, external fixation is often necessary to provide stable fixation with access to the wound. Joint penetration by a foreign body can cause a diagnostic dilemma. Radiographs can be helpful if they reveal an "air arthrogram." Injection of sterile normal saline into the joint can also be diagnostic. If the liquid exits the wound or laceration, joint penetration has occurred and requires imgation and debridement in the operating room.

Compartment Syndrome Compartment syndrome occurs when pressure is elevated within a confined fascia1 space. This causes circulatory compromise and can progress to tissue necrosis. Closed fractures and crush injuries with associated edema may cause compartment syndrome. Forearm and leg compartments are most often involved. Ischemic injury starts when tissue pressure is 30 mm Hg below mean arterial pressure.Z0 The pressure within the compartments surrounding a fracture should be measured if compartment syndrome is suspected. Commercially available tissue pressure monitors or other measuring devices, including electronic arterial pressure monitoring devices, can be used. The diagnosis of compartment syndrome in children can be difficult. Adults with compartment syndrome verbalize extreme pain and demonstrate pain with passive stretch of the muscles within the affected compartments, whereas children often have difficulty communicating their discomfort. The classic signs of compartment syndrome are the five Ps-pain, pallor, paresthesia, paralysis, and pulselessness. These signs are rather unreliable in children and may manifest late in the process. An increasing analgesia requirement is an important sign of compartment syndrome in children.'

CHAPTER

With early recognition and timely management, full recovery can be achieved. All external compression is removed from the limb, compartment pressures are measured, and, if elevated, the compartments are surgically decompressed. In the forearm, volar and dorsal fasciotomies are required. In the leg, all four compartments (anterior, lateral, deep posterior, and superficial posterior) must be released. This can be accomplished with two incisions. Without prompt intervention, the result is irreversible damage to soft tissues with loss of function, subsequent contractures, and d e f ~ r r n i t y . ~ ~

Femoral Neck Fracture Although rare in children, fractures of the femoral neck and intertrochanteric regon require attention (Fig. 19-10). These fractures frequently result from high-energy impact, including traffic accidents and falls from a height,6 and are associated with a high complication rate from avascular necrosis, coxa vara, nonunion, delayed union, . ~ ~upper ~ end of the and premature physeal c l o s ~ r eThe femur lies within the joint capsule. After roughly 4 years of age, blood is supplied primarily by retinacular vessels that course from distal in the neck to proximal in the head. Delay in treatment of a fracture at the neck is associated with increased risk of avascular necrosis of the head and destruction of the joint and can cause lifelong disability. Early decompression of the hip joint, reduction of the fracture, and internal fixation can minimize the complication^.^

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neurovascular structures. Some limbs may be unsalvageable owing to extensive damage, some can be reconstructed with a resulting dysfunctional limb, and others can be salvaged with a good outcome. The Mangled Extremity Severity Score rates injuries based on objective criteria at initial presentation, including skeletal and soft tissue injury, limb ischemia, shock, and patient age. Although it originally developed in a primarily adult pop~lation,~s can be a useful adjunct to managing lower extremity trauma in children.12 Segmental bone loss is rare in children and does not necessitate amputation. If periosteum can be preserved, the potential to reform bone is extensive. P r o ~ e rtechniquis of debridement and stabilization, along k t h adequate time, may produce good results in children. External fixation techniques can allow for bone transport and osteogenesis to replace lost bone and axial deformity. Power lawn mower injuries are uncommon, preventable injuries that cause significant morbidity in children.lOJ3.23 Direct contact with the blade leads to laceration of tissue, amputation, or devitalizing shredding of the extremity. Such injury can result in damage to the vasculature and growth plate, joint stiffness, infection, or amputation. If salvage is undertaken, treatment follows that of open fractures. In the case of amputation, preservation of bony length and retention of all viable soft tissue are important for the ultimate functional outcome. Amputation through the diaphysis of a child's bone frequently results in overgrowth of the bony stump through the skin. This is especially true of the fibula, tibia, and humerus and can necessitate cutting back the bone every few years.

Mangled Extremities Severely traumatized or mangled extremities in children must be assessed and treated through a multidisciplinary approach on a case-bycase basis. They may involve extensive injury to or segmental loss of skin, muscle, bone, and

, - Anteroposterior pelvis radiograph of a l4year-old boy shows a left femoral neck fracture that required internal fixation.

Spine Trauma Injuries of the spine in children can be divided into those affecting the cervical spine and those in the thoracic and lumbar spine (see also Chapter 21).Just as in other parts

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A pediatric backboard should have a torso mattress or an occiput recess to accommodate the child's relatively large head and avoid potentially dangerous cervical spine flexion. of the body, patterns of injury to the spine in children differ from those in adults. Radiographic imaging can be challenging. Principles of immobilization are different for children as well. Cervical spine injuries in children differ from those in adults.' Children have greater ligamentous laxity and weaker neck musculature. In addition, they have large heads relative to body size; this effect is more pronounced in younger children. Cervical spine injuries in children tend to occur higher in the neck and can be primarily ligamentous or apophyseal without bony fracture.lg When immobilizing a child on a backboard, the relatively large head should be considered; a child's backboard splint should have a recess for the occiput or a mattress for the torso to maintain the alignment of the cervical spine, avoiding flexion of the neck (Fig. 19-11).zl Radiographic evaluation of the pediatric cervical spine can be challenging. Pseudosubluxation, or the apparent forward displacement of C2 on C3 and, less commonly, C3 on C4, is a welldescribed plain radiographic finding in normal children younger than 8 years.Wther sources

A

of difficulty in interpreting radiographs include incomplete ossification, epiphyseal variation, and elasticity of the disks and vertebral bodies relative to the neural structures, which allows extensive injury to the soft tissues without evidence of abnormality on plain radiographs or SCIWORA (spinal cord injury without radiographic abnormality). MRI is helpful in evaluating soft tissues in cases of possible cervical spine ligamentous injury in children.14 Injuries to the thoracic and lumbar spine are rare in children. The growth of vertebral bodies occurs through the apophyses or growth centers on the cranial and caudal ends of the bodies. With compression injury, adolescents are at risk for traumatic displacement of the vertebral apophysis and the attached disk into the spinal canal, especially in the lumbar region." Symptoms are similar to those seen in central disk herniation, including muscle weakness and absent reflexes. This injury requires recognition and emergent surgical decompression. Lap-belt injuries occur in children when they violently flex over the seat belt and the posterior spine is distracted." A fracture propagates from the posterior portions of the vertebra to the disks or vertebral body in the front (Fig. 19-12). In addition to the vertebral injury, children can sustain abdominal and aortic injuries. Such injuries should be suspected when an abdominal contusion, or the telltale seat-belt sign, is evident in a trauma patient. These injuries require immobilization and possible internal fixation if the injury is ligamentous.

B

Lap-belt injury of L4 in a 15-year-old girl without neurologic injury. A, Lateral lumbar spine radiograph shows fra L4 body and the I~osteriorspine. B, Sagittal magnetic resonance image of the 11umbar spine shows the extensive bony and soft tissue

both the

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Child Abuse The maltreatment of children is a complex medical and social problem, and its recognition is key to management (see also Chapter 24). Fractures before walking age in the absence of metabolic disease or child abuse are rare. Fractures are the second most common manifestation of child abuse after skin lesi0ns.2~Suspicion of abuse must be raised when there is a discrepancy between history and injury, when multiple fractures are present in different stages of healing, or when bruising, metaphyseal fractures, or long bone fractures appear in children younger than 1 year.3.26 No social stratum is free of this problem.

REFERENCES 1. Akbarnia B, Torg JS, Kirkpatrick J: Manifestations of the battered child syndrome. J Bone Joint Surg Am 1974; 56:1159. 2. Bae DS, Kadiyala RK, Waters PM: Acute compartment syndrome in children: Contemporary diagnosis, treatment, and outcome. J Pediatr Orthop 2001;21:680. 3. Blakemore LC, Loder RT, Hensinger RN: Role of intentional abuse in children 1 to 5 years old with isolated femoral shaft fractures. J Pediatr Orthop 1996;16:585. 4. Canale ST, Bourland WL: Fracture of the neck and intertrochanteric region of the femur in children. J Bone Joint Surg Am 197'7;59:431. 5. Cattell HS, Filtzer DL: Pseudosubluxation and other normal variations in the cervical spine in children. J Bone Joint Surg Am 1965;47:1295. 6. Cheng JCY, Tang N: Decompression and stable internal fixation of femoral neck fractures in children can affect the outcome. J Pediatr Orthop 1999;19:338. 7. Copley LA, Dormans JP: Cervical spine disorders in infants and children. J Am Acad Orthop Surg 1998;6:204. 8. Davidson RS, Markowitz RI, Dormans JP, et al: Ultrasonographic evaluation of the elbow in infants and young children after suspected trauma. J Bone Joint Surg Am 1994;76:1804. 9. Davison BL, Weinstein SL: Hip fractures in children: A long-term follow-up study. J Pediatr Orthop 1992;12:355. 10. Dormans JP, Azzoni M, Davidson RS, et al: Major lower extremity lawn mower injuries in children. J Pediatr Orthop 1995;15:78. 11. Edvardsen P, Syversen SM: Overgrowth of the femur after fracture of the shaft in childhood. J Bone Joint Surg Br 1976;58:339. 12. Fagelman MF, Epps HR, Rang M: Mangled extremity severity score in children. J Pediatr Orthop 2002;22:182. 13. Farley FA, Senunas L, Freenfield ML, et al: Lower extremity lawn-mower injuries in children. J Pediatr Orthop 1996;19:669. 14. Flynn JM, Closkey RF, Mahboubi S, et al: Role of magnetic resonance imaging in the assessment of pediatric cervical spine injuries. J Pediatr Orthop 2002;22:573.

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15. Frankel VH, Nordin M: Basic Biomechanics of the Skeletal System. Philadelphia, Lea & Febiger, 1980. 16. Green NE, Swiontkowski MF: Skeletal Trauma in Children, 3rd ed. Philadelphia, WB Saunders, 2003. 17. Gustilo RB, Anderson JT: Prevention of infection in the treatment of one thousand and twenty-five open fractures of long bones. J Bone Joint Surg Am 1976;58:453. 18. Helfet DL, Howey T, Sanders R, et al: Limb salvage versus amputation: Preliminary results of the mangled extremity severity score. Clin Orthop 1990;256:80. 19. Henrys P, Lyne ED, Lifton C, et al: Clinical review of cervical spine injuries in children. Clin Orthop 1977; 129:172. 20. Heppenstall RB, Sapega AA, Scott R, et al: The compartment syndrome: An experimental and clinical study of muscular energy metabolism using phosphorus nuclear magnetic resonance spectroscopy. Clin Orthop 1988; 226:138. 21. Herzenberg JE, Hensinger RN, Dedrick DK, et al: Emergency transport and positioning of young children who have an injury of the cervical spine: The standard backboard may be hazardous. J Bone Joint Surg Am 1989;71:15. 22. Karrholm J, Jansson LI, Laurin S: Computed tomography of intraarticular supination-eversion fractures of the ankle in adolescents. J Pediatr Orthop 1981;1:181. 23. Loder RT, Brown KL, Zaleske DJ, et al: Extremity lawnmower injuries in children: Report by the Research Committee of the Pediatric Orthopaedic Society of North America. J Pediatr Orthop 1997;17:360. 24. McMahon P, Grossman W, Gaffney M, et al: Soft tissue injury as an indication of child abuse. J Bone Joint Surg Am 1995;77:1179. 25. Ogden JA: Skeletal Injury in the Child, 3rd ed. New York, Springer, 2000. 26. Rex C, Kay PR: Features of femoral fractures in nonaccidental injury. J Pediatr Orthop 2000;20:411. 27. Rockwood CA Jr, Wilkins KD, Beaty JH, et al: Fractures in Children, 5th ed. Philadelphia, Lippincott Williams & Wilkins, 2001. 28. Salter RB, Harris WR: Injuries involving the epiphyseal plate. J Bone Joint Surg Am 1963;45:587. 29. Shapiro F: Fractures of the femoral shaft in children: The overgrowth phenomenon. Acta Orthop Scand 1981; 52:649. 30. Skaggs DL, Mirzayan R: The posterior fat pad sign in association with occult fracture of the elbow in children. J Bone Joint Surg Am 1999;81:1429. 31. Smith WS, Kauffer H: Patterns and mechanisms of lumbar injuries associated with lap seat belts. J Bone Joint Surg Am 1969:51:239. 32. Stephens MM, Hsu LC, Leong JC: Leg length discrepancy after femoral shaft fractures in children: Review after skeletal maturity. J Bone Joint Surg Br 1989;71:615. 33. Techakapuch S: Rupture of the lumbar cartilage plate into the spinal canal in an adolescent: A case report. J Bone Joint Surg Am 1981;45:481. 34. Whitesides TE, Heckman MM: Acute compartment syndrome: Update on diagnosis and treatment. J Am Acad Orthop Surg 1996;4:209.

Hand, Soft Tissue, and knvenomation lnjuries Michael L. Bentz and Delora Mount

Evaluation of pediatric hand and soft tissue injuries requires a systematic approach that includes all relevant organ systems at the site of trauma.' A high index of suspicion is necessary to make an accurate diagnosis and exclude subtle problems, particularly in toddlers and infants who are unable to cooperate with a detailed examination. Injuries are triaged according to their threat to life. After such triage has taken place, the more peripheral and often more dramatic and distracting injuries can be better defined.Vhe history is important to define baseline function, previous injuries, right- or left-hand dominance, and the mechanism and timing of injury. The initial physical examination must define vascularity and perfusion because an ischemic or poorly perfused extremity necessitates emergent surgical intervention. Other findings can be handled in a less urgent fashion, after an orderly assessment is complete. The patient should be examined in a well-lighted area with the parents present to exert a calming influence over a frightened child and thus increase the reliability of findings. This chapter focuses on the acute evaluation and management of hand, soft tissue, and envenomation injuries to provide a foundation for the accurate triage of injured children.5.14

HAND AND SOFTTISSUE INJURIES Evaluation Vascularity The goal of the initial examination is to determine the presence or extent of vascular injury, hypoperfusion, or ischemia. Symptoms of ischemia include pallor, paresthesia, paralysis, pain, and lack of pulse. The digits should be pink and warm if the patient has not had hypothermic exposure or proximal tourniquet application. Normal capillary refill time is 3 seconds and is most accurately tested by compressing the lateral aspect of the distal phalanx adjacent to the nail plate. A delayed refill time indicates impaired arterial inflow, whereas a rapid refill

time suggests venous hypertension or insufficiency. The pulse should be palpated bilaterally at the radial, ulnar, and brachial arteries. Percutaneous Doppler ultrasonography can be used to qualitatively and quantitatively define inflow if the pulse cannot be detected or if it is asymmetrical. Allen's test is important to define the relative contributions of the radial and ulnar arteries to the palmar arches of the hand. The ulnar artery is the dominant source of inflow to the hand and continues into a patent palmar arch in 85% of uninjured hands.' Significant bleeding noted during the initial evaluation is managed by firm manual compression or, if the time until definitive intervention is expected to be prolonged, by proximal tourniquet application. A hemostat or clamp should not be placed blindly into the wound, because lack of blood flow may injure adjacent neural structures. Impaled or retained foreign objects should be left in situ until definitive management is possible because they may staunch the flow of blood from a vascular injury.

Peripheral Nerves Peripheral nerves should be evaluated after vascular inflow has been assessed. Isolated nerve injuries cause predictable neurologic deficits that manifest as abnormalities in sensation or motor function, depending on the location of injury.18 Vascular injuries can also cause neurologic deficits, particularly in subacute wounds; therefore, the evaluation of nerve and vascular injuries should generally occur in tandem. A clear concept of cross-sectional anatomy is helpful in visualizing potential at-risk structures. Evaluating the nerve function at the distal aspect of the hand can be used to screen for a more proximal nerve injury. The median nerve is responsible for sensation to the three and a half volar radial digits. The function of this nerve can be tested by a pinprick or, more objectively, by two-point tactile discrimination. Median nerve motor function can be tested by palpating the contraction of the abductor pollicis brevis and opponens pollicis muscles as the patient forms an "0"with the index finger

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The ability to form an "0'' with the index finger and thumb, Mnth palpable contraction of the thenar muscles , indicates an! intac median nerve.

and thumb (Fig. 20-1). The ulnar nerve supplies sensation to the one and a half ulnar digits. Motor function of this nerve is most accurately tested by palpating the contraction against the force of the first dorsal interosseous muscle while the fingers are spread (Fig. 20-2). There is no radial nerve motor innervation of the intrinsic hand muscles, so the motor function of the radial nerve is best screened by wrist and digit extension (Fig. 20-3). The radial nerves provide sensation to the three and a half dorsal radial digits of the hand to the level of the distal phalanges, although overlap is common. Serial examination can be quite helpful, and cooperation and a focused effort are essential for a reliable evaluation. Further, neurologic findings associated with compartment syndrome evolve over time and may not be obvious during the initial examination.l3

Digit spread with palp; traction of the first dorsal interosseous consistent with an intact ulnar nerve.

conscle is

Skeleton, Tendons, and Ligaments Although some skeletal injuries are obvious on routine examination, most require radiographic evaluation. Physical examination findings of fracture include deformity, crepitus, ecchymosis, pain, instability, and swelling. Anteroposterior, lateral, and oblique radiographs should be obtained for all but the most minor injuries to evaluate for fractures, dislocations, and foreign objects. Familiarity with the Salter-Harris classification of pediatric fractures is important because the specific fracture patterns offer prognostic information relevant to subsequent growth (see Chapter 19).'6,23 The presentation of frache tures has been well d o ~ u m e n t e d . ~ 2 . * Texamination and radiographic appearance are combined to accurately describe the fracture. Open fractures have an associated

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TRAUMA Digit and wrist extensiori demoInstrates radial nerve integrity because no muscles in the hand are innervated by radial nerves.

full-thickness soft tissue injury, whereas closed fractures do not. Simple fractures result in two bone fragments, whereas comminuted fractures involve several fragments. Greenstick fractures involve one cortex and are particularly relevant in children because of their malleable bones. The description of a fracture should also include information regarding length (shortened, elongated, normal), angulation (volar, dorsal, radial, ulnar), rotation (present or absent), and displacement as a percentage of normal alignment. Tendon injuries can be very difficult to diagnose, particularly in young or uncooperative children. In such cases, surgical exploration is necessary to definitely confirm certain injuries. The posture of the hand at rest gives information regarding tendon integrity. In a relaxed position, the hand should form a gentle cascade; this position results from passive tension of the tendons. With compression of the distal forearm, all digits should adopt flexion posturing as a result of the tenodesis effect. A digit that remains extended out of the cascade suggests

disruption of the flexor mechanism (Fig. 20-4). The flexor digitorum superficialis tendon to each of the four fingers is tested by holding the adjacent digits in a fixed position and allowing metacarpophalangealjoint flexion (Fig. 20-5). The flexor digitorum profundus and flexor pollicis longus tendons are evaluated by holding the middle phalanx and observing distal interphalangeal joint flexion. Ligament injuries can be difficult to diagnose, particularly in the presence of associated soft tissue or skeletal injuries.Z4 Abnormal joint stability is an indicator of disruption of the 1igaments.lZ If the opposite side is uninjured, joint stability should be compared with that side as an indicator of preinjury status. Plain and stress radiographs of an avulsion fracture at the site of ligament insertion can confirm clinical findings.

Soft Tissue A thorough determination of soft tissue injuries is important for a knowledgeable evaluation of wound healing,25 Forearm compression has failed to cause flexion of the index finger in this patient; this suggests flexor mechanism discontinuity to the index finger.

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Function of the flexor digitorum superficialis tendon is tested by demonstrating isolated metacarpophalangeal and proximal interphalangeal joint flexion. Flexor digitorum profundus tendon function is tested by holding the middle phalanx fixed and observing distal interphalangeal joint flexion.

but even more so for the evaluation of long-term function and outcome of primary or secondary reconstructive surgery. The amount of soft tissue present in the area of a wound determines the feasibility of primary repair of vascular, neural, and osteoligamentous injuries, and an adequate amount is required for proper healing. The size (measured objectively),shape, location, and general configuration of each wound is recorded, and the mechanism of injury and preinjury status of the patient are established. Obvious foreign objects are removed, although projectiles impaled through an extremity are left in situ until they can be managed definitively. Exposed vital structures as well as associated fractures and tendon injuries are noted.

Early Treatment Vascular Ischemia is one of the few surgical emergencies associated with upper limb trauma. Revascularization is a top priority after the correction of life-threatening injuries. Because irreversible changes start to occur after 4 hours of ischemia, expeditious surgical intervention is mandatory, especially if the ischemic tissue involves muscle. Primary vascular repair is the most effective procedure and is ideally accomplished by debridement, mobilization, and primary anastomosis of injured segments. Reversed vein grafts, which are frequently done with foot, forearm, saphenous, or cephalic veins, should be used liberally if tension or lack of tissue prevents easy approximation of adjacent segments. In general, all arteries and veins proximal to the elbow should be repaired. Repair of arterial injuries below the elbow should also be considered to prevent cold intolerance; however, only about half of these repairs remain patent.10 If necessary, the radial artery can be ligated primarily. Once repairs are complete, fasciotomy should be considered if ischemia has been prolonged,

soft tissue damage is significant, or adequate postoperative monitoring is not available.l~eria1examination should then be pursued in an effort to make an early diagnosis of recurrent ischemia or postsurgical thrombosis or bleeding. The role of anticoagulation therapy in this setting is controversial and is based on the surgeon's preference and experience.

Peripheral Nerves Injury to the peripheral nerves is not an emergency and can frequently be addressed when an adjacent vascular injury is being repaired. When a wound is clean, uninfected, and well vascularized, primary nerves should be repaired in an end-to-end fashion. Such repair can be facilitated through the mobilization of proximal and distal injured segments, which can reduce tension and augment blood flow. If mobilization of the injured segments cannot adequately repair the defect, interpositional nerve grafts can be used for definitive reconstruction. In such cases, early secondary repair in the first 10 days after injury is optimal. To ensure that the injured area remains intact, the involved limb should be splinted to minimize further proximal migration of the transected nerve before surgery and to relieve anastomotic tension.

Skeleton, Tendons, and Ligaments When injuries to the skeleton, tendons, or ligaments are diagnosed, restoration of normal or acceptable anatomy followed by appropriate immobilization is indicated. In children, an injury that is suspected but not objectively defined is particularly common. Hand fractures may not be evident on radiographs for several weeks. In this situation, presumptive treatment should be carried out, which usually involves immobilization of the potentially injured area, despite equivocal physical examination or radiographic findings. Immobilization is rarely contraindicated in children because it allows protection from further

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injury, improves pain control, and maintains local anatomy. Use of a splint (instead of a cast) is ideal because it allows swelling into a nonfixed space and limits the possibility of vascular compromise during the acute injury and postreduction periods. Anatomic reduction of fractures and dislocations can be done at the time of injury or in the following week, with good functional results.29 In the acute setting, excellent anesthesia can be obtained by performing a hematoma block. This is accomplished by injecting 2 to 3 mL of lidocaine 1% without epinephrine into the fracture site. Reduction in the subacute setting most commonly requires a traditional digital block. Particularly in smaller children, it must be kept in mind that the limiting dose of plain lidocaine is 4 mg/kg of body weight. A description of the reduction maneuvers for specific types of fractures is beyond the scope of this chapter, but in general, gentle manual traction or finger-trap distraction with simultaneous rotation or derotation allows improvement in many types of fractures and dislocation^.^ Postreduction radiographs should be obtained in most if not all patients before or after immobilization. The specific position of immobilization is less critical for children than adults because children are less prone to stiffening and tightening of the ligaments. The "position of safety" can always be used at least initially for splinting: the wrist is placed in 30 to 45 degrees of extension, the metacarpophalangeal joints are placed in 70 degrees of flexion, and the interphalangeal joints are left straight. Serial physical and radiographic examinations are tailored to the specific injury and clinical course.

Soft Tissue After soft tissue and associated vital structure injuries are documented, irrigation of all significant wounds should be performed with normal saline solution, after which foreign objects are removed and tissue that is clearly devitalized is debrided. These procedures may require a local anesthetic, which should be given only after a thorough neurologic examination has been completed. Simple lacerations and small surface-area avulsions can be closed primarily using the same layered closure method used for deep or gaping wounds under tension, Suture choice depends on the location, size, and cause of the wound, as well as the patient's age. A smaller child who requires sedation for the primary wound repair will be hypersensitive to suture removal, when sedation is usually not available. In such cases, absorbable sutures reinforced with Steri-strips and an adhesive are ideal. Permanent sutures should be used in older or cooperative patients to minimize the inflammatory response and avoid early scarring. The potential for scarring depends on the location of the wound and the mechanism of injury. Scarring can be minimized through judicious wound closure. Open wounds that cannot be closed primarily require more elaborate intervention. To bridge the gap between injury and wound closure, the wound must be managed and protected. Normal saline wet-to-wet dressings are a simple and effective way to provide limited debridement, allow the initiation of granulation, and prevent desiccation.

Povidone-iodine dressings should be reserved for shortterm use in infected wounds. Acetic acid solution (0.25%) is appropriate for wounds that have culture documentation of infection with Pseudomonas species. Quantitative wound biopsies should be reserved for nonthermal burns. If the skin defect is only partial thickness and no vital structures are exposed, split-thickness skin grafting or skin distraction is appropriate. Split-thickness skin grafts are used for larger wounds, less cosmetically significant wounds, or those in which the wound bed may not be optimal because of infection, inflammation, or ischemia. Full-thickness skin grafts contract less after revascularization and thus are ideal for cosmetically significant areas or those where wound contraction is undesirable. Local skin flaps can also be used in such settings, offering a cosmetically favorable replacement of like tissue. These skin flaps can be random if they have no specific blood supply or axial if the blood is supplied by a specific vessel." Regional muscle flaps can be used almost anywhere in the body, especially when highly vascularized tissue of significant bulk is required to cover exposed critical structures and fill dead space. Similar to axial pattern skin flaps, these muscle flaps are used on the basis of a known blood supply, which makes their dissection reliable and safe. Finally, when local tissue is not available or is inadequate to provide wound closure, microvascular free tissue transfer is indicated using specific donor "free flaps" to accomplish specific tasks.

Amputations Traumatic amputations in children should be considered for replantation by a qualified microsurgical team, given the excellent results obtained when compared with adult series.15 To optimize the chance of success, the amputated part should be wrapped in saline-moistened gauze, sealed in a plastic bag, and placed in a bag of ice and saline solution; the part must not contact the ice directly.

ENVENOMATION INJURIES Snakebites More than 2700 species of snakes exist; 115 of these species are indigenous to the United States, and only 19 of the 115 species are p o i ~ o n o u s .Pit ~ vipers, which are named for the pit located between their eyes and nostrils, account for most bites. Pit vipers include rattlesnakes, copperheads, and cottonmouth^.*^ Coral snakes represent the other poisonous family. Most bites occur during the summer months in the morning, late afternoon, or evening. Not all bites are associated with envenomation. Signs of envenomation include pain, edema, ecchymosis, nausea, vomiting, hypotension, disseminated intravascular coagulopathy, hemolysis, mental status changes, seizures, and death." The severity of signs is proportional to the degree of envenomation. Early intervention includes reassurance and support, immobilization, limb elevation, venous tourniquet application, and rapid transfer to the nearest medical facility. Cryotherapy and wound incision

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and suction are no longer recommended. Mild pit viper envenomations (characterized by mild pain, local edema, lack of systemic signs, and normal laboratory values) require up to 5 vials of antivenin; moderate envenomations (severe pain, extending edema, nausea, vomiting, neurologic signs, and abnormal laboratory values) require 10 to 15 initial vials of antivenin, with retreatment as necessary; and severe envenomations (rapid progression of local, systemic, and laboratory abnormalities) require an initial Antivenin is admindose of 15 to 20 vials of anti~enin.2~ istered intravenously only after a skin test has been done to rule out the possibility of an anaphylactic reaction. The initial dose for children is one and a half to two times that of adults because of the smaller circulating blood ~ . ~ ~ dosvolume and relative venom c o n ~ e n t r a t i o n .Initial ing should be followed by aggressive intravenous hydration. Fasciotomy should be considered but is seldom required.?"nitial management of bites from snakes from other countries is similar, although antivenin use requires adjustment, depending on the type of snake.2' In addition to its use for pit vipers from North America, antivenin is effective for bites from fer-de-lance, bushmaster, and cantil snakes, which are found in Central and South America. Australian species frequently known to cause envenomations include the common brown snake, mainland tiger snake, lowland copperhead, and red-bellied black snake.

Other Bite Injuries Gila monsters, which are found in the southwestern United States, and their relative the Mexican beaded lizard are active in late spring. These lizards inject venom as long as they cling to the victim. Wounds show edema, but tissue loss is less pronounced than that associated with envenomation by pit vipers; however, systemic signs can ultimately be similar. These injuries are managed by removing the animal from its victim, followed by local and systemic supportive care. Antivenin is not available. Radiographs should be obtained to exclude retained teeth." Black widow spiders are venomous New World spiders; the females are black with an hourglass-shaped red mark on the abdomen.%ocal signs of a bite can be limited, followed by systemic neuromuscular symptoms of diffuse rigidity and spasm that potentially lead to respiratory arrest approximately 1 hour later. Envenomations by black widow spiders are managed by local care, fluid and cardiovascular support, parenteral calcium gluconate, muscle relaxation, and antivenin.2,"11,z Scorpion stings in children have serious sequelae. Bark scorpions are the only toxic species in the United States; however, others are common in Mexico and equatorial countries. Local signs of envenomation are minimal, whereas systemic neuromuscular findings are present in the sympathetic and parasympathetic systems. Children are particularly susceptible to the severe cardiorespiratory and neuromuscular dysfunction associated with envenomation. Therapy of scorpion stings includes local wound care, topical ice, specific antivenin, and systemic support, including ventilation, control of

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tachyarrhythmias, and sedation. Treatment is similar to that for spider bites, although scorpion stings are generally less seri0us.2~ Finally, human bite wounds can pose some of the most challenging definitive management problems among .~ on the quantitative and all bite-induced i n j u r i e ~Based qualitative characteristics of oral flora, including the principal pathogen Eikenella corrodens, aggressive primary intervention is mandatory to achieve a satisfactory outcome in all these injuries. Thorough irrigation of penetrating bite wounds is mandatory, as well as broadspectrum antibiotic coverage, followed by frequent wound checks.

REFERENCES 1. Ablove RH, Moy OJ, Peimer CA: Pediatric hand disease: Diagnosis and treatment. Pediatr Clin North Am 1998;45: 1507-1524. 2. Allen C: Arachnid envenomations. Emerg Clin North Am 1992;10:269-298. 3. Banner W: Bites and stings in the pediatric patient. Curr Probl Pediatr 1988;18:1-69. 4. Bhende MS, Dandrea LA, Davis, HW: Hand injuries in children presenting to a pediatric emergency department. Ann Emerg Med 1993;22:1519-1523. 5. Binder LS: Acute arthropod envenomation: Incidence, clinical features and management. Med Toxic01 Adverse Drug Exp 1989;4:163-173. 6. Buncke GM, Buntic RF, Romeo 0: Pediatric mutilating hand injuries. Hand Clin 2003;19:121-131. 7. Coleman SS, Anson BJ: Arterial patterns in the hand based on a study of 650 specimens, Surg Gynecol Obstet 1961; 113:409424. 8. Eaton RG, LittlerJW: Joint injuries and their sequelae. Clin Plast Surg 1976;3:85-98. 9. Forks TP: Evaluation and treatment of poisonous snakebites. Am Fam Physician 1994;50:123-130. 10. Gelberman RH, et al: The results of radial and ulnar arterial repair in the forearm: Experience in three medical centers. J Bone Joint Surg Am 1982;64:383-387. 11. Hassen LB: Reptile and arthropod envenomations. Occup Med 1991;6:447-461. 12. Hastings H, Simmons BP: Hand fractures in children: A statistical analysis. Clin Orthop 1984;188:120-130. 13. Holden CEA: Compartmental syndromes following trauma. Clin Orthop 1975;113:95-102. 14. Innis PC: Office evaluation and treatment of finger and wrist injuries in children. Curr Opin Pediatr 1995; 7:83-87. 15. Jaeger SH, Tsai TM, Kleinert HE: Upper extremity replantation in children. Orthop Clin North Am 1981;12: 897-907. 16. Leclercq C, Korn W: Articular fractures of the finger in children. Hand Clin 2000;16:523-534. 17. McGregor IA, Morgan G: Axial and random pattern flaps. Br J Plast Surg 1973;16:202-213. 18. Moberg E: Evaluation of sensibility in the hand. Surg Clin North Am 1960;40:357-362. 19. Nofsinger CC, Wolfe SW: Common pediatric hand fractures. Curr Opin Pediatr 2002;14:42-45. 20. Rimsza ME, Zimmerman DR, Bergeson PS: Scorpion envenomation. Pediatrics 1980;66:298-302. 21. Rudolph R, et al: Snakebite treatment at a southeastern regional referral center. Am Surg 1995;61:767-772.

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22. Russell FE: Venomous arthropods. In Schacter LA, Hansen R (eds): Pediatric Dermatology. New York, Churchill Livingstone, 1988. 23. Salter RB, Harris WR: Injuries involving the epiphyseal plate. J Bone Joint Surg Am 1963;45:587-622. 24. Simmons BP, Lovallo JL: Hand and wrist injuries in children. Clin Sports Med 1988;7:495-512. 25. Stewart GM, Quan L, Horton MA: Laceration management. Pediatr Emerg Care 1993;9:247-250. 26. Stewart RM, et al: Antivenin and fasciotomy/debridement in the treatment of the severe rattlesnake bite. Am J Surg 1989;158:543-547.

27. Tibballs J: Diagnosis and treatment of confirmed and suspected snake bite: Implications from an analysis of 46 paediatric cases. Med J Aust 1992;156:270-274. 28. Weber RA, White RR: Crotalidae envenomation in children. Ann Plast Surg 1993;31:141-145. 29. Wood VE: Fractures of the hand in children. Orthop Clin North Am 1976;7:527-542.

Central Nervous System Injuries Thomas G . Luerssen

Injuries to the brain and spinal cord continue to be the major cause of mortality and morbidity from childhood trauma. Despite 25 years of intensive clinical research, no specific medical therapy for any traumatic neurologic injury has yet been defined. Nevertheless, there has been a steady and substantial advance in our understanding of the natural history of brain and spinal cord injuries; moreover, there have been changes in management that have clearly resulted in improved outcomes. We have now entered the era of "evidence-based medicine" whereby recommendations for disease and injury management are supposed to be derived from critical analysis of available scientific research. In the past decade, management strategies for central nervous system (CNS) injuries have been subjected to this type of analysis. These efforts have resulted in the publication ~ ~ , ~ ~ of of practice management g u i d e l i n e ~ . 2 , 2 l ,Analysis the clinical evidence and development of these recommendations represent a substantial amount of work by many of the leading experts in the field. Unfortunately, these reviews also uncovered a remarkable lack of strong scientific evidence on which to develop recommendations, especially in the pediatric age group, so most of the available recommendations regarding the diagnosis and treatment of neurologic injuries can be supported only by the lowest degree of medical certainty. Nevertheless, these published practice parameters are useful summaries of the current understanding of the various treatments of brain and spinal cord injury. These publications are referenced frequently in this chapter, and interested readers are encouraged to review these practice parameters and the citations of the analyzed literature that serve as the basis for the recommendations.

BASIC STRATEGY FOR TREATMENT OF CENTRAL NERVOUS SYSTEM INJURY One of the most enduring concepts underlying the management of brain and spinal cord injury is that of primary and secondary injury.IZ4The primary neurologic injury involves the immediate disruption of neuronal, axonal, and supportive structures and vascular tissues.

The magnitude and location of the primary injury, along with the variety of irreversible cellular processes that immediately ensue, something that has been referred to as "delayed primary injury," are directly related to the mechanism of injury. These immediate tissue disruptions are also considered to be self-limited and are, by definition, essentially untreatable. Given all of this, one can easily see that the primary brain injury is the major determinant of injury outcome. Obviously, the primary injury can be devastating and, in many high-energy mechanisms, immediately lethal. In persons not immediately killed by an injury, the primary injury triggers a cascade of intracellular and extracellular biochemical changes, both in the region of the injury and systemically, many of which are deleterious and cause acceleration and augmentation of the initial injury. These reactive processes represent the onset of what has been termed the "secondary injury." These secondary reactive processes can begin at almost any time after the injury and can persist for some time. The secondary injury not only results in new damage, both in the region of the primary injury and in areas of previously uninjured brain or spinal cord, but also causes deleterious effects in other organs and body systems. Systemic reactions commonly seen after brain or spinal cord injury include hypotension and hypoxia. It has clearly been shown that even brief and mild episodes of either hypoxia or hypotension can have profoundly deleterious effects on the outcome of both brain and spinal cord injury.28,123,141 Although it is well known that spinally injured patients can be rendered hypotensive by an isolated injury, it is now also clear that isolated brain injury can cause systemic hypotension. Multiple injuries, occult organ injuries, or other causes of exsanguination that result in hypovolemia are not required for this hypotensive response to occur. Of the early systemic complications, it appears that hypotension is much more deleterious to an acutely injured brain than hypoxia is. This is probably also true for an acutely injured spinal cord. Finally, it is clear that these complications can occur very early, frequently, and in many cases so briefly that they are either undetected or unreported, even in modern intensive care ~ n i t s . I 2 , ~ ~

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There are also other common systemic responses, many of which occur shortly after an injury but can also cause further injury even days after the institution of therapy. Hyperthermia, either from fever or as a result of overly aggressive warming, is harmful to an injured brain.'" Hyperglycemia, which is commonly seen in the stress response and can be aggravated by fluid administration or attempted nutrition, is also believed to be deleterious to acutely injured neurons.18.*7J4Y Tissue disruptions, commonly referred to as cerebral or spinal cord contusions, cause reactive changes in the tissues immediately surrounding the area of injury. A variety of tissue factors are released, such as those in the kallikrein-kinin system, and these factors can cause disturbances in microcirculation and the blood-brain or blood-spinal cord barrier that ultimately result in the complex entity that has generally been referred to as post-traumatic edema.l13 There are hypermetabolic responses related to neural tissue injury that may outstrip the local or regional substrate supply.13 Excitotoxic amino acids such as glutamate and aspartate are released from injured neurons." Post-traumatic seizures, especially prolonged subclinical seizures, may contribute to this response in the injured brain.172 Along with the reactive biochemical changes, expanding local hemorrhages caused by direct vascular injury can lead to further compression of adjacent vessels and result in an ischemic penumbra around the acute injury. Although the systemic and biochemical processes of secondary injury are complex, it appears that the pathophysiologic end point of all of them is ischemic damage. Ischemic neuronal damage is almost universally seen in the neuropathologic examination of patients who have suffered traumatic brain and spinal cord injUry.70,164 Even though numerous biochemical cascades have been identified and physiologically characterized, and many have been the target of pharmaceutical intervention, no drug has yet been shown to be specifically effective for the treatment of CNS injury. Trials of high-dose steroids, calcium channel blockers, free radical scavengers, and glutamate antagonists have been generally negative, although small and specific subgroups of patients were identified in post hoc analyses that may have benefited from one or another of these therapies. More concerning is that some groups of patients were apparently harmed by the administration of some of these agents." Despite this lack of development of a specific therapy, 20 years of clinical trials involved in the assessment of these agents have shown steady improvement in neurologic outcomes, more so in the arena of brain injury than in spinal cord injury. This trend toward improved outcome is almost certainly due to the realization that many of the ischemic processes can be prevented by aggressive application of systemic manipulation, beginning with the resuscitation phase of the injury and continuing through the period of acute therapy. The essential therapeutic strategies for brain and spinal cord injury are based on preventing ischemic injury by the aggressive support of intravascular volume and blood pressure at all times. The historical idea of restricting fluids in head-injured patients is no

longer accepted. The early use of vasopressors is encouraged. Reduction of focal vascular compression by removal of mass lesions and aggressive prevention and management of reactive brain or cord swelling to protect perfusion are procedures that are aimed at minimizing local and general ischemic injury. These three relatively simplistic concepts--support of systemic blood pressure, reduction of intracranial pressure to ensure cerebral perfusion, and removal of compressive lesions plus prevention of deleterious complications-are now the mainstay of management of brain and spinal cord injuries.

IMMEDIATE ISSUES: RESUSCITATION AND TRANSPORT OF INJURED CHILDREN Effective supportive and preventive therapy should begin as quickly after the injury as possible. Goals of the initial resuscitation are twofold: prevention of as much secondary injury as possible and prevention of any new primary injury before undertaking neurodiagnostic studies. One can accomplish the first goal by ensuring oxygenated perfusion of the brain and spinal cord by restoring and maintaining age-appropriate normal blood pressure and volume as early as possible. This action, coupled with restoring and maintaining normal ventilation, is, at least at this time, more important than the administration of any drug. The exact means of accomplishing this goal, that is, the type of resuscitation fluid or the means of ensuring ventilation, is probably less important than accomplishing the goal itself. Most current studies indicate that isotonic or slightly hypertonic saline solution is an appropriate fluid for resuscitating and maintaining blood pressure in neurologically injured patients,2*,2gx181 although the use of colloids and more highly concentrated hypertonic solutions is also being investigated. Tissue oxygenation is important, and therefore adequate airway and ventilation support is required. Early intubation by experienced personnel with appropriate analgesia and sedation will certainly accomplish this goal. However, the role of intubation of injured children (and adults) in the field is still controversial.77 It appears that this maneuver is associated with a relatively high complication rate and may not be warranted in many s i t u a t i 0 n s . 2 ~ ~ ~ ~ 2 7 ~ 1 ~ ~ For patients with possible spinal injuries, prevention of further injury begins with stabilization of the spine. This maneuver involves much more than the application of a collar or securing a child to a rigid board. It is important that normal anatomic alignment be maintained. Very young children have proportionately larger heads and therefore have a tendency toward cervical flexion when lying supine." A cervical collar alone does not completely immobilize an injured spine in a child.83 Specific attention should be directed to immobilizing the spine in an anatomic position, including ensuring a normal relative position of the head to the body. Young children require some additional elevation of the body so that the head falls back to a truly neutral position. Once these parameters have been achieved, that is, stabilization of the spine in an anatomic position and establishment of systemic blood pressure and respiration

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support, an injured child may be transported for definitive diagnosis and treatment of the injury.

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focal or diffuse. Accepting the caveat that many traumatic injuries are "mixtures" of focal and diffuse injury, one can still base individual management strategies on the initial appearance of the type of brain injury.

TRAUMATIC BRAIN INJURY Focal or Diffuse Brain Injury?

Epidemiology Despite the frequency of head injury in children, epidemiologic data in this area are relatively limited. A study in the United Kingdom indicated that 40% of all patients seen in emergency departments for the treatment of head injuries were children." It is important, however, to distinguish between "head injury" and "brain injury" in discussing outcomes and therapy, although it is probably equally important to group these entities in discussing mechanisms and prevention. Accordingly, population-based studies indicate an average incidence of clinically important head injury in children of about 185 per 100,000, with the incidence generally dropping with increasing age.I9zg6Boys are injured at a rate approximately twice that of girls. Overall, 85% of the brain injuries sustained in childAlthough hood are mild and not life threatening.97,111 severe brain injuries are rare, they still constitute a major concern in pediatric trauma management. Reports from pediatric trauma centers have indicated that well over half of all deaths resulting from blunt trauma in children are caused by a brain injury.l*lJ71 The severity and mechanism of brain injury seem to be linked to outcomes. The mechanism of injury is also age dependent. The most common mechanism resulting in head injury in children is a fall, but the usual falls in childhood are not associated with severe injuries. The major cause of severe brain injury in young children seems to be abuse. In older children, severe brain injury is most commonly seen in relation to motor vehicle accidents. Many accidental brain injuries that occur in children are preventable. Proper use of occupant restraints in motor vehicles can prevent up to 90% of the serious injuries to young children.'47 The implementation of a mandatory child restraint law in Michigan reduced the number of motor vehicle-related injuries in children by 25%.llWearing helmets for bicycle riding, as well as for other recreational activities such as skateboarding, skating, skiing, and horseback riding, should decrease the risk for brain injury,l2"148,167 although educational programs regarding helmet use have had only limited success thus far." Many falls are preventable. Vigilance regarding open windows and stairways, including the use of gates or bars, substantially reduces the occurrence of these injuries.

The Spectrum of Traumatic Brain Injury There are many ways to undertake an overview of the major types of traumatic brain injury. The author has come to prefer one that includes a relationship of injury types, mechanism, and natural history. The simplest way to do this is by categorizing major injury types as either

Focal injuries include contusions, lacerations, traumatic hematomas, and localized damage caused by expanding masses and shifts and distortions of the brain. Diffuse injuries include the spectrum of diffuse axonal injury (DAI), which encompasses what is commonly called cerebral concussion, as well as other diffuse insults such as global ischemia, systemic hypoxia, diffuse brain swelling, and diffuse vascular injury. Focal injuries are usually immediately apparent on admitting computed tomography (CT) scans. Nonetheless, they may be clinically asymptomatic. In contrast, diffuse injuries may show much less striking changes on early neuroimaging studies, even though the patient may exhibit profound alterations in consciousness and neurologic function. Focal injuries are more likely to require therapeutic surgical procedures, whereas diffuse injuries may require extensive diagnostic studies to determine the type and magnitude of the injury. Diffuse injuries are also more likely to require prolonged monitoring of intracranial pressure (ICP) to guide therapy. It is useful to discuss the characteristics of these types of injuries individually, but it is important to remember that in many cases, especially with more severe injuries, both injury types may be present.

Focal Brain Injury Most focal brain injuries are associated with impactrelated mechanisms. Because short falls are the most common cause of accidental head injury in childhood, cranial impacts and their resulting focal injuries are also common. Furthermore, impact mechanisms are associated with skull fractures, which are also commonly seen in the pediatric age group. In fact, about 20% of head-injured children who are admitted to the hospital have skull fractures.105 Despite the frequency of skull fracture in childhood, the majority of children with this injury will not require any intervention or suffer any complication directly related to the fracture. Therefore, the clinical importance of most skull fractures is that the fracture serves as an indicator of both the mechanism and severity of the head injury. Most studies of the importance of skull fractures have determined that the finding of a skull fracture in a head-injured patient is statistically associated with a higher likelihood that an expanding intracranial hematoma or a significant brain injuly is also present.'"8',101~1~)5~166 Furthermore, complex skull fractures, or the occurrence of multiple fractures, is generally associated with higher-energy mechanisms and therefore more severe injuries to the brain. As indicated earlier, most focal brain injuries are immediately apparent on initial neuroimaging studies and, depending on the size and location, result in focal neurologic dysfunction. The most common focal injury resulting from nonpenetrating mechanisms is a cerebral contusion (Fig. 21-1). It is generally a surface lesion

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This cerebral contusion underlying a linear skull

fracture (not demonstrated) was the result of a cranial impact, as demonstrated by the overlying soft tissue swelling and hemorrhage. The patient had no neurologic deficit.

related to cranial impact or brain movement over irregular intracranial surfaces or along the edges of dura. The clinical manifestation of cerebral contusions depends mostly on the extent of the initial injury, the amount of associated hemorrhage resulting in a mass effect, and the location of the contusion in the brain. Even though cerebral contusions may result in localized swelling, isolated lesions are not generally life-threatening. Many cerebral contusions are neurologically silent, only to be discovered on the initial CT scan underlying a skull fracture or along the anterior cranial base. When these injuries are symptomatic, they usually cause a focal neurologic deficit or seizures. The latter are thought to occur commonly in adults with acute cerebral contusion^.^^ However, the incidence of seizures in children with cerebral contusions appears to be no greater than that in children with either normal CT scans or epidural he ma to ma^.'^ Traumatic intracerebral hematomas are unusual lesions in the pediatric age group. The pathogenesis of these hemorrhages is unclear, but it seems likely to be related to disruption of central arterial blood vessels. Accordingly, these lesions are associated with more severe mechanisms of injury and with more profound neurologic dysfunction. In many cases these lesions are part of a larger picture of DAI, which is discussed later. Traumatic intracerebral hematomas are distinguished from hemorrhagic contusions by their lack of contact with the surface of the brain.67 They can be quite large and, because of the location, can leave a child with a profound neurologic deficit. Surgical evacuation can be considered if ICP is high, but in the author's experience,

neurologic outcomes are not improved by evacuation of these hematomas. Children seem to be uniquely prone to nonmissile-associated penetrating injuries of the skull and brain. These injuries are usually the result of a fall onto or being struck by sharp objects such as nails, pencils, sharp sticks, or lawn toys (Fig. 21-2). One of the major dangers of these injuries is that unless the offending object remains embedded, the entry wound may be hidden or seem trivia1.22,44,'26 Anterior penetration of the skull base can be transorbital, via the orbital roof, or through the nose or mouth. Thus, direct evidence of cranial penetration may not be visible or may be masked by local swelling. Penetrating injuries can result in focal contusions, intracerebral hemorrhages, and cerebral lacerations, but these lesions are usually silent because of their locations and small size. Deeper penetrations are more likely to be symptomatic, not only because the tissue injury is more extensive but also because of the potential for injuring major vessels. Many penetrating injuries become symptomatic in delayed fashion because of expansion of intracerebral hemorrhage, recognition of a cerebrospinal fluid (CSF) fistula, or the development of symptoms indicating infection. Therefore, a very high index of suspicion is required, and careful radiologic studies are called for whenever there is a possibility of subtle cranial penetration. Wood, glass, and residual bits of debris may be difficult to detect on routine imaging studies, including CT.76 Cranial penetrating injury is also strongly associated with direct cerebrovascular injury." Magnetic resonance imaging (MRI) with the addition of magnetic resonance angiography (MRA) or the increasingly useful modality of CT angiography (CTA) should be considered whenever there is evidence of deep cranial penetration or if substantial subarachnoid or focal intracerebral hemorrhage is present.

Diffuse Brain Injuries The majority of brain injuries occurring in childhood are diffuse injuries. Diffuse brain injuries are characterized by general disturbances in neuronal function that begin immediately at the time of injury. Despite this, brain structure is generally preserved on admitting CT scans. Diffuse injuries occur as a direct result of energy dissipation within the substance of the brain or as a result of systemic insults. All these injuries exist on a continuum from extremely mild, and apparently completely reversible, to lethal. Frequently, the different types of diffuse brain injury occur together or in sequence and can act synergistically to affect neurologic status and the outcome. Diffuse primary brain injuries are generally the result of angular or translational acceleration (or deceleration), with the amount of tissue disruption being roughly proportional to the amount of energy dissipated in the brain substance.'j8 As the amount of neuronal disruption increases, the depth and duration of neurologic dysfunction increase and the neurologic outcome worsens. There is a strong association with the appearance of certain hemorrhages on CT scan, specifically, subarachnoid hemorrhage, small but widespread

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A

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B

The occult injury frequently seen with low-velocity cranial penetration in young children is demonstrated. The patient was struck in the left parietal region by a lawn dart, and loss of consciousness did not occur. The lawn dart fell out immediately. The injury was misinterpreted as a minor scalp laceration and was closed with butterfly bandages. Three days later, fever and headache developed. A, Appearance of the entry wound before surgical exploration. B, Computed tomography shows a compound fracture and intracerebral hematoma. During surgery, hair, dirt, and bone fragments were removed from the cerebral cortex. I

intracerebral hemorrhages, and intraventricular hemorrhage (Fig. 21-3).l Finally, although the occurrence of traumatic, surgically accessible masses is not characteristic of diffuse brain injury, subdural hematomas are seen commonly along with DAI, and some of these subdural hematomas are large enough that surgical evacuation may be a necessary component of initial therapy. However, these subdural hemorrhages are better viewed as another marker of the diffuse brain injury rather than as a mass that should be treated in isolation, such as an epidural hematoma or hemorrhagic contusion. Like all brain injuries, diffuse primary brain injuries occur within a spectrum of severity. At one end of the spectrum is a very mild, transient physiologic disturbance in neurologic function that includes the syndromes commonly associated with "cerebral concussion," whereas at the other end is the progressively more damaging and ultimately lethal entity that is now called "diffuse axonal injury." The modern view of cerebral concussion is based on the pioneering work of Ommaya and Gennarelli,130J31 which defines concussive brain injuries as a graded set of clinical syndromes showing increasing disturbances in the level and content of consciousness. This definition

allows the inclusion of specific post-traumatic disturbances that are commonly seen in children after so-called mild head injuries, including confusion without amnesia, confusion associated with amnesia of varying depth and duration, and the classic loss of consciousness with and without transient sensorimotor paralysis or disturbances in respiration or circulation. As the amount of energy in the injury mechanism increases, tissue disruption occurs and results in DAI. It is now clear that the most common cause of prolonged coma from mechanical brain injury is DAI. Patients who have suffered DAI are unconscious from the time of injury and remain so for a prolonged period.66 It is not uncommon to note pupillary changes, skewed gaze, and decerebration. This constellation of symptoms had been called "brainstem contusion" in the era before MRI, and although isolated brainstem contusion can certainly occur, it is extremely rare. Instead, most patients in coma who appear to have brainstem dysfunction after closed head injury have suffered DAI. The findings on initial CT scanning depend on the severity of the injury and the degree of associated hemorrhage. In some cases the initial CT scan may be normal. Subsequently, the characteristic lesions may be discovered

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The "classic" appearance of diffuse axonal injury on an admitting computed tomographic scan includes subarachnoid and intraventricular hemorrhage, brain swelling, and small petechial hemorrhages throughout the brain.

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on MRI and can vary from some transient signal changes in the deep white structures to widespread hemorrhagic and nonhemorrhagic shearing injury. The characteristic CT scan appearance of DAI is multiple petechial hemorrhages in the deep white matter and central structures. However, the finding of intraventricular hemorrhage or focal subarachnoid hemorrhage specifically located in the prepontine cistern is also strongly suggestive of DAI.

Gunshot Wounds Injuries from firearms are a major public health problem in children. Because of the way these injuries are reported, it is difficult to determine the overall incidence of this injury in children. However, recent reports indicate that 10% of all childhood injury deaths are related to firearms, a number exceeded only by deaths from motor From vehicle accidents, drowning, and house fi~-es."J~~ the standpoint of management and outcome, there is little to differentiate gunshot injuries in children from those in adults. Poor outcome is related to the depth of coma, bilateral or transventricular injury, elevated ICP, and large intracerebral hemorrhages.~3Vonetheless, most authorities recommend aggressive treatment of all patients except those with clearly nonsurvivable inj~ries,"~ although substantial neurologic and cognitive deficits can be e~pected:""l2~ Injuries caused by nonpowder firearms, such as BB and pellet guns, are three times more frequent than true gunshot wounds in children,176 with adolescent males having the highest risk for injury.122 These injuries are generally less severe and therefore associated with lower mortality rates. Surgical treatment is not usually required for BB gun injuries. Pellet rifle injuries, because they are higher-velocity and larger-caliber missile injuries, are more

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severe and are probably best treated as true gunshot wounds.

Crush Injuries Young children are susceptible to the unusual static loading-type crushing injury to the skull. These injuries occur as a result of a heavy object's falling on a child or being run over by a vehicle. Crush injuries are dramatic in both clinical and radiographic findings (Fig. 21-4), but neurologic outcomes can be quite g ~ o d . ~ W u l t i p l e skull fractures are typical and include complex basilar skull fractures and facial fractures. CSF leaks and cranial nerve palsies are commonly seen. The mechanism of injury and the clinical findings would suggest overwhelming injury and a poor outcome. However, despite the initial appearance of the injury, many times major cortical structures are preserved. Therefore, if the child has survived the initial injury, aggressive multidisciplinary management can result in satisfactory long-term functional outcomes.

Inflicted Injuries By far, the most common cause of severe and lifethreatening brain injury in infants is inflicted injury (also see Chapter 24). All physicians involved in the care of injured children should be familiar with the clinical manifestations and characteristic radiographic findings of inflicted injuries. This entity has recently been reviewed in detai1.37~47Infants with an alteration in consciousness, with or without a new onset of seizures, retinal hemorrhages, and acute intracranial hemorrhages on CT scan, are likely to have suffered nonaccidental injuries, especially if the history of the injury is unknown or reported

B

A -

<:rushing-type injury in an infant. This computed tomographic (CT) scan (A) and 3-D reconstruction (B) show a cranial "burst" injury. Despite intracranial hemorrhage and dural laceration, the structure of the brain is preserved and decompressed. The child required dural and cranial reconstruction but recovered with minimal deficits. e

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to be minor. The additional finding of new or healing skeletal fractures or other solid organ injuries is pathognomonic for this injury. Comprehensive multidisciplinary evaluation by physicians with expertise in child abuse is indicated for all infants who are suspected to have been abused.

Initial Assessment of Brain-Injured Children The purpose of the initial assessment of a brain-injured patient is twofold. First and most important, one establishes a working diagnosis of the type and severity of the injury in order to direct the selection of initial therapies, as well as the planning and coordination of other diagnostic studies and the management of any associated systemic injuries. Second, one establishes a baseline to measure the effects, both positive and deleterious, of the therapies or interventions. Historically, the main focus of the initial assessment of brain-injured patients was determining the severity of the injury by assessing the level of consciousness. The most widely used evaluation instrument for this purpose is the Glasgow Coma Scale.'" This score, as it was designed, correlates well with 0utcome.2~However, with the improvements in transport and field resuscitation of severely injured patients, which usually requires the prehospital administration of analgesics and sedation, neurologic assessment to determine the type and severity of brain injury becomes less useful.'" Furthermore, there is a small, but important group of brain-injured patients who have little or no impairment in consciousness but subsequently deteriorate because of mass lesions or brain welling.86,."5,114

Recently, it has become clear that certain findings on CT also correlate well with outcome after brain injury. This radiographic assessment can be obtained rapidly and is not affected by any ongoing therapies. Regardless of the apparent level of consciousness, the early radiographic identification of injury types and the institution of appropriate management or monitoring have substantially improved the overall outcome after traumatic brain injury. Furthermore, it is now clear that a head-injured patient with a completely normal CT scan has an exceedingly low risk for either deterioration or poor outcome. In the author's experience, the CT scan has become the most important element of the early diagnosis of brain injury, especially in young children. The important CT scan findings involve not only the detection of potentially surgically accessible mass lesions but also the search for and detection of the constellation of findings typically seen with diffuse brain injury: subarachnoid, intraventricular, or intraparenchymal hemorrhage and what may be very subtle early signs of brain swelling, including compression of the perimesencephalic cisterns or shift or compression of the ventricular system. Early identification of the presence of diffuse brain injury on the CT scan is more important than the clinical impression of injury severity. These findings should influence the expectations for outcome and the decisions for monitoring and therapy. The severity of diffuse brain injury can be graded by the appearance of the admitting CT scan. As shown in Figure 21-5, these specific findings correlate well with outcome," and therefore one can make immediate management decisions. Most current practice parameters regarding the evaluation of head-injured patients include recommendations

Poor outcome for diffuse injury by type

BTCDB RCH

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Injury type on CT scan

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Effect of the appearance of the admission computed tomographic scan on outcome after injury. The data for this graph were generated from information reported from the Traumatic Coma Data Bank (TCDB)'17 and from unpublished data on 1000 consecutive pediatric patients admitted for brain injury to the James Whitcomb Riley Hospital for Children, Indianapolis, IN (RCH). Poor outcome is defined as severely disabled, vegetative survival, or death according to the Glasgow Outcome Scale.139 Definitions: Difftlse injury I: No visible intracranial pathology seen on computed tomography. Diffuse injury 11: Cisterns are present with a midline shift of 0 to 5 mm or the presence of lesion densities (or both); no high- or mixed-density lesions larger than 25 cc. Diffuse injury 111: Cisterns compressed or absent with a midline shift of 0 to 5 mm; no high- or mixed-density lesion larger than 25 cc. Diffuse injury IV: Midline shift greater than 5 mm; no high- or mixed-density lesion larger than 25 cc.

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for an early diagnostic CT s ~ a n . ~ , Essentially, " ~ ~ ~ 2 ~all~ ~ ~necessary element of the initial evaluation of a headpotentially severely injured patients, that is, those with an injured patient. alteration in consciousness, should undergo CT scanning as soon as they are physiologically stable and can be safely transported and maintained in the scanner. For Early Management of Severe Brain Injury head-injured children with apparently minor trauma, current recommendations allow for clinical assessment As stated previously, the primary objective of resuscitation of a brain-injured patient is to preserve cerebral perfusion and a period of observation without undertaking any during transport and evaluation. The ongoing objective neuroimaging, so long there is a clear history of a lowof therapy for severe brain injury is to optimize the perfuenergy mechanism and, at most, only a brief loss of sion of injured and uninjured brain and create a milieu consciousness. One should add that these children should that minimizes the chance for additional secondary also be completely asymptomatic and neurologically injury and maximizes the amount of neuronal recovery. normal and have no complicating medical disorders. One must do this while avoiding or reversing deleterious On the other hand, any child with a history of more than processes that would result in further neuronal injury a few seconds of unconsciousness, a seizure, or clinical or the expansion of hemorrhagic masses, including signs of cranial impact, skull fracture, cranial penetration, systemic complications that directly affect an injured or CSF leak or any child with headache, persistent vomiting, brain such as sepsis, acute lung injury, hyperglycemia, lethargy, or irritability should undergo CT scanning as ~ ~ , ~ ~children ~ who have been and coagulopathy. soon as p o ~ s i b l e . Finally, injured via high-energy mechanisms that result in apparA variety of treatment strategies have been propounded ently isolated chest, abdominal, or skeletal injuries should for the treatment of traumatic brain injury. Most of these undergo a CT scan of the brain before the administration therapies involve systemic manipulations to achieve what is of an anesthetic or the institution of narcotic analgesia believed to be either a therapeutic or a protective or sedation that would preclude accurate ongoing response. All the "newer" therapies have theoretical attracneurologic examination. tions, and their proponents report outcomes that appear It should be clear from the previous discussion that to be better than those of historical controls. However, at plain skull radiography has only a limited and secondary least so far, when these therapies have been tested directly role in the initial evaluation of head injury. CT scanning against what could be termed "standard therapies," no benwill detect most clinically important skull fractures. efits have been demonstrated. Consequently, the treatment Conversely, skull radiographs provide only limited inforrecommendations currently in place are essentially mation about the type and location of any brain injury. descriptions of how to apply the historically "standard" MRI is more sensitive than CT scanning for detecting therapies of controlled ventilation, fluid management, most brain pathology and has supplanted CT as the study sedation, and control of blood pressure and ICP. of choice for many neurologic disorders. However, for To do this one must understand as much as possible acute traumatic brain injury, all necessary information for about the patient's intracranial dynamics and optimize making management decisions is still provided by CT cerebral perfusion by removing surgically accessible scanning. In most circumstances, CT scanning is still more masses and managing ICP by safely manipulating, as quickly and easily obtained and is less costly than MRI. much as possible, cerebral blood volume (arterial and Finally, while acknowledging the expanding primary venous), CSF volume, and brain For severely injured and some less severely injured patients, institution role of neuroimaging in the diagnosis and management of traumatic brain injury, a careful physical and neurologc and manipulation of therapies are guided by the placeexamination is still extremely important. The entire head ment of an ICP monitor. ICP monitoring provides the basis for making many of the important management should be inspected for indications of impact, scalp injury, cranial deformities, and cranial or orbital penetration. decisions for brain-injured patients.lo7J20 The application of individual medical therapies is Documentation of cranial nerve function, especially pupilbeyond the scope of this chapter. However, it is important lary size, shape, and reactivity, is necessary and will serve to realize that each of the current therapies for elevated as comparison for serial examinations. Evidence of ICP has both general and specific effects and that each anterior basilar skull fractures, manifested by periorbital has complications associated with its use. The historically ecchymoses, nasal hemorrhage, or CSF rhinorrhea, is a common administration of high-dose steroids to braincontraindication to the placement of nasogastric tubes injured patients is no longer considered to be beneficial until the integrity of the anterior cranial skull base can and may, in fact, be harmful. Accordingly, the current be determined. Retroauricular bruising, hemotympanum, guidelines do not recommend that any specific therapy, otorrhagia, and CSF otorrhea are indicative of temporal for instance, hyperventilation, osmotic diuretics, or other bone fractures that may not be immediately evident on medications, be administered "prophylactically" or unistandard screening CT and may result in the delayed versally for brain-injured patients. It is also suggested that appearance of cranial neuropathy. In the event of possible specific therapies be applied in a logical sequence and inflicted injury, dilated funduscopic examination by an ~ of guided by ICP monitoring and frequent reassessment of ophthalmologist is r e c ~ m r n e n d e d .Documentation the level of consciousness and any apparent motor or response to therapy. The basic level of therapy for severe traumatic brain sensory deficits, along with notation of the presence of confounders to the examination such as intubation, injury includes controlled ventilation with maintenance medications, swelling, splints, and other factors, is still a of normal oxygenation and P a m P concentrations.

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Intubated patients should have adequate sedation and analgesia at all times. Intravascular volume should be supported at all times with blood and fluids to maintain normal hematocrit and electrolyte concentrations. Fluid restriction is not recommended. Hypotonic fluids should be avoided to prevent any trend toward hyponatremia. The head of the bed may be elevated to reduce intracranial venous pressure, as long as normal central venous pressure is maintained by adequate volume replacement. For many severe diffuse brain injuries, this level of therapy may be all that is necessary. Escalated therapies include the use of CSF drainage, usually by way of a ventricular catheter, osmotic diuresis with mannitol, and mild hyperventilation. Whenever escalation of therapy is considered, one must also escalate the physiologic monitoring for treatment effect and complications. Table 21-1 summarizes the author's approach to escalating medical therapy for brain injury, based on current treatment guidelines. A small percentage of patients require even more intensive therapy for

Treatment Evaluation and Resuscitation Restoration of normal blood pressure lntubation and ventilation Basic-Level Therapy Elevation of head of bed Keep head in neutral position Sedation and muscular paralysis Mechanical ventilation to maintain Paco, at 3540 mm Hg Maintain normal to slightly increased intravascuiar volume Normal fluid and electrolyte status (no fluid restriction); avoid anemia, hyperglycemia Body temperature normal to slightly hypothermic Escalated Therapy Ventricular cerebrospinal fluid drainage Mannitol Moderate hyperventilation to maintain Paco, at 3@35 mm Hg

Monitoring Systemic blood pressure and oxygenation Neurologic examination End-tidal CO,

elevated ICP, including high-dose barbiturates, intensive osmotic therapy, or intensive hyperventilation. These therapies have a higher complication rate and should therefore be used only when absolutely necessary and by physicians with experience in neurologic critical care. Surgical decision making for severely injured patients is usually straightforward. Clearly, cranial penetrating injuries, including compound skull fractures, require urgent surgical attention. The removal of large, surgically accessible mass lesions may be the first step in the overall therapeutic management of a severe brain injury. Other than that, the initial surgical procedures may be limited to the placement of an ICP monitor, a ventricular catheter, or both. These procedures can be performed at the bedside if necessary. In many cases, such as closed depressed fractures, burst fractures, or comminuted cranial and craniofacial fractures, surgical correction can be performed when the patient is stable or improving from the neurologic injury. Typically, the major surgical therapy for brain injury involves the removal of traumatic intracranial hematomas. The overall incidence of surgically accessible hematomas in children is substantially lower than that in adults, and the distribution of hematoma types is different. Subdural hematomas are most common in infants, but are rarely of a size that requires surgical removal. As discussed at the outset of this chapter, acute subdural hematomas in older children are generally more indicative of a severe diffuse injury (Fig. 21-6). Extradural hematomas are the

Systemic blood pressure and oxygenation lntracranial pressure Arterial Po, Pco2, and pH Weight, urine output, pulse, and pulse pressure Hemogram, serum electrolytes, glucose, and blood urea nitrogen Monitor and aggressively treat for fever and sepsis Computed tomography

Ventricular catheter Central venous pressure Serum osmolality and electrolytes

Intensive Therapy for Refractory lntracranial Pressure High-dose barbiturate therapy Continuous or compressed spectral electroencephalography Lumbar cerebrospinal fluid Barbiturate levels drainage if indicated Profound hyperventilation Jugular venous oxygen saturation, monitors of cerebral blood flow

I . Acute subdural hematoma. The hemorrhage overlying the hemisphere (left side of the image) seems small. Note, however, the extensive shift of the brain and the hemispheric swelling, which are indicative of severe diffuse injury.

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are destined to recover completely, usually without any intervention whatsoever. However, within this large group there exists a small fraction of patients who are harboring an enlarging hematoma or who are in the early stages of brain swelling. These patients are at increased risk for delayed but rapid deterioration that will result in death or disability. The focus of the evaluation of an apparently minor brain injury is to identify patients who are at risk for neurologic deterioration or delayed complications and to prevent either from 0 ~ c u r r i n g . l ~ ~ In many ways, diagnosis and management of these patients are more challenging and important than managing severe injuries because successful intervention results almost universally in good outcome^.^"^^^ Recommendations about this issue have been p ~ b l i s h e d .As ~ ,with ~ ~ ~other types of brain injury, early CT scanning is the lynchpin to accurate diagnosis and recognition of brain-injured patients at risk for deterioration.42-82,1°6,128 Identification of cisternal compresAcute extradural hematoma. Note the thickness of the sion, hemorrhagic shear and contusion, or small trauhemorrhagic mass, but also note the lack of shift in comparison to what matic hematomas indicates that the patient is at risk for is demonstrated with a subdural hematoma in Figure 216. This lack of deterioration regardless of the level of consciousness. swelling and shift is an indication of an uninjured brain responding These patients are candidates for frequent reassessment, normally to the expanding mass. As long as this mass is removed before including repeat neuroimaging, ICP monitoring, and even the onset of coma, mortality and morbidity are essentially nil. the early application of therapies to control intracranial dynami~s.~lOJ~~ Attention to intravenous fluid management appears to be of major importance because many of the children with apparently trivial brain injuries seem more common surgically accessible masses in children, to deteriorate in the face of even mild hyp0natremia.8~J59 especially older children who have suffered a cranial Therefore, maintenance fluids for these patients, as for impact (Fig. 21-7). Small epidural hematomas over the most patients with brain injury, should be normal saline cerebral convexity are likely to resolve without surgical or its equivalent.lR1There should also be close attention removal. Those that occur in more limited "spaces," such to maintaining normal intravascular volume and serum as the temporal fossa or the posterior fossa, are more electrolyte status. concerning, and even small epidural hematomas in these Although the identification of patients at risk for deterilocations may need to be removed. Large hemorrhagic oration includes the appearance of certain abnormalities contusions or traumatic intracerebral hematomas are on CT scanning, an even more important finding from very rare in the pediatric age group."' the burgeoning literature about CT scanning and head Given this, the decision for removal of a traumatic injury is emerging. Specifically, the finding of a comintracranial hematoma should be part of an overall treatpletely normal CT scan in a mildly injured patient is ment strategy for the brain injury. Clearly, removal of a associated with essentially no risk for life-threatening large extradural hematoma may be the only therapy d e t e r i ~ r a t i o n . " J ~Given ~ that additional information needed. On the other hand, in the setting of diffuse from a normal CT scan, a child with a history of an brain injury, removal of what would otherwise be considaccidental minor head injury who does not have a skull ered a nonsurgical intracranial mass can result in substanfracture, does not have a history of seizures, and is tial improvement in the intracranial volume/pressure asymptomatic may be released to competent caretakers relationships that are essential to maintaining adequate and not be admitted for observation. cerebral perfusion. Expanding on this concept is the recent For adolescents who suffer cerebral concussion as rediscovery of "therapeutic decompressive craniectomy." a result of sporting activities, there are now published There is a growing, yet completely anecdotal literature guidelines describing the evaluation and management about the role of cranial decompressive surgery in the overall management of severe traumatic brain injury.2~~" of such individuals, along with recommendations about when athletes may return to sporting activities after a The procedure clearly increases available "volume" and COnCUSSion~4,2~,~2,~~5 lowers ICP. However, it is not clear whether decompressive craniectomy provides an additional or unique benefit over standard medical therapy. It is also not clear when in the course of injury management that this surgical Early Complications of Head Injury option should be undertaken. Acute complications of head injury include those related to skull fractures, infectious processes associated with craManagement of "Minor" Brain Injuries nial penetration and CSF fistulas, and acute neurologic complications such as post-traumatic epilepsy. As with The vast rnajority of children with head injury have trivial, most aspects of head injury management, recognition of minor, or minimal primary brain injuries. These children 0

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patients with injuries that put them at risk for these complications, followed by appropriate diagnostic studies, monitoring, and when possible, intervention, is key to optimizing outcome.

Complications of SkuN Fractures Simple nondepressed or minimally depressed skull fractures will heal spontaneously. Widely diastatic or cranial burst fractures45 in young children are indications of dural injury and are not likely to heal without surgical reconst~uction.With modern neuroimaging, early tification of these injuries allows early elective repair, thereby avoiding the complication usually referred to in the literature as a "
sen-

Basilar SkuN Fractures The major issue of acute clinical importance for patients with presumed basilar fractures is that these fractures are potentially compound and therefore place the patient at increased risk for infection. The obvious indication of CSF leaking from the nose or ear is present in only 10% to 20% of cases.31.89 Therefore, other signs of basilar fracture must be searched for because these fractures are easily missed on routine neuroimaging studies. Such signs include bilateral orbital ecchymoses or swelling, signs of midface or orbital fracture, hemotympanum, otorrhagia, and Battle's sign. These patients are at increased risk for the development of meningitis for several weeks after the injury. Given this and in view of the fact that compounding of basilar fractures probably occurs more often than not without any evidence of CSF fistulas, it is necessary that parents and caretakers of children who are thought to have sustained a basilar fracture be counseled not only about the importance of recognizing CSF rhinorrhea or otorrhea if it should occur at home but also about the urgent importance of seeking immediate medical attention for children who have signs or symptoms even remotely suggestive of bacterial meningitis up to several weeks after the injury. Despite the increased risk for bacterial meningitis, the administration of prophylactic antibiotics has not been shown to centers are administering be benefi~ial.~"94J~Wome pneumococcal vaccine to patients with presumed basilar skull fractures, although it is not yet clear that such vaccination reduces the occurrence of pneumococcal meningitis. Basilar skull fractures are also associated with cranial neuropathies. The olfactory nerve is the most commonly injured of all cranial nerves and is especially at risk in patients with anterior basilar fractures. Fractures that

occur more posteriorly along the skull base or that include the orbit and midface place the optic nerves at risk. Visual loss may be acute or delayed, and ophthalmologic evaluation and follow-up are warranted. Basilar fractures involving the petrous bone can result in auditory, vestibular, or facial nerve injury, or any combination of these injuries. These patients may need otologic evaluation and audiometric studies.108

Direct Cerebrovascular Injuries Although traumatic intracranial aneurysms are exceedingly rare after closed head injury, more than 20% of all post-traumatic aneurysms occur in the pediatric age gro~p.2 Penetrating ~ injuries, especially stab wounds and deep penetrations, have a high incidence of vascular injury associated with them. Suspicion is raised when a large amount of subarachnoid hemorrhage or a focal intracerebral hemorrhage is seen on the CT scan. CTA or MRA (or both) can screen for injury, but in some cases diagnostic angiography should be performed. If the studies are not conclusive, early repeat imaging is warranted.

Post-traumatic Seizures One of the most common complications of brain injury, even mild brain injury, is epilepsy. Most studies indicate that the incidence of post-traumatic seizures is subRisk ~~ stantially higher in children than in a d u l t s . 9 1 ~ factors associated with post-traumatic epilepsy include younger age and increasing injury severity.",73 However, it is not clear that infants with inflicted injuries, who would have a very high incidence of early epilepsy, were excluded from these studies."JYIf one removes this particular group from the analysis, the incidence of post-traumatic epilepsy in children appears to be relatively low. A distinction must be made between early and late posttraumatic seizures. Early seizures are generally defined as those that occur within the first week after iniurv. For pediatric patients, this definition would include the so-called impact-related seizure that occurs in up to 10% , ~ ~ Jseizures O~ are of mildly head-injured ~ h i l d r e n . ~ ~These usually self-limited and the CT scan is normal. Treatment is not recommended, and the long-term outcome is This particular syndrome is almost never seen in head-injured adults, in whom early epilepsy is strongly associated with structural brain injury or subdural hematoma. For severely head-injured children, that is, children in coma or with structural injury on the admitting CT scan, there is limited and conflicting information regarding the clinical significance and management of early and late post-traumatic Current recommendations indicate that all patients with severe injury who experience recurrent seizures should be treated with anticonvulsant medication. Phenytoin is the most widely recommended drug for this purpo~e.~,~"hereis some evidence that prophylactic administration of phenytoin to severely head-injured patients reduces the incidence of early post-traumatic seizures, although it is not clear J

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that outcomes after the injury are improved by this therapy.V1 On the other hand, there is strong evidence that routine administration of anticonvulsants to severely head-injured patients neither reduces the incidence of late epilepsy nor improves the outcome of the injury. Therefore, administration of anticonvulsants as seizure prophylaxis beyond the first week after the injury is not recomrnended."."~'~

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highest mortality and morbidity of childhood head injuries. The reported mortality approaches 40%.4"49 Morbidity is also high, especially if the infant shows evidence of cerebral infarction or hypoxic-ischemic injury.

Outcomes affer Mild Brain Injuries

A syndrome of neurologic dysfunction that seems to be unique to young children has been called the "pediatric concussion syndrome." Shortly after what would seem like a mild cranial impact injury the child exhibits the acute onset of pallor, diaphoresis, and impaired responsiveness. CT scans are normal and the syndrome appears to resolve as rapidly as it occurs. The underlying mechanism is unknown, although it has been suggested that it may be a variation of post-traumatic epilepsy.'j2 Other much more rarely occurring transient neurologic disturbances have been reported after mild head injury in children, including transient cortical blindness, speech arrest, ataxia, receptive dysphasia, and CT scans are, again, normal, prolonged di~orientation.~lJ~8 and the symptoms resolve spontaneously. The etiology is not clear.

Mild brain injury, that is, a brain injury with a limited effect on consciousness and with preservation of brain structure, is by far the most common CNS injury in the pediatric age group. Over three quarters of all childhood head injuries are classified as mild.lo0J Only recently has attention turned to the long-term outcomes after cerebral concussion in children.'" Although there is still variability in defining mild head injury and the spectrum of severity 0 J "general ~ ' ~ concepts appear within that t a ~ o n o m y , ~ ~ "~ to be emerging in the available literature. First, somatic complaints such as headache, visual disturbances, light and noise intolerance, and dizziness and emotional disturbances such as depression, anxiety or irritability, and cognitive impairment, including poor school performance, are common in mildly brain-injured children in the days and weeks immediately after the injury.57 Second, so long as the child did not suffer any cognitive or behavioral disturbances before the brain injury, all of the early postconcussion symptomsjust described appear to resolve completely in no more than a few months.169

Outcomes after Traumatic Brain Injury

SPINAL CORD INJURY

There is substantial variability in the reporting of outcomes after childhood head injury. With the exception of infants suffering inflicted head injuries, the overall mortality from head injury in children is roughly half that reported for head injury of similar severity in adults.21 In larger series of patients, mortality for head injury in children is generally less than 5% for all levels of injury severity and lower than 20% in children defined as having "severe" injuries based on either the Glasgow Coma Scale or other injury severity scoring systems.l02,fllJ70 Factors related to poor outcomes include high-energy mechanisms, structural injury, swelling and shift on admitting CT scans, persistent or resistant elevations in ICP, the presence of chest or abdominal injuries, and systemic complications. Traumatic brain injury is the leading cause of acquired disability in childhood.9Vor children who survive traumatic brain injury, neurologic and cognitive outcomes are related to the child's age, the severity of injury, and the amount of permanent structural injury to Children who have suffered severe the brain.8~14~m~10'~l19 brain injury are likely to have persistent adverse effects on intellectual function, memory, attention, language, and behavior.'03 It is likely that these deficits have ongoing and perhaps compounding effects on learning and socialization. Consequently, it is possible that the overall neurobehavioral outcomes for significant childhood head injury are worse for children than for similarly injured adults. Outcomes after inflicted brain injuries deserve separate discussion. This particular injury is associated with the

Spinal cord injuries in children are rare, but the consequences of such injuries can be devastating. As with traumatic brain injury, modern neuroimaging has contributed considerably to the diagnosis and management of traumatic myelopathy. As discussed at the beginning of this chapter, the major therapeutic efforts for spinal cord injury are the same as for brain injury and are aimed at preventing new primary injury and ameliorating the secondary injury. The first objective is accomplished by maintaining anatomic alignment of the vertebral column during the period of resuscitation and evaluation. , ~ begins The second objective is much more d i f f i c ~ l tbut with supporting blood pressure and oxygenation. In general, the diagnostic and therapeutic algorithms for children with spinal and spinal cord injury are similar to those used to manage adult patients. Guidelines for the management of spinal cord injury have been published recently and summarize current kn~wledge.~' However, there are important differences in clinical manifestations, anatomy, radiographic findings, and management of spinal injuries in children, especially very young children. This section concentrates on these issues.

Postconcussion Syndromes

Epidemiology Less than 10% of spinal cord injuries or approximately 1000 new spinal cord injuries occur each year in ~ h i l d r e n ? ~ Vertebral column injuries that do not involve the spinal cord are much more common. In a series of 122 children,

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only half the children with vertebral injuries had neurologic deficits.7' The mechanisms and pattern of injury are related to both age and gender. In very young children, the male-tofemale ratio is roughly equal. In older children, the more "adult" distribution appears, with a male-to-female ratio of about 4:l. Approximately half of pediatric spinal injuries are the result of motor vehicle accidents. A quarter of injuries are the result of diving accidents. Clearly, prevention efforts directed at these two mechanisms alone would dramatically reduce the rate of spinal injury in children. The remaining major mechanisms of injury are falls and sporting activities, each of which accounts for about 10% of reported injuries. Younger children are more likely to be injured as the result of a fall, whereas older children are more likely to be injured in diving accidents or ~ports.~Jss Younger children tend to have spinal column injuries in the cervical region, whereas older children tend to have a distribution of spinal injuries similar to adu1ts.ls1 Children are more like$ to experience spinal cord injury without apparent vertebral fractures or dislocations. These characteristics are generally thought to be related to the anatomic properties of the juvenile spine and are independent of the mechanism of injury. The pediatric spine has several properties that essentially allow significant, self-reducing displacement of the vertebral column. These properties include increased elasticity of the joint capsules and ligaments, shallow and horizontally oriented facet joints, anterior wedging of the vertebral bodies, and poorly developed uncinate processes."," Furthermore, young children have disproportionately larger heads and weaker cervical musculature. All of these elements permit a wider range of flexion and extension and rostrocaudal distraction. The fulcrum of motion is higher in the juvenile spine, which explains the greater incidence of rostral injuries in children. This tendency decreases and the incidence of more characteristic vertebral fracture and dislocation increases with increasing age.I0 Finally, it is important to remember that 10% to 15% of spinal injuries in children involve "skip" injuries with vertebral or cord injuries at multiple level^.^^^^ Therefore, depending on t h e mechanism bf injury, when a child is determined to have spinal cord injury or vertebral disruption, the entire spinal axis should be surveyed for othe; injuries. ~njuriesto the thoracic and lumbar spine are uncommon in children. Less than 20% of all spinal injuries in children occur below the cervical spine.143Major mechanisms involve falls from heights and high-energy motor vehicle accidents, including the characteristic spinal distraction injury resulting from automobile lap belts.71

The Clinical Spectrum of Spine and Spinal Cord Injury Because spinal cord injury is rare in children, it may be overlooked, especially in the very young and those with multiple injuries. As discussed in the next section, the presence of apparently normal plain radiographic studies will not completely rule out either vertebral

instability or spinal cord injury. Therefore, one must have an increased index of suspicion based on injury mechanism and the neurologic findings. High-energy mechanisms such as motor vehicle accidents and falls from heights are more likely to cause spinal or spinal cord injury. An unconscious patient of any age should be assumed to have a spinal cord injury until a complete assessment is possible. The clinical indicator of spinal injury in awake patients is pain and muscular spasm or guarding against movement. Any child complaining of neck or back pain or stiffness after an injury needs a complete assessment of the integrity and stability of the spine. Children can suffer torticollis as the result of atlantoaxial rotatory subluxation. Rotatory subluxation can occur as the result of apparently minor injury or even a coughing spell. Such children are usually neurologically normal. Plain radiographs can be deceiving, but CT scan of the spine in the axial plane is diagnostic.162 The cardinal sign of a spinal cord injury is neurologic dysfunction below an anatomic spinal motor or sensory level. Complete or severe incomplete cord injuries with motor dysfunction are readily detectable in conscious patients. A spinal cord injury is generally manifested as symmetrical flaccid paralysis with sensory loss at the same anatomic level. There are strong indirect indicators of spinal cord injury in a comatose patient or those with multiple injuries. Cervical spinal cord injuries can cause profound systemic hypotension, a syndrome known as "neurogenic shock" and caused by disruption of sympathetic pathways below the level of injury. Unlike the more common hypovolemic shock, neurogenic shock is suggested by the finding of bradycardia in the face of hypotension. These patients are also vasodilated despite being hypothermic. Hypovolemic shock results in hypotension, tachycardia, and vasoconstriction. Other systemic findings suggesting spinal cord injury include paradoxical respiration, priapism, Horner's syndrome, and an inability to sweat. Less severe injuries may result in transient neurologic dysfunction, dysesthesias, focal weakness, sensory loss, or dissociation of motor and sensory function such as in Brown-Sequard or other central cord syndromes. Any history of transient neurologic dysfunction involving the limbs or bladder, regardless of duration and apparent complete recovery, must be taken as strong evidence of spinal cord injury.

Spinal Cord Injury without Radiographic Abnormality Spinal cord injury without radiographic abnormality (SCIWORA) was defined by Pang and Wilberger in 1982 to describe patients who exhibit objective findings of traumatic myelopathy with no evidence of fracture or ligamentous instability on routine screening plain radiography or CT scanning.137 SCIWORA is essentially an injury of children, especially younger children, and is probably directly related to the biomechanical properties of the juvenile spine outlined earlier. As with vertebral injury, there is a tendency toward more rostral injury with younger age. Younger children suffering SCIWORA are

CHAPTER

more likely to have severe or complete cord injuries than older children are. Severe s ~ i n a lcord iniurv in older children is more typically associated with a vertebral injury than with SCIWORA.72,132,136 Diagnosis of this syndrome is complicated by the frequent %ccurrence of delayed neurologic deficits. Many children with this injury will demonstrate neurologic deficits hours to days after the reported injury and in the absence of any further injury.136The mechanism of this delayed deterioration is unknown, but Pang has speculated that there is repeated injury to an already mildly injured spinal cord, either because of the innate normal flexibility of the spine or because of subtle ligamentous injury with increased segmental movement at the injury site.13" This argument is supported by the observation that recurrent SCIWORA may occur in about 20% of children who are not immobilized and that immobilization of the cervical spine markedly reduces the incidence of this phenomenon.142 ina ally, this syndrome was initially described before the widespread use of MRI for the diagnosis of spinal disease. Although it is still true that these children do not have evidence of bony injury or overt instability on plain spine radiographs or CT scans, most (but not all) patients will have evidence of spinal cord or ligamentous or other soft tissue injury on MRI.s4,4"6Vherefore,it is essential that all physiciaks who provide early evaluations of injured children be aware of this disorder and continue to consider the possibility of spinal or spinal cord injury, even when the initial radiographic studies may be reported as normal. J

i

Initial Assessment of Spine or Spinal Cord Injury Detection of spinal injury in a child can be challenging. As with brain injury, the initial clinical findings will guide the decision for selecting diagnostic imaging. Unlike brain injury, plain spine radiography is still an important initial tool for assessment of a spinally injured patient. Any child who has neck pain, muscular guarding of spinal movement, or a neurologic deficit or who has multiple injuries from a high-energy mechanism, especially one that includes "distraction" of the spine, such as would occur with a seat-belted passenger in a motor vehicle collision, has a spinal injury until proved otherwise. Older children who are normally conscious can express appropriate clinical symptoms and signs that indicate spinal or neural injury. Current recommendations indicate that an older child who is awake and conversant and who has no neurologic deficit, or a history of one, or any pain or tenderness along the posterior spinal midline needs no further radiographic assessment or other diagnostic studies.8i Such is not the case for younger children, who are at higher risk for occult spinal and spinal cord injury simply because they are unable to express complaints of pain.g8 Therefore, a lower threshold for radiographic screening must apply to younger children. There are now fairly well proven "decision rules" for performing screening radiographic studies, specifically, anteroposterior, lateral, and open-mouth odontoid views in adult patient^.^^.^^ These studies indicate that there is extremely low probability of injury and low yield on

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radiographic studies if patients exhibit the following five criteria: no midline cervical tenderness, no focal neurologic deficit, normal alertness, no intoxication, and no painful distracting injury. The application of these decision rules to pediatric patients suggested similar findings, although the number of very young children in the study cohort was limited.Ii3 Accordingly, the caveats about young children also apply to this recommendation. Radiographic surveys of the spine in pediatric patients are complicated by the normal anatomic variations in the juvenile spine that are described in the preceding section. Growth centers and synchondroses can be mistaken for traumatic injuries. The increased normal flexibility of the spine coimonly appears as "pseudosubluxation."24J58 Most pseudosubluxation occurs between the second and third vertebral bodies, with allowable displacement of up to 4 mm in children younger than 8 years. This movement, along with the normal anterior movement between the atlas and the dens,'" can be mistaken for ligamentous injury. Therefore, spinal radiographic studies obtained in children must be interpreted with caution and with complete familiarity with developmental anatomy of the spine. Flexion-extension radiographs can be used to rule out ligamentous injury of the-cervical spine in awake and cooperative patients. However, most studies investigating the utility of dynamic radiographs have indicated that instability is not likely to be detected on these studies if routine static studies show normal alignment in the neutral p ~ s i t i o n . ~ ' J ~ ~ CT scanning of the spine is extremely helpful for detecting subtle fracture, soft tissue swelling, and rotatory subluxation, as well as for defining congenital abnormalities and developmentally normal variations that may mimic fractures on plain radiographs. Furthermore, CT is a rapid and accurate way to detect compromise of the spinal canal or nerve root foramina after traumatic injury. However, many spinal injuries are ligamentous and may be missed if CT scanning is the only study performed. Therefore, CT should be viewed as an adjunctive study to plain radiography, not a substitute. MRI is now the best study to image the injured spinal cord and to detect subtle ligamentous and other soft " tissue injuries. As discussed earlier, many, but not all patients with SCIWORA will show abnormalities on MRI that confirm the clinical diagnosis. Findings on MRI correlate with outcome afterspinal cord i;juv.s5-6gJ55 However, it is not clear that the management decisions required for spinal cord injury in children have been altered by any findings on MRL8'

Early Management of Spinal Cord Injury As with traumatic brain injury, aggressive support of systemic perfusion and oxygenation is of paramount importance. Because children will tend to have more rostra1 cervical cord injuries, impaired respiratory function is likely to be a concern. Furthermore, gastric dilatation commonly accompanies acute spinal injuries, and this can add a substantial mechanical barrier to effective respiration. Therefore, early nasogastric decompression of the stomach should be considered. For midlevel and

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higher cervical injuries, elective intubation may be needed to support respiration until a comprehensive assessment of the injury is completed. Endotracheal intubation of a spinally injured child is technically challenging and should be performed by an expert without manipulating the relative position of the head and neck. Restoration and support of systemic blood pressure will result in maintenance of perfusion of the injured spinal cord. Patients with severe cord injuries, especially in the cervical portion, are at most risk for systemic hypotension. Although the initial resuscitation can be undertaken with intravascular volume loading, neurogenic hypotension should be treated with vasopressors. Resuscitation and maintenance of normal blood pressure in a patient with a spinal cord injury are complicated and may be aided by invasive monitoring of central venous pressure. The pharmacotherapy of spinal cord injury has been the subject of active research and scientific controversy. After completion and reporting of the second National Spinal Cord Injury Study (NASCISII),lVt was recommended that all patients with acute spinal cord injuries be administered high-dose methylprednisolone. The recommendations did not officially extend to pediatric patients, but most centers applied these treatment recommendations to all age groups. Despite a subsequent studylQhat appeared to confirm the initial findings, the methodology and conclusions of these studies have been At this time, the administration seriously que~tioned."~,87 of highdose steroids to spinally injured patients, including children, is listed as a treatment option that should be undertaken only with the knowledge that evidence suggesting harmful side effects is more consistent than any suggestion of clinical benefit.87 Early surgical therapy is rarely needed. Most pediatric fractures and dislocations can be reduced and maintained in anatomic alignment with a variety of orthotic devices, including a halo brace. Early surgical reduction and fusion are considered only for cases in which clear neurologic deterioration is occurring in the face of irreducible subluxation or compression from bone fragments, extruded disk material, or an enlarging hematoma. These issues are unusual in young children. Adolescents suffer injury types similar to adults and can be treated according to the surgical recommendations available for adult patients." There is limited scientific information about the advisability and outcomes of operative management of spinal injury in young children, although recent reports indicate that surgical instrumentation is becoming more common.s4-aAnatomic reduction of deformity, stabilization of clearly unstable injuries, and decompression of neural elements are indications cited for surgical treatment of spinal injury in children. Most of these goals can be accomplished nonoperatively. Current recommendations indicate that most vertebral injuries in young children should initially be treated nonoperatively, with surgical management reserved for persistent or progressive deformity or ligamentous in~tability.~~

Complications Children are subject to all the complications associated with spinal injury, including skin breakdown, infections,

deep venous thrombosis, autonomic dysreflexia, contraccures, spasticity, neurogenic bladder and bowel, and progressive spinal deformity.180 However, the single major acute complication of spinal cord injury in children is respiratory compromise. The most common cause of death in the acute phase of injury is respiratory failure.40 Aggressive pulmonary care is essential, and ventilatory support may be necessary until the accessory muscles of respiration can strengthen. Many of the other complications can be avoided or minimized by the early intervention of physiatrists and other rehabilitation specialists. The incidence of venous thromboembolism in spinally injured children has been reported, probably incorrectly, to be roughly similar to that in adults.lX0 However, series involving only pediatric patients indicate that this complication is extremely rare.144 Therefore, specific recommendations for prophylaxis of this possible complication vary widely. For adults and, presumably, older children and adolescents, thromboprophylaxis consisting of low-molecular-weight or low-dose heparin in combination with rotating beds, pneumatic compression stockings, or electrical stimulation is recommended for up to 12 weeks after the inj~ry.~7-'~0

Outcomes

The mortality associated with spinal cord injury in children has been reported to be 28%, which is significantly higher than the mortality rate for this injury reported in ad~1t.s.~"~" The majority of these deaths appeared to occur at the scene and would not be affected by current management strategies. For survivors of spinal injury, outcomes are related to the level and severity of injury. Complete injuries remain complete, and although limited functional improvement may be seen over time, full recovChildren with incomplete ery is not expe~ted.~2,7~,l"J~6 spinal cord injuries have a good chance of showing significant functional improvement, even to complete recovery.72.74 The cost of long-term care for these injuries is staggering. The lifetime cost of care for a child with a spinal cord injury ranges in the millions of d o l l a r s . ~ ~ J ~ ~ J ~ ~ This cost must be added to the loss of productivity that accompanies these devastating injuries. The adult employment rate for individuals suffering childhood spinal cord injury is about 50%.180Factors associated with successful employment were younger age at injury, less severe neurologic impairment, better education, longer duration of living with the sequelae of the injury, and ability to drive independently.

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the prevention of early posttraumatic seizures in children with moderate to severe blunt head injury. Ann Emerg Med 2004;43:435. 180. Zidek K, Srinivasan R: Rehabilitation of a child with a spinal cord injury. Semin Pediatr Neurol 2003;10:140. 181. Zornow MH, Prough DS: Fluid management in patients with traumatic brain injury. New Horizons 1995;3:488.

Vascular Injury Joseph J. Tepas I I I

the mechanism and mortality for 1368 children with at Principles of polysystem injury management have least one vascular injury recorded in the National undergone significant change during the past decade. Pediatric Trauma Registry (NPTR) between 1989 and The evolution of damage-control surgery; the progress 2001. Although this represents only 1.3% of registry cases, in understanding traumatic stress, especially as related the 13% crude mortality rate (compared with a 2.9% rate to the management of systemic inflammatory response for the entire registry) demonstrates the lethality of syndrome; and the emergence of increasingly sophistithese injuries and the variability of outcome based on cated imaging technology have all contributed to a body region affected (Table 22-2). more precise and effective system of care for the severely As in the adult population, vascular trauma can be injured. Included in this evolution has been continued divided into injuries that involve major truncal vessels refinement of the principles of evaluating and managing '~ of the predictive accuracy and extremity injuries that disrupt peripheral perfusion. vascular i n j ~ r i e s .Validation of clinical examination and better definition of indicaIn children, the latter are commonly associated with tions for arteriography have led to more timely operative skeletal fractures rather than penetrating injury. In fact, intervention based on effective resuscitation, accurate the incidence of vascular injury occurring in children assessment of associated injuries, and anticipation of with penetrating extremity trauma is remarkably low. reperfusion injury.'"17 With the emergence of endovasVictoroff et al.46reviewed their experience with 75 children sustaining 76 penetrating extremity injuries cular technology, acute management of some vascular (gunshot wounds) treated at National Children's injuries may well move from the operating room to the Medical Center from 1985 to 1989. There were no docuangiography suite. At the heart of managing vascular mented vascular injuries and only two nerve injuries injuries, however, is the technical repair of damaged caused by bullets or bullet fragments. The greater majority blood vessels and restoration of peripheral perfusion. of injuries were minor musculoskeletal disruption from Although the basic surgical skills required are similar for which recovery was quick and complete. Data from the patients of all ages, infants and children have unique char~ ~ , ~ listed ~ in Table 22-2 indicate a similarly low mortality acteristics that can present significant c h a l l e n g e ~ . " f l , ~ ~NPTR for extremity injuries, but with a significantly higher rate

EPIDEMIOLOGY In the adult population, most vascular injury is the result . ~ is not so for infants and of penetrating t r a ~ m a This ~hildren.2~).~() Blunt injury predominates in the pediatric population, with almost half of all vascular injuries in children resulting from this type of mechanism. Table 22-1 lists Region

1

Mechanism Penetrating Blunt Crush

Proportion (%) 52 47 1

Neck Chest Abdomen, pelvis Upper extremity Lower extremity

Mortality (%)

ICD9CM

Total No. No. No. Lived Died (%)

% Operated

900-901 901-902 902-903

249 161 374

196 98 248

53 (21) 63 (39) 126 (34)

41 70 50

903-904

497

494

3 (1)

21

904-905

326

318

8 (3)

36

I

ICD-9-CM,InternationalClassificationof Diseases, 9th ed, Clinical Modification.

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of vascular operative intervention, as indicated by International Classification of Diseases, 9th edition, Clinical Modification (ICD-9-CM) operative codes 35.00 through 39. Vascular injury in childhood has two distinct components. In addition to the inury resulting from external mechanical force, the increasing use of complex endovascular diagnostic and therapeutic procedures continues is associated with a low but consistent incidence of iatrogenic damage to vascular structure^.^^,^^^" With increasing refinement of technique and improved technology, however, this appears to be d e c r e a ~ i n g . ~ ~

EVALUATION General principles of assessment of acute vascular disruption are based on clinical evaluation. Regardless of cause, suspicion of vascular injury should stimulate a logical system of clinical assessment based first on the patient's history. During the initial clinical assessment, two immediate questions must be answered: (1) Is there evidence of disruption of the integrity of the circulatory system? (2) Is perfusion adequate? Despite the implied causal relationship of these two points, each can be deranged without immediate effect on the other. Prolonged postinjury spasm, a common characteristic of childhood vascular trauma, may cause peripheral ischemia in an otherwise anatomically intact vascular tree. Conversely, effective collateral circulation, enhanced by the absence of obliterative vascular disease, may sustain distal circulation despite deranged proximal flow. Thus, not every disruption of vascular flow produces immediate peripheral ischemia, and evidence of acute ischemia may not necessarily portend operative vascular injury. Regardless of circumstances, confirmation or restoration of cellular perfusion is the immediate priority in assessing any child with a vascular injury.32 Numerous investigators have validated the predictive accuracy of thorough clinical examination and, in the process, have refined the indications for arteriography.l"l6 The latter issue is especially important in pediatric patients because of the increased potential for additional iatrogenic injury. Frykberg et a1.16 demonstrated the predictive accuracy of "hard" signs of injury and recommended immediate operative intervention for any patient with active bleeding, expanding hematoma, pulse deficit, or bruit or thrill. Nonexpanding hematoma, hypotension, peripheral nerve deficit, or a history of bleeding from the wound were considered "soft" signs that required only clinical observation. Long-term follow-up of this population has confirmed the predictive accuracy of this approach and has validated the authors' initial recommendation that routine arteriography is not necessary for the management of proximity injury.S17For children, the issue of angiography is even more relevant because of the risk of iatrogenic injury to tiny vessels, contrast toxicity, and the increased frequency of persistent spasm as the major cause of ischemia. Reichard et a1.B analyzed the predictive accuracy of clinical signs in their review of 75 children with vascular injury treated on the pediatric trauma service

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at Cook County Hospital. Part of their report included a comparison to 12 children managed by an "adult" protocol that required arteriography. None of the studies performed for proximity alone was abnormal. All 10 children with vascular injury had hard signs. Four of 77 children with no vascular injury also manifested at least one hard sign, yielding a 100% sensitivity and 95% specificity of physical examination. Of note is that these data validate similar recommendations published by Meagher et a1." in 1979 and emphasize that arteriography for acute injury should be considered only if the risk of performance is outweighed by a risk of ischemia that cannot be defined by history and clinical signs.629.40 This is especially so when considering "one-shot" emergency department arteriography, despite recent reports of the safety and efficacy of this approach.'" For chronic injury, however, arteriography is considered essential for accurate planning of revascularization. Duplex Doppler, B-mode ultrasonography, multidetector computed tomography-angiography, and magnetic resonance angiography are newly established technologies in clinical imaging. The first two are reasonably portable and can define flow and flow velocity. Their role in the diagnosis of acute injury, however, has not been well established. The last two are the result of continued evolution of computer-enhanced imaging. They offer the capability of visualizing vascular anatomy and flow without direct invasion of the arterial tree.44Recent reports have demonstrated the value of these modalities in diagnosing suspected vascular injuries in children. Three-dimensional reconstructions can precisely define both the level of injury and the efficiency of collateral circulation (Fig. 22-1). Although noninvasive techniques avoid cannulation of the arterial tree, a higher volume of contrast material may be required. Patient selection must therefore consider the risk of arterial injury versus the potential toxicity of the contrast agent. Children usually do not suffer from atherosclerotic vascular disease. Because their vessels are elastic, they usually stretch and transiently deform, rather than rupture, in response to the application of force. The immediate effect of this is an increased potential for flow disruption secondary to intimal tears. The effect of such decreased flow may be acute ischemia or marginal insufficiency that stimulates increased collateralization. Whereas the former should be easily discernible on clinical examination, the latter can be very subtle and clinically silent. Therefore, functional and anatomic integrity of the circulation must be clinically confirmed and documented in every injured child. Of equal importance is the understanding that the unexplainable absence of palpable pulses, especially in the lower extremities, may be the result of preexisting rather than acute injury. If perfusion pressure is suddenly lowered because of other acute injuries, collateral circulation may become inadequate, and symptoms of progressive ischemia may emerge. In their analysis of the predictive accuracy of clinical findings of pediatric vascular injury, Reichard et al." extol the accuracy of the ankle-brachial index (ABI) as indicative of inadequate peripheral perfusion. Their data suggest that an ABI less than 0.99 indicates clinically critical vascular injury, reinforcing

378

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Computed tomographic angiogram from a 5-year-old

hit by a car. He underwent repair of transposition of the great vessels as an infant and was noted to have a pulseless right foot. Evaluation demonstrated a clinically silent femoral artery disruption.

intensive care nursery discharge data that suggest that the true incidence of vascular injury is higher than previously believed. In fact, findings reported by Seibert et a1.43 suggest that assessment of the peripheral pulses and measurement of the ABI should be part of the routine postdischarge assessment of any baby treated with an umbilical artery catheter.

TRAUMATIC INJURIES Traumatic injuries can be divided into those involving the trunk (neck and torso) and those involving the extremities (upper or lower). Each area presents unique challenges to accurate diagnosis and timely management.

Truncal Injuries Cervical vascular injuries appear to be rare in childhood. To test their proposed algorithm for the diagnosis of blunt cervical vascular injury, Rozycki et al.41reviewed injuries associated with a cervicothoracic seat-belt sign in 797 motor vehicle crash victims treated over 17 months by the Grady Memorial Hospital Trauma Service. The 3% of patients with carotid injury were all adults. No injuries were missed, and none were noted in children. With the gradual increase in compliance with childrestraint laws, the potential association between seat-belt marks and significant vascular injury will require continued

close follow-up. Cox's2 review of the operative management of 36 children with vascular injuries included 9 children with 11 carotid or jugular injuries. Eight of these were penetrating neck injuries. Mortality occurred in only two of the three hemodynamically unstable children. Torso vascular injuries are relatively rare in childhood. This is probably the result of the greater elasticity of young, healthy vessels. Although children are not immune to thoracic vascular disruption, most series that include pediatric patients demonstrate a low incidence compared with adults. Clinical reports of aortic injuries in children suggest that the natural history is no different from that of adults. Mortality is extremely high, especially for those children with a presenting systolic blood pressure below 90 mm Hg. Eddy et a1.8 reviewed the King County coroner's records over a 12-year period (1975 to 1987), and found 13 cases of aortic disruption in children. Only three of these children reached a hospital alive, and just one survived. Experience in the NPTR is somewhat more heartening, in that 26 of 54 children (48%) with aortic ruptures survived to hospital discharge. This representative sample from multiple contributing hospitals in North America is similar to that reported from a single institution by Cox et al.,' suggesting that the outcome from this catastrophic injury may be better than that consistently reported for adults. Major thoracic venous injuries are even less common and are usually associated with major pulmonary disruption. Because of the preponderance of blunt injury in the pediatric population, especially as a result of vehiclerelated mishaps, abdominal vascular injuries can and do occur.' Arterial disruption is far less common than venous disruption. Hypotension progressing to frank shock is the most common associated finding, making the decision to explore the abdomen relatively straightforward, expect when a solid viscus injury is the most likely cause. Fayiga et al.11 reviewed 18 years of experience in the operative management of pediatric blunt vascular injuries. Twenty-one major abdominal venous injuries were present in 17 patients and were lethal in 11 (65%). None of the abdominal venous injuries was recognized before laparotomy. As in numerous other series, survival was directly related to hemodynamic stability at presentation. Most complications were related to nonvascular injuries. The majority of vascular injuries were repaired directly, which parallels the experience from a similar series of 16 abdominal vascular injuries reported by Cox et al.,' wherein interposition grafts were required to repair only one aortic disruption and one superior mesenteric artery transection.

Extremity Injuries The vast majority of lower extremity vascular injuries are the result of blunt mechanisms, are arterial, and are commonly associated with skeletal f r a ~ t u r e . ~ J ~ . 2 * Popliteal injuries, in particular, are often the result of sports and cycling mishaps. Initial assessment must confirm the presence of palpable distal pulses and adequate capillary perfusion. Immediate reduction of

CHAPTER

displaced fracture fragments or subluxated joints often results in restoration of palpable distal pulses. If the duration of ischemia has been longer than 6 hours, the possibility of evolving compartment syndrome should prompt the consideration of fasciotomy.45 Interposition of reversed contralateral saphenous vein remains the treatment of choice for all disrupted segments. Synthetic material should be considered only as a last resort when autologous vessel cannot be harvested and fabricated into a patch or conduit.31Anastomoses are constructed using monofilament simple sutures.32 As the repair is being completed, the distal clamp is first released to confirm adequate backflow. The proximal clamp is then released to flush any residual air or clot before the final sutures are tied. Vasospasm, if significant, can usually be reduced by gentle mechanical dilation using coronary artery dilators. Veins should be repaired before arteries. Children who have undergone repair of venous injuries should be anticoagulated for 48 hours postoperatively. Some authors use heparin; others simply use dextran solutions for 2 to 3 days postoperatively. Reed et a1.3 reported their experience with seven children with popliteal artery injuries who underwent immediate operative repair. Four had blunt and three had penetrating injuries. Associated morbidity included three fractures, four severe soft tissue wounds, and one nerve injury. All patients underwent angiography. Three angiograms were intraoperative, so presumably the four preoperative studies were required to confirm the diagnosis. Treatment included two primary repairs and four vein graft bypasses. Anastomoses were spatulated and sutured in an interrupted fashion. One child required fasciotomy. There were no deaths, amputations, or reoperations. At the time of their report (1990), follow-up ranged between 10 and 42 months. All patients had normal Doppler pressures or distal pulses. These data illustrate the relationship between prompt, aggressive treatment and successful outcome. Other investigators report similar recommendations and emphasize that the high proclivity for prolonged vasospasm makes arterial anastomosis in childhood especially challenging.ll The vast majority of extremity vascular injuries in children are associated with axial skeletal disruption. In its most severe form, this combination of bone and soft tissue destruction can result in what has been called the "mangled extremity." It is usually characterized by major soft tissue avulsion that can be associated with significant tissue loss. Initial assessment must consider tissue viability, anticipated limb function, and the need for amputation of a potential source of massive tissue necrosis and sepsis. The Mangled Extremity Severity Score (MESS) has been proposed as an accurate system of evaluation and prediction of limb salvage (Table 22-3). Although originally devised for adults, Fagelman et al.1° demonstrated that the MESS had a predictive accuracy of 93% when retrospectively applied to 36 injured children. Vascular disruption associated with fractures must be addressed immediately so that subsequent axial skeletal repair will produce a viable extremity. Restoration of flow may be accomplished by temporary bypass until fracture fixation is achieved. When possible, venous repair should precede arterial repair.

22

Vascular Injury

1 Factor

379

score

1

Skeletal/soft tissue injury Low-energy (stab, simple fracture, pistol gunshot wound) Medium energy (open or multiple fractures, dislocation) High energy (high-speed crash, rifle gunshot wound) Very high energy (high-speed injury, gross contamination) Limb ischemia Reduced/absent pulse, normal perfusion Pulseless, paresthesias, poor capillary refill Cool, insensate, paralyzed, numb Shock Systolic blood pressure always >90 mm Hg Transient hypotension Persistent hypotension Age (yr) <30 30-50 >50 *Score doubled for ischemia >6 hr. MESS >7 = 100%prediction for amputation.

Devitalized tissue must be debrided, and fasciotomy should be considered. Nerve function must be evaluated and documented before debating amputation. Although . it is true that children recover amazing-lv well from what ", may initially appear to be devastating injuries, being permanently crippled by an insensate, immobile extremitv is a Door alternative to an active life with a functional and properly fitted prosthesis. The decision to amputate is therefore based on an assessment of limb viability and a prediction of limb functionality. The MESS serves as a Eeasonable guideline, but the ultimate decision rests with the surgeon, the child's parents, and, when possible, the child. Upper extremity vascular injury is usually associated with supracondylar fractures. Axillary stretch injuries, especially when associated with high-energy forces, such as vehicular ejection, may disrupt arterial or venous structures, producing a hematoma that is not as precisely definable as those seen with more distal injuries. In addition to signs of obvious blood loss, diffuse edema of the axilla or shoulder region and diminution of peripheral pulses should prompt angiographic confirkation of both the existence and the anatomic configuration of the injury. Supracondylar fractures may disrupt brachial arterial flow by direct injury or by compression, with or without prolonged spasm. As with the lower extremity, definitive management begins with an assessment of the adequacy of perfusion and confirmation of the vessel's integrity. Of interest is a recent report that describes use of the ipsilateral basilic vein as an ideal interposition graft for the reconstruction of vessels in which segmental loss has 0ccurred.2~Salvage from damage of upper extremity injuries is generally good, with return of functionality related to the nature of the associated musculoskeletal and neurologic disruption. The incidence of compartment syndrome as a result of prolonged ischemia in

380

PART

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the upper extremity is reported to be significantly lower than that for lower extremity injuries; however, careful follow-up for adequate perfusion and avoidance of postischemia muscle contracture must be part of longterm management.

IATROGENIC INJURY Despite the evolution of increasingly sophisticated methods of imaging for infants and children, the potential for damage to the vascular integrity of a small child or tiny infant remains ever present. There have been numerous reports over the past decade describing this ~ . ~ ~ have been case reports particular p r 0 b l e m . ' . l 2 , ~Many of complications from some usually innocuous maneuver of routine care. Demircin et al.,3 for example, reported an infant with brachial artery pseudoaneurysm resulting from inadvertent puncture during antecubital venipuncture. The lesion was repaired by direct suture under proximal compression. Gamba et al.19 reviewed their experience with iatrogenic vascular lesions in lowbirth-weight neonates. Of 335 infants encountered between 1987 and 1994, 9 (2.6%) were diagnosed with vascular injury. Mean birth weight was 880 g (range, 590 to 1450 g ) , although the mean weight at diagnosis was 1825 g (range, 1230 to 2730 g). Injuries were associated with venipuncture in seven of the nine cases and included six femoral arteriovenous fistulas, two of which were bilateral. One carotid lesion and five femoral arteriovenous fistulas were repaired using microvascular technique. Outcome as determined by follow-up clinical examination and D o ~ ~ l flow e r studies was excellent. leading the authors to emphasize the role of aggressive medical and microsurgical management of these injuries. In 1981 O'Neill et al."? reviewed their experience with the surgical management of 41 infants with-major thromboembolic problems associated with umbilical artery catheters. Although most complications were related to emboli distal to the femoral artery, eight infants required emergency operative intervention for acute aortic obstruction. Four infants underwent transverse aortic thrombectomies, three of whom recovered completely. As principles of umbilical artery catheter management have become better established, these problems appear to have become less frequent. The increasing use of extracorporeal membrane oxygenation has raised the question of the potential need to reconstruct cervical vessels, especially when the process of oxygenation support involves the use of both the carotid artery and the jugular vein. LaQuaglia et a1.2Vescribed their experience in nine children with iatrogenic arterial injuries repaired with microsurgery. An operating microscope was routinely used, and repair was performed using 9-0 to 11-0 nylon suture. Spasm was controlled with topical 2% lidocaine or papaverine. As microsurgical technique continues to evolve and better suture materials become available, this approach will become an increasingly valuable adjunc; ko the management of major injuries to tiny vessels. The femoral artery remains the most common site of iatrogenic injury. As noted earlier in the discussion of

.

L

traumatic injury, efficient collateralization of the pelvis and gluteal region may result in these lesions remaining clinically silent throughout most of childhood. Lin et a1.28 analyzed 1674 diagnostic or therapeutic catheterizations performed in 1431 infants between 1986 and 2001. Thirty-six procedures were required in 34 children. The authors stratified complications into nonischemic, acute femoral ischemia, and chronic femoral ischemia. Nonischemic lesions included pseudoaneurysms ( n = 4), arteriovenous fistulas ( n = 5), and groin hematomas ( n = 5 ) . All were repaired directly, using interrupted polydioxanone (PDS) or polypropylene (Prolene) sutures. Acute femoral ischemic lesions were the most common and required a variety of procedures from thrombectomy to patch repair. Chronic femoral ischemia was defined as evidence of flow disruption noted after 30 days post procedure. Seven children presented with clinical signs an average of 193 days (range, 31 to 842) after the index procedure. All seven were symptomatic with claudication, leg length discrepancy, or gait disturbance. Operative repair consisted of revascularization using reversed saphenous vein for ileofemoral bypass in five children and femorofemoral bypass in one child. Only one child required patch angioplasty. The authors' analysis of potential contributory factors identified a statistically significant predictive relationship for patient age younger than 3 years, more than three previous catheterizations, performance of a therapeutic versus simple diagnostic maneuver, and use of guiding catheters larger than 6 French. The value of this study lies both in the identification of potentially predictive factors and in the documentation of the relatively short time required for chronic ischemia to become symptomatic. Children at risk of vascular injury with any abnormal clinical finding must be followed for at least 5 years, and preferably through the start of adolescence. Limb length discrepancy as a result of disruption of a major vascular structure may not become manifest until years after the precipitating event.48 Recent reports have suggested that operative revascularization of iatrogenic injury before adolescence corrects some limb length discrepancy; however, these have been relatively small series and do not represent a consensus. As is the case with the management of traumatic injury, the high proclivity for spasm and the need to differentiate prolonged spasm from arterial disruption are challenging components of the initial assessment. Prolonged spasm is thought to be the result of intimal injury, which causes derangement of nitric oxide production and disrupts the control of arterial wall tensi0n.'~,~3 When endothelial-medial contact is lost, as can be caused by shearing friction from an oversized or overzealously placed catheter, underlying vascular smooth muscle is incapable of relaxation.2" Angiographic confirmation of spasm requires the additional risk of the very mechanism suspected of causing the problem. Computed tomography-angiography or magnetic resonance arteriography may be the solution to this clinical conundrum, although the dose and concentration of contrast must be carefully considered when comparing risk and benefit. The role of spasm in causing gangrene is controversial, despite case reports suggesting cause and effe~t.~2

CHAPTER

From a clinical perspective, once spasm has been confirmed to be the sole cause of diminished peripheral perfusion, management must focus on the confirmation of evidence of tissue viability and absence of signs of evolving compartment syndrome or peripheral ischemia. Assuming that the basic cause of acute spasm is at least partly related to intimal injury, the risk of thrombosis must be a primary consideration. Over the past few years, routine anticoagulation therapy has been supplemented by thrombolytic agents, especially urokinase.Z0 Recommended doses of urokinase vary and tend to be empirical. Up to 6000 U/kg per hour have been used in infants, with good success and no complications. Most recently, a report by Zenz et a1.49on the use of tissue plasminogen activator suggested that more rapid restoration of flow could be achieved with this drug.

Digital Ischemia Syndrome Intravenous catheter-related, ipsilateral digital ischemia may suddenly develop in infants or small children with an acute infectious disease, usually associated with dehydration and hypovolemia. In a review of 104 cases, Villavicencio et a1.47reported primary involvement of the hand in 68.2% of patients and of the foot in the remainder. The age of the patients ranged from 29 days to 36 months (mean age, 14 months). The infectious process was of respiratory origin in 27.8% of cases, localized to the gastrointestinal tract in 60.5%, and localized to other areas in 11.5%. The most frequently cultured microorganisms were Escherichia coli, Salmonella, Shigella, Streptococcus, Staphylococcus, Klebsiella, and Pseudomonas. Digital cyanosis usually occurs shortly after venous cannulation and is probably the result of venospasm provoked by the presence of an indwelling catheter. As described earlier, damaged endothelium may stimulate vasoconstriction. Immobilization causes constriction of the limbs and impairs the muscle action that is necessary to assist venous return. Persistence of these conditions increases extravascular pressure and gradually produces microcirculatory failure, leading to necrosis, which begins at the most distal areas of the digits. Treatment begins with the prompt recognition of persistent cyanosis, correction of the underlying systemic disorder, and immediate removal of the catheter. Anticoagulation should be initiated immediately. Lesions should be gently washed daily in warm water, and the involved limb should be actively and passively exercised through the full range of motion. Direct heating should be avoided because ischemic tissue burns at lower temperatures than normal. Small pieces of cotton should be placed between fingers or toes, and all lesions should be covered with sterile, dry dressings. Areas of dry gangrene do not require surgical removal. If some question of infection trapped under an eschar exists, the area can be gently elevated at its corners to allow adequate drainage. As is the case with arterial lesions, amputation should not be considered until clear demarcation has occurred.

22

Vascular Injury

381

SUMMARY Vascular injury in the pediatric population is considerably different from that encountered in adults. Traumatic injury presents a unique set of characteristics that reflect the epidemiology of pediatric trauma and, if carefully managed, can exploit the intrinsically healthy status of the child's vascular system. Iatrogenic injury is the price of miniaturization. It is a recognized trade-off for the dramatic advances that have made many lifesaving procedures possible. Attention to detail in those most at risk may not eliminate the problem but will at least reduce the incidence and raise awareness. Accurate diagnosis, timely revascularization, and aggressive management of reperfusion are essential for complete recovery and normal long-term growth. The key to success is a high index of suspicion, recognition of the unique characteristics discussed ealier, and aggressive operative intervention using the high level of precision that is the cornerstone of success in the surgical care of children.

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14. Friedman RJ, Jupiter JB: Vascular injuries and closed extremity fractures in children. Clin Orthop 1984;188: 112-119. 15. Frykberg ER: Advances in diagnosis and treatment of extremity vascular trauma. Surg Clin North Am 1995; 75:207-223. 16. Frykberg ER, Crump JM, Dennis JW,et al: Nonoperative observation of clinically occult arterial injuries: A prospective evaluation. Surgery 1991;109:85-96. 17. Frykberg ER, DennisJW, Bishop K, et al: The reliability of physical examination in the evaluation of penetrating extremity trauma for vascular injury: Results at one year. J Trauma 1991;31:502-511. 18. Furchgott RF, ZawadzkiJV: The obligatory role of endothelial cells in the relaxation of arterial smooth muscle by acetylcholine. Nature 1980;288:373-376. 19. Gamba P, Tchaprassian Z, Verlato F, et al: Iatrogenic vascular lesions in extremely low birth weight and low birth weight neonates. Vasc Surg 1997;26:643-646. 20. Giacoia GP: High-dose urokinase therapy in newborn infants with major vessel thrombosis. Clin Pediatr 1993; 32:231-237. 21. Harris LM, Hordines J: Major vascular injuries in the pediatric population. Ann Vasc Surg 2003;17:266269. 22. Hoover JD, Almond PS: Isolated pediatric peripheral vascular injury caused by blunt trauma: A new occurrence. J Trauma 2004;56:198-200. 23. Itani KM, Rothenberg SS, Brandt ML, et al: Emergency center arteriography in the evaluation of suspected peripheral vascular injuries in children. J Pediatr Surg 1993;28:677-680. 24. Klein MD, Coran AG, Whitehouse WM Jr, e t al: Management of iatrogenic arterial injuries in infants and children. J Pediatr Surg 1982;17:933-939. 25. Kuo PC, Schroeder RA: The emerging multifaceted roles of nitric oxide. Ann Surg 1995;221:220-235. 26. LaQuaglia MP, Upton J, May JW Jr: Microvascular reconstruction of major arteries in neonates and small children. J Pediatr Surg 1991;26:1136-1140. 27. Lewis HG, Morrison CM, Kennedy PT, et al: Arterial reconstruction using the basilic vein from the zone of injury in pediatric supracondylar humeral fractures: A clinical and radiological series. Plast Reconstr Surg 2003;111:1159 (discussion 1 164). 28. Lin Ph, Dodson TF, Bush RL, et al: Surgical intervention for complications caused by femoral artery catheterization in pediatric patients. J Vasc Surg 2001;34:1071-1078. 29. McCorkell SJ, Harley JD, Morishima MS, et al: Indications for angiography in extremity trauma. AJR Am J Roentgenol 1985;145:1245-1247. 30. Meagher DP Jr, Defore WW, Mattox KL, et al: Vascular trauma in infants and children. J Trauma 1979;19:532-536. 31. Milas ZL, Dodson TF, Ricketts RR: Pediatric blunt trauma resulting in major arterial injuries. Am Surg 2004;70:443447.

32. Mills RP, Robbs JV: Paediatric arterial injury: Management options at the time of injury. J R Coll Surg Edinb 1991; 36:13-17. 33. Moncada S, Higgs A: The L-arginine:nitric oxide pathway. N Engl J Med 1993;329:2002-2012. 34. Nehler MR, Taylor LM Jr, Porter JM: Iatrogenic vascular trauma. Semin Vasc Surg 1998;11:283-293. 35. O'Neill JA, Neblett WW, Born ML: Management of major thromboembolic complications of umbilical artery catheters. J Pediatr Surg 1981;16:972-978. 36. Pigula FA, Buenaventura P, Ettedgui JA, et al: Management of retroperitoneal arterial injury after heart catheterization in children. Ann Thorac Surg 2000;69:1582-1584. 37. Reed MK, Lowry PA, Myers SI: Successful repair of pediatric politeal artery trauma. Am J Surg 1990;160:287-290. 38. Reichard KW, Hall JR, Meller JL, et al: Arteriography in the evaluation of penetrating pediatric extremity injuries. J Pediatr Surg 1994;29:19-22. 39. Reichard KW, Reyes HM: Vascular trauma and reconstructive approaches. Semin Pediatr Surg 1994;3:124132. 40. Reid.JD,WeigeltJA, Thal ER, et al: Assessment of proximity of a wound to major vascular structures as an indication for arteriography. Arch Surg 1998;123:942-946. 41. Rozycki GS, Tremhlay L, Feliciano DV, et al: A prospective study for the detection of vascular injury in adult and pediatric patients with cervicothoracic seat belt signs.J Trauma 2002;52:618 (discussion 623). 42. Russo VJ: Ti-aumatic arterial spasm resulting in gangrene. J Pediatr Orthop 1985;5:486488. 43. SeibertJ, Northington FJ, Miers JF, et al: Aortic thrombosis after umbilical artery catheterization in neonates: Prevalence of complications of long-term follow-up. AJRAm J Roentgenol 1991;156:567-569. 44. Soares G, Ibarra R, Ferral H: Abnominal aortic injury in a child: intravenous digital substraction angiogram (rVDSA) for the diagnosis of pediatric vascular trauma. Pediatr Radio1 2003;33:563-566. 45. Uslu MM, Altun NS, Gila E, at al: Relevance of mangled extremity severity score to compartment syndromes. Arch Orthop Trauma Surg 1995;114:229-232. 46. Victoroff BN, Robertson WW Jr, Eichelberger MR, et al: Extremity gunshot injuries treated in an urban children's hospital. Pediatr Emerg Care 1994;lO:l-5. 47. Villavicencio JL, Gonzalez-Carna JL: Acute vascular problems of children. Curr Probl Surg 1985;22:1-85. 48. Whitehouse WM, Coran AG, Stanley IC, et al: Pediatric vascular trauma: Manifestations, management, and sequelae of extremity arterial injury in patients undergoing surgical treatment. Arch Surg 1976;111:1269-1275. 49. Zenz W, Muntean W, Beitzke A, et al: Tissue plasminogen activator (Alteplase) treatment for femoral artery thrombosis after cardiac catheterisation in infants and children. Br Heart J 1993;70:382-385.

Burns Dai H. Chung, Arthur I? Sanford, and David N. Herndon

In 1944 Lund and BrowderGg developed a diagram that allowed a quantifiable assessment of the percentage of total body surface area (TBSA) burned. While treating victims of the Coconut Grove fire in Boston in 1946, Cope and Moore18 were able to quantify the amount of fluid required to maintain the central electrolyte composition after "burn shock." In the 1960s the discovery of efficacious topical antimicrobial agents, such as 0.5% silver nitrate,75 mafenide acetate (Sulfamylon),68 and silver sulfadiazine ( S i l ~ a d e n e )had , ~ ~ a significant impact on reducing the incidence of burn wound sepsis. These and other advances in burn care during the past several decades have resulted in an overall i m ~ r & e d survival rate for major burn patients. In recent years, continued progress has been made in several areas of burn care. Early surgical excision of eschar and grafting have significantly minimized the incidence of burn wound sepsis and shortened the total length of hospital stay. Treatment with anabolic agents restores net positive nitrogen balance during the prolonged postburn hypermetabolic period. Acute recognition of inhalation injury and effective treatment have also improved the overall outcome for burn patients. These are but a few of the significant advances that have led to a further decline in burn-related deaths.Voday, the overall increased survival rate among major burn victims is most evident in the pediatric population, where the mortality rate is 50% in children 14 years and younger with 98% TBSA burns; in other age groups it is 50% for those with 75% TBSA burns."' Although the overall incidence of burn injuries has declined as a result of preventive measures and legislation, more than 1 million burn injuries still occur each year in the United States. Fortunately, most of these burn injuries are minor, but approximately 45,000 patients suffer moderate to severe burns that require hospitalization. Of these cases, 67% are young males, and 40% are children younger than 15 years3 As the second leading cause of accidental death in children younger than 5 years, burns resulted in 532 pediatric deaths in 2001. In 2002 an estimated 92,500 children younger than 14 years were treated in hospital emergency rooms for burn-related injuries (58,100 with thermal burns and 22,600 with scald burns)." Of the children aged 4

and younger who are hospitalized for burn-related injuries, 65% have scald burns, 20% have contact burns, and the remainder have flame burns. The majority of scald burns in infants and toddlers are from hot foods and liquids. Hot grease spills are notorious for causing deep burns to the involved areas. Hot tap-water burns, which can easily be prevented by installing special faucet valves so that water does not leave the tap at a temperature above 120°F (48.8"C), frequently result in large burned areas in children.' Children also suffer productrelated contact burns from curling irons, ovens, steam irons, and fireworks. Contact with the electrical current in wall outlets also causes a significant percentage of injuries, as does contact with electrical cords. Child abuse also represents a significant cause of burns in children (Fig. 23-1). Burns with bilateral symmetry or a stockingdistribution, particularly t; the dorsum of hands, along with a delay in seeking medical attention, should raise the suspicion of child abuse. In the adolescent age group, flame burns are more common, frequently occurring as a result of experimenting with fire and volatile agents.

, . Scald burn of lower extremities in an infant. Bilateral stocking distribution with well-demarcated margins is consistent with a burn injury resulting from child abuse.

383

384

PART

I1

TRAUMA

PATHOPHYSIOLOGY As the largest organ in the body, the skin maintains fluid and electrolyte homeostasis, guards against harmful environmental insults, and acts as a barrier to infection. Other important functions include thermoregulation, metabolism of vitamin D production, and processing of neurosensory inputs. The total surface area of skin ranges from 0.2 to 0.3 m2 in a typical newborn and 1.5 to 2.0 m2 in an adult, making up nearly 15% of total body weight. Anatomically, the epidermis is composed primarily of epithelial cells, specifically keratinocytes. The process of epidermal maturation from the basal layer of keratinocytes to desquamation generally takes about 2 to 4 weeks. The dermis is made up of fibroblasts, which produce collagen and elastin, and is subdivided into a superficial papillary dermis and a deep reticular dermis. The papillary dermis and reticular dermis are separated by a plexus of nerves and blood vessels. The reticular dermis and fatty layer contain skin appendages, such as hair follicles, sweat glands, and sebaceous glands. Therefore, burns involving the deep dermis are generally insensate to touch and painful stimuli. Thermal injury results in coagulation necrosis of the epidermis and varying degrees of injury to the underlying tissue. The extent of burn injury depends on the temperature, duration of exposure, skin thickness, ability of the skin to dissipate heat, and specific heat of the causative agent. For example, the specific heat of fat is higher than that of water; therefore, grease burns often result in much deeper burns than do scald burns from water with the same temperature and duration of exposure. Thermal energy is easily transferred from high-energy molecules to those of lower energy during contact, through the process of heat conduction. The skin generally provides a barrier to the transfer of energy to deeper tissues; therefore, much of the burn injury is confined to this layer. However, local tissue response to the zone of initial burn injury can lead to progressive destruction of surrounding tissue. The area of cutaneous burn injury is divided into three zones: coagulation, stasis, and hyperemia (Fig. 23-2). The zone of coagulation comprises the initial burn eschar, where cells become irreversibly damaged and necrotic at the time of injury. The area immediately surrounding the necrotic area is a zone of stasis, where most cells are initially viable but tissue perfusion becomes progressively

impaired from the local release of inflammatory mediators such as thromboxane A2,arachidonic acid, oxidants, and cytokines.95 Their influence on the microcirculation results in the formation of platelet thrombus, neutrophil adherence, fibrin deposition, and vasoconstriction, which lead to cell necrosis. However, adequate wound care and resuscitation may reverse this process and prevent extensive cell necrosis. Thromboxarie A2 inhibitors can significantly improve dermal blood flow to decrease the zone of stasis.19 Antioxidants as well as bradykinin antag~ ~ , ~ ~of onists also improve local blood f l o ~ . Inhibition neutrophil adherence to endothelium with anti-CD18 or anti-intercellular adhesion molecule monoclonal antibodies improves tissue perfusion in animal models.H,% Peripheral to the zone of stasis lies the zone of hyperemia, which is characterized by vasodilatation and increased blood flow as part of the inflammatory response. The burn-induced inflammatory response is not limited to the local wound in burns involving greater than 40% TBSA. A massive systemic release of thromboxane A2, along with other inflammatory mediators (bradykinin, leukotrienes, catecholamines, activated complement, vasoactive amines), imposes a major physiologic burden on the cardiopulmonary, renal, and gastrointestinal (GI) systems.97 Decreased plasma volume due to increased capillary permeability and subsequent plasma leak into the interstitial space can lead to depressed cardiac function. As a result of low cardiac output, renal blood flow can decrease, leading to a diminished glomerular filtration rate. Activation of other stress-induced hormones and mediators, such as angiotensin, aldosterone, and vasopressin, can further compromise renal blood flow, resulting in 0liguria.7~If not properly treated, this condition can progress to acute tubular necrosis and renal failure, which is associated with a poor outcome for burn patients.61 Atrophy of small bowel mucosa occurs as a result of increased epithelial apoptosis and decreased epithelial proliferation.l~l7JO0Intestinal permeability to macromolecules, which are normally repelled by an intact mucosal barrier, increases after a burn i n j ~ 1 r y . 1 ~ ~ ~ ~ ~ Transient mesenteric ischemia is thought to be an important contributing factor to increased intestinal permeability, which can result in a more frequent incidence of bacterial translocation and subsequent endotoxemia. Burn injury also causes a global depression of immune function. Macrophage production is decreased; neutrophils are impaired in terms of their functions such

.

-

Three zones of

burn injury: coagulation, stasis, and hyperemia.

Subcutaneous

Superficial 2" burn

Deep 2" burn

CHAPTER

23

Burns

385

as diapedesis, chemotaxis, and phagocytosis; cytotoxic ~ - 1 ~ m p h o c ~activity te is decreased: These impaired functions of neutrophils, macrophages, and T lymphocytes contribute to an increased risk for infectious complications after burns.j,6,"',7sfi4J01

First Aid A burn patient must immediately be removed from the source of burn injury, and potential life-threatening injuries must be quickly assessed and addressed independent of the cutaneous burns, as in the case of a multiple trauma victim. Burned clothing and metal jewelry are removed. Immediate cooling by pouring cold water onto the surface of burn wounds must be used with caution to avoid hypothermia. After the removal of clothing, the patient should be kept warm in blankets. With chemical burns, wounds should be irrigated with copious amounts of water, taking care not to spread the chemical to adjacent uninvolved areas. Attempts to neutralize chemicals are contraindicated, as this process may produce additional heat and increase the burn injury. As with any trauma patient, burn patients are quickly assessed through primary and secondary surveys. In the primary survey, airway, breathing, and circulation are assessed, and any potential life-threatening conditions are identified and treated quickly. Symptoms such as wheezing, tachypnea, and hoarseness indicate impending major airway problems; the airway must be rapidly secured with intubation and 100% oxygen support. Oxygen saturation is monitored using a pulse oximeter, and chest expansion is observed to ensure equal air movement. However, adequate oxygen saturation does not mean that the airway is protected, because children have the ability to compensate until just before catastrophic airway collapse occurs. Circumferential full-thickness burns to the chest can significantly impair respiratory function by constricting the trunk and preventing adequate chest expansion. If necessary, escharotomy should be performed to allow better chest expansion and subsequent ventilation. Blood pressure may be difficult to obtain in burned patients with charred extremities. Pulse rate can be used as an indirect measure of intravascular volume; the presence of tachycardia is an indication of the continued need for aggressive fluid resuscitation. Burn depth is categorized according to the involved layers of skin: epidermis, papillary dermis, reticular dermis, subcutaneous fat, and underlying structures (Fig. 23-3). First-degree burns are confined to the epidermis, which is intact, erythematous, and painful to touch. The application of topical ointment containing aloe Vera and the administration of oral nonsteroidal anti-inflammatory agents constitute standard treatment. First-degree burns (e.g., sunburn) heal spontaneously without scarring in 7 to 10 days. Second-degree burns are divided into superficial and deep, based on the depth of dermal involvement. Superficial second-degree burns are limited to the papillary dermis and are typically erythematous and painful with blisters. These burns spontaneously

Reticular

Deep

I

-2"-Burn - - -I

I I I I

Subcutaneous fat

3" Burn I ------I , Bum depth. Firstdegree burns are confined to the epidermis. Superficial seconddegree burns involve the papillary dermis, and deep seconddegree burns involve reticular dermis. Thirddegree burns are full-thickness injuries through the epidermis and dermis. (Adapted from Wolf S, Hemdon DN: Burns. In Townsend CM J r [ed]: Textbook of Surgery, 17th ed. Philadelphia, WB Saunders, 2004, p 571.)

re-epithelialize in 10 to 14 days from retained epidermal structures and may leave only slight skin discoloration. Deep second-degree burns extend into the reticular layer of the dermis. The deep epidermal appendages allow some of these wounds to heal slowly over several weeks, usually with significant scarring. Third-degree burns are full-thickness injuries resulting in complete destruction of the epidermis, dermis, and dermal appendages and are characterized by a dry, leathery eschar that is insensate to any stimuli. Without any residual epidermal or dermal appendages, such burn wounds heal by re-epithelialization from the edges. Fourthdegree burns, typically resulting from profound thermal or electrical injury, involve organs beneath the layers of the skin, such as muscle and bone. An accurate and rapid determination of burn depth is vital to the proper management of burn injuries. In particular, the distinction between superficial and deep dermal burns is critical, as this dictates whether the burn can be managed without surgical procedures. Unfortunately, the determination of whether an apparent deep dermal burn will heal in 3 weeks is only about 50% accurate, even when made by an experienced surgeon. Early excision and grafting provide better results than nonoperative therapy for such indeterminate burns. More precise, objective methods to determine burn depth include techniques such as laser Doppler flowmetry and fluorescein to determine blood flow; ultrasonography to detect denatured collagen; and light reflectance of the Ultimately, burn wound biopsy is the most precise diagnostic too1j3; however, it is not clinically useful because it is invasive and indicates only the static condition of the wound. It also requires an experienced pathologist to interpret histologic findings. Despite these modern technologies, clinical observation is still the most reliable method of determining burn depth.

386

PART

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TRAUMA

Full-thickness circumferential burns to the extremities produce a constricting eschar, which may result in vascular compromise to the distal tissues, including nerves. Accumulation of tissue edema beneath the nonelastic eschar impedes venous outflow, resulting in a compartment syndrome and eventually affecting arterial flow. When distal pulses are absent on palpation or Doppler examination, escharotomies of the extremities are performed to avoid vascular compromise of the limb tissues, after confirmation of the absence of a central circulation problem. Using either a scalpel or electrocautery, escharotomies are performed at the bedside along the lateral and medial aspects of the involved extremities (Fig. 23-4). When the hands are involved, incisions are carried down onto the thenar and hypothenar eminences and along the dorsolateral aspects of the digits, taking care to avoid injury to the neurovascular bundle. Because injuries requiring escharotomy are typically full thickness, minimal bleeding is encountered. If vascular compromise has been prolonged, reperfusion after an escharotomy may cause reactive hyperemia and further edema formation in the muscle compartments. Ischemia-reperfusion injury also releases free oxygen radicals, resulting in transient hypotension. If increased compartment pressures are noted, fasciotomy should be performed immediately to avoid permanent ischemic injuries to the nerves and soft tissues. Intravenous (IV) access should be established immediately to infuse lactated Ringer's solution according to resuscitation guidelines. Peripheral IV access is preferred, but femoral venous access is an ideal alternative in patients with massive burns. If the only IV access available is through burned tissue, this route should be chosen for immediate resuscitation and later changed to a more

appropriate site under sterile conditions. When vascular access is problematic in small children with burned extremities, the intraosseous route is an alternative in those younger than 6 years. A nasogastric tube is placed in all patients with major burns to combat the onset of gastric ileus. Almost immediate enteral nutrition can be initiated via a transpyloric feeding tube. A Foley catheter is placed to accurately monitor urine output as a measure of end-organ perfusion. Admission laboratory studies should include complete blood count, type and crossmatch for packed red blood cells, chemistry, urinalysis, coagulation profile, and chest radiograph. If inhalation injury is suspected, arterial blood gas with carboxyhemoglobin level should also be determined to guide respira
a

Fluid Resuscitation

.

-

Escharotomies. The incisions are made on the

medial and lateral aspects of the extremity. Hand escharotomies are performed on the medial and lateral digits and on the dorsum of the hand. (From Eichelberger MR [ed]: Pediatric Trauma: Prevention, Acute Care, Rehabilitation. St Louis, Mosby, 1993, p 569.)

Appropriate fluid resuscitation should begin promptly upon securing IV access. Peripheral IV access is sufficient in the majority of small to moderate burns. Saphenous vein cutdowns are useful in cases of difficult access; in children, however, percutaneous femoral central venous access may be easier and more reliable. There are many fluid resuscitation guidelines for delivering various concentrations of colloid and crystalloid solutions. The Parkland formula (4 mL of lactated Ringer's solution per kilogram of body weight per percentage of TBSA burned) is most widely used, but children's fluid resuscitation requirements should be based on body surface area rather than weight. Because children have' a greater body surface area in relation to weight, weight-based formulas can underresuscitate children with minor burns and may grossly overresuscitate those with extensive burns.36TBSA can be rapidly estimated from height and weight using standard nomograms (Fig. 23-6). The Galveston formula (Shriners Hospital for Children) uses 5000 mL/m%urned plus 2000 mL/m2 TBSA of lactated Ringer's solution given over the first 24 hours after the injury, with half the volume administered during the first 8 hours and the remaining half over the next 16 hours (Table 23-2).

CHAPTER

23

Burns

10

Adult (Rule of nines) a

-

Modified "rule of nines" for pediatric patients. (From Herndon DN [ed]: Total Burn Care, 2nd ed. Philadelphia, WB Saunders,

2002, p 429.)

albumin is added 12 hours after the injury. After the first 24 hours, 3'750 mL/m2 burned of lactated Ringer's solution is given to replace evaporative fluid loss, plus 1500 mL/m2 TBSA per 24 hours for maintenance. A dextrose-containing solution, such as 5% dextrose with one quarter to one half normal saline, is used as the primary solution. Children younger than 2 years are susceptible to hypoglycemia due to limited glycogen stores; therefore, lactated Ringer's solution with 5% dextrose is given during the first 24 hours after burns.

Regardless of which guidelines are used, the primary goal of fluid resuscitation is to achieve adequate organ tissue perfusion. Fluid administration should be titrated to maintain a urine output of greater than 1 mL/kg per hour. Approximately 50% of administered fluid is sequestered in nonburned tissues in 50% TBSA burns, owing to the increased capillary permeability that occurs, particularly in the first 6 to 8 hours after injury.z1 During this period, large molecules leak into the interstitial space to increase extravascular colloid osmotic pressure. Therefore, to maintain intravascular osmotic pressure,

Area Head Neck Anterior trunk Posterior trunk Buttock Genitalia Upper arm Lower arm Hand Thigh

<1Year 19 2 13 13 2.5 1 4 3 2.5 5.5 5 3.5

1-4 Years

17 2 13 13 2.5 1 4

3 2.5 6.5 5 3.5

5-9 Years

10-14 Years

13 2 13 13 2.5 1 4

3 2.5 8

5.5 3.5

I

Burn size estimates based on the area burned are more precise than the rule of nines for pediatric patients.

1 5 Years

Adult

11 2 13 13 2.5 1

9 2 13 13 2.5 1

7 2 13 13 2.5 1

4

4

4

3 2.5 8.5 6 3.5

3 2.5 9 6.5 3.5

3 2.5 9.5 7 3.5

388

PART

I1

~eibht

TRAUMA

For children of normal height for weight

-

, Standard nomogram for the determination of body surface area based on height and weight. A straight line drawn between the height and weight measurements determines the total body surface area in square meters.

- 1.30 80 7- 1.20 70--1.10 -

-

6 --0.20

4--0.15

-

Children often d o not exhibit clinical signs of hypovolemia until more than 25% of the circulating volume is depleted and complete cardiovascular collapse is imminent. Tachycardia reflects a compensatory response to hypovolemia, but caution is needed to avoid overinterpreting this finding, because reflex tachycardia

due to postinjury catecholamine response is common. A lethargic child with decreased capillary refill and cool, clammy extremities needs prompt attention. Measurement of arterial blood pH and base deficit values can also reflect the adequacy of fluid resuscitation. Hyponatremia is a frequent complication in pediatric burn patients

-

First 24 Hours

--

Parkland

Brooke

Galveston

-Thereafter

Lactated R~nger'ssolut~on4 mL/kg/% TBSA burned; 50% total volume during first 8 hr after injury and remaining 50% over subsequent 1 6 hr Lactated Ringer's solution (with colloid 0.5 mL/kg/% TBSA burned) 2 mL/kg/% TBSA burned; 50% total volume during first 8 hr after injury and remaining 50% over subsequent 1 6 hr Lactated Ringer's solution (12.5 g albumin/L added 1 2 hr after injury) 5000 mL/m2 burned + 2000 mL/m2 total; 50% total volume during first 8 hr after injury and remaining 50% over subsequent 1 6 hr

L

TBSA, total body surface area.

5% dextrose wlth Na+, K+, and album~nto ma~nta~n normal serum electrolytes and colloid oncotic pressure Titrate to maintain urine output 0.5-1.0 mL/kg/hr

3750 mL/m2 burned + 1500 mL/m2 total; substitute IV fluid volume with enteral formula

__1

CHAPTER

after aggressive fluid resuscitation. Frequent monitoring of serum chemistry with appropriate correction is required to avoid severe electrolyte imbalance. A serious complication such as central pontine myelinolysis can occur as a result of careless, rapid correction of hypernatremia.' Hypertonic saline resuscitation can be beneficial in treating bum-induced shock.74~96This process maintains intravascular volume more effectively by removing fluid from the interstitial space through osmosis, thus decreasing generalized tissue edema. However, it is not widely used because of the potential risk of hypernatremia, hyperosmolarity, renal failure, and alkalosis.""g7 Some favor the use of a modified hypertonic solution-adding an ampule of sodium bicarbonate to each liter of lactated Ringer's solution during the first 24 hours of re~uscitation.'~ After initial first aid and the start of appropriate fluid resuscitation, transferring the patient to a tertiary burn center should be considered. Burn units with experienced multidisciplinary teams are best prepared to treat patients with major burns. In addition to physicians and nurses, respiratory and rehabilitation therapists play a critical role in the management of acute burns. Any patient who sustains a "major burn injury," as defined by the American Burn Association (Table 23-3), should be transferred to a nearby burn center for further care.

Topical Antimicrobials Proper wound care is guided by an accurate assessment of burn depth and size. First-degree burns require no dressing, but the involved areas should be kept out of direct sunlight. They are generally treated with topical ointments for symptomatic pain relief. Superficial seconddegree burns are treated with daily dressing changes and topical antimicrobials. They can also be treated with simple application of petroleum gauze or synthetic dressings to allow rapid, spontaneous re-epithelialization.Deep second- and third-degree burns require excision of eschar and skin grafting.

Second- and third-degree burns > l o % TBSA in patients aged < I 0 or >50 yr Second- and third-degree burns >20% TBSA in other age groups Third-degree burns >5% TBSA in any age group Burns involving the face, hands, feet, genitalia, perineum, and skin overlying major joints Significant chemical burns Significant electrical burns, including lightning injury Inhalation injury Burns with significant concomitant trauma Burns with significant preexisting medical disorders Burns in patients requiring special social, emotional, and rehabilitative support (including suspected child abuse and neglect) TBSA, total body surface area.

23

Burns

389

Antimicrobial Agent

Characteristics

Silver sulfadiazine (Silvadene)

Broad-spectrum activity and painless; does not penetrate eschar; impairs epithelialization; leukopenia Broad-spectrum activity, including Pseudomonas; penetrates eschar; painful in second-degree burns; may cause metabolic acidosis (inhibits carbonic anhydrase inhibitor) and inhibition of epithelialization Broad-spectrum activity; does not penetrate eschar; discolors contacted areas; may cause hyponatremia, methemoglobinemia Painless, but limited antimicrobial activity Inhibits fungal growth; frequently used in combination with Silvadene Effective against Staphylococcus Broad-spectrum activity, but possible systemic absorption Effective against almost all microbes

Mafenide acetate (Sulfamylon; 10% cream or 5% soaks)

Silver nitrate (0.5%)

Bacitracin/Polysporin Nystatin Mupirocin (Bactroban) Povidone-iodine Dakin solution (0.025%)

Table 23-4 lists topical antimicrobial agents used for the management of burn wounds. None of these agents effectively prevents the colonization of organisms that are commonly harbored in the eschar, but they maintain the bacterial quantity at less than 10' to lo5 colonies per gram of tissue. Routine punch quantitative wound biopsy can indicate impending burn wound sepsis and possible failure of skin graft from infection. Silver sulfadiazine (Silvadene) is the most commonly used topical agent for burn wound dressings. Although it does not penetrate eschar, it has a broad spectrum of efficacy and soothes the pain associated with seconddegree burns. Silver sulfadiazine on fine mesh gauze can be used separately or in combination with other antimicrobial agents, such as nystatin. This combination, providing additional antifungal coverage, has significantly reduced the incidence of Candida infection in burned patients.z.24 The most common side effect is leukopenia; however, this is caused by margination of white blood cells and is only transient." When the leukocyte count falls below 3000 cells/mm" changing to another topical antimicrobial quickly resolves this complication. Mafenide acetate (Sulfamylon) is more effective in penetrating eschar and is therefore frequently used in third-degree burns. Fine mesh gauze impregnated with Sulfamylon (10%water-soluble cream) is applied directly to the burn wound. Compared with silver sulfadiazine, Sulfamylon has a much broader spectrum of efficacy, including coverage against Pseudomonas and Enterococcus. It is also available in a 5% solution to soak burn wounds, eliminating the need to perform frequent dressing changes. Sulfamylon is a potent carbonic anhydrase inhibitor, so it can cause metabolic acidosis. This side effect can usually be avoided by limiting its use to only 20% TBSA at any one time and rotating application sites

390

PART

I1

TRAUMA

every several hours with another topical agent, such as Silvadene. Additionally, it is painful when applied, limiting its use in an outpatient setting, especially with children. In addition to 5% Sulfamylon solution, 0.5% silver nitrate and 0.025% sodium hypochlorite (Dakin solution) are available. These solutions-are generally poured onto gauze dressings on the wound, avoiding the need for frequent dressing changes and the potential loss of grafts or healing cells. Silver nitrate is painless on application and has broad coverage, but its side effects include electrolyte imbalance (hyponatremia, hypochloremia) and dark gray or black stains. A new commercially available dressing containing biolog~callyactive silver ions' (Acticoat) retains the effectiveness of silver nitrate without the side effects. Dakin solution is effective against most microbes, including Pseudomonas. However, it requires frequent dosing because of the inactivation of hypochlorite when it comes in contact with protein; it can also retard healing - cells.38 Petroleum-based antimicrobial ointments such polymyxin B, bacitracin, and Polysporin are painless and transparent, allowing easier monitoring of burn wounds. These agents are generally effective only against gram-positive organisms, and their use is limited to facial burns, small areas of partial-thickness burns, and healing donor sites. Like Silvadene, these petroleumbased agents can be used in combination with nystatin to suppress skin Candida colonization.

Wound Dressings Superficial second-degree burns can be managed using various methods. Topical antimicrobial dressings using Silvadene are most commonly used, but synthetic dressings such as Biobrane and Opsite offer the unique advantage of eliminating frequent, painful dressing changes and tissue fluid loss. The general principle of these synthetic products is to provide sterile coverage of superficial second-degree burn wounds to allow rapid, spontaneous re-epithelialization of the involved areas. Biobrane is a thin, synthetic material composed of an inner layer of nylon coated with porcine collagen and an outer layer of rubberized silicone. It is pervious to air but not to fluids and is available in simple sheets or preshaped gloves (Fig. 23-7).@jAfter placement on clean, fresh, superficial second-degree burn wounds using Steri-strips and bandages, the Biobrane dressing dries up, becoming adherent to burn wounds within 24 to 48 hours. Once the dressing is adherent, the covered areas are kept open to air and examined closely for the first few days to detect any signs and symptoms of infection. As epithelialization occurs beneath the Biobrane, the sheet is easily peeled off the wound. If serous fluid accumulates beneath the Biobrane, sterile needle aspiration can preserve its use. However, if foul-smelling exudate is detected, the Biobrane should be removed and topical antimicrobial dressings applied. Alternatively, Opsite or Tegaderm can be used to cover superficial second-degree burn wounds. Commonly used as postoperative dressings in surgical patients, both are relatively inexpensive, are easy to apply, and provide

, Biobrane glove. Biobrane is an ideal synthetic wound coverage material for superficial second-degree burns. It promotes rapid re-epithelialization without painful dressing changes.

an impervious barrier to the environment. Their transparent nature allows easy monitoring of covered second-degree burn wounds. Despite lacking any special biologic factors (e.g., collagen and growth factors) to enhance wound healing, they promote a spontaneous re-epithelialization process. Biobrane and Opsite are preferred to topical antimicrobial dressings when dealing with small, superficial second-degree burn wounds, especially in outpatient settings, to avoid the pain associated with dressing changes. TransCyte, composed of human fibroblasts that are then cultured on the nylon mesh of Biobrane, is another option. Synthetic and biologic dressings are also available to provide coverage for full-thicknessburn wounds. Integra, which is made of a collagen matrix with an outer silicone sheet, is a synthetic dermal substitute for the treatment of full-thickness burn wounds. After the collagen matrix engrafts into the wound in approximately 2 weeks, the outer silicone layer is replaced with epidermal autografts. Epidermal donor sites heal rapidly without significant morbidity, and Integra-covered wounds scar less; however, they are susceptible to wound infection and must be monitored carefully. Alloderm is another dermal substitute with decellularized preserved cadaver dermis. These synthetic dermal substitutes have tremendous potential for minimizing scar contractures and improving cosmetic and functional outcome. Temporary wound coverage can be achieved using biologic dressings, such as xenografts from swine and allografts from cadaver donors. Particularly useful when dealing with large TBSA burns, biologic dressings can provide immunologic and barrier functions of normal skin. The areas of xenograft and allograft are eventually rejected by the immune system and sloughed off, leaving healthy recipient beds for subsequent autografts. Although extremely rare, the transmission of viral diseases from allograft is a potential concern.

Excision and Grafting Early excision with skin grafting has been shown to decrease operative blood loss and length of hospital stay

CHAPTER

and ultimately improve the overall survival of burn p a t i e n t ~ . ~ ' ~ ~ V y p i c a tangential lly, excision of a fullthickness burn wound is performed within 3 days of injury, after relative hemodynamic stability has been achieved. The accurate determination of burn depth is vital to proper management. In particular, distinguishing between superficial and deep thermal burns is critical, as this dictates whether the burn wound can be treated with dressing changes alone or requires surgical excision. Eschar is sequentially shaved using a powered dermatome (Zimmer) or knife blades (Watson, Weck) until a viable tissue plane is achieved. Early excision of eschar (usually <24 hours after burns) generally decreases operative blood loss, owing to the actions of vasoconstrictive substances such as thromboxane and catecholamines. Once the burn wound becomes hyperemic 48 hours after injury, bleeding during excision of the eschar can be excessive. Tourniquet and subcutaneous injections of epinephrine-containing solution can lessen-the blood loss, but these techniques may hinder the surgeon's ability to differentiate viable from nonviable tissue.'O A topical hemostatic agent such as thrombin can also be used, but it is expensive and not very effective against excessive bleeding from open wounds. In patients with deep full-thickness burns, electrocautery is used to rapidly excise eschar with minimal blood loss. More importantly, the earlier the excision, the less blood loss is anticipated in burns greater than 30% of TBSA.2Wowever, with scald burns it is more difficult to assess the burn depth initially; therefore, such burns require a more conservative approach, with delayed excision. Ideally, the excised burn wound is covered with autografts. Burns wounds less than 20% to 30% of TBSA can be closed at one operation with split-thickness autografts. Split-thickness autografts are harvested using dermatomes, and donor sites are dressed with petroleumbased gauze, such as Xeroform or Scarlet Red. Opsite can also be used to cover donor sites. Sheet autografts are preferred for a better long-term aesthetic outcome, but narrowly meshed autografts (1:l or 2:l) have the advantages &limiting the total surface area of donor harvest and allowing better drainage of fluid at the grafted sites. With massive burns, the closure of burn wounds is achieved by a combination of widely meshed autografts (4:1 to 6:l) with allograft (2:1) overlay (Fig. 23-8). Repeat grafting is required for large burns, with sequential harvesting of split-thicknessautograft from limited donor

23

Burns

391

sites until the entire burn wound is closed. As the meshed autografts heal, allografts slough off, but the formation of significant scar is a major disadvantage of this techniaue. Therefore, the use of widelv meshed graft is avoided in the face and functionally important hands. A full-thickness graft that includes both dermal and epidermal components provides the best outcome with diminished contracture and in wobnd coverage: " better pigment match. However, its use is generally limited to small areas, owing to the lack of abundant full-thickness donor skin. The limitation of donor sites in massively burned patients is partially addressed with the use of systemic recombinant human growth hormone. Administration of " growth hormone results in accelerated donor site healing, allowing more frequent donor site h a r ~ e s t . ~ ~ . ~ ~ In one study, growth hormone hastened donor site healing time'byan average of 2 days, which ultimately shortened the length of hospital stay from 0.8 to 0.54 day per percent of TBSA burned." These effects of growth hormone are thought to be due to stimulation of insulinlike growth factor-1 (IGF-1) release, along with the induction of IGF-1 receptors in the burn wound.44 Insulin given alone can also decrease donor site healing time from 6.5 to 4.7 days.8' Decreasing the time between each harvest by 1 day can significantly impact the total length of hospital stay in massively burned patients who require multiple grafting procedures. Administration of ~ r o w t hhormone in burned children was also associated " with a 23% reduction in total cost of hospital care for a typical 80% TBSA burn.39 Recently, the use of cultured keratinocytes from the patient's own skin has generated considerable interest as a potential solution for massively burned patients The concept of using with limited donor ~ites.~l,86,91 cultured skin to provide complete coverage is appealing but there are several problems to overcome before it can be widely used. Cultures of keratinocytes grow slowly and, once grafted, are very susceptible to mechanical trauma, resulting in only 50% to 70% graft take. Although a recent report showed that patients with greater than 80% TBSA burns receiving conventional treatment had shorter hospital stays than patients receiving cultured epithelial graft^,^ the latter technology is a potentially attractive concept to treat massively burned patients.

HYPERMmABOLIC RESPONSE

(//

.

l ~ x c i s e wound d

-

Wound coverage with 4:l meshed autograft and 2:l meshed allograft overlay. (From Eichelberger MR [ed]: Pediatric Trauma: Prevention, Acute Care, Rehabilitation. St Louis, Mosby, 1993, p 581.)

Burn patients demonstrate a dramatic increase in metabolic rate. Better understanding of the mechanisms involved in the hypermetabolic response in burn injuries is one of the factors responsible for decreased mortality from massive burns over the last 3 decades. The hypermetabolic response-which is generally greater with increasing burn size but reaches a plateau at 40% TBSA b u r n ~ ~ ~ - -characterized is by increased energy expenditure, oxygen consumption, proteolysis, lipolysis, and nitrogen losses. These physiologic changes are induced by the up-regulation of catabolic agents such cortisol, catecholamine, and glucagon, which act synergistically to increase the production of glucose, a principal fuel

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during acute i n f l a m m a t i ~ n Cortisol .~~ stimulates gluconeogenesis and proteolysis and sensitizes adipocytes to lipolytic hormones. Catecholamines stimulate the rate of glucose production through hepatic gluconeogenesis and glycogenolysis, as well as the promotion of lipolysis and peripheral insulin resistance, in which serum insulin levels are elevated but cells become resistant.j8 The increase in glucagon, which is stimulated by catecholamines, further promotes gluconeogenesis. A significant protein catabolism occurs in severe burns. Cortisol is catabolic and is partially responsible for the loss of tissue protein and the negative nitrogen balance. In addition, burn injury is associated with decreased levels of anabolic hormones, such as growth hormone and IGF-1, which contributes significantly to net protein loss. The synthesis of protein (which is essential for the production of collagen for wound healing), antibodies, and leukocytes to participate in the immune response requires a net positive nitrogen balance. Excess catecholamines in postburn patients also contribute to persistent tachycardia and-lipolysis. The consequences of these physiologic insults are cardiac failure and fatty infiltration of the liver. Growth hormone and IGF-1 levels are decreased after burn injury. Pharmacologic agents have been used to attenuate catabolism and stimulate growth despite a burn injury.77 Growth hormone, insulin, IGF-1, IGF-binding protein9, testosterone, and oxandrolone improve nitrogen balance and promote wound healing.2"37z47,82,gg Exogenous administration of recombinant human growth hormone, which increases protein synthesis, has been shown to improve nitrogen balance, preserve lean muscle mass, The anabolic and increase the rate of wound healing.44,98 action of growth hormone appears to be mediated by an increase in protein synthesis, whereas IGF-1 decreases protein degradation. Growth hormone also enhances wound healing by stimulating hepatic and local production of IGF-1 to increase circulating and wound site levels.3g Plasma growth hormone levels; which are decreased following severe burns, can be restored by the administration of recombinant growth hormone (0.2 mg/kg per day) in massively burned children to accelerate skin graft donor site wound healing and shorten hospital stay by more than 25% (Fig. 23-9)." The treatment of severely burned children with recombinant human growth hormone has been shown to be safe and efficacious. Growth hormone given during acute hospitalization maintains growth in severely burned children.83 Height velocity improved during the first 2 years after burn injury in growth hormone-treated patients when compared with control patients. Recombinant human growth hormone also stimulates bone formation and muscle protein synthesis by up-regulation of IGF-1, successfully abating muscle catabolism and ~ s t e o p e n i a . ~ ~ In severely burned patients, muscle anabolism can result from the administration of submaximal dosages of insulin by stimulating muscle protein synthesis. Insulin administration has also been demonstrated to improve skin graft donor site healing and wound matrix f0rmation.2~Testosterone production is greatly decreased after severe burn injury, which may last for months in postpubertal males. Increased protein synthesis with

Placebo Nutropin Protropin Donor site healing time for groups receiving either placebo (normal saline, n = 26) or recombinant growth hormone (Nutropin 0.2 mg/kg/day, n = 20; or Protropin 0.2 mg/kg/day, n = 20). A significant reduction in average healing time is noted with both forms of recombinant growth hormone when compared with control patients (mean f SEM; * P< 0.05 versus placebo). (From Giipin DA, Barrow RE, Rutan RL, et al: Recombinant human growth hormone accelerates wound healing in children with large cutaneous burns. Ann Surg 1994;220:19.) I

-

testosterone administration is accompanied by a more efficient utilization of intracellular amino acids derived from protein breakdown and an increase in the inward transport of amino acids. An increase in net protein synthesis is attainable in adults with large burns by restoring testosterone concentrations to the physiologic range.2R An analogue of testosterone with less androgenic effect, oxandrolone, has been used in acute and rehabilitating adult burn patients, with promising results with regard to weight gain. Oxandrolone alone has been shown to enhance protein synthesis efficiency, which improves muscle protein metabolism in severely burned children.gO The use of a beta blocker, propranolol, has been shown to lower resting heart rate and left ventricular work and to decrease peripheral lipolysis while maintaining lean body mass,7without adversely affecting cardiac output or 2~," beta the ability to respond to cold s t r e s ~ . ~ ~ 1Recently, blockade using propranolol during hospitalization has been shown to attenuate hypermetabolic response and reverse muscle protein catabolism in burned children (Fig. 23-10).43 Propranolol was given at a standard starting dose (1.98 mg/kg per day) and then titrated to decrease heart rate approximately 20% from baseline values. After 2 weeks of treatment, resting energy expenditure and oxygen consumption had increased in the control group. In contrast, patients in the proprano101 group had significant decreases in these variables. Concurrently with the decline in energy expenditure, beta blockade also improved the kinetics of skeletal

CHAPTER

Control group (n=12)

.-c

E

Propranolol group (n=12)

Z

0

-

O.lOl

-0.10

At baseline

At 2 wk

,

Mean change from baseline in the net balance of ~nuscleprotein synthesis and breakdown during 2 weeks of treatment with propi~anolol.Valties were obtained from a 5-hour kinetic study using isotopically labeled phenylalanine. Asterisk (*) indicates a significant difference between the two groups (P=0.001 by t-test) and a significant difference between the baseline value and the value at 2 weeks ( P = 0.002 by paired t-test). (From Hcl-ndon DN, Hart DW, Wolf SE, et al: Reversal of catabolism by beta-blockade after severe burns. N Engl J Med 2001;345:1223.)

muscle protein. The muscle protein net balance improved by 82% compared with pretreatment baseline values, whereas it decreased only 27% in untreated controls.43 Further, administering propranolol to burned children also receiving human growth hormone has salutary cardiovascular effects, decreases the release of free fatty acids from adipose tissue, and increases the liver's efficiency in handling secreted free fatty acids and verylow-density lipoproteins. Administration of propranolol has also been shown to decrease peripheral lipolysis and fat deposition in the liver of burn patients.43 Ketoconazole is an inhibitor of steroid ring synthesis and blocks the production of cortisol, indicating a potential use in the modulation of hypermetabolism.

cost-effectiveagents for the treatment of the hypermetabolic responses to trauma. Further, the role of nutrition in supporting the hypermetabolic response to trauma is often overlooked, but it clearly plays a part.

23

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393

NUTRITION The metabolic rate of patients with burns increases from 1.5 times the normal rate in a patient with 25% TBSA burns to 2 times the normal rate in those with 40% TBSA burns.3Xhildren are particularly vulnerable to protein-calorie malnutrition because of their proportionally less body fat and smaller muscle mass, in addition to increased metabolic demands. This malnutrition is associated with dysfunction of various organ systems, including the immune system, and delayed wound healing. Therefore, optimal nutritional support must be provided to maintain and improve vital organ functions. Feeding tubes are generally placed under fluoroscopic guidance immediately after the initial evaluation of burns, and enteral nutrition is started within hours after injury. Early enteral feedings have been shown to decrease the level of catabolic hormones, improve nitrogen balance, maintain gut mucosal integrity, and hyperalidecrease overall hospital stay.15~7%xVlthough mentation can deliver sufficient calories, its use in burn patients has been associated with deleterious effects on immune function; small bowel mucosal atrophy, with an increased incidence of bacterial translocalion: and a ~ ~ . ~ ~ nutrition is always predecrease in ~ u r v i v a l .Enteral ferred to parenteral nutrition and is associated with a decreased metabolic rate and lower incidence of sepsis in burn patients. Several formulas are used to calculate caloric requirement in burn patients. Both the Curreri formula (25 kcal/ kg plus 40 kcal/% TBSA burned) and the modified Harris-Benedict formula (calculated or measured resting metabolic rate times injury factor) use the principle of providing maintenance calories plus the additional calories reauired related to the burn size. Similar to fluid resuscitation guidelines, caloric requirements based on total and burned body surface area rather than weight are more appropriate for pediatric burn patients (Table 23-5)."-" The exact nutrient requirements of burn patients are not clear, but it is generally accepted that maintenance of energy requirement and replacement of protein losses are vital. The recommended enteral tube feedings should have 20% to 40% of the calories as protein, 10% to 20% as fat, and 40% to 70% as carbohydrates. Milk is one of the least expensive and best tolerated forms of nutrition, but sodium supplementation may be needed to avoid dilutional hyponatremia. There are also various commercially available enteral formulas, such as Vivonex and PediaSure, to choose from.

Infant and toddler Child

2100 kcal/m2 total 1800 kcal/m2 total 1500 kcal/m2 total

+ 1000 kcal/m2 burned + 1300 kcal/m2 burned

+ 1500 kcal/m2 burned

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Analgesia Burn wound treatment and rehabilitation therapy produce pain in patients of all ages. Infants and children do not express their pain in the same way adults do and may display fear, anxiety, agitation, tantrums, depression, and withdrawal. With older children, allowing them to participate in their own wound care can give them some sense of control and alleviate fear and pain. Various combinations of analgesics and anxiolytic medications are used effectively during procedures and dressing changes (Table 23-6). Successful pain management of burned children requires an understanding that pain is associated with the burn depth and phase of wound healing. Pain management protocols should be tailored to control background pain as well as particular procedurerelated painful stimuli. Physical therapy, which is vital to optimize good functional outcome, can be provided more effectively with appropriate pain control; however, absolute caution must be exercised to prevent any potential complications due to overmedication at the time of exercise therapy. In children as young as 5 years old, patient-controlled analgesia may be an ideal option to provide a steady-state background infusion of narcotic with an additional bolus regimen.'l Burn injuries are traumatic for burned children as well as for their families. Burn care professionals must do everything they can to make the experience as tolerable as possible while assisting burn patients to a successful recovery.

Sedatives and Anxiolytics Ketamine is a commonly used procedural sedativeanesthetic in burn patients. Derived from phencyclidine, it is characterized by dissociative anesthesia and has excellent analgesic properties. Given at a dose of 1.0 to 2.0 mg/kg intravenously or 5.0 to 7.0 mg/kg intramuscularly, the effect is rapid, but with a relatively short

Agent

Dose

Indication

Morphine sulfate

0.05-0.1 mgfkg IV or 0.3 mg/kg PO

Meperidine

1.0-2.0 mgfkg PO or IV

Ketamine

1.0-2.0 mgfkg IV or 5.0-7.0 mgfkg IM

Diazepam Chloral hydrate Midazolam

1.0-2.0 mg PO or IV 250-500 mg PO 0.25-0.5 mgfkg PO or IV

Lorazepam

0.03 mgfkg PO or IV

Acute pain; procedures and dressing changes Acute pain; procedures and dressing changes Surgery; procedures and dressing changes Preoperative; anxiety Preoperative; insomnia Anxiety; used in combination with narcotics Background anxiety

duration of action. In addition, ketamine is frequently used as an anesthetic agent for operative procedures, without compromising airway reflexes. The use of ketamine is contraindicated in patients with increased intracranial pressure. Benzodiazepines are commonly used to control burn-related anxiety as well as to enhance the effects of narcotics for pain control. Lorazepam (Ativan) at a dosage of 0.03 mg/kg orally or intravenously is an effective anxiolytic agent. It is also useful as a hypnotic agent to improve patient restfulness in the acute care setting. Diazepam (Valium) has a longer duration of action than lorazepam, making it useful in more chronic settings. Diazepam also improves muscle relaxation, which can facilitate rehabilitative therapy. Midazolam (Versed) has a rapid onset of action; peak plasma levels are achieved within 30 minutes, with a half-life of 2 to 5 hours. It is commonly used to achieve the desired level of sedation for procedures and dressing changes. Because it induces anterograde amnesia, it is commonly used as a premedication on the day of surgery.

Antibiotics The use of perioperative IV antibiotics has had a tremendous impact in improving the survival of major burn patients in the past 2 decades. Bacteria colonized in a burn eschar can potentially shed systemically at the time of eschar excision, contributing to sepsis and other organ system infection. Empirically, a broad-spectrum IV antibiotic regimen (e.g., vancomycin, third-generation cephalosporins, and penicillins) is given perioperatively to patients with greater than 40% TBSA burns to protect against Streptococcus, Staphylococcus aurew, and Pseudomonas. The antibiotic regimen is subsequently modified, depending on sensitivities identified by quantitative cultures of the excised eschar. In acute burns, a gram-positive coccus is generally the predominant organism involved, but colonization with gram-negative organisms and even fungi is frequently encountered in chronic burn wounds, and these organisms must be covered with appropriate IV antibiotics during excision and grafting. In addition to burn wound sepsis, graft loss may be attributed to the presence of an infected wound at the time of skin grafting or colonization of the grafted bed shortly after surgery. The most common organisms responsible for graft loss are beta-hemolytic streptococci ( S . pyogenes, S. agalactiae, or S. viridans). They are generally sensitive to thirdgeneration cephalosporins and fluoroquinolones. The emergence of multiresistant bacteria, such as methicillinresistant S. aureus, has become a serious problem for burn centers. Therefore, IV antibiotics should be used with diligence, but only for perioperative coverage and treatment of an identified source of infection.

INHALATION INJURY Inhalation injury is a major cause of death in burn patients. The mortality rate for children with isolated cutaneous burns is 1% to 2% but increases to approximately

CHAPTER

40% in the presence of inhalation i n j ~ r y . ~Inhalation ~,~2 injury is caused primarily by inhaled toxins such as fumes, gases, and mists. Although the supraglottic region can be injured by both thermal and chemical insults, tracheobronchial and lung parenchymal injuries rarely occur as a result of direct thermal damage because the heat disperses rapidly in the larynx. Hypoxia, increased airway resistance, decreased pulmonary compliance, increased alveolar epithelial permeability, and increased pulmonary vascular resistance may be triggered by the release of vasoactive substances (thromboxane A2, CSa, and CSa) from damaged epithelium.93 Neutrophil activation plays a critical role in this process, and pulmonary function has been shown to improve with the use of a ligand binding to E-selectins (inhibiting neutrophil adhesion) and anti-interleukin-8 (inhibiting neutrophil chemotaxis). Another significant form of respiratory tract pathology is the sloughing of ciliated epithelial cells from the basement membrane, resulting in exudate formation. The exudate, which consists of lymph proteins, coalesces to form fibrin casts. These fibrin casts are frequently resistant to routine pulmonary toilet and can create a "ball-valve" effect in localized areas of lung, eventually causing barotrauma. The diagnosis is usually made based on clinical history and physical examination findings during the initial evaluation. Victims trapped in a house fire with excessive smoke and fumes are likely to have sustained severe inhalation injury. Facial burns with singed hair and carbonaceous sputum suggest the presence of inhalation injury. Hoarseness and stridor suggest significant airway obstruction, so the airway should be secured immediately with endotracheal intubation. Patients who present with disorientation and obtundation are likely to have elevated carbon monoxide levels (carboxyhemoglobin >lo%). Cyanide toxicity as a result of the combustion of common household items may also contribute to unexplained metabolic collapse. Diagnostic tools, such as bronchoscopy and xenon-133 scanning, are more than 90% accurate in determining the presence of inhalation injury. Fiber-optic bronchoscopic examination of the airway at the bedside (avoiding the need to transport critically injured burn patients to the nuclear medicine department) is usually sufficient to identify airway edema and inflammatory changes of the tracheal mucosa such as hyperemia, mucosal ulceration, and sloughing. It remains the gold standard to confirm the presence of scan with xenon 133 can inhalation inj~ry.~Wentilation also identify regions of inhalation injury by assessing respiratory exchange and excretion of xenon by the lungs.'" The treatment of inhalation injury begins at the scene of the burn accident. The administration of 100% oxygen rapidly decreases the half-life of carbon monoxide. The airway must be secured with intubation in patients exhibiting signs and symptoms of imminent respiratory failure. Aggressive pulmonary toilet with physiotherapy and frequent suctioning is vital to prevent any serious respiratory complications. Humidified air is delivered at high flow, and bronchodilators and racemic epinephrine are used to treat bronchospasm. lV heparin has been shown to reduce tracheobronchial cast formation, improve minute ventilation, and lower peak inspiratory

23

Burns

395

pressures after smoke inhalation. Inhalation treatments such as 20% acetylcysteine nebulized solution (3 mL every 4 hours) plus nebulized heparin (5000 to 10,000 units with 3 mL normal saline every 4 hours) are effective in improving the clearance of tracheobronchial secretions and minimizing bronchospasm, thereby significantly decreasing reintubation rates and r n ~ r t a l i t y . ' ~ , ~ ~ The presence of inhalation injury generally requires increased fluid resuscitation, up to 2 mL/kg per percent TBSA burned more than would be required for the same size burn without an inhalation injury. In fact, pulmonary edema that is associated with inhalation injury is not prevented by fluid restriction; rather, inadequate resuscitation may increase the severity of pulmonary injury by the sequestration of polymorphonuclear cells.40 Steroids have not been shown to be of any benefit in inhalation injury. Prophylactic IV antibiotics are not indicated but are started if there is a clinical suspicion of pneumonia. Early pneumonia is usually the result of gram-positive organisms such as methicillin-resistant S. aureus, whereas later infection is caused by gramnegative organisms such as Pseudomonas. Serially monitored sputum cultures and bronchial washings should guide antibiotic therapy.

NONTHERMAL INJURIES

Chemical Burns Children often accidentally come in contact with various household cleaning products. Treatment of chemical burns involves the immediate removal of the causative agent and lavage with copious amounts of water, taking care to avoid hypothermia and to ensure that the effluent does not contact uninjured areas. Fluid resuscitation is also started. Decontamination is not performed in a tub; rather, the wounds are irrigated toward a drain, such as in a shower. After copious irrigation, wounds should be covered with topical antimicrobial dressing, and appropriate surgical plans should be made. Rapid recognition of the offending chemical agent is crucial to proper management.ZYWhen in doubt, the local poison control center should be contacted to identify the chemical composition of the product involved. The common offending chemical agents can be classified as alkali or acid. Alkalis, such as lime, potassium hydroxide, sodium hydroxide, and bleach, are among the most common agents involved in chemical injuries. Mechanisms of alkali-induced burns are saponification of fat, resulting in increased cell damage from heat, extraction of intracellular water, and formation of alkaline proteinates with hydroxyl ions. These ions induce further chemical reaction in the deeper tissues. Attempts to neutralize alkalis are not recommended, because the chemical reaction can generate more heat and add to the injury. Acid burns are not as common. Acids induce protein breakdown by hydrolysis, resulting in the formation of an eschar, and therefore do not penetrate as deeply as alkaline burns. Formic acid injuries are rare but can result in multiple systemic effects, such as metabolic acidosis, renal failure, intravascular

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hemolysis, and acute respiratory distress syndrome. Hydrofluoric acid burns are managed differently from other acid burns.94 After copious local irrigation with water, fluoride ions must be neutralized with topical application of 2.5% calcium gluconate gel. If not appropriately treated, free fluoride ions can cause liquefaction necrosis of the affected tissues, including bones. Because of potential hypocalcemia, patients should be closely monitored for prolonged QT intervals.

Electrical Burns Electrical burns are rare in children, accounting for only 3% to 5% of all admitted burn patients. Electrical burns are categorized as either high- or low-voltage injuries.50 High-voltage injuries are characterized by varying degrees of local burns and destruction of deep tissues.",84 Electrical current enters a part of the body and travels through tissues with the lowest resistance, such as nerves, blood vessels, and muscles. Heat generated as electrical current passes through deep tissues with relatively high resistance, such as bones, and damages adjacent tissues that may not be readily visible. Skin is mostly spared owing to its high resistance to electrical current. Primary and secondary surveys, including electrocardiograms, should be completed. If the initial electrocardiogram is normal, no further monitoring is necessary; however, any abnormal findings require continued monitoring for 48 hours and appropriate treatment of dysrhythmias when detected.85 The key to the management of electrical burns lies in the early detection and proper treatment of injuries to deep structures. Edema formation and subsequent vascular compromise are common in extremities. Fasciotomies are frequently necessary to avoid potential limb loss. If myoglobin is present in urine, vigorous hydration, with the administration of sodium bicarbonate to alkalinize the urine and mannitol to achieve diuresis and to act as a free radical scavenger, is indicated. Repeated wound exploration and debridement of affected areas are required before ultimate wound closure because there is a component of delayed cell death and thrombosis. The mechanism of electrical burn injury is to overwhelm the cellular systems that operate at millivolt or milliamp levels, so cells that survive the initial injury may slowly die over a week's time as ion gradients deteriorate and thrombosis of the microvasculature proceeds. Electrical injuries may also have a thermal, nonconductive component as the electricity flashes. This is treated as if it were a conventional thermal burn. Low-voltage injury is similar to thermal injury without the transmission of electrical current to deep tissues and usually requires only local wound care.

OUTPATIENT BURNS The majority of pediatric burns are minor, often resulting from scalds involving less than 10% TBSA or contact with hot objects causing small, isolated areas of thermal injury. Such burns are usually partial-thickness

skin injuries and can be treated on an outpatient basis. After an initial assessment, the burn wound is gently washed with water and a mild soap with appropriate pain control. Blisters can be left intact when they are small and unlikely to rupture spontaneously, especially on the palms of the hand, because they provide a natural barrier against the environment and are beneficial to avoid daay dressing changes. Spontaneous resorption of the fluid occurs in approximately 1 week with the re-epithelialization process. Larger areas of blisters should be debrided, and topical antimicrobial dressings applied. Silvadene is most commonly used owing to 2s broad-spectrum antimicrobial properties, as well as its soothing effect on superficial second-degree burns. However, because silver sulfadiazine can imwede ewithelization, its use should be discontinued when healing partial-thicknesswounds are devoid of necrotic tissue and evidence of re-epithelialization is noted. Alternatively, antimicrobial dressings with triple antibiotic ointment (neomycin, bacitracin, and polymyxin B sulfate) or Polysporin, which has no negative effect on epithelialization, are commonly used. For small, superficial partial-thickness burns, nonmedical white Petrolatumimpregnated fine mesh or porous mesh gauze (Adaptic), or fine mesh absorbent gauze impregnated with 3% bismuth tribromophenate in a nonmedicinal petrolatum blend (Xeroform), is usually sufficient, without the need for topical antimicrobials. Superficial burns of the face can be treated with the application of triple antibiotic ointment without any dressings. The frequency of dressing change varies from twice daily to once a week, depending on the size and depth of the burn and the amount of drainage. Those who advocate twice-daily dressing changes base their care on the use of topical antimicrobials whose half-life is about 8 to 12 hours. Others who use petrolatum-based or bismuth-impregnated gauze recommend less frequent dressing changes-once every 3 to 5 days. The use of synthetic wound dressings is ideal for the outpatient treatment of superficial partial-thickness b ~ r n s . ~ % e n applied appropEiately to fresh, partial-thickness wounds, Biobrane adheres to the wound rapidly and is very effective in promoting re-epithelialization in 1 to 2 weeks (see Fig. 23-7). Although daily dressing changes are eliminated, Biobrane-covered wounds should still be monitored closely for signs of infection.

REHABILITATION Acute Therapy Rehabilitation therapy is an essential component of burn care. During the acute phase of burn care, splints are used to prevent joint deformities and contractures. Made of thermoplastic materials, which are amenable to heat manipulation, splints are fitted individually to each patient. Application of splints at all times except during exercise periods can prevent the severe contractures that occur in patients with large burns. Patients are mobilized out of bed immediately after the graft takes, and aggressive physical therapy is provided.

CHAPTER

After t h e acute phase, hypertrophic scar formation is a major concern. Burn d e p t h , patient age, a n d genetic factors all play a n important role i n hypertrophic scar formation. I n general, d e e p second-degree b u r n wounds, requiring 3 weeks o r m o r e to heal, produce hypertrophic scarring. Children a r e m o r e p r o n e t o hypertrophic scar formation than adults are, probably because of t h e high rate of cell mitosis associated with growth. Constant pressure applied 24 hours a day is t h e most effective m e t h o d t o minimize hypertrophic scar formation; pressure garments should b e worn until scars mature. Scar maturation usually occurs 6 t o 18 m o n t h s after injury; in younger patients, scars mature a t a m u c h slower rate. I n addition to splints a n d pressure garments, exercise therapy is a crucial c o m p o n e n t of rehabilitation therapy. Families should receive thorough instruction o n a program of range-of-motion exercises a n d muscle strengthening.

Extended Therapy Burn survivors a n d their families n e e d rehabilitation therapy for extended periods o n both a physical a n d a psychological level. All must deal with feelings ranging from guilt to post-traumatic stress. In o n e study, a g r o u p of surgeons reviewed t h e images of 12 b u r n survivors with 80% o r greater TBSA b u r n e d a n d 70% third-degree burns, a n d predicted their status with respect to scarring a n d future employability. They predicted that all t h e patients would experience difficult psychological adjustments, a n d that many would require multiple operations in t h e reconstructive phase.45-In reality, t h e patients received twice as many operations as predicted, yet three quarters of these children demonstrated normal adjustm e n t a n d emotional growth. W h e n this longitudinal study was followed f o r additional 10 years, t h e children's emotional assessment scores were equal to those of their uninjured peers. T h a t s o few of these survivors developed serious ps~chologicala n d social difficulties is a striking testament to h u m a n resilience.

REFERENCES 1. Ayus JC, Arieff AI: Hyponatremia and myelinolysis. Ann Intern Med 1997;127:163. 2. Baptiste MS, Feck G: Preventing tap water burns. Am J Public Health 1980;70:727. 3. Barillo DJ, Goode R: Fire fatality study: Demographics of fire victims. Burns 1996;22:85. 4. BarretJP, Wolf SE, Desai MH, et al: Cost-efficacy of cultured epidermal autografts in massive pediatric burns. Ann Surg 2000;231:869. 5. Bjerknes R, Vindenes H, Laerum OD: Altered neutrophil functions in patients with large burns. Blood Cells 1990; 16:127. 6. Bjerknes R, Vindenes H, Pitkanen J, et al: Altered polymorphonuclear neutrophilic granulocyte functions in patients with large burns. J Trauma 1989;29:847. 7. Breitenstein E, Chiolero RL, Jequier E, et al: Effects of beta-blockade on energy metabolism following burns. Burns 1990;16:259.

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8. Brigham PA, McLoughlin E: Burn incidence and medical care use in the United States: Estimates, trends, and data sources. J Burn Care Rehabil 1996;17:95. 9. Brink JA, Sheets PW, Dines KA, et al: Quantitative assessment of burn injury in porcine skin with high-frequency ultrasonic imaging. Invest Radio1 1986;21:645. 10. Brown M, Desai M, Traber LD, et al: Dimethylsulfoxide with heparin in the treatment of smoke inhalation injury. J Burn Care Rehabil 1988;9:22. 11. Bucky LP, Vedder NB, Hong HZ, et al: Reduction of burn injury by inhibiting CDIsmediated leukocyte adherence in rabbits. Plast Reconstr Surg 1994;93:1473. 12. Burn Injury Fact Sheet. Washington, DC, National Safe Kids Campaign; 2004. 13. Carter EA, Gonnella A, Tompkins RG: Increased transcellular permeability of rat small intestine after thermal injury. Burns 1992;18:117. 14. Chance WT, Nelson JL, Foley-Nelson T, et al: The relationship of burn-induced hypermetabolism to central and peripheral catecholamines. J Trauma 1989;29:306. 15. Chiarelli A, Enzi G, Casadei A, et al: Very early nutrition r supplementation in burned patients. Am J Clin ~ u t 1990; 51:1035. Chung DH, Evers BM, Townsend CM Jr, et al: Burninduced transcriptional regulation of small intestinal ornithine decarboxylase. Am J Surg 1992;163:157. Chung DH, Evers BM, Townsend CM Jr, et al: Role of polyamine biosynthesis during gut mucosal adaptation after burn injury. Am J Surg 1993;165:144. Cope 0 , Moore FD: The redistribution of body water. Ann Surg 1947;126:1016. DelBeccaro EJ, Robson MC, Heggers JP, et al: The use of specific thromboxane inhibitors to preserve the dermal microcirculation after burning. Surgery 1980;87:137. Demling RH, LaLonde C: Early postburn lipid peroxidation: Effect of ibuprofen and allopurinol. Surgery 1990; 107:85. Demling RH, Mazess RB, Witt RM, et al: The study of burn wound edema using dichromatic absorptiometry. J Trauma 1978;18:124. Desai MH, Herndon DN: Eradication of Candida burn wound septicemia in massively burned patients. J Trauma 1988;28:140. Desai MH, Herndon DN, Broemeling L, et al: Early burn wound excision significantly reduces blood loss. Ann Surg 1990;211:753. Desai MH, Rutan RL, Heggers JP, et al: Candida infection with and without nystatin prophylaxis: An 11-year experience with patients with burn injury. Arch Surg 1992; 127:159. Drost AC, Burleson DG, Cioffi WG Jr, et al: Plasma cytokines following thermal injury and their relationship with patient mortality, burn size, and time postburn. J Trauma 1993;35:335. Du GB, Slater H, Goldfarb IW: Influences of different resuscitation regimens on acute early weight gain in extensively burned patients. Burns 1991;17:147. Ferrando AA, Chinkes DL, Wolf SE, et al: A submaximal dose of insulin promotes net skeletal muscle protein synthesis in patients with severe burns. Ann Surg 1999;229:11. Ferrando AA, Sheffield-Moore M, Wolf SE, et al: Testosterone administration in severe burns ameliorates muscle catabolism. Crit Care Med 2001;29:1936. Fitzpatrick KT, Moylan JA: Emergency care of chemical burns. Postgrad Med 1985;78:189. Fox CL Jr, Rappole BW, Stanford W: Control of Pseudornonas infection in burns by silver sulfadiazine. Surg Gynecol Obstet 1969;128:1021.

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31. Gallico GG 3rd, O'Connor NE, Compton CC, et al: Permanent coverage of large burn wounds with autologous cultured human epithelium. N Engl J Med 1984;311:448. 32. Gamelli RL, He LK, Liu H: Macrophage suppression of granulocyte and macrophage growth following burn wound infection. J Trauma 1994;37:888. 33. Gerding RL, Emerman CL, Effron D, et al: Outpatient management of partial-thickness burns: Biobrane versus 1% silver sulfadiazine. Ann Emerg Med 1990;19:121. 34. Gilpin DA, Barrow RE, Rutan RL, et al: Recombinant human growth hormone accelerates wound healing in children with large cutaneous burns. Ann Surg 1994; 220:19. 35. Goran MI, Peters EJ, Herndon DN, et al: Total energy expenditure in burned children using the doubly labeled water technique. Am J Physiol 1990;259(4 Pt 1):E576. 36. Graves TA, Cioffi WG, McManus WF, et al: Fluid resuscitation of infants and children with massive thermal injury. J Trauma 1988;28:1656. 37. Hart DW, Wolf SE, Ramzy PI, et al: Anabolic effects of oxandrolone after severe burn. Ann Surg 2001;233:556. 38. Heggers JP, Sazy JA, Stenberg BD, et al: Bactericidal and wound-healing properties of sodium hypochlorite solutions: The 1991 Lindberg Award. J Burn Care Rehabil 1991; 12:420. 39. Herndon DN, Barrow RE, Kunkel KR, et al: Effects of recombinant human growth hormone on donor-site healing in severely burned children. Ann Surg 1990;212:424. 40. Herndon DN, Barrow RE, Linares HA, et al: Inhalation injury in burned patients: Effects and treatment. Burns Incl Therm Inj 1988;14:349. 41. Herndon DN, Barrow RE, Stein M, et al: Increased mortality with intravenous supplemental feeding in severely burned patients. J Burn Care Rehabil 1989;10:309. 42. Herndon DN, Gore D, Cole M, et al: Determinants of mortality in pediatric patients with greater than 70% fullthickness total body surface area thermal injury treated by early total excision and grafting. J Trauma 1987;27:208. 43. Herndon DN, Hart DW, Wolf SE, et al: Reversal of catabolism by beta-blockade after severe burns. N Engl J Med 2001;345:1223. 44. Herndon DN, Hawkins HK, Nguyen TT, et al: Characterization of growth hormone enhanced donor site healing in patients with large cutaneous burns. Ann Surg 1995;221:649. 45. Herndon DN, LeMaster J, Beard S, et al: The quality of life after major thermal injury in children: An analysis of 12 survivors with greater than or equal to 80% total body, 70% third-degree burns. J Trauma 1986;26:609. 46. Herndon DN, Parks DH: Comparison of serial debridement and autografting and early massive excision with cadaver skin overlay in the treatment of large burns in children. J Trauma 1986;26:149. 47. Herndon DN, Ramzy PI, DebRoy MA, et al: Muscle protein catabolism after severe burn: Effects of IGF-l/IGFBP-3 treatment. Ann Surg 1999;229:713. 48. Herndon DN, Stein MD, Rutan TC, et al: Failure of TPN supplementation to improve liver function, immunity, and mortality in thermally injured patients.J Trauma 1987;27:195. 49. Herndon DN, Thompson PB, Traber DL: Pulmonary injury in burned patients. Crit Care Clin 1985;1:79. 50. Hildreth MA, Herndon DN, Desai MH, et al: Caloric needs of adolescent patients with burns. J Burn Care Rehabil 1989;10:523. 51. Hildreth MA, Herndon DN, Desai MH, et al: Current treatment reduces calories required to maintain weight in pediatric patients with burns. J Burn Care Rehabil 1990;11:405.

52. Hildreth MA, Herndon DN, Desai MH, et al: Caloric requirements of patients with burns under one year of age. J Burn Care Rehabil 1993;14:108. 53. Ho-Asjoe M, Chronnell CM, Frame JD, et al: Immunohistochemical analysis of burn depth. J Burn Care Rehabil 1999;20:207. 54. Honeycutt D, Barrow R, Herndon D: Cold stress response in patients with severe burns after beta-blockade. J Burn Care Rehabil 1992;13(2 Pt 1):181. 55. Huang PP, Stucky FS, Dimick AR, et al: Hypertonic sodium resuscitation is associated with renal failure and death. Ann Surg 1995;221:543. 56. Hunt JL, Agee RN, Pruitt BA Jr: Fiberoptic bronchoscopy in acute inhalation injury. J Trauma 1975;15:641. 57. Hunt JP, Hunter CT, Brownstein MR, et al: The effector component of the cytotoxic T-lymphocyte response has a biphasic pattern after burn injury. J Surg Res 1998;80:243. 58. Jahoor F, Herndon DN, Wolfe RR: Role of insulin and glucagon in the response of glucose and alanine kinetics in burn-injured patients. J Clin Invest 1986;78:807. 59. Jarrett F, Ellerbe S, Demling R: Acute leukopenia during topical burn therapy with silver sulfadiazine. Am J Surg 1978;135:818. 60. Jerath MR, Schomacker KT, Sheridan RL, et al: Burn wound assessment in porcine skin using indocyanine green fluorescence. J Trauma 1999;46:1085. 61. Jeschke MG, Barrow RE, Wolf SE, et al: Mortality in burned children with acute renal failure. Arch Surg 1998;133:752. 62. Kimura R, Traber LD, Herndon DN, et al: Treatment of smoke-induced pulmonary injury with nebulized dimethylsulfoxide. Circ Shock 1988;25:333. 63. Klein GL, Wolf SE, Goodman WG, et al: The management of acute bone loss in severe catabolism due to burn injury. Horm Res 1997;48(Suppl 5) :83. 64. Klimpel GR, Herndon DH, Stein MD: Peripheral blood lymphocytes from thermal injury patients are defective in their ability to generate lymphokine-activated killer (LAK) cell activity. J Clin Immunol 1988;8:14. 65. Laberge LC, Ballard PA, Daniel RK: Experimental electrical burns: Low voltage. Ann Plast Surg 1984;13:185. 66. La1 S, Barrow RE, Wolf SE, et al: Biobrane improves wound healing in burned children without increased risk of infection. Shock 2000;14:314. 67. LeVoyer T, CioE WG Jr, Pratt L, et al: Alterations in intestinal permeability after thermal injury. Arch Surg 1992;127:26. 68. Lindberg RB, Moncrief JA, Switzer WE, et al: The successful control of burn wound sepsis.J Trauma 1965;5:601. 69. Lund CC, Browder NC: The estimation of areas of burns. Surg Gynecol Obstet 1944;79:352. 70. Marano MA, O'Sullivan G, Madden M, et al: Tourniquet technique for reduced blood loss and wound assessment during excisions of burn wounds of the extremity. Surg Gynecol Obstet 1990;171:249. 71. McDonald AJ, Cooper MG: Patient-controlled analgesia: An appropriate method of pain control in children. Paediatr Drugs 2001;3:273. 72. Mileski W, Borgstrom D, Lightfoot E, et al: Inhibition of leukocyte-endothelial adherence following thermal injury. J Surg Res 1992;52:334. 73. Mochizuki H, Trocki 0 , Dominioni L, et al: Mechanism of prevention of postburn hypermetabolism and catabolism by early enteral feeding. Ann Surg 1984;200:297. 74. Monafo WW: The treatment of burn shock by the intravenous and oral administration of hypertonic lactated saline solution. J Trauma 1970;10:575. 75. Moyer CA, Brentano L, Gravens DL, et al: Treatment of large human burns with 0.5 per cent silver nitrate solution. Arch Surg 1965;90:812.

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76. Moylan JA .Jr, Wilmore DW, Mouton DE, et al: Early diagnosis of inhalation injury using 133 xenon lung scan. Ann Surg 1972;176:477. 77. Murphy KD, Lee JO, Herndon DN: Current pharmacotherapy for the treatment of severe burns. Expert Opin Pharmacother 2003;4:369. 78. Myers SI, Minei JP, Casteneda A, et al: Differential effects of acute thernial injury on rat splanchnic and renal blood flow and prostanoid release. Prostaglandins Leukot Essent Fatty Acids 1995;53:439. 79. Nwariaku FE, Sikes PJ, Lightfoot E, et al: Effect of a bradykinin antagonist on the local inflammatory response following thermal injury. Burns 1996;22:324. 80. O'Reilly TJ, Spence RJ, Taylor RM, et al: Laser Doppler flowrnetry evaluation of burn wound depth. J Burn Care Rehabil 1989;10:l. 81. Park DH, Hwang JW, Jang KS, et al: Use of laser Doppler flowmetry for estimation of the depth of burns. Plast Reconstr Surg 1998;101:1516. 82. Pierre EJ, Barrow RE, Hawkins HK, et al: Effects of insulin on wound healing. J Trauma 1998;44:342. 83. Ramirez KJ, Wolf SE, Barrow RE, et al: Growth hormone treatment in pediatric burns: A safe therapeutic approach. Ann Surg 1998;228:439. 84. Robson MC, Murphy RC, Heggers JP: A new explanation for the progressive tissue loss in electrical injuries. Plast Reconstr Surg 1984;73:431. 85. Robson MC, Smith DJ: Care of the thermal injured victim. In Jurkiewicz MJ, Krizek TJ, Mathes SJ, et al (eds): Plastic Surgery: Principles and Practice. St Louis, CV Mosby, 1990. 86. Rue I,W 3rd, Cioffi WG, McManus WF, et al: Wound closure and outcome in extensively burned patients treated with cultured autologous keratinocytes. J Trauma 1993; 34:662. 87. Ryan CM, Yar~nush ML, Burke JF, et al: Increased gut permeability early after burns correlates with the extent of burn irljjury. Crit Care Med 1992;20:1508. 88. Saito H, Trocki 0 , Alexander JW, et al: The effect of route of nutrient administration on the ~lutritionalstate, catabolic hormone secretion, and gut mucosal integrity after burn injury. JPENJ Parenter Enteral Nutr 1987;ll:l.

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89. Shamoon H, Hendler R, Sherwin RS: Synergistic interactions among antiinsulin hormones in the pathogenesis of stress hyperglycemia in humans..J Clin Endocrinol Metab 1981;52:1235. 90. Sheffield-Moore M, Urban RJ, Wolf SE, et al: Short-term oxandrolone administration stin~ulatesnet muscle protein synthesis in young nlen. J Clin Endocrinol ~ e t a b 1999;84:2705. 91. Sheridan RL, Tompkins RG: Cultured autologous epithelium in patients with burns of ninety percent or niore of the body surface. .J Trauma 1995;38:48. 92. Tht~mpsonPB, Herndon DN, Traber DI., et al: Effect on mortality of inhalation in-jnry.J Trauma 1986;26:163. 93. Traber DL, Herndon DN, Stein MD, et al: The pulmonary lesion of smoke inhalation in an twine model. Circ Shock 1986;18:311. 94. Trevino MA, Herrmann GH, Sprout WI,: Treatment of severe hydrofluoric acid exposures. J Occup Med 1983; 252361. 95. Vo IIT, Papworth GD, Delarley PM, et al: A study of vascular response to thermal injury on hairless mice by fibre optic confocal imaging, laser Doppler flowmetry and conventional histolo.gy. Burns 1998;24:319. 96. Warden GD: Burn shock resuscitation. WorldJ Surg 1992; 16:16. 97. Warden GD: Fluid resuscitation and early management. In Herndon DN (ed): Total Burn Care. Philadelphia, WB Saunders, 1996, p 53. 98. Wilmore DW, Moylan JA .Jr, Bristow BF, et al: Anabolic and e high caloric feedeffects of human growth h o r m o ~ ~ ings following thermal injury. Surg Gynecol Obstet 1974; 138:875. 99. Wolf SE, Barrow RE, Herndon 1)N: Growth horrnone and IGF-I therapy in the hypercatabolic patient. Baillieres Clin Endocrinol Metab 1996;10:447. 100. Wolf SE, Ikeda H, Matin S, et al: (;utaneous burn increases apoptosis in the gut epithelium of mice. J Am Coll Surg 1999;188:10. 101. Zedler S, Faist E, Ostermeier B, et al: Postburn constitutional changes in T-cell reactivity occur in CD8+ rather than in CD4+ cells. J Trauma 1997;42:872.

Child Abuse and Birth Injuries -

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Dennis W. Vane

CHILD ABUSE Child abuse encompasses physical abuse, sexual abuse, emotional abuse, and neglect. This maltreatment of children has become a significant focus of attention in our society. The media routinely publish accounts of the alleged traumatic and sometimes fatal abuse of children among all socioecorlomic classes and levels of celebrity. The myth that child abuse and other violence in the home occur only among the poor and the uneducated has been debunked. Child abuse is a worldwide problem that affects all levels of society. Prevention and effective treatment depend on the timely detection of epidemiologic situations that lend themselves to the maltreatment of children. Unfortunately, the "minor" status of children leads to the justifiable issue of the relative rights of parents and guardians. Religious and societal "norms" have created barriers to the identification of victims in many nations. Around the globe, relatively few nations have addressed this problem at all.3 In the United States and Canada, legislation aimed at identifying child abuse and neglect ~* that time, was enacted beginning in the 1 9 6 0 ~ . Since the reporting of child abuse to civil authorities has been mandated for almost all professionals dealing with children. The legislation protects the reporting individual from liability (usually by using the phrase "suspicion of' or "injuries consistent with"), supersedes all professionalclient privilege, and sometimes even imposes penalties for failure to report abuse.45

age groups, maltreatment of children generally increases with age. In teenagers, the incidence of abuse is thought to be twice that in preschool children.54 Patterns of child abuse occur with differing frequencies over the social strata. Sexual and emotional abuse have no socioeconomic associations,whereas physical abuse and neglect are more frequently associated with p o ~ e r t y . ~ ~ Often several types of abuse are perpetrated on the same child or within the same familv. Additionallv. ,, abuse commonly occurs in families with other forms of intrafamilial violence, such as spousal abuse and violence among sibling^.^" Child abuse is a self-perpetuating social and economic problem. Problems with substance abuse and depression are reportedly two to three times more likely in abused children than in the general population, and abused children are likely to be far more physically aggressive with their peers."<3Vt is estimated that approximately 30% of abuse victims eventually abuse their own children.PO Some authors have suggested that this perpetual cycle of abuse is attributable in part to changes in the neuroendocrine system influencing arousal, learning, growth, and the individual's pain threshold.") What is clear is that the incidence of child abuse is significantly underreported, because professional contact or recognition is often required to identify abuse in the first place. Physicians must recognize not only abuse that has already occurred but also the factors indicating a high potential for abuse if this dramatic worldwide problem is to be prevented.

Epidemiology Estimates in the United States indicate that approximately 1.4 million children under the age of 18 suffer some sort of maltreatment every year.54 This represents between 2% and 3% of the population. In about 160,000 children, this maltreatment is considered physically serious or life threatening. Between 1000 and 2000 deaths are attributed to child abuse each year in the United States, and 80% of those children are younger than 5 years. Forty percent of the deaths occur in the first year of life.4R Although deaths occur predominantly in the younger

Presentation Physicians must be aware that abused children are often withdrawn and avoid eye contact with their interviewers. Interviewers must be cognizant of the fact that children often respond with answers that they think will please the interviewer, so care must be taken not to influence the child's responses. Young children are prone to associative fabrication, which may influence or even alter reality. The clinical history in suspected child abuse cases should include a detailed history of the family situation,

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unrelated caregivers, substance abuse in the household, and any history of past abuse. Even with these indicators, child abuse is extremely hard to accurately diagnose. Given the wide spectrum of abuse, presenting symptoms vary accordingly. In the youngest victims, the diagnosis often depends on physical signs such as bruising, patterned burn injuries, retinal hemorrhages, and long bone fractures. Among all children, presentations that should raise a high level of suspicion in the clinician include multiple injuries in different stages of healing; injuries not consistent with the history provided by the caregiver; a history that changes when retold, particularly when the incident was "unwitnessed"; and injuries to the perineum. Wisslow71 provided an excellent summary of the presenting physical injuries in cases of child abuse and neglect (Table 241). In children, essentially any injury can be the result of abuse; however, particular injuries and injury patterns have a high degree of association with abuse.

Traumatic Brain lnjury Head injury is perhaps the most common injury associated with child abuse, and it is certainly the most devastating.

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Penetrating head injury is relatively rare in abuse victims, and most head injuries occur in younger children.36 Blunt injury most commonly manifests as "shaken baby syndrome" or, more accurately, "shaken impact syndrome," in which the insult is caused by an acceleration and deceleration of the brain within the cranial compartment due to violent shaking (Fig. 241). Recent studies indicate that some sort of contact with an object is necessary for the classic brain injury to occur, but that object may be relatively soft and produce no external indication of trauma.21Angular forces created during shaking and eventual percussion against an object result in rotation of the brain within the skull. This causes diffuse axonal injury and tearing of the subdural bridging veins, often resulting in subdural hematoma. Spontaneous subdural hematoma or its occurrence from unintentional trauma is uncommon in children, so its presence should raise the suspicion of child abuse. Acute contact with stationary objects results in the characteristic multiple skull fractures associated with repetitive injury. Secondary brain injury is also frequently associated with abuse, resulting in intracranial hemorrhage, anoxia secondary to apnea, hypoperfusion, cardiac arrest, and potentially herniation of the brainstem." Brain injury secondary to

Subnormal growth Weight, height, or both less than 5th percentile for age Weight less than 5th percentile for height Decreased velocity of growth Head injuries Torn frenulum of upper or lower lip Unexplained dental injury Bilateral black eyes with history of single blow or fall Traumatic hair loss Retinal hemorrhage Diffuse or severe central nervous system injury with history of minor to moderate fall (<3m) Skin injuries Bruise or burn shaped like an object Bite marks Burn resembling a glove or stocking or with some other distribution suggestion an immersion injury Bruises of various colors (in different stages of healing) lnjury to soft tissue areas that are normally protected (thighs, stomach, upper arms) Gastrointestinal or genitourinary injuries Bilious vomiting Recurrent vomiting or diarrhea witnessed only by parent Chronic abdominal or perineal pain with no identifiable cause History of genital or rectal pain lnjury to genitals or rectum Sexually transmitted disease Bone injuries Rib fracture in the absence of major trauma, such as a motor vehicle accident Complex skull fracture after a short fall ( ~ 1 . 2m) Metaphyseal long bone fracture in an infant Femur fracture (any configuration) in a child younger than 1yr Multiple fractures in various stages of healing Laboratory studies Implausible or physiologically inconsistent laboratory results (polymicrobial contamination of body fluids, sepsis with unusual organisms, electrolyte disturbances inconsistent with the child's clinical state or underlying illness, wide and erratic variations in test results) Positive toxicologic tests in the absence of a known ingestion or medication Bloody cerebrospinal fluid (with xanthochromic supernatant) in an infant with altered mental status and no history of trauma

L From Wissow LS: Child abuse and neglect. N Engl J Med 1995;332:1425-1431.

I

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A

I . .

B

A and R, Shaketl baby syndrome is often recognizable by external bruising about the chest, shoulders, and neck caused by the finge1-s and hands.

abuse carries a reported mortality rate of 15% to 38%, which is significantly higher than that of similar injuries caused by unintentional trauma.2' Nonfatal outcomes in abused children with traumatic brain injuries are also significantly worse than in those whose injuries were sustained unintentionally.24 Nonenhanced computed tomography is considered the most appropriate diagnostic tool for the identification of intentional head injury. Intracranial lesions are easily identified, as are the often associated skull fracture^.^^ Although most commonly seen in younger children, head injury associated with child abuse occurs in older children as well. Whereas external signs of trauma are infrequent in younger children, older children usually present with visible injuries secondary to violent external trauma. These injuries are often severe, with poor outcornes.4J The identification of retinal hemorrhage has been deemed almost pathognomonic of child abuse's; however, recent studies indicate that retinal hemorrhage occurs in cases of nonintentional injury as well, including normal vaginal delivery, which can cause compression of the

baby's soft skull.*8,25The presence of retinal hemorrhage from nonintentional injury is so rare, however, that it should stimulate a high level of suspicion for child abuse. When it is identified, the physician should begin an appropriate workup to investigate that possibility.

Fractures It is postulated that approximately 80% of child abuse cases in the United States are identified radiographically.12 Fractures secondary to child abuse can be found in any age group, although fractures in older children are more commonly from high-impact unintentional injury.I0 The presence of a long bone fracture in any child younger than 2 years has a high association with ~-l~ halie historically intentional i n ~ u r y . ~Investigators associated several fracture types with abuse, but it is probably more accurate to state that all fracture types can be associated with multiple causes. Spiral fractures, once reported as the most common type of fracture in abuse victims, have been replaced in more recent studies with al are the result single transverse f r a c t ~ r e s . ~ q p i rfractures

CHAPTER

of torsional force applied to the extremity secondary to rotation of some sort. Transverse fractures are the result of a direct injury to the bone. This information should be used by the evaluating physician in conjunction with the history of injury to determine whether the history coincides with the presenting injury. Diaphyseal fractures of the long bones are the most common fractures associated with child abuse, particularly those of the tibia, femur, and humerus. If the child is not ambulatory, the association between these fractures and abuse is extremely high.46 Epiphyseal-metaphyseal fractures, although much less common than diaphyseal injuries, are reportedly far more specific for intentional injury.17 The forces required to sustain these injuries greatly exceed the forces normally associated with falls and other minor trauma. Epiphyseal-metaphysealfractures are also commonly known as corner fractures or buckethandle fractures. Type 1 fractures of the femur and humerus have a high association with abuse when encountered outside of the neonatal period.26This is particularly true if the history of injury does not contain significant high-force violent trauma. These injuries require considerable force to occur and, when nonintentional, are commonly associated with significant soft tissue damage and other injuries. Other types of Salter-Harris injuries do not appear to have a strong association with intentional abuse. Clavicular fractures can also be associated with abuse, but there is a low specificity. Clavicular fractures of either end rather than the midshaft are usually the result of significant traction or the trauma of shaking5()Rib fractures, in contrast, have an extremely high association with abuse. It is postulated that the relatively elastic rib cage in children prevents most fractures secondary to accidental trauma. When fractures of the ribs do occur, the association with abuse is high-up to 82%.8 Spinal fractures are rare in children, as is cord injury. The difficulty in diagnosing vertebral body injuries and the relatively protected spine make any association with abuse difficult to determine. Suffice it to say that any injury of the spine or spinal cord requires an extremely violent force, and the cause must be carefully investigated. It is critical for any physician treating children to investigate all fractures, particularly in the younger age groups. Minimal trauma does not commonly cause fractures, except when associated with other pathology. Getting an accurate history is critical. The presence of multiple fractures associated with a history of minimal trauma always requires an investigation for potential child abuse. The identification of multiple fractures, particularly when the age of the fractures is different, is almost pathognomonic of abuse. When abuse is suspected, skeletal surveys are indicated. The American College of Radiology has published standards for these survey^.^

Burns Burns are a fairly common indication of child abuse, representing approximately 20% of pediatric burn injuries. Abuse victims often have characteristic patterns of burn infliction that physicians should be aware of.45 Common patterns include circumferential burns,

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Punctate injuries or burns of the extremities caused by a recognizable object such as a fork indicate child abuse. -

4

particularly when the burns are on more than one extremity; "pattern" burns or branding; burns to the buttocks, genitalia, or perineum; and punctate or cigarette burns (Fig. 242). Burn victims who are abused are usually younger than unintentional burn victims and have a history of being burned in the bathroom." The demographics of intentionally burned children are striking. These children are often being raised by single mothers or are in foster care, they are in homes where other children have previously been removed because of abuse, and there is an almost 40% chance that past abuse has already been in~estigated.~" With burns, the history of injury is critical and is often inconsistent with the burn pattern. The burn itself often exhibits uncharacteristic features, such as lack of splash marks from falling liquids, consistent depth throughout the burn rather than the normal "feathering" of depth, and larger surface areas than expected based on the history. These burns, which are often the result of immersion, present with clear lines of demarcation, indicating that the child was unable to move during the incident and was probably restrained. Inflicted burns to the buttocks and perineum often occur in children being toilet trained when a caregiver becomes frustrated over an "accident." The depth of burn is also important. It takes approximately 1.5 seconds to cause a second-degree burn in adult skin immersed in water at 150" F. That is certainly more time than anyone would keep his or her hands immersed volitionally. A complete history and physical examination are necessary in any child seen for burns or the suspicion of abuse. Other signs of abuse are often discernible, such as healed or healing fractures or possibly perineal injuries. Additionally, recent data indicate that some burn injuries mimic chronic skin conditions." Thus, a high level of suspicion must be maintained when clinicians see lesions that d o not present in characteristic locations or do not respond to normal therapy. Given the high incidence of recurrence in burn injury, physicians must ensure that the child is discharged to a safe environment.

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Thoracoabdominal lnjury Fortunately, significant thoracoabdominal injury secondary to child abuse is uncommon, estimated to occur in about 5% of abused children.61 Unfortunately, thoracoabdominal injury is the second leading cause of death in these children, following head injury.55 Any type of blunt or penetrating abdominal injury can be caused intenti0nally.~~~~9-~~~~~~61 Injuries commonly result from severe blows to the abdomen or chest cavity, and as previously stated, rib fractures in children should raise the suspicion of abuse.8 Most important, the clinician must ascertain the history of injury to determine whether the injury is consistent with the mechanism described. For example, recent reports indicate that a simple fall down a flight of stairs does not generate the force or dynamics necessary for a hollow viscus perforation.34 Similarly, significant head injury requires a mechanism generating more force than simply rolling out of bed. Injuries to the perineum should always lead to a consideration of child abuse. Aside from bums to the perineum, discussed previously, injuries resulting from abuse tend to be penetrating in nature. Rectal or vaginal trauma resulting in laceration should routinely be investigated, as should lacerations in the penile and scrota1 region. Abuse may involve retained foreign bodies as well. The physician should always investigate anal and vaginal orifices that appear to be dilated, particularly those that may result in incontinence. Signs of abuse to the perineum are often chronic, and areas of scar and old lacerations should be noted. The radiographic and diagnostic workup for children suffering thoracoabdominal abuse is identical to that for unintentional injury. Recommendations for appropriate scans and diagnostics have been updated by the American Academy of Pediatrics? Management of these injuries is also the same as for unintentional thoracoabdominal i n j ~ r i e s . ~ ~ . ~ ~

BIRTH INJURIES Birth injury is estimated to occur in 6 to 8 of every 1000 live births in the United States, but it is responsible for around 2% of the perinatal mortality.65 Injury most commonly occurs in babies with macrosomia but can also be associated with fetal organomegaly, mass lesions, prematurity, protracted labor, precipitous delivery, breech presentation, and cephalopelvic dissociation. The development and widespread use of prenatal ultrasonography, along with other advances in perinatal care, have allowed the early identification of many of these factors, along with recommendations for the delivery of such high-risk infants.Z8

Soft Tissue Injury The most common birth iniurv encountered is iniurv to the soft tissue. This can present as a hematoma (often cephalohematoma), simple cutaneous bruising, - or fat necrosis manifesting as subcutaneous masses. These lesions resolve spontaneously within months and require no treatment other than reassurance of the parents. J

,

J

Less commonly, lacerations secondary to instrumentation may occur. These lacerations can usually be closed with adhesive strips or cutaneous glue rathkr than sutures. Suturing may be necessary, however, when adhesive closure cannot achieve the appropriate cosmetic result. Fine material should always be used, and healing is usually excellent. Lacerations are rarely deep, but if they are, standard precautions for wound exploration should be followed. Torticollis has been ascribed to birth trauma or intrauterine rnalpositioning.63 The cause is debatable, because torticollis has been found in infants who were delivered by cesarean section as well as in those delivered vaginally. The classic presentation is a small, firm mass in the body of the sternocleidomastoid muscle. The head is tilted toward the mass, with the face classically turned to the contralateral side. Physical therapy performed by the parents is successful in the vast majority of cases, and surgical intervention is rarely indicated. Facial asymmetry may result in untreated lesions.

Fractures The most common fracture associated with birth trauma is clavicular, occurring in about 2.7 of every 1000 bii-th~.5~ The fracture is noticed when the infant does not move the arm or swelling occurs over the clavicle. The fracture is commonly in the midshaft and generally requires no treatment, although some authors recommend figure-ofeight splints or pinning the baby's shirtsleeve to the chest on the affected side.*' Occasionally, because of shoulder dystocia, the clavicle may be intentionally f r a c t ~ r e d . ~ Fractures of the humerus usually occur in either the shaft or the proximal epiphysis. Epiphyseal fractures are difficult to diagnose because of a lack of ossification points in the neonatal epiphysis. Associated neurologic findings may be noted with fractures of the humerus, ,~~ including Erb's palsy and radial nerve p a l ~ y . 9Shoulder dislocation is most likelv not related to birth trauma but rather to intrauterine causes or therapy for Erb's palsy.' Distal fractures and dislocations of the radial head may also occur and are often associated with breech delivery.l~f;6 Proximal fractures of the humerus can be successfully treated by bandaging the arm to the chest in a neutral position for epiphyseal injuries and by strapping the arm to the chest with an abduction device or possibly a posterior splint for shaft fract~res.~Z Birth trauma can cause fractures of the femur at almost any location. Breech delivery and high birth weight are predisposing factors.67 Presentation consists of abnormal rotation of the lower extremity, pain, or swelling. Treatment involves application of a traction device, spica cast, or both.68 Reduction should be close to anatomic, because overgrowth and remodeling of the femur are not usually dramatic.5l

,

Neurologic Injury Brachial plexus injury is the most common neurologic birth injury30 Approximately 21% of these injuries are associated with a shoulder dystocia at birth. Erb's palsy

CHAPTER

24

Child Abuse and Birth Injuries

405

( C 3 t o C 5 ) is t h e m o s t c o m m o n o f t h e brachial plexus Perforation o f t h e esophagus o r cricopharyngeus c a n injuries and usually resolves spontaneously, with little residalso occur. In m o s t cases o f birth trauma t o t h e chest, ual effect. Presentation involves a lack of m o t i o n o f t h e expectant observation is indicated. T h e clinical course affected shoulder, with t h e l i m b adducted and internally dictates t h e n e e d for operative intervention. H i g h perrotated t o t h e prone position. Distal sensation and hand forations o f t h e esophagus and cricopharyngeus can function are usually normal. Even after aggressive physical usually b e treated b y observation o r occasionally therapy, about 2% o f cases are permanent.29 Lower injuries drainage.65 Lower lesions require drainage o r operative of t h e C 6 t o T 1 cervical roots (Klumpke's palsy) present repair. W i t h early identification, results are excellent. with a lack of hand and wrist function. T h e s e lesions may Perforation o f t h e esophagus c a n also result f r o m placeb e accompanied b y Homer's syndrome, with t h e associated m e n t o f a gastric t u b e i n t h e neonatal period. physical findings. Microsurgical repair has b e e n described Liver h e m a t o m a is t h e m o s t c o m m o n intra-abdominal injury secondary t o birth trauma (Fig. 2 4 3 ) . T h e usual for recalcitrant brachial plexus injuries, with relatively presentation is a n e m i a , b u t it c a n also b e shock.27 good success, b u t this should b e reserved only for infants Diagnosis is usually m a d e by ultrasonography, b u t a failing aggressive physical therapy.60 Phrenic nerve paralysis is a c o m m o n l y associated finding and should be invest h o r o u g h investigation m a y b e necessary t o rule o u t tigated whenever brachial plexus injury is identified. o t h e r hepatic masses i n a n e w b o r n . T r e a t m e n t is usually Isolated brachial plexus injury can cause significant shoulexpectant a n d includes v o l u m e resuscitation a n d correcder abnormalities, and therapy should n o t b e d e l a ~ e d . ~ t i o n o f a n y h y p o t h e r m i a o r coagulopathy. Occasionally, Phrenic nerve injury c a n also occur i n i ~ o l a t i o n . ~ ~operative intervention is necessary w h e n t h e baby is Treatment of phrenic nerve injury d e p e n d s o n t h e severity unstable o r c o n t i n u e d h e m o r r h a g e occurs. Hemostatic o f t h e respiratory embarrassment experienced b y t h e a g e n t s a p p e a r t o b e m o r e h e l p f u l t h a n a t t e m p t s at child. Asymptomatic injuries should not b e treated; s u t u r e repair i n stopping hepatic bleeding i n newborns.'' In any case, control o f hepatic h e m o r r h a g e is very diffiinjuries resulting i n respiratory i m p a i r m e n t should b e cult i n this age group. treated with diaphragmatic plication o r o t h e r procedures designed t o reduce t h e paradoxical m o v e m e n t o f S p l e n i c i n j u r y is rare a n d p r e s e n t s m u c h l i k e t h e diaphragm w i t h r e ~ p i r a t i o n . ~ ? h e p a t i c injury. Intra-abdominal b l o o d m a y b e t h e Certainly t h e m o s t devastating neurologic birth injuries o n l y presenting sign, a n d as i n h e p a t i c injury, o t h e r a t m~e n t i n c l u d e s involve t h e central nervous system. Lesions o f t h e cervical pathology m u s t b e ruled o ~ t T .r e ~ e x p e c t a n t observation a n d c o r r e c t i o n o f coagulopathy spine are rare but are devastating w h e n t h e y occur. T h e o r h y p o t h e r m i a . O p e r a t i v e i n t e r v e n t i o n is d i f f i c u l t cause o f injury is usually a vaginal delivery with a b r e e c h a n d usually results i n s p l e n e c t o m y . H e m o s t a t i c agents o r transverse lie.2 As with all cervical spine injuries, h i g h lesions require mechanical ventilation, a n d lower lesions m a y also b e u s e f u l . As w i t h splenic injury, i n j u r y t o t h e adrenal glands have devastating physical sequelae. Survival is poor i n is u n c o m m o n b e c a u s e o f t h e relative protection proneonates with c o m p l e t e transection. Partial injury m a y m i m i c cerebral palsy.40 vided b y t h e thoracic ribs. T h e presentation m a y b e Subdural, subarachnoid, intraventricular, and intrah e m o r r h a g e o r adrenal i n s u f f i c i e n c y i n severe cases. parenchymal bleeds have also b e e n associated with birth Injury c a n also b e identified f r o m calcifications f o u n d on a radiograph t a k e n later i n l i f e . A s w i t h all intratrauma. O u t c o m e is d e p e n d e n t o n t h e e x t e n t of t h e lesion a b d o m i n a l solid organs, investigation o f h e m a t o m a s and t h e presentation. Usually these lesions are secondary requires a w o r k u p t o r u l e o u t o t h e r pathology, s u c h as t o v a c u u m extraction,23,70 which is also implicated as t h e cause o f subgaleal cephalohematoma. Although m o s t underlying tumor. hematomas resolve without incident o r sequelae, approximately 25% have b e e n reported t o cause death i n affected neonates." Traction injury t o t h e internal carotid artery has also b e e n reported i n difficult births. O u t c o m e f r o m these injuries is varied and d e p e n d s o n t h e e x t e n t o f vascular damage and collateral perfusion.62 Similarly, direct injury to t h e optic nerve has b e e n described.39 T h e m o s t c o m m o n central nervous system injury duri n g childbirth is anoxic brain d a m a g e a n d t h e resultant "cerebral palsy." T h e cause is controversial, b u t difficult delivery is a c o m m o n association. T r e a t m e n t o f neurologic b i r t h t r a u m a is usually expectant, with aggressive physical therapy. Recalcitrant peripheral injuries have responded t o surgical repair.

Thoracoabdominal Injury Injuries t o t h e chest are believed t o b e t h e result of pressure o n t h e thoracic cavity. P n e u m o t h o r a x , p n e u m o m e diastinum, a n d chylothorax have b e e n described.sz69

. . A Ultraso~lographyof the abdomen clcarly demonstrates this hepatic hematoma caused by birth trauma, which resolved spontaneously. Lesions like this call be followed by ultrasonography; if they persist, other causes such as neoplasm must be investigated.

I

406

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TRAUMA

REFERENCES 1. Akbarnia BA, Silberstein MJ, Rend RJ, et al: Arthrography in the diagnosis of fractures in the distal end of the humerus in infants. J Bone Joint Surg Am 1986;68:599-601. 2. Allen JP: Birth injury to the spinal cord. Northwest Med 1986;69:323-326. 3. Al-Moosa A, Al-Shaiji J, Al-Fadhli A, et al: Pediatricians' knowledge, attitndes and experience regarding child maltreatment in Kuwait. Child Abuse Negl 2003;27: 1161-1178. 4. Al-Qattan MM: Classification of secondary shoulder deformities in obstetric brachial plexus palsy. J Hand Surg [Br] 2003;28:483-486. 5. American Academy of Pediatrics: Diagnostic imaging of child abuse. Pediatrics 2000;105:1345-1348. 6. American College of Radiology: Standards for Skeletal Surveys in Children. American College of Radiology, 1997. 7. Babbitt DP, Cassidy RH: Obstetrical paralysis and dislocation of the shoulder in infants. J Bone Joint Surg Am 1968; 50:1447-1452. 8. Barsness KA, Cha E, Bensard DD, et al: The positive predictive value of rib fractures as an indicator of nonaccidental trauma in children. J Trauma 2003;54:1107-1110. 9. Bianco AJ, Schlein AP, Kruse RI, et al: Birth fractures. Minn Med 1972;55:471-474. 10. Blakemore LC, Loder RT, Hensinger RN: Role of intentional abuse in children 1 to 5 years old with isolated femoral shaft fractures. J Pediatr Orthop 1996;16:585-588. 11. Blocker SH, TernbergJL: Traumatic liver laceration in the newborn: Repair with fibrin glue. J Pediatr Surg 1986; 21:369-371. 12. Brown T: Radiography's role in detecting child abuse. Radio1 Techno1 1995;66:389-390. 13. Budeni! DL, Farber MG, Mirchandani HG, et al: Ocular and optic nerve hemorrhages in abused infants with intracranial injuries. Ophthalmology 1994;101:559-565. 14. Caffey J : Multiple fractures in the long bones of infants suffering from chronic subdural hematoma. AJR Am J Roentgen01 1946;56:163-173. 15. Cameron CM, Lazoritz S, Calhoun AD: Blunt abdominal injury: Simultaneously occurring liver and pancreatic injury in child abuse. Pediatr Emerg Care 1997;13:334336. 16. Cameron JM, Rae LJ: Atlas of the Battered Child Syndrome. Edinburgh, Churchill Livingstone, 1975. 17. Chapman S: Radiological aspects of non-accidental injury. J R Soc Med 1990;83:67-71. 18. Choi HJ, Lee SY, Yang H, et al: Retinal haemorrhage in vivax malaria. Trans R Soc Trop Med Hyg 2004;98:387-389. 19. Coant PN, Kornberg AE, Brody AS, et al: Markers for occult liver injury in cases of physical abuse in children. Pediatrics 1992;89:274278. 20. De Bellis MD, Putnam FW: The psychobiology of child maltreatment. Child Adolesc Psychiatr Clin N Am 1994; 3:663-678. 21. Deputy S: Shaking-impact syndrome of infancy. Semin Pediatr Neurol 2003;10:112-119. 22. Dodge KA, Bates JE, Petit GS: Mechanisms in the cycle of violence. Science 1990;250:1678-1683. 23. D y e r D: Problems after vacuum-assisted childbirth. Nursing 2002;32:74. 24. Ewing-Cobbs L, Kramer L, Prasad M, et al: Neuroimaging: Physical and developmental findings after inflicted and noninflicted traumatic brain injury in young children. Pediatrics 1998;102:300-307. 25. Forbes BJ, Christian CW, Judkins AR, et al: Inflicted childhood neurotrauma (shaken baby syndrome): Ophthalmic findings. J Pediatr Ophthalmol Strabismus 2004;41:80-88.

26. Forlin E, Guille J, Kumar S, et al: Transepiphyseal fractures on the neck of the femur in very young children. J Pediatr Orthop 1992;12:164168. 27. French CE, Waldstein G: Subcapsular hemorrhage of the liver in the newborn. Pediatrics 1982;69:204-208. 28. Friesen CD, Miller AM, Rayburn WF: Influence of spontaneous or induced labor on delivering the macrosomic fetus. Am J Perinatol 1995;12:63-66. 29. Gherman RB, Ouzounian JG, Goodwin TM: Brachial plexus palsy: An in utero injury? Am J Obstet Gynecol 1999;180:1303-1307. 30. Gherman RB,Ouzounian JG, Satin AJ, et al: A comparison of shoulder dystocia-associated transient and permanent brachial plexus palsies. Obstet Gynecol 2003;102:544548. 31. Heider TR, Priolo D, Hultman CS, et al: Eczema mimicking child abuse: A case of mistaken identity.J Burn Care Rehabil 2002;23:357-359. 32. Holmes SJ, Robins LN: The role of parental disciplinary practices in the development of depression and alcoholism. Psychiatry 1988;51:2436. 33. Hultman CS, Priolo D, Cairns BA, et al: Return to jeopardy: The fate of pediatric burn patients who are victims of abuse and neglect. J Burn Care Rehabil 1998;19:367-376. 34. Huntimer CM, Muret-Wagstaff S, Leland NI,: Can falls on stairs result in small intestine perforations? Pediatrics 2000; 106:301-305. 35. Johnson DL, Boa1 D, Baule R: The role of apnea in nonaccidental head injury. Pediatr Neurosurg 1995;23:305-310. 36. Keenan HT, Runyan DK, Marshall SW: A population-based study of inflicted traumatic brain injury in young children. JAMA 2003;290:621-626. 37. Keller MS: Blunt injury to solid abdominal organs. Semin Pediatr Surg 2004;13:106-111. 38. Keller MS, Stafford PW, Vane DW: Conservative management of pancreatic trauma in children. .J Trauma 1997;42: 1097-1100. 39. Khalil SK, Urso RG, Mintz-Hittner HA: Traumatic optic nerve injury occurring after forceps delivery of a term newborn. J Pediatr Ophthalmol Strabismus 2003;7:146-147. 40. Koch BM: Neonatal spinal cord injury. Arch Phys Med Rehabil 1979;60:378-381. 41. Kogutt MS, Swischuk LE, Fagan CJ: Patterns of injury and significance of uncommon fractures in the battered child syndrome. Radiology 1974;121:143-149. 42. Langer JC, et al: Plication of the diaphragm for infants and young children with phrenic nerve palsy. .J Pediatr Surg 1988;23:749-751. 43. Lee ACW, Ou Y, Fong D: Depressed skull fractures: A pattern of abusive head injury in three older children. Child Abuse Negl 2003;27:1323-1329. 44. Lemperg R, Liliequist B: Dislocation of the proximal epiphysis of the humerus in newborns. Acta Paediatr Scand 1970;59:377-380. 45. Lenoski EF, Hunter KA: Specific patterns of inflicted burn injuries. J Trauma 1977;17:842-846. 46. Loder RT, Bookout C: Fracture patterns in battered children. J Orthop Trauma 1991;5:428-433. 47. Ludwig S, Kornberg AE (eds): Child Abuse: A Medical Reference, 2nd ed. New York, Churchill Livingstone, 1992. 48. McClain PW, SacksJ, Froehlke RG, et al: Estimates of fatal child abuse and neglect, United States, 1979 through 1988. Pediatrics 1993;91:338-343. 49. McKibben L, De Vos E, Newberger EH: Victimization of mothers of abused children: A controlled study. Pediatrics 1989;84:531-535. 50. Merten DF, Radkowski MA, Leonidas JC: The abused child: A radiological appraisal. Radiology 1983;146377-381. 51. Mitchell WC, Coventry MB: Osseous injuries in the newborn. Minn Med 1959;42:1-4.

CHAPTER

52. Moucha CS, Mason DE: Distal humeral epiphyseal separation. Am J Orthop 2003;32:497-500. 53. Nakagawa H, Yamanchi M, Kusuyama T, et al: Cervical as a comemphysema secondary to pneumomediastint~n~ plication of childbirth. Ear Nose Throat.] 2003;82: 948-951. 54. National Center on Child Abuse and Neglect: Study Findings: Study of National Incidence and Prevalence of Child Abuse and Neglect: 1988. Washington, DC, Department of Health and Human Services, 1988. 55. National Pediatric Trauma Registry. Boston, Tufts University. 56. Ng CS, Hall CM, Shaw DG: The range of visceral manifestations of non-accidental injury. Arch Dis Child 1997;77: 167-174. 57. Oppenheim WL, Davis A, Growdon WA, et al: Clavicle fractures in the newborn. Clin Orthop 1990;250:176-180. 58. Pirtan G, Pamberger P, Blab E, et al: Common tasks and problems it1 paediatric tranma radiology. Eur J Radiol 2003;48: 103-124. 59. Perdomo Y, Fiore N, Reyna T: Splenic injury presenting with isolated scrota1 findings in a stable newborn. J Pediatr Surg 2003;38: 1673-1675. 60. Piatt JH: Birth injuries of the brachial plexus. Pediatr Clin North Am 2004;51:421-440. 61. Purdue GF, HuntJL: Burn injuries. In Ludwig S, Kornberg AE (eds): Child Abuse: A Medical Reference, 2nd ed. New York, Churchill Livingstone, 1992, pp 105-116.

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62. Robertson WC, Pettigrew I><::"<:ongenital" Homer's syndrome and carotid dissection. J Neuroimaging 2003;13: 367-370. 63. Sanerkin BG, Edwards P: Birth injury to t h e sternocleidomastoid muscle. J Bone Joint Snrg Rr 1066;48:441. 64. Sartorelli KH, Vane DW: The diagnosis and management of children with blunt injury of the chest. Se~ninPediatr Surg 2004;13:98-105. 65. Schullinger JN: Birth trauma. Pediatr (:lin North Am 1993;40:1351-1358. 66. Siffert RS: Displacement of the distal hurnel-a1epiphysis in the newborn inf'ant.,J Bone Joint Surg An1 191i3;45:165-169. 67. Theodorou SD, Ierodiaconou MN, Mitsou A: Obstetrical fractnre-separation of' the nppel. femoral epiphysis. Acta Orthop Scand 1982;53:239-243. 68. T~twbinR, Crawford AH: Neonatal tra~~rnatic proximal femoral epiphysiolysis. Pediatrics 1!)79;(i3:456-459. S: Neonatal subgaleal hemorrhage 69. Uchil D, Arulk~~maran and its relationship to delivery by vacutlnl extraction. Obstet Gynecol Surv 2003;58:687-693. 70. Whitby EH, Griffiths PD, Ruttcr S, et al: Freq~~ency and natural history of subdnral haernorrhages in babies and relation to obstetric factors. Lancet 2003;362:841i-85l. 71. Wissow LS: Child abuse and neglect. N Engl J Med 1995;332:1425-1431.

Principles of Pediatric Oncology, Genetics of Cancer, and Radiation Therapy Matthew J. Krasin and Andrew M. Davidoff

A number of milestones in the evolution of cancer therapy have come from the field of pediatric oncology. The first clear evidence that chemotherapy could provide effective treatment for childhood malignancy occurred in 1950, when Farber4 reported temporary cancer remission in children with acute lymphoblastic leukemia (ALL) treated with the folic acid antagonist aminopterin.41 The first successful use of a multidisciplinary approach to cancer treatment occurred in the 1950s and 1960s through the collaborative efforts of pediatric surgeons, radiation therapists, and pediatric oncologists aiming to improve the treatment of Wilms' tumor in children." Such a multidisciplinary approach is now used throughout the field of oncology. The successful use of a combination of chemotherapeutic agents to cure Hodgkin's disease and ALL during the 1960s led to the widespread use of combination chemotherapy to treat virtually all types of pediatric cancers. Since the late 1980s, neuroblastoma has been the paradigm for the use of therapies of variable intensity, depending on risk stratification determined by clinical and biologic variables, including molecular markers. Other advances in pediatric oncology have included the development of interdisciplinary, national cooperative clinical research groups to critically evaluate new therapies, the efficacy of dose-intensive chemotherapy programs in improving the outcome of advanced-stage solid tumors, and the supportive care necessary to make the latter approach possible. The development and application of these principles and advances have led to substantially increased survival rates for children with cancer and profound improvements in their quality of life. Additionally, advances in molecular genetic research in the past 2 decades have led to an increased understanding of the genetic events in the pathogenesis and progression of human malignancies, including those of childhood. A number of pediatric malignancies have served as models for molecular genetic research. Chromosomal structural changes, activating or inactivating mutations of relevant genes or their regulatory elements, gene

amplification, and gene imprinting may each play a role in different tumor types. In some instances, these genetic events occur early in tumorigenesis and are specific for a particular tumor type, such as chromosomal translocation t(11;22) (q24;q12) in Ewing's sarcoma; other aberrations occur in a variety of different tumor types and are almost always associated with additional genetic changes, such as chromosome l p deletion in neuroblastoma and Wilms' tumor. Some alterations involve oncogenes-genes that, when activated, lead directly to cancer-whereas others involve tumor suppressor genes, whose inactivation allows tumor progression. The result of alterations in these genetic elements, regardless of the mechanism, is disruption of the normal balance between proliferation and death of individual cells. These discoveries have highlighted the utility of molecular analysis for a variety of purposes, including diagnosis, risk stratification, and treatment planning; the understanding of syndromes associated with cancer; genetic screening and genetic counseling; and prophylactic treatment, including surgical intervention. Soon, treatment regimens are likely to be individualized on the basis of the molecular biologic profile of a patient's tumor. In addition, molecular profiling will lead to the development of new drugs designed to induce differentiation of tumor cells, block dysregulated growth pathways, or reactivate silenced apoptotic pathways.

EPIDEMIOLOGY AND SURVIVAL STATISTICS Cancer in children is uncommon; it represents only about 2% of all cancer cases. Nevertheless, after trauma, it is the second most common cause of death in children older than 1 year. Each year, approximately 130 new cases of cancer are identified per million children younger than 15 years (or about 1 in 7000). This means that in the United States, about 9000 children younger than 15 years are diagnosed with cancer each year, in addition

412

PART

III

MAJORTUMORS OF CHILDHOOD

Type of Cancer

Percentage of Total

Leukemia Brain tumors Lymphoma Neuroblastoma Sarcoma Wilms' tumor Germ cell tumors Osteosarcoma Retinoblastoma Liver tumors

30

been outstanding, progress in the treatment of others, such as metastatic neuroblastoma and rhabdomyosarcoma, has been modest. Therefore, there is still a need for significant improvement in the treatment of childhood cancer.

22

15 8 7 6

to 4000 patients aged 15 to 19 years.15*Leukemia is the most common form of cancer in children, and brain tumors are the most common solid tumor of childhood (Table 25-1). Lymphomas are the next most common malignancy in children, followed by neuroblastoma, soft tissue sarcomas, Wilms' tumor, germ cell tumors, osteosarcoma, and retinoblastoma. A slightly different distribution is seen among 15- to 19-year-olds, in whom Hodgkin's disease and germ cell tumors are the most frequently diagnosed malignancies; non-Hodgkin lyrnphoma, nonrhabdomyosarcoma soft tissue sarcoma, osteosarcoma, Ewing's sarcoma, thyroid cancer, and melanoma also occur with an increased incidence. In general, the incidence of childhood cancer is greatest during the first year of life, peaks again in children aged 2 to 3 years, and then slowly declines until age 9. The incidence then steadily increases again through adolescence. Each tumor type shows a different age distribution pattern, however. Variations by gender are also seen. For example, Hodgkin's disease, ALL, brain tumors, neuroblastoma, hepatoblastoma, Ewing's sarcoma, and rhabdomyosarcoma are more common in boys than in girls younger than 15 years, whereas only osteosarcoma and Ewing's sarcoma are more common in boys than in girls older than 15 years. However, girls in the older age group have Hodgkin's disease and thyroid cancer more frequently than boys do. Distribution also varies by race: white children generally have a 30% greater incidence of cancer than do black children. This difference is particularly notable for ALL, Ewing's sarcoma, and testicular germ cell tumors. The probability of surviving childhood cancer has improved greatly since Farber induced the first remissions in patients with ALL. In the early 1960s, approximately 30% of children with cancer survived their disease. By the mid-l980s, about 65% of children with cancer were cured, and by the mid-1990s, the cure rate had increased to nearly 75%.12' These great strides resulted from three important factors: (1) the sensitivity of childhood cancer, at least initially, to available chemotherapeutic agents; (2) the treatment of childhood cancer in a multidisciplinary fashion; and (3) the treatment of most children in major pediatric treatment centers in the context of a clinical research protocol using the most current and promising therapy. Although progress in the treatment of some tumor types such as ALL and Wilms' tumor has

MOLECULAR BIOLOGY OF CANCER During normal cellular development and renewal, cells evolve to perform highly specialized functions to meet the physiologic needs of the organism. Development and renewal involve tightly regulated processes that include continued cell proliferation, differentiation to specialized cell types, and programmed cell death (apoptosis). An intricate system of checks and balances ensures proper control over these physiologic processes. The genetic composition (genotype) of a cell determines which pathway or pathways will be followed in exerting that control. In addition, the environment plays a crucial role in influencing cell fate: cells use complex signal transduction pathways to sense and respond to neighboring cells and their extracellular milieu. Cancer is a genetic disease whose progression is driven by a series of accumulating genetic changes influenced by hereditary factors and the somatic environment. These genetic changes result in individual cells acquiring a phenotype that provides them with a survival advantage over surrounding normal cells. Our understanding of the processes that occur in malignant cell transformation is increasing; many discoveries in cancer cell biology have been made by using childhood tumors as models. This greater understanding of the molecular biology of cancer has also contributed significantly to our understanding of normal cell physiology.

Normal Cell Physiology CeN Cycle Genetic information is stored in cells and transmitted to subsequent generations of cells through nucleic acids organized on chromosomes as genes. A gene is a functional unit of heredity that exists on a specific site or locus on a chromosome, is capable of reproducing itself exactly at each cell division, and is capable of directing the synthesis of an enzyme or other protein. The genetic material is maintained as DNA formed into a double helix of complementary strands. The backbone of each strand is made up of linked sugar and phosphate groups to which complementary bases-a purine (adenine or guanine) and a pyrimidine (cytosine or thymine)-are connected by hydrogen bonds. DNA normally exists in a tightly wound complex maintained by histone proteins in the nucleus. Unwinding of the DNA is required for its activation. The complementary nature of the two DNA strands allows DNA to be exactly replicated during cell division: each strand serves as a template for the synthesis of the second strand. The cell must ensure that synthesized DNA (3 billion base pairs) has been accurately copied. DNA replication errors that go uncorrected potentially alter the function of normal cell regulatory proteins.

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Principles o f Pediatric Oncology, Genetics o f Cancer, and Radiation Therapy

Protein synthesis begins with the transcription of a single strand of messenger RNA (mRNA) from a DNA template. RNA contains the pyrimidine uracil, instead of the DNA base thymine, and a pentose sugar, ribose, instead of the deoxyribose sugar found in DNA. After transcription, the mRNA undergoes modifications that affect its sequence, length, physical form, and stability. Following this, translation of the mRNA template into the sequence of amino acids that constitutes a polypeptide occurs. Additional post-translational modifications can then be made to these newly synthesized proteins. These proteins, whose sequence is dictated by the DNA of a given cell, are responsible for an enormous range of activities within the cell and direct, in particular, the cell's division cycle, by which cells proliferate. The molecular machinery used to control the cell cycle is highly organized and tightly regulated (Fig. 25-1).I34 Normal growth results from the progression of cells

A Mitosis

Resting Phase

apoptosis (death)

3

Growth

terminal differentiation I

.

Synthesis

A, The cell cycle. Normal cell growth proceeds in an orderly fashion, with cells proceeding through the cycle of DNA replication (S) and mitosis (M). These cycles are separated by two intervening phases of growth (G, and G P ) Cells . are signaled to leave the cycle to enter a resting state, to differentiate,or to die. B, Cell signal transduction. Proto-oncogene products (examples in parentheses) are involved in all aspects of signal transduction that move the cell through the cell cycle. The process begins when extracellular growth factors bind to a transmembrane growth factor receptor, thereby inducing the protein kinase activity of the receptor. Other proteins bind to the phosphorylated receptor and transmit a signal to the nucleus through membrane-bound and cytoplasmic messengers. This activates nuclear transcription factors, which bind to DNA and affect the transcription of growth-relatedgenes. GTP, guanosine triphosphate.

413

through cycles of DNA replication (S phase) and cell division or mitosis (M phase). These two phases of the cell cycle are separated by two intervening growth phases (GI and G2). Cells can also temporarily leave the cell cycle and enter a resting state called Go. Signals that stimulate or inhibit cellular growth converge on a set of evolutionarily conserved enzymes that drive cell cycle progression. Two classes of proteins, cyclins and cyclindependent kinases, form complexes that mediate progression through the cell cycle by sequentially phosphorylating target proteins. Cyclin-dependent kinase inhibitors regulate the activity of the cyclin-dependent kinases and serve as a "braking" system for the cell cycle machinery. In addition, various "checkpoints" exist to halt progression through the cell cycle during certain environmental situations or times of genetic error resulting from inaccurate synthesis or damage. Two of the most well-studied participants in the cell cycle checkpoint system are p53 and retinoblastoma (RB) proteins.1" In normal circumstances, cells divide and terminally differentiate, thereby leaving the cell cycle, or they enter a resting state. Inactivation of the effectors of cell cycle regulation or the bypassing of cell cycle checkpoints can result in dysregulation of the cell cycle-a hallmark of malignancy.

Signal Transduction Signal transduction pathways regulate all aspects of cell function, including metabolism, cell division, death, differentiation, and movement. Multiple extracellular and intracellular signals for proliferation or quiescence must be integrated by the cell, and it is this integration of signals from multiple pathways that determines the response of a cell to competing and complementary signals. Extracellular signals include growth factors, cytokines, and hormones; the presence or absence of adequate nutrients and oxygen; and contact with other cells or an extracellular matrix. Signaling mediators often bind to membrane-bound receptors on the outside of the cell, but they may also diffuse into the cell and bind receptors in the cytoplasm or on the nuclear membrane. Binding of a ligand to a receptor stimulates the activities of small-molecule second messengers-proteins necessary to continue the transmission of the signal. Signaling pathways ultimately effect the activation of nuclear transcription factors that are responsible for the expression or silencing of genes encoding proteins involved in all aspects of cellular physiology. Receptors with tyrosine kinase activity are among the most important transmembrane receptors. They are composed of an extracellular ligand-binding domain, a transmembrane domain, and an intracellular, cytoplasmic, tyrosine kinase domain. The binding of ligand to a receptor may cause a conformational change in the receptor or lead to the linking of the receptoreto one or more other receptors. Either event results in activation of the receptor. The tyrosine kinase domain, in particular, is responsible for conveying signals intracellularly by phosphorylating internal substrates directly or by activating associated tyrosine kinases. Several important transmembrane receptors with protein kinase activity have been identified and grouped

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in families on the basis of structural ~imi1arities.I~~ These families include the epidermal growth factor receptors (EGFRs), fibroblast growth factor receptors, insulin-like growth factor (IGF) receptors, platelet-derived growth factor (PDGF) receptors, transforming growth factor recep tors, and neurotrophin receptors (Trks). Abnormalities of members of each of these families are often found in pediatric malignancies and therefore are thought to play a role in their pathogenesis. Characteristic abnormalities of these receptors often form the basis of both diagnostic identification of certain tumor types and, more recently, targeted therapy for tumors with these specific abnormalities.

Programmed Cell Death Multicellular organisms have developed a highly organized and carefully regulated mechanism of cell suicide in order to maintain cellular homeostasis. Normal development and morphogenesis are often associated with the production of excess cells, which are removed by the genetically programmed process called apoptosis. Cells undergoing apoptosis have distinct morphologic features (plasma membrane blebbing, reduced volume, nuclear condensation), and their DNA is subjected to endonucleolytic cleavage. Apoptosis is initiated by the interaction of "death ligands," such as tumor necrosis factor-a (TNF-a), Fas, and TNF-related apoptosis-inducing ligand (TRAIL), with their respective receptors. This interaction is followed by aggregation of the receptors and recruitment of adapter proteins to the plasma membrane, which activate caspa~es.'~)~ Caspases are a large family of proteases that function in both the initiation of apoptosis in response to proapoptotic signals and the subsequent effector pathway that disassembles the cell. Thus, apoptosis limits cellular expansion and counters cell proliferation. Because cell survival signals may also be activated through pathways mediated by nuclear factor KB, the fate of a cell is determined by the balance between death signals and survival s i g n a l ~ . ~ W t hsignals er arising from cellular stress (e.g., DNA damage, hypoxia, oncogene activation) may also effect cell cycle arrest or apoptosis. An alternative to cell death mediated by receptorligand binding is cellular senescence, which is initiated when chromosomes reach a critical length. Eukaryotic chromosomes have DNA strands of unequal length, and their ends, called telomeres, are characterized by speciesspecific nucleotide repeat sequences. Telomeres stabilize the ends of chromosomes, which are otherwise sites of significant instability.'"Wver time and with each successive cycle of replication, chromosomes are shortened by failure to complete replication of their telomeres. Thus, telomere shortening acts as a biologic clock, limiting the life span of a cell. Germ cells, however, avoid telomere shortening by using telomerase, an enzyme capable of adding telomeric sequences to the ends of chromosomes. This enzyme is normally inactivated early in the growth and development of an organism. Persistent activation or the reactivation of telomerase in somatic cells appears to contribute to the immortality of transformed cells.

Malignant Transformation Alteration or inactivation of any of the components of normal cell regulatory pathways may lead to the dysregulated growth that characterizes neoplastic cells. Malignant transformation may be characterized by cellular dedifferentiation or failure to differentiate, cellular invasiveness and metastatic capacity, or decreased drug sensitivity. Tumorigenesis reflects the accumulation of excess cells that results from increased cell proliferation and decreased apoptosis or senescence. Cancer cells do not replicate more rapidly than normal cells, but they show diminished responsiveness to regulatory signals. Positive growth signals are generated by proto-oncogenes, so named because their dysregulated expression or activity can promote malignant transformation. These protooncogenes may encode growth factors or their receptors, intracellular signaling molecules, and nuclear transcription factors (Table 25-2). Conversely, tumor suppressor genes, as their name implies, control or restrict cell growth and proliferation. Their inactivation, through various mechanisms, permits the dysregulated growth of cancer cells. Also important are the genes that regulate cell death. Their inactivation leads to resistance to apoptosis and allows the accumulation of additional genetic aberrations. Cancer cells carry DNA that has point mutations, viral insertions, or chromosomal or gene amplifications, deletions, or rearrangements. Each of these aberrations can alter the context and process of normal cellular growth and differentiation. Although genomic instability is an inherent property of the evolutionary process and normal development, it is through genomic instability that the malignant transformation of a cell may arise. This inherent instability may be altered by inheritance or exposure to destabilizing factors in the environment. Point mutations may terminate protein translation, alter protein function, or change the regulatory target sequences that control gene expression. Chromosomal alterations create new genetic contexts within the genome and lead to the formation of novel proteins or to the dysregulation of genes displaced by aberrant events. Genetic abnormalities associated with cancer may be detected in every cell in the body or only in the tumor cells. Constitutional or germline abnormalities either are inherited or occur de novo in the germ cells (sperm or oocyte). Interestingly, despite the presence of a genetic abnormality that might affect growth regulatory pathways in all cells, people are generally predisposed to the development of only certain tumor types. This selectivity highlights the observation that gene function contributes to growth or development only within a particular milieu or physiologic context. Specific tumors occur earlier and are more often bilateral when they result from germline mutations than when they result from sporadic or somatic alterations. Such is often the case in two pediatric malignancies, Wilms' tumor and retinoblastoma. These observations led Knudson81 to propose a "two-hit" mechanism of carcinogenesis in which the first genetic defect, already present in the germline, must be complemented by an additional spontaneous

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Principles of Pediatric Oncology, Genetics of Cancer, and Radiation Therapy

415

Oncogene Family

Proto-oncogene

Chromosome Location

Tumor

Growth factors and receptors

Erb 6 2 Trk Src H-ras c-myc N-myc

17q21 9q22 7pll 11~15.1 18q24 2p24

Glioblastoma Neuroblastoma Rhabdomyosarcoma,osteosarcoma, Ewing's sarcoma Neuroblastoma Burkitt's lymphoma Neuroblastoma

Chromosome Location

Tumor

Protein kinase Signal transducers Transcri~tionfactors

Syndrome Familial polyposis coli Familial retinoblastoma WAGR* Denys-Drasht Beckwith-Wiedemannt Li-Fraumeni Neurofibromatosis type 1 Neurofibromatosis type 2 Von Hippel-Lindau

Tumor Suppressor Gene -APC

RE WT1 WT1 WT2 (?) ~ 5 3 NFI NF2 VHL

5q21 13q24 11~13 11~13 11~15 17q13 17q11.2 22q12 3~25-26

Intestinal polyposis, colorectal cancer Retinoblastoma, osteosarcoma Wilms' tumor Wilms' tumor Wilms' tumor, hepatoblastoma, adrenal Multiple (see text) Sarcomas, breast cancer Neurofibroma, neurofibrosarcoma, brain tumor Renal cell cancer, pheochromocytoma, retinal angioma, hemangioblastoma

'Wilms' tumor, aniridia, genitourinary abnormalities, mental retardation. tWilms' tumor, pseudohermaphroditism, mesangial sclerosis, renal failure. ?Multipletumors, hemihypertrophy, macroglossia, hyperinsulinism.

mutation before a tumor can arise. In sporadic cancer, cellular transformation occurs only when two (or more) spontaneous mutations take place in the same cell. Much more common, however, are somatically acquired chromosomal aberrations, which are confined to the malignant cells. These aberrations affect growth factors and their receptors, signal transducers, and transcription factors. The general types of chromosomal alterations associated with malignant transformation are shown in Figure 25-2. Although a low level of chromosomal instability exists in a normal population of cells, neoplastic transformation occurs only if these alterations affect a growth-regulating pathway and confer a growth advantage.

DNA Content Normal human cells contain two copies of each of 23 chromosomes; a normal "diploid" cell therefore has 46 chromosomes. Although cellular DNA content, or ploidy, is accurately determined by karyotypic analysis, it can be estimated by the much simpler method of flow cytometric analysis. Diploid cells have a DNA index of 1.0, whereas near-triploid cells have a DNA index ranging from 1.26 to 1.76. The majority (55%) of primary neuroblastoma cells are triploid or near triploid (e.g., having between 58 and 80 chromosomes), whereas the remainder are near diploid (35 to 57 chromosomes) or near Neuroblastomas tetraploid (81 to 103 chromo~omes).~6 consisting of near-diploid or near-tetraploid cells usually have structural genetic abnormalities (e.g., chromosome l p deletion and amplification of the MYCN oncogene), whereas those consisting of near-triploid cells are characterized by three almost complete haploid sets of

chromosomes with few structural abnormalities.16 Importantly, patients with near-triploid tumors typically have favorable clinical and biologic prognostic factors and excellent survival rates compared with those who have near-diploid or near-tetraploid tumors."'

Chromosomal Translocations Many pediatric cancers, specifically hematologic malignancies and soft tissue neoplasms, have recurrent, nonrandom abnormalities in chromosomal structure, typically chromosomal translocations (Table 25-3). The most common result of a nonrandom translocation is the fusion of two distinct genes from different chromosomes. The genes are typically fused within the reading frame and express a functional, chimeric protein product that has transcription factor or protein kinase activity. These fusion proteins contribute to tumorigenesis by activating genes or proteins involved in cell proliferation. For example, in Ewing's sarcoma the consequence of the t(11;22) (q24;qlZ) translocation is a fusion of EWS, a transcription factor gene on chromosome 22, and FLI-1, a gene encoding a member of the ETS family of transcription factors on chromosome 1 The resultant chimeric protein, which contains the DNA binding region of FLI-I and the transcription activation region of EWS, has greater transcriptional activity than does EWS alone.98 The EWS-FLI-1 fusion transcript is detectable in approximately 90% of Ewing's sarcomas. At least four other EWS fusions have been identified in Ewing's sarcoma; fusion of EWSwith ERG (another ETS family member) accounts for an additional 5% of cases.'S7 Alveolar rhabdomyosarcomas have characteristic translocations between the long arm of chromosome 2 (75% of cases) or the short

416

PART

I1 I

MAJORTUMORS OF CHILDHOOD

Monosomy 14

\

Trisomy

IGain

/

Amplification

Telomere Short Arm

Centromere Long Arm

Telomere

/

d

Interstitial deletion

Transl cation

chromosomal

1

lntra

m >oIal

.

del (1p33)

t(1;14) (p33;q11.2)

inv(14) (q11.2q32)

-

Spectrum of gross chromosomal aberrations using chromosomes 1 and 14 as examples. HSR, homogeneously staining regions (From Look AT, Kirsch IR: Molecular basis of childhood cancer. In Pizzo PA, Poplack DG [eds]: Principles and Practices of Pediatric Oncology. Philadelphia: Lippincott-Raven, 1997, p 38.)

arm of chromosome 1 (10% of cases) and the long arm of Translocations that generate chimeric. proteins with chromosome 13. These translocations result in the fusion increased transcriptional activity also characterize desmoplastic small round cell tumor,88myxoid l i p o s a r ~ o m a , l ~ ~ of PAX3 (at 2q35) or PAX7 (at lp36) with FKHR, a gene encoding a member of the forkhead family of transcription extraskeletal myxoid chrondrosarcoma,27 malignant factors." The EWS-FLJ-1 and PAX7-FKHR fusions appear melanoma of soft parts,l54 synovial sarcoma,28 congenital fibrosarc0ma,14~ cellular mesoblastic nephroma,12' to confer a better prognosis for patients with Ewing's sarcoma and alveolar rhabdomyosarcoma, re~pectively.~,~~ and dermatofibrosarcoma protuberans.109

CHAPTER

25

Principles of Pediatric Oncology, Genetics of Cancer, and Radiation Therapy

Tumor

Fusion Transcript -----

Ewing's sarcoma, primitive neuroectodermal tumor

FLII-EWS ERG-EWS ETVI-EWS EIAF-EWS FEV-EWS WTI-EWS FLl1-EWS SSX1-SM SSX2-SM PAX3-FKHR PAX7-FKHR AJFI-EWS CHOP-TLS(FUS) CHOP-EWS CHN-EWS COLIAI-PDGFB EN6-NJRK3 ? ?

Desmoplastic small round cell tumor Synovial sarcoma Alveolar rhabdomyosarcoma

' 1

Malignant melanoma of soft part (clear cell sarcoma) Myxoid liposarcoma Extraskeletal myxoid chondrosarcoma Dermatofibrosarcoma protuberans and giant cell fibroblastoma Congenital fibrosarcoma and mesoblastic nephroma Lipoblastoma

417

From Davidoff AM, Hill DA: Molecular genetic aspects of solid tumors in childhood. Semin Pediatr Surg 2001;10:106-118.

Proto-oncogene Activation Proto-oncogenes are commonly activated in transformed cells by point mutations or gene amplification. The classic example of proto-oncogene activation by a point mutation involves the cellular proto-oncogene RAS. RASfamily proteins are associated with the inner, cytoplasmic surface of the plasma membrane and function as intermediates in signal transduction pathways that regulate cell proliferation. Point mutations in RAS result in constitutive activation of the RAS protein and, therefore, the continuous activation of the RAS signal transduction pathway. Activation of RAS appears to be involved in the pathogenesis of a small percentage of pediatric malignancies, including leukemia and a variety of solid tumors. Gene amplification (i.e., selective replication of DNA sequences) enables a tumor cell to increase the expression of crucial genes whose products are ordinarily tightly controlled. The amplified DNA sequences, or amplicons, may be maintained episomally (i.e., extrachromosomally) as double minutes-paired chromatin bodies lacking a centromere-or as intrachromosomal, homogeneously staining regions. In about one third of neuroblastomas, for example, the transcription factor and proto-oncogene MYCN is amplified. MYCN encodes a 64kDa nuclear phosphoprotein (MycN) that forms a transcriptional complex by associating with other nuclear proteins expressed in the developing nervous system and other tissues.@Increased expression of MycN increases the rates of DNA synthesis and cell proliferation and shortens the GI phase of the cell cycle.g4The MYCN copy number in neuroblastoma cells can be amplified 5- to 500-fold and is usually consistent among primary and metastatic sites and at different times during tumor evolution and treatment.15 This consistency suggests that MYCN amplification is an early event

in the pathogenesis of neuroblastoma. Because gene amplification is usually associated with advanced stages of disease, rapid tumor progression, and poor outcome, it is a powerful prognostic indicator.l7l1" The cell surface receptor gene ERBB2 is another proto-oncogene that is commonly overexpressed due to gene amplification, an event that occurs in breast cancer, osteosarcoma, and Wilms' tumor.l14 Comparative genomic hybridization studies have shown that a gain of genetic material on the long arm of chromosome 17 (17q) is perhaps the most common genetic abnormality in neuroblastomas: such gain occurs in approximately 75% of primary t u r n ~ r s . ~ ~ W h r o m o s o m e 17q gain is strongly associated with other known prognostic factors but may be a powerful independent predictor a i 17q n most often results of adverse o u t ~ o m e . ~ ~ of from an unbalanced translocation of this region to other chromosomal sites, most frequently l p or 1lq. The term unbalanced indicates that extra copies of 17q are present, in addition to the normal chromosome 17. Although it is unclear what the crucial gene or genes are on 17q and how extra copies of 17q contribute to the malignant phenotype of neuroblastoma, the existence of 17q amplification in neuroblastoma suggests the presence of a proto-oncogene on 17q.

Inactivation of Tumor Suppressor Genes Tumor suppressor genes, or antioncogenes, provide negative control of cell proliferation. Loss of function of the proteins encoded by these genes, through deletion or mutational inactivation of the gene, liberates the cell from growth constraints and contributes to malignant transformation. The cumulative effect of genetic lesions that activate proto-oncogenes or inactivate tumor suppressor genes is a breakdown in the balance between cell

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M ~ J O TUMORS R OF CHILDHOOD

proliferation and cell loss due to differentiation or apoptosis. Such imbalance results in clonal overgrowth of a specific cell lineage. The first tumor suppressor gene to be recognized was the retinoblastoma susceptibility gene, RB. This gene encodes a nuclear phosphoprotein that acts as a "gatekeeper" of the cell cycle. RB normally permits cell cycle progression through the GI phase when it is phosphorylated, but it prevents cell division when it is unphosphorylated. Inactivating deletions or point mutations of RB cause the protein to lose its regulatory capacity. The nuclear phosphoprotein p53 has also been recognized as an important tumor suppressor gene, perhaps the most commonly altered gene in all human cancers. Inactivating mutations of the $153gene also cause the p53 protein to lose its ability to regulate the cell cycle. The p5P gene is frequently inactivated in solid tumors of childhood, including osteosarcoma, rhabdomyosarcoma, brain tumors, anaplastic Wilms' tumor, and a subset of In addition, chemotherapy-resistant neuroblastoma.7~7*~*6 heritable cancer-associated changes in the $153 tumor suppressor gene occur in families with Li-Fraumeni syndrome, an autosomal dominant predisposition for rhab domyosarcoma, other soft tissue and bone sarcomas, premenopausal breast cancer, brain tumors, and adrenocortical carcinomas.95 Other tumor suppressor genes include Wilms' tumor 1 ( WTI), neurofibromatosis 1 (MI), and von Hippel-Lindau ( VHL). Other tumor suppressor genes are presumed to exist but have not been definitively identified. For example, early karyotype analyses of neuroblastoma-derived cell lines found frequent deletion of the short arm of chromosome 1.18 Deletion of genetic material in tumors suggests the presence (and subsequent loss) of a tumor suppressor gene, but no individual tumor suppressor gene has been identified on chromosome l p . Functional confirmation of the presence of a l p tumor suppressor gene came from the demonstration that transfection of chromosome l p into a neuroblastoma cell line results in morphologic changes of differentiation and ultimately cell senescence.5 Approximately 20% to 35% of primary neuroblastomas exhibit l p deletion, as determined by fluorescent in situ hybridization (FISH),and the smallest common region of loss is located within region 1~36.51Deletion of l p is also common in Wilms' tum0r.~2

Metastasis Metastasis is the spread of cancer cells from a primary tumor to distant sites and is the hallmark of malignancy. The development of tumor metastases is the main cause of treatment failure and a significant contributing factor to morbidity and mortality resulting from cancer. Although the dissemination of tumor cells through the circulation is probably a frequent occurrence, the establishment of metastatic disease is a very inefficient process. It requires several events, including the entry of the neoplastic cells into the blood or lymphatic system, the survival of those cells in the circulation, their avoidance of immune surveillance, their invasion of foreign (heterotopic) tissues, and the establishment of a blood supply to permit expansion of the tumor at the distant site.

Simple, dysregulated cell growth is not sufficient for tumor invasion and metastasis. Many tumors progress through distinct stages that can be identified by histopathologic examination, including hyperplasia, dysplasia, carcinoma in situ, invasive cancer, and disseminated cancer. Genetic analysis of these different stages of tumor progression suggests that uncontrolled growth results from progressive alteration in cellular oncogenes and inactivation of tumor suppressor genes, but these genetic changes driving tumorigenicity are clearly distinct from those that determine the metastatic phenotype. Histologically, invasive carcinoma is characterized by a lack of basement membrane around an expanding mass of tumor cells. Matrix proteolysis appears to be a key part of the mechanism of invasion by tumor cells, which must be able to move through connective tissue barriers, such as the basement membrane, to spread from their site of origin. The proteases involved in this process include the matrix metalloproteinases and their tissue inhibitors. The local environment of the target organ may profoundly influence the growth potential of ~ various cell surface extravasated tumor ~ e l l s . 4The receptors that mediate interactions between tumor cells and between tumor cells and the extracellular matrix include cadherins, integrins (transmembrane proteins formed by the noncovalent association of a and P subunits), and CD44, a transmembrane glycoprotein involved in cell adhesion to hyaluronan.144 Tumor cells must decrease their adhesiveness to escape from the primary tumor, but at later stages of metastasis, the same tumor cells need to increase their adhesiveness during arrest and intravasation to distant sites.

Angiogenesis Angiogenesis is the biologic process of new blood vessel formation. This complex, invasive process involves multiple steps, including proteolytic degradation of the extracellular matrix surrounding existing blood vessels, chemotactic migration and proliferation of endothelial cells, the organization of these endothelial cells into tubules, the establishment of a lumen that serves as a conduit between the circulation and an expanding mass of tumor cells, and functional maturation of the newly formed blood v e ~ s e 1 . 5 0Angiogenesis ~~~~ involves the coordinated activity of a wide variety of molecules, including growth factors, extracellular matrix proteins, adhesion receptors, and proteolytic enzymes. Under physiologic conditions, the vascular endothelium is quiescent and has a very low rate of cell division, such that only 0.01% of endothelial cells However, in response to hormonal are di~iding.~O,~O,l2~ cues or hypoxic or ischemic conditions, the endothelial cells can be activated to migrate, proliferate rapidly, and create lumens. Angiogenesis occurs as part of such normal physiologic activities as wound healing, inflammation, the female reproductive cycle, and embryonic development. In these processes, angiogenesis is tightly and predictably regulated. However, angiogenesis can also be involved in the progression of several pathologic processes in which there is a loss of regulatory control, resulting in persistent growth

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Principles o f Pediatric Oncology, Genetics o f Cancer, and Radiation Therapy

of new blood vessels. Such unabated neovascularization occurs in rheumatoid arthritis, inflammatory bowel disease, hemangiomas of childhood, ocular neovascularization, and the growth and spread of tumors.49 Compelling data indicate that tumor-associated neovascularization is required for tumor growth, invasion, and metasta~is.~.47~4*,~~6 A tumor in the prevascular phase (i.e., before new blood vessels have developed) can grow to only a limited size, approximately 2 to 3 mm3. At this point, rapid cell proliferation is balanced by equally rapid cell death by apoptosis, and a nonexpanding tumor mass results. The switch to an angiogenic phenotype with tumor neovascularization results in a decrease in the rate of a p o p tosis, thereby shifting the balance to cell proliferation and tumor growth.71,gl This decrease in apoptosis occurs, in part, because the increased perfusion resulting from neovascularization permits improved nutrient and metabolite exchange. In addition, the proliferating endothelium may supply, in a paracrine manner, a variety of factors that promote tumor growth, such as IGF-I and IGF-II.G4 In experimental models, increased tumor vascularization correlates with increased tumor growth, whereas restriction of neovascularization limits tumor growth. Clinically, the onset of neovascularization in many human tumors is temporally associated with increased tumor growth,'" and high levels of angiogenic factors are commonly detected in blood and urine from patients ' ~ ~addition, the number with advanced m a l i g n a n ~ i e s .In and density of new microvessels within primary tumors have been shown to correlate with the likelihood of metastasis, as well as the overall prognosis for patients with a wide variety of neoplasms, including pediatric tumors such as neuroblastoma and Wilms' tumor.'JOl It has become increasingly evident that the regulation of tumor angiogenesis is complex: new blood vessel formation occurs as the result of competing pro- and antiangiogenic signals originating in multiple tissues.23 Specific genetic events in certain cancers, such as altered expression of the $153 tumor suppressor gene32Jj3 or the human EGFR gene,8YJj".'" not only affect the cell cycle but also play a role in angiogenesis by modulating key signals (e.g., u p regulating the expression of vascular endothelial growth factor [VEGF] or down-regulating the expression of the endogenous angiogenesis inhibitor thrombospondin 1). Metastasis also appears to be dependent on angiogenesis.45," This dependence is probably due to several factors. First, new blood vessels in the primary tumor provide increased opportunities for the shedding of tumor cells into the circulation. Also, disruption of the basement membrane by proteases released by the proliferating endothelial cells may contribute to the metastatic Finally, successful growth of potential of a t~mor.~9J** metastatic cells in foreign target organs depends on the stimulation and formation of new blood vessels, perhaps even when cells metastasize to the bone marrow.

MOLECULAR DIAGNOSTICS The explosion of information about the human genome has led not only to an improved understanding of the molecular genetic basis of tumorigenesis but also to the

419

development of a new discipline: the translation of these molecular events into diagnostic assays. The field of molecular diagnostics has developed from the need to identify abnormalities of gene or chromosome structure in patient tissues and as a means of supporting standard histopathologic and immunohistochemical diagnostic methods. In most instances, the result of genetic testing confirms light microscopic and immunohistochemistrybased diagnosis. In some instances, however (e.g.,primitive, malignant, small round cell tumor; poorly differentiated synovial sarcoma; lipoblastic tumor), molecular analysis is required to make a definitive diagnosis. The molecular genetic methods most commonly used to analyze patient tumor material include direct metaphase cytogenetics or karyotyping, FISH, and reverse transcriptase polymerase chain reaction (RT-PCR). Additional methods, such as comparative genomic hybridization, loss of heterozygosity analysis, and complementary DNA (cDNA) microarray analysis, may eventually become part of the routine diagnostic repertoire but are currently used as research tools at referral centers and academic institutions. Each standard method is summarized in Table 25-4. As with any method, molecular genetic assays have advantages and disadvantages, and it is important to understand and recognize their limitations. It is also necessary to know the specific type of material required for each molecular assay. Surgeons can best appreciate the fine balance between minimizing the trauma and tissue disruption associated with a biopsy procedure and obtaining enough tissue for diagnosis, molecular genetic studies, and tissue banking for future analysis. The value of molecular genetic analysis of patient tissue is not limited to aiding histopathologic diagnosis. Many of the most important markers provide prognostic information as well. MYCN amplification in neuroblastomas,16 for example, is strongly associated with biologically aggressive behavior. Amplification of this gene can be detected by routine metaphase cytogenetics or by FISH, and current neuroblastoma protocols include the presence or absence of MYCNamplification in their stratification schema. Some fusion gene variants are also thought to influence prognosis. In initial studies, two examples noted to confer relatively favorable prognoses are the type 1 variant fusion of E W F L I l in Ewing's sarcoma or primitive neuroectodermal tumorB and the PAX7-EKHR fusion in alveolar rhabdomyo~arcoma.~ Complementary DNA microarray technology is likely to lead to the discovery of many more prognostically relevant genes. New technologies are emerging that permit accurate, high-throughput analysis or "profiling" of tumor tissue: gene expression can be analyzed by using RNA microarrays, and proteins by using proteomics. These approaches identify a unique "fingerprint" of a given tumor that can provide diagnostic or prognostic information. Proteomic analysis can also identify unique proteins in patients' serum or urine; such a profile can be used for early tumor detection, to distinguish risk categories, and to monitor for recurrence. Microarray analysis has also been used to characterize the response of tumor cells to stimuli such as stress, hypoxia, and therapy by analyzing a tumor cell's entire complement of RNA. The commercial availability of

420

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M.410~TUMORS OF CHILDHOOD

Purpose --

Cytogenetics

Low-resolution analysis of metaphase chromosomes of cells grown in culture

In situ hybridization

Detection of translocations, amplifications, and gene deletions by hybridization of nucleic acid probes to specific DNA or mRNA sequences

PCR and RT-PCR

Extremely sensitive detection of DNA sequences and mRNA transcripts for the demonstration of fusion genes, point mutations, and polymorphisms

L

Advantages

Disadvantages

Does not require a priori knowledge of genetic abnormalities Available in most diagnostic centers

Requires fresh, sterile tumor tissue for growth in culture

Can be applied to chromosomal preparations as well as cytologic specimens, touch preparations, and paraffin sections Morphologic correlation is possible Multiple probes can be assayed at the same time Rapid (usually only 2 days) Highest sensitivity and specificity of all molecular diagnostic techniques DNA sequencing of PCR products can confirm results and provide additional information Requires minimal tissue Versatile; can be applied to fresh tissue as well as formalin-fixed, paraffinembedded tissue Morphologic correlation is possible Presence of normal tissue usually does not affect test results Rapid (usually 3-5days)

Low sensitivity; detects only large structural abnormalities No histologic correlation Slow and technically demanding (may take several weeks to perform) Cannot detect small deletions or point mutations Interpretation can be difficult, especially with formalin-fixed, paraffin-embedded material Only a limited number of specific nucleic acid probes are available commercially Formalin-fixation diminishes sensitivity Combinatorial variability within fusion gene partners requires appropriate redundant primer design to avoid false-negative test results Extreme sensitivity requires exacting laboratory technique to avoid falsepositive test results

-

mRNA, messenger RNA; PCR, polymerasechain reaction; RT-PCR, reverse transcriptase polymerase chain reaction. From Davidoff AM, Hill DA: Molecular genetic aspects of solid tumors in childhood. Sernin Pediatr Surg 2001;10:106-118.

various precoated kits and their ease of use have led to widespread application of this approach. The procedure involves the hybridization of complementary strands of labeled DNA or RNA from tumors with known genes or oligonucleotides derived from the genome. The known genes or oligonucleotides are attached to a solid support, the microarray. Hybridization is detected by fluorescence. Once the quality and consistency of sample material can be refined and data management and statistical analyses validated and standardized, gene profiling microarrays will probably be used routinely to analyze pediatric malignancies.

CHILDHOOD CANCER AND HEREDITY Advances in molecular genetic techniques have also improved our understanding of cancer predisposition syndromes. Constitutional gene mutations that are hereditary (i.e., passed from parent to child) or nonhereditary (i.e., de novo mutations in the sperm or oocyte before fertilization) contribute to an estimated 10% to 15% of pediatric cancer~.~Ig Constitutional chromosomal abnormalities are the result of an abnormal number or structural rearrangement of the normal

46 chromosomes and may be associated with a predisposition to cancer. Examples are the predisposition to leukemia seen with trisomy 21 (Down syndrome) and to germ cell tumors with Klinefelter's syndrome (47XXY). Structural chromosomal abnormalities include interstitial deletions resulting in the constitutional loss of one or more " genes. Wilms' tumors may be sporadic, familial, or associated with specific genetic disorders or recognizable syndromes. A better understanding of the molecular basis of Wilms' tumor has been achieved largely through the study of the latter two types of tumors. The WAGR syndrome (Wilms' tumor, aniridia, genitourinary abnormalities, and mental retardation) provides an easily recognizable phenotype for grouping children likely to have a common genetic abnormality. Constitutional deletions from chromosome llp13 are consistent in children with WAGR s y n d r o m ~and ~ ~ also occur in approximately 35% of those with sporadic Wilms' tumor." A study of a large series of patients identified the gene deleted from chromosome llp13 as WT1.Z This gene encodes a nuclear transcription factor that is essential for normal kidnev and gonadal developmentN8 and appears to act as a tumor suppressor,but its precise role is unclear at this time. Aniridia in patients with WAGR syndrome is thought to

CHAPTER

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Principles of Pediatric Oncology, Genetics of Cancer, and Radiation Therapy

occur after the loss of one copy of the PAX6gene located close to WTl on chromosome 11.143 Denys-Drash syndrome, which is characterized by a very high risk of Wilms' tumor, pseudohermaphroditism, and mesangial sclerosis leading to early renal failure, is associated with germline mutations in the DNA binding domain of WT1.li2 The mutated WT1 protein appears to function by a dominant negative effect. Only 6% to 18% of sporadic Wilms' tumors have WTl r n u t a t i o n ~ . ~ 2 2 ~ ~ ~ In another subset of ~atients with Wilms' tumor, there is loss of genetic material'in a region distal to the WTl locus toward the telomeric end of chromosome 11 (1lp15) .30 It has therefore been suggested that there is a second Wilms' tumor susceptibility gene, tentatively named WT2, in llp15. Loss of heterozygosity at this locus has also been described in patients with Beckwith-Wiedemann syndrome, a congenital overgrowth syndrome characterized by numerous growth abnormalities as well as a predisposition to a variety of malignancies, including Wilms' t~mor.~"SeeChapter 27.) Neurofibromatosis type 1 (NFI) is one of the most common genetic disorders. The NFl protein normally inhibits the proto-oncogene RAS, but in patients with NF1, mutation of one copy of the gene combined with deletion of the other permits uncontrolled RAS pathway activation. These patients are then susceptible to myelogenous disorders, benign tumors, gliomas, and malignant peripheral nerve sheath tumors. An inherited predisposition to pediatric cancers is also associated with Li-Fraumeni syndrome (which results from inactivating mutations of the $153gene and puts patients at risk for osteosarcoma. rhabdomvosarcoma, adrenocortical carcinoma, and brain tumors, among other tumors), familial retinoblastoma (which results from inactivating mutations of the RB gene and puts patients at risk for osteosarcoma as well as retinoblastoma), familial adenomatous polyposis, and multiple endocrine neoplasia syndromes. Another set of inherited risk factors is reprksented by mutations of DNA repair genes (so-called caretaker genes), as seen in xeroderma pigmentosa and ataxia-telangiectasia.80 Understanding these complex syndromes and their pathogenesis is important in efforts to screen for early detection and, possibly, for prophylactic therapy.

GENErIC SCREENING Along with an increased understanding of the molecular basis of hereditary childhood cancer has come the opportunity to identify children who are at high risk of malignancy and, in some cases, to intervene before the cancer develops or when it is still curable. Two examples include familial adenomatous polyposis and familial thyroid cancer. Familial adenomatous polyposis is an autosomal dominant inherited disease in which hundreds to thousands of adenomatous intestinal polyps develop during the second and third decades of life. Mutations of the adenomatous polyposis coli (APC) gene on chromosome 5q21 occur in approximately 80% of kindreds of persons who have the disease.i08."7 These mutations initiate

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the adenomatous process by allowing clonal expansion of individual cells that, over time, acquire additional genetic abnormalities that lead to the development of invasive colorectal carcinoma.~Vrophylacticcolectomy is recommended for patients with this germline mutation, although the most appropriate timing for this intervention in children with familial adenomatous polyposis is controversial. These patients are also at increased risk of hepatobla~toma.~~ Medullary thyroid carcinoma (MTC) is a rare malignancy that may occur sporadically or as part of two syndromes: multiple endocrine neoplasia (type 2A or 2B) syndrome or familial MTC syndrome. In children, MTC is much more likely to occur in association with a familial syndrome. An apparently 100% association between germline RET mutationsio4and MTC guides the recommendation for prophylactic thyroidectomy in affected patients. There is no effective adjuvant treatment other than surgery for MTC, highlighting the need for early intervention. Patients with germline M57' mutations should also be screened for pheochromocytoma, which occurs in 50% of patients with multiple endocrine neoplasia type 2A, and hyperparathyroidism, which occurs in 35% of such patients.72 In addition, patients who are at risk for MTC or have newly diagnosed MTC, as well as their relatives, should be screened for the germline RET mutation so that appropriate surgical and genetic counseling can be given.

GENERAL PRINCIPLES OF CHEMOTHERAPY Cytotoxic agents were first noted to be effective in the treatment of cancer in the 1960s, after alkylating agents such as nitrogen mustard gas, used during World War 11, were observed to cause bone marrow hypoplasia. Chemotherapy is now an integral part of nearly all cancer treatment regimens. The overriding goal of cancer chemotherapy is to maximize tumoricidal effect (efficacy) while minimizing adverse side effects (toxicity). This goal can be difficult to achieve, however, because the dose at which tumor cells are affected is often similar to the dose that affects normal proliferating cells, such as those in the bone marrow and gastrointestinal tract. Despite the early promise of chemotherapy and the observation that most tumor types are initially sensitive to chemotherapy, often exquisitely so, the successful use of chemotherapy is often thwarted by two factors: the development of resistance to the agent and the agent's toxicity to normal tissues. Nevertheless, chemotherapy remains an integral part of therapy when used as an adjunct to treat localized disease or as the main component to treat disseminated or advanced disease. A number of principles and terms are essential to the understanding of chemotherapy as a therapeutic anticancer modality. Adjuuant chemotherapy refers to the use of chemotherapy for systemic treatment following local control of a clinically localized primary tumor, generally by surgical resection or radiation therapy. The goal in this setting is to eliminate disease that is not detectable by standard investigative means at or beyond the primary tumor's site. Neoadjuuant chemotherapy refers

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to chemotherapy delivered before local therapeutic modalities, generally in an effort to improve their efficacy; to treat micrometastatic disease as early as possible, when distant tumors are smallest; or to achieve both of these aims. Induction chemotherapy refers to the use of chemotherapeutic agents as the primary treatment for advanced disease. In general, chemotherapy given to children with solid tumors and metastatic disease at the time of first examination has a less than 40% chance of effecting long-term, disease-free survival. Exceptions include Wilms' tumor with favorable histologic features, germ cell tumors, and paratesticular rhabdomyosarcoma, but most children with metastatic disease are at high risk of disease recurrence or progression. Combination chemotherapy refers to the use of multiple agents, which generally have different mechanisms of action and nonoverlapping toxicities, that provide effective, synergistic antitumor activity and minimal side effects. The efficacy of combination chemotherapy is explained by ~~ states that a the Goldie-Coldman h y p o t h e ~ i s ,which tumor's response to an individual drug reflects the individual tumor cells' sensitivity to that drug. The chance of a tumor developing a resistance phenotype depends on the rate of mutation and the number of tumor cells or tumor size. Once a single tumor cell becomes resistant to a given agent, the tumor can no longer be cured by that agent. Combining agents with different mechanisms of action decreases the likelihood that a tumor cell will develop resistance to any or all agents and is therefore more likely to effect a cure. Pharmacokinetics describes the relationship between time and the plasma concentration of a drug, and drug exposure is quantified by calculating the area under the curve of the graph of drug concentration against time. The pharmacokinetics of a drug is influenced by its absorption, distribution, metabolism, clearance, half-life, and excretion and by the presence of active metabolites. The interpretation of pharmacokinetic data requires an understanding of the relation between plasma concentration of the drug and its anticancer effect. The dose-response curve for a given agent is usually sigmoidal, with a threshold level, lag phase, linear response, and plateau. The slope of the linear phase is often quite steep, and this steepness implies a significant loss of efficacy with a slight dose reduction. Therefore, the delivery of a maximum tolerated dose, to ensure that the dose range of the linear phase has been exceeded, has become a basic principle of chemotherapy. Dose intensity can be maximized by increasing the total dose of an agent or by shortening the interval between doses. Inappropriate dose reduction may lead to residual tumor cells not being eliminated. The therapeutic index is the ratio of beneficial to harmful effects. An emerging theory regarding optimal chemotherapeutic dosages that is somewhat counter to the longstanding and widely used approach of maximum tolerated dose is metronomic dosing. This new approach, which entails the continuous delivery of a low dose of chemotherapeutic agents, may be effective for two reasons. First, because most agents are cell-cycle specific (i.e., they kill only cells that are at specific points in the cell cycle), only a fraction of tumor cells is susceptible

at any given time. Therefore, a longer duration of exposure to an agent may result in more tumor cells being susceptible. Second, metronomic dosing may allow the agent to target the endothelial cells that constitute the expanding tumor vasculature, as well as the tumor cells themselves. The traditional scheduling of cytotoxic therapy-the administration of a maximum tolerated dose, followed by a rest period to allow the recovery of affected normal tissue (notably the bone marrow and gastrointestinal tract)-may also permit the recovery and proliferation of the more slowly dividing endothelial cells in a tumor bed and thereby permit tumor regrowth.20 A metronomic schedule in which cytotoxic drugs are administered continuously or at least more frequently, without a treatment-free interval. and at a lower total dose may therefore be more effective at controlling tumor progression, even if the tumor cells themselves are resistant to the drug.20 This approach appears to be true for cytotoxic drugs and antiangiogenic agents. The rational design of chemotherapy treatment programs and clinical trials involves an understanding of the mechanisms of action of these agents, their metabolism, and their toxicity profiles. Most agents used to treat tumors in children affect the synthesis or function of nucleic acids (DNA or RNA) in malignant and normal cells. Therefore, these agents can kill tumor cells but can also affect normal tissue. The mechanisms of action and side effects of commonly used agents are listed in Table 25-5. Alkylating agents interfere with cell growth by covalently cross-linking DNA and are not cell-cycle specific. Antitumor antibiotics intercalate into the double helix of DNA and break the DNA strands. Antimetabolites are truly cell-cycle specific because they interfere with the use of normal substrates for DNA and RNA synthesis, such as purines and thymidine. The plant alkaloids can inhibit microtubule function (vinca alkaloids, taxanes) or DNA topoisomerases (camptothecins inhibit topoisomerase I; epipodophyllotoxins inhibit topoisomerase 11), and these actions also lead to breaks in DNA strands. Topoisomerases are a class of enzymes that alter the supercoiling of double-stranded DNA. They act by transiently cutting one (topoisomerase I) or both (topoisomerase 11) strands of the DNA to relax the DNA coil and extend the molecule. The regulation of DNA supercoiling is essential to DNA transcription and replication, when the DNA helix must unwind to permit the proper function of the enzymatic machinery involved in these processes. Thus, topoisomerases maintain the transcription and replication of DNA. The common toxic effects of these agents are also listed in Table 25-5. Most toxicity associated with chemotherapy is reversible and resolves with cessation of treatment. Other side effects may be reversed by giving specific antidotes such as leucovorin for toxicity associated with methotrexate. Leucovorin acts in the same way in the body as folic acid does, but it does not negate the therapeutic efficacy of methotrexate. However, some chemotherapeutic agents may have lifelong effects. Of particular concern is that certain drugs can lead to a second malignancy. Most notable is the development of leukemia after the administration of the epipodophyllotoxins and ~yclophosphamide.~45

1 Class of Drug

Agent

Synonyms

Brand Name Mechanism of Action

Common Toxic Effects

Alkylating agents

Carboplatin

CBCDCA

Paraplatin

Cisplatin

CDDC

Platinol

A, H, M (esp. thrombocytopenia), N/V A, N/V, R (significant), ototoxicity, neuropathy

Cyclophosphamide

CTX

Cytoxan

lfosfamide

l FOS

lfex

DTlC

Dacarbazine Temozolomide Nitrogen mustard

Melphalan

Antimetabolites

Temodar Mustargen

L-PAM

Alkeran

Busulfan

Busulfex

Cytarabine

Cytosar

Fluorouracil

Several

Mercaptopurine

Antibiotics

TMZ Mechlorethamine

6-MP

Purinethol

Methotrexate

MTX

Trexall

Dactinomycin

Actinomycin D Cosmegen

Bleomycin

BLEO

Anthracyclines Daunomycin

Daunorubicin Cerubidine

Blenoxane

Platination, intra- and interstrand DNA cross-linking Platination, intra- and interstrand DNA cross-linking Alkylation, intra- and interstrand DNA cross-linking Alkylation, intra- and interstrand DNA cross-linking Methylation Methylation

Site of Activation

Method of Elimination

Susceptible Solid Tumors

Renal

BT, GCT, NBL, STS

Renal

BT, GCT, NBL, OS

A, N/V, SIADH, M, R, cardiac, cystitis

Liver

Hepatic, renal (minor)

Broad, BMT

A, CNS, N/V, M, R, cardiac, cystitis

Liver

Hepatic, renal (minor)

Broad

H, N/V, M, hepatic vein thrombosis CNS, N/V, M

Liver

Renal

NBL, STS

Spontaneous

Renal

BT

Spontaneous hydrolysis

BT

Spontaneous hydrolysis

NBL, RMS, BMT

Renal

BMT

Target cell

Biotransformation

Limited

Target cell

Biotransformation, Gastrointestinal renal (minor) carcinomas, liver tumors Biotransformation, Limited renal (minor)

Alkylation, intra- and interstrand DNA, cross-linking Alkylation, intra- and interstrand DNA cross-linking Alkylation, intra- and interstrand DNA cross-linking

A, M (significant), N/V, mucositis, vesication, phlebitis, diarrhea M, N/V, mucositis, diarrhea

Inhibits DNA polymerase, incorporated into DNA Inhibits thymidine synthesis, incorporated into DNA/RNA lnhibits thymidine synthesis, incorporated into DNA/RNA Blocks folate metabolism, inhibits purine synthesis

M, N/V, diarrhea, CNS CNS, N/V, M, cardiac, diarrhea, mucositis, skin, ocular H, M, mucositis

A, H, M, N/V, P mucositis

Target cell

CNS, H, M, R, mucositis, skin

Renal, hepatic (minor)

OS

DNA intercalation, strand breaks DNA intercalation, strand breaks

A, H, M, N/V, mucositis, vesication I? skin, mucositis

Hepatic

RMS, W

Hepatic, renal

GCT

DNA intercalation, strand breaks, free radical formation

A, M, N/V, cardiac, diarrhea, vesication, potentiates XRT reaction

Hepatic

Limited

1

Continued

1

Class of Drug

Plant alkaloids

Susceptible Solid Tumors

Hepatic

Broad

Topoisomerase II inhibitor, A, M, N/V, mucositis, DNA strand breaks neuropathy, diarrhea Topoisomerase II inhibitor, A, M, N/V, mucositis, DNA strand breaks neuropathy, diarrhea

Renal

Broad

Degraded

Broad

Inhibits tubulin polymerization, blocks mitosis Inhibits tubulin polymerization, blocks mitosis

A, SIADH, neuropathy, vesicant

Hepatic

Broad

A, M, mucositis, vesication

Hepatic

GCT

Renal

NBL, RMS

Hepatic, renal (minor)

NBL, RMS

Degraded

Limited

Hepatic, renal (minor)

BT

Synonyms

Brand Name Mechanism of Action

Common Toxic Effects

Adriamycin

Doxorubicin

Adriamycin

DNA intercalation, strand breaks, free radical formation

A, M, N/V, cardiac, diarrhea, mucositis, vesication, potentiates XRT reaction

Epipodophyllotoxins Etoposide

VP-16

VePesid

VM-26

Vumon

Vinca alkaloids Vincristine

VCR

Oncovin

Vinblastine

VLB

Velban

Teniposid

Taxanes Paclitaxel

Taxol

Interferes with microtubule formation

A, M, cardiac, mucositis, CNS, neuropathy

Taxotere

Interferes with microtubule formation

A, neutropenia, cardiac, mucositis, CNS, neuropathy

TPT

Hycamtin

lrinotecan

CPT-11

Camptosar

Topoisomerase I inhibitor, A, H, M, N/V, mucositis, diarrhea, skin DNA strand breaks Topoisomerase I inhibitor, A, H, M, N/V, diarrhea DNA strand breaks

L-Asparaginase

Erwinia

Elspar

Docetaxel

Camptothecins Topotecan

Miscellaneous

Method of Elimination

Agent

Corticosteroids

L-Asparagine depletion, inhibits protein synthesis Nuclear receptormediated apoptosis

Site of Activation

Liver, gastrointestinal tract

CNS, H, coagulopathy, pancreatitis, anaphylaxis Avascular necrosis, hyperglycemia, hypertension, myopathy, pancreatitis, peptic ulcers, psychosis, salt imbalance, weight gain

Liver

Toxic effects: A, alopecia; CNS, central nervous system toxicity; H, hepatotoxicity;M, myelosuppression;N/V, nausea and vomiting; P, pulmonary toxicity; R, renal toxicity; SIADH, syndrome of inappropriate antidiuretic hormone; XRT, radiotherapy.Solid tumors: BMT, conditioningforbone marrow transplantation; BT, brain tumor; EWS, Ewing'ssarcoma; GCT, germ cell tumors; NBL, neuroblastoma; OS, osteosarcoma; RMS, rhabdomyosarcoma;STS, soft tissue sarcoma; W, Wilms' tumor.

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Principles of Pediatric Oncology, Genetics of Cancer, and Radiation Therapy

Finally, understanding the metabolism of chemotherapeutic agents is important. Certain agents require metabolism at a specific site or organ for their activation or are eliminated from the body by a specific organ (see Table 25-5). The processes of activation and elimination require normal organ function (e.g., the liver for cyclophosphamide); therefore, children with liver or kidney failure may not be able to receive certain agents.

Risk Stratification Major advances in the variety of chemotherapeutic agents and dosing strategies used to treat pediatric cancers in the past 30 years are reflected in improved patient survival rates. Regimen toxicity (including late effects, which are particularly important in the pediatric population) and therapeutic resistance are the two main hurdles preventing further advancement. As more information about diagnostically and prognostically useful genetic markers becomes available, therapeutic strategies will change accordingly. With molecular profiling, patients can be categorized to receive a particular treatment on the basis of not only the tumor's histopathologic and staging characteristics but also its genetic composition. Some patients whose tumors show a more aggressive biologic profile may require dose intensification to increase their chances of survival. Patients whose tumors do not have an aggressive biologic profile may benefit from the lower toxicity of less intensive therapy. Such an approach may allow the maintenance of high survival rates while minimizing long-term complications of therapy in these patient populations. The paradigm for the use of different therapeutic intensities on the basis of risk stratification drives the management of pediatric neuroblastoma. There is increasing evidence that the molecular features of neuroblastoma are highly predictive of its clinical behavior. Most current studies of the treatment of neuroblastoma are based on risk groups that take into account both clinical and biologic variables. The most important clinical variables appear to be age and stage at diagnosis, and the most powerful biologic factors appear to be MYCN status, ploidy (for patients younger than 1 year), and histopathologic classification. These variables currently define the Children's Oncology Group risk strata and therapeutic approach. At one extreme, patients with low-risk disease are treated with surgery alone; at the other extreme, patients at high risk for relapse are treated with intensive multimodality therapy that includes multiagent, doseintensive chemotherapy; radiation therapy; and stem cell transplantation. Other factors such as 17q gain, l p deletion, caspase 8 inactivation, and TrkA/B expression are currently being evaluated and may help further refine risk assessment in the future. The management of other solid pediatric tumors is also shifting to riskdefined treatment. For example, the next protocol for the management of patients with Wilms' tumor is likely to include risk stratification and therapy adjustment based on molecular analysis of the primary tumor for 16q and l p deletions.

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Targeted Therapy Another major change in the approach to the treatment of cancer has been the concept of targeted therapy. Until recently, the development of anticancer agents was based on the empirical screening of a large variety of cytotoxic compounds without particular regard to disease specificity or mechanism of action. Now, one of the most exciting prospects for improving the therapeutic index of anticancer agents, as well as overcoming the problem of therapy resistance, involves targeted therapy. As the molecular bases for the phenotypes of specific malignancies are being elucidated, potential new targets for therapy are becoming more clearly defined. The characterization of pathways that define malignant transformation and progression has focused new agent development on key pathways involved in the crucial processes of cell-cycle regulation, receptor signaling, differentiation, apoptosis, invasion, migration, and angiogenesis, which may be perturbed in malignant tissues. Information about the molecular profile of a given tumor type can be assembled from a variety of emerging methods, including immunohistochemistry, FISH, RT-PCR, cDNA microarray analysis, and proteomics. This information can then be used to develop new drugs designed to counter the molecular abnormalities of the neoplastic cells. For example, blocking oncogene function or restoring suppressor gene activity may provide tumor-specific therapy. In addition, molecular profiling may lead to the development of drugs designed to induce differentiation of tumor cells, block dysregulated growth pathways, or reactivate silenced apoptotic pathways. Some agents target alterations in the regulation of cell proliferation. Herceptin (trastuzumab) is a monoclonal antibody that binds to the cell surface growth factor receptor ERBBP with high affinity and acts as an antiproliferative agent when used to treat ERBB2overexpressing cancer cells." It is currently being tested against ERBB2-positive tumors such as osteosarcoma and Wilms' tumor. Pediatric high-grade gliomas that overexpress EGFR may be amenable to a similar therapeutic agent, gefitinib (Iressa), a small-molecule inhibitor of EGFR (ERBBI). I 4 In addition, small-molecule tyrosine kinase inhibitors, such as imatinib (Gleevec), designed to block aberrantly expressed growth-promoting tyrosine kinases-ABL in chronic myelogenous leukemial4' and c-KIT in gastrointestinal stromal tumorsyl-are being evaluated in clinical trials. Imatinib may also be useful in treating pediatric tumors in which PDGF signaling plays a role in tumor cell survival and growth. Other kinase inhibitors, such as flavopiridol, target cyclin-dependent kinases that modulate the cell cycle,77whereas rapamycin (sirolimus) inhibits the mammalian target of rapamycin (mTOR), a protein whose activation1y9normally leads to increased translation of proteins necessary for cell proliferation. Inhibitors of farnesyl transferase (the enzyme responsible for the activation of RAS), such as R115777, are also being tested in clinical trials. Although activating mutations are very common in adult malignancies, they are rare in pediatric tumors. However, the RAS pathway is occasionally activated by upstream growth factors or

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oncogenic proteins in such pediatric diseases as juvenile myelomonocytic leukemia, certain brain tumors, and NF1, so agents such as R115777 are being tested against these conditions as well. Also of potential therapeutic utility are small-molecule inhibitors that recognize antigenic determinants on unique fusion peptides or one of the fusion peptide partners in tumors that have chromosomal translocations (e.g., sarcomas). Tumors that depend on autocrine pathways for growth (e.g., overproduction of IGF-I1 in rhabdomyosarcoma or PDGF in dermatofibrosarcoma protuberins) may be sensitive to receptor blocking mediators (e.g., antibodies to the IGF-I1 or PDGF receptor). Other agents target alteration of the cell death and differentiation pathways. Caspase 8 is a cysteine protease that regulates programmed cell death, but in tumors such as neuroblastoma, DNA methylation and gene deletion combine to mediate the complete inactivation of caspase 8, almost always in association with MYCN amp1ifi~ation.l~~ Methylation of cytosine residues in genomic DNA is quite common and usually occurs at cytosine residues adjacent to guanosine. DNA methylation is important in the transcriptional repression or silencing of certain genes, particularly developmentally regulated genes. Caspase 8-deficient tumor cells are resistant to apoptosis mediated by death receptors and doxorubicin; this resistance suggests that caspase 8 may be acting as a tumor suppressor. However, brief exposure of caspase &deficient cells to demethylating agents, such as decitabine, or to low levels of interferon-y can lead to the re-expression of caspase 8 and the resensitization of the cells ;o chemotherapeutic drug-induced a p o p tosis. Histone deacetylase also seems to have a role in gene silencing associated with resistance to apoptosis69; therefore, histone deacetylase inhibitors such as depsipeptide are also b e i n g tested for the treatment of certain pediatric malignancies. Finally, cells with alterations in programmed cell death as a result of the persistence or reactivation of telomerase activity, which somatic cells normally lose after birth, can be targeted by various telomerase inhibitors. An example of targeting cell differentiation comes from neuroblastoma. in which different neurotrowhin receptor pathways appear to mediate the signal for both cellular differentiation and malignant transformation of sympathetic neuroblasts to neuroblastoma cells. ~ e u r o t r o ~ h i are n s expressed in a wide variety of neuronal tissues and other tissues that require innervation. They stimulate the survival, maturation, and differentiation of neurons and exhibit a developmentally regulated ~~ and their Trk pattern of e x p r e s ~ i o n . "Neurotrophins tyrosine kinase receptors are particularly important in the development of the sympathetic nervous system and have been implicated in the pathogenesis of neuroblastoma. Three receptor-ligand pairs have been identified: TrkA, TrkB, and TrkC, which are the primary receptors for nerve growth factor, brain-derived neurotrophic factor (BDNF), and neurotrophin 3 (NT-3), re~pectively.~ TrkA appears to mediate the differentiation of developing neurons or neuroblastoma in the presence of nerve growth factor ligand and to mediate apoptosis in the absence of nerve growth factor.90Conversely, the

TrkB-BDNF pathway appears to promote neuroblastoma cell survival through autocrine or paracrine signaling, especially in MYChramplified tumors.lOTrkCis expressed in-apprdximately 25%-of neuroblastomas and is sL-0ng-1~ associated with TrkA e x p r e ~ s i o n .Studies '~~ are ongoing to test agonists of TrkA in an attempt to induce cellular differentiation. Conversely, blocking the TrkB-BDNF signaling pathway with ~rk-specifictyrosine kinase inhibitors such as CEP-751 may induce apoptosis by blocking crucial survival pathways.40,'" This targeted approach has the attractive wotential for increased swecificitv and lower toxicity than conventional cytotoxic chemotherapy.

INHIBITION OF ANGIOGENESIS Because tumor growth and spread appear to be dependent on angiogenesis, inhibition of angiogenesis is a logical anticancer strategy. This approach is particularly appealing for several reasons. First, despite the extreme molecular and phenotypic heterogeneity of human cancer, it is likely that most, if not all, tumor types, including hematologic malignancies, require neovascularization to achieve their full malignant phenotype. Therefore, antiangiogenic therapy may have broad applicability for the treatment of cancer. Second, the endothelial cells in a tumor's new blood vessels, although rapidly proliferating, are inherently normal and mutate slowly. They are therefore unlikely to evolve a phenotype that is insensitive to an angiogenesis inhibitor, unlike the rapidly proliferating tumor cells, which undergo spontaneous mutation at a high rate and can readily generate drugresistant clones. Finally, because the new blood vessels induced by a tumor are sufficiently distinct from established vessels to permit highly specific targeting73J$l angiogenesis inhibitors should have a high therapeutic index and minimal toxicity. The combination of conventional chemotherapeutic agents with angiogenesis inhibitors appears to be particularly effective. The first clinical demonstration that an angiogenesis inhibitor could cause regression of a tumor came with the use of interferon-a in a patient treated for lifeAn increasing threatening pulmonary hernangi~ma.~") number of natural and synthetic inhibitors of angiogenesis, which inhibit different effectors of angiogenesis, have since been identified, and many of these agents have been tested in clinical trials. Minimal toxicity has been observed for these agents. Examples include drugs that directly inhibit endothelial cells, such as thalidomide and combretastatin; drugs that block activators of angiogenesis, such as bevacizumab (Avastin), a recombinant humanized anti-VEGF antibody, or "VEGF trap"; drugs that inhibit endothelium-specific survival signaling, such asvitaxin, an anti-integrin antibody; and drugs with nonspecific mechanisms of action, such as celecoxib and interleukin-12 (IL-12). The National Cancer Institute has set up a Web site that lists all the ongoing clinical trials of angiogenesis inhibitors (http://www.cancer.gov/clinicaltrials/developments/anti-angio-table) . Because antiangiogenic therapy may be only tumoristatic, tumor progression may resume when the growth restrictions of angiogenesis inhibition are discontinued.

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25

Principles of Pediatric Oncology, Genetics of Cancer, and Radiation Therapy

Therefore, chronic delivery of antiangiogenic agents may be required. Gene therapy, with its potential for sustained expression, may provide a more practical method than chronic protein administration for the long-term delivery of angiogenesis inhibitors.43

IMMUNOTHERAPY The immune system has evolved as a powerful means to detect and eliminate molecules or pathogens that are recognized as "foreign." However, because tumors arise from host cells, they are generally relatively weakly immunogenic. In addition, malignant cells have evolved several mechanisms that allow them to elude the immune system. These mechanisms include the ability to down-regulate the cell surface major histocompatibility complex molecules required for activation of many of the immune effector cells, to produce immunosuppressive factors, and to variably express different proteins that might otherwise serve as targets for the immune system in a process known as antigenic drift. Nevertheless, because of the large number of mutations and chromosomal aberrations occurring in cancer cells, which results in the expression of abnormal, new, or otherwise silenced proteins, it is likely that most if not all cancers contain unique, tumor-associated antigens that can be recognized by the immune system. Examples include the fusion proteins commonly found in pediatric sarcomas and the embryonic neuroectodermal antigens that continue to be produced by neuroblastomas. Recruiting the immune system to help eradicate tumor cells is an attractive approach for several reasons. First, circulating cells of the immune system have ready access to even occult sites of tumor cells. Second, the immune system has powerful effector cells capable of effectively and efficiently destroying and eradicating targets, including neoplastic cells. Initial efforts to recruit the immune system to recognize and destroy tumor cells by using cytotoxic effector mechanisms that are T-cell dependent or independent focused on recombinant cytokines. Cytokines act by directly stimulating the immune system66 or by rendering the target tumor cells more immunogenic. More recently, however, since the discovery that gene transfer can be used to markedly increase the immunogenicity of a tumor, tumor cellbased vaccine approaches have been used. For example, tumor cells transfected with genes that encode cytokines show a substantial increase in their immunogenicity, which allows them to act as an antitumor vaccine when injected into a Transduced tumor cells appear to be much more immunogenic than low doses of cytokines injected directly into lesions. Because the cytokines are produced locally by the transduced tumor cells, there are none of the adverse effects associated with the administration of cytokines at the high systemic doses needed to induce antitumor responses. This gene transfer approach also permits tumor cell targeting without the identification of specific tumor-associated antigens. Because of the concern that tumor cells may not present antigens appropriately to host immune effector cells, alternative vaccine strategies have been used in which

427

tumor lysates or antigenic peptides are delivered to autologous dendritic cells-the immune system's antigenpresenting cells. This approach can expand specific T-cell populations and mediate tumor regression.54 An extension of this approach using gene-modified, cytokine-expressing dendritic cells is being evaluated in preclinical studies.136Other preclinical studies have shown that the tumor antigen-specific immune response can be further enhanced by the administration of immunostimulatory CpG oligodeoxynucleotides after vaccination with cytokine-expressing tumor ~ e 1 l s . l ~ ~ Neuroblastoma has been the most popular target for immunotherapy in the pediatric population. Clinical trials of the treatment of neuroblastoma by transferring cytokine genes into autologous or allogeneic tumor cells have shown that gene-modified, cytokine-expressing tumor cell vaccines have little toxicity and can induce J2~ an antitumor immune r e ~ p o n s e . ~ ~ J 2Neuroblastoma cells are sensitive to antibody-dependent cell-mediated cytotoxicity, as well as to complement-dependent cytotoxicity.25 Although a particular neuroblastoma antigen has not been defined, murine monoclonal antibodies have been raised against the ganglioside GD2, a predominant antigen on the surface of neuroblastoma cells. These antibodies elicited therapeutic responses,26-65but with substantial toxicity, particularly neuropathic pain."' Because the induction of antibody-dependent cellmediated cvtotoxicitv with anti-GD2 antibodies is enhanced by cytokines such as granulocyte-macrophage colonystimulating factorlll and interleukin-2 (IL-2),67 current antineuroblastoma antibody trials are evaluating the use of a humanized, chimeric anti-GD2 antibody (ch14.18) with these cytokines and a fusion protein (hu14.18:IL2) that consists of the humanized 14.18 antibody linked genetically to human recombinant IL-2.

GENERAL PRINCIPLES OF RADIATION THERAPY Radiation therapy is one of the three primary modalities used to manage pediatric cancers in the modern era. Its use, alone or combined with surgery and systemic chemotherapy, forms the basis of management of many forms of childhood malignancy. Radiation therapy is delivered to an estimated 2000 or more children per year for the primary treatment of tumor types as diverse as leukemia, brain tumors, sarcomas, Hodgkin's disease, neuroblastoma, and Wilms' tumor." Delivery of radiation therapy in the pediatric setting differs from that in the adult setting because of the balance between curative therapy and an anticipated long life span during which long-term morbidity may result from the therapy.

Clinical Considerations Radiation therapy for the management of pediatric cancer is most frequently combined with surgery and chemotherapy as part of a multidisciplinary treatment plan. Although radiation therapy is used as a single modality in adult oncology, the sensitive nature of

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pediatric tumors requires the use of a combined therapy approach to maximize tumor control while minimizing the long-term side effects of treatment. Radiation may be delivered preoperatively, postoperatively (relative to a definitive surgical resection), or definitively without surgical management. Systemic therapy may also be integrated into this management approach.

Definitive Irradiation Definitive radiation therapy is an alternative to surgical resection of primary solid tumors. It is often the only local therapeutic approach for children and adolescents with leukemia or lymphoma.flz52 Although it is considered the only treatment option for unresectable tumors, definitive radiation therapy may be used as an alternative to surgical resection to allow the preservation of an organ or function while maintaining excellent local tumor control. Definitive radiation therapy for rhabdomyosarcoma has been used as an alternative to surgical resection, which has potentially greater morbidity; it has achieved high rates of local tumor control while allowing preservation of function." The Ewing's sarcoma family of tumors may also be considered candidates for definitive radiation therapy as an alternative to surgery. With careful patient selection, excellent local tumor control rates can be maintained while reducing or avoiding the morbidity associated with difficult surgical rese~tions.~~~125

Preoperative lrradiation Preoperative radiation therapy may be used in several situations. Targeting of a localized tumor is straightforward in the preoperative setting, when the tumor has clearly defined margins undisturbed by a surgical procedure. The volume of normal, healthy tissues receiving high doses of radiation may be reduced, because the areas at risk for disease involvement can be better defined. Preoperative radiation therapy has been used in the management of Wilms' tumor to decrease the chance of tumor rupture7j and in the management of nonrhabdomyosarcoma soft tissue sarcoma and Ewing's sarcoma to facilitate surgical resection.34.110 One of the limitations of preoperative radiation, however, particularly in patients with sarcoma, may be the slightly higher incidence of postoperative wound complications.~*~

Postoperative Irradiation Postoperative radiation therapy combined with surgical resection is the most common application of adjuvant radiation treatment in the United States. Despite some degree of difficulty in targeting, a postoperative approach allows a review of the histologic studies of the complete tumor specimen, including identification of the tumor margins and the response to any previous therapy. Wound healing complications appear to be reduced with this approach, and the radiation dose can be more accurately tailored to the pathologic findings after primary resection.

Interactions of Chemotherapy and Radiation Most children's cancers are managed with systemic chemotherapy. In children receiving radiation therapy as well as systemic chemotherapy, issues of enhanced local efficacy and enhanced local or regional toxicity need to be considered. Solid tumors that are frequently treated with combined chemotherapy and radiation therapy include Wilms' tumor, neuroblastoma, and sarcomas. These tumors are subdivided into those in which chemotherapy is given concomitantly with radiation therapfsx6I and those in which it is given sequentially, before or after radiation therapy.",i5,gWhen delivering radiation therapy concurrently with or temporally close to a course of chemotherapy, several issues must be considered.

Chemotherapeutic Enhancement of Local Irradiation Several systemic chemotherapeutic agents used against pediatric tumors may enhance the efficacy of radiation therapy when delivered concomitantly. Cisplatin, 5-fluorouracil, mitomycin C, and gemcitabine, for example, Concomitant are well-known radiation sen~itizers.2~~"~2~ delivery of any of these drugs with radiation therapy may require that they be administered at a dose and schedule different from those typically used when the drugs are delivered alone. Despite the potential of increased toxicity, significant improvements in local tumor control have been shown in randomized studies of concomitant drug and radiation therapy.2~4"

lrradiation Combined with Agents Having Limited or No Sensitizing Effect In the management of pediatric malignancies, radiation is often combined with systemic therapy not to increase its local efficacy but to allow continued delivery of systemic therapy to control micrometastatic or metastatic disease. Agents combined with radiation therapy in this setting are common in the management of pediatric sarcomas and include ifosfamide and etoposide, which are delivered concurrently with radiation therapy for Ewing's sarcoma, and vincristine and cyclophosphamide, which are delivered concurrently with radiation therapy Although local toxicity may for rhabdomyosarcoma.38~~1 be increased by such an approach, this risk is often outweighed by the benefit of continuously delivered systemic therapy, particularly in tumors associated with a high incidence of micrometastatic disease.

Agents That Increase Radiation Toxicity Several agents significantly increase the local toxicity of radiation. For this reason, these agents are not given concomitantly with irradiation and are often withheld for a period after the completion of radiation therapy. The two most notable agents are doxorubicin and actinomycin, both of which can induce significant skin and

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Principles of Pediatric Oncology, Genetics of Cancer, and Radiation Therapy

mucosal toxicity when delivered concurrently with radiation therapy.z4,29The camptothecins (including irinotecan and topotecan) also potentiate mucosal toxicity when delivered concurrently with radiation therapy.58J00 Although this increase in toxicity suggests a possible increase in local efficacy, this benefit has not been noted with current treatment approaches and chemotherapeutic dosing guidelines. For this reason, these agents are avoided during the delivery of radiation therapy and are withheld for 2 to 6 weeks after the completion of treatment. The current era of systemic therapy continues to broaden with the availability of many new agents that target molecular pathways. It is important to consider the possibility of new toxicities when combining novel agents with a known therapy such as radiation.

429

radiation beams from the conventional directions: anterior, posterior, and lateral. Limitations of this approach are related to the ability of conventional radiographs to accurately convey the location of tumor-bearing tissue. Although treatment beams are oriented around the tumor, adjacent normal tissues also receive high doses of radiation. Depending on the accuracy of the delineation of adjacent normal tissues on radiographs, the dose to those tissues may not be known. Radiation is delivered via a photon beam generated by a linear accelerator.

Image-Guided Radiation Therapy

Image-guided radiation therapy comprises a group of techniques that deliver radiation to a defined volume usually delineated by computed tomography (CT) or magnetic resonance imaging (MRI). Relatively low doses may be incidentally delivered to surrounding normal Delivery of Fractionated Radiation Therapy tissues. Radiation therapy may be described as image guided when four criteria are met: (1) three-dimensional Conventional, external beam irradiation is delivered in imaging data (CT or MRI) are acquired with the patient a fractionated form. Fractionation implies daily doses of in the treatment position; (2) imaging data are used to radiation delivered 5 days per week and amounting to the delineate and reconstruct the tumor volume and normal prescribed dose for a particular tumor type. Radiation tissues in three dimensions; (3) radiation beams can be delivered once daily at a fraction size between 1.5 and freely oriented in three dimensions in the planning 2.0 Gy on 5 days per week is considered "conventionally" and delivery processes, and structures traversed by the fractionated. This daily dose is well tolerated by normal beam can be visualized with the eye of the beam; and tissues adjacent to the tumor and appears to effect local tumor control in many tumor systems. (4) the distribution of doses received by the tumor volume and any normal tissue is computable on a pointThere has been interest in the hyperfractionation by-point basis in three-dimensional space. Several of radiation therapy to treat pediatric malignancies, different methods of delivering image-guided photon most notably brain tumors and solid tumors, to try to are currently in use and are discussed here. ,~~ overcome the biologic resistance of m a l i g n a n c i e ~ . ~ ~radiation Although the efficacy of altered fractionation is unproved in the management of children's cancers, there are sevConformal Radiation Therapy eral reasons to consider alternative treatment schedules The delivery of three-dimensional conformal radiation with a documented efficacy equivalent to that of conventherapy allows specific targeting of tumor volumes on tional fractionation. Hyperfractionation, with a dose of the basis of imaging studies performed with the patient less than 1.5 Gy per fraction, may allow the delivery in the treatment position. This method of delivery uses of standard total doses of radiation but with fewer late multiple fields or portals, with each beam aperture effects. Accelerated hyperfractionated radiation therapy, shaped to the tumor volume, and is performed daily. in which the overall treatment time is compressed, may Beam modifiers such as wedges are used to conform the have the benefit of allowing a short course of radiation radiation beam to the tumor and to ensure that the therapy between other therapies, including systemic thertumor volume receives a homogeneous dose. Conformal apy or bone marrow transplantation. This approach has radiation therapy has been intensively studied in adults and is curbeen used in children with neurobla~toma8~ with head and neck cancer, lung cancer, and prostate rently being investigated in the management of Hodgkin's cancer and has been shown to excel when the target disease in patients undergoing bone marrow transplantavolume is convex and crucial structures do not invagition. Alterations of treatment fractionation continue to nate the target volume. Available data demonstrate that be studied in the pediatric setting, but their potential it has low toxicity despite high doses of radiation to the benefit must be weighed against the difficulties of delivtarget volume.10g ering multiple treatments per day, particularly to young children who require general anesthesia for treatment.

Intensity-Modulated Radiation Therapy

Radiation Therapy Treatment Techniques Traditional Radiation Therapy The planning and delivery of traditional, or conventional, radiation therapy are based on nonvolumetric imaging studies (i.e., conventional radiographs). Patients are positioned in a manner that allows the orientation of

Intensity-modulated radiation therapy is another method of delivering external beam radiation that requires imaging of the patient in the treatment position and delineation of target " volumes and normal tissues. Radiation is delivered to the target as multiple small fields that do not encompass the entire target volume but collectively deliver the prescribed daily dose. Intensitymodulated radiation therapy differs from conformal

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radiation therapy in that it (1) increases the complexity and time required for the planning and delivery of treatment; (2) increases the amount of quality-assurance work required before treatment is delivered; (3) increases dose heterogeneity within the target volume, such that some intralesional areas receive a relatively high dose; and (4) can be used to treat concave targets while sparing crucial structures that invaginate the target volume. The last point holds promise for better protecting normal tissue and reducing late toxic effects. Preliminary data from adult patients given intensity-modulated radiation therapy demonstrate its potential for reducing treatment toxicity when applied to pediatric brain tumors and other adult tumors.7"

Brachytherapy Brachytherapy is a method of delivering radiation to a tumor or tumor bed by placing radioactive sources within or adjacent to the target volume, usually at the time of surgical resection and under direct vision. Planning of the dose to be delivered to the target volume is accomplished after resection and may use CT or MRI studies; the appropriate strength of the radioactive source is determined prospectively. Sources commonly used in children include iridium 192 and iodine 125. Brachytherapy may consist of either low dose-rate treatments (approximately 40 to 80 cGy per hour) or high dose-rate treatments (approximately 60 to 100 cGy per minute). Low dose-rate treatments are delivered over a period of days, often while the patient remains hospitalized, whereas high dose-rate treatments are divided into fractions and delivered on several days over 1 to 2 weeks. The primary advantage of brachytherapy is that a radiation source can be placed into or adjacent to the tumor, often at the time of resection. Preoperative planning and cooperation between the surgical and radiation oncology teams are necessary to ensure the appropriate and accurate implementation of brachytherapy. Nonrhabdomyosarcoma soft tissue sarcomas and some rhabdomyosarcomas are the pediatric tumors most commonly treated with brachytherapy.1°2J15 Most other pediatric solid tumors are not amenable to brachytherapy, however, because of the tumor's behavior (e.g., radioresistance) or its anatomic location (e.g., retroperitoneal).

Other Delivery Methods Several other means of delivering radiation to primary tumor sites are used in adult and pediatric oncology. Intraoperative radiation therapy has been used intermittently after resection in the management of localized tumors." Although of limited availability in the United States, intraoperaGve radiation therapy has the distinct advantage of allowing the operative tumor bed to be visible in the operating theater while radiation is delivered, thereby enhancing the accuracy of delivery and providing the opportunity to displace or temporarily move mobile crucial structures (e.g., bowel, bladder) from the field of delivery. The primary limitation of intraoperative radiation therapy is-that it can deliver only a single fraction of radiation, usually in the 10 to 20 Gy range.

Radiation tolerances of normal tissues that cannot be removed from the treatment field must be respected and may limit the ability to deliver an effective treatment dose. Proton radiation therapy and other approaches using heavy charged particles have been investigated at a limited number of centers. The primary benefit of therapy with proton or other heavy charged particle beams is the capacity to end the radiation beam at a specific and controllable depth. This may allow the protection of healthy, normal tissues directly adjacent to tumorbearing tissues.74 However, the use of proton therapy is limited because of the expense of constructing a suitable treatment facility; only a small number of institutions are so equipped. Although interest in proton therapy decreased in the late 1990s, it has now resumed, and several new facilities are currently under construction in the United States. With appropriately designed studies and comparisons with current state-of-the-art imageguided therapy delivered with photon beams, a determination of the potential benefits of this treatment modality may be made.

Palliative Radiation Therapy For many patients, the management of cancer, particularly pediatric cancer, focuses on curative therapy incorporating surgery, radiation therapy, and chemotherapy in a multidisciplinary plan. Despite substantial success in the management of pediatric cancer, many children experience disease recurrence and ultimately die from their malignancy. Although it is far less frequently discussed, palliative radiation therapy is often a valid intervention.68 Implicit in the concept of palliative radiation therapy is that its purpose is to treat a symptom. The ultimate goal of a palliative approach is to maintain quality of life for patients who will not survive their disease while minimizing the number of disruptive interventions they must undergo. Radiation oncologists are often asked to palliate symptoms from painful sites of disease, particularly those with bony involvement, and symptoms resulting from compression of vital structures, including spinal cord, peripheral nerves, and respiratory tract. Delivery of radiation in this setting is identical to that of curative radiation, with radiation delivered on a daily basis. Close attention is paid to the symptoms being palliated, while treatment-related effects are minimized. A palliative course of therapy is highly individualized, and its success or failure depends on the histologic diagnosis, previous therapy, duration of symptoms, and symptom being treated.

Acute and Late Toxicities of Radiation Therapy The treatment-related effects of radiation therapy, both acute and chronic, are well described for pediatric and adult patients, but unfortunately, their incidence and relation to the dose and volume of treatment are poorly ~haracterized.~Wistorically,treatment-related effects have been classified as acute or late; an arbitrary time point of 90 days after the completion of treatment

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defines the division between the two classifications. Current guidelines for assessing adverse events related to treatment no longer recognize this arbitrary distinction, but the use of early and late time points is instructive in the discussion of radiation-related effects. Essentially all such effects originate from within the confines of the treatment beams, usually the high-dose regions of treatment. The most common early and late treatmentrelated effects arising from radiation are listed in Table 25-6. Despite the arbitrary nature of the division into early and late effects, this classification distinguishes effects from which the patient is likely to recover completely from those that are likely to be permanent. Early treatment-related effects, if managed appropriately, will resolve as normal, healthy tissues adjacent to the tumorbearing tissues gradually recover from the effects of radiation. The period of recovery can range from days to months, but the patient is often left with minimal sequelae. Treatment-related effects that are observed later, after the completion of radiation therapy, are more likely to be chronic or permanent. They appear to be related to the normal healing response of healthy irradiated tissue, resulting in the formation of an unwanted effect such as fibrosis. Many late treatment effects can be managed but are not reversible. For children receiving curative therapy, long-term effects are a primary concern and are best managed with a preventive approach. Some of the long-term effects of treatment in children should be ameliorated by limiting the volume of normal tissue irradiated at high doses and by implementing approaches that minimize the radiation dose to adjacent healthy tissues.

1 Organpite Skin Subcutaneous tissue Mucosa Central nervous system

Acute

Chronic

Erythema Desquamation Edema Mucositis Edema Headache

Atrophy Hyperpigmentation Fibrosis Ulceration Necrosis Myelitis Decline in cognition Cataract Retinopathy Dry eye Hypothyroidism Pericarditis Myocarditis Pulmonary fibrosis Necrosis

Eye

Conjunctivitis

Thyroid Heart

-

Lung Bowel

Pneumonitis Nausea Diarrhea

Kidney

-

Bladder

Muscle

Dysuria Urgency Frequency Edema

Bone

-

Nephritis Renal insufficiency Hemorrhagic cystitis

Fibrosis Hypoplasia Premature physis closure Hypoplasia

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GENERAL PRINCIPLES OF STEM CELL TRANSPLANTATION Infusion or transplantation of hematopoietic cells capable of reconstituting the hematopoietic system is used in two broad instances. First, hematopoietic stem cell transplantation (HSCT) can be used to replace missing or abnormal components of a defective hematopoietic system. Second, HSCT can be used to reconstitute elements of the hematopoietic system destroyed by intensive chemotherapy or radiation therapy for solid tumors or disorders of the hematopoietic system itself. The transplanted cells can be the patient's own (i.e., autologous), in which case the cells are obtained before the administration of myelosuppressive therapy, or they may come from a donor (i.e., allogeneic) who is generally an HLA-identical sibling, a mismatched family member, or a partially matched unrelated donor. The latter two circumstances require immunosuppressive and graft engineering strategies to permit successful engraftment and avoid graft-versus-host disease. Hematopoietic progenitor cells are usually obtained from the bone marrow or peripheral blood. They are the crucial component of the transplant because they are capable of self-renewal and, therefore, long-term production of cells of the various hematopoietic lineages. Occasionally, when available, banked umbilical cord blood may be used as the source of hematopoietic stem cells (HSCs). In general, although autologous cells are the safest to use for HSCT, they may be contaminated with tumor cells. Graft-versus-host disease, which may occur with allogeneic HSCT, can be life threatening, but a modest graft-versus-host reaction may be beneficial if directed against the host's tumor cells. Bone marrow is normally harvested from the posterior iliac crest to a total volume of 10 to 20 mL/kg body weight of the recipient. Peripheral blood stem cells are harvested after their mobilization with recombinant granulocyte colony-stimulating factor, given daily for up to a week before harvest. The exact nature of the crucial cellular component responsible for the reconstitution of the hematopoietic system is unknown, but the number of cells having the surface marker CD34 has been shown to be related to the rate of engraftment.g"efore HSCT, the recipient receives a preparative (or "conditioning") chemotherapeutic regimen. This treatment serves several purposes, including killing residual tumor cells, providing immunosuppression for allogeneic HSCT, and providing "space" in the marrow into which transplanted HSCs can engraft. Before reinfusion, the HSC product may be manipulated ex vivo to enrich it for putative progenitor cells (e.g., CD34+ or CD133+ cells), using positive or negative selection methods, to facilitate hematopoietic reconstitution; to remove donor T lymphocytes, thereby decreasing the risk of graft-versus-host disease in allogeneic HSCT, or to purge contaminating tumor cells from the product used inautologous HSCT. Complications of HSCT can be significant. The most common early complication is infection, which results from the transient but profound immunosuppression of the patient, combined with the breakdown of mucosal barriers. Another common complication is veno-occlusive disease, which is characterized clinically by painful

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enlargement of the liver, jaundice, and fluid retention. Ultrasouild examination shows reversal of flow in the portal vein. Liver biopsy samples show a classic histologic appearance of obliterated hepatic venules and necrosis of centrilobular hepatocytes. There is no specific treatment for this condition; only supportive care can be given, and mild or moderate veno-occlusive disease is self-limited. Other acute complications of HSCT include graft-versus-host disease, a process mediated by donor T cells targeting host cells with antigenic disparities, and graft failure. Late complications include chronic graftversus-host disease, endocrine insufficiency, secondary malignancies, growth failure, and other sequelae related to the use of total-body irradiation as part of some preparatory regimens. Nevertheless, despite the toxicity, HSCT is now an integral part of successful therapy for many high-risk malignancies in children.

CLINICAL TRIALS As previously stated, the past 40 years have seen a significant increase in overall survival rates for children with cancer. This increase has been achieved through the development of new drugs and treatment approaches, improved supportive care, and better diagnostic modalities to permit earlier cancer detection. The benefits of these ad\lances have been confirmed by carefully designed and analyzed clinical trials. Because childhood cancer is relatively rare, excellent organization and planning of these trials are essential. In the United States and other participating countries, clinical trials are largely conducted by the Children's Oncology Group, with smaller pilot studies being run by large individual institutions or small consortia. Clinical trials are generally divided into three phases. Phase I studies are designed to evaluate the potential toxicity of a new diagnostic or therapeutic agent. Small numbers of patients are usually required for a phase I study, which typically uses a dose-escalating design in which cohorts of patients are observed for signs of toxicity before they advance to higher doses. The end point of this type of study is generally a determination of the safety of the agent o r the maximum tolerated dose (or both). However, the increasing number of biologic reagents being introduced and tested may require a shift to the assessment of the optimal biologic dose. Enrollment in a phase I toxicity study is often restricted to patients whose disease has not responded to conventional or "standard-oEcare" therapy. Phase I1 trials are conducted to determine whether a new agent or treatment approach is sufficiently efficacious to warrant further study. Phase I1 agents are often given to newly diagnosed patients before they begin o r just after they complete standard therapy. The testing of new agents in an "upfront window" (i.e., before standard therapy) has been shown not to have an adverse effect on the efficacy of delayed standard therapy. Finally, phase 111 studies are designed to compare the efficacy of an experimental therapy with that of standard therapy. They are best done as prospective, randomized trials, but often, because of small patient numbers, a phase 111 study is

done by comparing the efficacy of an experimental therapy with that of standard therapy given to historic control subjects. It is through such systematic assessment of the risks and benefits of new therapies that approaches are rejected o r accepted as the new standard of care and the field of pediatric oncology is advanced.

CONCLUSION Advances in molecular genetic research in the past 2 decades have led to increased understanding of the genetic events in the pathogenesis and progression of human malignancies, including those of childhood. A number of pediatric malignancies serve as models for the molecular genetic approach to cancer. The pediatric experience highlights the utility of molecular analysis for a variety of purposes. Demonstration of tumor-specific translocations by cytogenetics, FISH, and RT-PCR confirms histopathologic diagnoses. Detection of chromosomal abnormalities, gene overexpression, and gene amplification is used in risk stratification and treatment planning. Elucidation of pathways involving tumor suppressor genes has increased our understanding of syndromes associated with cancer and has led the way for genetic screening and counseling and pl-ophylactic surgical intervention. And in the near f i ~ t u r e , translation of the molecular profile of a given tumor will form the basis of a new therapeutic approach. Treatment will be tailored such that patients with biologically highrisk tumors receive intensified regimens to achieve a cure, whereas patients with biologically low-risk tliinors may experience a cure and benefit from the lower toxicity of nonintensive therapy. Elucidation of the complex molecular pathways involved in tumorigenesis will also encourage the production of targeted anticancer agents with high specificity, efficacy, and therapeutic index.

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109. O'Brien KP, Seroussi E, Dal Cin P, et al: Various regions within the alpha-helical domain of the COLlAl gene are fused to the second exon of the PDGFB gene in dermatofibrosarcomas and giant-cell fibroblaitomas. Genes Chromosomes Cancer 1998;23:187-193. 110. O'Sullivan B, Davis AM, Turcotte R, et al: Preoperative versus postoperative radiotherapy in soft-tissue sarcoma of the limbs: A randomised trial. Lancet 2002;359:2235-2241. 111. Ozkaynak MF, Sonde1 PM, Krailo MD, et al: Phase I study of chimeric human/murine anti-ganglioside G(D2) mon- oclonal antibody (ch14.18) with granulocyte-macrophage colonv-stimulating. factor in children with neuroblastoma u immediately after hematopoietic stem-cell transplantation: A Children's Cancer Group Study. J Clin Oncol 2000;18: 4077-4085. 112. PelletierJ, Bruening W, Kashtan CE, et al: Germline mutations in the Wilms' tumor suppressor gene are associated with abnormal urogenital development in Denys-Drash syndrome. Cell 1991;67:437-447. 113. Petit AM, Rak J, Hung MC, et al: Neutralizing antibodies against epidermal growth factor and ErbB-2/neu receptor tyrosine kinases down-regulate vascular endothelial growth factor production by tumor cells in vitro and in vivo: Angiogenic implications for signal transduction therapy of solid tumors. Am J Path01 1997;151:1523-1530. 114. Pinthus JH, Fridman E, Dekel B, et al: ErbB2 is a tumor associated antigen and a suitable therapeutic target in Wilms' tumor. J Urol 2004;172:16441648. 115. Pisters PW, Harrison LB, Leung DH, et al: Long-term results of a prospective randomized trial of adjuvant brachytherapy in soft tissue sarcoma. J Clin Oncol 1996; 14:859-868. 116. Pluda JM: Tumor-associated angiogenesis: Mechanisms, clinical implications, and therapeutic strategies. Semin Oncol 1997;24:203-218. 117. Powell SM, Petersen GM, Krush AJ, et al: Molecular diagnosis of familial adenomatous polyposis. N Engl J Med 1993;329:1982-1987. 118. Pritchard-Jones K, Fleming S, Davidson D, et al: The candidate Wilms' tumour gene is involved in genitourinary development. Nature 1990;346:194197. 119. Quesnel S, Malkin D: Genetic predisposition to cancer and familial cancer syndromes. Pediatr Clin North Am 1997;44:791-808. 120. Rabbitts TH, Forster A, Larson R, et al: Fusion of the dominant negative transcription regulator CHOP with a novel gene FUS by translocation t(12;16) in malignant liposarcoma. Nat Genet 1993;4:175-180. 121. Riccardi VM, Sujansky E, Smith AC, et al: Chromosomal imbalance in the aniridia-Wilms' tumor association: 1l p interstitial deletion. Pediatrics 1978;61:604610. 122. Ries LG: Childhood cancer mortality. In Ries LG, Smith MA, Gurney JG, et a1 (eds): Cancer Incidence and Survival among Children and Adolescents: United States SEER Program 1975-1995. National Cancer Institute, 1999, pp 165-169. 123. Risau W: Mechanisms of angiogenesis. Nature 1997;386: 671-674. 124. Robinson BW, Ostruszka L, Im MM, et al: Promising combination therapies with gemcitabine. Semin Oncol 2004; 31:2-12. 125. Rodriguez-Galindo C, Spunt SL, Pappo AS: Treatment of Ewing sarcoma family of tumors: current status and outlook for the future. Med Pediatr Oncol 2003;40: 276287. 126. Rousseau RF, Haight AE, Hirschmann-Jax C, et al: Local and systemic effects of an allogeneic tumor cell vaccine combining transgenic human lymphotactin with interleukin-2 in patients with advanced or refractory neuroblastoma. Blood 2003;101:1718-1726.

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Biopsv Techniques for khildren with Cancer James D. Geiger and Douglas C. Barnhart

The importance of biopsy techniques has increased as the use of preoperative chemotherapy has become common for many childhood cancers. In the past, definitive diagnosis was made at the time of surgical resection of the primary tumor. Currently, many children undergo percutaneous or open incisional biopsy rather than initial resection. Moreover, with a better understanding of the molecular changes associated with these malignancies, definitive diagnosis and accurate staging can be accomplished with smaller specimens. This should lead to less morbidity associated with the diagnosis of solid malignancies in children. There has been a progression toward less invasive techniques to obtain a diagnosis-from complete surgical extirpation to incisional biopsy to percutaneous needle biopsy and minimal-access surgery. This change in practice has been driven not only by the evolution of surgical technique but also by an improved understanding of the molecular markers used for both diagnosis and risk stratification in pediatric solid malignancies. Ironically, this progression has complicated rather than simplified the selection of biopsy techniques in individual cases, because multiple factors must be considered. Percutaneous needle biopsy,I"" minimal-access surgical biopsy,'4 and open biopsy are all safe and effective ways of obtaining an initial diagnosis as well as verifying recurrent or metastatic disease. However, the success of these techniques is obviously dependent on individual institutional experience, which must be considered when selecting a biopsy technique. In addition, it is critical to realize that many of the advances in risk stratification and improved therapy for pediatric malignancies have been facilitated by the development of large tumor banks and the associated biolou studies. Without large biopsy specimens, these tumor banks and the development of research cell lines would not have been possible. For a number of tumors, including neuroblastoma, the collection of such specimens is important to further our understanding of the disease. There has been significant progress toward risk-stratified treatment regimens.18 As this stratification becomes

more complex, the type of information needed from biopsy specimens also becomes more individualized. In order to select the biopsy method that will be the least morbid yet yield all the information necessary to stratify an individual patient, the surgeon must be knowledgeable about the stratification schema that will be used for multimodality therapy. This concept can be exemplified by considering two patients with abdominal masses suggestive of neuroblastoma, both of whom have apparent metastatic disease in the bone marrow, and their treatment under the current Children's Oncology Group (COG) schema.57 The first patient is younger than 1 year, and this child's treatment group could be low, intermediate, or high risk. This determination requires N-myc amplification status, International Neuroblastoma Pathology Classification status, and DNA ploidy, which necessitates sampling of the primary lesion. In contrast, an older child with a similar presentation would be classified as high risk. Therefore, one could consider confirming the diagnosis and assigning a risk group based on bone marrow biopsies alone. Clearly, knowledge of multimodality therapy is essential in the selection of a biopsy technique.

HANDLING OF SPECIMENS Historically, most diagnoses were based on the histologic appearance of tumor tissue on permanent sections using hematoxylin and eosin stains. This was supplemented by the use of immunohistochemistry,which could similarly be performed on formalin-fixed specimens. There has been extensive progress in the molecular diagnosis of childhood malignancies, including recognition of genetic aberrations that have both diagnostic and prognostic signifi~ance."~"~l Techniques used to detect these changes include reverse transcriptase-polymerase chain reaction," fluorescent in situ hybridization, microarray a n a l y s i ~and , ~ ~flow cytometry. Inappropriate specimen handling can preclude the completion of these analyses. For example, phenotypic classification of lymphoma cannot be performed using flow cytometry on formalin-fixed lymph nodes. Given the

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rapidly evolving field of molecular diagnosis, it is essential that the surgeon consult with the pathologist regarding specimen handling before performing the biopsy.

PERCUTANEOUS NEEDLE BIOPSY Fine-needle aspiration was first introduced as a technique for obtaining specimens for cytopathology by Grieg and Gray in 1904.l'Jereb et al.Z9reported success with the use of needle biopsy for the diagnosis of pediatric solid tumors in 1978. Subsequently, extensive experience from multiple institutions has confirmed the accuracy and safety of both needle aspiration and core needle biopsy techniques. The appeal of these techniques is that they permit diagnosis without a significant delay in the institution of multimodality therapy and, in some situations, can be performed as outpatient procedures. Needle biopsies are often performed under either general anesthesia or sedation. In selected older children, some sites may be biopsied under local anesthesia alone using these methods.j4 Percutaneous needle biopsies may be performed by palpation in the extremities and other superficial locations, such as lymph nodes. Deeper biopsies require either ultrasonography or computed tomography (CT) guidance. Ultrasonography can be supplemented with Doppler mode; it allows the clear identification of large vessels and other structures and provides real-time visualization Some l core needle devices as the needle is a d ~ a n c e d . ~ also deposit a small air bubble, which allows verification of the site that was biopsied. CT permits clear visualization of the aerated lung10 and is not obscured by bowel gas. It also allows for measurement and planning of the depth of biopsy.lg Decision making regarding image guidance occurs in conjunction with the radiologist; ideally, biopsies should be performed with both modalities.

of molecular techniques and electron microscopy to supplement light microscopy has increased the histiotype specificity of FNAB and may lead to its increased application in pediatric solid m a l i g n a n c i e ~ . 2 ~ - ~ ~ The most straightforward application of FNAB is the verification of metastatic or recurrent disease in the setting of a previously characterized primary tumor.z6 In this context, documenting the presence of malignant cells is often sufficient to guide further clinical decisions. This least invasive biopsy method is particularly appealing in patients who may already be immunologically or otherwise physiologically compromised. There is an increasing body of literature to support the use of FNAB in the diagnosis of sarcomas. Fine-needle " aspirates have provided a definitive diagnosis of osteosarcoma in 65%l2 to 92%32of patients; this technique is as accurate in children as it is in adults. The use of FNAB in soft tissue tumors has been facilitated by the recognition of cytogenetic abnormalities and fusion proteins that are specific to these tumor types.30.31However, caution should be exercised when using FNAB in this setting, because the reported series come from a limited number of institutions with extensive experience in the interpretation of this cytology. FNAB has not been widely used for the diagnosis of small round blue cell tumors of childhood. However, with the increasing availability of ancillary studies such as electron microscopy, immunocytochemistry, DNA ploidy, cytogenetics, and fluorescent in situ hybridization, its use may become more common.3 Use of FNAB for the evaluation of head and neck masses in children has been ~~,~~ reported to have good sensitivity and s p e c i f i ~ i t y .The results of these series should be interpreted with caution, however, because the majority of these aspirates diagnosed reactive lymphadenopathy; the number of new malignant diagnoses was small. Additionally, false-negative results occurred frequently in patients who were ultimately diagnosed with lymphoma in other series (not specifically isolated to the head and neck) .5*

FINE-NEEDLE ASPIRATION BIOPSY Fine-needle aspiration biopsy (FNAB) has the obvious appeal of being the least invasive biopsy technique. It is typically performed using a 22- to 25-gauge needle with multiple passes into the lesion if necessary. Successful diagnosis using FNAB requires coordination with an experienced cytopathologist; to improve the diagnostic yield, the specimens should be examined immediately after they are taken. Additional aspirations may be taken if initial samples are inadequate.52 Large series with fineneedle aspirates in both children and adults have confirmed the safety of the technique.l6s3I Historically, diagnosis using FNAB was based primarily on cytologic appearance with conventional stains and light microscopy. In adult patients with a higher prevalence of carcinomas, FNAB is a popular method of confirming the presence of malignancy in suspicious lesions. In adults, a diagnosis of carcinoma and determination of the primary site are often sufficient to make initial treatment decisions. However, given the fact that multimodality therapy is histiotype specific in pediatric patients, FNAB is used less frequently in children. The recent application

CORE NEEDLE BIOPSY The obvious advantage of core needle biopsy over FNAB is that it provides a large enough sample to allow histologic examination rather than only cytologic examination. Additionally, it can provide sufficient tissue for molecular evaluation. Despite the widespread use of this technique in adults, its application in children is not as common. Several series have reported the efficacy and safety of this technique in more than 280 ~ h i l d r e n . ~ ~ , ~ ~ , ~ ~ , ~ ~ Various core needle devices may be used, typically ranging in size from 14 gaugeM 4 0 18 gauge.lg Needles are designed so that a cutting sheath advances over the core of the needle to obtain a tissue biopsy that is protected within the sheath as the needle is withdrawii. This cutting sheath may be advanced either manually (e.g., Tru-Cut by Allegiance) or by a spring-loaded firing system (e.g., Monopty by Bard) (Fig. 26-1). There are no data directly comparing the quality of specimens obtained with these two types of systems in pediatric malignancies. The faster deployment of the spring-loaded systems may

CHAPTER

Two commonly used core needle biopsy devices. The upper device is a 14gauge Tru-Cut needle (Allegiance). It is advanced into the region of interest, and then the inner needle is advanced. The outer sheath is manually advanced over the inner needle to obtain a core. The lower device is a 16-gauge Monopty biopsy device (Bard). I t is spring-loaded and is activated after the tip is advanced into the region of interest. The spring-loaded mechanism automatically sequentially advances the obturator and the cannula.

result in less crush artifact, which has been demonstrated in pediatric kidney biopsies." Regardless of the system used, visual inspection of the core biopsy is necessary to verify adequate sampling. Many patients in these series required only a single pass to acquire adequate tissue. Repeated passes were made if inadequate initial samples were obtained. Success with core needle biopsy has been demonstrated in a wide variety of anatomic locations, including the neck, mediastinum, lung, peritoneal cavity, liver, retroperitoneum, kidney, adrenal gland, pelvis, and extremitie~.l"s~~~~~s* The diagnostic accuracy in malignant disease observed in four series is summarized in Table 261. The sensitivity of the biopsy technique is acceptable, but there were clearly problematic cases in which the incorrect diagnosis was made. These inaccuracies may have been avoidable with additional clinical history19 or additional sampling. In some of the discordant cases, the uncertainty of the diagnosis was recognized immediately and addressed with repeat percutaneous or open biopsy. Core needle biopsy tends to be more accurate in detecting metastasis or recurrence than for obtaining the initial diagnosis.

Author/Year

No. of Patients (Total/Malignancy)

Klose et a134/1991 Somers et a154/1993

39/16 25/23

Skoldenberg et a151/2002 Guimaraes et a119/2003

110/84 54/54

82 82

Biopsy Techniques for Children with Cancer

439

No patients in these series suffered procedure-related death or required operative intervention for procedural complications. One series reported a significant decrease in hematocrit requiring transfusion in 3% of core needle biopsy procedures, and 10% of patients undergoing a transthoracic biopsy required a thoracostomy tube.s1 Given the risk of pneumothorax and the variability of lesion position with respiration, core needle biopsy of pulmonary lesions merits special consideration. Connolly et al.l0 reported their experience with core needle biopsy of small lung lesions in children in 1999. Biopsies were performed under CT guidance with a coaxial needle system while the child was under general anesthesia. All imagmg studies and biopsies were performed on complete exhalation. Adequate core tissue samples were obtained for diagnosis in 83% of patients, with the average size of the lesion being 9 mm. When adequate cores were not obtained, aspiration cytology was performed and raised the overall diagnostic yield to 94%. Twenty-seven percent of patients had small pneumothoraces, but none were symptomatic or required drainage. Needle track tumor recurrence represents an oncologic complication specific to this biopsy technique. Estimates of - , this complication in adults vary widely, ranging from 3.4%in hepatocellular carcinomas3 to 0.01% in thoracic tumor^.^ The incidence of this complication is influenced by several factors. Immunologic, chemotherapeutic, and radiotherapeutic effects decrease the likelihood of needle track recurrence. The larger needles used for core needle biopsies are associated with a greater risk than are the fine needles used for aspiration.Z1 There are two reported cases of needle track recurrence in children with Wilms' tumors.*

MINIMAL-ACCESS SURGERY The widespread use of minimal-access surgery, including laparoscopy and thoracoscopy, has had a significant impact on general pediatric surgery over the last 15 years. Both techniques are now being used in cancer diagnosis and therapy. Gans and BerciI4reported their initial experience with multiple endoscopic techniques in children in 19'71. Interestingly, one of the chief applications of peritonoscopy that they advocated was to guide the biopsy of metastatic implants. The application of both laparoscopy and thoracoscopy has now grown to include the initial diagnosis of childhood malignancies and the assessment of refractory or metastatic disease.

Sensitivity (%) 100 88

26

Comments Correct histiogenetic classification in all tumors 4 discordant cases, including neuroblastoma diagnosed as ganglioneuroma 1 6 cases failed to yield diagnosis due to inadequate specimen In 4 cases, initial interpretation was changed, including Wilms' tumor diagnosed as neuroblastoma

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Laparoscopy Laparoscopy affords several advantages in the evaluation of the abdominal cavity in children with cancer. First, it provides the opportunity to examine the entire peritoneal cavity and perform a systematic examination of all peritoneal surfaces. The entire length of the bowel can be examined, along with its mesentery and lymph nodes. Multiple biopsies can easily be obtained. The second chief advantage of laparoscopy is the decreased physiologic stress it produces in these children, who may already be critically ill. Finally, as in all minimally invasive procedures, postoperative pain is reduced and recovery is hastened.'Vhe chief disadvantages of laparoscopy are the limited ability to assess retroperitoneal structures and the loss of tactile evaluation of deep lesions. Diagnostic laparoscopy and biopsy have been used in several settings in the management of children with solid malignancie~."~~ Biopsies obtained using laparoscopic techniques have a high rate of success in yielding diagnostic tissue.'"47 1,aparoscopy allows the surgeon to obtain larger tissue samples than may be obtained with core needle biopsy. This is particularly relevant if larger samples are required for biologic studies. In the initial diagnosis, laparoscopy aids in identifying the site of origin of large abdominal masses. Laparoscopy is superior to CT in assessing intraperitoneal neoplasms and for the evaluation of ascites.7 For example, laparoscopy allows the direct determination of whether a pelvic mass arises from the ovary or the bladder neck, which may be difficult to distinguish by radiologic studies. Direct visualization via laparoscopy has been used to assess the resectability of hepatobla~toma.2~ During the course of treatment, laparoscopy may be used to assess for new metastatic disease or to assess for initial tumor response as a secondlook procedure. One area of concern about the use of laparoscopy in cancer patients is port site recurrence. This complication has been observed in a variety of adult malignancies, most notably in adenocarcinoma of the colon and gallbladder.40This complication is most frequently reported after resection of an unexpected gallbladder carcin~ma.~%ases of port site recurrence have also occurred in adults after the resection of liposarcoma2bnd cervical carcinoma.' More recent reports cite a very low rate of port site recurrence in adult patients with upper gastrointestinal") and renal malignancies.15 Data are relatively limited concerning this issue in children. The COG retrospective study of 85 children noted no port site recurrences.Z4 In a survey of Japanese pediatric laparoscopic surgeons, there were no port site recurrences following 85 laparoscopic and 44 thoracoscopic procedures.27 It should be noted, however, that 104 of these tumors were neuroblastomas, with many being detected by mass screening; the general applicability of these data may therefore be limited. Given the differences in tumor biology between adult adenocarcinomas and pediatric neoplasms,which often have a marked response to neoadjuvant therapy, it is difficult to generalize from the adult literature. Certainly, additional surveillance for port site recurrence of pediatric tumors is merited.

Laparoscopy in children is typically performed under general anesthesia to facilitate tolerance of pneumoperitoneum. The only absolute contraindication to laparoscopic evaluation is cardiopulmonary instability that would prevent safe insufflation of the peritoneal cavity. The supine position is used most commonly and affords a complete view of the peritoneal cavity. To facilitate visualization, a 30-degree laparoscope is used, along with at least two additional ports for manipulation and retraction. Ascites should be collected for cytologic analysis, and all peritoneal surfaces should be inspected. Incisional biopsies can be performed using laparoscopic scissors. Hemostasis is achieved using a combination of electrocautery and hemostatic agents (as discussed later in the section on open incisional biopsy) or by tissue approximation via laparoscopic suturing. Biopsy specimens are typically retrieved using a specimen bag. This reduces the chance of specimen destruction during retrieval and may decrease the risk of port site recurrence. Cup biopsy forceps can be used to obtain specimens as well. Core needle biopsies can be directed by laparoscopy and used to sample retroperitoneal, intraperitoneal, or hepatic masses. For deep-seated tumors, such as intrahepatic lesions, laparoscopic ultrasonography can be used to guide biopsy procedures and to compensate for the inability to palpate tissues."sx Complications associated with the laparoscopic dia<posis and treatment of solid tumors in children are infrequent. The need to convert to an unplanned open operation has similarly been low.24,2X,4x

Thoracoscopy Thoracoscopy was first reported by Jacobus in 1910 as a technique for the lysis of pleural adhesions resulting from tuberculosis. The initial experience with its use in children was reported by Rodgers and Talbert in 1976.4? They described nine children, including two oncology patients (Ewing's sarcoma and recurrent Hodgkin's lymphoma). Since this initial report, thoracoscopy has become widely used for the evaluation of thoracic lesions in children, for several reasons. Primarily, postoperative pain associated with thoracoscopic biopsy or resection is markedly decreased compared with conventional open thoracotomy. Moreover, thoracoscopy allows near-complete visualization of all parietal and visceral pleural surfaces, which cannot be accomplished with a thoracotomy. Additionally, in most children, the mediastinum does not contain a significant amount of adipose tissue and therefore can be inspected thoracoscopically. Although primary neoplasms of the lung are rare in children, pulmonary lesions are often a confounding issue in the treatment of children with cancer."?he most common tumor to have early pulmonary metastases is Wilms' tumor. Pulmonary metastases are also common with bone and soft tissue sarcomas, hepatic tumors, teratocarcinomas, and melanomas. Thoracoscopy is frequently used to evaluate for metastases either at the time of initial diagnosis or after follow-up imaging. A common clinical scenario is difficulty in distinguishing an opportunistic

CHAPTER

A

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Biopsy Techniques for Children with Cancer

441

B

Computed tomography (CT) scans obtained at the time of diagnosis of a new abdominal mass in a 5-year-old boy. A, Abdominal and pelvic CT scans show a large leftsided renal mass. B, Chest CT scan demonstrates a single 8-mm pulmonary nodule in the left upper lobe. No other pulmonary lesio~lswere identified. At the time of nephrectomy, a thoracoscopic excisional biopsy of the lung lesion was performed. Final pathology of the kidney demonstrated a stage I1 favorable-histology Wilms' tumor, and the lung pathology showed a hyalini~edgranuloma.

infection from new metastatic lung disease during the course of therapy. In areas with endemic granulomatous disease, thoracoscopy can also be helpful at the time of diagnosis (Fig. 26-2). The diagnostic accuracy of thoracoscopic biopsies in this setting is very high.44,47,4*,j" Mediastinal lesions can also be biopsied or resected '~~~ provides clear using t h o r a c o ~ c o p y . ~Thoracoscopy visualization of both the anterior and posterior mediastinum, even in small children, and we prefer it over mediastinoscopy for the evaluation of mediastinal lesions in children. The only absolute contraindications to thoracoscopy are complete obliteration of the pleural space and inability to tolerate single-lung ventilation when complete collapse of the lung is required. Thoracoscopy in children is typically performed under general anesthesia with mechanical ventilation. Visualization is facilitated by single-lung ventilation, if possible, and supplemented with insufflation. In older children, this may be accomplished with a double-lumen endotracheal tube. In smaller children, the left lung can be isolated by right mainstem bronchial intubation. Left mainstem intubation is difficult, and the tube frequently dislodges into the right side with positioning. Right lung deflation is performed by endotracheal intubation and right bronchial occlusion with either a dedicated bronchial blocker or a Fogarty catheter placed using rigid bronchoscopy. Fogarty catheter size is based on age: #3 for patients 4 years and younger and #5 for those i s be inflated and deflated aged 5 to 12 y e a r ~ . ~ q hmay during the procedure as needed. If selective ventilation is difficult to achieve or poorly tolerated by the patient, low-pressure insufflation (5 to 10 cm of water pressure) with carbon dioxide will assist with visualization. The anesthesiologist must monitor for any adverse effects from this controlled tension pneumothorax. It can

be rapidly evacuated if necessary but is typically well tolerated. Typically, the child is placed in lateral thoracotomy position. Hyperextension of the chest increases the intercostal space and facilitates movement of the thoracoscopy ports. This positioning should be adjusted for mediastinal lesions. For anterior lesions, a more supine position is used; for posterior lesions, the patient is positioned more prone. The initial port is placed at the midaxillary line using blunt dissection. Additional ports are placed under thoracoscopic guidance at sites based on the location of the lesion of interest. A 30-degree thoracoscope is helpful in achieving complete visualization of all pleural surfaces. Complete inspection is also facilitated by the use of multiple port sites. Careful correlation to cross-sectional imaging is essential to successful thoracoscopic sampling, particularly of smaller lesions. Pleura-based or subpleural pulmonary lesions are often apparent when the lung is deflated. These can be resected using endoscopic stapling devices and retrieved using specimen bags. Identification of deeper lesions is more challenging. After complete collapse of the lung, palpation of the parenchyma allows the identification of larger lesions. Biopsy of smaller lesions can be based on anatomic location if CT localization is specific, such as apical, lingular, or basilar lesions. CT-guided localization may be performed preoperatively with placement of a fine wire23 or injection of methylene blue4%r stained autologous blood.36 These localization techniques have been very effective in obtaining accurate diagnoses in ~hildren."9~4" Intrathoracic ultrasonography may be helpful in localizing deeper parenchymal lesions.53However, this technique is not widely used, and assessment of its efficacy in children is limited. In the future, image-guided biopsies will likely be accomplished with intraoperative magnetic resonance imaging or CT guidance.

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After sampling of the tissues is completed, the pneumothorax can be evacuated with a small catheter placed on water seal. Unless extensive pulmonary biopsies are performed or the lung is otherwise diseased, a thoracostomy tube is not required. Most children can be discharged the next day, and chemotherapy can be started pr0mptly.~6 Thoracoscopic techniques are highly effective in achieving a diagnosis. Most pediatric series report success in obtaining accurate diagnostic tissue in almost licatio diagnostic ns thoraall ~ a s e s . 2 4 , ~ ~ ~ ~ ~ ~ ~ W o m pduring coscopy are rare. Pneumothorax or persistent air leak may occur in children with underlying parenchymal lung disease or those requiring high-pressure ventilatory support. There is the potential for injury to subdiaphragmatic organs during initial trocar placement owing to elevation of the diaphragm during single-lung ventilation.

OPEN INCISIONAL BIOPSY Incisional biopsy remains the gold standard with regard to the quality of tissue sampling if complete excision will not be performed. Laparotomy or thoracotomy allows large samples to be obtained under direct vision, which can provide improved diagnosis compared with needle biopsies. For example, in the National Wilms' Tumor Study Group-4, open biopsy was more successful than core needle biopsy at identifying anaplasia.22 Correlation with preoperative imaging allows multiple samples to be obtained if there is inhomogeneity within the tumor that causes concern about sampling error. The ability to obtain larger specimens is beneficial not only in providing tissue for molecular diagnosis and prognosis but also in providing samples for tissue banking and creation of cell lines. Samples obtained from these biopsies provided the clinical material that allowed the development of the molecular diagnostic and prognostic techniques referred to earlier. Further stratification of risk, to allow more precise risk-based therapy, remains a major focus for pediatric oncology trials. Finally, specimens that are tissue-banked from these larger specimens can be used for investigational therapies, such as vaccines, in individual patients. There are several important factors when performing an open biopsy. The initial biopsy should take into consideration the ultimate operative treatment of the tumor. For example, the incision for biopsy of an extremity mass should be oriented parallel to the axis of the limb, and care should be taken to avoid undermining subcutaneous or fascia1planes. This allows subsequent wide local excision to be performed, with minimal additional resection of tissue owing to the biopsy. Likewise, testicular masses should be biopsied only through an inguinal approach; a scrota1 biopsy incision could require the addition of a hemiscrotectomy to the subsequent orchiectomy. Laparotomy for biopsy should be planned to allow subsequent resection through extension of the same incision. Significant distortion of anatomic relations can occur with large retroperitoneal tumors, and attention must be paid to avoid injury to structures such as the ureters, bile

duct, or major vascular structures that may be distracted over the mass. The most common intra-abdominal tumors in children tend to be vascular, and bleeding from the biopsy site is the most common serious complication. Strategies to reduce perioperative hemorrhage include normalization of coagulation parameters preoperatively and adequate operative exposure. Cauterization of the tumor capsule may help control bleeding, but we have found that direct pressure after packing the biopsy site with oxidized cellulose, combined with procoagulants (described later), is more efficient than generous cautery of the biopsy base. If possible, closure of the tumor capsule can aid with hemostasis. Supplements to achieve hemostasis can include topical agents, fibrin sealants, and recombinant factor VIIa. Commercially available topical products include gelatin foam pads, microfibrillar collagen, and oxidized cellulose, which is available as fabric and cottonoid. Fibrin sealants are composed of fibrinogen, thrombin, and calcium; mixture of these components as they are delivered to the tissue results in the rapid formation of a fibrin clot.46 Recombinant factor VIIa was originally developed to treat patients with hemophilia who had developed inhibitors; however, it has increasingly been used to treat patients with severe bleeding without a preexisting bleeding disorder. There are numerous reports of its use in trauma and a randomized trial showing its efficacy in radical prostate~tomy.~" Its effective use to control hemorrhage after biopsy of a hepatoblastoma has been reported," and we have had success in controlling bleeding from a hepatic metastasis from Wilms' tumor. This is an expensive therapy, and although its risks are poorly characterized, initial experience suggests a low rate of thromboembolic complications.~ One of the important roles of a surgeon is providing adequate tissue for diagnosis and risk stratification. Traditionally, the open biopsy served this purpose extremely well and can be accomplished with low morbidity. In the future, the need for open biopsy will diminish with further advances in molecular diagnosis that require only small tumor specimens or perhaps no biopsy of the primary tumor at all. A thorough understanding of the potential diagnoses and their treatment, as well as coordination between the surgeon and oncologist, is critical to determining the appropriate approach in each individual patient.

REFERENCES 1. Abramowicz, M: Novoseven for nonhemophilia hemostasis. Med Lett 2004;46:1181. 2. Agostini A, et al: Port site metastasis after laparoscopy for uterine cervical carcinoma. Surg Endosc 2003;17: 1663-1665. 3. Akhtar M, et al: Fine-needle aspiration biopsy diagnosis of small round cell tumors of childhood: A com~rehensive approach. Diagn Cytopathol 1999;21:81-91. 4. Aslam A, Spicer RD: Needle track recurrence after biopsy of non-metastatic Wilms' tumor. Pediatr Surg Int 1996;ll: 416417. 5. Ayar D, et al: Needle-track metastasis after transthoracic needle biopsy. J Thorac Imaging 1998;13:2-6.

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6. Barro C , et al: Successful use of recombinant factor VIIa for severe surgical liver bleeding in a 5-month-old baby. Haemophilia 2004;10:183-185. 7. Barth RA, et al: A comparison study of computed tomography and laparoscopy in the staging of abdominal neoplasms. Dig Dis Sci 1981;26:253-256. 8. Berber E, Siperstein AE: Laparoscopic ultrasound. Surg Clin North Am 2004;84:1061-1084. 9. Bown N: Neuroblastoma tumour genetics: Clinical and biological aspects. J Clin Pathol 2001;54:897-910. 10. Connolly BL, et al: CT-guided percutaneous needle biopsy of small lung nodules in children. Pediatr Radiol 1999;29: 342-346. 11. Dagher R, et al: Molecular confirmation of Ewing sarcoma. J Pediatr Hematol Oncol 2001;23:221-224. 12. Dodd LG, et al: Utility of fine-needle aspiration in the diagnosis of primary osteosarcoma. Diagn Cytopathol 2002;27:350-353. 13. Friederich PW, et al: Effect of recombinant activated factor VII on perioperative blood loss in patients undergoing retropubic prostatectomy: A double-blind placebwontrolled randomised trial. Lancet 2003;361:201-205. 14. Gans SL, Berci G: Advances in endoscopy of infants and children. J Pediatr Surg 1971;6:199-233. 15. Gill IS, et al: Laparoscopic radical nephrectomy in 100 patients: A single center experience from the United States. Cancer 2001;92:1843-1855. 16. Gonzalez-Campora R: Fine needle aspiration cytology of soft tissue tumors. Acta Cytol 2000;44:337-343. 17. Grieg ED, Gray AC: Lymphatic glands in sleeping sickness. BMJ 1904;1:1252. 18. Grosfeld JL: Risk-based management of solid tumors in children. Am J Surg 2000;180:322-327. 19. Guimaraes AC, et al: Computed tomography-guided needle biopsies in pediatric oncology. J Pediatr Surg 2003; 38: 10661068. 20. Gurley AM, et al: The utility of ancillary studies in pediatric FNA cytology. Diagn Cytopathol 1992;8:137-146. 21. Haddad FS, Somsin AA: Seeding and perineal implantation of prostatic cancer in the track of the biopsy needle: Three case reports and a review of the literature. J Surg Oncol 1987;35:184191. 22. Hamilton TE, et al: Open biopsy is superior to needle for detection of anaplasia in patients with Wilms' tumor. Paper presented at the American Pediatric Surgical Association meeting, 2004. 23. Hanninen EL, et al: Computed tomography-guided pulmonary nodule localization before thoracoscopic resection. Acta Radiol 2004;45:284288. 24. Holcomb GW 3rd, et al: Minimally invasive surgery in children with cancer. Cancer 1995;76:121-128. 25. Horiguchi A, et al: Port site recurrence after laparoscopic resection of retroperitoneal liposarcoma. J Urol 1998; 159:1296-1297. 26. Howell LP: Changing role of fine-needle aspiration in the evaluation of pediatric masses. Diagn Cytopathol 2001;24:65-70. 27. Iwanaka T, et al: No incidence of port-site recurrence after endosurgical procedure for pediatric malignancies. Pediatr Surg Int 2003;19:200-203. 28. Iwanaka T, et al: Endosurgical procedures for pediatric solid tumors. Pediatr Surg Int 2004;20:39-42. 29. Jereb B, Us-Krasovec M,Jereb M: Thin needle biopsy of solid tumors in children. Med Pediatr Oncol 1978;4:213-220. 30. Kilpatrick SE, Garvin AJ: Recent advances in the diagnosis of pediatric soft-tissue tumors. Med Pediatr Oncol 1999;32: 373-376.

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31. Kilpatrick SE, et al: Is fine-needle aspiration biopsy a practical alternative to open biopsy for the primary diagnosis of sarcoma? Experience with 140 patients. Am J Clin Pathol 2001;115:59-68. 32. Kilpatrick SE, et al: The role of fine needle aspiration biopsy in the diagnosis and management of osteosarcoma. Pediatr Pathol Mol Med 2001;20:175-187. 33. Kim SH, et al: Needle-tract implantation in hepatocellular carcinoma: Frequency and CT findings after biopsy with a 19.5-gauge automated biopsy gun. Abdom Imaging 2000; 25:246-250. 34. Klose KC, et al: CT-guided percutaneous large-bore biopsies in benign and malignant pediatric lesions. Cardiovasc Intervent Radiol 1991;14:78-83. 35. Liu ES, et al: Fine needle aspiration biopsy of pediatric head and neck masses. Int J Pediatr Otorhinolaryngol 2001;60:135-140. 36. McConnell PI, Feola GP, Meyers RL: Methylene blue-stained autologous blood for needle localization and thoracoscopic resection of deep pulmonary nodules. J Pediatr Surg 2002; 37: 1729-1731. 37. Mobley DL, Wakely PE Jr, Frable MA: Fine-needle aspiration biopsy: Application to pediatric head and neck masses. Laryngoscope 1991;I01:469-472. 38. Montorsi M, et al: Laparoscopy with laparoscopic ultrasound for pretreatment staging of hepatocellular carcinoma: A prospective study.J Gastrointest Surg 2001;5:312-315. 39. Mora J, Gerald WL, Cheung NK: Evolving significance of prognostic markers associated with new treatment strategies in neuroblastoma. Cancer Lett 2003;197:119-124. 40. Paolucci V, et al: Tumor seeding following laparoscopy: International survey. WorldJ Surg 1999;23:989-995,discussion 996-997. 41. Pappo AS, et al: Biology and therapy of pediatric rhabdomyosarcoma. J Clin Oncol 1995;13:2123-2139. 42. Partrick DA, Rothenberg SS: Thoracoscopic resection of mediastinal masses in infants and children: An evaluation of technique and results. J Pediatr Surg 2001;36:1165-1167. 43. Partrick DA, et al: Successful thoracoscopic lung biopsy in children utilizing preoperative CT-guided localization. J Pediatr Surg 2002;37:970-973, discussion 970-973. 44. Rao BN: Present day concepts of thoracoscopy as a modality in pediatric cancer management. Int Surg 1997;82:123-126. 45. Rodgers BM, Talbert JL: Thoracoscopy for diagnosis of intrathoracic lesions in children. J Pediatr Surg 1976;ll: 703-708. 46. Rousou J, et al: Randomized clinical trial of fibrin sealant in patients undergoing resternotomy or reoperation after cardiac operations: A multicenter study. J Thorac Cardiovasc Surg 1989;97:194203. 47. Saenz NC, et al: The application of minimal access procedures in infants, children, and young adults with pediatric malignancies. J Laparoendosc Adv Surg Tech A 1997;7: 289-294. 48. Sailhamer E, et al: Minimally invasive surgery for pediatric solid neoplasms. Am Surg 2003;69:56&568. 49. Schaeff B, Paolucci V, Thomopoulos J: Port site recurrences after laparoscopic surgery: A review. Dig Surg 1998;15:124134. 50. Shoup M, et al: Port site metastasis after diagnostic laparoscopy for upper gastrointestinal tract malignancies: An uncommon entity. Ann Surg Oncol 2002;9:632-636. 51. Skoldenberg EG, et al: Diagnosing childhood tumors: A review of 147 cutting needle biopsies in 110 children. J Pediatr Surg 2002;37:50-56. 52. Smith MB, et al: A rational approach to the use of fine-needle aspiration biopsy in the evaluation of primary and recurrent neoplasms in children. J Pediatr Surg 1993;28:1245-1247.

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53. Smith MB, et al: A prospective evaluation of an endoscopic ultrasonic probe to detect intraparenchymal malignancy at pediatric thoracoscopy. J Laparoendosc Surg 1996;6: 233-237. 54. Somers JM, et al: Radiologically-guided cutting needle biopsy for suspected malignancy in childhood. Clin Radio1 1993;48:236-240. 55. Tan GM, Tan-Kendrick AP: Bronchial diameters in childrenuse of the Fogarty catheter for lung isolation in children. Anaesth Intensive Care 2002;30:615-618.

56. WaldhausenJH, Tapper D, Sawin RS: Minimally invasive surgery and clinical decision-making for pediatric malignancy. Surg Endosc 2000;14:250-253. 57. Weinstein JL, Katzenstein HM, Cohn SL: Advances in the diagnosis and treatment of neuroblastoma. Oncologist 2003;8:278-292.

Wilms' Tumor Edward PTagge, Patrick B. Thomas, and H. Biemann Othersen, Jr.

Wilms' tumor continues to be a subject of intense interest, involving both clinical and basic science investigations. With the aid of five cooperative protocols by the National Wilms' Tumor Study Group ( M S G ) , there has been marked improvement in survival. In the fourth NWTSG study ( M S - 4 ) , the 2-year relapse-free survival rate for children with low-risk Wilms' tumor exceeded 91%.60 However, there continue to be a variety of unsolved problems. Anaplastic tumors, clear cell sarcomas of the kidney, and rhabdoid tumors of the kidney are still relatively resistant to therapy. Ten percent of patients have prognostic variables, including unfavorable histology, chromosomal loss on l p and 16q, and diploidy. Patients with lung or liver metastases, major tumor spillage during resection, remote lymph node involvement, and bilateral tumors all have worse outcomes. In addition, there is an increasing appreciation of the long-term morbidity of successful cancer therapy in children. Finally, the underlying molecular basis of Wilms' tumor is quite complex and remains unclear. This chapter briefly summarizes the new information available, focusing on the conclusions of NWTS-4, a preliminary discussion of the results of NWTS-5, and an overview of future directions in Wilms' tumor management.

HISTORY Pathologic descriptions of the tumor now known as nephroblastoma were written as early as 1872.44In 1879 Osler realized that physicians were reporting renal tumors in children and giving them different names, though they were all describing the same type of solid tumor.l()Theclassic article was presented in 1899 when Wilms (a surgeon) reviewed the literature and added seven cases of his own, describing the clinical picture that now bears his name.'" Initially, surgical excision was the only therapeutic option, but the prognosis was grim. However, in 1916 radiation therapy was added by Friedlander,5()and Ladd improved the surgical technique, increasing the survival rate to 20%.8Whemotherapywith actinomycin D and vincristine was eventually added, and this combination of surgical excision, postoperative

irradiation, and chemotherapy ushered in the modern era, with a 2-year survival rate of 81% Because Wilms' tumor is an infrequent occurrence in the United States, it was realized that collaborative research was mandatory to obtain statistically significant numbers of patients. Thus the NWTSG was established in 1969. The original membership included institutions from the Children's Cancer Study Group, the Pediatric Division of the Southwest Oncology Group, and the Pediatric Division of the Cancer and Leukemia Group B. The initial goals of the M S G were to improve the survival of children with Wilms' tumor and other renal tumors, to study the long-term outcome of children treated successfully by identifying adverse effects, to study the epidemiology and biology of Wilms' tumor, and to make information regarding successful treatment strategies for Wilms' tumor available to physicians around the world. The therapeutic studies conducted by the NWTSG eventually involved more than 250 pediatric oncology treatment centers in the United States, Canada, and several other countries. During its final years, approximately 450 to 500 patients with Wilms' tumor were entered annually, including 70% to 80% of all cases in the United States. In 2001 the NWTSG merged with the Children's Cancer Group, the Pediatric Oncology Group (POG), and the Intergroup Rhabdomyosarcoma Study Group to form a new national organization, the Children's Oncology Group (COG). Patient entry into the NWTSG clinical trial protocols was completed in 2002, and future clinical trials will be conducted by the renal disease committee of the COG. The "NWTS" designation will still be used for the continuing study of late effects.

EPIDEMIOLOGY Worldwide, Wilms' tumor affects approximately 1 child per 10,000 younger than 15 years.l"I9 Wilms' tumor represents approximately 6% of childhood cancers in the United States, and the total incidence is estimated at 450 to 500 cases a year." Incidence rates appear to be slightly elevated for blacks (both American and African) in comparison to whites but are only half as great among Asians.

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Several case-control studies have suggested that paternal occupation, maternal hormone exposure during pregnancy, or genetic predisposition may increase the risk for Wilms' tumor. The median age at onset is 38 months in the NWTS series, with the onset in girls occurring on average 6 months later than in boys. Patients with bilateral tumors, aniridia, cryptorchism or hypospadias, Beckwith-Wiedemann syndrome, or intralobar nephrogenic rests tend to be diagnosed much younger than average (median age, 17 to 27 months). Those with familial disease or multicentric tumors have intermediate age-at-onset distributions, whereas those with perilobar nephrogenic rests are diagnosed at older ages. Wilms' tumor shows a strong association with certain congenital anomalies: WAGR syndrome (Wilms' tumor, aniridia, genitourinary malformations, and mental retardation), Beckwith-Wiedemann syndrome (an overgrowth syndrome characterized by exomphalos, visceromegaly, macroglossia, and hyperinsulinemic hypoglycemia), and hemihypertr~phy.~~ Urologic anomalies, such as lobular nephromegaly, hypospadias, and cryptorchidism, are often seen with Wilms' tumor. WAGR syndrome is a rare genetic disorder and is associated with a defect in chromosome llp13. Most children with WAGR syndrome are diagnosed at birth because the aniridia is usually obvious. However, less than 1% of children with Wilms' tumor have WAGR syndrome. Aniridia is a severe eye disease characterized by iris hypoplasia; both sporadic cases and familial cases with an autosomal dominant inheritance exist. Some of the svoradic cases are caused by large chromosomal deletions involving the Wilms' tumor gene (WAGR syndrome), resulting in an increased risk of developing Wilms' tumor. A recent review of cancer and aniridia cases found that patients with sporadic aniridia have a relative risk of 67 (confidence interval, 8.1 to 241 ) of developing Wilms' tumor.66 Denys-Drash syndrome is characterized by pseudohermaphroditism, progressive glomerulopathy, and Wilms' tumor. Genetically it is associated with mutations of the Wilms' tumor 1 ( W T I )gene. More than 90% of patients with Denys-Drash syndrome who carry constitutional intragenic W T l mutations are at high risk for the development of Wilms' tumor. In fact, prophylactic bilateral nephrectomy in two patients with missense mutations in the WTI gene was recently reported.75 A small percentage of Wilms' tumors are familial in nature. The pattern of transmission for hereditary Wilms' tumor is likely autosomal dominant, with incomplete and variable penetrance.lsJl2 Although some familial cases involve mutations in WTI, more are associated with the familial Wilms' tumor genes FWTl at 17q and FWT2 at 19q, for which fine-scale mapping is currently in progress.

MOLECULAR BIOLOGY AND GENEilCS The development of Wilms' tumor is thought to involve changes in a number of genes that function to control

normal kidney development and growth." Roughly 2% of children diagnosed with Wilms' tumor have a relative who was also diagnosed with Wilms' tumor. The occurrence of these rare Wilms' tumor families suggests that an altered gene is important in the development of this nephroblastic tumor. Other factors point to the importance of an underlying genetic predisposition. Wilms' tumors can occur bilaterally in approximately 5% to 10% of affected children.Z9 In addition, nephrogenic rests, potentially premalignant lesions, are found within the kidneys of 30% to 40% of children with Wilms' tumors. Wilms' tumor is an important model for the study of fundamental mechanisms of carcinogenesis. Statistical evidence to support the involvement of a tumor suppressor gene in the pathogenesis of Wilms' tumor was initially provided by Knudson and Strong in 1972.82According to Knudson's hypothesis of tumor suppressor genes, patients with a familial cancer syndrome inherit one chromosome with an inactive tumor suppressor gene locus because of germline mutation. The counterpart tumor suppressor gene on the remaining paired chromosome is subsequently inactivated by a somatic muration, leading to the formation of cancer. Knudson extended his famous two-hit model of carcinogenesis, originally proposed for retinoblastoma, to Wilms' tumor. In this model, children who were susceptible to retinoblastoma or Wilms' tumor were born with a constitutional DNA mutation in one allele of a presumed tumor suppressor gene-so-called loss of heterozygosity (LOH). Thus, only one new genetic event, the deletion or inhibition of the paired allele, would be needed for tumorigenesis to occur. This condition would increase the likelihood of bilateral tumor formation and an earlier age of onset compared with sporadic cases. subsequent review of chromosomal LOH revealed that the maternal allele was lost in 52 of 53 tumors demonstrating this trait.30 This surprising fact implies that chromos~malloss from a tumor is not a random event and that the alleles of the Wilms' tumor suppressor locus are not equivalent. This functional difference between the maternal and paternal alleles of a gene is termed genomic imprinting. However, the genetics of Wilms' tumor are even more complex than originally believed. More recent evidence suggests that some bilateral and multifocal Wilms' tumors may arise from somatic mosaicism rather than a germline mutation, contradicting the central tenet of the two-hit model.6 The biologic pathways leading to the development of Wilms' tumor involve several genetic loci, including two genes on chromosome 1lp--one on chromosome 1lp13 (the Wilms' tumor suppressor gene W T l ), and the other on chromosome 1lp15 (the putative Wilms' tumor suppressor gene WT2). In addition, loci at l p , 7p, 16q, and 17p (the p53 tumor suppressor gene) are believed to harbor genes involved in the biology of Wilms' tumor. More recent studies have localized two familial predisposition genes on chromosomes 19 and 17, but their actual identification is still ongoing. It is also known that predisposition in some families is due to neither WT1 nor the chromosome 19 or 17 genes, implying that other Wilms' tumor predisposition genes exist.

CHAPTER

The mapping of the genetic loci associated with Wilms' tumor resulted from a combination of clinical observations, karyotype analyses, and molecular genetic studies. In 1964 Miller et aLg8reported an association between aniridia and Wilms' tumor. Subsequently, the rare complex of developmental anomalies known as the WAGR syndrome was described, in which more than 30% of affected children developed Wilms' tumor.lol Karyotypic analvsis of those children demonstrated a deletion in the short arm of one copy of chromosome 11 at band 13.116 The observation that the rare WAGR syndrome was invariably associated with interstitial deletions of chromosome~llpl3,and that tumor tissue at this same locus often displayed LOH, ultimately led to the cloning of the first Wilms' tumor gene WTl.2O,52 WT1 is a complex gene encoded by 10 exons. Cells that express WTl produce four distinct WTI messenger RNAs (mRNAs), which reflect alternative splicing patterns of the transcription products of the WTl gene. The WTl protein is between 45 and 49 kD in size, depending on which mRNA splice variant is translated into protein. The carboxyl terminus of the WT1 protein contains four zinc finger domains, which is a protein motif known to facilitate binding to DNA in a sequence-specific pattern. This implies that WT1 is a transcriptional factor regulating yet unknown targeted genes. WT1 has important functions during genitourinary development, evidenced by its highly restricted temporal and spatial expression in glomerular precursors and by the failure of kidney development in WTl-null mice. In addition to its function in genitourinary development, a role in hematopoiesis is suggested by WTl's aberrant expression in a subset of acute human leukemias. WTI is also expressed in mesothelial cells; a specific oncogenic chromosomal translocation fusing the N-terminal domain of the Ewing's sarcoma gene EWS to the three C-terminal zinc fingers of WTl underlies desmoplastic small round cell tumor.86 Ninety percent of patients with the even rarer DenysDrash syndrome harbor germline mutations in WTl. Most are missense mutations resulting in single amino acid s u b stitutions. Microscopic examination of the kidney in patients with the WAGR and Denys-Drash syndromes often reveals intralobar nephrogenic rests.8 The existence of dominant negative mutations of WT1 is supported by the observation of specific constitutional mutations of WTI in children with Denys-Drash syndrome.31J09 Unlike children with the WAGR syndrome, in whom large deletions on 1lp13 are seen,loYthose with Denys-Drash syndrome have only point mutations of the WTl gene.losInterestingly, the phenotypic effects of these constitutional WTI mutations are far more severe than those resulting from complete deletion of WTl, suggesting that the altered WT1 protein in patients with Denys-Drash syndrome is dysfunctional and acts in a dominant-negative f a ~ h i o n . ~ , ~ ~ WTl is mutated in approximately 20% of all patients with Wilms' tumors. The frequency of germline WTl mutations in patients with bilateral Wilms' tumor and of detectable WTl mutations in Wilms' tumor specimens is low. Linkage at the WTl locus has been excluded in most

27

Wilms' Tumor

447

familial cases." Inherited WTI alterations have also been observed in a few small families with Wilms' tumor, but studies of large families have demonstrated that their inherited predisposition to Wilms' tumor is not due to an altered WTl gene. A recent review of cancer cases and aniridia in Denmark found that patients with sporadic aniridia have a relative risk of 67 (confidence interval, 8.1 to 241) of developing Wilms' tumor." However, patients with the WAGR syndrome or Denys-Drash syndrome each account for less than 1% of all children with Wilms' tumor. The role of WTl mutations in patients with unilateral Wilms' tumor not associated with congenital syndromes seems to be limited, because less than 15% have mutations of WTl.5l

In a subset of Wilms' tumors, LOH has been demonstrated for markers at the llp15 locus, with maintenance of heterozygosity for the llp13 Karyotypes of Wilms' tumors have demonstrated DNA loss at the llp15 locus. Here, several genes (IGF2, p577KIP2, H19, KVL.QT1) that regulate somatic growth are subject to dysregulated imprinting, including the gene for Beckwith-Wiedemann syndrome (BWS).This is the location for the putative second Wilms' tumor gene, WT2, which has yet to be cloned.85 BWS may result from overexpression of a gene at l l p 1 5 that normally has only the paternal copy of the gene expressed (a process called genomic imprinting). In fact, karyotypic analysis has demonstrated a constitutional duplication of the paternal l l p 1 5 chromosomal fragment in some children with BWS. Other children with the syndrome have two grossly normal copies of chromosome 11, both inherited from the father (thus there is no maternal copy)-a phenomenon called uniparental i ~ o d i s o m y .It~ is ~ ,believed ~~ that inheritance of two copies of the paternal gene for BWS would double the expression of this gene, resulting in the overgrowth features. Much interest has centered on insulin-like growth factor 2 (IGF2), which resides at llp15, as the candidate WT2 gene because it is subjected to genomic imprinting. However, to date, no direct evidence has implicated this factor in the pathogenesis of BWS or Wilms' tumor. Investigators in Japan identified a paternally expressed imprinted gene, PEG8/IGF2AS, in this locus.lo3It is transcribed in the opposite direction to the IGF2 transcripts, and some gendkic regions are shared with the I G F ~ gene. Interestingly, PEG8/IGF2AS and IGF2 were found to be overexpressed in Wilms' tumor samples, at levels 10 to 100 times greater than in normal kidney tissue neighboring the tumors. These findings imply that PEG8/IGF2AS may be a marker for Wilms' tumor and also suggest the possibility that PEG8/IGF2AS is one of the candidate ~ i l m stumor ' genes.

Additional Wilms' Tumor Loci The existence of an additional Wilms' tumor locus on the long arm of chromosome 16 (16q) has been suggested by

448

PART

III

MAJOR TUMORS OF CHILDHOOD

tumor LOH for 16q in approximately 20% of Wilms' tumor specimens (compared with a 5% background rate).?#-78.9"Preliminary analysis by Grundy et al.69 in 232 patients with Wilms' tumor suggested the LOH for 16q was a statistically important adverse prognostic factor. When compared with patients without LOH, the relapse rate was 3.3 times higher ( P = 0.01), and the mortality rate was 12 times higher ( P < 0.01), in patients with LOH for 16q. The same study also reported LOH for l p in 12% of Wilms' tumor patients, along with relapse and mortality rates that were three times higher than for patients without l p LOH (not statistically significant). Because of these data. NWTS5 studied the effect of LOH for 16a and l p on the prognosis for Wilms' tumor patients. Linkage analyses in four large families with an inherited susceptibility to Wilms' tumor have implicated the existence of yet another Wilms' tumor Genes at 1lp13, 1 lp15, and 16q have been determined not to play a role in the Wilms' tumors of those families, and detailed linkage analyses will be required to determine the chromosomal location of the familial Wilms' tumor gene. Glypican-3 (GPC3) is a heparan sulfate proteoglycan that can bind to growth factors, such as IGF2. One report noted increased exvression of GPC3 in Wilms' tumor and hepatoblastoma, suggesting a growth-promoting or neutral activity for this gene.l" Another study determined the presence of sequence variants of GPC3 in tumor and normal tissue from 41 male patients with Wilms' tumor.138 Two nonconservative single base changes were present in tumor tissue only, implying a possible role for GPC3 in Wilms' tumor develovment. Investigators from Columbia University performed a survey of gene expression in Wilms' tumor using oligonucleotide microarrays,87 identifylng 357 genes differentially expressed between Wilms' tumors and fetal kidneys. Wilms' tumors systematically overexpressed genes corresponding to the earliest stage of metanephric development and underexpressed genes corresponding to later stages. This signature set was enriched in genes encoding transcription factors PAX2I" and HOXA11, as well as the metastasis-associated transcription factor EMF.

CLINICAL PRESENTATION In the past, most children presented with an asymptomatic abdominal mass, usually noted by a family member (Fig. 27-1). The availability of modern imaging techniques, such as ultrasonography (US) and computed tomography (CT), has allowed the early evaluation of abdominal pain and the discovery of nonpalpable renal masses. Early symptoms include microscopic hematuria (in one third of patients) and other urinary disturbances, malaise, weight loss, and anemia. Occlusion of the left renal vein by tumor extension may obstruct the left spermatic vein, with a resultant varicocele. In addition, tumor thrombus may progress up the inferior vena cava into the heart (right atrium) and cause cardiac malfunction. Occasionally, an acute abdominal crisis occurs after rupture of a Wilms' tumor as a result of a relatively minor abdominal injury. The physical examination should include careful palpation of the abdomen and measurement of blood pressure.

.

. Large tumor mass in the superior portion of the kidney. The tumor bulge was felt by a visiting grandmother.

Wilms' tumor usually presents with a round, smooth, palpable flank mass. Patients with Wilms' tumor may have hypertension secondary to tumor production of renin or renal vascular compression by the mass. Finally, it is important to identify genitourinary anomalies and the presence of aniridia or hemihypertrophy.

DIAGNOSIS No definitive diagnostic blood or urine test for Wilms' tumor exists, although there has been interest in the diagnostic utility of vascular endothelial growth factor (VEGF),81hya1uronan:Z and basic fibroblastic growth factor (bFGF).? Advances in imaging technology have improved the ability to detect Wilms' tumor and its precursor, nephroblastomatosis, as well as the spread of tumor to other organs.55 However, in terms of imaging, there is still wide variation in clinical practice compared with the guidelines recommended by the NWTSG. The preferred radiologic method for evaluating children with suspected Wilms' tumor is CT (Fig. 27-2),with US particularly suited for the detection of venous extension. Magnetic resonance imaging (MRI) identifies blood vessel involvement, although it is not one of the NWTSG recommended preoperative studies (Fig. 27-3). CT of the abdomen may also identify lesions in the contralateral kidney or liver. A plain chest radiograph is taken to evaluate for pulmonary metastasis. CT of the chest is controversial because lesions not visible on radiographs but seen on CT are difficult to interpret. A recent study looked at whether identifylng minimal pulmonary metastatic disease by chest CT in patients with Wilms' tumors and normal

CHAPTER

Wilms' Tumor

449

B

A 9

27

-

A, Abdominal computed tomography scan demonstrating a large tumor mass in the left kidney. B, Bivalved left kidney with tumor.

chest radiographs could predict children at increased risk of pulmonary relapse.105 A retrospective analysis of 449 children entered into the United Kingdom Children's Cancer Study Group (UKCCSG) Second Wilms' Tumor Study between July 1986 and September 1991 was performed.

When only stage I patients were analyzed, there was a significant difference between the pulmonary relapse rate of 43% (3 of 7) in the CT-positive group and 10% (5 of 48) in the CT-negative group (P = 0.02). Importantly, 4 of 8 patients with stage I disease with pulmonary relapse died.

SCREENING Children with BWS and idiopathic hemihypertrophy are at increased risk for developing Wilms' tumor. A recent report evaluating patients from the BWS Registry and previously published studies noted that children with BWS and hemihypertrophy benefited from US screening at intervals of 4 months or less,24 although false-positive screening examinations did result in unnecessary surgery. The National Institutes of Health performed a costbenefit analysis of screening for Wilms' tumor and hepatoblastoma in children with BWS.Y%suming that US examinations were performed three times a year from birth until age 7 years, screening a child with BWS from birth until age 4 years resulted in a cost per life-year saved of $9,642; continuing until age 7 years resulted in a cost per life-year saved of $14,740.

PATHOLOGY

.

Coronal section of a magnetic resonance image demonstrating bilateral Wilms' tumors almost totally replacing normal kidney tissue. No vascular involvement was noted on this study.

The classic Wilms' tumor is composed of the three components seen in normal kidney differentiation: blastema, tubules, and stroma (Fig. 27-4). These components are believed to recapitulate the differentiation of the normal nephron unit. Classic Wilms' tumors are known to be heterogeneous with respect to component proportions and to exhibit aberrant adipose tissue, skeletal muscle, cartilage, and bone. Wilms' tumors may also contain only

450

PART

I I1

M q l o ~TUMORS OF CHILDHOOD

distribution of anaplasia and requires that anaplastic nuclear changes be confined to sharply restricted foci within the primary tumor. The overall incidence of anaplasia varies from 3.2% to 7.3%.14J41Anaplasia is rarely seen in tumors of patients younger than 2 years at diagnosis; its incidence increases to about 13% in patients older than 5 years." A higher incidence has recently been reported in female patients and in non-Caucasian patients.l4.'41 Anaplastic Wilms' tumors frequently show aneuploidy and mutations in the tumor suppressor gene p53.Il3

Clear Cell Sarcoma of the Kidney

.

Medium-power microscopic view ( ~ 1 0 0H&E ; stain) of Wilms' turnor with tripartite histology. Epithelial elements consist of tubules (lower right-hand portion of image) and abortive tubular structures. The majority of the slide contains cellular blastema with small round primitive cells with scant cytoplasm. The mesenchymal elements have a looser spindle cell configuration.

one of these components (monophasic Wilms' tumors); such tumors can be difficult to distinguish from other childhood tumors. Other renal tumors that may be clinically confused with Wilms' tumors are congenital mesoblastic nephroma, clear cell sarcoma of the kidney, and rhabdoid tumor of the kidney. Congenital mesoblastic nephromas are lowgrade spindle cell tumors that recur locally but rarely metastasize. Clear cell sarcomas and rhabdoid tumors initially were believed to be variants of Wilms' tumors, and they were included as "unfavorable histology" in NWTSI. However, with better histologic, immunohistochemical, and molecular characterization of these two tumors, it has been found that neither has a relationship to Wilms' tumors. Indeed, both types of tumors have distinct histopathologic characteristics, aggressive behavior, and a poor response to treatment. Although Wilms' tumors have an excellent prognosis, each of the three cellular components can exhibit focal or diffuse anaplasia, which is a major indicator of a poor outcome. The presence of anaplasia is currently the only criterion for "unfavorable histology" in a Wilms' tumor. Anaplasia denotes the presence of gigantic polypoid nuclei within the tumor sample. Recognition of this change requires both (1) nuclei with major diameters at least three times those of adjacent cells, with increased chromatin content; and (2) the presence of multipolar or otherwise recognizably polypoid mitotic figures. The criteria distinguishing focal from diffuse anaplasia were recently modified. The original definition of focal anaplasia was based on the amount of anaplasia present. Any tumor with anaplastic nuclear changes present in less than 10% of microscopic fields was originally designated as having focal anaplasia. This criterion permitted inclusion when anaplasia was present throughout the tumor, albeit at low density, and cases of anaplasia in extrarenal sites or in metastatic deposits. The new definition emphasizes the

Also known as "bone metastasizing renal tumor of childhood,"g4clear cell carcinoma of the kidney is a distinctive renal neoplasm of childhood that has a propensity for a more widespread pattern of metastases than Wilms' tumor, including bone, brain, and soft tissue. This tumor has a high rate of recurrence and mortality, and it is essential that this entity be recognized to facilitate the early administration of more effective chemotherapy regimens than those employed for Wilms' tumor. There are several variants of clear cell sarcoma of the kidney, including the classic pattern, the hyalinizing pattern, and the epithelioid pattern.

Rhabdoid Tumor of the Kidney Rhabdoid tumor of the kidney is a distinctive renal neoplasm most often encountered in infants younger than 1 year; it is uncommon in patients older than It is extremely aggressive and is the most 5 year~.6,1~~ prognostically unfavorable pediatric renal neoplasm. The most distinctive features of rhabdoid tumor of the kidney are large cells with large, vesicular nuclei (Fig. 27-5); a prominent single nucleolus; and the presence of cytoplasmic inclusions composed of whorled masses of intermediate filaments. Another distinctive feature is the aggressive, invasive pattern of this lesion (Fig. 27-6). Rhabdoid tumor of the kidney has a diverse immunohistochemical profile, and the same cell can be positive for many supposedly incompatible epitopes for epithelial, myogenous, neural, and mesenchymal cell types. Features that are helpful in identifying rhabdoid tumor of the kidney include the presence of hypercalcemia and widespread lymphogenous and hematogenous metastases in an infant.

Nephrogenic Rests In a kidney with Wilms' tumor, associated renal develop mental abnormalities called nephrogenic rests (nephroblastomatosis) are often present (Fig. 2777).These rests are small foci of persistent primitive blastemic cells that are normally found in neonatal kidneys.9 The kidneys of virtually all children with inherited susceptibility to Wilms' tumor contain nephrogenic rests, thereby providing evidence of a constitutional defect in kidney development. In addition, 25% to 40% of children with sporadic

CHAPTER

.

High-power microscopic view (x400) of tumor cells with eccentric nuclei and prominent, glassy, inclusion-like eosinophilic cytoplasm. These features merit the descriptor "rhabdoid (muscle like).

Wilms' tumor have nephrogenic rests within the nearby "normal" kidney t i s ~ u e . ~ A report from our group noted that the same somatic mutation of WI'I was present in the Wilms' tumor and in the nearby nephrogenic rests, providing molecular evidence that nephrogenic rests may be premalignant lesions.lo7 The association between nephrogenic rests and the genetic loci implicated in Wilms' tumor may also be reflected in the anatomic location of these premalignant le~ions.~~Wephrogenic rests developing at the periphery of the renal lobe (perilobar nephrogenic rests) are usually found in children with BWS. Intralobar nephrogenic rests, which may arise anywhere in the renal lobe, are typically found in children with aniridia or other features associated with I.Ir7l.Vhese observations suggest that the various Wilms' tumor genes may be

27

Wilms' Tumor

451

.

Low-power microscopic view (x20) of nephrogenic rest, with aggregates of primitive metanephric tissue with dark-staining blastema and primitive tubule formation. Normal tubules are present in the lower left portion of the image.

involved in distinct developmental pathways in the kidney and that their inactivation may interrupt normal kidney development at specific times.

STAGING The following staging system was used in the NWTS-5 protocol and was modified from previous NWTSG trials. Stage I: The tumor is limited to the kidney and is completely resected. It did not rupture and was not biopsied before removal. The renal capsule has an intact outer surface. The vessels of the renal sinus are not involved, and there is no evidence of tumor at or beyond the margins of resection. Stage 11: The tumor extends beyond the kidney but is completely resected. There is regional extension of tumor (i.e., penetration of the renal capsule or extensive invasion of the renal sinus). The blood vessels outside the renal parenchyma, including those of the renal sinus, contain tumor. The tumor was biopsied (except for fine-needle aspiration) before removal, or there was spillage of tumor before or during surgery that is confined to the flank and does not involve the peritoneal surface. There is no evidence of tumor at or beyond the margins of resection. Stage 111: Residual nonhematogenous tumor is present, confined to the abdomen. Any one of the following may occur:

Medium-power microscopic view ( ~ 1 0 0 showing ) "tongue" of tumor within a vascular channel, an indicator of extensive angiolymphatic invasion. I

1. Lymph nodes within the abdomen or pelvis are found to be involved by tumor (renal hilar, para-aortic, or beyond). 2. The tumor has penetrated through the peritoneal surface. 3. Tumor implants are found on the peritoneal surface.

452

PART

III

MAJORTUMORS OF CHILDHOOD

4. Gross or microscopic tumor remains postoperatively (e.g., tumor cells are found at the margin of surgical resection on microscopic examination). 5. The tumor is not completely resectable because of local infiltration into vital structures. 6. Tumor spill, not confined to the flank, occurred either before or during surgery.

Operative Therapy Despite the advances in multimodal treatment of Wilms' tumor, surgical staging and tumor resection remain the central components of therapyl2"Fig. 27-8). The surgeon must remove the tumor, determine the intra-abdominal stage by lymph node sampling, and carefully examine the liver and the contralateral kidney. Even if the tumor is considered nonresectable, an open biopsy furnishes an adequate sample of the tumor and allows intra-abdominal staging. The surgical guidelines for management of a possible Wilms' tumor have been clearly outlined. A large transabdominal, transperitoneal incision is recommended for adequate exposure. Thoracic extension may occasionally be necessary. The celiotomy must be large enough to avoid excessive tumor manipulation, which has been associated with increased intraoperative tumor spill. Complete exploration of the abdomen is required. The contralateral kidney should be palpated before nephrectomy to exclude bilateral Wilms' tumors. Gerota's fascia must be incised, the kidney turned to visualize its posterior surface, and any suspicious areas biopsied. Then the lateral peritoneal reflection over the tumor is opened, and the colon is reflected medially. The renal vein and inferior vena cava are palpated carefully to rule out extension of the tumor into the vein. Ideally, this determination should be made by preoperative US. If tumor extension is present, this should be removed en bloc with the kidney. Patients with extension of tumor thrombus above the level of the hepatic veins are probably best managed with preoperative chemotherapy to facilitate shrinkage of the intravascular thrombus. An attempt should be made to first expose and ligate the renal vessels to lessen the chance of hematogenous

Stage IV: Hematogenous metastases (e.g., lung, liver, bone, brain) or lymph node metastases outside the abdominopelvic region are present. Pulmonary nodules not detected on chest radiographs but visible on chest CT do not mandate treatment with whole-lung irradiation, and such patients are treated according to the stage of the renal tumor. Stage V: Bilateral renal involvement is present at diagnosis. An attempt should be made to stage each side according to the foregoing criteria, based on the extent of disease before biopsy.

TREATMENT All children with Wilms' tumor should have the benefit of therapy from a team of pediatric physicians consisting of radiologists, pathologists, oncologists, surgeons, anesthesiologists, and radiotherapists. Cosentino et al.33 reported their 25-year experience with Wilms' tumor at Children's Memorial Hospital in Chicago. They noted an increased survival in patients who were treated primarily at their specialized children's hospital compared with those who had surgical excision of Wilms' tumor by general surgeons and general urologists followed by subsequent referral.

A •

-

B A, Schematic of the extent of a large Wilms' tumor. B, Large tumor and left kidney after removal

CHAPTER

spread of tumor cells; however, initial ligation should not be performed if it would be technically difficult or dangerous. The analysis of surgical factors in NWTS-1 and NWTS2 showed that delayed ligation of the renal vein did not produce any deleterious effects.84 However, intraoperative pulmonary embolism has been reported, and early vein ligation may avert this c0mplication.l2~Care should be taken to avoid rupture of the tumor capsule and tumor spill. The adrenal gland may be left in place if it is not abutting the tumor; if it is (as with superior pole lesions), the adrenal gland should be removed with the neoplasm. The ureter is ligated and divided as low as possible because of the risk of urothelial tumor extension. The tumor and the uninvolved portion of the kidney are mobilized and removed intact. Tumors that involve contiguous structures should be biopsied and staged. These patients can be treated with chemotherapy to shrink the tumor, thereby allowing nephrectomy with preservation of the contiguous organs. Radical en bloc resection of nonessential structures (e.g., tail of the pancreas, segment of diaphragm) should be undertaken only if the surgeon is sure that all disease can be completely removed. If residual neoplasm must be left behind, a biopsy should be done, and the site identified with metallic clips. The use of titanium clips is strongly recommended, as ferromagnetic clips can interfere with CT. Clips are best applied by placing a nonabsorbable suture in the structure to be marked and attaching the clip to the suture. Partial nephrectomy is generally not indicated in patients with unilateral Wilms' tumor. Exceptions include children with synchronous or metachronous bilateral disease or solitary kidneys. The recommended approach for these patients is initial biopsy followed by combination chemotherapy before definitive surgical resection. The surgeon should assign a local-regional stage to the tumor based solely on the operative findings. The presence or absence of disease in hilar and regional lymph nodes is an extremely important factor in accurate staging and choice of appropriate therapy. Routine lymph node sampling from the iliac, para-aortic, and celiac areas must be done for accurate staging. Involved or suspicious lymph nodes should be excised, but formal lymph node dissection is not recommended. For accurate staging, it is also important to determine the extent of any peritoneal soilage. The peritoneum is considered "soiled" if there has been a biopsy, there is tumor spill, or the tumor has ruptured. Preoperative incisional or percutaneous needle biopsy using either the anterior or posterior approach is considered local spillage. Incisional biopsy during

Week

0

1

2

3

v

v

v

A

4

5

A

A, dactinomycin (45 !&&/kg);

6

7

8

A

v

v

v

v

453

Wilms' Tumor

operation before nephrectomy is considered local spillage unless, in the surgeon's judgment, the entire peritoneal cavity has been soiled in the process (diffuse spill). Tumors are sometimes adherent to adjacent structures (e.g., colon, spleen, diaphragm). Tumors and adherent tissues that are removed en bloc entail no tumor spill. Those that are removed as separate specimens-the neoplastic tissue having been cut across in the process-are considered to involve tumor spill (local or diffuse). When tumor rupture occurs preoperatively and tumor cells are disseminated throughout the peritoneal cavity, the patient's disease is classified as stage 111, and radiation therapy must be delivered to the entire peritoneal surface (abdomen and pelvis). Tumors may be inoperable because of size, extension into the suprahepatic portion of the inferior vena cava, or other reasons. Past experience in the NWTSG and studies conducted by the Societe Internationale d'oncologie Pediatrique (SIOP) have shown that pretreatmentwith chemotherapy almost always reduces-the bulk of the tumor and renders it resectable."~"~",Ii7~133 It is recommended that all patients undergo initial exploration to assess operability and obtain a biopsy specimen of the tumor, because the staging error rate in nonbiopsied renal masses is 5% to 10%. Patients who are staged by imaging studies alone are also at risk for understaging or overstaging, leading to inappropriate treatment. Once there is adequate reduction in the tumor's size to facilitate nephrectomy, definitive resection should be completed. In general, radiographic re-evaluation should be performed at week 5. Radiographic evidence of persistent disease can occasionally be misleading, because the tumor's failure to shrink could be due to predominance of skeletal muscle or benign elements. 1f the tumor remains inoperable, biopsy of both the primary tumor and accessible metastatic lesions should be performed. Patients with progressive disease have a very poor prognosis and require treatment with a different, more intensive chemotherapy regimen. '21

Chemotherapy Because patients in the United States are treated based on NWTSG protocols, the recently completed NWTS-5 chemotherapy regimens are applied in this section. As a rule, chemotherapy follows radical nephrectomy and lymph node sampling, except in the case of bilateral disease or inoperable tumors. The specific treatment plan varies by stage, patient age, tumor weight, and histology.

9

10

A

v

27

v

V, vincristine (0.05 mg/kg); V*, vincristine (0.067 mglkg).

v

11 12 13 --

14

15

16

17

18

A

A

A

v*

v*

v*

454

III

PART

Week 0

M A ~ O TUMORS R OF CHILDHOOD

1 2 3 4

A

5

D+

6

7

8 9 10 11 12 13 14 15

V

V

A

v v v v

v

v

D+ V V

16 17 18 19 20 21 22 23 24

A

D*

A

v*

v*

v*

D* v*

A

v*

XRT A, dactinomycin (45 pg/kg IV); D*, doxorubicin (1.0 rng/kg IV); D+, doxorubicin (1.5 rng/kg IV); V, vincristine (0.05 mg/kg IV); V*, vincristine (0.067 mg/kg IV); XRT, radiation therapy.

Patients fitting into the following scenarios are treated with nephrectomy and chemotherapy regimen EE-4A (Table 27-I), using dactinomycin and vincristine:

Wilms' tumor.54For more than 30 years, SIOP has recommended that the diagnosis of Wilms' tumor be based on imaging and metabolic exclusion of neuroblastoma, or preoperative percutaneous biopsy, and that treatment . start with chemotherapy to improve the stage distribution and decrease the complication rate. Initial SIOP studies disclosed that preoperative chemotherapy and radiotherapy reduced the incidence of tumor spill at surgery.40 subsequent authors have continued to emphasize the benefits of this approach, stating that preoperative chemotherapy results in easier operations with significantly fewer tumor ruptures and a favorable stage distribution, without putting the patient at increased risk of postoperative morbidity or reduced survival.'2," A recent . prospective SIOP study compared . 4week and &week preoperative chemotherapy in patients older than 6 months with unilateral Wilms' tumor.'" No advantage was found with prolonged preoperative treatment for any of the following factors: percent stage I, intraoperative tumor rupture rate (1% versus 3 % ) , 2-year event-free survival (84%), and 5-year overall survival (92% versus 87%). The NWTSG does not recommend wreowerative needle biopsy of unilateral Wilms' tumor because the sample is small, intra-abdominal staging cannot be done, and needle biopsy may cause local spread, intratumor bleeding, or, rarely, rupture. In addition, NWTSG studies have not shown intraoperative rupture to be a major problem, and treatment without pathologic confirmation may cause diagnostic error. his concern was emphasized b; Zoeller et al.,I4Owho reported both emergency surgery

Stage I, favorable histology, age younger than 24 months, tumor weight less than 550 g. Stage I, favorable histology, age older than 24 months, tumor weight greater than 550 g. Stage I, focal or diffuse anaplasia. Stage 11, favorable histology. Patients fitting into the following scenarios are treated with nephrectomy, abdominal irradiation, and tripledrug chemotherapy regimen DD-4A (Table 27-2): Stage 111, favorable histology. Stage I1 or 111, focal anaplasia. Stage favorable histology or focal anaplasia. (Pulmonary nodules not detected on chest radiographs but visible on CT do not mandate treatment with whole-lung irradiation. The decision to administer whole-lung irradiation is at the discretion of the investigator.) Patients fitting into the following scenarios are treated with nephrectomy, abdominal irradiation using 1080 cGy, and four-drug chemotherapy regimen I (Table 27-3):

L

Stages I1 to IV,diffuse anaplasia. Stages I to IV,clear cell sarcoma of the kidney. There is no universal agreement about the timing of chemotherapy and surgery for resectable unilateral

-Week 0

1 2 3 4 5

6

7

8 9 10

11 12 13

v

v

v

D

D

v

v

v C E

v

v

14 15 16 17 18 19 20 21 22 --- 23 24

D

C*

v C E

v* C*

L

v* C E

D

D

v*

v* C*

C*

C E

.

XRT L P ~ -

--

C, cyclophosphamide (14.7 mg/kg/day x 5 IV); C*, cyclophosphamide (14.7 mg/kg/day x 3 IV); D, doxorubicin (1.5 rng/kg IV); E, etoposide (3.3 mg/kg/day x 5 IV); V, vincristine (0.05 mg/kg IV); V*, vincristine (0.067 rng/kg IV); XRT, radiation therapy.

CHAPTER

performed because of tumor rupture and incorrect diagnosis of renal cell carcinoma in a small cohort of children treated by the SIOP protocol. In the United States, extensive experience has accumulated using preoperative therapy for children with Wilms' tumor. However, preoperative chemotherapy is considered most appropriate for children with bilateral tumors in whom parenchyma-sparing procedures are desirable,"' patients with inoperable tumors, and those with extensive intravascular tumor extension. The NWTSG concern is that patients staged by imaging studies alone are at risk for understaging or overstaging. If one chooses to give preoperative therapy based on imaging alone (with or without a needle biopsy), the local tumor should be considered a stage 111 lesion, and treatment should include regimen DD-4A for patients with favorable or focal anap&sia histology or unknown histology and regimen I for patients with diffuse anaplasia histology. The UKCCSG Wilms' Tumor Study 3 has adopted preoperative chemotherapy for Wilms' tumors but Eequires a prechemotherapy biopsy for histologic diagnosis. A recent review of the usefulness and safety of prechemotherapy biopsy noted that biopsy material was not diagnostic in 4% of patients, and in 12% the biopsy revealed tumors other than Wilms' tumor.13Wf the 182 children who had percutaneous cutting needle biopsy, a fall in hemoglobin (20% of cases) and local pain (19%') were the most-common complications. One child required emergency nephrectomy due to massive intratumoral bleeding, another had tumor rupture and subsequently died, and a third developed a needle tract tumor recurrence 8 months after the biopsy.

Radiotherapy Since the early decades of the 20th century, radiation therapy has played an important role in the management of Wilms' tumor. In the past, high radiation doses and eccentric field arrangements were responsible for significant late toxicity; however, examination of long-term survivors and information obtained from the NWTSG and SIOP studies have allowed us to tailor radiation fields and doses to provide high levels of local tumor control with minimal late effects.39 Patients with stage " I and I1 tumors with favorable histology do not require abdominal irradiation. Children with stage I anaplastic Wilms' tumor do not receive abdominal irradiation, but those with stages I1 to IV do. All ~ a t i e n t swith clear cell sarcoma of the-kidney receive postoperative radiotherapy. All stage I11 patients are given postoperative irradiation totaling 1080 cGy in 6 fractions. Tumor bed irradiation is usedwhen only hilar lymphadenopathy is present or when there is residual disease confined to the flank. The field is extended across the midline to include all the vertebral bodies at the levels concerned, but not far enough to overlap any portion of the contralateral kidney. The portals are extended (e.g., for the entire length of the para-aortic chains) when these nodes are involved. Total abdominal irradiation is given when there is diffuse

27

Wilms' Tumor

455

peritoneal seeding, gross tumor spillage within the abdominal cavity during surgery, or preoperative intraperitoneal rupture. For stage IV patients, infradiaphragmatic irradiation is given if the primary tumor would have qualified as stage 111; otherwise, no abdominal radiotherapy is administered. When stage IV patients have pulmonary metastases, both lungs are treated, regardless of the number and location of visible metastases. The portals cover both lungs, specifically including the apices and posterior inferior portions, and 1200 cGy is administered in 8 fractions.

TREATMENT CHALLENGES lntracaval and Atrial Extension Tumors that extend into the renal vein or vena cava present particular pr0blems.2~ Preoperative US usually demonstrates the extent of any problem accurately. Pulmonary tumor embolus is a risk, and infracardiac caval occlusion and exploration are recommended. When the proximal extent of the thrombus can be clearly established, the vena cava is occluded above that point and opened, and the tumor thrombus is removed. Some prefer to open the cava without proximal occlusion and insert a large-bore, open-ended suction tube into the vein and advance it as the tumor is sucked out. If the tumor is adherent to the wall of the vena cava, removal by balloon catheter is required. A recent report illustrated an unusual case in which the tumor within the cava was tightly adherent to the venous wall and required complete excision of the vena cava and left renal vein and a portion of the iliac system.115 Free-floating and adherent tumors are classified as stage 11, but if the tumor invades the wall of the vein, it should be considered stage 111.49 Most authors agree that tumor growth into the suprahepatic vena cava and atrium requires cardiopulmonary However, if the tumor bypass when managed ~urgically.~~ can be localized and controlled below the atrium, resection without the use of cardiopulmonary bypass may limit morbidity. Lodge et al.90described a technique in which tumor thrombectomy was performed without the use of cardiopulmonary bypass. They used transesophageal echocardiography to localize the tumor thrombus and an upper midline extension of the transverse abdominal incision to obtain intrapericardial control of the inferior vena cava (Fig. 27-9A) before extracting the tumor thrombus from the infrahepatic vena cava (Fig. 27-9B). Previous data showed that primary surgical removal of tumors with intracaval extension is associated with an ~~~ increased incidence of surgical c o m p l i ~ a t i o n s .This was particularly true for those patients with extension above the level of the hepatic veins or even farther into the right atrium. These extensive tumors can be managed with preoperative chemotherapy to facilitate Preoperative shrinkage of the intravascular thrornbu~.l2~ therapy allows the caval tumor extension to shrink or even totally disappear, thereby obviating the need for cardiopulmonary bypass for removal of the tumor thrombus.

456

A

.

PART

III

MAJOR TUMORS OF CHILDHOOD

B -

A, Close-up intraoperative procedure. The surgeon's hand is displacing the liver down, exposing the suprahepatic inferior vena cava below the diaphragm. Just above that, the diaphragm has been incised, along with the pericardium, in anticipation o f intrapericardial control o f the inferior vena cava. B, Intraoperative picture o f extraction o f tumor embolus from the vena cava below the liver.

A recent review detailed the outcomes of children who had intravascular extension into the inferior vena cava or atrium.l2Wf 2731 patients in NWTS-4, 165 (6%) had intravascular extension of Wilms' tumor. The level of extension was the inferior vena cava in 134 (4.9%) and the atrium in 31 (1.1%). Sixty-nine patients (55 with inferior vena cava extension and 14 with atrial extension) received preoperative therapy. Complications during preoperative chemotherapy were seen in five patients. in 39 The intravascular extension of the tumor recressed " of 49 children with comparable pre- and post-therapy radiographic studies, including 7 of 12 in whom the tumor regressed from an atrial location, thus obviating the need for cardiopulmonary bypass. Surgical complicG tions occurred in 36.7% of the children in the atrial group and 17.2% in the inferior vena caval group. The frequency of surgical complications was 26% in the primary resection group versus 13.2% in the group undergoing preoperative therapy. When all the complications of therapy were considered, the incidence of complications among those receiving preoperative therapi was not statistically different from the incidence among those undergoing primary resection. The difference in 3-year relapse-free survival (76.9% for 165 patients with intravascular extension; 80.3% for 1622 patients with no extension) was not statistically significant. Thus, preoperative treatment facilitated resection by decreasing the extent of the tumor thrombus. but the overall fkauencv of complications was similar in both groups.

Bilateral Tumor Patients who present with bilateral Wilms' tumor (stage V) account for approximately 5% of all cases (Fig. 27-10).

The surgical management of these patients remains controversial. Some groups have advocated bilateral nephrectomy followed by transplantation. Another approach uses ex vivo tumor dissection followed by autotransplantation in an attempt to preserve functioning renal tissue.41 However, reviews of children treated with preoperative chemotherapy based on NWTS regimens indicate that they have an excellent prognosis; survival rates for those having a favorable histology exceed 80% at 2 yearsll.'" and 70% at 10 years after diagnosis.I00 However, there is an increased risk of renal failure in these patients. Concerns regarding the impact of hyperfiltration injury on patients

a

-

Abdominal computed tomography scan showing

bilateral Wilms' tumor. The darker-appearing tumor tissue has totally replaced the left kidney and is in the posterior portion o f the right kidney.

CHAPTER

with less than 50% of the renal parenchyma remaining after resection, and the presence of renal failure in 5.4% of long-term survivors of bilateral Wilms' tumor, have resulted in a more conservative surgical approach in these patients. Identifying these patients at the time of initial diagnosis is important to facilitate renal-sparing surgery. The study by Coppes et al.27 identified the joint presence of perilobar nephrogenic rests and intralobar nephrogenic rests, or the presence of perilobar nephrogenic rests in children diagnosed during the first year of life, as important risk factors. These features did not predict all future events, however, and further study is warranted. Patients treated by preoperative chemotherapy have an equivalent survival to those undergoing initial radical surgery, but more renal units can be preserved in those given preoperative chemotherapy. Thus, radical excision of the tumor should not be attempted at the initial operation. Partial nephrectomy or wedge excision can be performed at the initial operation only if all tumor can be removed, with preservation of the majority of renal parenchyma on both sides. Bilateral biopsies should be obtained to confirm the presence of Wilms' tumor in both kidneys and define the histologic type. Discordant pathology may be observed in 4% of cases. Suspicious lymph nodes should be biopsied, and a surgical stage assigned to each side. For patients fitting the following scenarios, chemotherapy regimen EE-4A (see Table 27-1) should be administered after the initial surgical biopsy and staging: Bilateral stage I with favorable histology or focal or diffuse anaplasia. Bilateral tumors, one or both kidneys evaluated as stage 11, with favorable histology. For patients fitting the following scenarios, chemotherapy regimen DD-4A (see Table 27-2) is used: Bilateral stage I1 with focal anaplasia. Bilateral stage I11 or IV with favorable histology or focal anaplasia. Patients with bilateral stage 11, 111, or IV tumor with diffuse anaplasia are treated initially with regimen I (see Table 27-3). The response to therapy should be evaluated after week 5 by CT scan to assess the reduction in tumor volume and the feasibility of partial resection. At the time of the second-look procedure, partial nephrectomy should be done only if it will not compromise tumor resection and only if negative margins can be obtained. If there is extensive tumor involvement precluding partial resection in one kidney, complete excision of tumor from the least involved kidney is performed. If this procedure leaves a viable and functioning kidney, radical nephrectomy is performed to remove the opposite kidney. If there is a possibility that the remaining kidney can be salvaged, only a biopsy should be obtained, and the extent of disease delineated with titanium clips. Additional chemotherapy is then given, and the patient is reassessed before week 12. If there is persistent disease, the patient should receive radiation therapy.

27

Wilms' Tumor

457

Approximately 1% of children with unilateral Wilms' tumor develop contralateral disease. Coppes et al.2' assessed the demographic and histologic features associated with metachronous bilateral Wilms' tumor by reviewing all children registered during the first four NWTSs.27 Fifty-eight of 4669 registered children developed metachronous bilateral Wilm's tumor. The cumulative incidence of contralateral disease 6 years after initial diagnosis decreased from greater than 3% in NWTS-1 to approximately 1.5% in the three subsequent studies (P=0.08). Patients with nephrogenic rests had a significantly increased risk of metachronous disease; this was particularly true for young children (20 of 206 aged younger than 12 months, compared with 0 of 304 aged older than 12 months). A report from the Children's Hospital of Philadelphia reviewed the experience with renal salvage procedures in patients with bilateral Wilms' tumor.2Wrom 1982 to 1997, 23 children with bilateral Wilms' tumor were treated with partial nephrectomy, including 7 who were also treated with brachytherapy. Anaplasia was the most significant factor associated with an unfavorable outcome (P= 0.003). The authors concluded that (1) preoperative chemotherapy followed by nephron-sparing surgery is indicated in patients with bilateral Wilms' tumor, except those with diffuse anaplasia, and (2) brachytherapy should be considered for local disease involving chemoresistant tumors.

Tumor in Horseshoe Kidney Wilms' tumor arising within a horseshoe kidney presents a difficult diagnostic and therapeutic challenge (Fig. 27-1 1A). The incidence of horseshoe kidneys in the general population is 1 in 400.76 Neville et al."" described 41 of 8617 patients (0.48%) enrolled in the NWTSG from 1969 to 1998 who developed a Wilms' tumor in a horseshoe kidney, suggesting that Wilms' tumor is 1.96 times more common in patients with horseshoe kidney than in the general population. In their study, horseshoe kidney was not recognized preoperatively in 13 patients, 10 of whom were evaluated with CT. Primary surgical resection was performed in 26 patients, and 15 children were treated with preoperative chemotherapy after biopsy. Surgical complications occurred in 14.6% of patients, including two urine leaks, two ureteral obstructions, and one ureteral injury. Although 37% of Wilms' tumors arising in a horseshoe kidney were judged inoperable at initial exploration, all were amenable to resection after chemotherapy. Present NWTSG recommendations are as follows: At initial exploration, if the tumor is resectable and involves only one side of the horseshoe kidney, resection is recommended. In bilateral cases, accurate surgical staging should be performed via biopsies of all tumors and any suspicious lymph nodes. The patient should then receive stage-appropriate adjuvant therapy, followed by secondlook surgery approximately 6 weeks later to assess tumor response and perform definitive resection if possible (Fig. 27-llB). Despite the frequency of tumor entrance into the collecting system in these difficult cases, the overall incidence of surgical complications in patients with horseshoe kidneys is similar to that reported for other NWTS patients.11gJ22

458

PART

I I1

M A ~ OTc'MoRS R OF CHI~.DHOOD

B

A

.

.

A, Massive midliile Wilms' tumor in a horseshoe kidney. R, Same tumor after preoperative chcn~otiierapy.Tlwrr has been marked shrinkage, inaking the tumor amenable to resection, leaving two functioning renal unit5 on both sides of the spine.

Partial Nephrectomy Partial nephrectomy for unilateral disease remains controversial. A SIOP report examined the experience with partial nephrectomy for children with renal tumors." Surgical criteria for partial resection included tumor confined to one pole of the kidney and occupying less than a third of the kidney, no invasion of the renal vein or collecting system, and clear margins around the tumor. Using these criteria, 13 of 90 cases were suitable for partial nephrectomy. Of these 13 patients, 5 underwent partial nephrectomy. None of the 5 patients had a positive margin or recurrent local disease, and ipsilateral renal function was preserved in all cases.

No patient with recurrent anaplastic histol~~gy survived. Only three patients received high-dose chemotherapy with autologous stem cell rescue, indicating significant progress in the treatment of recurrent favorable-histology Wilms' tumor using salvage regimens with conventional chemotherapy. Early recognition of recurrence may improve outcome. Researchers from the United Kingdom recently studied serum VEGF levels in 13 children with Wilms' tumor.'* Before surgery, the median VEGF level was 20 ng/mL; by the week after operation, levels had fallen to 1.9 ng/mL (P < 0.001, ANOVA). Six months after tumor resection, three of the children had died. A VEGF level greater than10 ng/mL 3 months after surgery suggested tumor recurrence in the three patients who died.

Recurrent Disease Shamberger et al.u4 reviewed the data for the 100 NWTS 4 patients (out of 2482) who developed local recurrence. The greatest relative risk for local recurrence was observed in patients with stage I11 disease, unfavorable histology, and tumor spill during surgery. Multiple regression analysis indicated that tumor spill and the absence of lymph node biopsy were associated with an increased relative risk of recurrence. Survival after local recurrence was poor, with a 2-year survival rate of 43%. Survival was also dependent on initial stage; those who received more therapy before relapse had a worse prognosis. This study demonstrated that tumor spill results in an increased risk of local relapse and reaffirmed the importance of lymph node sampling so that tumors are neither understaged nor undertreated. A recent retrospective review of 54 patients with recurrent Wilms' tumor observed that the 5-year overall survival estimates were 63.6% for patients treated after 1984, compared with 20.6% for patients treated before 1984.42

PROGNOSTIC FACTORS Histology Early on, the prognostic importance of Wilms' tumor histology was appreciated, with the 12% of Wilms' accounting for more tumors with "unfavorable histolo
27

CHAPTER

prognosis was similar to that of similarly staged patients with favorable histology. Patients with stage IV disease and diffuse anaplasia h a d a 4year relapse-free survival ~~ treatment with the four-drug regirate of 1 6 . 7 %despite men, indicating a need for further intensification of therapy. Recently, mutational analysis of 140 Wilms' tumors showed an association between Wilms' tumors with anaplastic features and the occurrence of p53 mutations.3 because a $153mutation had aiso been identified in a Wilms' tumor with favorable histologic features, it remained to be determined whether p53 alterations can be used as a molecular marker for ana~lasticWilms' tumors or as a marker for an adverse outcome. To address that question, investigators st~idied97 Wilms' tumors for p53 expression and correlated expression with outcome.130 They detected $153in 13 of 97 tumors and found that it was associated with disease relapse (39% versus 17%;P= 0.06) but not anaplasia. Among p53negative patients, only 5% had metastatic disease, compared with 31% of p53positive patients ( P = 0.038). Overall survival at 1 year was 94% for p53negative patients and 85% for p53positive patients ( P = 0.34). In 2002, SIOP noted that certain histologic features that remain after preoperative chemotherapy, such as blastema, are of prognostic significance, whereas others are not. Therefore, in the next SIOP trials and study, a revised classification of renal tumors will be followed for treatment purposes: completely necrotic (low-risk tumors), blastemic (high-risk tumors), and others (intermediate-risk tumors)

ow ever,

Wilms' Tumor

459

Conflicting data were presented by 13 member laboratories of the U.K. Cancer Cytogenetics Group.'Vn a review of 127 abnormal kawotyr>es, univariate survival analysis showed no significant adverse effects for karyotype complexity, l p loss, or 1l p loss. The poor outcome of cases with 16q loss was of borderline significance, and the association between relapse risk and gain of l q material was not significant. Only monosomy 22 was a significant marker of poor outcome (13 cases showing 50% relapse-free survival at 5 years, compared with 79% survival for the remaining 114 cases; P = 0.02). Hing et a1.73 undertook an analysis of comparative cenomic hvbridization of 58 samules of favorabie-histol" ogy Wilms' tumors taken at initial diagnosis or relapse. Gain of l q was significantly more frequent in the relapse group (27 of 46 [59%] versus 5 of 21 [24%]; P = 0.019). This result suggests that identifying l q gain at diagnosis could be used to select patients with an increased risk of relapse who might benefit from early treatment intensification. Lu et al."konfirmed this study, noting that in 18 cases of Wilms' tumor with favorable histology, relative overexpression of genes on the long arm of chromosome 1 was seen in all tumors that relapsed, but in none that remained in remission. >

, x

Gene Expression

Examining the expression of tyrosine kinase (Trk) receptors in 39 children with Wilms' tumor, Eggert et al.46 noted that children with high levels of full-length TrkB mRNA (TrkBfull) had a significantly greater risk of death than children whose tumors had little or no TrkBfull expression ( P = 0.02). The 5-year relapse-free DNA Content survival was 100% for patients with low tumor expression Increased tumor cell DNA content has been correlated of TrkBfull, compared with 65% for those with high with a more favorable prognosis in children with a variety tumor expression of TrkBfull ( P < 0.003). Conversely, children with tumors that expressed high mRNA levels of tumors, including embryonal rhabdomyo~arcoma,~~~ of a functionally inactive truncated TrkB receptor and acute lymphoblastic 1eukemia.l34 neurobla~torna,"~ (TrkBtrunc) had a greater 5-year relapse-free survival than For Wilms' tumor, however, the data have been mixed; did children with low levels of TrkBtrunc (95% versus aneuploidy was associated with a worse prognosis among 68%; P= 0.005). patients with favorable-histology Wilms' tumors in one Ghamen et al." evaluated the prognostic value of variseries70 but not in another.5 More recently, possible chroous apoptosis-associated regulatory proteins, such as Bcl-2, mosomal prognostic factors have been identified by Bax, and Bcl-X, in a group of 61 Wilms' tumors. An Grundy et al.," who evaluated DNA gain and loss for sevincreased expression of Bcl-2 was observed in the eral chromosomal segments. In a study of 232 children blastemic component of increasing pathologic stages, registered during NWTS-3 and NWTS-4, LOH of 16q while a gradual decline of Bax expression was observed. markers was present in 17.2% of tumor tissue and was Univariate analysis showed that blastemic Bcl-2 expression associated with a statistically significantly worse 2-year and the Bcl-2/Bax ratio were indicative of clinical progresrelapse-free and overall survival. LOH of chromosome sion, and blastemic Bcl-2 expression was a prognostic l p markers, present in tumor tissue from 11% of chilmarker for clinical progression, independent of stage. dren with Wilms' tumor, was associated with poorer relapse-free and overall survival rates, which were of borderline statistical significance ( P = 0.08 and 0.12, respectively). In contrast, LOH for l l p markers or duplication Growth Factors of l q , present in 33% and 25% of cases, respectively, was Previous reports noted that the sera and urine of chilnot associated with any difference in outcome. Study of dren with Wilms' tumor often contain increased concenthe prognostic significance of tumor cell DNA content trations of hyaluronan. Using a mouse heterotransplant was continued in NWTS-5, with the hope that newly conmodel, Loworn et aL9' noted that the sera of mice supportfirmed DNA variables will facilitate the tailoring of treating tumor growth had a median hyaluronan concentration ment to anticipated outcome.

1

460

PART

III

MAJORTUMORS OF CHILDHOOD

of 9379 pg/L, compared with a median concentration of The 2 416 pg/L in animals not supporting tumor g r o ~ t h . ~ highest serum hyaluronan concentrations were detected in animals harboring blastema-predominant tumors with an unfavorable histology. Complete resection of established tumors also resulted in the return of serum hyaluronan to preheterotransplant concentrations. Lin et a1.88 measured bFGF levels in preoperative and postoperative urine samples from 97 patients with Wilms' tumor. Urinary bFGF was elevated in 42% of preoperative samples, and higher-stage tumors resulted in higher preoperative levels. Patients with relapse or persistent disease had significantly elevated postoperative bFGF levels. Kayton et a1.81 detected VEGF with increasing frequency and quantity in a mouse model of Wilms' tumor. Lung metastases occurred in 8 of 10 animals with VEGF-positive tumors but in only 3 of 11 animals with VEGF-negative tumors, an association that was statistically significant.VEGF was found in 10 of 12 clinical Wilms' tumor specimens tested. Davidoff et a1.M developed adeno-associatedvirus vectors containing the soluble, truncated form of VEGF receptor-2 (Flk-1), a known inhibitor of endothelial cell activation. Significant antitumor efficacy was observed in two murine models of pediatric kidney tumors. Tumor development was prevented in 10 of 15 mice (67%), with significant growth restriction of tumors in the remaining mice.

OUTCOMES NWTSG Results Five therapeutic studies have been completed: NWTS-1 (1969-1974),NWTS-2 (1975-1979),NWTS-3 (1980-1985), NWTS-4 (19861995), and NWTS-5 (1995-2002). Five-year survival percentages for patients enrolled in NWTS protocols were 79.7% for 1969-1974 enrollees, 81.6% for 1975-1979, 86.3% for 1980-1984, 88.6% for 1985-1989, and 90.4% for 1990-1995. These are among the highest for all childhood cancers. The major conclusions of NWTS-1, -2, and -3 were as follows: 1. Postoperative irradiation therapy of the renal bed is not necessary for stage I tumors or for stage 11 tumors with favorable histology. 2. Survival of patients with stage 111, favorable-histology tumors is best when therapy consists of dactinomycin, vincristine, and doxorubicin combined with 1000 cGy radiation therapy to the flank, or dactinomycin and vincristine combined with 2000 cGy radiation therapy. 3. Cyclophosphamide does not improve the prognosis when added to the treatment of stage IV favorablehistology tumors. As a result of these studies, the 2-year survival rate of children diagnosed with Wilms' tumor rose from 20%47 to 90%."-37 NWTS-4 found that pulse-intensive actinomycin D and doxorubicin dosing is as efficacious as and less toxic than the traditional divided-dose method; it is also more

cost-effective, saving an estimated $790,000 a year.60.61 NWTS-4 also revealed that 6 months of treatment for stage I1 to IV favorable-histologytumors is equivalent to 15 months of treatment. Ritchey et a1.'22 examined the incidence of surgical complications among patients enrolled in NWTS-4. In a random sample of 534 patients, 68 patients (12.7%) experienced 76 complications. Intestinal obstruction was the most common complication (5.1% of patients), followed by extensive hemorrhage (1.9%), wound infection ( 1.9%), and vascular injury (1.5%). Intravascular extension into the inferior vena cava, nephrectomy performed through a flank or paramedian incision, and tumor diameter 10 cm or greater were also associated with an increased risk of surgical complications. NWTS-4 also demonstrated that surgical rupture of the tumor must be prevented, because spills produce an increased risk of local relapse.124 NWTS-5 (also know as POG 9440 and CCG 4941) opened in July 1995 and closed in June 2002. It had a variety of objectives, including to (1) evaluate the importance of various biologic prognostic factors; (2) decrease the morbidity of treatment by limiting initial therapy; (3) improve the survival of patients with unfavorablehistology tumors, including Wilms' tumor with diffuse anaplasia, clear cell sarcoma of the kidney, and malignant rhabdoid tumor of the kidney; and (4) study the biology and pathology of patients who present with bilateral Wilms' tumor. The results from NWTS-5 with regard to the genetic implications for clinical outcome are still being analyzed and have not been published. Of particular interest in NWTS-5 was the management of small stage I tumors. Green and Jaffe,"" in a 1979 review, had suggested that nephrectomy might be adequate therapy for patients younger than 24 months with tumors weighing less than 550 g. A subsequent review of children treated during NWTS-1, -2, and -3 supported the hypothesis that NWTS regimens had not improved the excellent prognosis among this group of children."" Thus a "surgery only" arm was developed for investigation in NWTS-5. By March 31, 1998,69 patients had been entered in the surgery-only treatment arm. Nine patients relavsed: three in the tumor bed or abdomen. one in the pleural space, four in bilateral lungs, and one in the contralateral kidney. The relapse-free survival percentage at 2 years was 82.1%, far below the established relapse-free su-rvivalpercentage cutoff of 95%. Thus the surgery-only trial was suspended.

European Results Results from Europe have been similar to NWTS results. For instance, the results of the UKCCSG Second Wilms' Tumor Study were reported in 2OOO.gg Four-year eventfree survival was as follows: stage 1 with favorable histology, 94%; stage I1 with favorable histology, 91%; and stage 111 with favorable histology, 84%. The outlook for patients with anaplastic or rhabdoid variants was poor. A recent Italian review of 98 nephroblastoma patients treated in three consecutive SIOP trials resulted in a 5-year cure rate of 90%.7Wlinicalcourse was influenced mainly by diffuse anaplasia and, to a minor extent,

CHAPTER

27

Wilms' Tumor

461

be more vulnerable to the delayed adverse sequelae of cancer therapy, such as effects on growth, fertility, and neuropsychological function. Wilms' tumor patients have known risk factors for cardiac, renal, and pulmonary toxicity. NWTS-1 demonstrated that the risk of congestive heart failure persisted for 8 to 12 years or more from the time of anthracycline treatment. Patients treated in NWTS-1 to -4 were reviewed to determine the frequency of congestive heart failure and the risk factors for it following Wilms' tumor treatment with doxorubicin.62 The cumulative frequency of congestive heart failure was 4.4% at 20 years among patients treated initially and 17.4% at 20 years among Specialized Tumors those treated for relapsed Wilms' tumor. The relative risk of congestive heart failure was increased in females A review of 4669 patients treated with NWTS-3 and and by cumulative doxorubicin dose, lung irradiation, NWTS-4 protocols yielded 53 children with BWS.lI1 BWS and left abdominal irradiation. A more recent report patients were more likely to present with lower-stage noted that the most important predictor of worsening tumors (P= 0.0001). The overall survival rate at 4 years cardiac performance was total anthracycline dose: for BWS patients was nearly identical to that of patients patients receiving less than 240 mg/mZ showed no carwithout BWS (89% versus 90%). Twenty-one percent of diac deterioration more than 10 years after the end of patients with BWS had bilateral disease. BWS patients treatment.lZg enrolled in NWTS4 had smaller tumors than those Children with Wilms' tumor are also at risk for renal enrolled in NWTS3 (P=0.02), suggesting that US screendysfunction from a variety of factors, including radiation ing may be efficacious. therapy, use of nephrotoxic chemotherapy agents, a Argani et a1.l reviewed 351 cases of clear cell sarcoma theoretical risk due to hyperfiltration,43 and the possible of the kidney, including 182 cases entered in NWTS-1 to involvement of a genetic component (e.g., patients with -4. Overall survival was 69%, and multivariate analysis Denys-Drash syndrome). In 1996 Ritchey et al.l18 revealed four independent prognostic factors for surreported the spectrum of renal failure in 55 of 5823 vival: treatment with doxorubicin, stage, age at diagnosis, patients treated in NWTS-1 to -4, noting that the risk of and tumor necrosis. renal failure at 16 years was 0.6% for all unilateral-disease The results for children with the WAGR syndrome patients and 13% for bilateral-disease patients. were analyzed and reported by Breslow et al.17 Of the Survivors of childhood cancer are also at increased 8533 patients enrolled between 1969 and 2002 by the risk of developing a second malignant neoplasm, both NWTSG, 64 patients (0.75%) had the WAGR syndrome. leukemias and solid tumors. The cumulative risk at Comparing WAGR and non-WAGR patients, the average 20 years varies between 3% and 10% over several studies birth weights (2.94 and 3.45 kg), median ages at diagnosis and is 5 to 20 times greater than that expected in the (22 and 39 months), percentage with bilateral disease general population.65,*2"he incidence of second malig(17% and 6%),metastatic disease (2% and 13%),favorablenancies following Wilms' tumor in NWTS patients was histology tumors (100% and 92%), and intralobar initially reported in 1988; 15 second malignancies were nephrogenic rests (77% and 22%) all differed. Survival identified among 2438 patients, and the observed-toestimates for WAGR and non-WAGR patients were simiexpected ratio, or standardized incidence ratio, was lar at 4 year (95% versus 92%) but significantly different 8.5.18 These results were updated in 1996, and a similar at 27 years (48% versus 86%). Five late deaths among standardized incidence ratio of 8.4 was observed, with WAGR patients were from end-stage renal disease. 43 second malignant neoplasms occurring. Three breast cancers were found, and the relative risk in multivariate analysis was 12. To help characterize cases of secondary Treatment Morbidity and Mortality acute myelogenous leukemia on NWTSG protocols, Shearer et a1.126 reviewed the 7 patients with that disease An increasing number of children with Wilms' tumor among the 43 identified as having second malignant can expect to be cured, reflecting the undisputed neoplasms. All patients received chemotherapy regimens progress made in the treatment of children with this that included doxorubicin1° or etoposide,' and 6 were renal cancer. However, there is an increasing awareness treated with infradiaphragmatic irradiation. The median standardized of the late effects of cancer therapy.4"he latency period from initial diagnosis of the renal neomortality ratio observed in the' Childhood Cancer plasm to development of secondary acute myelogenous Survivor Study was 9.6 overall and 14.1 for the 5-year surleukemia was 3 years (range, 1.2 to 4 years). vivors of Wilms' tumor. Cumulative mortality was 1.8%, 3.1%, and 5.0% at 10, 15, and 20 years, re~pectively.~~ Radiation therapy has a variety of adverse effects. One study, designed to estimate the reduction in adult stature Some of the effects occur immediately after-treatment induced by radiation therapy of the spine in children (e.g., after the administration of certain chemotherapy) treated for Wilms' tumor, noted that height reductions and are usually transient, but they may become permawere dependent on dose, portal size, and age at treatnent. Although children seem to tolerate acute toxicities children were more often affected. m e n ~ . 7Younger ~ of therapy better than adults do, the growing child may

by lymph node involvement. A total of 2535 cases registered in 34 population-based cancer registries in 16 European countries were included in a recent EUROCARE report.Il0 The overall, 5-year survival of all children diagnosed from 1985 to 1989 was 83%. There was significantly lower survival among patients registered in the formerly socialist countries of Estonia, Poland, and Slovakia; overall European survival was slightly lower compared with results reported from the United States and Australia.

0

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Observed height deficits were 4.1 c m for 5 7 patients who received 15 to 24 Gy a t a mean age of 5 5 months; there was n o height deficit a m o n g 1 6 children who received doses less than 1 5 Gy a t a m e a n age of 83 months. Another retrospective study was undertaken to determine t h e possible effect of radiation therapy, chemotherapy, o r both o n live births, birth weight, a n d frequency of congenital malformations i n pediatric Wilms' tumor survivors." A questionnaire was distributed a m o n g survivors of Wilms' tumor treated in NWTS1 to -4. Respondents reported 427 pregnancies. Women who received flank radiation therapy were a t increased risk of fetal malposition a n d premature labor, a n d t h e offspring of these women were a t risk for low birth weight, premature birth, a n d the occurrence of congenital malformations. Importantly, fertility can b e preserved i n child r e n with Wilms' tumor after upper abdominal radiation therapy (10 to 20 Gy) that does n o t include the entire pelvis.8o

FUTURE DIRECTIONS For the first time since 1969, the NWTS is n o t conducting a clinical trial of treatment protocols. Current a n d future efforts a r e focused o n using the large cohort of former Wilms' t u m o r patients to study the long-term effects of diagnosis a n d treatment in survivors a n d to better understand the pathogenesis a n d cause of Wilms' tumor. T h e NWTS is currently conducting a Late Effects Study (LATE, also known as P O G 9442 a n d CCG 4941L), which o p e n e d i n October 1995, designed to identify treatment-related conditions that may develop in participants who were originally treated in o n e of the five clinical trials. LATE is a federally funded, multi-institutional observational study that follows participants a n d their children throughout their lives t o continue monitoring treatment results a n d possible late effects. T h e specific study objectives include the following:

1. Determine the incidence of life-threatening medical conditions in survivors of Wilms' tumor. 2. Determine mortality rates in former Wilms' tumor

3. Determine the risk of serious pregnancy complications a n d other adverse reproductive events in survivors of Wilms' tumor. 4. Determine the frequency of Wilms' tumor a n d o t h e r cancers i n the children a n d o t h e r family members of Wilms' tumor patients. 5. Identify the most informative subgroups of Wilms' tumor patients for use by molecular biologists a n d epidemiologists. By identifjing the treatment a n d host factors associated with excess mortality, interventions may b e develo p e d to target those a t highest risk. Now that 90% of children with Wilms' tumor a r e being cured, it is most important to focus attention o n t h e duration a n d quality of life in the survivors. Future Wilms' tumor protocols will b e d o n e through the COG. These protocols are still in development a t the time of this writing.

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118. Ritchey ML, Green DM, Thomas PR, et al: Renal failure in Wilms' tumor patients: A report from the National Wilms' Tumor Study Group. Med Pediatr Oncol 1996;26:75-80. 119. Ritchey ML, Kelalis PP, Breslow N, et al: Surgical complications after nephrectomy for Wilms' tumor. Surg Gynecol Obstet 1992;1992:507-514. 120. Ritchey ML, Kelalis PP, Haase GM, et al: Preoperative therapy for intracaval and atrial extension of Wilms' tumor. Cancer 1993;71:41044110. 121. Ritchey ML, Pringle K, Breslow N, et al: Management and outcome of inoperable Wilms' tumor: A report of National Wilms' Tumor Study-3. Ann Surg 1994;220:683-690. 122. Ritchey ML, Shamberger RC, Haase G, et al: Surgical complications after primary nephrectomy for Wilms' tumor: Report from the National Wilms' Tumor Study Group. J Am Coll Surg 2001;192:63-68. 123. Ross JH, Kay R: Surgical considerations for patients with Wilms' tumor. Semin Urol Oncol 1999;17:33-39. 124. Shamberger RC, Guthrie KA, Ritchey ML, et al: Surgeryrelated factors and local recurrence of Wilms' tumor in National Wilms' Tumor Study 4. Ann Surg 1999;229: 292-297. 125. Shamberger RC, Ritchey ML, Haase GM, et al: Intravascular extension of Wilms' tumor. Ann Surg 2001;234:116-121. 126. Shearer P, Kapoor G, Beckwith JB, et al: Secondary acute myelogenous leukemia in patients previously treated for childhood renal tumors: A report from the National Wilms' Tumor Study Group. J Pediatr Hematol Oncol 2001;23:109-111. 127. Shurin SB, Gauderer MW, Dahms BB, et al: Fatal intraoperative pulmonary embolization of Wilms' tumor. J Pediatr 1982;101:559-562. 128. Smith MB, Xue H, Strong LC, et al: Forty-year experience with second malisznancies after treatment of childhood cancer: Analysis of outcome following the development of the second malignancy. J Pediatr Surg 1993;28:1342-1348. 129. Sorensen K, Levitt GA, Bull C, et al: Late anthracycline cardiotoxicity after childhood cancer: A prospective longitudinal study. Cancer 2003;97:1991-1998. 130. Sredni ST, de Camargct B, Lopes LF, et al: Immunohistochemical detection of p53 protein expression as a prognostic indicator in Wilms' tumor. Med Pediatr Oncol 2001;37:455-458. 131. Tagge EP, Hanson P, Re GG, et al: Paired box gene expression in Wilms' tumor. J Pediatr Surg 1994;29:134141. 132. Toretsky JA, Zitomersky NL, Eskenazi AE, et al: Glypican-3 expression in Wilms' tumor and hepatoblastoma. J Pediatr Hematol Oncol 2001;23:496-499. 133. Tournade MF, Com-Nougue C, de KrakerJ, et al: Optimal duration of preoperative therapy in unilateral and nonmetastatic Wilms' tumor in children older than 6 months: Results of the Ninth International Society of Pediatric Oncology Wilms' Tumor Trial and Study. J Clin Oncol 2001;19:488-500. 134. Trueworthy R, Shuster J,Look T, et al: Ploidy of lymphoblasts is the strongest predictor of treatment outcome in B-progenitor cell acute lymphoblastic leukemia of childhood: A Pediatric Oncology Group Study. J Clin Oncol 1992;10:606-613. 135. Vujanic GM, Kelsey A, Mitchell C, et al: The role of biopsy in the diagnosis of renal tumors of childhood: Results of the UKCCSG Wilms' tumor study 3:Med Pediatr Oncol 2003;40:18-22. 136. Vujanic GM, Sandstedt B, Harms D, et al: Revised International Society of Paediatric Oncology (SIOP) working classification of renal tumors of childhood. Med Pediatr Oncol 2002;38:79-82. 0

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137. Weeks DA, Beckwith JB, Mierau GW, et al: Rhabdoid tunlor of kidney: A report of 111 cases from the National Wilms' Tumor Study Pathology Center. Am J Surg Pathol 1989;13:439-458. 138. White GR,Kelsey AM, Varley JM, et al: Somatic glypican 3 (GPC3) mutations in Wilms' tumour. Br J Cancer 2002; 86:1920-1922. 139. Wilms M: Die Mischgeschwuelste der Niere. In Leipzig, 1899, Arthur Georgi.

140. Zoeller G. Pekrun A. Lakomek M. et al: Wilms' tumor: The problem of diagnostic accuracy in children undergoing preoperative chemotherapy without histological tumor verification. J Urol 1994;151:169-171. 141. Zuppan CW, Beckwith JB, Luckey DW: Anaplasia in unilateral Wilms' tumor: A report from the National Wilms' Tumor Study Pathology Center. Hum Pathol 1988;19: 1199-1209.

Neuroblastoma Jay L. Grosfeld

Neuroblastoma is one of the most common solid tumors in infancy and childhood. This neoplasm, of neural crest origin, may arise in the adrenal medulla and along the sympathetic ganglion chain from the neck to the pelvis. The clinical course is quite variable, as this highly malignant tumor demonstrates unusual behavior. Although instances of spontaneous regression and tumor maturation from a malignant to a benign histologic form have been the disease is progressive in many cases. Survival in children with other malignancies, such as Wilms' tumor, rhabdomyosarcoma, acute lymphocytic leukemia, germ cell tumors, Hodgkin's disease, and non-Hodgkin's lymphoma, has been significantly improved by the aggressive use of combined treatment modalities, but the outlook for many children with advanced neuroblastoma remains dismal.'j,27,67,74,77,83,116 This neoplasm exhibits great heterogeneity in its behavior and represents a significant challenge to practitioners caring for affected children. Primitive neuroblasts can be identified in the fetal adrenal gland in the 10th to 12th intrauterine week. The nodules increase in number by 20 weeks' gestation but gradually diminish in number toward the end of gestation. Neuroblastoma in situ in the adrenal gland is seen in 1 of every 260 neonates who die of congenital heart disease and in as many as 1 in 39 infants in the first 3 months of life who die from other causes. The clinical incidence of the tumor is approximately 1 in 7500 to % 2 ~ , ~ ~ , ~ ~is responsible 10,000 ~ h i l d r e n . ~ ~Neuroblastorna for 10% of all childhood tumors and 15% of all cancer deaths. The exact cause remains unknown. There are 700 cases diagnosed annually in the United States. Approximately 40% of cases are diagnosed by age 1 year, 75% by 7 years, and 98% by 10 years.Z7 More than half the patients are younger than 2 years at the time of diagnosis.7Weuroblastoma is slightly more common in boys than in girls, with a ratio of 1.2:1.0.27~74It is the most common intra-abdominal malignancy in newborns. Although a decrease in cancer incidence and mortality has been observed in adults, the incidence of cancer in infants in the United States increased from 189 cases per million to 220 cases per million from 1980 to 1990.1'5 Male infants have an increased rate of central nervous system tumors, neuroblastoma, and retinoblastoma, while girls have an

increased rate of teratoma and hepatoblastoma.nj The embryonal nature of neuroblastoma has been well documented by its identification on prenatal ultrasonography, and the tumor has been known to rarely invade the placenta during the antenatal period.X.'2.~6,~0~,1()9,146,17II226 More than 55 cases of antenatally discovered neuroblastoma have been reported in the literature since the original description by Fenart et al. in 1983." The masses are usually identified during ultrasound examinations performed after 32 weeks' gestation. The earliest reported instance was observed at 18 weeks.10" Mothers of infants with congenital neuroblastoma occasionally experience flushing and hypertension during pregnancy as a result of catecholamine released from the fetal tumor in utero. The neo~lasmhas been described in twins on many occasions, and familial occurrences in both mother and child and father and son have been reported.37.70.171 Concordance for neuroblastoma in twins-during infancy indicates that hereditary factors may be predominant, whereas discordance in older twins suggests that a random mutation may be more important. The median age for the occurrence of familial neuroblastoma is 9 months, in contrast to 18 months in the general population. Maris et al.I4j observed that 20% of patients with familial neuroblastoma have bilateral or multifocal tumors and reported evidence for a hereditary neuroblastoma predisposition locus on chromosome 16~12-13.Neuroblastoma has been observed in infants with Beckwith-Wiedemann syndrome (BWS), neurofibromatosis (von ~ecklin~hausen's disease), Hirschsprung's disease, central hypoventilation syndrome (Ondine's curse), fetal alcohol syndrome, and in offspring of mothers taking phenytoin (fetal hydantoin syndrome) for seizure d i s 0 r d e r s . ~ ~ ~ ~ ~ ~ ~ ~ , ~ ~it~is2unlikely 0 W t h o uthat g h environmental factors play an important role in causing this tumor, neuroblastoma has been noted among infants of mothers receiving medical therapy for vaginal infection during pregnancy and with paternal occupational exposure to electromagnetic fields.27 Neuroblastoma may occur at any site where neural crest tissues are found in the embryo. The neuroblast is derived from primordial neural crest cells that migrate from the mantle layer of the developing spinal cord. Tumors may arise in the neck, posterior mediastinum,

468

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MAJORTUMORSOF CHILDHOOD

Mediastinal 20%

I Neck <5% 1 ::$ ',

8

I Adrenal 50% 1 . - .

Distribution of cases of neuroblastoma at each of the primary tumor sites. Primary tumors most commonly occur in the adrenal gland.

retroperitoneal (paraspinal) ganglia, adrenal medulla, ~ 75% , ~ ~ of , ~cases, ~,~~ and pelvic organ of Z u ~ k e r k a n d l . ~In the tumor is located in the retroperitoneum, in either the adrenal medulla (50%) or the paraspinal ganglia (25%). In 20% of cases, the primary tumor is in the posterior mediastinum. Less than 5% of tumors occur in the neck or pelvis (Fig. 28-1).27,73,74,83Primary intracranial S . addition, ~ ~ , ~ ~a~ cerebral neuroblastoma also O C C U ~ In teratoma in an infant may occasionally contain foci of neuroblastoma. Rare cases of neuroblastoma arising in the bladder have also been reported.60The fate of the neuroblasts can follow one of three clinical pathways: (1) spontaneous regression, (2) maturation by differentiation from neuroblastoma to a benign ganglioneuroma, or most frequently, (3) rapid progression to a highly malignant tumor that is often resistant to treatment.

MASS SCREENING In an effort to identify early cases of neuroblastoma that were amenable to cure, mass screening programs were initiated in Japan in 1985, evaluating urinary vanillylmandelic acid (VMA) and homovanillic acid (HVA) levels in infants a t 6 months of age. These studies'identified a large number of infants with neuroblastoma. The survivalin these cases was exceptionally high compared with the survival in patients who present with clinical disease diagnosed by conventional methods. The Japanese screening effort doubled the actual incidence of neuroblastoma than 1 vear but neither decreased the in-infants vounger , " number of cases observed in older children nor improved Sawada the survival of children older than 1 year.19~27J99~200 et al.199,200reported a 96% survival rate in 170 cases of neuroblastoma identified bv screening.. " These observations suggest that neuroblastomas identified by screening were most likely biologically favorable tumors that spontaneouslv, re~resskd.199 However, a small number of screened " patients have had tumors with unfavorable biologic markers and a poor prognosis, and a few screened patients who tested negative at age 6 months later (at 12 to 18 months of age) developed highly aggressive n e u r o b l a s t o m a ~ . ~ ~ ~ In general, mass screening has provided important information regarding the natural history of this enigmatic tumor and has identified a group of tumors that

clearly regress and represent a biologically favorable form of tumor, in contrast to that noted in older children.147 Prospective, population-based, controlled screening trials in Quebec minimized the rate of false-positive cases but had an overall sensitivitv of onlv 45%.The results A~German ~ study were similar to the findings in J a ~ a n . 2 offered screening to 2.6 million infants between 9 and 18 months of age. This effort identified 149 cases of neuroblastoma in 1800 screened infants, demonstrating a predictive value of 8%.202 The German investigators estimated that two thirds of the tumors detected by screening would have regressed spontaneously. The potential risks were highlighted by the fact that all three children who died in the group detected by screening had localized disease and succumbed from complications of treatment. These studies in North ~ m e r i c aand Europe suggest that screening may result in an overdiagnosis of neuroblastoma and the institution of unnecessary therapies.201 However, the results observed in screening studies are valuable and should help minimize treatment in a substantial subset of infants diagnosed with early-stage neuroblastoma that has an excellent chance of either maturing or spontaneously regressing.239 In a limited trial of expectant observation in 11 patients with localized disease detected by mass screening, all tumors decreased in size during the observation period.2" Oue et al.l69 observed 22 patients with tumors that were identified by screening; 13 (59%) spontaneously regressed, and 9 underwent resection for increasing size. Although none had N-myc amplification, other unfavorable biologic factors were noted in 8 babies, including diploidy, unfavorable histology, and chromosomal deletion ( l p ) ,yet all the babies survived.169Some have suggested that there are compelling medical and psychologi~lreasons (especially among parents in false-positive cases) for the cessation of neuroblastoma screening.54238 Following the cessation of screening elsewhere in the world, the Ministry of Health in Japan discontinued its mass screening program in April 2004.169

CLINICAL PRESENTATION Neuroblastoma is a tumor with multiple clinical manifestations related to the site of the primary tumor, the presence of metastases, and the production of certain metabolic tumor by-products. Fifty percent to 75% of reported cases present with an abdominal mass. The tumor may be hard, nodular, fixed, and painful on palpation. Generalized symptoms including weight loss, failure to thrive, abdominal pain and distention, fever, and anernia.27.73.74.83 Hypertension is found in 25% of cases and is related to the production of catecholamines by the tumor. Instances of hypercalcemia have been observed in association with neuroblastoma, and hernoperitoneum caused by sudden spontaneous rupture of the nedplasm has also been rep0rted.~22~ Neoplasms arising in the upper mediastinum or neck may involve the stellate ganglion and cause Horner's syndrome, characterized by ptosis, miosis, enophthalmos, anhydrosis, and heterochromia of the iris on the affected side.73,74,83 Metastases to the bony orbit may produce

CHAPTER

28

Neuroblastoma

469

An autoimmune phenomenon related to an antigenantibody complex has been suggested.9,19j.207Of interest is the fact that these unusual neurologic symptoms may persist even after tumor resection. Poor school performance and learning deficits are not uncommon-in these children.l95,196 Infants with neuroblastoma, ganglioneuroblastoma, and, occasionally, benign ganglioneuroma may present with intractable diarrhea characterized by watery, exploThe diarrhea is related sive stools and hyp0kalemia.42,~~J2~ to the production of vasoactive intestinal polypeptide . Child with bilateral orbital ecchyrnoses ("panda eyes" (VIP) by the t~mor.%,58,74,12~ These tumors often have or "raccoon eyes") resulting from orbital metastases from somatostatin receptors. neuroblastoma. Neuroblastoma may. spread by direct extension into surrounding structures, lymphatic infiltration, or hematogenous metastases. Regional and distant lymph proptosis or bilateral orbital ecchymosis-often referred nodes, liver, bone marrow, and bone cortex are frequently to as "panda eyes" or "raccoon eyes" (Fig. 28-2). The latin~olved.~2,7~,~7,83~9~~~65 Patients with bone cortex metastases ter finding in a child without a history of trauma should have an ominous prognosis. Bone metastases occur in sites always raise the index of suspicion for the presence of a containing red marrow and involve the metaphyseal areas malignancy. Mediastinal tumors may be associated with of long bones in addition to the skull, vertebral column, pelvis, ribs, and sternum.27~74J7.83Bone lesions may cause respiratory distress, due to the tumor's interference with extreme pain. In some cases, the clinical presentation may lung expansion, and dysphagia caused by extrinsic pressure on the esophagus (Fig. 28-3)..i~66~74~24Wediastinalbe characterized by a child's refusal to walk because of leg and paraspinal retroperitoneal lesions may manifest with pain due to bone metastases. Occasionally, patients with paraplegia related to tumor extension through an interadvanced disease present with a bleeding diathesis related vertebral foramen, resulting in a dumbbell- or hourglassto thrombocytopenia from extensive involvement of bone shaped lesion that may cause extradural compression of marrow and interference with hepatic production of clot8 , 2patients, ~2 cauda the spinal ~ o r d . ~ " ~ ~ 8 p ~ ~In~ ,a~ 9few ting factors by liver metastases. Multiple subcutaneous equina syndrome has also been observed. Pelvic tumors skin nodules and hepatomegaly may occur in infants with may be associated with bladder and bowel dysfunction. stage IV-S neuroblastoma. Hematogenous metastases to Anemia is often related to bone marrow invasion by the the brain, spinal cord, and heart are unusual. Brain metastumor. Excessive catecholamine production by the tases usualiv manifest in older children with headaches tumor may result in flushing, sweating, and irritability. Lung metastases are found on chest and ~eizures.'~Jl~ radiographs in only 4% of patients."' This may be the Acute cerebellar ataxia, characterized by opsomyoclonus result of direct extension to the lung from mediastinal and nystagmus ("dancing eye syndrome"), has been observed.g~1~1~1g5~196~~07 TWOthirds of these cases have lymph nodes or diffuse hematogenow-spread, presenting occurred in infants with mediastinal neuroblastoma. The with a radiographic pattern that may be confused with pulmonary edema or interstitial pneumonia.222 Occasionally, involuntary muscular contractions and random eye movements are unrelated to metastases. The cause of lung involvement by intralymphatic metastases (not seen on chest radiographs) is noted at autopsy. this unusual presentation of neuroblastoma is unknown.

A

B

A, Plain chest radiograph shows the presence of a left upper thoracic tumor. B, Computed tomography scan documents a mass in the posterior nlediastinum that contains calcium, suggestive of a neuroblastoma.

470

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DIAGNOSIS Diagnosis of neuroblastoma is made through a variety of imaging and isotopic studies, serum and urine determinations, and histologc and genetic evaluation of tumor tissue. On the plain abdominal radiograph, approximately 50% of cases may show finely stippled tumor calcification.73,74,77 Radiographs also may show displacement of bowel gas by a mass. Paraspinal widening is commonly found with celiac axis tumors. Chest radiographs may show a posterior mediastinal tumor or paraspinal widening above the diaphragm from extension of an abdominal tumor. Computed tomography (CT) can demonstrate tumor calcification ~ ~ ~ CT in approximately 80% of cases (Fig. 2 8 - 4 ) . *With studies using contrast enhancement, one can often distinguish kidney and liver from adrenal and paraspinal lesions and evaluate for intracranial extension of skull metastases.is??,7Wagnetic resonance imaging (MRI) is extremely useful in detecting intraspinal tumor extension and, in some instances, the tumor's relationship to major vascular structures. Helical (spiral) CT with three-dimensional reconstruction is also a useful method of evaluating this latter relationship. The workup of patients with retroperitoneal tumors includes an initial upright radiograph of the abdomen, an ultrasound examination to distinguish a cystic from a solid lesion, and an evaluation for potential obstruction or compression of the inferior vena cava. As a rule, obstruction of the inferior vena cava in patients with neuroblastoma suggests the presence of an ~,'~ CT is perinitially unresectable l e ~ i o n . ~Abdominal formed with intravenous contrast material so that an intravenous urogram can be acquired during the same In most instances, paraspinal or adrenal neuroblastoma causes lateral or downward displacement of the ipsilateral kidney or ureter (or both). A separate intravenous urogram is not necessary. A long bone survey, isotopic bone scintigraphy (using the bone-seeking isotopes technetium and metaiodobenzylguanidine [MIBG]), and multiple MIBG also bone marrow aspirates are also 0btained.7~,75,77.93 images the primary tumor in the adrenal medulla. Isotopic bone scans show a close correlation with the radiographic

skeletal survey and are occasionally more sensitive." Falsepositive bone scans can occur in cases of recent bone trauma or inflammation. The bone-seeking isotopes are picked up by metastatic foci in the bone and by the punctate calcifications in the primary tumor (Fig. 28-5).73,74 Demonstration of the bone-seeking isotope in a retroperitoneal or posterior mediastinal mass suggests that the lesion is a neuroblastoma. Although angiography was once performed to evaluate many childhood tumors, this test is rarely used today because vascular structures can be readily identified by other imaging studies such as helical CT or magnetic resonance angiography (Fig. 28-6). Pelvic neuroblastoma may manifest with both urinary symptoms and constipation. The tumor, usually palpable on rectal examination, must be differentiated from presacral teratoma, yolk sac tumor, nonosseous Ewing's tumor, and pelvic rhabdomyosar~oma.~~,~s Because neuroblastoma is a tumor derived from neural crest cells, it may secrete hormonal products and is likely a member of the amine precursor uptake and decarboxylation (APUD) family of tumors. More than 90% of children with neuroblastoma have tumors that produce high levels of catecholamines or their by-products. Quantification of catecholamine by-product secretion is Adrenaline, best done by 24hour urine c01lection.l~~ noradrenaline, dopamine, metanephrine, HVA, VMA, and vanillylglycolic acid levels are determined. Children with immature, more undifferentiated tumors tend to excrete higher levels of certain by-products (e.g., HVA).73 Patients with more mature tumors excrete more VMA. In rare instances, however, the tumor does not secrete excessive catecholamines. Prasad et al.177suggested that these are parasympathetic neuroblastomas that secrete increased levels of acetylcholine and fail to metabolize tyrosine to dopamine. Patients with advanced malignancy have elevated urine concentrations of cystathionine and homoserine; increased serum levels of neuron-specific enolase, ferritin, and lactic dehydrogenase; and, in 25%

-

Adoniinal computed tomography shows a retroperitoned1 mass with stippled calcificatioil, consistent with neuroblastoma.

.

1'2'-MIBG scintiscarl shows the presence of bone metastases and uptake of the isotope in a prirrlary tumor in the adrenal gland.

CHAPTER

A

28

471

Neuroblastoma

6

Helical computed tomography scan with three-dimensional reconstruction of a neuroblastoma arising near the celiac axis. A, Anterior view indicates that the tumor does not involve the branches of the celiac axis. B, Lateral view demonstrates that the superior mesenteric artely passes through the tumor. (SPPco1orplale.j

of cases, sera positive for carcinoembryonic antiAlthough these observations are of historgen.m~167~216.'28,'44 ical interest, none of these serum levels are independent prognostic factors, nor are they currently used to determine treatment. Although histologic examination of tissue is the key to the conclusive diagnosis of neuroblastoma, in advanced disease, rosettes of tumor cells in bone marrow aspirate and increased urinary excretion of VMA or other catecholamine by-products are often indicative of the diagnosis. 1mmunolog;lc analysis of bone marrow aspirate may be more sensitive than conventional analysis in detecting tumor ce1ls.l" Serial immunocytologic analysis of peripheral blood samples have also identied circulating neuroblasts, documenting tumor dissemination.

STAGlNG Various staging schemes for neuroblastoma were used in the past, including Evans's criteria from the Children's

1

Stage

IIB 111 IV IV-S

Description

Cancer Group (CCG)," the St. Jude staging system" used by the Pediatric Oncology Group (PO(;), a TNM (tumor, lymph node, metastasis) status system employed by the International Union Contra Cancer in Europe, and the Japanese Neuroblastoma Study Group staiing system. These staging criteria were in basic agreement regarding localized, completely resected lesions; instances of metastasis to the bone cortex; and infant5 with Evans's stage IV-S tumors. They disagreed on other aspects of staging, including Evans's stage 111 cases and the importance of lymph node involvement. In 1988 an international staging - ., system , way devised that established a common set of criteria that could be used worldwide and would permit the accrual of large numbers of cases and valid comparisons of data (Table 28-1) .29 The International Neuroblastoma Staging System (INSS) uses certain features of the POG and CCG sistems 'and identifies distinct prognostic groups. These criteria were revised by Brodeur et al. in 1993.ZHIn 2001 the CCG and POG merged with the National Wilms' Tumor

-

--

--

--

Localized tumor confined to area of origin; complete excision, with or without microscopic residual disease; ipsilateral and contralateral lymph nodes negative (nodes attached to primary tumor and removed en bloc with it may be positive) Unilateral tumor with incomplete gross excision; ipsilateral and contralateral lymph nodes negative Unilateral tumor with complete or incomplete excision; positive ipsilateral, nonadherent regional lymph nodes; contralateral lymph nodes negative Tumor infiltrating across the midline with or without lymph node involvement; or unilateral tumor with contralateral lymph node involvement; or midline tumor with bilateral lymph node involvement or bilateral infiltration (unresectable) Dissemination of tumor to distant lymph nodes, bone, bone marrow, liver, or other organs Localized primary tumor as defined for stage I or II with dissemination limited to liver, skin, or bone marrow (limited to infants younger than 1yr)

From Brodeur GM, PritchardJ, Berthold F, et al: Revision of the internationalcriteria for neuroblastomadiagnosis, stagingand response to treatment. J Clin Oncol 1993;11:1466-1477; Brodeur GM, Seeger RC, BarrettA, et al: Internationalcriteria for diagnosis, staging, and responseto treatment in patients with neuroblastoma.J Clin Oncol 1988;6:1874-1881.

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a high MKI, and a dismal outcome. A report by Shimada et a1?12 documented that both histology and ~ - & c a m ~ l i fication provided prognostic information that was independent of staging. Neuroblastomas with N-myc amplification have a characteristic histopathologic phenotype and a rapidly progressive clinical course. The International Neuroblastoma Pathology Classification (INPC) adopted the Shimada classification ~ - 4 ~age-linked ~~2~~ with some minor m o d i f i ~ a t i o n s . ~ ~This PATHOLOGY AND HISTOLOGY classification is both prognostically significant and bioThe pathologic classification of neuroblastoma has been logically relevant. The current system subdivides the revised, and histologic features of the tumor have been undifferentiated subtype into undifferentiated and poorly 2~2 established that have important prognostic v a l ~ e . l l l ~ 2 ~ ~ ~differentiated tumors; changes the name of stroma-rich, The most useful system developed is the Shimada classiwelldifferentiated tumors to ganglioneuroma maturing; fication, which divides neuroblastic tumors into ageand adds a descriptive Schwannian, stroma-dominant related favorable and unfavorable histologic categories Age remains a critical character to gangli0neuroma.2~~ based on whether the tumor exhibits a stroma-rich or prognostic factor, and the grade of differentiation and MKI have different prognostic effects, depending on the stroma-poor appearance (Table 28-2).2l Stroma-rich tumors are characterized by extensive Schwannian patient's age at diagnosis. Although the presence of calstroma and signs of neuroblastic differentiation (i.e., cification was thought to favorably influence survival, developed nuclear and cytoplasmic features of ganglion further studies demonstrated that calcification does not Favorable cells). Stroma-poor tumors contain immature, undifferhave an independent prognostic impa~t.~~l>208 Shimada histology was associated with an 85% survival entiated neural crest cells and have a high mitotic karyorrhexis index (MKI). The MKI refers to nuclear rate, compared with 41 % for unfavorable histologic types. fragmentations and is determined by the sum of the All ganglioneuroblastoma nodular (GNBn) cases were number of necrotic tumor cells, the number of cells with initially classified as unfavorable tumors. Umehara et al.230 were the first to define subsets of these specific neoplasms mitosis, and the number of cells with malformed, lobulated, that exhibit different behavior. Peuchmaur et al.l73 or pyknotic nuclei per 5000 cells examined. The MKI varies with age; a high MKI value in infants younger than recently revised the INPC by dividing GNBn cases into two prognostic subsets-favdrable and unfavorable. The 18 months is greater than 200/5000 cells, and for those older than 18 months it is greater than 100/5000 cells. All favorable type was associated with an 86% event-free surpatients older than 5 years have unfavorable histology. vival, whereas the unfavorable type (two thirds of cases) Stroma-poor tumors often have N-myc amplification, had only a 32% event-free survival. Children with the favorable subset of GNBn have an overall survival of greater than 90%, compared with 33.2% for the unfavorable GNBn subset (Fig. 28-'7).17' Large cell neuroblastoma has been identified as a distinct phenotype with aggressive clinical behavior.22Vhese tumors have unfavorable histologic features, including monomorphous undifferentiated neuroblasts, a low incidence of calcification, and a high " MKI. Immunohistochemical studies Favorable Unfavorable showed that large cell neuroblastoma cells stained posiAppearance Histology Histology tive for neuron-specific enolase, prodrug gene products, Stroma rich Well differentiated Ganglioneuroblastoma, and tyrosine hydroxylase and were negative for CD99.229 (ganglioneuroma) nodular On gross examination, neuroblastoma usually appears Ganglioneuroblastoma, as a highly vascular purple-gray mass that is often solid intermixed but occasionally cystic. The tumor has an easily ruptured, Stroma poor friable pseudocapsule that may lead to significant hemor(i.e., neurorhage during operative manipulation. The tumor is often blastoma) necrotic, especially the undifferentiated form. Mature MKI <4% MKI >4%or Age < I 8 mo tumors (ganglioneuromas) have a more solid consistency undifferentiated and frequently have a fleshy white color. The histologic MKI >2% or Age 18-60 mo MKI <2% and pattern may be quite variable. Primitive stroma-poor differentiating undifferentiated or poorly differentiated neuroblastomas may be indistinguishable from other None All Age >5 yr small, blue round dell tumors such as Ewing's tumor, rhabdomyosarcoma, or primitive neuroectodermal tumors. The neuroblast is a small round cell consisting MKI, mitotic karyorrhexis index. predominantly of the nucleus without much cytoplasm. From Shimada H, Chatten J, Newton WA Jr, et al: Histopathologic prognostic factors in neuroblastoma: Definition of subtypes of ganglioneuroblastoma and an age-linked Immature, undifferentiated tumors are characterized bv classification of neuroblastoma.J Natl Cancer lnst 1984;73:405-416;Shirnada H, closely packed small spheroid cells without any special Stram DO, Chatten J, et al: Identification of subsets of neuroblastomas by combined arrangement or differentiation.I42 Nuclei may appear histopathologic and N-myc analysis. J Natl Cancer lnst 1995;87:1470-1476. cone shaped and are hyperchromic. Rosette formation Study and Rhabdomyosarcoma Study Group to form the Children's Oncology Group (COG), which now employs the INSS for all cases of neuroblastoma. At my institution, 266 cases of neuroblastoma were staged as follows: 14 (5.2%) stage I, 52 (19.6%) stage II,62 (23.4%) stage 111,117 (44%) stage IV, and 21 (7.8%) stage IV-S.

-"

CHAPTER

International Neuroblastoma Pathology Classification. FH, favorable histology; GNBn, ganaglioneuroblastoma nodular; MKI, mitotic karyorrhexis index; %MKC, mitotic and karyorrhectic cells; UH, unfavorable histology; * classic GNBn (single, macroscopically visible, usually hemorrhagic nodule in stroma-rich, stroma-dominant tissue background; ** MKC 2%, 100 of .5000 cells; MKC 4%, 200 of 5000 cells. (From Peuchmaur M, d ' h o r e ES, Joshi W, et al: Revision of the International Neuroblastoma Pathology Classification: Confirmation of favorable and unfavorable prognostic subsets in ganglioneuroblastoma, nodular. Cancer 2003;98:22742281.)

r >50%

t

Neuroblastoma

Absent+Ganglioneuroma maturing subtype

I

Ganglioneuroblastorna nodular classic*

Schwannian development

L

GNBn variant (with or without macroscopic b visible nodule(s)*

0 or >50%

Undifferentiated

+-

Differentiated

I -

Differentiating

. k

may be observed and is considered a sign of early tumor differentiation (Fig. 28-8). The center of each rosette is formed by a tangle of fine nerve fibers. More matureappearing, stroma-rich tumors may contain cells that resemble normal ganglion cells, with an admixture of

. - Hlstolog~cappearance of rosettes of neuroblastoma

FH

b~resentq~an~lioneuroblastoma intermixed

visible nodules

cells from a bone m a r m aspirate, an early sign of tumor dlfferennanon

473

Absent-+Microscopic neuroblastic foci

Neuroblastoma

, .

28

FH

UHIFH

UHIFH

%MKC'*

Age

Any MKI

Any age

UH

>4%

Any age

UH

Any MKI

>1.5 yr

UH

<4%

<1.5 yr

FH

>5 yr

UH

<4%

~ 1 . yr 5

FH

>4%

>1.5 yr

UH

<2%

1.5-5.0 yr

FH

>2%

1.5-5.0 yr

UH

Any MKI

Histology

histologic components characterized by abundant nerve filaments, neuroblastic rosettes, and ganglion cells all seen in a single microscopic field.70."7 On electron microscopy, neurofibrils and electrondense, membranebound neurosecretory granules may be observed. The neurosecretory granusles may be the site of conversion of dopamine to norepinephrine. These ultrastructural findings and genetic identification of the tumor tissue can usually separate neuroblastoma from other small cell tumors. Instances of spontaneous maturation from a highly malignant, undifferentiated neuroblastoma to a ganglioneuroblastoma and subsequently a benign ganglioneuroma have been observed. Ambros et al.11 reported that maturing neuroblastomas consist of both Schwann cells and neuronal cells, including ganglion cells. Schwann cells have normal numbers of chromosomes and triploid flow cytometry, in contrast to other neuronal cells, including ganglion cells.11These observations suggest that Schwann cells may be a reactive population of normal cells that invade a neuroblastoma recruited or attracted by trophic factors and may be responsible for tumor maturation and serve as an antineuroblastoma agent.10J~~2~chwann cells also produce angiogenesis inhibitors that induce endothelial cell apoptosis and may limit tumor growth by restricting angiogene~is.~~.~~

474

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BIOLOGIC AND G E N n I C ALTERATIONS Unique oncogenes are observed in tumors, such as N-myc and ras 0ncogenes.'"2~ Amplification of N-myc (>lo copies) is associated with advanced disease, tumor progression, and a poor outcome, especially in children older than 1 year.'5x7.'!).1.5'2-15X:212 Overexpression of N-myc probably impairs differentiation and promotes the proliferation of N-myc immature neural crest-derived cells.2"z"he proto-oncogene is located on the short arm of chromosome 2p24. Double minutes and long, nonbanding staining regions have been observed at this site and may represent amplified cellular genes. Approximately 30% of patients with neuroblastoma have tumors with N-myc amplification. More than 90% of patients with N-myc amplification have rapidly progressive disease and are reistant to therapy. DNA flow cytometry studies evaluating tumor ploidy indicate that children with diploid tumors have a worse outcome than those with aneuploid (hyperdiploidy or triploidy) turn or^.^^^^^ N-myc amplification is commonly associated with chromosome l p deletion and diploidy.30,89 Diploid tumors are commonly associated with an unbalanced gain of chromosome 17q, even in the absence of N-myc.11~27~"~144 Allelic loss of l l q and 14q and gains of 4q, 6q, l l q , and 18q have also been observed (Table 28-3).27 High expression of the neurotropin Trk-A (a highaffinity nerve growth factor receptor) is associated with a good prognosis and is inversely related to N-myc.lS7Jj8 Trk-A is observed in young infants and in those with stage I and stage IV-S tumors and indicates a very favorable o ~ t c o m e . l "Trk-A ~ ~ ~ is ~ associated with neural cell

Genetic Feature

Associated Factors

Risk Group

N-myc amplification (2p24 locus)

Diploidy or tetraploidy Allelic loss of l p , high Trk-B, advanced disease (stage Ill, IV)

High

More aggressive tumor associated with N-myc amplification Occurs concurrently with N-myc amplification

High Risk related to N-myc

Often associated with N-myc 70%-80%are near diploid tumors associated with disease progression

High

Few associated with N-myc amplification

Intermediate; decreased survival in patients without N-myc amplification

Allelic gain 17q gain Gain at 4q, 6p, 7q, l l q , 18q observed Allelic loss lp36

I

differentiation and tumor regression and may play a role in angiogenic inhibition. The low-affinity nerve growth factor receptor gene is another proto-oncogene that has a prognostic effect similar to Trk-A and probably influences cellular maturation.'"z7Jz() In contrast, high expression of Trk-B with its ligand BDNF may provide an autocrine survival pathway in unfavorable tumors, particularly those ~ ~ ~ ' ~patients ~ have with N-myc a m p l i f i ~ a t i o n . 2 7 ~These more advanced disease, are usually older than 1 year, and have a dismal 0utcome.27J00.~~"rk-C expression has also been identified in neuroblastoma and is usually observed in lower-stage tumors that do not express N-myc.z7,"0 Another gene has been cloned, the multidrug resistance (MDR)-associated protein gene, that is associated with chemotherapy resistance, overexpression of N-myc, and a poor outcome.lm Similarly, elevated P-glycoprotein levels are associated with progressive disease and a poor outcome.""2" Telomerase is increased in tumor cells and maintains cell viability by preserving the telomeres that . ~ ~ ~is~an ~ ~inverse protect the end of c h r o m ~ s o m e sThere relationship between telomerase levels and outcome in neuroblastoma and a direct correlation between telomerase levels and N-myc amplifi~ation.2~ CD44 is a glycoprotein found on the cell surface of a number of tumors, including neuroblastoma. High expression of CD44 is associated with a favorable outcome. In contrast, nm23 overexpression is observed in instances of advanced and The ganglioside GD2 is aggressive ne~roblastoma.14~ found on human neuroblastoma cell membranes, and increased levels are associated with active disease and tumor progression. Gangliosides inhibit the tumorspecific immune response.15'

llq

Correlates with LOH 14q Correlates with LOH l l q , inverse relationship with l p and N-myc Predisposition 16~12-13 Association Chromosome 1 0 (Ret-oncogene) 11~15.5

Intermediate

Familial neuroblastoma Multifocal and bilateral neuroblastoma

Low

Hirschsprung's disease Beckwith-Wiedemannsyndrome

Variable Low

LOH, loss of heterozygosity. Note: This table does not include changes in the genetic expression of Trk-A, -B, and -C; the multidrug-resistant protein gene; telomerase; or others that are covered elsewhere in this chapter.

1

CHAPTER

28

Neuroblastoma

475

Evaluation of the relationship between tumor angiogendisease had operative resection, but many had microesis and outcome in infants with neuroblastoma demonscopic residual disease or tumor that extended into an strates that increased tumor vascularitv characterized bv intervertebral foramen, making complete resection microvessel density correlates with advanced dissemiimpossible. Some of these patients received localized nated disease and the likelihood of metastase~.~~,~9~",ls3 radiotherapy. Others received only operation, despite Angiogenesis is controlled by the balance of humoral the presence of residual tumor; these patients had only a stimulators, inhibitors, and signal transduction pathways.40 75% to 80% cure rate.74,124,164 Angiogenesis is associated with N-myc amplification, unfaBecause of the wide variabilitv in tumor behavior in vorable histology, and poor outcome. Neuroblastoma stage I1 patients with residual disease and the poor surproduces angiogenic factors that induce blood vessel vival of those with more advanced tumors (stages I11 and IV), it became apparent that additional information was growth, including vascular endothelial growth factor required to determine the appropriate treatment. (VEFG), platelet-derived growth factor (PDGF-A), stem cell factor, and their respective receptors Flk-1, PDGFR, During the past 2 decades, a number of biologic and and C-kit.l5 Komuro et a1.'22 demonstrated that high genetic factors have been identified that are important VEGF-A expression correlated with stage IV disease and prognostic indicators and currently influence therapy. suggested that it could be a target for antiangiogenic therBased on the impact of the new INSS, the use of the apy. Kaicker et a1.H' noted that VEGF antagonists inhibit INPC, and the identification of numerous biologic and nkoangiogenesis and tumor growth in e ~ p ~ r i m e n tneual genetic characteristics as risk factors and predictors of roblastoma in athymic mice with xenograft neuroblasoutcome, a risk-based management system has been develNewer treattoma cell line NGP. They also found that thalidomide oped to determine treatment.27~74.208-210~213 suppressed angiogenesis 'and reduced microvessel denment protocols individualize treatment using risk factors sity but not tumor growth. Kim et al."' and Rowe et al.Ig3 as medictors of outcome in an effort to maximize survival. also demonstrated inhibition of tumor growth in experiminimize long-term morbidity, and improve the quality of mental neuroblastoma models using antiangiogenic life. Current protocols are now based on low-, intermedistrategies. Imatinib mesylate, a compound used to treat ate-, and high-risk tumor categorization (Table 28-4). patients with gastrointestinal stromal tumors, has been Good outcomes are associated with stage I, 11, and IV-S shown to decrease the growth of neuroblastoma in vivo patients who are younger than 1 year and have hyperand in vitro, decrease cell viability, and increase apoptosis diploid DNA flow cytometry, favorable histology, less (by ligand-stimulated phosphorylation of C-kit and than one copy of N-myc, high Trk-A expression, and PDGFR) in a severe combined immunodeficiency (SCID) absence of chromosome l p abnormalities. In contrast, a mouse model.15 Davidoff et a1.4Wemonstrated that gene poor prognosis is likely in children older than 1 year with therapy using in situ tumor cell transduction with retroadvanced tumors (stages I11 and IV), more than 10 viral vectors can deliver angiogenesis inhibitors for the copies of N-myc, low Trk-A expression, diploid DNA Flk-1 receptor and restrict tumor-induced angiogenesis ploidy, allelic loss of lp36, and unfavorable histology. and tumor growth. For low-risk patients, surgical excision of the tumor is The Bcl-2 family of proteins is responsible for relaying usually curative and avoids the risks associated with apoptotic signals that influence tumor cell regression chemotherapy. Intermediate-risk patients are usually and is expressed in most neuroblastomas. The Bcl-2 gene treated with surgery and standard chemotherapy. The a protein that prevents neuronal cell death poor prognosis in high-risk patients justifies a much (apoptosis). The level of Bcl-2 expression is high in more intense treatment regimen, including combination advanced cases associated with a poor outcome and low chemotherapy followed by complete surgical excision (if in cases demonstrating tumor apoptosis (regression) and possible), radiation therapy to achieve local control, expression may aiso play a role differentiation. High ~ c l - 2 myeloablative treatments, and bone marrow rescue. .~~ of in acquired resistance to c h e m ~ t h e r a p y Subgroups the Bcl-family include Bcl-xL, which inhibits apoptosis, and Bcl-xS, which induces natural cell death. VEGF upOPERATIVE MANAGEMENT regulates Bcl-2 expression and promotes neuroblastoma cell survival by altering apoptosis and its regulation Complete surgical removal of the primary tumor proteins.14 Elevated caspase levels (enzymes responsible remains an essential component of treatment in the vast for apoptotic signaling) are associated with an improved majority of cases. Operative procedures are performed outcome in neuroblastomas that demonstrate favorable using endotracheal general anesthesia and careful monbiologic features.Y7 itoring. Appropriate large-bore intravenous catheters are placed in the upper limbs. Adequate intravenous access is important because these tumors are quite vascular, and blood loss may be excessive. Body temperature, oxygen satRISK-BASED MANAGEMENT uration, electrocardiogram, and pulse rate are monitored. For many years, the choice of therapy in neuroblastoma The blood pressure must also be carefully monitored intravaried with the extent of disease at the time of diagnosis, operatively to detect sudden hypertension caused by Total excision or the patient's age, and the ~tage.2"~,~~2" excessive catecholamine release from the tumor. excision of as much tumor as possible in localized cases In patients with primary tumors located in the I lesions were resulted in the best outcome~.6~,~"~tage retroperitoneum, the operation is performed through a t i e nstage ts I1 managed by operation a l ~ n e . ~ ~ ~ ~ W a with long, transverse transperitoneal-supraumbilical incision.

476

PART

III

MAJORTUMORS OF CHILDHOOD

INSS Stage

Age

N-myc Status*

I IIA/IIB

0-21 yr >365 days 365 days-21 yr 365 days-21 yr 365 days-21 yr <365 days <365 days >365 days-21 yr >365 days-21 yr >365 days-21 yr <365 days <365 days >365 days-21 yr <365 days <365 days <365 days <365 days

Any Any Nonamplified Amplified Amplified Nonamplified Amplified Nonamplified Nonamplified Amplified Nonamplified Amplified

111

IV

IV-S

Any Nonamplified Nonamplified Nonamplified Amplified

lNPC (Histology)

Favorable Unfavorable Any Any Favorable Unfavorable Any Any Any Any Favorable Any Unfavorable Any

DNA Ploidyt

Risk Group Low Low Low Low High lntermediate High lntermediate High High lntermediate High High Low lntermediate lntermediate High

*N-myc nonamplified=1 copy, amplified >1 copy. tDNA index>l (aneuploid)or=l (diploid). INPC, International Neuroblastoma Pathology Classification; INSS, InternationalNeuroblastomaStaging System. Modified from Children's Oncology Group protocols by LaBerge JM: Neuroblastoma. In O'NeillJA Jr, GrosfeldJL, FonkalsrudEW, Coran AG (eds): Principlesof Pediatric Surgery, 2nd ed. St Louis, Mosby, 2003.

In some cases, a bilateral subcostal chevron incision or a thoracoabdominal incision may be required. The peritoneal space is entered, and on either side, the colon is reflected medially and inferiorly by incising the attachments to the lateral abdominal wall. The spleen and pancreas are mobilized and displaced upward and medially for left-sided tumors. For right-sided tumors, the duodenum and head of the pancreas can be mobilized and retracted medially and the liver attachments divided to improve exposure (Fig. 28-9). In most children with localized disease, all or most of the tumor can be removed successfully. The patient's condition should not be jeopardized by an overzealous surgical attempt at initial resection. En bloc contiguous resection of normal surrounding structures, such as the spleen, stomach, pancreas, and colon, can almost always be avoided. In some cases, it is impossible to separate an adrenal or paraspinal neuroblastoma from the ipsilateral kidney, and nephrectomy may be necessary. It is important to excise any suspicious para-aortic and perirenal lymph nodes for staging purposes. A routine retroperitoneal lymph node dissection is usually not performed. The margins of the tumor resection are marked with titanium clips to guide the port if radiation is required and will reduce the scatter effect noted with other types of metal clips on follow-up CT scan. Because neuroblastoma may have a friable pseudocapsule, careful handling of the tumor during dissection is important to avoid tumor spill and hemorrhage. Neuroblastoma often adheres to or surrounds the great vessels, and special care should be taken to identify and spare the blood supply to important visceral structures, such as the branches of the celiac axis and superior mesenteric artery. Primary adrenal tumors may be fed by

a number of small arteries. The major venous drainage is usually constant, directly to the inferior vena cava on the right side and into the left renal vein and subdiaphragmatic vessels on the left. Although there is no good evidence that partial excision and reduction of tumor bulk favorably affect the prognosis for this highly malignant childhood neoplasm, an improved response to adjunctive therapy has been observed when tumor resection has ~ ~ ~ ~aggressive ~ ~ ~ ~ palliative been a c c o m p l i ~ h e d .Overly debulking that places the child at risk for life-threatening hemorrhage is not indicated. Following a good response to initial chemotherapy, the tumor often shrinks and can be removed during a delayed primary resection or at a second-look operative Inferiorly located paraspinal and primary pelvic tumors often require careful dissection to separate the lesion from the bifurcation of the aorta and inferior vena cava. The tumor frequently extends into the intervertebral foramina (Fig. 28-10). Minimally invasive surgical techniques have also been emvloved for selected cases of n e u r o b l a ~ t o m a . ~ ~ ' Adrenal tumors initially detected by mass screening have been excised laparoscopically by a number of investigators.l23,160 Yamamoto et a1.'3Vescribed three cases of adrenal neuroblastoma in which the lesions were less than 20 mm in diameter. They used a five-trocar technique and kept the intra-abdominal pressure for the pneumoperitoneum less than 4 mm Hg. The well-encapsulated tumors were completely excised; they were placed in a plastic bag and removed through the 10-mm trocar site. All had favorable histology, and none had Nmyc amplification. No recurrences w&e observed. Kouch et al.l25 described laparoscopic resection of six adrenal tumors less than 4 cm in size. There were no conversions L

,

CHAPTER

28

Neuroblastoma

477

Adrer blood

igated adrenal vessels

or tumor recurrence in the abdomen or at the port sites. Iwanaka et a1.107 used laparoscopy for tumor biopsy in advanced cases of neuroblastoma and compared the minimally invasive resection of tumors to open excision via laparotomy. There was no significant difference in the length of procedure or blood loss; however, time to start chemotherapy, interval to postoperative oral intake, and length of hospital stay were less following laparoscopic Lagausie We et al.52 described nine tumor r e ~ e c t i o n . ~ ~ ~ J O cases of adrenal neuroblastoma treated by the laparoscopic approach. Two were detected prenatally, and seven were noted postnatally, including three with stage IV disease. The mean age was 38 months (range, 2 months to 9 years). Complete excision was accomplished in eight children, and one had to be converted to an open procedure. In three cases, one or more lymph nodes were also excised. There were no deaths and one port site infection. These and other reports suggest that in selected cases, laparoscopic biopsy and tumor excision are both safe and effective.32 Mediastinal tumors are usually approached through a standard posterolateral thoracotomy incision. Excision of

A, Tumor of the right adrenal gland. B, The colon attachments are taken down, and the duodenum and head of the pancreas are mobilized and retracted medially. C, The adrenal vessels are controlled and divided, and the tumor is excised. The arterial blood supply of the tumor comes from a number of small vessels from the right renal artery, aorta, and diaphragmatic branches. Venous drainage is usually consistent with direct drainage to the vena cava on the right side. The kidney can often be spared. The tumor bed is displayed at the conclusion of the resection.

the pleura and the endothoracic fascia around the tumor usually allows entry into an appropriate dissection plane. Mobilization of the tumor from the rib edges is accomplished with both sharp and blunt dissection. It is important to identify and either ligate or clip specific intercostal blood vessels feeding and draining the tumor. The tumor may be attached to a number of sympathetic ganglia and intercostal nerves and often extends, in one or more areas, into the intervertebral foramina (Fig. 28-11).4866,155243 It may be impossible to remove every bit of tumor at the foramina1 sites. Small primary tumors have been successfully removed by thoracoscopic techniques. Thoracoscopy is also useful in obtaining tissue for biopsy. In patients with neurologic symptoms (including paraplegia) associated with dumbbell tumors, prompt MRI and an urgent laminotomy to .excise extradural tumor and relieve cord compression are recommended before attempting intrathoracic resection of the tumor. The mediastinal resection can be delayed a short time to allow the patient's neurologic symptoms to improve. If extradural tumor is present on imaging studies but the patient is asymptomatic, chemotherapy is initiated and

478

PART

III

MAJORTUMORS OF CHILDHOOD

-

I A, Lower retroperitoneal paraspinal neuroblastoma and its relationship to the bifurcation of the aorta and ureter. B, Tumor may extend into the vertebral foramina. C, Photograph of the operative field after resection of a right-sided pelvic neuroblastoma. Note the vascular loops placed around the iliac arteries, right iliac vein, and ureter to facilitate a safe dissection. (C, see colmplate.)

may shrink the tumor and avoid the need for laminotomy or laminectomy. The choice of therapy for intraspinal tumor extension is still somewhat controversial. Plantaz et a1.'74 reviewed 42 patients in France and recommended initial chemotherapy followed by surgical removal of residual disease. Yiin et al.242 described 13 cases of neuroblastoma with symptomatic spinal cord

compression and neurologic deficits. Ad1 the patients were treated initially with chemotherapy: three recovered, four improved, and six worsened and became paraplegic. Two of the six recovered after laminectomy. Those authors recommended spinal cord decompression for patients who have neurologic deterioration on chemotherapy. Sandberg et a].'" described the treatment

CHAPTER

--

-

28

Neuroblastoma

479

e A, Right posterolaterai thoracotonly incision used for the excision of a posterior mediastinal neuroblastoma. B, Relationship of the tumor to surrounding tissues. C, The turnor is mobilized and retracted anteriorly, exposing numerous intervertebral extensions. The tumor extensions are divided at the vertebral foramina, leaving small remnants of residual tumor behind. This does not adversely influence the outcome.

Tumor extensions

C

of 46 patients with epidural or neural foramina1 tumor involvement. Nine were low-risk patients with normal neurologic examinations who remained neurologically intact following operation or chemotherapy. Four lowrisk patients with high-grade spinal cord compression improved or remained stable after surgical intervention, but two who were treated with chemotherapy had worsening deficits. Eleven of 12 high-risk patients with normal neurologic examinations and without radiographic high-grade spinal cord compression were treated with chemotherapy and had no neurologic deterioration. Of 16 high-risk patients with high-grade spinal cord compression, 7 of 10 treated initially with chemotherapy and all 6 who underwent initial surgery improved or remained stable. Spinal deformities occurred in 12.5% (2 of 16) treated nonoperatively and in 30% (9 of 30) who underwent operation. The authors concluded that patients with high-risk tumors and spinal involvement but normal neurologic examinations should be offered chemotherapy, with the understanding that a small percentage may require operations for progressive neurologic deficits. Chemotherapy may be avoided in patients with low-risk tumors who can be offered a potentially curative procedure. Patients and their families should be made aware that operative intervention may be associated with subsequent spinal deformity in as many as 30% of cases.Ig8 Cervical neuroblastoma is often localized and has a favorable outcome.n' Haddad et a1.,86 in a study of 43 cervical neuroblastomas, identified four risk factors that were associated with increased operative morbidity: adherence to vascular structures, tumor size, friability, and dumbbell tumors. Imaging studies may show a solid mass with vascular displacement and narrowing.2 Tumors arising in the neck or upper mediastinum often involve

the stellate ganglion. If not present preoperatively, resection may result in postoperative Horner's syndrome.2.7" This is a relatively minor consequence outweighed by complete tumor excision and survival, but the patient's family should be made aware of this possible complication. Special attention should be given to protecting the brachial plexus and the phrenic, vagus, and recurrent laryngeal nerves. Whether additional therapy is necessary for stage I1 tumors depends on the patient's risk assessment based on age, tumor histology, and presence of adverse biologic and genetic factors (e.g., >10 copies of N-myc, chromosome l p deletion, diploid flow cytometry, unfavorable histology).j4Thirteen percent of stage I1 cases have high-risk prognostic factors and require aggressive chemotherapy. Patients with more advanced disease (stage 111) often require more aggressive treatment, including operative resection (if possible), multiagent chemotherapy, and initial local irradiation. Stage I11 tumors in the pelvis or near the celiac axis are often unresectable initially. After chemotherapy, however, the tumor frequently becomes small enough to be excised at a second-look operation.74-83Patients with stage I11 disease have an improved ~ , ~ type ~ of adjuncoutlook after complete r e s e ~ t i o n . jThe tive therapy depends on tumor resectability, histology, and biologic and genetic characteristics affecting risk for that specific neoplasm. Completely resected tumors with favorable prognostic factors may require less intensive chemotherapy. In contrast, patients with incomplete tumor resection are usually treated with local irradiation to the tumor bed and more dose-intensive chemotherapy regimens. Those with high-risk unresponsive tumors may benefit from intensive cytoablative chemotherapy followed by autologous bone marrow transplantation (BMT).31,84,14"14Wigh-risk stage 111 cases can usually be

480

PART

III

MAJORTUMORS OF CHILDHOOD

patients with a complete response to chemotherapy and tumor resection,78,84,218data concerning the biologic characteristics of the surviving patients were often lacking, and an independent effect of gross tumor resection could not be demonstrated.134 More recently, LaQuaglia et a1.135 reviewed 141 INSS stage IV patients and reaffirmed that the rate of gross tumor resection improved with more intense chemotherapy. The probability of local tumor progression was 50% in unresected patients, compared with 10% in those with gross total resection. The overall survival rate was 50% in resected patients, versus 11% in patients with unresected tumors.'" Aggressive surgical management is occasionally associated with late complications in survivors, including ipsilateral atrophy of the kidney following adrenal resection and ejaculatory problems following pelvic tumor excision.l26 Of interest is the very favorable outlook noted in patients with stage 111 and IV tumors arising in the pelvis following complete tumor r e s e c t i ~ n . ~ ~ , ~ ~

predicted by the presence of adverse biologic features, such as age older than 1 year, unfavorable tumor histology, and more than 10 copies of N-rnyc.148J49 The marrow is purged for tumor cells with multiple monoclonal antibodies before BMT.151 Emwlovment of BMT earlv in the management of unresponsive tumors with high-risk biologic factors results in a better outcome than if BMT is attempted as a lastditch effort in patients with progressive disease.149,151,178In recent years, the use of autologous stem cell transplantation has replaced traditional BMT in many childhood cancer facilities. The CCG compared initial resection at diagnosis with delayed primary resection and second-look procedures for initially inoperable stage IV tumors. Complete resection was possible in 62% of the initial group, 77% of delayed primary operations, and 66% of second-look procedures.84 The risk of concomitant nephrectomy and the incidence of postoperative complications were lower in children in the delayed primary resection Because there was no difference in survival among the three groups (40% among complete responders at 3 years), delayed primary resection after chemotherapy was considered the wrocedure of choice in children with stage IV tumors. The role of primary tumor resection in patients with stage IV disease is unsettled. In patients who respond completely or partially to chemotherapy, it has been my practice to perform a delayed primary or second-look operation to remove all possible residual tumor. There are conflicting reports concerning the efficacy of complete resection i n itage IV disease.-~aaseet al.,84 reporting for the CCG, described a survival advantage for stage IV patients with complete resection following delayed primary excision after chemotherapy. In contrast, reports by Kiely1I6and Shorter et al.215 suggest that there is no survival advantage for stage IV patients with complete resection. However, LaQuaglia et a1.,134in a report of 70 stage IV patients, noted that gross tumor resection and a higher-intensity chemotherapy protocol resulted in improved overall survival. Although some studies have shown an improved survival in stage IV 1

,

NEUROBLASTOMA IN INFANCY Infants younger than 1 year at diagnosis have a significantly improved outcome. At the Riley Hospital for Children, the survival rate was 76% for infants younger than 1 year and only 32% for older patients (Fig. 28-12).7Vhisfavorable outlook for patients younger than 1 year extends across all stages, including infants with stage IV metastatic disease. The incidence of stage IV lesions in infants younger than 1 year is 30%, compared with 60% to 70% in older patients.76 ~1tho;gh resection of the primary tumor in stage IV disease is controversial, in my personal experience, the only infant survivors had excision of the primary tumor.76 Similarly, a CCG report described 7 of 11 infants with stage fi disease who had complete delayed primary tumor resection and remained disease free for more than 5 year^.^^,^^ Infants with stage IV disease respond better to chemotherapy than older children do; 50% of Bar graph d e m o n strates t h e improved survival i n infants with neuroblastoma w h o are younger t h a n 1 year.

Percent survival

I

I*

2

Under 1 yr

0

10

20

30

40 Percent

50

60

70

80

CHAPTER

infants have a complete response to treatment, compared with 22% of older children.85 This observation suggests that resolution of metastases may have a greater impact on length of survival than the surgical excision does. Further, this implies that surgical resection is beneficial in some infants and should be a t t e m ~ t e dwhen disseminated disease is controlled by chemotherapy. Paul et al.170 documented a 75% 5-year survival rate in 24 stage IV patients younger than 1 year, compared with a 10% survival rate for older patients with stage TV tumors. Patients were treated with nitrogen mustard, vincristine, dacarbazine, doxorubicin, cyclophosphamide, and cislat tin without BMT. Schmidt et al.204observed a 93% surviva1 rate in infants younger than 1 year with stage IV disease without N-myc amplification; however, those with more than 10 copies of the N-myc oncogene had rapidly progressive disease and often succumbed despite chemotherapy.204 Therefore, more intensive chemotherapy regimens and BMT may be necessary to attain a cure, especially in highly selected infants presenting with adverse biologic markers. 1

STAGE IV-S The most unusual group of patients with neuroblastoma are those infants younger than 1 year with stage IVS disease, characterized by hepatomegaly, subcutaneous nodules, and positive bone marrow, that would otherwise be classified as stage I or 11 primary tumor. Stage IV-S cases account for approximately 30% of patients with neuroblastoma

A

28

Neuroblastoma

481

of these recognized in the first year of life.7"reatment patients is somewhat controversial. Some infants may die as a result of complications of stage IV-S disease rather than tumor progression. Complications of severe hepatomegaly include respiratory insufficiency, caused by significant elevation of the diaphragm by the large, tumor-filled liver; coagulopathy; and renal compromise due to compression by the mass (Fig. 28-13).",45,50,76,236Vomiting may occur because of a change in the gastroesophageal angle related to the diaphragmatic elevation, resulting in gastroesophageal reflux, protein-calorie malnutrition, and aspiration pneumonia. Total parenteral nutrition may be a useful Most fatalities in stage IV-S therapeutic adjunct.l"J",2" cases occur in infants younger than 2 months with severe symptoms related to hepatomegaly, who do not tolerate ~2 therapy as well as older infants d 0 . ~ " ~ Symptomatic hepatomegaly caused by tumor infiltration may benefit from low-dose irradiation to the liver in the range of 600 to 1200 Gy, administered in doses of 100 to 150 Gy/day.21,76s83 Although some early reduction in the size of the liver is seen, and peripheral edema may resolve in a few weeks, complete resolution may take 6 to 15 months.76Resolution of the liver mass is probably related more to the natural course of stage IV-S disease than to radiotherapy. Administration of low-dose cyclophosphamide 5 mg/kg per day is a reasonable treatment alternative. Although some investigators advocate the insertion of a Dacronreinforced Silastic sheet to create a temporary ventral abdominal wall hernia to accommodate the enlarged liver and reduce intra-abdominal pressure, I have not

B

A, Six-week-old infant presented with abdominal dister tio on and hepatomegaly. B, Appearance of the liver at laparotomy. There were multiple metastatic nodules, and the biopsy confirmed the diagnosis of stage IV-S neuroblastoma.

482

PART

III

MAJORTUMORS OF CHILDHOOD

found this technique to be effective.205Mortality due to septic complications after insertion of an external Silastic sheet has been observed.".76 To reduce the risk of infec~~ the use of an tion, Lee and A p p l e b a ~ m lrecommend internal polytetrafluorethylene patch to create a temporary ventral hernia. The graft can be removed in stages as the bulk of the hepatic mass regresses over time. Survival of these unusual infants with remote metastases is greater than 80%, often without specific treatment. Table 82-5 summarizes the results reported in 12 studies of stage IV-S neuroblastoma, with an overall 86% survival rate. Most patients with stage IV-S disease (>go%) have favorable genetic and biologic factors, including high Trk-A expression, no N-myc amplification, favorable histology, and no evidence of allelic loss of chromosome 1p.This suggests that the majority of stage IV-S tumors undergo spontaneous regression. Although most patients with stage IV-S disease do well, Wilson et a1.S6 reported 18 cases with a heterogeneous tumor presentation and a survival rate of only 50%, including three patients with N-myc amplification. The presence of adverse genetic and biologic prognostic factors suggests that this subset of patients ( 4 0 % ) requires more aggressive therapy. Of interest is that infants with multiple subcutaneous nodules seem to have the most favorable outlook. This may be due to increased immunologic activity as a result of tumor being present in multiple ~ i t e s . 7Increased ~ uptake of major histocompatibility complex (MHC) class I antigen by neuroblastoma cells in vitro and in vivo may influence the outcome favorably.22O Infants with stage IV-S disease have normal levels of MHC class I surface antigen expression, whereas those with stages I to IV have low levels.220 Sugio et al.224 reported that down-modulation of MHC class I antigen expression is associated with increased amplification of the N-myc oncogene in patients with advanced disease. In 2002 ~ickversonei a1.'62 described 80 infants with stage IV-S disease from the CCG. Fifty-eight cases were managed without specific therapy. All 44 asymptomatic patients survived without treatment. Symptomatic patients were treated with cyclophosphamide 5 mg/kg

Author (Year) D'Angio et al (1971)45 Breslow et al (1971)23 Nitschke et al (1980)l65 Nickerson et al (1985)163 Blatt et al (1987)21 Wilson et al (1991)236 Suarez et al (1991)223 DeBernardi et al (1992)50 Grosfeld et al (1993)76 Hatchitanda et al (1996)ss Nickerson et al (2000)162 Schleiermacher et al (2003)203 Total

No. of Patients

94 460

per day for 5 days and hepatic radiation at a dose of 4.5 Gy over 3 days. Five of six deaths occurred in symptomatic infants younger than 2 months. Event-free 5-year survival was 86%, and overall survival was 92%. Early intervention is indicated in stage IV-S patients with lifethreatening complications (e.g+, hepatosplenomegaly, coagulopathy, renal failure).76Ja Surgical resection did not alter outcome. More aggressive chemotherapy is also required in those cases in which the tumor demonstrates more than 10 copies of N-myc, chromosome l p deletion, ~2,2~~ of or other adverse biologic m a r k e r ~ . ~ ~ JAmplification N-myc may be observed in 1 of 12 patients with stage IV-S tumors who develop progressive disease and succumb, despite having a favorable prognostic stage. In 2003 Schleiermacher et al.,203in a report concerning 94 babies with stage IV-S neuroblastoma in France, observed an 88% overall survival and recommended a more intensive regimen using cisplatin and etoposide for those who require therapy. Some infants with stage IV-S have survived without resection of the primary tumor (in some, the primary tumor may not be identified). Knowing that resection of the primary tunlor may have some benefit in infants with stage IV tumors, resection of the primary neoplasm should be accomplished when feasible, especially in high-risk stage IV-S cases with any unfavorable characteristics.76

CYSTIC NEUROBLASTOMA Cystic neuroblastomas are relatively rare and are often identified on prenatal ultrasound examinations.227 They characteristically occur in the adrenal gland, and almost all are diagnosed in early infancy (Fig. 28-14). Few are calcified, and only 10% are associated with elevation of

No. of Survivors (%) 14 (88) 18 (95) 11(100) 31 (89) 8 (73) 9 (50) 28 (75) 63 (83) 17 (81) 36 (80) 74 (92) 83 (88) 392 (85)

Photograph of a cystic neuroblastoma of the adrenal gland in a 5-month-old baby that required complete excision. The patient was managed by surgery alone and is a long-term survivor.

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28

Neuroblastoma

483

urinary VMA and HVA levels.187 They are associated with children with resectable localized neuroblastoma with a benign behavior and a favorable outcome. There is favorable biologic and genetic characteristics. For stage I and most stage I1 patients, surgery alone is all that is necsome evidence that these lesions have a tendency to es~ary.6~,7~28Vtage I1 patients with poor prognostic biologic e regress and undergo spontaneous i n v ~ l u t i o n . ~ ~ ~ o m investigators have recommended observation alone, with and genetic factors, however, are at higher risk and should close serial sonogram monitoring of the mass during the be treated more aggressively with multiagent chemotherfirst few months of life to be sure that the tumor mass apy, including cisplatin, doxorubicin (Adriamycin) , cyclophosphamide, and etoposide (W-16). For advanced shrinks, indicating tumor regression. Operative reseccases (stages I11 and IV), the mainstay agents throughout tion should be reserved for those tumors that fail to the 1970s and early 1980s included cyclophosphamide, regress or that increase in size. When resection is indivincristine, and dacarbazine.6lfj4.67 Treatment failures cated, surgery is the only therapy recommended. The received doxorubicin and teniposide (VM-26). COG has initiated a prospective study of observation only Although these chemotherapy protocols did not effecfor cases of cystic neuroblastoma. It uses strict criteria in tively increase the cure rate of stage IV patients, such treatterms of tumor volume (
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and decreases bone marrow tumor involvement, was by screening the number of tyrosine hydroxylase mRNA Reynolds et al.,183,185 in a shown to be usefu1.~51J84~~33 transcripts. phase 111 randomized trial in high-risk patients, showed that high-dose pulse therapy with 13-cis-retinoic acid given after completion of intensive chemoradiation (with RADIATION THERAPY or without auotologous BMT) significantly improved event-free survival. In phase I studies, the cytotoxic synIn general, the role of radiation therapy in the managethetic retinoid 4HPR (fenretinide) achieved multilog ment of neuroblastoma has become more limited in cell kills in neuroblastoma cell lines resistant to transrecent years. Once a mainstay of treatment, radiation and 13-cis-retinoic acid and was better tolerated when therapy is used primarily (1) to control local disease in ceramide modulators were used to reduce toxicity. instances of incomplete tumor resection or local recurFenretinide has also been shown to exhibit antiangiorence, (2) to reduce the tumor burden in preparation genic properties.l86 for BMT, and (3) for palliation in patients with refractory Other high-intensity, compressed chemotherapy proend-stage disease or painful rneta~tases.~3~81~~3,143 tocols include the use of high-dose cyclophosphamide, External beam radiation is associated with considercarboplatin, and etoposide with granulocyte colonyable toxicity in growing children, resulting in growth disstimulating factor to mobilize peripheral blood stem turbance, bony deformity, endocrine deficiency, cells and enhance hematopoietic reconstitution of neuhypoplastic soft tissue changes, skin atrophy, and, of trophils and platelets. The stem cells are harvested by greater concern, secondary malignancies in the radiation leukapheresis for later reinfusion. Mesna is used to avoid portal. Techniques used to decrease radiation-induced high-dose cyclophosphamide-induced hemorrhagic cystitoxicity include hyperfractionating the radiation dose, tis. After dose-intense induction, surgical intervention is which usually does not reduce the desired antitumor employed to resect the primary tumor and any bulky effect, and avoiding the simultaneous administration of metastases. Peripheral blood stem cell infusion is used to chemotherapy agents that may enhance the radiation reconstitute the marrow after myeloablative treatment. effect.133Brachytherapy and intraoperative radiotherapy Immunoglobulin G levels are monitored and replaced can better confine the radiation effect to the target tissue with gamma globulin. Sulfamethoxazole and fluconazole and spare surrounding normal tissue^.^^.^^^ Although are given prophylactically to avoid opportunistic early local control can be achieved, only 38% of stage IV patients given intraoperative radiotherapy survived after Pneumocystis cam'nii and fungal infection. With regard to BMT, patients who receivied purged 3 years. Some patients still require supplemental exterautologous cells responded better than those getting nal beam radiation, and postoperative ureteral stricture, allogeneic cells, mainly because of a higher toxic death renal artery stenosis, and neuropathies have been described.83 Haas-Kogan et a1.80described an experience rate and an increased incidence of graft-versus-host disusing intraoperative radiotherapy in 23 cases of high-risk ease in the latter group.I48Patients with high-risk stage IV disease have a better outcome with BMT, especially if neuroblastoma and noted that this technique was effecO only J ~ ~ in patients who had gross total resection of the they have amplification of the N-myc ~ n c o g e n e . ~ ~ ~ J ~ tive These newer chemotherapy pilot programs resulted in primary tumor." All patients with partial tumor resection improved survival of stage I11 patients older than 2 years had recurrence, despite radiotherapy, and subsequently at diagnosis from 36% to 86%; survival of stage IV died. There are few data to support the efficacy of this patients (older than 1 year) increased from 11% to 37% therapy. Intraoperative radiotherapy is sometimes cumat 3 years of age and was 23% at 6 years of age.148J49 bersome to perform, especially in institutions that do not There is a high risk of Epstein-Barr virus-associated lymhave an operative suite in the radiotherapy department phoproliferative disease with highly immunosuppressive or radiation therapy equipment (including linear acceltherapies.l7WIogeneic BMT, especially when supported erators) in the operating room. Under these circumby T-cell-depleted stem cell products, is a risk factor. stances, after attempted tumor resection, the patient has Although the risk after autologous BMT is low (3.5%), to be transported under general anesthesia for the treatthere is an increased risk when sequentially high-dose ment to take place. chemotherapy is supported by CD34+-selected periphChildren with refractory advanced neuroblastoma with eral blood stem cells. Median time to lymphoproliferawidespread involvement often suffer severe pain due to tive disease was 3 months post transplant. All patients metastases. Kang et a1.lI3 employed targeted radiotherapy with lymphoproliferatiave disease were in the selected using submyeloablative doses of II3l-MIBG to achieve CD34+ group; treatment was with rituximab and gancidisease palliation. The treatment stabilized disease, clovir. In many centers, peripheral blood stem cell transrelieved pain, or improved performance status, with 31% plantation has replaced autologous BMT as the method of patients showing an objective response to treatment. of choice. Obtaining blood can be accomplished on an They concluded that this modality is useful for treating outpatient basis with less pain and anxiety, and stem cell end-stage neuroblastoma. Targeted radiation therapy transplantation is associated with fewer complications with MIBG has also been used in combination with and less toxicity. Tumor cells can be purged from the myeloablative chemotherapy and proton beam radiation sample. Kanold et al.114 reported that ex vivo expansion of for recurrent and refractory neuroblastoma. Proton beam autologous perihperal blood CD34+cells provided a purge therapy has the advantage of delivering radiation more effect in children with neuroblastoma, documented precisely than conventional methods. As it becomes

CHAPTER

more widely available, it may play a greater role in the management of children with neuroblastoma requiring radiation treatrnent.2' Deutsch and T e r ~ a decribed k~~ the use of radiotherapy (300 to 1000 cGy) for palliative treatment of symptomatic metastases to bone. The most common treatment sites were the skull, spine, hip, and femur. Twenty-nine percent of patients survived 1 year or longer (range, 1 to 52 months). Only 8% survived more than 3 years.

IMMUNOTHERAPY In the 1970s and 1980s, it was observed that tumor regression in neuroblastoma suggests that an immunologic mechanism may be involved, resulting from an unusual Lymphocytes from chiltumor-host relation~hip.~J~,~OJ7~ dren with neuroblastoma were observed to inhibit colonies of neuroblasts in culture but not cells from other tumors.20 Sera from patients with progressive disease contain a blocking antibody that prevents a lymphocytemediated cytotoxic response and inhibits lymphocyte .~~~~~ blastogenesis to p h y t o h e m a g g l ~ t i n i n s Lymphocytes from patients with neuroblastoma also have a decreased systemic and in situ natural killer activity.71 In experimenand hyperthertal studies, operative electrocoag~lation~~5 mia resulting from high-intensity focused ultrasonography induced immunity in mice with neuroblastoma. A major problem is that advanced neuroblastoma cells are MHC class I deficient and evade immunorecognition. Although immunotherapy evolved slowly, this has changed with the production of recombinant interleukin-2 (IL-2), a cytokine that can mediate immunoreactivity and cancer regression.lg2 IL-2 is produced by helper T lymphocytes. The interaction of antigens with T lymphocytes activates lymphoid cells to express receptors for IL-2. Stimulation of IL-2 secretion leads to expansion of immune cells and effective immunity. Newer molecular biologic techniques have been developed to identify genes that encode cancer antigens and their immunogenic peptides. Immune cells can be generated against the antigens present on cancer cells that are the potential targets of immune therapy.lg2 Vertuani et al.2" reported that retinoids and T-cellbased immunotherapy may be an effective combination for the treatment of neuroblastoma. Retinoids serve as multistep modulators of the MHC class I presentation pathway and sensitize neuroblastomas to cytotoxic lympho~ytes.l8",~8"2"The use of tumor cell vaccines derived from irradiated cells transduced with IL-2 or interferon, targeted 1121-MIBG therapy, and I'31-labeled anti-GD2 antibody therapy have been attempted alone or in combination with BMT, however, data are not yet available to document the efficacy of these treatments.148Raffaghello et a1.180 employed an anti-GD2 antibody in nude mice with neuroblastoma and noted increased long-term survival and decreased metastatic spread in a dose-dependent manner in treated mice compared with controls. Cheung et a1.3 suggested that immunotherapy using ganglioside GD2 monoclonal antibody should be directed at minimal disease and must be used in conjunction with

28

Neuroblastoma

485

dose-intensive chemotherapy to be effective. Kushner et a1.1" described the management of seven patients who relapsed with widespread disease after initial treatment with surgery alone for locoregional neuroblastoma. They received dose-intensive chemotherapy, anti-GD2 3F8 antibody, and targeted radiotherapy using 1'"-lableled 3F8 if they had assessable disease, or 3F8, granulocytemacrophage colony-stimulating factor, and 13-ci~retinoic acid if they were in remission. Five of the seven patients remained in remission from 4 to 8 years later.'" The same group reported that high-dose cyclophosphamide, irinotecan, and topotecan were effective in achieving remission and inducing an immunologic state conducive to antibody-based passive immunotherapy (using 3F8 antibody) in resistant n e u r o b l a ~ t o m a . ~ ~ ~ Dendritic cells are potential targets for immunotherapy. They can enhance growth and differentiation of CD40activated B lymphocytes, directly affect natural killer cell function, and act as antigen presenters.I8l Redlinger et a1.182 noted that advanced neuroblastoma impairs dendritic cell differentiation and function in adoptive immunotherapy. It has been shown that in neuroblastoma, gangliosides inhibit dendritic cell function. IL-12 is a potent proinflammatory cytokine that enhances the cytotoxic activity of T lymphocytes and resting natural killer cells.l82 In a murine model of neuroblastoma, Shimizu et al.214 demonstrated that IL-12 transduced dendritic cell vaccine (with an adenoviral vector expressing IL-12) resulted in a complete and sustained antitumor response. Tumor regression was associated with a high infiltration of dendritic cells and viable T cells.

PROGNOSIS For many years, the age of the patient and the stage of disease at the time of diagnosis were the two key independent variables determ
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the better the prognosis.142 Others noted that a more mature histology may be associated with the same dismal outcome as in patients with undifferentiated neuroIn patients with metastatic disease, the presence bla~ts.l2~ of more mature elements seemed to improve-the outlook and was associated with increased surviva1.67~77,218 Shimada et a1.211 subsequently classified the histopathology of neuroblastoma -into favorable and unfaGorable types, characterized by a stroma-rich appearance for the former and a stroma-poor appearance for the latter. The Shimada classification was also age related. The impact of Shimada histology class on prognosis proved to be important, especially when associated with other prognostic biologic variables, particularly amplification of the N-myc oncogene and allelic loss on the short arm of chromosome 1 (lp36).2l2 The current INPC (which embraced and modified the Shimada classification) further divided cases into subsets of favorable and unfavorable histologic types and is a highly significant N- mYC independent predictor of progno~is.~~~,~~3,208,212,213 amplification is seen in approximately 30% of neuroblastoma cases and has an important role in modulating the malignant phenotype in neuroblastoma.27J48.157 The prognostic value of N-myc is independent of stage and age. N-myc is associated with a poor response to treatment,-rapidly progressive disease, and a diimal outcome. Although attempts to stimulate tumor maturation with nerve growth factor, adrenergic agonists, papaverine, prostaglandins, exogenous cyclic adenosine monophoswere successful in the laborabhate,-and hwerthermia , tory setting, there was minimal clinical evidence of their usefulness.3"73.Y7-137~234The use of retinoids as a promoter of differentiation. however. has rekindled interest in this concept and has been successful in prolonging survival in advanced cases during clinical trials.151 The addition of cis-retinoic acid to the treatment protocol for high-risk cases of neuroblastoma following BMT or peripheral stem cell transplantation is now standard practice.27 Nakagawara et al.1573158 reported that high levels of the proto-oncogene Trk-A, a receptor for the neurotrophin nerve growth factor, were associated with excellent survival in infants with neuroblastoma. Trk-A receptor is activated by nerve growth factor and may have an important role in spontaneous regression and tumor differenis associated with younger patients, t i a t i ~ n . I ~ ~Trk-A J" lower-stage disease, and absence of N-myc expression. Trk-A also down-regulates angiogenic factor expression and the number of microvessels in neuroblastoma tumor cell lines. Multivariate analysis, however, suggests that Nmyc is a more important independent prognostic factor. In contrast, Trk-B, another neurotropin receptor, is often associated with N-mycamplification and, due to its ligand BDNF, may provide a tumor cell survival or growth advantage.159 The Trk-B-BDNF pathway also contributes to enhanced angiogenesis, tumorigenicity, cell survival, and drug resistance.27~100Trk-C (similar to Trk-A) is identified in lower-stage tumors without N-myc amplification.2' The Bcl-2 oncoprotein is responsible for relaying apoptotic signaling and is expressed by most neuroblastomas. Increased Bcl-2 expression in neuroblastoma is L

associated with inhibition of chemotherapy-induced - , apoptosis and a poor 0 u t c o m e . ~ ~ . 2 ~Decreased ,",~~ expression of caspases (enzymes resoponsible for executing the apoptotic signal) is also associated with a dismal outcome. In contrast, increased expression of caspases in neuroblastomas with favorable biologic features is associated with an improved outcome. Tumors with high CD44 cell surface expression are usually well differentiated and result in improved survival. Cellular DNA content is a predictor of response to chemotherapy in infants with unresectable neuroblastoma. Flow cytometry studies show that hyperdiploidy and triploidy are associated with a favorable outcome, whereas diploid tumors have a poor outcome. Similar to N-myc, DNA ploidy is of prognostic value independent of stage and age, and the two factors (N-myc and ploidy) together provide important complementary prognostic information for infants.ll.27 DNA ploidy flow cytometry correlates well with response to chemotherapy and outcome. The survival rate for patients who present with opsoclonus and nystagmus ("dancing eye syndrome") is approximately 90%. This syndrome is seen more frequently (>60%) in patients with primary mediastinal tumors, in patients with stage I or I1 disease, and in infants younger than 1 year.g1207In addition, these tumors are often more histologically mature. Presence of the dancing eye syndrome in patients who present with advanced tumors and N-myc overexpression, however, is associated with a poor outcome." Despite tumor resection and adrenocorticotropic hormone treatment, the neurologic symptoms in sk-vivors (including learning disabilities and attention deficits) may persist for many years.121,195,1Y6 The outlook is also improved for patients who present with the hypokalemic watery diarrhea syndrome associated Serum VIP with a VIP-producing neurogenic t~mor.~2,58,127 levels can serve as a tumor marker in these cases, in which the tumor often does not secrete catecholamines. These patients frequently have tumors that are more mature and well differentiated (e.g., ganglioneuroblastoma). VIP production has also been observed in cases of benign ganglioneuroma, again suggesting that these lesions have a more benign behavior. Somatostatin receptors are expressed more frequently in tumor tissue from patients with lower-stage disease and favorable histology without N-myc amplification. These observations suggest that somatostatin receptor expression is a favorable prognostic factor.154J7Y Children with advanced neuroblastoma frequently show evidence of protein-calorie malnutrition associated with immunoincompetence, based on anergy to a variety rd of skin test a n t i g e n ~ . ~ ~ " l ~ W c keta a1.18Wemonstrated that patients with stage IV neuroblastoma who were malnourished at diagnosis had more treatment delays and a significantly worse outcome than adequately nourished counterparts with similar disease severity: These observations suggest that a nutritional assessment at diagnosis should be a component of the patient's staging.lS8In addition, Van Eys et al.231and Rickard et a1.'8XJ8%howed that significant nutritional depletion occurs with multimodal cancer therapy and thai total parenteral nutrition -

~

-

CHAPTER

28

Neuroblastoma

487

(low, intermediate, and high) that determine future can replete and maintain the patient's nutritional status treatment protocols. ~isk-basedmanagement permits during intensive tumor therapy. In a recent study, individualized care for each patient based on age, INSS Sala et a1.1" reported that the incidence of malnutrition stage, INPC histology, and biologic and genetic characin children with advanced neuroblastoma was 50%. They teristics that affect the behavior of each t~mor.27,~~,2~" stressed the importance of nutritional status and its This avoids unnecessary and potentially harmful possible influence on the course of the disease and treatment in patients categorized as having low-risk survival. Of interest is a study from Toronto, Canada, that tumors who may do well with surgery alone (and occaimplies that mandatory folic acid fortification of floursionally observation alone in highly selected cases). initially intended to reduce the incidence of neural tube It allows the physician to reserve the most aggressive defects-was associated with a 60% decrease in the incidence of neuroblastoma in the province of O n t a r i ~ . ~ ~ treatment protocols for children with the highest-risk tumors and the most guarded prognosis. At present, the Previously, Laug et a1.l" demonstrated that stage IV outlook is best in low-risk patients: infants younger than patients with a high urinary HVA/VMA ratio have a sig1 year, patients with localized tumors that can be comnificantly worse outlook. A greater production of HVA pletely excised (stages I and 11) with favorable INPC hismay be indicative of a primitive and immature tumor tology and low-risk biologic and genetic factors, and with more malignant potential. Hann et a1.87 reported infants with stage IV-S disease. Infants with cystic neurothat 63% of patients with stage IV disease had high blastomas detected on prenatal sonograms also have a serum ferritin levels, which was predictive of a poor progvery favorable outcome. In patients with stage IV-S disnosis, especially in girls older than 2 years. A number of ease and those with cvstic, multifocal, or bilateral tumors studies showed that neuroblastic tumors produce biologic characteristics, observation alone ~ *favorable *~ increased serum levels of neuron-specific e n ~ l a s e . ~ ~ ~and may be reasonable. Close sonographic monitoring of Zeltzer et a1.*" documented that neuron-specific enolase these cases in the first year of life is important to be sure levels are elevated in 96% of patients with metastatic disthat the tumor shrinks and undergoes regression. ease and that high serum levels are associated with a Increase in tumor size is an indication for operative poor prognosis, particularly in infants. Elevated serum intervention. Intermediate-risk cases include stage I11 lactic dehydrogenase levels are also associated with a patients (according to the INSS) without adverse biopoor prognosis in localized neuroblastoma."6 The proglogic risk factors and stage IV patients younger than nostic role of the multidrug resistance gene ( a - 1 ) in 1 year without biologic risk factors. Problem areas that High levels of the neuroblastoma is controversial.~6~~66 continue to require special attention include (1) infants MDR-associated protein gene (located on chromosome older than 1 year; ( 2 ) high-risk patients, including stage 16), however, is associated with a poor outcome. This I1 patients older than 1 year with high N-myc expression effect is independent of stage, N-myc, and Trk-A status.lG6 and unfavorable histology and those with advanced disAlthough these earlier observations were of interest and ease (stages I11 and IV) and adverse prognostic biologic shed light on the behavior of this enigmatic neoplasm, in and genetic variables; and (3) the prevention and treatthe present era, age, INSS stage, N-myc status, allelic loss ment of complications of aggressive multimodal therapy. at the lp36 locus, unbalanced 17q gain, and INPC are The last include conventional and total-body irradiation now considered the key predictors of outcome for neudamage, immunosuppression, cardiac and renal toxicity, roblastoma. The current survival rates are greater than scoliosis, adverse effect on growth and development, 90% for low-risk cases, 70% to 75% for intermediate-risk delayed sexual maturation, learning disabilities, and the cases, and 25% to 30% for high-risk cases. The overall occurrence of second neoplasms, including renal survival at 3 years is 50%.27 tUmors.27,68,l94 A better understanding of factors influencing tumor regression and differentiation and tumor-host immune SUMMARY AND FUTURE DIRECTIONS interactions is required. In children with high-risk tumors, identifying additional tumor markers and targetThis common pediatric malignancy remains an enigma ing effective monoclonal antibodies against the tumor; because of the high variability in tumor behavior. The developing improved techniques to clear the bone marprimitive neuroblastic tumor may follow one of three row of tumor cells; employing new and more effective possible pathways: spontaneous regression (apoptosis), chemotherapy programs (with or without total-body irradifferentiation and maturation to a benign ganglioneudiation); hematologic rescue with autologous purged roma, or, more commonly, tumor proliferation and peripheral blood stem cell infusions; and using growth rapid malignant progression. Fetal ultrasonography and factors (e.g., granulocyte colony-stimulating factor) and infant screening programs have clearly demonstrated other biologic tumor modulators (cis-retinoic acid) to that some tumors spontaneously regress. Age-related protect against infection and promote regression and histopathologic studies have clarified that some tumors differentiation may control the progression of disease (favorable histology) differentiate and mature, whereas and improve the outlook for this highly malignant others (unfavorable histology) are undifferentiated tumor. Despite some improvements in outcome using neoplasms that respond poorly to treatment and have a high-intensity treatments, the outlook for patients with rapidly progressive course and fatal outcome. advanced disease remains dismal, with less than half Recognition of important biologic (and genetic) charsurviving. Alternative treatment protocols using novel acteristics can categorize these tumors into risk groups

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and less toxic biologically based therapies (targeted proapoptotic, antiangiogenic, and immunotherapies) will no doubt be tested in the next few years in an attempt to improve the outcome of children with advanced neuroblastoma and diminish the toxicity associated with the current high-intensity but relatively ineffective treatment programs. Molecular profiling of the genetic changes that occur in neuroblastoma will likely permit a more concise classification system to predict outcome and further define the choice of specific therapy, which may include targeting the genes, proteins, and signaling pathways responsible for malignant progression of the tumor.27

REFERENCES 1. Abrams HL, Siegelman SS, Adams DF, et al: Computed tomography versus ultrasound of the adrenal gland: A prospective study. Radiology 1982;143:121-128. 2. Abramson SJ, Berdon WE, Ruzal-Shapiro C, et al: Cervical neuroblastoma in eleven infants-a tumor with favorable prognosis: Clinical and radiologic (US, CTR, MRI) findings. Pediatr Radio1 1993;23:253-257. 3. Acharya S, Jayabose S, Kogan S, et al: Prenatally diagnosed neuroblastoma. Cancer 1997;80:304310. 4. Adams GA, Shochat SJ, Smith EI et al: Thoracic neuroblastoma: A pediatric oncology group study. J Pediatr Surg 1993;28:372-377. 5. Adkins ES, Sawin R, Gerbing RB, et al: Efficacy of complete resection for high risk neuroblastoma: A Children's Cancer Group study. J Pediatr Surg 2004;39:931-936. 6. Akeson R, Seeger RC: Interspecies neural membrane antigens on cultured human and murine neuroblastoma cells. J Immunol 1977;118:1995-2003. 7. Allen RW Jr, Ogden B, Bentley FL, Jung AL: Fetal hydantoin syndrome: Neuroblastoma and hemorrhagic disease in a neonate. JAMA 1980;44:14641465. 8. Al-Rashid RA, Cress C: Hypercalcemia associated with neuroblastoma. Am J Dis Child 1979;133:838-841. 9. Altman A, Baehner RL: Favorable prognosis for survival in children with coincident opsomyoclonus and neuroblastoma. Cancer 1976;37:846-852. 10. Ambros IM, Attarbashi A, Rumpler S, et al: Neuroblastoma cells provoke Schwann cell proliferation in vitro. Med Pediatr Oncol 2001;36:163-168. 11. Ambros IM, Zellner A, Roald B, et al: Role of ploidy, chromosome lp, and Schwann cells in the maturation of neuroblastoma. N Engl J Med 1996;334:1505-1511. 12. Anders D, Kindermann G, Pfeifer U: Metastasizing fetal neuroblastoma with involvement of the placenta simulating fetal erythroblastosis. J Pediatr 1973;82:50-53. 13. Beckwith JB, Perrin EV: In-situ neuroblastoma: A contribution to the natural history of neural crest tumors. Am J Pathol 1963;43:1089-1104. 14. Beirle EA, Strande LK, Chen MK: VEGF upregulates bcl-2 expression and is associated with decreased apoptosis in neuroblastoma cells. J Pediatr Surg 2002;7: 467-471. 15. Beppu K, Jaboine J, Merchant MS, et al: Effect of imatinib mesylate on neuroblastoma tumorigenesis and VEGF expression. J Natl Cancer Inst 2004;96:46-55. 16. Bernardi J, et al: Prognostic value of MDRl gene expression in neuroblastoma: Results of a multivariate analysis. Prog Clin Biol Res 1994;385:111.

17. Bernstein I , Hellstrom KE, Wright PW, et al: Immunity to tumor antigens: Potential implications in human neuroblastoma. J Natl Cancer Inst 1976;57:711-715. 18. Berthold F, Kassenbohmer R, Zieschang J: Multivariate evaluation of prognostic factors in localized neuroblastoma. Am J Hematol Oncol 1994;16:107-115. 19. Bessho F, Hashizume K, Nakajo T, et al: Mass screening in Japan increased the detection of infants with neuroblastoma without a decrease in cases in older children. J Pediatr 1991;119:237-241. 20. Bill AH: Immune aspects of neuroblastoma: Current information. Am J Surg 1971;122:142-147. 21. Blatt JB, Deutsch M, Wollman MR: Results of therapy in stage IV-S neuroblastoma with massive hepatomegaly. Int J Radiat Oncol Biol Phys 1987;13:1467-1471. 22. BlattJB, Fitz G, Mirro J: Recognition of central nervous system metastases in children with metastatic primary extracranial neuroblastoma. Pediatr Hematol Oncol 1997;14:233-241. 23. Breslow N, McCann B: Statistical estimation of prognosis for children with neuroblastoma. Cancer Res 1971; 31:1098-1103. 24. Brock CE, Ricketts RR: Hemoperitoneum from spontaneous rupture of neonatal neuroblastoma. Am J Dis Child 1982;136:370-371. 25. Brodeur GM: Molecular basis for heterogeneity in human neuroblastoma. Eur J Cancer 1995;31A:505-510. 26. Brodeur GM: Schwann cells as antineuroblastoma agents. N Engl J Med 1996;334:1537-1539. 27. Brodeur GM: Neuroblastoma: Biological insights into a clinical enigma. Nat Rev Cancer 2003;3:203-216. 28. Brodeur GM, Pritchard J, Berthold F, et al: Revision of the international criteria for neuroblastoma diagnosis staging and response to treatment. J Clin Oncol 1993;11:1466-1477. 29. Brodeur GM, Seeger RC, Barrett A, et al: International criteria for diagnosis of staging and response to treatment in patients with neuroblastoma. J Clin Oncol 1988;6: 18741881. 30. Caron H, van Sluis B, de Kraker J, et al: Allelic loss of chromosome l p as a predictor of unfavorable outcome in patients with neuroblastoma. N Engl J Med 1996;334: 225-230. 31. Caste1 V, Bedal MD, Bezanilla JL, et al: Treatment of stage 111 neuroblastoma with emphasis on intensive induction chemotherapy: A report from the Neuroblastoma Group of the Spanish Society of Pediatric Oncology. Med Pediatr Oncol 1995;34:29-35. 32. Caste1 W, Heidelberger KP, Bromberg J, et al: Expression of the apoptosis-suppressing protein bcl-2 in neuroblastoma is associated with unfavorable histology and N-myc amplification. Am J Pathol 1993;143:1543-1550. 33. Castleberry RP, Pritchard J, Ambros P, et al: The International Neuroblastoma Risk Groups (INRG): A preliminary report. Eur J Cancer 1997;33:2113-2116. 34. Castleberry RP, Shuster JJ,Smith EI: Pediatric Oncology Group experience with the International Staging System criteria for neuroblastoma. J Clin Oncol 1994;12: 2378-2381. 35. Chan HS, Haddad G, Thorner PS, et al: P-glycoprotein expression as a predictor of the outcome of therapy for neuroblastoma. N Engl J Med 1991;325:1608-1614. 36. Chang THT, Prasad KN: Differentiation of mouse neuroblastoma cells in-vitro and in-vivo, induced by cyclic adenosine monophosphate (CAMP).J Pediatr Surg 1976; 112347-858. 37. Chatten J, Voorhees ML: Familial neuroblastoma: Report of a kindred with multiple disorders including

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38. 39. 40. 41. 42. 43. 44. 45. 46. 47. 48.

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50.

51.

52. 53. 54. 55. 56. 57.

58.

neuroblastoma in four siblings. N Engl J Med 1967;277: 1230-1236. Cheung NK: Monclonal antibody-based therapy for neuroblastoma. Curr Oncol Rep 2000;2:547-551. Cheung NK, Kushner BH, Yeh SD, et al: 3F8 Monoclonal antibody treatment of patients with stage 4 neuroblastoma: A phase I1 study. Int J Oncol 1998;12:1299-1306. Chlenski A, Liu S, Cohn SL: The regulation of angiogenesis in a neuroblastoma. Cancer Lett 2003;197:47-52. Coldman AJ, Fryer CJ, Elwood JM, Sonley MJ: Neuroblastoma: Influence of age at diagnosis, stage, site and sex on prognosis. Cancer 1980;46:1896-1901. Cooney DR, Voorhees ML, FisherJE, et al: Vasoactive intestinal polypeptide producing neuroblastoma. J Pediatr Surg 1982;17:821-825. Cushing H, Wolbach SB: Transformation of malignant paravertebral sympathicoblastoma into benign ganglioneuroma. Am J Path01 1927;3:203. D'Angio GJ, Evans AE: Experience with cyclic low-dose total body irradiation for metastatic neuroblastoma [abstract]. Proc Am Soc Clin Oncol 1982;23:52. D'Angio GJ, Evans AE, Koop CE: Special pattern of widespread neuroblastoma with a favorable prognosis. Lancet 1971;1:10461049. Dastur DK: Cerebral ganglioglioneuroblastoma: An unusual brain tumor of the neuron series. J Neurol Neurosurg Psychiatry 1982;45:139-142. Davidoff AM, Kandel J:Antiangiogenic therapy for the treatment of pediatric solid malignancies. Semin Pediatr Surg 2004;13:53-60. Davidoff AM, Leary MA, Ng CT, et al: Retroviral vector producer cell mediated angiogenesis inhibition restricts neuroblastoma growth in-vivo. Med Pediatr Oncol 2000;35:638-640. Davidoff AM, Leary MA, Ng CY,et al: Gene therapy mediated expression by tumor cells of the angiogenesis inhibitor Flk-1 results in inhibition of neuroblastoma growth in-vivo.J Pediatr Surg 2001;36:30-36. DeBernardi B, Pianca C, Boni L, et al: Disseminated neuroblastoma (stage IV and IV-S) in the first year of life: Outcome related to age and stage. Italian Cooperative Group on Neuroblastoma. Cancer 1992;70:1625-1633. DeBernardi B, Conte M, Mancini A, et al: Localized resectable neuroblastoma: Results of the 2nd study of the Italian Cooperative Group for Neuroblastoma. J Clin Oncol 1995;13:884893. de Lagausie P, Berribi D, Michon J, et al: Laparoscopic adrenal surgery for neuroblastoma in children. J Urol 2003;170:932-935. Deutsch M, Tersak JM: Radiotherapy for symptomatic metastases to bone in children. Am J Clin Oncol 2004;27:128-131. Dobrovoljski G, Kerbl R, Strobl C, et al: False-positive results in neuroblastoma screening: The parents' view. J Pediatr Hematol Oncol 2003;25:1418. Dole M, Nunez G, Merchant AK, et al: Bcl-2 inhibits chemotherapy induced apoptosis in neuroblastoma. Cancer Res 1994;54:3253-3259. Dreyfus M, Neuhart D, BaldaufJ, et al: Prenatal diagnosis of cystic neuroblastoma. Fetal Diagn Ther 1994;9:269-272. Eggert A, Ikegaki N, KwiatkowskiJ, et al: High-level expression of angiogenic factors is associated with advanced tumor stage in human neuroblastomas. Clin Cancer Res 2000;6:1900-1908. El-Shafie M, Samuel D, Klippel CH, et al: Intractable diarrhea in children with VIP-secreting ganglioneuroblastoma. J Pediatr Surg 1983;18:3436.

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59. Emery LG, Shields M, Shah MR, et al: Neuroblastoma associated with Beckwith-Wiedemann syndrome. Cancer 1983;52:176-179. 60. Entz-Werle N, Marcellin L, Becmeur F, et al: The urinary bladder: An extremely rare location of pediatric neuroblastoma. J Pediatr Surg 2003;38:E10-E12. 61. Evans AE, Albo V, D'Angio GJ, et al: Cyclophosphamide treatment of patients with localized and regional neuroblastoma: A randomized study. Cancer 1976;38:655-660. 62. Evans AE, D'Angio GJ, Randolph JG: A proposed staging for children with neuroblastoma. Cancer 1971;27: 374378. 63. Evans AE, Gerson J , Schnaufer I,: Spontaneous regression of neuroblastoma. Natl Cancer Inst Monogr 1976;44:49-54. 64. Evans AE, Heyn RN, Newton WA Jr, Leikin SL: Viscristine sulfate and cyclophosphamide for children with metastatic neuroblastoma. JAMA 1969;207:1325-1327. 65. Fenart D, Deville A, Donzeau M, Bruneton JN: Neuroblastome retroperitoneal diagnostique in utero. J Radiol 1983;64:359-361. 66. Filler RM, Traggis DG, Jaffe N, Vawter GF: Favorable outlook for children with mediastinal neuroblastoma. J Pediatr Surg 1972;7:136-143. 67. Finklestein JZ, Klemperer, MA, Evans AE, et al: Multiagent chemotherapy for children with metastatic neuroblastoma: A report from the Children's Cancer Study Group. Med Pediatr Oncol 1979;6:179-188. 68. FleitzJM, Wooten-Gorges SC, Wyatt-AshmeadJ, et al: Renal cell carcinoma in long-term survivors of advanced stage neuroblastoma early in childhood. Pediatr Radiol 2003; 33:540-545. 69. French AE, Grant R, Weitzman S, et al: Folic acid food fortification is associated with a decline in neuroblastoma. Clin Pharmacol 2003;74:288-294. 70. Gerson JM, Chatten J, Eisman S: Familial neuroblastomaa follow-up. N Engl J Med 1974;190:487. 71. Gerson JM, Herberman RB: Systemic and in-situ natural killer activity in patients with neuroblastoma. In Evans AE (ed): Advances in Neuroblastoma Research. New York, Raven Press, 1980. 72. Green AA, Hayes FA, Hustu HO: Sequential cyclophosphamide and doxorubicin for induction and complete remission in children with disseminated neuroblastoma. Cancer 1981;48:2310-2317. 73. GrosfeldJL: Neuroblastoma: A 1990 overview. Pediatr Surg Int 1991;6:9-13. 74. Grosfeld JL: Risk based management of childhood solid tumors. J Am Coll Surg 1999;189:407-425. 75. Grosfeld JL, Ballantine TVN, Baehner RL: Experience with "second-look operations in pediatric solid tumors. J Pediatr Surg 1978;13:275-280. 76. Grosfeld JL, Rescorla FJ, West KW, Goldman J: Neuroblastoma in the first year of life: Clinical and biologic factors influencing outcome. Semin Pediatr Surg 1993;2:37-46. 77. GrosfeldJL, Schatzlein M, Ballantine TVN, et al: Metastatic neuroblastoma: Factors influencing survival.J Pediatr Surg 1978;13:59-65. 78. Grosfeld JL, West KW, Weber TR: The role of second-look procedures in the management of retroperitoneal tumors in children. J Pediatr Hematol Oncol 1984;6:441-447. 79. Haas D, Ablin AR, Miller C, et al: Complete pathologic maturation and regression of stage IV-S neuroblastoma without treatment. Cancer 1988;62:818-825. 80. Haas-Kogan DA, Fisch BM, Wara WB, et al: Introperative radiation therapy for high risk neuroblastoma. Int J Radiat Oncol Biol Phys 2000;47:985-992.

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81. Haas-Kogan DA, Swift PS, Eslch M, et al: Impact of radiotherapy for high risk neuroblastoma: A Children's Cancer Group study. Int J Radiat Oncol Biol Phys 2003; 56:28-39. 82. Haase GM: Head and neck neuroblastomas. Semin Pediatr Surg 1994;3:194202. 83. Haase GM, LaQuaglia MP: Neuroblastoma. In Ziegler M, Azizkhan RG, Weber TR (eds): Operative Pediatric Surgery. New York, McGraw-Hill, 2003, pp 1181-1191. 84. Haase GM, O'Leary MC, Ramsay NK, et al: Aggressive surgery combined with intensive chemotherapy improves survival in poor risk neuroblastoma. J Pediatr Surg 1991; 26:1119-1123. 85. Haase GM, Wong KY, deLorimier AA, et al: Improvement in survival after excision of the primary tumor in stage I11 neuroblastoma. J Pediatr Surg 1989;24:194200. 86. Haddad M, Triglia.jM, Helardot P, et al: Localized cervical neurob1astoma:-prevention of surgical complications. Int J Pediatr Otorhinolaryngol 2003;67:1361-1367. 87. Hann JL, et al: Serum ferritin levels as a guide to prognosis in stage IV neuroblastoma [abstract]. Proc Am Soc Clin Oncol 1983;24:72. 88. Hatchitanda Y, Hata J: Stage IV-S neuroblastoma: A clinical, histological and biological analysis. Hum Path01 1996;27:1135-1 138. 89. Hayashi Y, Kanmda N, Inaba T, et al: Cytogenetic findings and prognosis in neuroblastoma with emphasis on marker chromosome 1. Cancer 1989;63:125-132. 90. Hayes FA, Green AA, CasperJ, et al: Clinical evaluation of sequentially scheduled cisplatin and VM-26 in neuroblastoma: Response and toxicity. Cancer 1981;48:1715-1718. 91. Hayes FA, Green AA, Hustu HO, Kumar ML: Surgicopathologic staging of neuroblastoma: Prognostic significance of regional lymph node metastases. J Pediatr 1983;102:59-62. 92. Hayes F, Green AA, Mauer AM, et al: Correlation of cell kinetics and clinical response to chemotherapy in disseminated neuroblastoma. Cancer Res 1977;37:3766-3770. 93. Heisel MA, Miller JH, Reid BS, Siege1 SE: Radionuclide bone scan in neuroblastoma. Pediatrics 1983;71:206-209. 94. Hellstrom I, Hellstrom KE, Pierce GE, Bill AH: Demonstration of cell bound humoral immunity against neuroblastoma cells. Proc Natl Acad Sci U S A 1968;60: 1231-1238. 95. Hellstrom KE, Hellstrom I: Lymphocyte mediated cytotoxicity and blocking serum activity to tumor antigens. Adv Immunol 1974;18:209-217. 96. Helson L, Ghavimi F, Wu CJ, et al: Carcinoembryonic antigen in children with neuroblastoma. J Natl Cancer Inst 1976;57:725-726. 97. Helson L, Helson C, Peterson RF, Das SK: A rationale for the treatment of metastatic neuroblastoma. J Natl Cancer Inst 1976;57:727-729. 98. Hiyama E, Yokoyama T, Hiyama K et al: Multifocal neuroblastoma: Biologic behavior and surgical aspects. Cancer 2000;88:1955-1963. 99. Hiyama E, Yokoyama T, Ichikawa T, et al: Poor outcome in patients with advanced stage neuroblastoma and coincident opsomyoclonus syndrome. Cancer 1994;74: 1821-1826. 100. Ho R, Eggert A, Hishiki T, et al: Resistance to chemotherapy mediated by TrkB in neuroblastoma. Cancer Res 2002;62:6462-6466. 101. Ho TC, EstroffJA, Kozakewich H, et al: Prenatal detection of neuroblastoma: A ten year experience from the DanaFarber Cancer Institute and Children's Hospital. Pediatrics 1993;92:358-364.

102. Holcomb GW: Minimally invasive surgery for solid tumors. Semin Surg Oncol 1999;7:184192. 103. Holgersen LO, Subramanian S, Kirpekar M, et al: Spontaneous resolution of antenatally diagnosed adrenal masses. J Pediatr Surg 1996;31:153-155. 104. Ikeda H, Iehara T, Tsuchida Y, et al: Experience with the International Neuroblastoma Staging System and pathology classification. Br J Cancer 2002;86:1110-1116. 105. Ikeda H, Suzuki N, Takahashi A, et al: Surgical treatment of neuroblastomas in infants under 12 months of age. J Pediatr Surg 1998;33:1246-1250. 106. Ishimoto K, Kiyokawa H, Fujita H, et al: Problems of mass screening for neuroblastoma: Analysis of false negative cases. J Pediatr Surg 1990;25:398-401. 107. Iwanaka T, Arai M, Ito M, et al: Surgical treatment for abdominal neuroblastoma in the laparoscopic era. Surg Endosc 2001;15:751-754. 108. Iwanaka T, Arai M, Kawashima H, et al: Endosurgical procedures for pediatric solid tumors. Pediatr Surg Int 2004;20:39-42. 109. Jennings RW, LaQuaglia MP, Leong K, et al: Fetal neuroblastoma: Prenatal diagnosis and natural history. J Pediatr Surg 1993;28:1168-1174. 110. Jiang TH, Yang CP, Hung IJ, et al: Brain metastases in children with neuroblastoma-a single institution experience. Med Pediatr Oncol 2003;41:570-571. 111. Joshi W, Cantor AB, Altschuler G, et al: Age-linked prognostic categorization based on a new histologic grading system of neuroblastoma. Cancer 1992;69:2183-2196. 112. Kaicker S, McCRudden KW, Beck L, et al: Thalidomide is anti-angiogenic in a xenograft model of neuroblastoma. Int J Oncol 2003;23:1651-1655. 113. Kang TI, Brophy P, Hickeson M, et al: Targeted radiotherapy with submyeloablative doses of 1'"-MIBG is effective for disease palliation in highly refractory neuroblastoma. J Pediatr Hematol Oncol 2003;25:769-763. 114. Kanold J, Halle P, Tchirkov A, et al: Ex-vivct expansion of autologous PB CD34+ cells provide a purge effect in children with neuroblastoma. Bone Marrow Transplant 2003;32:485-488. 115. Kenney LB, Miller BA, Gloeker-Reis LA, et al: Increased incidence of cancer in infants in the United States 1980-1990. Cancer 1998;82:1396-1400. 116. Kiely EM: The surgical challenge of neuroblastoma. J Pediatr Surg 1994;29:128-133. 117. Kim ES, Soffer SZ, Huang J, et al: Distinct response of experimental neuroblastoma to combination antiangiogenic strategies. J Pediatr Surg 2002;37:518-522. 118. King D, Goodman J, Hawk T, et al: Dumbbell neuroblastoma in children. Arch Surg 1975;110:888-891. 119. Kinney H, Faix R, Brazy J: The fetal alcohol syndrome and neuroblastoma. J Pediatr 1980;66:130-132. 120. Kogner P, Barbani G, Dominici C, et al: Co-expression of messenger RNA for Trk protooncogene and low affinity nerve growth factor receptors in neuroblastoma with favorable prognosis. Cancer Res 1993;53:20442050. 121. Koh PS, Raffensperger J, Berry S, et al: Long-term outcome in children with opsoclonus myoclonus and ataxia and coincident neuroblastoma. J Pediatr 1994;125: 712-716. 122. Komuro H, Kaneko S, Kaneko M, et al: Expression of angiogenic factors and tumor progression in human neuroblastoma. J Cancer Res Clin Oncol 2001;127:739-743. 123. Komuro H, Makino S, Tahara K: Laparoscopic resection of an adrenal neuroblastoma detected by mass screening that grew in size during the observation period. Surg Endosc 2000;14:297.

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supportive care or minimal therapy: A Children's Cancer Group study. J Clin Oncol 2000;18:477-486. 163. Nickerson HJ, Nesbit ME, Grosfeld JL, et al: Comparison of stage IV and IV-S neuroblastoma in the first year of life. Med Pediatr Oncol 1985;13:261-268. 164. Ninane J, Pritchard J, Morris Jones PH, et al: Stage I1 neuroblastoma: Adverse prognostic significance of lymph node involvement. Arch Dis Child 1982;57:438-442. 165. Nitschke R, Cangir A, Crist W, Berry DH: Intensive chemotherapy for metastatic neuroblastoma: A Southwest Oncology Group study. Med Pediatr Oncol 1980;8: 281-288. 166. Norris MD, Bordow SD, Marshall GM, et al: Expression of the gene for multidrug resistance associated protein and outcome in patients with neuroblastoma. N Engl J Med 1996;334:231-238. 167. Odelstad L, Pahlman S, Lackgren G, et al: Neuron specific enolase: A marker for differential diagnosis of neuroblastoma and Wilms' tumor. J Pediatr Surg 1982;17: 381-385. 168. Oue T, Fukuzawa M, Kusafuka T, et al: In situ detection of DNA fragmentation and expression of bcl-2 in human neuroblastoma: Relation to apoptosis and spontaneous regression. J Pediatr Surg 1996;31:251-257. 169. Oue T, Inoue M, Yoneda A, et al: Profile of neuroblastoma detected by mass screening, resected after observation without treatment: Results of the Wait and See pilot study. J Pediatr Surg 2005;40:359-363. 170. Paul SR, Tarbell NJ, Korf B, et al: Stage IV neuroblastoma in infants: Long-term survival. Cancer 1991;67:1493-1497. 171. Pegelow CH, Ebbin AJ, Powars D, Towner JW: Familial neuroblastoma. J Pediatr 1975;87:763-765. 172. Perkins DG, Kopp CM, Haust MD: Placental infiltration in congenital neuroblastoma. Histopathology 1980;4: 383-389. 173. Peuchmaur M, d'Amore ES,Joshi W, et al: Revision of the International Neuroblastoma Pathology Classification: Confirmation of favorable and unfavorable prognostic subsets in ganglioneuroblastoma, nodular. Cancer 2003; 98:22742281. 174. Plantaz D, Rubie H, Michon J, et al: The treatment of neuroblastoma with intraspinal extension with chemotherapy followed by surgical removal of residual disease: A prospective study of 42 patients-results of the NBL 90 study of the French Society of Pediatric Oncology. Cancer 1996;3:521-525. 175. Ponzoni M, Bocca P, Chiesa V, et al: Differential effects of N-4hydroxyphenylretinamide and retinoic acid on neuroblastoma cells: Apoptosis and differentiation. Cancer Res 1995;55:853-861. 176. Powell JL, Buniz NJ, Callahan C, et al: An unexpectedly high incidence of Epstein-Barr virus lymphoproliferative disease after CD34+ selected autologous peripheral blood stem cell transplant in neuroblastoma. Bone Marrow Transplant 2004;33:651-657. 177. Prasad KN, Mandal B, Kumar S: Demonstration of cholinergic cells in human neuroblastoma and ganglioneuroma. J Pediatr 1973;82:677-679. 178. Pritchard J, McElwain TJ, Graham-Pole J: High dose melphalan with autologous bone marrow for treatment of advanced neuroblastoma. Br J Cancer 1982;45:86-94. 179. Qualman SJ, O'Diorisio MS, Fleshman DJ, et al: Neuroblastoma: Correlation of neuropeptide expression in tumor tissue with other prognostic factors. Cancer 1992; 70:2005-2012. 180. Raffaghello L, Marimpietri D, Pagnan G, et al: Anti-GD2 monoclonal antibody immunotherapy: A promising strategy

181. 182. 183. 184. 185. 186. 187. 188. 189. 190.

191. 192. 193. 194. 195.

196.

197. 198. 199. 200. 201.

in the prevention of neuroblastoma relapse. Cancer Lett 2003;197:205-209. Redlinger RE, Shimizu T, Remy T, et al: Cellular mechanisms of interleukin-12 mediated neuroblastoma regression. J Pediatr Surg 2003;38:199-204. Redlinger RE Jr, Mailliard RB, Barksdale EM: Neuroblastoma and dendritic cell function. Semin Pediatr Surg 2004;13:61-71. Reynolds CP: bifferentiating agents in pediatric malignancies: Retinoids in neuroblastoma. Curr Oncol Rep 2000;2:511-518. Reynolds CP, Kane DJ, Einhorn PA, et al: Response of neuroblastoma to retinoic acid in vitro and in vivo. Prog Clin Biol Res 1996;366:203-211. Reynolds CP, Matthay KK, Villablanca JG, et al: Retinoid therapy of high risk neuroblastoma. Cancer Lett 2003;197:185-192. Ribatti D, Raffaghello L, Marimpietri D, et al: Fenretinide as an anti-angiogenic agent in neuroblastoma. Cancer Lett 2003;197:181-184. Richards ML, Gundersen AE, Williams MS: Cystic neuroblastoma of infancy.J Pediatr Surg 1995;30:13541357. Rickard KA, Detamore CM, Coates TD, et al: Effect of nutrition staging on treatment delays and outcome in stage IV neuroblastoma. Cancer 1983;52:587-598. Rickard KA, Grosfeld JL, Kirksey A, et al: Reversal of protein-energy malnutrition in children during treatment of advanced neoplastic disease. Ann Surg 1979;190:771-781. Rill DR, Santana VM, Roberts WM, et al: Direct demonstration that autologous bone marrow transplantation for solid tumors can return a multiplicity of tumorigenic cells. Blood 1994;84:380-383. Riley RD, Heney D, Jones DR, et al: A systematic review of molecular and biological tumor markers in neuroblastoma. Clin Cancer Res 2004;10:412. Rosenberg SA: Development of effective immunotherapy for the treatment of patients with cancer. J Am Coll Surg 2004;198:685-696. Rowe DH, Huang J, Li J, et al: Suppression of primary tumor growth in a mouse model of human neuroblastoma. J Pediatr Surg 2000;35:977-981. Rubino C, Adjadj E, Guerin S, et al: Long-term risk of second malignant neoplasms after neuroblastoma in childhood: Role of treatment. Int J Cancer 2003;107:791-796. Rudnick C, Khakoo Y, Antunes NL: Opsoclonusmyoclonus-ataxia syndrome in neuroblastoma: Clinical outcome and antineural antibodies-a report from the Children's Cancer Group study. Med Pediatr Oncol 2001;36:612-622. Russo C, Cohn SL, Petruzzi MJ, et al: Long term neurologic outcome in children with opsoclonus-myoclonus associated with neuroblastoma: A report from the Pediatric Oncology Group. Med Pediatr Oncol 1997;28: 284288. Sala A, Pencharz P, Barr RD: Children, cancer and nutrition-a dynamic triangle in review. Cancer 2004;lOO: 677-687. Sandberg DI, Bilsky MH, Kushner BH, et al: Treatment of spinal involvement in neuroblastoma patients. Pediatr Neurosurg 2003;39:291-298. Sawada T, Sugimoto T, Kawakatsu H, et al: Mass screening for neuroblastoma in Japan. Pediatr Hematol Oncol 1991;8:93-109. Sawada T, Todo S, Fujita K, et al: Mass screening of neuroblastoma in infancy. Am J Dis Child 1982;136:710-712. Schilling FH, Parker C: Mass screening in neuroblastoma: The European experience. In Brodeur GM, Sawada T,

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242. Yiin J, Chang CS, Jan YJ, Wang YC: Treatment of neuroblastoma with intraspinal extension. J Clin Neurosci 2003; 10:579-583. 243. Young DG: Thoracic neuroblastoma/ganglioneuroma. J Pediatr Surg 1983;18:37-41. 244. Zeltzer PM, Marangos PJ, Parama AM, et al: Raised neuron specific enolase in the serum of children with metastatic neuroblastoma: A report from the Children's Cancer Study Group. Lancet 1983;2:361-363.

245. Ziegler MM, Vega A, Koop CE: Electrocoagulation induced immunity-an explanation for regression of neuroblastoma. J Pediatr Surg 1980;15:3437. 246. Zimmerman RA, Bilaniuk CT: CT of primary and secondary craniocerebral neuroblastoma. AJR Am J Roentgen01 1980;135:1239-1242.

Nonmalignant Tumors of the Liver Philip C. Guzzetta, Jr.

Primary liver tumors constitute less than 3% of tumors seen in the pediatric population, and only one third of Despite the rarity of those tumors are benign.2~*~~"~66" benign liver tumors, recommendations for diagnostic evaluation and management can be made, based on the experience gained from centers with a relatively large number of patients. Benign tumors may be epithelial (focal nodular hyperplasia, hepatocellular adenoma), mesenchymal (infantile hepatic hemangioendothelioma, cavernous hemangioma, mesenchymal hamartoma), or other (teratoma, inflammatory pseudotumor). Nonparasitic cysts, although not technically neoplasms, are also discussed in this chapter. One of the more interesting aspects of benign liver tumors in children is their predilection to occur in patients with other conditions. Hepatocellular adenomas have long been associated with the use of oral contraceptives in adults. Children are at risk for hepatocellular adenoma when they have received androgen therapy for aplastic anemia, have chronic iron overload from transfusion in P-thalassemia, or have received corticosteroids after renal transplantation.8 Patients with type I glycogen storage disease are at increased risk for hepatocellular adenomahand focal nodular h y p e r p l a ~ i a liver ~ ~ ; hamartomas may occur in children with tuberous sclerosis.33

CLINICAL PRESENTATION Most children with benign liver tumors present with a painless right upper quadrant abdominal mass or hepatomegaly. Symptoms of gastrointestinal compression, such as constipation, anorexia, or vomiting, may also be present. If the mass is painful, the pain is usually dull and aching and is caused by expansion of the liver capsule or compression of the normal surrounding structures. Jaundice and weight loss are uncommon except in infants with infantile hepatic hemangioendothelioma (IHH), and those signs should raise the suspicion that the lesion is malignant. Acute abdominal pain may be caused by bleeding into the mass or into the peritoneum, particularly in hepatocellular adenomas, although this problem is rarely seen in children. Children may present with congestive heart failure (CHF) and thrombocytopenia,

which is known as Kasabach-Merritt syndrome when associated with a vascular anomaly such as IHH." Cutaneous hemangiomas are seen in about half the children with IHH,25,"".%nd the rapid liver enlargement with IHH can cause abdominal compartment syndrome and respiratory distress.52 CHF without significant thrombocytopenia can also be seen with liver arteriovenous malformation (AVM)zO or mesenchymal hamartoma.") Fetal hydrops has been identified by prenatal ultrasonography in some fetuses with IHHZ1 or mesenchymal h a m a r t ~ m a . ~ ~

DIAGNOSIS Laboratory Tests Serum alpha fetoprotein (AFP) is present in very high concentrations at birth (48,000 f 35,000 ng/mL) and rapidly declines to adult levels of less than 10 ng/mL by 8 months of age (Table 29-1).7"hus, in infants younger than 8 months, AFP levels must be interpreted in the context of this dramatic change. Markedly elevated AFP

I Age

No. of Patients

AFP Level f SD (ng/mL)

Premature Newborn Newborn-2 wk 2 wk-l mo 1mo 2 mo 3 mo 4 mo 5 mo 6 mo 7 mo 8 mo From Wu JT, Book L, Sudar K: Serum alpha fetoprotein (AFP) levels in normal infants Pediatr Res 1981: 5:50.

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levels in a child with a liver mass almost certainly means that the mass is malignant, although milder elevation may be encountered with some benign lesions such as mesenchymal hamartoma"' or teratoma.'j6As mentioned previously, significant thrombocytopenia associated with a liver mass is usually part of the Kasabach-Merritt syndrome due to IHH. Hypothyroidism may also occur in IHH27; thyroid function tests should be done routinely in these children, because hypothyroidism significantly impacts their management.42

-

-

Imaging Techniques The initial imaging study in a child presenting with an abdominal mass should be a supine radiograph of the abdomen, looking for calcifications within the mass. The next imaging study should be an abdominal sonogram with Doppler spectral analysis, followed by computed tomography (CT) with intravenous contrast (Fig. 29-1).6 Magnetic resonance imaging (MRI) may be indicated, depending on the sonogram and CT scan results, especially when surgical resection is planned and more detailed information about the vascular anatomy relative to the tumor is desired. Arteriography is reserved for children with IHH or, rarely, mesenchymal harnart0ma4.~ with CHF, in whom embolization of the tumor blood supply is needed for treatment. Liver-spleen radionuclide scans are seldom helpful in differentiating liver masses and thus are unnecessary in centers that have CT and MRI. The use of percutaneous biopsy under sonogram or CT guidance in children with benign tumors is generally discouraged (unless excision of the tumor would pose a major risk to the child), because establishing a diagnosis on the basis of a small sample may be problematic for the pathologist, and because resection is the proper therapy for most of these tumors. The findings on imaging studies are discussed in the sections on each individual tumor.

.

-

Contrastenhanced abdominal computed tomogra-

phy scan of a &month-old female infant with a large hemangioendothelioma of the left hepatic lobe. Note the cential area ofnecrosis.

VASCULAR TUMORS

infantile ti^ ~

~

~

~

~

~

i

~

IHH is by far the most common benign liver tumor in children. Increasingly, IHH is being diagnosed prenatally, and similar to affected neonates, the fetus may be asymptomatic or profoundly i11.z1,55Symptomatic children present before 6 months of age 80% of the time, with many presenting in the newborn period.25,"," The most common physical finding is hepatomegaly. The disease has a wide range " of severitv, ,. with some children being " asymptomatic and others having life-threatening CHF, abdominal compartment syndrome, and severe thrombocytopenia. I* most series, the female-to-male ratio is 2:1, and about half the children have a cutaneous hemangioma as well as IHH.1i,'5,9 In infants, IHH, can be reliably diagnosed by abdominal sonogram and dynamic contrast-enhanced CT. Lesions are usually present throughout the liver but may be localized to a few hepatic segrnents.'j8 On ultrasonography, multifocal, echolucent nodules usually have high-flow vessels, while solitary lesions have a more heterogeneous echogenicity.'j Before the administration of intravenous contrast, these lesions have low attenuation on CT; with contrast, they enhance diffusely or ent tripe tally.^ MRI of IHH reveals the extent of disease, the flow characteristics, and .~ the high rate of accuracy in the flow ~ t r u c t u r eDespite diagnosing IHH by imaging techniques, AFP and catecholamine levels should be obtained, because occasionally a hepatoblastoma or stage IV-S neuroblastoma is misdiagnosed as IHH.2" Dehner and Ishak12 identified two microscopic patterns of IHH. Type 1, the more common histologic pattern, is characterized by an orderly arrangement of dilated and compressed endothelium-lined vascular spaces supported by reticulin fibers with benign cytologic features. In their review, 17 of 23 lesions were type 1. Type 2 lesions have a more aggressive histologic appearance, with more complex and irregular branching structures within the vascular lumens. Endothelial cells are more hyperchromatic and pleomorphic than in type 1 lesions, although mitoses are uncommon. In Dehner and Ishak's series, the mortality rate was higher for patients with type 2 than type 1 tumors, but more recent series report a favorable outcome regardless of type. Thus, the histopathology of the tumor does not seem to correlate with prognosis. Management of these tumors depends on the severity of symptoms and the location of the lesion. When the lesion is asymptomatic and little hepatomegaly is present, observation is the appropriate therapy, as long as the diagnosis can be made with a high degree of certainty on the basis of noninvasive radiographic studies. Unless there is serious concern that the lesion is malignant, percutaneous or open biopsy is discouraged because of the risk of significant hemorrhage. Treatment of a symptomatic child is directed first toward uharmacologic " control of the tumor with corticosteroids,25355,59 interferon (IFN),y,18~ i n c r i s t i n e ,or ~~ cy~lophospharnide.2~ Despite initial enthusiasm for IFN therapy for IHH, there aEe concerns about serious side

~

~

CHAPTER

effects with both IFN-alpha 2a3 and IFN-alpha 2b.6 In addition, the therapy takes weeks to months to be effective, which is too long in critically ill neonates to be clinically useful. The success rate of any medical therapy is difficult to assess because of the wide disparity in disease severity and the fact that the usual singlecenter experience is fewer than 20 patients. In my experience, however, very ill neonates with CHF and thrombocytopenia due to diffuse or multifocal lesions are seldom improved with medical therapy alone. Embolization is most effective in children with disease restricted to only a few of the eight hepatic segments,68 but some success has been reported in children with diffuse IHH as we11.6 Diffuse IHH lesions frequently have extrahepatic arterial collaterals arising from the superior mesenteric, phrenic, intercostal, and internal mammary arteries, as well as some blood supply from the portal venous system.6,20This makes complete elimination of the blood flow by embolization virtually impossible. Although hepatic artery ligation was recommended as treatment for IHH in the past, it prevents effective embolization and thus should be avoided. If disease progression occurs despite embolization, hepatic resection11355 or even liver transplantationll,36 may be needed if the child is to survive. Radiation therapy has been used to treat these lesions,5',53 but the long-term effect of hepatic radiation in an infant is unknown, and there is one disturbing report that described three children with angiosarcoma of the liver who had previously been treated for IHH with radiation therapy.lg Estimates of survival rates with IHH are unreliable because of the variability of the disease and the wide range of treatment approaches, but in children younger than 6 months with CHF, reported survival rates are between 45% and 90% for this "benign" tumor.11,25,55

29

Nonmalignant Tumors of the Liver

497

venous system. Similar to patients with hemangioendotheliomas, patients with hepatoportal AVMs usually present before 6 months of age, many in the newborn period, with hepatomegaly, CHF, and a bruit over the liver.14 In older children and adults,. hepatic AVM may occur as part of hereditary hemorrhagic telangiectasia, also known as Osler-Weber-Rendu Angiography is diagnostic, and embolization is therapeutic in some but it is necessary to eliminate the extensive collaterals for successful closure of the AVM.614 Fatal complications from the embolization of liver AVMs have been reported.71 Steroids have no place in the management of these lesions, and AVMs not managed successfully with embolization may be controlled with hepatic arterial ligation.23~24 x

Mesenchymal Hamartoma Mesenchymal hamartoma (MH) usually presents as a painless right upper quadrant abdominal mass in a child Some patients may have eviyounger than 2 years.13,37,64 dence of CHF,45,60 and, similar to IHH, MH has been .~~ proposed that MH diagnosed ~ r e n a t a l l yEdmondson17 arises from a mesenchymal rest that becomes isolated from the normal portal triad architecture and differentiates independently. The tumor grows along bile ducts and may incorporate normal liver tissue. Because the blood vessels and bile ducts are components of the mesenchymal rest, the biologic behavior of the tumor varies with the relative predominance of these tissues within the loose connective tissue stroma (mesenchyma) that surrounds them. Thus, the tumor may present as a predominantly cystic structure (Fig. 29-2) that enlarges rapidly because of fluid accumulation,61 or it may be predominantly vascular and present with CHF.60

Hemangioma Hemangioma is the most common vascular liver tumor in adults; in children, however, hemangiomas are usually incidental findings in asymptomatic patients.12 Hemangomas have widely dilated, nonanastomotic vascular spaces lined with flat endothelial cells and supported by fibrous tissue on microscopic examination.12 Review of the literature on hemangioma in children is problematic, because some authors have called the lesions hemangiomas when the patient's age and clinical presentation were more In addition, consistent with hemangioend~thelioma.~O because the preferred treatment for these lesions is not surgical, there is usually no specimen for the accurate assessment of histopathology. In children, the risk of hemorrhage with hemangiomas is low; thus, unless the patient is having pain or disability from hepatomegaly, no treatment is recommended. In contrast, adults with giant hemangiomas (>4 cm in diameter) are generally treated by resection.lxj7

Arteriovenous Malformation An AVM may occur within the liver parenchyma or outside the liver between the hepatic artery and the portal

- Cross section of a pathology specimen of a left hepatic lobectomy for mesenchymal hamartoma in a 10-month-old male infant.

498

PART

III

MAJORTUMORS OF C H I I . ~ H O O D

. - .

Contrast-enhanced abdommal computed tomography scan of a recurlent ~nesenchymalhamartoma of the right hepatic lobe, prev~ouslytreated by unroofing It was wbsequently managed successfully by pat tlal r ~ g hhepatlc t lobectomy

Von Schweinitz et al." suggested that fat-storing (Ito) cells of the immature liver may be involved in the development of MH. Serum AFP levels are usually normal in children with The radiMH, but they may be mildly ele~ated.~I,*0 ographic features of these tumors are consistent and distinguishing; abdominal sonography and CT demonstrate a single, usually large, fluid-filled mass with fine internal se~tationsand no cal~ifications.~2 Management must be tempered by the understanding ,~ there that MH usually follows a benign c o ~ r s ealthough have been reports of malignant transformation.46.j0 In general, complete operative resection is the procedure of choice, if it can be accomplished safely. Huge lesions or those that involve both lobes may be treated by unroofing and marsupializing the cysts, although the lesion may recur after incomplete resection (Fig. 29-3). MH is an entity distinct from the liver hamartomas associated with tuberous sclerosis. The latter are smaller, multifocal lesions that may be associated with angiomyolipomas in other locations, such as the kidney; they are rarely symptomatic and usually present in children older than 2 or 3 years. These hamartomas have little clinical significance, but their presence may be helpful in diagnosing tuberous sclerosis.33

Hepatocellular Adenoma Although isolated lesions are encountered in childhood, hepatocellular adenoma (HCA) is most commonly observed in adults in association with the use of anabolic corticosteroids or estrogen. HCA has been described in children treated with anabolic steroids and multiple blood transfusions for chronic anemia,s and it is expected in children with type I glycogen storage disease.26 several mechanisms for the developBianchi-roposed ment of HCA in patients with type I glycogen storage disease, including (1) regional imbalance in insulin and

glucagon metabolism, because these hormones are important in the regulation of hepatocyte proliferation and regeneration; (2) response to glycogen overload; and (3) oncogene activation. Microscopic examination of these adenomas reveals hepatocytes in sheets and cords oriented along sinusoids without a ductal component. The cells have glycogenfilled cytoplasm and small nuclei without mitoses. Adjacent liver and vessels are compressed but not invaded. The Children usually do not have coexisting cirrho~is.~ histologic pattern is similar to that of a well-differentiated hepatocellular carcinoma, and development of hepatocelluar carcinoma within an unresected HCA has been rep~rted.~~,~~ In children, HCA generally presents as an asymptomatic hepatic mass. The mass is solid on ultrasonography and CT. Liver enzyme and AFP levels are normal. A feature unique to this lesion is its propensity for intraperitoneal hemorrhage from spontaneous rupture. In adults, intraperitoneal bleeding is almost always seen in patients receiving estrogen therapy, and tumor regression may occur with the cessation of hormone administration. In patients with glycogen storage disease and HCA, tumor regression may occur with the correction of metabolic dist~rbances.~ Because of the known association between HCA and hepatocellular carcinoma, resection of HCA is recommended when it occurs in a child who is not receiving steroids and does not have glycogen storage disease. If resection cannot be accomplished without substantial risk, observation of the lesion while monitoring the serum AFP level may be appropriate. If the AFP level begins to increase or the lesion is significantly symptomatic, and if the risk of resection is unacceptably high, liver transplantation may be the best alternative.

Focal Nodular Hyperplasia Focal nodular hyperplasia (FNH) in children presents as an irregularly shaped, nontender liver mass. It is frequently found incidentally at laparotomy for another cause or on radiographic studies performed for another indication. The female-to-male ratio for FNH is approximately 4:1.'j3 FNH is occasionally seen with vascular malformations and hemangiomas in the liver,70and it has been postulated that the lesions represent an unusual response to injury or ischemia.17On abdominal sonography, the lesions may be isoechoic, hypoechoic, or hyperechoic to normal liver parenchyma and may be multiple in 10% to 15% of patients. The classic central scar may not be seen on ultrasonography. CT typically shows a hypervascular lesion with a dense stellate central scar. Conventional arteriography or magnetic resonance angiography shows a hypervascular mass with feeding arteries entering the periphery and converging on the central portion of the tumor. Some cases of fibrolamellar hepatocellular carcinoma are radiographically indistinguishable from FNH, which is a cause for concern if the diagnosis is being made without a biopsy.43There are reports of adult patients who have FNH and hepatocellular carcinoma simultaneously.44

.

CHAPTER

29

Nonmalignant Tumors of the Liver

499

Because this lesion is predominantly solid, it is difficult to differentiate it from other benign or malignant tumors by imaging studies. Invariably, the serum AFP level is normal. Fever, leukocytosis, and high C-reactive protein level in a child with a solid liver mass and normal AFP level are suggestive of an inflammatory pseudotumor of the liver. This lesion is thought to be an inflammatory reaction to some insult, although the instigating cause is usually unknown. Because it is difficult to diagnose this lesion without a large biopsy or resection of the lesion, most children undergo resection, which is curative.",54

Nonparasitic Cysts

Surgical view of focal nodular hyperplasia within the left lobe of the liver in a 2-year-old child treated by left lateral lobectomy.

On gross examination, the lesions are nonencapsulated, occasionally pedunculated, and quite firm (Fig. 294). Microscopic examination shows proliferation of hepatocytes and bile ducts and the pathognomonic central fibrosis. These lesions rarely become malignant, and hemorrhage is rare. Therefore, expectant therapy is appropriate when removal might be associated with significant morbidity, the child is asymptomatic, and the diagnosis has been made conclusively by radiographic studies, normal AFP levels, and biopsy.jl

OTHER TUMORS Teratoma There have been fewer than 25 case reports of hepatic teratoma in children.663'2 These children are invariably younger than 1 year, and calcification is usually present within the lesion, helping to differentiate it from other tumors. Some of these lesions have met the criteria for ~l AFP levels may be an intrahepatic fetus in f e t ~ . Serum elevated with a teratoma, but only mildly elevated in comparison to the levels seen with hepatoblastoma. Resection is the procedure of choice for a teratoma because of the risk of malignancy in any immature elements of the tumor.

Inflammatory Pseudotumor Inflammatory pseudotumor of the liver is rare. These lesions are generally seen in children older than 3 years but have been reported in younger children as well.

Nonparasitic cysts of the liver are rare and occur more commonly in adults than in children. Although they may be present and symptomatic at birth, most of these cysts are asymptomatic and are identified incidentally at autopsy or laparotomy. Symptoms are related to abdominal distention or displacement of adjacent structures. These lesions occur with equal frequency in males and females.1Wonparasitic cysts are generally unilocular and lined by cuboidal or columnar epithelium, characteristic of bile ducts. The cyst fluid is typically clear or brown, and bile is rarely present. Pathologic studies suggest that nonparasitic cysts arise from congenital or secondary obstruction of peribiliary glands. These glands normally arise from the ductal plate at the hepatic hilum around the seventh week of gestation and continue to proliferate until adolescence.15 Symptomatic cysts can be effectively treated by simple unroofing, marsupialization," or sclerotherapy.49 If biliary communication is suspected, cholangiography may identify the source and allow the communicating ductule to be oversewn. Cystic dilatation of the intrahepatic ducts may also present as a mass, although jaundice and cholangitis are often associated with this problem. Resection of the affected lobe is the preferred therapy." If MH appears to be completely cystic on imaging, it may be misdiagnosed as a nonparasitic cyst. Post-traumatic bile cysts result from ductal disruption and intrahepatic accumulation of bile. These lesions can be treated by percutaneous drainage or, in some cases, by biliary sphincterotomy to reduce the bile duct pressure and lessen the biliary leak." Resection is rarely necessary for post-traumatic cysts. Multiple parenchymal cysts associated with hereditary polycystic kidney disease are generally asymptomatic and so small that they do not require intervention. Epidermoid cysts differ from other nonparasitic cysts, in that the lining epithelium is squamous rather than cuboidal. This histologic characteristic has led to the theory that these lesions may be foregut bud anomalies trapped in the hepatic substance. Although these lesions are rare, there has been a report of malignant degeneration. Thus, resection is the appropriate m a n a g e r n ~ n t . ~ ~ ACKNOWLEDGMENT The author thanks W. Raleigh Thompson, MD, for his contribution to this chapter in the fifth edition of this book.

500

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MAJORTUMORS OF CHILDHOOD

REFERENCES 1. Baer HU, Dennison AR, Moulton W, et al: Enucleation of giant hemangiomas of the liver. Ann Surg 1992;216:673. 2. Baggenstoss AH: Pathology of tumors of liver in infancy and childhood. In Pack G, Islami A (eds): Tumors of the Liver. New York: Springer-Verlag, 1970, p 240. 3. Barlow CF, Priebe CJ, Mulliken JB, et al: Spastic diplegia as a complication of interferon alpha-2a treatment of hemangiomas of infancy.J Pediatr 1998;132:527. 4. Barnhart DC, Hirschl RB, Garver KA, et al: Conservative management of mesenchymal hamartoma of the liver. J Pediatr Surg 1997;32:1495. 5. Bianchi L: Glycogen storage disease I and hepatocellular tumors. Eur J Pediatr 1993;152:S63. 6. Burrows PE, Dubois J, Kassarjian: Pediatric hepatic vascular anomalies. Pediatr Radiol 2001;31:533. 7. Buscarini E, Buscarini L, Danesino C, et al: Hepatic vascular malformations in hereditary hemorrhagic telangiectasia: Doppler sonographic screening in a large family. J Hepatol 1997;26:111. 8. Chandra RS, Kapur SP, Kelleher J, et al: Benign hepatocellular tumors in the young: A clinicopathologic spectrum. Arch Pathol Lab Med 1984;108:168. 9. Chang E, Boyd A, Nelson CC, et al: Successful treatment of infantile hemangiomas with interferon-alpha-2b. J Pediatr Hematol Oncol 1997;19:237. 10. Cohen RC, Myers NA: Diagnosis and management of massive hepatic hemangiomas in childhood. J Pediatr Surg 1986;21:6. 11. Daller JA, Bueno J, Gutierrez J, et al: Hepatic hemangioendothelioma: Clinical experience and management strategy. J Pediatr Surg 1999;34:98. 12. Dehner LP, Ishak KG: Vascular tumors of the liver in infants and children. Arch Pathol 1971;92:101. 13. DeMaioribus CA, Lally KP, Sim K, et al: Mesenchymal hamartoma of the liver. Arch Surg 1990;125:598. 14. Dickman PS, Meza MP, Newman B: Hepatic vascular malformations. Pediatr Pathol Lab Med 1995;15:155. 15. Donovan MJ, Kozakewich H, Perez-Atayde A: Solitary nonparasitic cysts of the liver: The Boston Children's Hospital experience. Pediatr Pathol Lab Med 1995;15:419. 16. Dubois J, Hershon L, Carmant L, et al: Toxicity profile of interferon alfa-2b in children: A prospective evaluation. J Pediatr 1999;135:782. 17. Edmondson HA: Differential diagnosis of tumors and tumor like lesions of liver in infancy and childhood. Am J Dis Child 1956;91:168. 18. Ezekowitz RAB, Mulliken JB, Folkman J: Interferon alfa-2a therapy for life-threatening hemangiomas of infancy. N Engl J Med 1992;326:1456. 19. Falk H, Herbert JT, Edmonds L, et al: Review of four cases of childhood hepatic angiosarcoma-elevated environmental arsenic exposure in one case. Cancer 1981;47:382. 20. Fellows KE, Hoffer FA, Markowitz RI, et al: Multiple collaterals to hepatic infantile hemangioendotheliomas and arteriovenous malformations: Effect on embolization. Radiology 1991;181:813. 21. Gembruch U, Baschat AA, Gloeckner-Hoffmann K, et al: Prenatal diagnosis and management of fetuses with liver hemangiomata. Ultrasound Obstet Gynecol 2002; 19:454. 22. Hata Y, Sasaki F, Matuoka S, et al: Inflammatory pseudotumor of the liver in children: Report of cases and review of the literature. J Pediatr Surg 1992;27:1549. 23. Hazebroek FWJ, Tibboel D, Robben SGF, et al: Hepatic artery ligation for hepatic vascular tumors with arteriovenous and arterioportal venous shunts in the newborn: Successful

management of two cases and review of the literature. J Pediatr Surg 1995;30:1127. Heaton ND, Davenport M, Karani J, et al: Congenital hepatoportal arteriovenous fistula. Surgery 1995;117:170. Holcomb GW, O'Neill JA, Mahboudi S, et al: Experience with hepatic hemangioendothelioma in infancy and childhood. J Pediatr Surg 1988;23:661. Howell RR,Stevenson RE, Ben-Menachem Y, et al: Hepatic adenomata with type 1 glycogen storage disease. JAMA 1976;236:1481. Huang SA, Tu HM, Harney JW, et al: Severe hypothyroidism caused by type 3 iodothyronine deiodinase in infantile hemangiomas. N Engl J Med 2000;343:185. Hurvitz SA, Hurvitz CH, Sloninsky L, et al: Successful treatment with cyclophosphamide of life threatening diffuse hemangiomatosis involving the liver. J Pediatr Hematol Oncol 2000;22:527. Ingram JD, Yerushalmi B, Connell J, et al: Hepatoblastoma in a neonate: A hypervascular presentation mimicking hemangioendothelioma. Pediatr Radiol 2000;30:794. Ishak KG: Primary hepatic tumors in childhood. In Popper H, Schaffner F (eds): Progress in Liver Diseases, vol 5. New York, Grune & Stratton, 1976, p 636. Ito H, Kishikawa T, Toda T, et al: Hepatic mesenchymal hamartoma of an infant. J Pediatr Surg 1984;19:315. Janes CH, McGill DB, LudwigJ, et al: Liver cell adenoma at the age of 3 years and transplantation 19 years later after development of carcinoma: A case report. Hepatology 1993;17:583. Jozwiak S, Pedich M, Rajszys P, et al: Incidence of hepatic hamartomas in tuberous sclerosis. Arch Dis Child 1992; 67:1363. Kamata S, Nose K, Sawai T, et al: Fetal mesenchymal hamartoma of the liver: Report of a case. J Pediatr Surg 2003;38:639. Kasabach HH, Merritt KK: Capillary hemangioma with extensive purpura: Report of a case. Am J Dis Child 1940;59:1063. Kasahara M, Kiuchi T, Haga H, et al: Monosegmental living-donor liver transplantation for infantile hepatic hemangioendothelioma. J Pediatr Surg 2003;38:1108. Lack EE: Mesenchymal hamartoma of the liver: A clinical and pathologic study of nine cases. Am J Pediatr Hematol Oncol 1986;8:91. Litwin DEM, Taylor BR, Greig P, et al: Nonparasitic cysts of the liver: The case for conservative surgical management. Ann Surg 1987;205:45. Longmire WP, Mandiola SA, Gordon HE: Congenital cystic disease of the liver and biliary system. Ann Surg 1971;174:711. Luks FI, Yazbeck S, Brandt ML, et al: Benign liver tumors in children: A 25 year experience. J Pediatr Surg 1991; 26:1326. Magnus KG, Millar AJW, Sinclair-Smith CC, et al: Intrahepatic fetus-in-fetu: A case report and review of the literature. J Pediatr Surg 1999;34:1861. Mason KP, Koka BV, Eldredge EA, et al: Perioperative considerations in a hypothyroid infant with hepatic haemangioma. Paediatr Anaesth 2001;11:228. Meyers RL, Scaife ER: Benign liver and biliary tract masses in infants and toddlers. Semin Pediatr Surg 2000;9:146. Muguti G, Tait N, Richardson A, et al: Hepatic focal nodular hyperplasia: A benign incidentaloma or a marker of serious hepatic disease? HPB Surg 1992;5:171. , Mulrooney DA, Carpenter B, Georgieff M, et al: Hepatic mesenchymal hamartoma in a neonate: A case report and review of the literature. J Pediatr Hematol Oncol 2001; 23:316.

CHAPTER

46. O'Sullivan MI, Swanson PE, Knolll, et al: Undifferentiated embryonal sarcoma with unusual features arising within mesenchymal hamartoma of the liver: Report of a case and review of the literature. Pediatr Dev Pathol 2001;4:482. 47. Perez J, Pardo J, Gomez C: Vincristine-an effective treatment of corticoid-resistant life- threatening infantile hemangiomas. Acta Oncol 2002;41:197. 48. Pizzo CJ: Type I glycogen storage disease with focal nodular hyperplasia of the liver and vasoconstrictive pulmonary hypertension. Pediatrics 1980;65:341. 49. Raboei E, Luoma R: Definitive treatment of congenital liver cyst with alcohol. J Pediatr Surg 2000;35:1138. 50. Ramanujam TM, Ramesh JC, Goh DW, et al: Malignant transformation of mesenchymal hamartoma of the liver: Case report and review of the literature. J Pediatr Surg 1999;34:1684. 51. Reymond D, PlaschkesJ, Ridolfi Luthy A, et al: Focal nodular hyperplasia of the liver in children: Review of follow-up and outcome. J Pediatr Surg 1995;30:1590. 52. Ricketts RR, Stryker S, Raffensperger JG: Ventral fasciotomy in the management of hepatic hemangioendothelioma. J Pediatr Surg 1982;17:187. 53. Rotman M, John M, Stowe S, et al: Radiation treatment of pediatric hepatic hemangiomatosis and coexisting cardiac failure. N Engl J Med 1980;302:852. 54. Sakai M, Ikeda H, Suzuki N, et al: Inflammatory pseudotumor of the liver: Case report and review of the literature. J Pediatr Surg 2001;36:663. 55. Samuel M, Spitz L: Infantile hepatic hemangioendothelioma: The role of surgery. J Pediatr Surg 1995;30:1425. 56. SchullingerJN, Wigger HJ, Price JB, et al: Epidermoid cysts of the liver. J Pediatr Surg 1983;18:240. 57. Schwartz SI, Husser WC: Cavernous hemangioma of the liver: A single institution report of 16 resections. Ann Surg 1987;205:456. 58. Scioscia PJ, Dillion PW, Cilley RE, et al: Endoscopic sphincterotomy in the management of posttraumatic biliary fistula. J Pediatr Surg 1994;29:3. 59. Selby DM, StockerJT, Waclawiw MA, et al: Infantile hemangioendothelioma of the liver. Hepatology 1994;20:39.

29

Nonmalignant Tumors of the Liver

501

60. Smith WL, Ballantine TVN, Gonzalez-Crussi F: Hepatic mesenchymal hamartoma causing heart failure in the neonate. J Pediatr Surg 1978;13:183. 61. Srouji MN, Chatten J, Schulman WM, et al: Mesenchymal hamartoma of the liver in infants. Cancer 1978;42:2483. 62. Stanley P, Hall TR, Woolley MM, et al: Mesenchymal hamartomas of the liver in childhood: Sonographic and CT findings. AJR Am J Roentgen01 1986;147:1035. 63. Stocker JT, Ishak KG: Focal nodular hyperplasia of the liver: A study of 21 pediatric cases. Cancer 1981;48:336. 64. Stocker JT, Ishak KG: Mesenchymal hamartoma of the liver: Report of 30 cases and review of the literature. Pediatr Pathol 1983;1:245. 65. Tesluk H, Lawrie J: Hepatocellular ademona: Its transformation to carcinoma in a user of oral contraceptives. Arch Pathol Lab Med 1981;105:296. 66. Todani T, Tabuchi K, Watanabe Y, et al: True hepatic teratoma with high alpha fetoprotein in serum. J Pediatr Surg 1977;12:591. 67. von Schweinitz D, Gomez Dammeier B, Gluer S: Mesenchymal hamartoma of the liver-new insight into histogenesis. J Pediatr Surg 1999;34:1269. 68. Warmann S, Bertram H, Kardorff R, et al: Interventional treatment of infantile hepatic hemangioendothelioma. J Pediatr Surg 2003;38:1177. 69. Weinberg AG, Finegold MJ: Primary hepatic tumors of childhood. Hum Pathol 1983;14:512. 70. Whelan TJ, Baugh J, Chandor S: Focal nodular hyperplasia of the liver. Ann Surg 1973;177:150. 71. Whiting JH, Korzenik JR, Miller FJ, et al: Fatal outcome after embolotherapy for hepatic arteriovenous malformations of the liver in two patients with hereditary hemorrhagic telangiectasia. J Vasc Interv Radio1 2000; 11:855. 72. Witte DP, Kissane JM, Askin FB: Hepatic teratomas in children. Pediatr Pathol 1983;1:81. 73. Wu JT, Book L, Sudar K: Serum alpha fetoprotein (AFP) levels in normal infants. Pediatr Res 1981;15:50.

Liver lumors James B. Atkinson and Daniel A. DeUgarte

Malignant liver neoplasms account for 1% of all pediatric malignancies and are the third most common intra-abdominal neoplasm after neuroblastoma and nephroblastoma. The two primary malignant neoplasms of the liver are hepatoblastoma and hepatocellular carcinoma. Survival has significantly improved for hepatoblastoma with the advent of new chemotherapy protocols and advances in liver surgery. The prognosis for hepatocellular carcinoma remains poor. Complete resection is required for cure.

EPIDEMIOLOGY Hepatoblastoma and hepatocellular carcinoma have a different incidence, age distribution, genetic basis, and associated risk factors (Table 30-1). From 1979 to 1996, the incidence of hepatoblastoma rose from 0.6 to 1.2 per million U.S. residents younger than 20 years, and that of hepatocellular carcinoma decreased from 0.45 to 0.29 per million.'4 Hepatoblastoma and hepatocellular carcinoma both occur more frequently in male^.^^,^^ Hepatoblastoma usually occurs in children aged 6 months to 3 years, whereas hepatocellular carcinoma occurs in older children and adults.

I

1

Hepatoblastoma Incidence 1.2 cases per million12 Age distribution 6 rno to 3 yr Risk factors Beckwith-Weidemann syndrome Familial adenomatous polyposis Hemihypertrophy Low birth weight26.54 5-yr survival 52% to 75%12,40.47,55

Hepatocellular Carcinoma ---0.29 cases per million12 >5 yr Hepatitis B virus Cirrhosis Liver disease

18%to 28%11.26

1

Hepatoblastoma is associated with Beckwith-Wiedemann syndrome, familial adenomatous polyposis, hemihypertrophy, and low birth weight.l",'",44360,66The most common genetic aberrations involve chromosomes lp, lq, 2q, 4q, 7q, 8q, 12p, 17q, 20, 22q, Xp, and Xq.6"71,7Wepatoblastoma has also been associated with stabilizing mutations of p-catenin and activation of Wnt/p-catenin signaling.6 Up-regulation of insulin-like growth factor 2 has also been observed in hepatoblastomas and may be mediated by the overexpression of PLGAl oncogene, a transcrip~~ tional activator on the 8q c h r o m o ~ o m e .Cytogenetic abnormalities have not led to the identification of a causal factor nor been shown to influence prognosis. The cause of hepatoblastoma remains unclear, but recent theories suggest that hepatoblastoma is derived from a pluripotent hepatic stem cell or oval stem cell that can differentiate into both hepatocytes and biliary epithelial cells. Both hepatoblastoma cells and oval stem cells express markers for these two lineages. Further, the structural features of hepatoblastoma resemble those found in distinct phases of h e p a t ~ g e n e s i s . ~ ' , ~ ~ The association between very low birth weight (VLBW) and hepatoblastoma may be explained by a higher likelihood of genetic abnormalities or the susceptibility of the immature liver to the effects of intensive perinatal therapy (e.g., oxygen, diuretics, radiation). In one study, hepatoblastoma patients had a longer duration of and more aggressive perinatal therapy than did birth weightmatched controls.54VLBW infants may also be at higher risk of developing advanced h e p a t ~ b l a s t o m a . ~ ~ o m e reports have suggested that infants with VLBW or other conditions associated with hepatoblastoma might benefit from screening with serial ultrasound examinations and serum alpha fetaprotein (AFP) monitoring to increase the likelihood of early detection." However, a cost-benefit analysis of screening for hepatoblastoma in high-risk patients must be performed before it is applied routinely. Hepatocellular carcinoma occurs predominantly in the setting of underying liver disease and cirrhosis. In young children, hepatocellular carcinoma has been associated with tyrosinemia and other inherited metabolic disorders.76 The incidence of hepatocellular carcinoma in the United States is higher in Asians and foreign-born children.10.14 In Taiwan, hepatocellular carcinoma occurs

CHAPTER

503

Liver Tumors

elevated serum transaminase levels are occasionally observed.57 Diagnosis is ultimately made with biopsy. An algorithm for the diagnosis and treatment of malignant liver neoplasms is presented in Figure 30-1. The most sensitive laboratory test for hepatoblastoma and hepatocellular carcinoma is serum AFP level. AFP is produced in the fetal liver and yolk sac, and levels decline to adult values during the first 6 months after birth. Although AFP can be used effectively as a tumor marker, it is nonspecific. Serum AFP levels are elevated in over 90% of hepatoblastomas and in approximately 70% of hepatocellular carcinomas.13~" Falsely elevated serum AFP levels can be noted in hepatitis, cirrhosis, hemangioendothelioma, germ cell tumor, testicular tumor and gallbladder carcinoma. Normal AFP levels have been observed with both well-differentiated and immature hepatoblastomas and frequently occur with the fibrolamellar variants of hepatocellular c a r c i n o m a . l ~ JSerum 3 ~ ~ AFP levels can be used to monitor chemotherapeutic efficacy and to detect disease recurrence. Rarely, hepatoblastoma may secrete Phuman chorionic gonadotropin, associated with sexual precocity.

predominantly in hepatitis B viral carriers.14 Hepatitis B vaccinations led to a significant decrease in the rate of hepatocellular carcin0ma.~,"~46A Taiwanese study comparing hepatocellular carcinoma in children and adults demonstrated that hepatitis B viral infection was always present in children (100% versus 80%), the frequency of liver cirrhosis was similar (70%), and the rate of resectability was lower in children (18% versus 56%).1°

CLINICAL FEATURES AND LABORATORY DATA Most patients with liver tumors present with an abdominal mass, and more than two thirds of liver tumors are malignant." Although most patients are asymptomatic, some note abdominal distention, anorexia, weight loss, pain, nausea, and fatigue. An abdominal computed tomography (CT) or ultrasound scan is obtained, which usually reveals a solid liver mass. Laboratory studies should include complete blood cell count, chemistry panel, liver function tests, coagulation profile, and serum AFP levels. Thrombocytosis is present in 60% of cases.7Unemia and

Algorithm for the diagnosis and treatment of a liver mass. AFP, alpha fetoprotein; CBC, complete blood count; CT, computed totnography; CXR, chest radiograph; LFT, liver function tests; MRI, magnetic rcsonance imaging; PT/PTT, prothrombin time/partial thromboplastin time; US, ultrasound.

30

Liver Mass

.

Diagnostic lmaging (US andlor CT)

-w

Solid

Vascular or Cystic

&

J. Staaina Workaroup: Labs (AFP, CBC, LFTs, PTIPTT, Chemistry) CXR Chest CT MRI

*

J. Surgery for Exploration

Resectable

Angiography IResection vs. Obsewation

(+) Metastasis

I

7

Not Resectable

Biopsy

J.

Neoadjuvant Chemotherapy

lmaging Resection

4

I

Not Resectable

3. Chemotherapy (* Chemotherapy for Stage I - Pure Fetal Histology)

Follow-UP

Original AFP

Serial AFP

t

Original AFP Normal

Serial Imaging

1

504

PART

III

M A ~ TUMORS R OF CHII.DHOOD

IMAGING Imaging is helpful both for diagnostic purposes and to assess tumor resectability. Ultrasonography or CT of the abdomen is performed initially to assess the tumor.Z3 A chest radiograph or CT scan of the chest should also be obtained to rule out metastatic disease. Ultimately, imaging should delineate the size and location of tumors, evaluate for metastastic disease, and determine whether vascular invasion of the portal vein, hepatic veins, or inferior vena cava is present. Although advances in imaging have improved the ability to predict resectability, the ultimate assessment is made in the operating room by the surgeon. Ultrasonography is helpful for the initial evaluation and to assess vascular involvement. Liver lesions can be categorized sonographically as solid, cystic, or vascular. Malignant liver neoplasms are usually well-defined hyperechoic (solid) lesions on ultrasonography.15 Color Doppler ultrasonography is helpful in diagnosing venous thrombosis and vascular shunts within the tumor." It has also been used intraoperatively to aid in determining vascular involvement and tumor resectability. CT with intravenous and gastrointestinal contrast enhancement is useful to delineate tumor type, size, and location and to detect regional lymphadenopathy. Abdominal CT usually reveals a mass with low attenuation. Helical CT with three-dimensional reconstruction can be performed in complex cases that require nonstandard resections.

A

Magnetic resonance imaging (MRI) and magnetic resonance angiography are especially helpful in determining the tumor's relationship to the hepatic vasculature and biliary anatomy. Liver tumors have homogeneous hypointensity on T1-weighted images and hyperintensity on T2-weighted images." Three-dimensional reconstruction can significantly enhance the surgeon's ability to predict resectability (Fig. 30-2). Angiography was used in the past to delineate the anatomy of the hepatic vasculature, but with the availability of MRI and contrast-enhanced CT, it is rarely required for the diagnostic evaluation of malignant liver neoplasms. Angiography is used in some cases to perform selective chemoembolization as a therapeutic intervention.

DIFFERENTIAL DIAGNOSIS AND HISTOLOGY Diagnosis is ultimately made with biopsy using percutaneous, laparoscopic, or open approaches. Fine-needle aspiration can be sufficient for diagnosis. Some groups permit the initiation of neoadjuvant chemotherapy based on clinical criteria when those clinical features are highly suggestive of hepatoblastoma or hepatocellular carcinoma.13 However, given the significant error rate in clinical diagnosis, we strongly advocate biopsy in all cases.'" The distribution of malignant and benign primary hepatic tumors of children is shown in Table 30-2. Hepatoblastoma and hepatocellular carcinoma are of

B

A, Magnetic resonance imaging o f a &month-old cklild demonstrates a 10-cm right hepatic mass. B, Magnetic resonance angiography with three-dimensional reconstruction allows image roctation and delineation o f vascular anatomy. Compression o f the intrahepatic vena cava demonstrates unresectability.

CHAPTER

Tumor Malignant Hepatoblastoma Hepatocellular carcinoma Sarcoma Benign Benign vascular tumor Mesenchymal hamartoma Adenoma Focal nodular hyperplasia Other

30

Liver Tumors

505

% of Patients 43 23 6

13 6 2 2 5

Adapted from Weinberg AG, Finegold MJ: Primary hepatic tumors of childhood. Hum Pathol 1983;14:512-537.

epithelial origin and account for more than 90% of malignant liver neoplasms.76Primary liver neoplasms can also be of mesenchymal origin; of these, sarcomas are the most common. Undifferentiated embryonal sarcomas and rhabdomyosarcoma usually occur in children aged 5 to 10 years. They are associated with a normal serum AFP level and are vimentin positive on staining.74Other reported malignancies include the malignant transformation of mesenchymal hamartoma,58 angiosarcoma, cholangiocarcinoma, rhabdoid tumor,"g immature teratoma, and c h o r i o c a r ~ i n o m aMetastatic .~~ disease to the liver is relatively uncommon in children. Histologic classification of hepatoblastomas has minimal predictive value in determining prognosis. Uniform criteria have not been established, but most pediatric pathologists have simplified the classification into epithelial and mixed (epithelial and mesenchymal) types. The epithelial type is subdivided into fetal, embryonal, macrotrabecular, and small cell undifferentiated types.60 Small cell undifferentiated histology may confer an unfavorable outcome.22 Conversely, pure fetal histology (PFH) with minimal mitotic activity (<2 mitoses/l0 400x microscopic fields) has been associated with significantly improved event-free survival (Fig. 30-3).4"7"n fact, adjuvant chemotherapy is no longer routinely recommended by the Children's Oncology Group for children who undergo complete resection of hepatoblastomas with PFH. With respect to hepatocellular carcinoma, it has been proposed by some investigators that patients with a fibrolamellelar variant may have a higher resection rate and improved survival than those with the typical ~ariant.~z,33 However, Katzenstein et a1." observed that although the median survival may be longer, no difference is noted when a stage-for-stage comparison is made between the fibrolamellar variant and other cell types.

STAGlNG Multiple staging systems have been proposed to classify both hepatoblastoma and hepatocellular carcinoma. The system currently used by the Pediatric Oncology

Photomicrograph demonstrates pure fetal histology (PFH) with minimal mitotic activity (<2 mitoses/l0 400x microscopic fields). In stage I hepatoblastoma, PFH has been associated with significantly improved event-free survival.

Group (POG) in the United States and the German Cooperative Pediatric Liver Tumor Study Group is shown in Table 30-3.21,49This classification scheme is based on the postoperative extent of disease. Approximately 5% of hepatoblastomas that are completely resected (stage I) disease is have PFH with low mitotic a~tivity.~Wesidual defined as microscopic (stage 11), macroscopic (stage 111), or extrahepatic or metastatic (stage IV).Approximately 20% of hepatoblastomas have distant metastasis at the , ~ ~ , ~ ~ , ~ ~carcinoma usually time of d i a g n o s i ~ . * ~Hepatocellular presents at a more advanged stage than hepatoblastoma does.lS29 Although the POG staging system is useful in determining the postoperative prognosis, it does not provide information on the preoperative extent of disease. To assess tumor response and resectability before and after neoadjuvant chemotherapy, the International Society of Pediatric Oncology (SIOP) developed the PRETEXT (pretreatment extent of disease) staging ~ y s t e m .The ~ ~ ,PRETEXT ~~ system is based on radiologic findings and describes both the number and the location of involved liver sectors and takes into account invasion of the hepatic and portal veins as well as extrahepatic and metastatic disease (Fig. 30-4). For example, a group 111, p, m tumor has three out of four sectors involved by tumor, with ingrowth of the portal vein and metastasis.

Stage

Description

I* II

Complete resection Microscopic residual tumor Macroscopic residual tumor Distant metastasis

*Stage I hepatoblastoma can be subdivided into (1) pure fetal histology with minimal mitotic activity and (2) all other histologic types.

506

PART

I1I

MAJORTUMORSOF CHILDHOOD

p ' p "v R

L

3 adjoining sectors FREE

" @pp 4

v

A, 2 sectors in one lobe FREE

L medial and R anterior sectors FREE

The SIOP pretreatment grouping system

L

R

p

J

@p @ L lat. sector FREE

A2

R post. sector FREE

number of (PRETEXT) liver involvement of sectors describes involved based the extent on and the takes into account metastasis (m), ingrowth of vena cava (v) and portal vein ( p ) , and extrahepatic (e).

'32 L med. sector FREE R ant. sector FREE

"@'p no FREE sector

@metastases

@ingrowth vena portae

@ ingrowth vena cava

@extrahepatic extension

This staging system has allowed oncologists to compare positioned such that the surgeon has access to the neck, tumor response to different neoadjuvant regimens. chest, abdomen, and groins. In the event that additional Other classification schemes that have been developed access or more extensive exposure is needed, these for hepatoblastoma include those by the ~ a ~ a n e s e areas will be easily accessible within the sterile field. Society of Pediatric Surgeons and TNM classifications.6* The Trendelenburg position lowers the caval and In children, hepatocellular carcinoma also has been hepatic venous pressures and minimizes the risk of air investigated using the POG and PRETEXT staging sysembolism. tems.l"Zg In adults, the Okuda and Barcelona Clinic An initial subcostal incision can be used to evaluate the clas~ifications9"~8 have been used to take into account tumor's location and extent. The remainder of the both the extent of tumor involvement and the severity of abdomen is searched for any evidence of metastatic disease liver disease. not detected by preoperative studies. Once a decision is made to proceed with resection, the incision is extended across the abdomen. In older children, a midline extension toward the xiphoid provides even wider exposure of SURGERY the liver and tumor. The primary goal of surgery is complete anatomic resecThe liver and tumor are completely mobilized from all tion. Resectability can be compromised by multifocality, anatomic attachments. The triangular ligament is divided bilobar involvement, portal vein or vena cava thrombosis, from the left hepatic vein to its termination at the left vascular invasion, para-aortic lymphadenopathy, extendiaphragm. The right lobe of the liver is then retracted sion to the hepatic hilum, and distant metastasis. In from the right diaphragm, and the bare attachments are centrally located tumors, hepatic vein involvement may divided by cautery. As the liver is delivered through the preclude safe resection. In general, nonanatomic liver incision, the remaining attachments of the right adrenal resections should be avoided because of a higher rate gland and several branches of the infrahepatic vena cava of incomplete tumor resection and local relapse.20 When are divided to completely mobilize the liver. histo10,gy demonstrates microscopic residual disease Additional mobilization of the infrahepatic vena cava following resection, reoperation shbuld be strongly conis then performed such that the vena cava above the sidered to extend the margins of resection when anatomorigin of the renal veins to the junction with the hepatic ically feasible. parenchyma is encircled and contrblled with a vessel Successful hepatic resection requires careful planning loop. With complete mobilization of the liver, a final and supportive care. An experienied pediatric zkesthes; assessment of the plan for resection is made. The portal ologist is essential. The first step in the operative structures can be palpated bimanually through the foraprocedure is placement of reliable large-bore venous men of Winslow for evidence of tumor invasion and the cathetes, arterial monitoring lines, and supplemental presence of frequently encountered vascular anomalies. peripheral venous catheters. The patient -should be The retrohepatic vena cava should be assessed for location

CHAPTER

within the hepatic parenchyma or evidence of tumor invasion. Finally, a careful assessment of the relationship between the tumor and the hepatic veins should be made. The accuracy of this assessment may be enhanced by preoperative images and intraoperative ultrasonography. Unexpected invasion of the remaining solitary hepatic vein is the most common cause of positive resection margins, severe intraoperative hemorrhage, and postoperative liver failure due to acute portal hypertension from hepatic vein injury (Budd-Chiari syndrome). Once this assessment is completed, the mobilized tumor and liver can be evaluated for the required resection. Options include a standard right or left hepatic lobectomy, extended right or left lobectomy, or, in rare cases, a central or segmentally based anatomic resection. The sequence of the dissection is similar in all cases. Once the tumor and liver have been mobilized and the surgeon determines that the tumor is resectable, attention is directed to a vascular dissection of the portal structures. The hepatic artery, common bile duct, and portal vein are identified near the duodenum and distal to the branching of the pancreaticoduodenal artery. The gallbladder is dissected from the liver, and the cystic duct is ligated. A vascular dissection of the common duct, hepatic artery, and portal vein is then performed, with identification and ligation of the structures supplying the intended segment or lobe of the liver and tumor. As the hepatic arterial and portal venous branches are ligated, a line of demarcation appears to guide the parenchymal dissection. Once the portal dissection is complete, attention is directed to the retrohepatic inferior vena cava. The liver and tumor are rotated to the left, exposing the course of the vena cava. A tedious and careful dissection of the vena cava is performed beginning distally and working superiorly toward the hepatic veins. Myriad small paired branches can be identified, dissected, and ligated as the vena cava is freed from the hepatic parenchyma. In difficult cases, the Pringle maneuver, clamping across the remaining portal vasculature and clamping the supra- or infradiaphragmatic vena cava, may facilitate dissection. Clamping of the portal structures should be limited to 15 minutes, with the total clamp time not to exceed 60 minutes. At the conclusion of this portion of the surgery, the vena cava will be entirely free except for the major hepatic veins. The final portion of the vascular dissection is the identification and division of the appropriate hepatic veins. The right, middle, and left hepatic veins originate very close to the surface of the liver. The course of the veins is extremely short until they combine into the structure of the atrium of the heart. Before beginning the resection, it is critical that involvement at the hepatic veins has been accurately assessed. Intraoperative ultrasonography can be of great assistance in planning the surgical approach to these important structures. Because the veins branch rapidly after entering the substance of the liver, it is technically much safer to divide them in the parenchyma if the tumor margins allow the use of this technique. Marking the surface of the liver with cautery just distal to the hepatic veins to be divided guides

30

Liver Tumors

507

parenchymal dissection and is safer than attempting extrahepatic ligation of the veins. When the tumor or anatomy does not permit intraparenchymal division of the hepatic veins, wide exposure and careful dissection should be used to isolate and divide the veins. Frequently, this can be delayed until most of the parenchyma has been divided and the specimen is nearly ready for delivery to the pathologist. The surgeon should not hesitate to obtain supradiaphragmatic control of the vena cava when control of the hepatic veins is difficult to achieve. Upon completion of the vascular dissection, a line of demarcation should be visible to guide the parenchymal dissection. Cautery may be used to circumferentially mark the line of resection 3 to 5 mm in deep. Particular care should be taken to mark the course of the parenchymal dissection in the area of the previously dissected portal structures and through the previously identified path to control the hepatic veins. The anesthesiologist should be alerted at this point to prepare for the potential blood loss associated with parenchymal dissection. The parenchymal dissection in the classic operation may proceed with blunt and finger fracture technique or by passing ligatures around bundles of hepatic parenchyma, tying the suture, and cutting through the parenchyma to reveal the vascular and biliary structures. Depending on surgeon preference, the Harmonic Scalpel (Ethicon Endosurgery, Cincinnati, Ohio), the Integra Selector (Integra, Plainsboro, N.J.), or the TissueLink device (TissueLink, Dover, N.H.) may be used to facilitate dissection. Although these devices aid in a precise dissection, the key to a successful and relatively blood-free parenchymal dissection is a complete vascular dissection before dividing the parenchyma. Knowledge of the three-dimensional segmental anatomy of the liver described by Couinard (Fig. 30-5) is essential in planning liver resections (Fig. 30-6). Segmentectomy involves resection of a single segment. A right hepatic lobectomy involves resection of segments V, VI, VII, and VIII and ligation of the right hepatic artery, right portal

The anatomy of the liver is divided into segments as described by Couinard.

508

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Standard anatomic liver resections are based on the segmental anatomy of the liver. Left lobectomy (formerly left lateral segmentectomy) excises segments I1 and 111; left hepatectomy, segments 11, 111, and IV,extended left hepatectomy, segments 11, 111, IV, V, and VIII (and occasionally I); right hepatectomy, segments V, VI, VII, and VIII; and extended right hepatic lobectomy (formerly right trisegmentectomy), segments IV, V, VI, VII, and VIII (and occasionally I). GB, gallbladder; IVC, inferior vena cava; LHV, left hepatic vein; MHV, middle hepatic vein; PV, portal vein; RHV, right hepatic vein.

vein, right hepatic biliary duct, and right hepatic vein. The liver parenchyma is divided through the median portal fissure on a line between the gallbladder fossa and the vena cava. The large distal branch and the smaller branches of the middle hepatic vein supplying these segments must also be divided. An extended right hepatic lobectomy (right trisegmentectomy) includes resection of segments I, IV, and V through VIII. The right and middle hepatic veins are divided. The liver parenchyma is divided along the falciform ligament and left portal fissure. In addition, the branches of the left hepatic artery, portal vein, and hepatic biliary duct to segments I and IV are ligated. Left lobectomy involves resection of segments 11, 111, and N and ligation of the left hepatic artery, left portal vein, left hepatic biliary duct, and left hepatic vein. The liver parenchyma is divided through the median portal fissure. The branches of the middle hepatic vein to segment IV are also divided. A left lateral segmentectomy involves resection of segments I1 and 111. The branches of the left hepatic artery, portal vein, and hepatic biliary duct to these segments are ligated. An extended left hepatic lobectomy (left trisegmentectomy) involves resection of segments I through IV, V, and VIII. The liver

parenchyma is divided along the right portal fissure. The left hepatic artery, left portal vein, left hepatic biliary duct, and left and middle hepatic veins are ligated. The branches of the right hepatic artery, right portal vein, and right hepatic biliary duct to segments V and VIII are also ligated. When only segments IV, V, and VIII are involved with tumor, central hepatic resection (mesohepatectomy) can be performed.34 Branches to the left portal vein to segment IV are divided in the umbilical fissure. The middle hepatic vein and right anterior sectoral pedicles are ligated. Central hepatic resection offers the advantage of preserving normal hepatic parenchyma (either segments 1-11 or VI-VII), which would ordinarily be removed in a standard anatomic resection (i.e., extended right or left lobectomy) . When the tumor is not resectable using standard anatomic resections, novel techniques have been used. Hepatic vein reconstruction using portal vein or synthetic graft has been performed when the hepatic vein or vena cava is involved by tumor.g When all hepatic veins are involved, one approach is to rely on venous outflow through the inferior hepatic vein, allowing resection of all segments except V and VI (we have no personal experience with this technique) .67 In the most challenging cases, tumor resection can be performed ex vivo (on the back table) using methods developed for liver transplantation. Blood flow to the heart is preserved with venovenous bypass. Following hepatectomy, the liver is infused with University of Wisconsin solution and placed in an ice bath. Back-table tumor resection and hepatic vein-vena cava reconstruction are performed before reim~lantation.2~ Upon completion of the resection, adequate hemostasis is achieved. Special attention is given to the raw surface of the remaining liver for both bleeding and bile leak. Drains are placed in the suprahepatic and subhepatic spaces. Complications following hepatic resection include bleeding, subphrenic abscess, biliary fistula, wound infection, and biliary obstruction. Several advances in anesthesia and surgical technique have improved resection rates and decreased perioperative mortality to less than 5%. When the operation is complicated by severe bleeding, total vascular isolation can be achieved by clamping the supra-and infrahepatic inferior vena cava in combination with the Pringle maneu~er.~' Bleeding can then be controlled before proceeding with resection. Vascular staplers can be used to transect hepatic vessels, resulting in reduced operative time and blood loss.77Vascular staplers, ultrasonic dissection, laser, Harmonic Scalpel, finger fracture, sharp dissection, and Kelly clamp have all been used to divide liver parenchyma. Argon beam coagulation and fibrin glue can be used to help control bleeding from the residual liver tissue. Laparoscopic liver resections have also been described in adults45 and have potential applications in children. Standard anatomic resections can lead to the loss of a significant percentage of liver parenchyma: right extended lobectomy, 85%; right lobectomy, 65%; left lobectomy, 35%; segmental or wedge resection, 3% to 15%.

CHAPTER

30

Liver Tumors

509

Most children with otherwise normal liver parenchyma can easily adapt to major resections with compensatory hyperplasia of the remaining liver. However, neonates have immature livers and are particularly susceptible to developing postoperative hepatic insufficiency manifested by hypoglycemia, hypoalbuminemia, and hypoprothrombinemia. Maintenance intravenous fluids contain 10% dextrose. Supplemental albumin and vitamin K can be administered for the first postoperative week. Oral feedings can usually be resumed in 2 to 3 days. Chemotherapy is usually withheld for 3 weeks in patients who have had extensive resections or compromised liver function to permit adequate liver replication to occur.

LIVER TRANSPLANTATION Ultimately, up to 6% of patients with hepatoblastoma will require orthotopic liver transplantation (Fig. 30-7).23,54 Liver trans~lantationshould be considered for everv child presenting with involvement of all four sectors of the liver or involvement of three sectors when complete tumor excision by partial hepatectomy is unlikely. A contraindication to liver-transplantation is the presence of extrahepatic disease following chemotherapy. Several reports describe favorable outcomes following In ~ a t i e n t s liver trans~lantationin children.1,3,32,51,5',54,61 who undergo primary liver transplantation for hepatoblastoma following neoadjuvant chemotherapy, 10-year survival rates of 85% have been achieved.51Tumor recurrence appears to be more frequent in children with a previous attempt at hepatic resection. In patients who undergo "rescue" liver transplantation following partial hepatectomy, the 5-year overall survival is 30% to 50%. positive margins after an initial attempt at resection is associated with a particularly poor prognosis. These results suggest that heroic attempts at partial hepatectomy should be avoided, and liver transplantation should be considered when the potential for complete resection B is in question.51 Computed tomography scan demonstrates a multifocal For hepatocellular carcinoma, liver transplantation hepatoblastoma. Despite a good response to chemotherapy, liver has the thkoretical advantage of removing n6t only the transplantation is the only hope for cure. tumor but also the entire diseased preneoplastic liver. Most centers restrict transplantation for hepatocellular carcinoma to patients with single tumors 5 cm or smaller of lifelong immunosuppression, which may enhance or three nodules 3 cm or smaller.3gThe overall 5-year survival rate following liver transplantation for hepatotumor recurrence or secondary malignancies. cellular carcinoma is 60% to 70% in adult series48 The scarcity of cadaveric donors, especially in the pediatric age group, has led to the use of segmental ADJUVANT THERAPY grafts from living donors or split-liver cadaveric donors. Living, related donor transplantation for tumors has been Although cure ultimately requires complete resection, associated with improved graft survival and outcome.76 chemotherapy remains the mainstay of adjuvant therapy Total hepatectomy in these patients should include for hepatoblastoma and hepatocellular carcinoma. removal of the retrohepatic inferior vena cava. This need Neoadjuvant chemotherapy has been advocated for the has discouraged the use of split livers in this population. purposes of downstaging disease, improving the likeliIn cases in which a segmental graft is used, reconstruchood of complete resection, and ultimately improving tion of the vena cava can be achieved with either a long-term survival.16 The disadvantage of neoadjuvant preserved allogeneic iliac vein or the internal jugular therapy is that nonresponders can experience disease vein procured from the living donor.C4lDisadvantages of progression, and ultimately the tumor can be upstaged transplantation include the associated expense and risks or become unresectable. Therefore, imaging and serum

510

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MATORTUMORS OF CHILDHOOD

AFP levels should be performed routinely to assess for response when neoadjuvant therapy is used. There are several chemotherapeutic regimens. Regimens with cisplatin, vincristine, and 5-fluo;ouracil have had comparable results to those with cisplatin and The SIOP advodoxorubicin, with fewer side effe~ts.2~3~~ cates cis~latinand doxorubicin and attributes better tolerance of this regimen to lower doses of doxorubicin.13 A German study group utilizes cisplatin, ifosfamide, and doxorubicin as its chemotherapeutic regimen.Z1 Results were similar to SIOP's, but toxic-ity was greater. Etoposide (W-16)and carboplatin are used for recurrent or unresponsive disease. Early reports suggest that irinotecan may be a promising chemotherapeutic agent in refractory or relapsed h e p a t ~ b l a s t o m a . ~ , ~ Wofs eantiangiogenic agents, including anti-vascular endothelial growth factor antibody and topotecan, resulted in reduction of tumor volume in ex~erimentalliver tumors.42,43 Neoadjuvant therapy has had a significant impact in improving resectability in hepatoblastoma, but outcomes are less favorable in children with hepatocellular carcinoma. Up to 50% to 70% of stage 111hepatoblastomas can

C

be rendered resectable after neoadjuvant chemotherapy.49 In stage 111 hepatocellular carcinoma, however, resection can be achieved in only 10% to 36% of patients following chemotherapy (Fig. 30-8).l"Z9 Radiation therapy has a limited role in the management of hepatoblastoma and hepatocellular carcinoma. Current cooperative trials provide for permissive use of radiation therauv in chiidren with residual disease. However, the ultimate goal remains complete surgical resection as the only effective for cure. In the hope of avoiding the systemic side effects of standard adjuvant therapies, novel and less toxic treatment modalities have been sought. One proposed strategy that selectively targets tumor cells is suicide gene therapy.27 This strategy involves the expression of a gene that converts a membrane-permeable nontoxic prodrug into a toxic agent (suicide drug) in tumor cells only. For example, in vivo models for hepatocellular carcinoma have used a replication-deficien; adenovirus carrying suicide ,~~ genes such as Escherichia coli c y t ~ s i n e . ~ .A' ~transcriptional control element like that for AFP is used to selectively express the suicide gene in tumor cells. L ,

D

Neoadjuvant chemotherapy can significantly decrease tumor size and ultimately make lobectomy easier and safer. Prominent calcification is seen after chemotherapy, and the right portal vein is noted to be patent.

CHAPTER

30

Liver Tumors

511

ABLATIVE THERAPIES Patients with lesions that cannot be anatomically resected and those who are not candidates for transplantation can be considered for local ablative therapies, including chemoembolization, radiofrequency ablation, percutaneous injection of ethanol, and cryoablation.2,",64 Ablative therapies offer palliation and may prolong survival but rarely achieve a cure. Alternatively, ablative therapies can act as a bridge to transplantation until a suitable donor becomes available. Radiofrequency ablation uses a needle electrode inserted into the tumor that delivers alternating current in the range of radiofrequency waves to cause focal thermal injury. Larger lesions require multiple overlapping applications, each lasting 10 to 20 minutes. Cryoablation uses direct freezing and thawing to cause cell death by protein denaturation, cell membrane disruption, and hypoxia. Intraoperatively, the Pringle maneuver can be performed to decrease the warming effects of larger blood vessels passing through or near the site to be ablated. Usually, two freeze cycles lasting 15 to 20 minutes each are followed by spontaneous thaw cycles. The goal of ablative therapies is to incorporate a l-cm rim of normal tissue. This can be confirmed sonographically by the presence of echogenic microbubbles with radiofrequency ablation or a round, echogenic expanding rim with cryoablation. Intrahepatic arterial chemoembolization has the potential to improve chemotherapeutic response and allow for contralateral liver hyperplasia. The procedure involves angiographic placement of a catheter into the main feeding artery of the tumor. Doxorubicin (Adriamycin) dispersed in lipiodol and cisplatin is infused, and embolization is then performed with Gelfoam." Drug levels within the tumor can reach 50 to 400 times that used in conventional chemotherapy without an increase in systemic toxicity. Reports concerning chemoembolization in children have been limited, but subsequent surgical resectability has been achieved in some case^.^,^^," Complications of chemoembolization include hepatic artery thrombosis and gastric ulceration. Chemoembolization can also be used before transplantation when systemic neoadjuvant chemotherapy has failed.4

1

1 Stage

Hepatocellular Hepatoblastoma Carcinoma

I (pure fetal histology) I (other histologic types) I (hepatocellular carcinoma) II Ill IV

1 0 0 % (n = 9 ) 91% (n = 4 3 ) 1 0 0 % (n = 7) 64% (n = 8 3 ) 25% (n = 4 0 )

I

I

88% (n = 8 ) - (n = 0 ) 8% ( n = 2 5 ) 0% (n = 1 3 )

Data adapted from Ortega JA, Dougless EC, FeusnerJH, et al: Randomizedcomparison of cisplatin/vincristine/Auorouracil and cisplatin/continuous infusion doxorubicin for treatment of pediatric hepatoblastoma:A report from the Children's Cancer Group and the Pediatric Oncology Group. J Clin Oncol2000;18:2665-2675; and Katzenstein HM, Krailo MD, Malogolowkin MH, et al: Hepatocellular carcinoma in children and adolescents: Resultsfrom the Pediatric Oncology Group and the Children's Cancer Group IntergroupStudy. J Clin Oncol2002;20: 2789-2797.

100% ( n = 3) for stage 11, 68% ( n = 25) for stage 111, and 21 % ( n = 14) for stage 1V.a The primary predictor for poor prognosis in hepatoblastoma and hepatocellular carcinoma is metastatic disease.*OJ3,21Multifocality, size, and lack of response to chemotherapy are also predictive of poor prognosis in hepatocellular carcinoma.13 Although metastatic disease portends a worse prognosis, some metastatic lesions have a complete response to chemotherapy. Pulmonary resection should be considered in selected patients with lung lesions that persist after chemotherapy. Following hepatic resection, most patients receive postoperative chemotherapy. Patients should be followed closely to ensure that serum AFP levels return to normal and that the neoplasm does not recur. In those patients who present with normal AFP levels, serial ultrasonography or CT can be performed to screen for recurrence.

CONCLUSION PROGNOSIS AND FOLLOW-UP The 5-year survival rate for hepatoblastoma has markedly improved from 35% 3 decades ago to 75% in some series.14,17,50,flfiThe prognosis for hepatocellular carcinoma remains dismal, with 5-year overall survival rates of that are successfully less than 18% to 28%.l"2"esions resected have a better prognosis, with 91% to 100% 5-year survival in hepatoblastoma and 30% to 54% for hepatoResults for estimated 5-year cellular car~inoma.~0,~"~"57,7s event-free survival reported by the Intergroup Hepatoma Study are summarized in Table 30-4. The German Cooperative Pediatric Liver Tumor Study Group had similar results for disease-free survival in hepatoblastoma (mean follow-up 58 months): 89% ( n = 27) for stage I,

Advances in anesthesia, surgical technique, and chemotherapy have led to a significant improvement in the prognosis of children with hepatoblastoma. Outcomes for hepatocellular carcinoma remain poor. Liver transplantation is useful in patients with unrectable tumors. Continued cooperation of multi-institutional pediatric cancer study groups will be required to achieve additional advances in the treatment of malignant liver neoplasms. ACKNOWLEDGMENT

We are grateful to Marcio Malogolowkin, MD, chair of the Liver Tumor Subcommittee of the Children's Oncology Group and director of the Bone and Soft Tissue Tumor Program

512

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at Children's Hospital, Los Angeles, for his review of the manuscript.

REFERENCES 1. Achilleos OA, Buist LJ, Kelly DA, et al: Unresectable hepatic tumors in childhood and the role of liver transplantation. J Pediatr Surg 1996;31:1563-1567. 2. Ahrar K, Gupta S: Hepatic artery embolization for hepatocellular carcinoma: ~ e c h n i ~ u patient e, selection, a i d outcomes. Surg Oncol Clin N Am 2003;12:105-126. 3. Al-Qabandi W, Jenkinson H, Buckels JA, et al: Orthotopic liver transplantation for unresectable hepatoblastoma: A single center's experience.J Pediatr Surg 1999;34:1261-1264. 4. Arcement CM, Towbin RB, Meza MP, et al: Intrahepatic chemoembolization in unresectable pediatric liver malignancies. Pediatr Radiol 2000;30:779-785. 5. Boechat MI, Kangarloo H, Ortega J, et al: Primary liver tumors in children: Comparison of CT and MR imaging. Radi~lo~gy 1988;169:727-732. 6. Buendia MA: Genetic alterations in hepatoblastoma and hepatocellular carcinoma: Common and distinctive aspects. Med Pediatr Oncol 2002;39:530-535. 7. Cao G, Kuiryama S, Gao.1, et al: Gene therapy for hepatocellular carcinoma based-on tumour-selective suicide gene expression using the alpha-fetoprotein (AFP) enhancer and a housekeeping gene promoter. Eur J Cancer 2001; 37:140-147. 8. Chang MH, Chen CJ, Lai MS, et al: Universal hepatitis B vaccination in Taiwan and the incidence of hepatocellular carcinoma in children. N Engl J Med 1997;336: 1855-1859. 9. Chardot C, Saint-Martin C, Gilles A, et al: Living related liver transplantation and vena cava reconstruction after total hepa~ectomyincluding vena cava for hepatoblastoma. Transplantation 2002;73:90-92. 10. Chen JC, Chen CC, Chen WJ, et al: Hepatocellular carcinoma in children: Clinical review and comparison with adult cases. J Pediatr Surg 1998;33:1350-1354. 11. Clericuzio CL, Chen E, McNeil DE, et al: Serum alphafetoprotein screening for hepatoblastoma in children with Beckwith-Wiedemann syndrome or isolate hemihyperplasia. J Pediatr 2003; 143:270-272. 12. Craig JR, Peters RL, Edmondson HA, et al: Fibrolamellar carcinoma of the liver; a tumor of adolescents and young adults with distinctive clinico-pathologic features. Cancer 1980;46:372-379. 13. Czauderna P, Mackinlay G, Perilongo G, et al: Hepatocellular carcinoma in children: Results of the first prospective study of the International Society of Pediatric Oncology group. J Clin Oncol 2002;20:2798-2804. 14. Darbari A, Sabin KM, Shapiro CN, et al: Epidemiology of primary hepatic malignancies in US children. Hepatology 2003;38:560-566. 15. de Campo M, de Campo JF: Ultrasound of primary hepatic tumours in children. Pediatr Radiol 1988;19:19-24. 16. Evans AE, Land VJ, Newton WA, et al: Combination chemotherapy (vincristine, Adriamycin, cyclophosphamide, and 5-fluorouracil) in the treatment of children with malignant hepatoma. Cancer 1982;50:821-826. 17. Exelby PR, Filler RM, Grosfeld JL: Liver tumors in children with particular reference to hepatoblastoma and hepatocellular carcinoma: American Academy of Pediatrics Surgical Section Survey-1974. J Pediatr Surg 1975;lO: 329-337.

18. Feusner J, Plaschkes J: Hepatoblastoma and low birth weight: A trend or chance observation? Med Pediatr Oncol 2002;39:508-509. 19. Finegold MJ: Chemotherapy for suspected hepatoblastoma without efforts at surgical resection is a bad practice. Med Pediatr Oncol 2002;39:484486. 20. Fuchs J, Rydzynski J, Hecker H, et al: The influence of preoperative chemotherapy and surgical technique in the treatment of hepatoblastoma-a report from the German Cooperative Liver Tumour Studies HB 89 and 94. Eur J Pediatr Surg 2002;12:255-261. 21. Fuchs J, Rydzynski J, Von Schweinitz D, et al: Pretreatment prognostic factors and treatment results in children with hepatoblastoma: A report from the German Cooperative Pediatric Liver Tumor Study HB 94. Cancer 2002;95:172-182. 22. Haas JE, Feusner JH, Finegold MJ: Small cell undifferentiated histology in hepatoblastoma may be unfavorable. Cancer 2001;92:3130-3134. 23. Helmberger TK, Ros PR, Mergo PJ, et al: Pediatric liver neoplasms: A radiologic-pathologic correlation. Eur Radiol 1999;9:1339-1347. 24. Hemming AW, Reed AI, Langhan MR, et al: Hepatic vein reconstruction for resection of hepatic tumors. Am Surg 2002;235:850-858. 25. Hughes LJ, Michels W: Risk of hepatoblastoma in familial adenomatous polyposis. Am J Med Genet 1992;43:1023-1025. 26. Ikeda H, Hachitanda Y, Tanimura M, et al: Development of unfavorable hepatoblastoma in children of very low birth weight: Results of a surgical and pathologic review. Cancer 1998;82:1789-1796. 27. Kanai F: Transcriptional targeted gene therapy for hepatocellular carcinoma by adenovirus vector. Mol Biotechnol 2001;18:243-250. 28. Kanai F, Lan KH, Shiratori Y, et al: In vivo gene therapy for alpha-fetoprotein-producing hepatocellular carcinoma by adenovirus-mediated transfer of cytosine deaminase gene. Cancer Res 1997;47:561-565. 29. Katzenstein HM, Krailo MD, Malogolowkin MH, et al: Hepatocellular carcinoma in children and adolescents: Results from the Pediatric Oncology Group and the Children's Cancer Group Intergroup Study. J Clin Oncol 2002;20:2789-2797. 30. Katzenstein HM, Krailo MD, Malogolowkin MH, et al: Fibrolamellar hepatocellular carcinoma in children and adolescents. Cancer 2003;97:2006-2012. 31. Katzenstein HM, Rigsby C, Shaw PH, et al: Novel therapeutic approaches in the treatment of children with hepatoblastoma. J Pediatr Hematol Oncol 2002;24:751-755. 32. Koneru B, Flye MW, Bussutil RW, et al: Liver transplantation for hepatoblastoma: The American experience. Ann Surg 1991;213:118-121. 33. Lack EE, Neave C, Vawter GI? Hepatocellular carcinoma: Review of 32 cases in childhood and adolescence. Cancer 1983;52:1510-1515. 34. LaQuaglia MP, Shorter NA, Blumgart LH: Central hepatic resection for pediatric tumors. J Pediatr Surg 2002;37: 98G989. 35. Lau WY, Leung TW, Yu SC, et al: Percutaneous local ablative therapy for hepatocellular carcinoma: A review and look into the future. Ann Surg 2003;237:171-179. 36. Lee CL, KOYC: Hepatitis B vaccination and hepatocellular carcinoma in Taiwan. Pediatrics 1997;991351-353. 37. Liu DC, Vogel AM, Gulec S, et al: Hepatectomy in children under total hepatic occlusion. Am Surg 2003;69:539-541. 38. Llovet JM, Bru C, Bruix J: Prognosis of hepatocellular carcinoma: The BCLC staging classification. Semin Liver Dis 1999;19:329-338.

CHAPTER

39. LlovetJM, Burroughs A, BruixJ: Hepatocellular carcinoma. Lancet 2003;362:1907-1917. 40. Malogolowkin MH, Stanley P, Steele DA, et al: Feasibility and toxicity of chemoembolization for children with liver tumors. J Clin Oncol 2000; 18:1279-1284. 41. Martinez JA, Rigamonti W, Rahier J, et al: Preserved vascular homograft for revascularization of pediatric liver transplant: A clinical, histological, and bacteriological study. Transplantation 1999;68:672-677. 42. McCrudden KW, Hopkins B, Frischer J, et al: Anti-VEGF antibody in experimental hepatoblastorna: Suppression of tumor growth and altered angiogenesis. J Pediatr Surg 2003;38:308-314. 43. McCrudden KW, Yokoi A, Thosani A, et al: Topotecan is anti-angiogenic in experimental hepatoblastorna. J Pediatr Surg 2002;37:857-861. 44. Molmenti EP, Wilkinson K, Molmenti H, et al: Treatment of unresectable hepatoblastoma with liver transplantation in the pediatric population. Am J Transplant 2002;2:535-538. 45. Morino M, Morra I, Rosso E, et al: Laparoscopic vs open hepatic resection: A comparative study. Surg Endosc 2003; 17:19141918. 46. Ni Y-H, Change M-H, Huang L-M, et al: Hepatitis B virus infection in children and adolescents in a hyperendemic area: 15 years after mass hepatitis B vaccination. Ann Intern Med 2001;135:796. 47. Ohashi M, Kanai F, Tateishi K, et al: Target gene therapy for alpha-fetoprotein-producing hepatocellular carcinoma by ElB55k-attenuated adenovirus. Biochem Biophys Res Commun 2001 ;282:529-535. 48. Okuda K, Ohtsuki T, Obata H, et al: Natural history of hepatocellular carcinoma and prognosis in relation to treatment: Study of 850 patients. Cancer 1985;56:918-928. 49. Ortega JA, Douglass EC, Feusner JH, et al: Randomized comparison of cisplatin/vincristine/fluorouracil and cisplatin/continuous infusion doxorubicin for treatment of pediatric hepatoblastoma: A report from the Children's Cancer Group and the Pediatric Oncology Group. J Clin Oncol 2000;18:2665-2675. 50. Ortega JA, Krailo MD, Hans JE, et al: Effective treatment of unresectable or metastatic hepatoblastoma with cisplatin and continuous infusion doxorubicin chemotherapy: A report from the Children's Cancer Study Group. J Clin Oncol 1991;9:2167. 51. Otte JB, Aronson DC, Brown J, et al: Liver transplantation for hepatoblastoma: Results from the International Society of Pediatric Oncology (SlOP) study SIOPEL-1 and review of the world experience. Pediatr Blood Cancer 2004; 42:7483. 52. Otte JB, Aronson D, Vraux H, et al: Preoperative chemotherapy, major liver resection, and transplantation for primary malignancies in children. Transplant Proc 2001; 28:2393. 53. Oue T, Fukuzawa M, Kusafuka T, et al: Transcather arterial chemoembolization in the treatment of hepatoblastoma. J Pediatr Surg 1998;33:1771-1775. 54. Oue T, Kubota A, Okuyama H, et al: Hepatoblastoma in children of extremely low birth weight: A report from a single perinatal center. J Pediatr Surg 2003;38:134137. 55. Palmer RD, Williams DM: Dramatic response of multiply relapsed hepatoblastoma to irinotecan (CPT-11). Med Pediatr Oncol 2003;41:78-80. 56. Perilongo G, Brown J, Shafford E, et al: Hepatoblastoma presenting with lung metastases: Treatment results of the first cooperative, prospective study of the International Society of Pediatric Oncology on childhood liver tumors. Cancer 2000;89:1845-1853.

30

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57. Pritchard J, Brown J, Shafford E, et al: Cisplatin, doxorubicin, and delayed surgery for childhood hepatoblastoma: A successful approach-results of the first prospective study of the International Society of Pediatric Oncology. J Clin Oncol 2000;18:3819-3828. 58. Ramanujam TM, Ramesh JC, Goh DW, et al: Malignant transformation of mesenchymal hamartoma of the liver: Case report and review of the literature. J Pediatr Surg 1999:34:16841686. 59. Ravindra KV, Cullinane C, Lewis IT, et al: Long-term survival after spontaneous rupture of a malignant rhabdoid tumor of the liver. J Pediatr Surg 2002; 10:1488-1490. 60. Rowland JM: Hepatoblastoma: Assessment of criteria for histologic classification. Med Pediatr Oncol 2002:39: 478-483. 61. Ruck P, Xiao JC: Stem-like cells in hepatoblastorna. Med Pediatr Oncol 2002;39:504507. 62. Sasaki F, Matsunaga T, Iwafuchi M, et al: Outcome of hepatoblastoma treated with the JPLT- 1 (Japanese Study Group for Pediatric Liver Tumor) Protocol-1: A report from the Japanese Study Group for Pediatric Liver Tumor. J Pediatr Surg 2002;37:851-856. 63. Sato M, Ishida H, Konno K, et al: Liver tumors in children and young patients: Sonographic and color Doppler findings. Abdom Imaging 2000;25:596-601. 64. Scaife CL, Curley SA: Complication, local recurrence, and survival rates after radiofrequency ablation for hepatic malignancies. Surg Oncol Clin N Am 2003;12:243-255. 65. Schnater JM, Aronson DC, Plaschkes J, et al: Surgical view of the treatment of patients with hepatoblastoma: Results from the first prospective trial of the International Society of Pediatric Oncology Liver Tumor Study Group. Cancer 2002;94:1111-1120. 66. Sindhi R, Rosendale J, Mundy D, et al: Impact of segmental grafts on pediatric liver transplantation: A review of the United Network for Organ Sharing Scientific Registry Data (1990-1996).J Pediatr Surg 1999;34:107-111. 67. Superina RA, Bambini D, Filler RM, et al: A new technique for resecting "unresectable" liver tumors. J Pediatr Surg 2000;35:12941299. 68. Surace C, Leszl A, Perilongo G, et al: Fluorescent in situ hybridization (FISH) reveals frequent and recurrent numerical and structural abnormalities in hepatoblastoma with no informative karyotype. Med Pediatr Oncol 2002; 39:536-539. 69. Szavay PO, Wermes C, Fuchs J, et al: Effective treatment of infantile choriocarcinoma in the liver with chemotherapy and surgical resection: A case report. J Pediatr Surg 2000; 35:11341135. 70. Tanimura M, Matsui I, Abe J, et al: Increased risk of hepatoblastoma among immature children with a lower birth weight. Cancer Res 1998;58:303'2-3035. 71. Terracciano LM, Bernasconi B, Ruck P, et al: Comparative genomic hybridization analysis of hepatoblastomi reveals high frequency of X-chromosome gains and similarities between epithelial and stromal components. Hum Path01 2003;34:864871. 72. Tsuchida Y, Ikeda H, Suzuki N, et al: A case of welldifferentiated, fetal-type hepatoblastoma with very low serum-alpha-fetoprotein. J Pediatr Surg 1999;12:1762-1764. 73. von Schweinitz D, Hadam MR, Welte K, et al: Production of interleukin-lp and interleukin-6 in hepatoblastoma. Int J Cancer 1993;53:728. 74. Webber EM, Morrison KB, Pritchard SL, et al: Undifferentiated embryonal sarcoma of the liver: Results of clinical management in one center. J Pediatr Surg 1999;34:1641-1644.

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75. Weber RG, Pietsch T, von Schweinitz D, et al: Characterization of genomic alterations in hepatoblastomas: A role for gains on chromosomes 8q and 20 as predictors of poor outcome. Am J Path01 2000;157:571-578. 76. Weinberg AG, Finegold MJ: Primary hepatic tumors of childhood. Hum Pathol 1983;14:512-537. 77. Yanaga K, Nishizaki T, Yamamoto K, et al: Simplified inflow control using stapling devices for major hepatic resection. Arch Surg 1996;131:103-106.

78. Zatkova A, Rouillard.JM, Hartmann W, et al: Amplification and overexpression-of the IGFP regulator PLAGI in hepatoblastoma. Genes Chromosomes Cancer 2004;39: 126-137. 79. Zimmerman A: Pediatric liver tumors and hepatic ontogenesis: Common and distinctive pathways. Med Pediatr Oncol 2002;39:492-503.

Gastrointestinal Tumors Patrick A. Dillon and Robert I? Foglia

Primary gastrointestinal (GI) tumors are relatively uncommon in infants and children. GI malignancies account for approximately 1.2% of all pediatric cancer cases.4 The clinical presentation and histopathology of GI tumors in children can differ significantly from those seen in adults. In addition, the discovery of genetic markers and the use of immunohistochemistry have allowed a more thorough identification of these tumors, although these same advances have made it difficult to assess their true incidence. The most common presenting symptoms are nonspecific and include abdominal pain, vomiting, and rectal bleeding. The duration of symptoms is often several weeks before diagnosis, and emergent surgery for intestinal ~ , ~ ~ not a common obstruction may be r e q ~ i r e d .Although diagnosis, the possibility of a GI malignancy should be considered in any child with signs and symptoms of intestinal obstruction, intractable abdominal pain, and alteration in bowel habits or GI bleeding. In addition, children with bowel disorders should receive a detailed and vigorous diagnostic evaluation, including contrast studies, ultrasonography, computed tomography (CT), and endoscopy to both confirm the diagnosis and detect the extent of disease.31

GASTROINTESTINAL STROMAL TUMORS Epidemiology Gastrointestinal stromal tumors (GISTs) are rare tumors of the GI tract. The incidence is difficult to determine, owing to changes in nomenclature, cellular origin, and diagnostic criteria. Classification has also been hindered by published reports that contain only a few patients, the mixing of benign and malignant tumors, and failure to separate primary and recurrent GISTs.12 In addition, GISTs have been grouped together, regardless of anatomic location, making prediction of their clinical behavior difficult.j7 The median age at presentation is between the 5th and 6th decades of life; these tumors are considered rare in patients younger than 40 years. Gender distribution

is equal. The most common site of origin is the stomach (50% to 70%), followed by the small intestine (20% to 30%),colon or rectum ( l o % ) ,and esophagus ( 5 % ) .The mesentery or omentum may occasionaily be the site of origin for GIST.39,43 GIST is currently classified as a mesenchymal tumor of the GI tract and is thought to originate from the interstitial cell of Cajal, an intestinal pacemaker cell." Historically, smooth muscle tumors such as leiomyomas and leiomyosarcomas and neural tumors such as schwannomas and malignant peripheral nerve sheath tumors have been categorized as GISTs. However, histologic and immunohistochemical features now distinguish GISTs from tumors of smooth muscle origin.

Association with Other Conditions In 1977 Carney et a1.7 reported the rare association of gastric leiomyosarcoma, functioning extra-adrenal paraganglioma, and pulmonary chondroma in unrelated young women. The patients' young age, the multifocal locations, and the multiple organ involvement raised the possibility of an inherited disorder, but thus far, no genetic link has been identified." primary feature of Carney's triad is gastric stromal tumors. These tumors are usually located along the lesser curve or antrum and produce few local symptoms; continued growth can lead to mucosal ulceration and GI bleeding, and serosal involvement is common. The multifocal nature of the tumor can lead to local recurrence as well as widespread but slowly progressive metastatic lesions. Traditional adjuvant therapy has been unsuccessful in treating metastatic disease.6 Despite the possible development of additional gastric tumors in the remaining stomach, less than total gastrectomy, if feasible, is likely the best initial operation to avoid the complications of total gastrectomy, particularly in teenage patients., Patients treated in this manner should be advised that new gastric tumors may develop and should be re-examined at 3-year intervals. Evaluation for adrenal tumors in patients with gastric stromal sarcomas or pulmonary chondromas (or both) should be considered, and a family history should

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be obtained from patients with Carney's triad. However, family screening and genetic counseling for the disorder are not currently rec~mrnended.~ A subset of GIST has been identified and is commonly referred to as GI autonomic nerve tumor (GANT). There have been very few cases of GANT reported in the pediatric population. However, in small series of pediatric patients, there is a female predominance, and symptoms may include abdominal pain, fullness, emesis, and a palpable abdominal mass." GANT can arise in any part of the GI tract, with the small intestine being the most common site in adults. As is the case with GIST, when GANT occurs in children, it tends to favor the stomach as the primary site of origin." The majority of pediatric patients have localized disease at the time of diagnosis, and surgical resection of the tumor is the treatment of choice. Currently there appears to be no defined role for chemotherapy or radiation. In children, localized disease and small tumor size at the time of diagnosis likely aid in the more favorable long-term prognosis compared with adults. Immunocytochemical and ultrastructural evaluation is required to differentiate these tumors from GIST, and established criteria for malignancy are not currently available for the pediatric p o p ~ l a t i o n . ~ ~

Clinical Presentation At the time of presentation, most patients have experienced some symptoms, most often generalized abdominal pain, dyspepsia, and occult GI bleeding. Irondeficiency anemia, which can be present in children, should prompt an investigation to rule out the GI tract as the source of the anemia." Less commonly, patients present with a palpable abdominal mass or intestinal obstr~ction.~"tandard imaging studies to assist in the diagnosis include plain radiographs and CT; there also appears to be a potential role for whole-body fluorodeoxyglucose positron emiscan be helpful in identifysion tomography.~~ndoscopy ing a tumor mass, especially if the tumor is located in the stomach or the proximal small intestine.

Pathology GISTs are defined as cellular spindle cell, epithelioid, or occasionally pleomorphic mesenchymal tumors of the GI tract that express the KIT (CD117, stem cell factor receptor) protein, as detected using immunohistochemistry. Additional cell type markers such as CD34, smooth muscle actin, desmin, and S-100 protein are used to establish a diagnosis of GIST.S%ttempts to predict the outcome of GIST rely on traditional pathologic criteria such as size, stage, extent of tumor invasion into mucosa or surrounding organs, mitotic index, and nuclear pleomorphism. Although these criteria have been useful in predicting GIST behavior, no single feature is consistently reliable when it comes to predicting 0utcorne.2~Morphologic features that are associated with malignant gastric stroma1 tumors include tumor size greater than 7 cm, high cellularity, mucosal invasion, and mitotic count greater than 5 mitoses per 50 high-powered fields. All these

factors must be considered when distinguishing benign from malignant gastric stromal tumors." Recently, a mutation in the c-kit gene on exon 11 was identified in GIST. Patients found to have this mutation showed an increased risk of recurrence and higher mortality compared with GIST patients without the c-kit m ~ t a t i o n . ~ "

Treatment Complete surgical resection of GISTs, along with any possible pseudocapsules, is the recommended approach. Although wide margins are not thought to be necessary, en bloc resection may require complete or partial organ negative removal to achieve clear margin~.~Uchieving pathologic margins is generally not difficult, because GISTs tend to hang from, and do not diffusely infiltrate, the organ of origin. Consequently, wedge resection of the stomach or segmental resection of the intestine provides adequate therapy; wide resection has no known benefit.49 In addition, because the status of the microscopic margins does not appear to be important for survival, vital structures should not be sacrificed if gross tumor clearance has already been attained-'2 GIST rarely metastasizes to lymph nodes, so lyrnphadenectomy is seldom ~ a r r a n t e d . ~ ~ The high rate of local and distant recurrence underscores the need for adjuvant therapy. GIST has traditionally been resistant to radiotherapy and all previously available systemic treatments. However, the ability of imatinib td reduce tumor size significantly has changed the management of GIST. Imatinib is a signal transduction inhibitor that exerts its activity in GIST through the blockade of the adenosine triphosphate binding site of KIT, a transmembrane receptor protein-tyrosine kinase. Imatinib has been successful in treating patients with chronic myeloid leukemia and other Philadelphia chromosome-positive leukemias. The use of imatinib for GIST patients is based on the hypothesis that imatinib can block the constitutive activity of KIT receptor tyrosine kinase in the cells of GISTs.13 With the use of imatinib, surgical resection may be possible for GIST patients with widespread metastatic disease who would otherwise not be candidates for surgery. This therapy may also decrease the incidence of postoperative GIST recurrence and spread and thereby extend lives. Although the trials of adjuvant and neoadjuvant imatinib are ongoing, it appears reasonable to suggest that surgery be considered the first option for patients with resectable GISTs, followed by enrollment in a clinical trial of imatinib as a postoperative adjuvant in cases of incomplete resection, tumor spillage, or other high-risk factors. For cases of recurrent or metastatic GIST, a Gal of imatinib, followed by surgical resection, should be considered.

Survival The long-term survival following surgical resection of GIST varies in published series and is especially difficult to determine in children, because most reports either contain small numbers of patients or include primarily adult patients (Table 31-1). Moreover, given the recent

CHAPTER

Institution

Years Covered

Mayo Clinic MSKCC MCV MDACC MGH MSKCC

1950-1974 1949-1973 1951-1984 1957-1997 1962-1986 1982-1998

No. of Patients Evaluated

31

Gastrointestinal Tumors

No. of Patients Completely Resected (%)

5-Year Survival (%)

52 (48) 20 (53) 30 (59) 99 (52) 40 (73) 80 (40)

50 65 63 48 35 54

517

MCV, Medical College of Virginia; MDACC, MD Anderson Cancer Center; MGH, Massachusetts General Hospital; MSKCC, Memorial Sloan-KetteringCancer Center.

changes in the recognition and pathologic categorization of these tumors, many older series may contain tumors that are not actually GISTs. Despite these obstacles, several factors appear to be useful in predicting long-term outcome following surgical resection: tumor size, mitotic index, and location (Table 31-2). Improved survival is noted when tumors are less than 5 cm, compared with those 5 to 10 cm; in turn, this intermediate group of tumors has a better prognosis than those greater than 10 cm. Low-grade tumors have a mitotic index of less than 10 per 50 high-powered fields, whereas high-grade tumors have an index of greater than 10 per 50 high-powered fields. Tumor location has also been found to predict prognosis, with gastric tumors having an improved survival compared with GISTs in other locations.46

ESOPHAGEAL AND GASTRIC CANCER Esophageal or gastric cancer in a child is extremely rare. According to Surveillance, Epidemiology, and End Results (SEER) data from the National Cancer Statistics Branch, esophageal carcinoma was diagnosed in 10,441 patients between 1988 and 1996. Of those patients, only three (0.03%) were between 10 and 19 years of age, and no patients were younger than 10 years.20

1 ---Factor Size Cellularity Nuclear pleomorphism Necrosis Mitosis Infiltrative growth attern Metastasis c-kit Mutation

Benign*

Malignant

<5 cm Low Absent to minimal Absent < @ Iper 30-50/ HPF Absent

>5 cm High May be prominent Present 1-5 or more per 10/HPF May invade adjacent structures Present Frequently present

Absent Absent

*No single feature is absolutely predictive of benign behavior. Tumor size, mitotic rate, and presence or absence of necrosis appear to be the most important factors in predictingbehavior. HPF, high-powered field, 400x.

Despite the rarity of esophageal cancer, there are known risk factors associated with a predisposition for tumor development. With regard to esophageal adenocarcinoma, the development of Barrett's esophagus secondary to chronic gastroesophageal reflux disease (GERD) is the primary risk factor. Pediatric populations that appear to be at increased risk for the development of Barrett's esophagus secondary to chronic GERD include children with severe neurologic deficits, such as cerebral palsy, and those with congenital defects involving the esophagus, such as esophageal atresia and tracheoesophageal fistula.lVhe overall incidence of Barrett's esophagus has been estimated by Hassall'8 to be 0.02% among young patients with severe GERD and associated risk factors; the incidence of Barrett's changes is probably even lower for those without risk factors. Nevertheless, adenocarcinoma of the esophagus has been documented in adolescents with long-standing GERD, and surveillance with upper endoscopy and multiple stepwise biopsies may benefit those children who have the mucosal changes of Barrett's es~phagus.~" Barrett's changes can also be seen with the retained cervical esophagus following esophageal replacement surgery. A history of this type of surgery requires the control of gastric pH and long-term surveillance endoscopy with biopsy of the retained upper esophageal segment. Depending on the technique and approach, esophageal replacement surgery for patients with esophageal atresia may result in retention of the distal esophageal segment. This remnant can cause severe chronic esophagitis and Barrett's changes requiring surgical resection. Because Barrett's esophagus is a premalignant lesion and can lead to the development of esophageal adenocarcinoma, the distal segment of esophagus should be removed at the time of esophageal replacement surgery.4xThere have also been case reports of esophageal carcinomas arising in children after chemical injuries to the esophagus. Endoscopic follow-up with biopsies should be considered for patients with Barrett's esophagus and for those with chemical injuries to monitor for the development of malignant changes.47 Between 1997 and 2001, the SEER database reported a gastric cancer incidence of 0.1% for patients younger than 20 years rrom a total of 15,274 cases reported.5" Despite the rarity of gastric adenocarcinoma in children, there are several case reports of adenocarcinoma of the

518

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MAJORTUMORS OF CHII.DHOOD

stomach in children as young as 2 '/2 years.'' The tumors can arise from any anatomic location in the stomach38; symptoms may be quite vague but can include epigastric pain, weight loss, vomiting, and anemia. In addition, symptoms associated with esophageal achalasia have been reported in conjunction with gastric adenocarcinoma.'.17

CARClNOlD TUMORS Epidemiology Carcinoid tumors originate from neuroendocrine cells found along the primitive GI tract. These neoplasms originate from the same progeny cells as other GI cells and are part of the amine precursor uptake and decarboxylation (APUD) system.59 Pediatric carcinoid tumors can occur in the GI tract-stomach, small intestine, appendix (most common), and rectum-as well as in extraintestinal sites such as the lung. Although carcinoid tumors of the appendix are rare in children and adolescents, they are nevertheless the most common GI tumor , ~ O incidence is difficult to among this age g r o ~ p . l ~ The assess in the pediatric population because most large series include retrospective data that may exclude certain types of carcinoid tumor, but the reported incidence appears to be in the range of 0.08% to 0.169%,16.52 or approximately 1.14 per million children per year,42 with a slight female predominan~e.2"4~

Although symptoms may be atypical and carcinoid size can be variable, there is no report of carcinoid syndrome ass* ciated with carcinoid tumors confined to the appendix.16.52 In contrast to patients with appendiceal or incidental carcinoid tumors, pediatric patients with extra-appendiceal carcinoid tumors, such as in the lung or liver, are often symptomatic and have diffuse disease at the time of diagnosis. Broaddus et al.5reported that 46% of their patients with extra-appendiceal carcinoids had recurrent tumor or metastasis following the initial diagnosis or disseminated disease at the time of diagnosis.

Treatment For pediatric carcinoid tumors limited to the appendix, surgical resection of the appendix is the treatment of choice and often results in a cure. Long-range follow-up reveals either minimal or no recurrence of disease and The most a rare likelihood of metastatic di~ease.l~,~O~" important factor in surgical decision making for carcinoid tumors of the appendix is the size of the tumor. For carcinoids less than 2 cm in diameter, appendectomy alone is usually adequate. Histologic evidence of invasion into the mesoappendix and tumors that involve the base of the appendix are indications for performance of a right hemicolectomy, regardless of tumor diameter. Carcinoid tumors larger than 2 cm in diameter, those with high-grade malignancies, and goblet cell adenocarcinoids are also indications to proceed with a right hemicolectomy.2"

Diagnosis Pediatric carcinoid tumors are often discovered during an operation for presumed appendicitis or incidentally during surgery unrelated to the carcinoid tumor. Although clinical signs consistent with acute appendicitis or suggestive of a gynecologic pathology may result in exploration, true inflammatory changes of the appendix are often not seen.1° The lack of inflammation may be the result of appendiceal carcinoid tumors typically being located in the distal portion of the appendix; thus, proximal obstruction of the appendiceal lumen is not seen (Fig. 31-1).16,23

Pathology Important pathologic tumor characteristics include size, histologic subtype, mesoappendiceal involvement, and lymph node status. Carcinoids can also be graded as benign, borderline malignant, low-grade malignant, or high-grade malignant, although a more precise and uniform classification system may identify patients who would benefit from more aggressive surgery." Van Eeden et al.js attempted to address this issue by requesting that the World Health Organization apply the current classification of lung neuroendocrine tumors to all neuroendocrine tumors of the GI tract as well.

COLORECTAL ADENOCARCINOMA

,

.

Location of appendiceal carcinoids (%).

Adenocarcinoma of the colon and rectum is the most common cancer of the GI tract, with an annual incidence in the United States of approximately 148,300 cases and 56,600 deaths. The lifetime risk of colorectal cancer in the general population is 5% to 6%.30 Colorectal cancer is the second most common cancer of the alimentary tract in children, following liver tumors. Colorectal cancer is rare in children, however, with an incidence between 1.3 and 2 cases per million lives.41256 Although cancer of the colon has been diagnosed in a child as young as 9 months old, most pediatric cases occur in the second decade of life; the median age at

CHAPTER

Familial polyposis syndromes Inflammatory bowel disease, especially ulcerative colitis Hereditary nonpolyposis syndromes Previous ureterosigmoidostomy Chronic parasitic infection Previous radiation therapy Diet high in fat and low in fiber Possible exposure to environmental chemicals and radiation

diagnosis is 15 to 19 years.35,45,53 The development of carcinoma of the colon appears to be associated with several predisposing factors (Table 31-3). These include a diet high in fat and cholesterol and low in fiber, exposure to environmental chemicals and radiation, polyposis syndromes, inflammatory bowel disease, hereditary nonpolyposis syndromes, urinary diversion with a previous ureterosigmoidostomy, chronic parasitic infection, and previous radiation therapy. The cause of the tumor can be categorized as sporadic in approximately 75% of patients, familial in approximately 10% to 20% of patients who have at least two firstdegree relatives with colon cancer (but no defined genetic pattern), genetic (polyposis syndromes) in approximately 1% of patients, inflammatory bowel disease in approximately 1%, and hereditary nonpolyposis syndromes in approximately 5% to 6%. Although diet has a putative role in the development of colon cancer in adults, no similar studies have been done to support this role in children. Various environmental factors are associated with tumor formation. In one study, exposure to herbicides was found in 10 of 13 children who developed colon cancer.44 Colorectal cancer differs greatly between adults and children. These differences include the presenting signs and symptoms, primary site of the tumor, pathologic findings, stage, and prognosis.

Association with Other Conditions Because the sporadic form of pediatric colorectal carcinoma accounts for approximately '75% of cases, this suggests that 25% of childhood cases have some associated predisposing condition. Sporadic colon cancer in young patients appears to be an aggressive disease whose morphology and natural history differ from those of familial adenomatous polyposis, hereditary nonpolyposis colorectal cancer, and adult colon cancer. Tumor development most likely occurs secondary to tumor suppressor gene involvement, loss of heterozygosity, or a mutational event." Several genetic disorders carry a significant risk for the subsequent development of colon carcinoma and are characterized as polyposis syndromes. They include Gardner's syndrome (adenomatous polyps and soft tissue and bone tumors), Turcot's syndrome (familial

31

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adenomatous polyps and central nervous system tumors), and familial polyposis coli. Both Gardner's syndrome and familial polyposis are autosomal dominant disorders and are associated with adenomatous polyps in both the colon and the small intestine. Bassey3 has shown that the incidence of colon carcinoma in patients with familial polyposis is 50% by 28 years of age and that the eventual likelihood of colon cancer approaches 100%. Patients who have an APC mutation or who have one or more first-degree relatives with familial adenomatous polyposis are at high risk, and screening with flexible sigmoidoscopy should begin by age 10 to 12 years. Patients with colonic polyps, a verified APC germline mutation, or both require annual endoscopic examination. As patients reach their teens and 20s, the increased number of polyps may prevent adequate and safe colonoscopic polypectomy. When this occurs, prophylactic surgery should be performed to remove the affected colon. Surgical options include subtotal colectomy with end ileostomy or ileorectal anastomosis followed by annual endoscopy of the remaining rectum. Currently, many patients are candidates for total abdominal proctocolectomy with a restorative small bowel pouch anal anastomosis. Peutz-Jeghers syndrome is associated with the appearance of hamartomatous polyps. The incidence of colon carcinoma in patients with Peutz-Jeghers syndrome is 2% to 3%. Likewise, juvenile polyposis seems to have an increased potential for the development of colon ~arcinoma.g,2~,5~ Recommendations for colon resection are based on the likelihood of the development of malignancy. The entire surface of the colon can be carpeted with thousands of polyps in these patients. Realistically, the ability to carry out surveillance and identify suspicious lesions is low. There is little question that colectomy is the appropriate treatment for patients with familial polyposis, Gardner's syndrome, and Turcot's syndrome. Because of the relatively low incidence of malignancy with PeutzJeghers syndrome and juvenile polyposis, surveillance is a reasonable strategy. There is a clear-cut and progressively increasing likelihood of the development of colon carcinoma in patients with ulcerative colitis. This risk is approximately 20 times greater than that in the general population and is related to the total length of time a patient has ulcerative colitis.24 After the first 10 years with ulcerative colitis, the likelihood of cancer development increases from 1% to 2% per year.15 Several important features noted in patients with ulcerative colitis who develop colon carcinoma include occurrence at a young age, prevalence of multiple sites of malignancy, and a higher likelihood of malignancy in patients with colitis involving the entire colon than in those with only left-sided colitis.2" Crohn's disease is another type of inflammatory bowel disease in which the risk for colon cancer is up to 20 times greater than that in the general population." The likelihood of malignancy is related in part to the amount of bowel involved. However, cancer can develop in areas of colon that appear grossly normal," which in some ways makes the diagnosis of a malignancy in a patient with Crohn's disease more difficult than in a patient with

520

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ulcerative colitis. Therefore, regular surveillance protocols and random biopsies are especially important. In patients with inflammatory bowel disease, a contrast enema and colonoscopy are the mainstays of surveillance. Biopsies should be performed on any suspicious areas and randomly during the colonoscopy. Hereditary nonpolyposis colorectal cancer, or Lynch syndrome, has an autosomal dominant inheritance and is the most common form of hereditary colorectal can~er.8,~ It' accounts for approximately 1% to 3% of all cases of colorectal cancer and is five times more prevalent than familial polyposis-related colon This type of colorectal cancer usually presents with proximal colon lesions (approximately 70% are proximal to the splenic flexure), and patients develop cancer at a younger age (mean, approximately 45 years) than patients with Hereditary nonpolypocolorectal cancer in genera1.22~~~ sis colorectal cancer is also notable for the development of synchronous and metachronous extracolonic cancers, such as carcinoma of the endometrium, ovary, stomach, small bowel, pancreas, hepatobiliary tract, brain, and upper uroepithelial tract.37 Ureterosigmoidostomy performed for urinary diversion in patients with bladder exstrophy and other genitourinary anomalies is associated with colon cancer. Eraklis and Folkman" reported that 5% of patients with a ureterosigmoidostomy developed colon cancer, in each case at the site of the ureteral implant. Experimental data have implicated chronic inflammation caused by the mixture of feces and urine at the implant site as a cause of the cancer, especially when the urine has been infected. Patients with this type of urinary diversion warrant close follow-up and should undergo annual sigmoidoscopy. Children with a primary cancer treated with radiation are at risk for the subsequent development of colorectal carcinoma in the radiation field. LaQuaglia et al.3" described one patient who had resection of a Wilms' tumor, received radiation to the retroperitoneal area, and subsequently developed cancer of the left colon. Others have reported two cases of colorectal cancer as a second malignancy following treatment of a retroperitoneal rhabdomyosarcoma and a Wilms' tumor, both treated with resection and radiation therapy,14The first child was a 1year-old boy whose retroperitoneal rhabdomyosarcoma was treated with preoperative radiation, surgery, and chemotherapy. At 2 years of age he developed radiation colitis and, subsequently, adenomatous polyps. At age 11 years a rectal adenocarcinoma developed (Fig. 31-2). The second child had a Wilms' tumor treated at 9 months of age with surgery and radiation therapy. He also developed radiation colitis and, subsequently, multifocal adenocarcinoma of the colon 42 years later. Results of immunohistochemical studies were positive for the p53 antigen in both tumors in the latter patient and in the adenomas of the first patient. It is speculated that the radiation caused a p53 mutation, which led to the neoplasia.

Diagnosis In children with colorectal tumors, common presenting symptoms include abdominal pain in almost all patients;

.

-

Contrast enema in an 11-year-old boy who had

previously been treated with radiation for a retroperitoneal rhabdomyosarcoma. The radiograph shows almost complete obstruction in the rectum.

nausea and vomiting in 40% to 70%; and a change in bowel habits and the development of constipation, particularly with left-sided lesions. Physical findings that are often noted in these patients include abdominal distention, tenderness, and a mass. More than half these children have chemical evidence of blood in the stool. A history of rectal bleeding may be elicited in approximately one third of patients and is more prevalent in those with cancer of the left colon and rectum. Significant weight loss affects 20% to 30% of patients. The median length of time from the onset of symptoms to presentation is often several months; at least one report cited almost a year between the onset of sympcan be delayed if the toms and the diagn~sis.~Wiagnosis patient's symptoms are attributed to more common pediatric conditions such as appendicitis, intussusception, or gastroenteritis." Another possible explanation for the delay in diagnosis may be adolescents' tendency to hide symptoms owing to embarrassment." Rectal bleeding, which may also be a sign of benign pathology such as polyps or hemorrhoids, should raise the suspicion for a colorectal malignancy; early diagnosis depends on a high index of suspicion.3' Steinberg et al." considered a

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• Contrast enema in a 14year-old patient who presented with a I-month history of abdominal pain and constipation. Complete obstruction in the transverse colon is demonstrated.

delayed diagnosis to have occurred if the patient's symptoms had been present for longer than 3 months; they found that five of nine patients with colon cancer had had symptoms for 3 to 36 months (mean, 11 months) before the diagnosis of cancer. This delay in diagnosis may be an important factor contributing to the advanced stage of disease in many of these children. On the basis of the signs and symptoms at presentation, two scenarios can develop. In the first, the clinical diagnosis is an acute surgical abdomen caused by appendicitis or peritonitis. In this case, the child is often taken directly to the operating room. The second, more common scenario occurs when intestinal obstruction is diagnosed. Radiographic evaluation usually demonstrates a mass lesion in the colon, and a contrast enema identifies the point of obstruction (Fig. 31-3). Depending on the location of the lesion, sigmoidoscopy or colonoscopy allows biopsy and diagnosis. In adults, most lesions are rectosigmoid in location and can be identified by sigmoidoscopy. In contrast, childhood colorectal cancer is relatively evenly distributed throughout the colon; one third of tumors are located in the right colon."".4" Colonoscopy is often the technique of choice to obtain a biopsy for diagnosis.

Pathologic Characteristics Two characteristics of colorectal tumors differ markedly in children and adults: stage and histologic type of adenocarcinoma. Approximately 40% of adults with colon cancer have tumors in which regional lymph nodes are involved or have distant metastases (Dukes' stage C or D lesions).

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In children, more than 80% of tumors are Dukes' stage C or D.3"45,53In addition, the histologic finding of a mucinous type of adenocarcinoma is found in over half the children with colorectal tumors. The mucinous subtype has an aggressive course and is known to metastasize e a r l ~ . ~ q hisi sat least one order of magnitude greater than the approximate 5% incidence of mucinous adenocarcinoma in adults with colon cancer. There is no obvious reason why this mucinous histologic type is seen so frequently in childhood colon carcinoma. The synergy of the more advanced stage of disease at the time of diagnosis and the increased frequency of a mucinous subtype (which carries a poor prognosis) contributes to the poor prognosis in these patients. The microsatellite status of the lymph nodes is thought to identify distinct pathways of genetic development in pediatric patients with colorectal cancer. Patients with colorectal cancer and high-frequency microsatellite instability were more likely to have multiple synchronous or metachronous colorectal cancers and were diagnosed at a younger age than those with microsatellite ~tability.~" Microsatellite instability is not, however, predictive of a family history of colorectal cancer or of unique phenotypic features.ll The utility of carcinoembryonic antigen (CEA) has been well established in adults with colon cancer, but there is little evidence of a similar utility in pediatric patients. Rao et a1.4"dentified 4 of 20 patients with Dukes' stage C or D lesions who had normal antigen levels at the time of diagnosis.4-n a longitudinal evaluation of these children, CEA levels correlated with an increase or decrease in tumor burden in 60% of patients; unfortunately, the other 40% had normal antigen levels despite progressive disease. At this time, CEA levels have not been shown to correlate well with response to treatment in children.

Treatment The wrimam treatment for colon cancer in children is surgical resection consisting of a wide excision of the involved colon, the mesentery, and the lymphatic drainage area. Unfortunately, resection for cure is possible in only 40% to 69% of pediatric patients; these percentages are much lower than those in adults with colon The ovaries and the omentum are common sites of metastasis. If resection for cure is performed, omentectomy and, in female patients, oophorectomy are appropriate. No specific chemotherapy protocols are available for of chemotherthese children. In most studies, some hn>e , apy was given, and radiation therapy has been used in selected patients. Although anecdotal case reports indicate that one or both of these methods mav result in success, no data document the benefit of either chemotherapy or radiation therapy for cure or palliation. The overall rate and duration of survival among children with colon carcinoma are dismal; studies-often show that less than 5% of patients survive 5 years.* More recently, LaQuaglia et a1.35 reported survival in 8 of 29 patients (28%) with a median follow-up of 4.7 years.

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Survival was directly related to complete resection. I n patients who h a d resection for cure, predictors of survival included n o d e involvement o r high histologic grade. T h e primary aim of treatment i n pediatric colon cancer is complete resection during t h e initial surgery. With t h e p o o r survival even in patients who have undergone complete resection, adjuvant chemotherapy is appropriate. T h e use of chemotherapy, combined with second-look surgery in selected cases, may improve survival.

Summary T h e biolo
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11. Datta RV, LaQuaglia MP, Paty PB: Genetic and phenotypic correlates of colorectal cancer in young patients. N Engl J Med 2000;342:137-138. 12. DeMatteo RP, LewisJ, Leung D, et al: Two hundred gastrointestinal stromal tumors: Recurrence patterns and prognostic factors for survival. Ann Surg 2000;231:51-58. 13. Demetri GD, von Mehren M, Blanke CD, et al: Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors. N Engl J Med 2002;347:472-480. 14. Densmore TL, Langer JC, Molleston JP, et al: Colorectal adenocarcinoma as a second malignant neoplasm following Wilms' tumor and rhabdomyosarcoma. Med Pediatr Oncol 1996;27:556-560. 15. Devroede GJ, Taylor WF, Sauer WG, et al: Cancer risk and life expectancy of children with ulcerative colitis. N Engl J Med 1971;285:17-21. 16. Doede T, Foss HD, WaldschmidtJ: Carcinoid tumors of the appendix in children: Epidemiology, clinical aspects and procedure. Eur J Pediatr Surg 2000;10:372-377. 17. Dokucu AI, Ozturk H, Kilinc N, et al: Primary gastric adenocarcinoma in a 2.5-year-old girl. Gastric Cancer 2002;5:237-239. 18. Eisenberg BL, Judson I: Surgery and imatinib in the management of GIST: Emerging approaches to adjuvant and neoadjuvant therapy. Ann Surg Oncol 2004;11:465-475. 19. El Serag HB, Bailey NR, Gilger M, Rabeneck L: Endoscopic manifestations of gastroesophageal reflux disease in patients between 18 months and 25 years without neurological deficits. Am J Gastroenterol 2002;97:1635-1639. 20. Eloubeidi MA, Desmond R, Arguedas MR, et al: Prognostic factors for the survival of patients with esophageal carcinoma in the US: The importance of tumor length and lymph node status. Cancer 2002;95:14341443. 21. Eraklls AJ, Folkman MJ: Adenocarcinoma at the site of ureterosigmoidostomies for exstrophy of the bladder. J Pediatr Surg 1978;13:730-734. 22. Fitzgibbons RJ Jr, Lynch HT, Stanislav GV, et al: Recognition and treatment of patients with hereditary nonpolyposis colon cancer (Lynch syndromes I and 11). Ann Surg 1987;206:289-295. 23. Goede AC, Caplin ME, Winslet MC: Carcinoid tlimour of the appendix. Br J Surg 2003;90:1317-1322. 24. Greenstein AJ, Sachar DB, Smith H, et al: Cancer in universal and left-sided ulcerative colitis: Factors determining risk. Gastroenterology 1979;77:290-294. 25. Greenstein AJ, Slater G, Heimann TM, et al: A comparison of multiple synchronous colorectal cancer in ulcerative colitis, familial polyposis coli, and de novo cancer. Ann Surg 1986;203:123-128. 26. Gryfe R, Kim H, Hsieh ETK, et al: Tumor microsatellite instability and clinical outcome in young patients with colorectal cancer. N Engl J Med 2000;342:69-77. 27. Haider N, Kader M, McDermott M, et al: Gastric stromal tumors in children. Pediatr Blood Cancer 2004;42:186-1 89. 28. Hassall E: Co-morbidities in childhood Barrett's esophagus. J Pediatr Gastroenterol Nutr 1997;25:255-260. 29. Hassall E, Dimmick JE, Magee JF: Adenocarcinoma in childhood Barrett's esophagus: Case documentation and the need for surveillance in children. Am J Gastroenterol 1993;88:282-288. 30. Jemal A, Thomas A, Murray T, Thun M: Cancer statistics, 2002. CA Cancer J Clin 2002;52:23-47. 31. Karnak I, Ciftci AO, Senocak ME, Buyukpamukcu N: Colorectal carcinoma in children. J Pediatr Surg 1999; 34:1499-1504. 32. Kamak I, Kale G, Tanyel FC, Buyukpamukcu N: Malignant stromal tumor of the colon in an infant: Diagnostic difficulties and differential diagnosis. J Pediatr Surg 2003;38:245-247.

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33. Kerr JZ, Hicks MJ, Nuchtern JG, et al: Gastrointestinal autonomic nerve tumors in the pediatric population: A report of four cases and a review of the literature. Cancer 1999;85:220-230. 34. Kindblom LG, Remotti HE, Aldenborg F, Meis-KindblomJM: Gastrointestinal pacemaker cell tumor (GIPACT): Gastrointestinal stromal tumors show phenotypic characteristics of the interstitial cells of Cajal. Am J Pathol 1998; 152:1259-1269. 35. LaQuaglia MP, Heller G, Filippa DA, et al: Prognostic factors and outcome in patients 21 years and under with colorectal carcinoma. J Pediatr Surg 1992;27:1085-1089. 36. Leichtner AM: Intestinal neoplasms. In Walker WA, et a1 (eds): Pediatric Gastrointestinal Disease. Philadelphia, BC Decker, 1991. 37. Lynch HT, de la Chapelle A: Hereditary colorectal cancer. N Engl J Med 2003;348:919-932. 38. McGill TW, Downey EC, Westbrook J, et al: Gastric carcinoma in children. J Pediatr Surg 1993;28:1620-1621. 39. Miettinen M, Lasota J: Gastrointestinal stromal tumorsdefinition, clinical, histological, immunohistochemical, and molecular genetic features and differential diagnosis. Virchows Arch 2001;438:1-12. 40. Moertel CL, Weiland LH, Telander RL: Carcinoid tumor of the appendix in the first two decades of life. J Pediatr Surg 1990;25:1073-1075. 41. Odone V, Chang L, Caces J, et al: The natural history of colorectal carcinoma in adolescents. Cancer 1982;49:171&1720. 42. Parkes SE, Muir KR, a1 Sheyyab M, et al: Carcinoid tumours of the appendix in children 1957-1986: Incidence, treatment and outcome. Br J Surg 1993;80:502-504. 43. Pidhorecky I, Cheney RT, Kraybill WG, Gibbs JF: Gastrointestinal stromal tumors: Current diagnosis, biologic behavior, and management. Ann Surg Oncol 2000; 7:705-712. 44. Pratt CB, Rivera G, Shanks E, et al: Colorectal carcinoma in adolescents: Implications regarding etiology. Cancer 1977;40(5 Suppl) :24642472. 45. Rao BN, Pratt CB, Fleming ID, et al: Colon carcinoma in children and adolescents: A review of 30 cases. Cancer 1985;55:1322-1326. 46. Roberts PJ, Eisenberg B: Clinical presentation of gastrointestinal stromal tumors and treatment of operable disease. Eur J Cancer 2002;38(Suppl5):S37-S38.

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47. Schettini ST, Ganc A, Saba L: Esophageal carcinoma secondary to a chemical injury in a child. Pediatr Surg Int 1998;13:519-520. 48. Shamberger RC, Eraklis AJ, Kozakewich HP, Hendren WH: Fate of the distal esophageal remnant following esophageal replacement. J Pediatr Surg 1988;23:1210-1214. 49. Shiu MH, Farr GH, Papachristou DN, Hajdu SI: Myosarcomas of the stomach: Natural history, prognostic factors and management. Cancer 1982;49:177-187. 50. Skinner MA, Plumley DA, Grosfeld JL, et al: Gastrointestinal tumors in children: An analysis of 39 cases. Ann Surg Oncol 1994;1:283-289. 51. Soper RT: Gastrointestinal neoplasms. In: Ashcraft KW, Holder TM (eds): Pediatric Surgery. Philadelphia, W.B. Saunders, 1993, pp 464469. 52. Spunt SL, Pratt CB, Rao BN, et al: Childhood carcinoid tumors: The St Jude Children's Research Hospital experience. J Pediatr Surg 2000;35:1282-1286. 53. Steinberg JB, Tuggle DW, Postier RG: Adenocarcinoma of the colon in adolescents. Am J Surg 1988;156:460-462. 54. Stemper TJ, Kent TH, Summers RW: Juvenile polyposis and gastrointestinal carcinoma: A study of a kindred. Ann Intern Med 1975;83:639-646. 55. Surveillance, Epidemiology, and End Results (SEER) Program. SEER 1975-2001. SEER Stat Database. Bethesda, Md, National Cancer Institute, DCCPS, Surveillance Research Program, Cancer Statistics Branch, 2004. 56. Symonds DA, Vickery AL: Mucinous carcinoma of the colon and rectum. Cancer 1976;37:1891-1900. 57. Trupiano JK, Stewart RE, Misick C, et al: Gastric stromal tumors: A clinicopathologic study of 77 cases with correlation of features with nonaggressive and aggressive clinical behaviors. Am J Surg Pathol 2002;26:705-714. 58. Van Eeden S, Quaedvlieg PF, Taal BG, et al: Classification of low-grade neuroendocrine tumors of midgut and unknown origin. Hum Pathol 2002;33:1126-1132. 59. Van Gompel JJ, Sippel RS, Warner TF, Chen H: Gastrointestinal carcinoid tumors: Factors that predict outcome. World J Surg 2004;28:387-392. 60. Volpe A, Willert J, Ihnken K, et al: Metastatic appendiceal carcinoid tumor in a child. Med Pediatr Oncol 2000; 34:218-220. 61. Weedon DD, Shorter RG, Ilstrup DM, et al: Crohn's disease and cancer. N Engl J Med 19'73;289:1099-1103.

Rhabdomyosarcoma Richard J. Andrassy

Rhabdomyosarcoma (from the Greek rhabdos, meaning "rod"; mys, "muscle"; and sarkos, "flesh") is a primary malignancy in children and adolescents that arises from embryonic mesenchyma with the potential to differentiate into skeletal muscle. Rhabdomyosarcoma (RMS) accounts for more than 50% of all soft tissue sarcomas in children and is thus the most common soft tissue sarcoma. Sarcomas in adults arise mostly in the extremities, whereas RMS in children can occur anywhere there is skeletal muscle, as well as in sites with no skeletal muscle (e.g., urinary bladder, bile ducts). RMS can arise at any site and in any tissue except bone. The most common sites are the head and neck region and the genitourinary tract, with only 20% occurring in the extremities. The original distinction of soft tissue sarcomas and bone sarcomas from epithelial and hematopoietic tumors is attributed to Virchow, who in the mid-1850s propounded a theory of "cellular pathology" that ascribed the origin of tumors to specific types of cells.99 The first case of RMS was described by Webner in 1854 in a 21-year-old patient with a tongue tumor.97 In 1946 Stoutlo"eported a series of adults with a malignant condition of the trunk and limbs. In 1954 Pack et al.79 described a group of children with RMS of the skeletal muscle. In 1958 Horn et al." proposed a classification of this tumor into four subgroups: embryonal, alveolar, botryoid, and pleomorphic. During those early years, surgery was the only therapy available, and radical excision was the standard. Survival rates were poor except in selected sites where total excision was possible by means of radical surgery, such as amputation or pelvic exenteration. Survival rates of 7% to 70% were seen, depending on site.78 In 1950 Stobbe et a1.lo5demonstrated improved outcomes in head and neck sites when radiation therapy was added after incomplete resection of RMS. In 1961 Pinkel et al." advocated adjuvant chemotherapy after complete surgical excision and postoperative radiation therapy, which was the beginning of the multimodal approach to solid tumors. Recognizing the value of this multimodal approach, as well as the relative rarity of these tumors, the leadership of three cooperative pediatric cancer research groups in the United States (the Children's Cancer Study Group and the pediatric sections of the Cancer and Leukemia

Group B and the Southwest Oncology Group), in concert with the National Cancer Institute, formed the Intergroup Rhabdomyosarcoma Study (IRS) Group in 1972 to investigate the therapy and biology of RMS and undifferentiated sarcoma in previously untreated patients younger than 21 years old. Since then, five successive clinical protocols involving almost 5000 patients have been completed: IRM (1972 to 19'78),IRSII (1978 to 1984), IRSIII (1984 to 1991), IRS-lV Pilot (for patients with advanced disease only; 1987 to 1991), and IRS-IV (1991 to 1997).*,2~"x~~,18 Based on lessons learned from these studies, IRS-V was opened in 1997 for patients with low-risk disease (i.e., with a good prognosis for survival) and expanded in 1999 to other patients. Although the trend has been toward far less mutilating surgery, the surgeon plays an important role in initial biopsy and staging, primary re-excision, appropriate wide local resection, and second-look operations. The surgeon should be an early participant in thk multimodal approach to treatment.

EPIDEMIOLOGY RMS is the third most common solid tumor in infants and children, after neuroblastoma and Wilms' tumor. There are approximately 250 to 300 new cases per year in the United States. There is a slightly greater incidence in males compared with females (3:2) and in Caucasians compared with non-Caucasians (12:5). The peak age at presentation is bimodal, with the primary peak occurring between 2 and 5 years of age and the secondary peak between 15 and 19 years. Patients with RMS appear to have a higher incidence of other congenital anomalies." Both RMS and Wilms' tumor are associated with an increased incidence of genitourinary anomalies. RMS is also linked to anomalies of the central nervous system." Patients with von Recklinghausen's neurofibromatosis have an increased risk of RMS.423101 The Li-Fraumeni familial cancer svndrome, first reported in 1969, includes soft tissue sarcomas occurring in siblings and cousins; parents and other relatives have a variety of malignancies, including RMS, adrenocortical

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carcinoma, glioblastoma, breast cancer, and lung cancer."," This svndrome is an autosomal dominant disorder and is frequently associated with a germline mutation of p53.66 Breast cancer in mothers is the major associated malignancy in families of children with soft tissue malignancy.lo7A review of the mothers of 13 children with RMS showed that their risk of breast cancer was 3 to 13.5 times greater than that of controls.13 Other somewhat weaker associations with fetal alcohol syndrome, maternal exposure to marijuana or cocaine, x-ray exposure, and employment as a health care worker have been s ~ g g e s t e d . " , ~ ~ , ~ ~ RMS has also been observed in association with Beckwith-Wiedemann syndrome, a fetal overgrowth syndrome associated with abnormalities on chromosome llp15, where the gene for insulin-like growth factor I1 (IGF-11) is located.28 The two histologic subtypes of RMS-embryonal and alveolar-have distinct genetic alterations that may play a role in the pathogenesis of these tumors. In alveolar RMS, there is a characteristic translocation between the long arm of chromosome 2 and the long arm of chromosome 13, referred to as t(2;13) (q35;q14). This translocation fuses the PAX?gene (believed to regulate transcription during early neuromuscular development) with the FKHR gene (a member of the forkhead family of transcription factors). It is believed that this fusion transcription factor may inappropriately activate the transcription of genes that contribute to a transformed phenotype. The variant t(1;13) (p36;q14) fuses the PAX7 gene located on chromosome 1 with FKHR Patients with tumors expressing the PAX-FKHR fusion tend to be younger and are more likely to present with an extremity lesion, suggesting a distinct clinical phenotype. Polymerase chain reaction assays are now available that allow confirmation of the diagnosis of alveolar RMS based on the presence of these fusion genes.28363,7',H0 Embryonal RMS is known to involve loss of heterozygosity at the l l p 1 5 locus, with loss of maternal genetic information and duplication of paternal genetic information. This is the location of the IGF-IIgene. IGF-I1 has been demonstrated to stimulate the " growth of RMS cells, whereas the blockade of this factor using monoclonal antibodies inhibits tumor growth both in vitro and in vivo.l13 Several other solid neoplasms are associated with genomic deletions on the short arm of chromosome 11, including Wilms' tumor, hepatoblastoma, and neuroblastoma. The MyoD family of genes codes for DNA binding proteins that regulatk the iranscription of DNA sequences encoding myogenic proteins such as desmin, creatine kinase, and myosin."g."' In RMS, the down-regulation of this gene does not occur, so that MyoDl expression l ~ ~biologic signifremains at high levels in tumor ~ e l 1 s .The icance of this overexpression is not clear; however, the detection of high levels of the MyoDl gene product may be used to diagnose RMS.la The c h a n"~ ein a cell's DNA content has been described in a variety of tumors and may have some prognostic significance. The DNA content of embryonal RMS tumors ranges between diploid and hyperdiplbid (1.1 to 1.8 times the normal amount of DNA). It has been reported that diploid embryonal RMS tumors may have

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a worse prognosis than hyperdiploid tumors. Near tetraploidy was associated with alveolar histology.28,53 RAS oncogene mutations have been described in RMS cell lines and tumor specimens. It is not known whether these alterations are involved in RMS tumor pathogenesis or reflect secondary abnormalities that occur during tumor progression.28 Aberrant expression of the M E 1 oncogene in embryonal and alveolar RMS tumor samples and established cell lines has been described. MET encodes the receptor for HGF/scatter factor, which is known to control cell motility and invasion in epithelial cells. It is hypothesized that the overexpression of MET may provide RMS cells with the same property as embryonal myoblasts, allowing them to migrate into surrounding connective tissues.31

PATHOLOGY FWS cells arise from undifferentiated mesodermal tissue and fall into the broader category of the small, round, blue cell tumors of childhood. The differentiation of specific tumor type is accomplished by a combination of light microscopy, immunohistochemical techniques, electron microscopy, and molecular genetic techniques. The characteristic feature that permits a tumor to be classified as RMS is the identification of a myogenic lineage. Typically, this consists of the light microscopic identification of cross-striations that are characteristic of skeletal muscle or rhabdomyoblasts.4,fl3Skeletal muscle or muscle-specific proteins can be identified by immunohistochemical staining. Histologically, RMS is classified as a small, round, blue cell tumor of childhood, a category that also includes neuroblastoma, Ewing's sarcoma, small cell osteogenic sarcoma, non-Hodgkin's lymphoma, and leukemia. Each of the two major subtypes of RMS has a characteristic histologic appearance. Embryonal RMS is the most common histologic subtype, constituting more than 30% of all newly diagnosed tumors. This embryonal subtype, particularly the botryoid and spindle cell variants, was thought to have a much better prognosis, but there is now controversy whether the histologic subtype or the site of the tumor is the strongest indicator of prognosis. Botryoid RMS, described as a "cluster of grapes," is seen in cavitary structures and has a good prognosis. The spindle cell variants arise disproportionately in the paratesticular region but may also be seen in the head and neck, ~ ~ , ~ )subtypes especially the orbit, and the e ~ t r e m i t i e s . These are almost always associated with limited disease, behave less aggressively than the classic embryonal tumors, and have an extremely good prognosis; however, both types account for only 5% to 6% of all MS.") The pathologic description of RMS as a tumor of myogenic lineage was first advanced in 1958 by Horn et aL50 These investigators proposed the first c1,assificationscheme that divided RMS into four different pathologic types (embryonal, botryoid, alveolar, and pleomorphic). This system has been used for decades and was modified into a "universal" system by an international group of pediatric pathologists in 1994. This system ascribes prognostic significance to each histologic subtype by classifying

526

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CLINICAL PRESENTATION

I. Favorable prognosis a. Botryoid b. Spindle cell II. Intermediate prognosis a. Embryonal b. Pleomorphic (rare) Ill. Poor prognosis a. Alveolar (including solid variant) b. Undifferentiated From Asmar L, et at: Agreement among and within groups of pathologistsin the classification of rhabdomyosarcoma and related childhood sarcomas: Report of an internationalstudy of four pathology classifications.Cancer 1994;74:2579.

them into groups with favorable, intermediate, and poor prognoses (Table 32-1) . l The alveolar variant accounts for approximately 20% of tumors and frequently arises in the extremities, trunk, or perineum; these tumors have an unfavorable prognosis." The alveolar variant is characterized by a prominent alveolar arrangement of stroma and dense, small, round tumor cells resembling those of lung tissue. A subtype is the "solid" alveolar RMS, characterized by an architecture of dense cellular sheets lacking any intercellular stroma but with cytologic features identical to those found in the classic alveolar tumors. Undifferentiated sarcoma is a poorly defined category of sarcomatous tumor whose cells show no evidence of myogenesis or other differentiation.75.76 The distribution of histologic subtypes is shown in Table 32-2. A number of monoclonal antibodies have been shown to react with elements of RMS and have been useful in its diagnosis. These include antibodies to desmin, musclespecific actin, sarcomeric actin, and myoglobin. All have been used to confirm the myogenic lineage of cells and, when used in combination, have very good specificity and sensitivity."' MyoDl was mentioned earlier; other nonmyogenic protein products that can be identified in these tumors include cytokeratin, neuron-specific enolase, S-100 protein, and Leu-7.

Histologic Type Embryonal Alveolar Undetermined Undifferentiated Botryoid Extraosseous Ewing's

Percentage

--

53 19 18 7 5 3

From Newton WA, et al: Pathology of rhabdomyosarcoma and relatedtumors. In Maurer HM, Ruymann FB, Pochedly C (eds): Rhabdomyosarcomaand Related Tumors in Children and Adolescents. Boca Raton, Fla, CRC Press, 1991.

The clinical presentation of RMS depends on the site of origin of
CHAPTER

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527

DIAGNOSIS The diagnosis of RMS is usually made by direct open biopsy. There are no helpful markers or specific imaging studies. The pathologist is expected to identify the histologic subgroups of RMS to allow adequate staging and to direct therapy. For this purpose, several grams of tissue are needed. Biopsies of genitourinary RMS are frequently performed using the endoscope. Needle biopsies that are performed to establish the diagnosis of prostatic RMS are difficult to interpret and must include several cores. Trunk and extremity RMS should have excisional or incisional biopsy, with the incision placed so that it will not interfere with the incision required for subsequent wide local excision. This usually means an axial incision in extremities. Wide local excision with clear margins is the ultimate goal. Regional lymph nodes are evaluated, depending on the location of the primary tumor. Trunk and extremity lesions have a high incidence of lymph node involvement, and sentinel lymph node mapping is advi~ed.~~,74 Patients with RMS require a complete workup before definitive surgery. The preoperative evaluation includes imaging, blood work, and bone marrow evaluation. The complete preoperative or pretreatment evaluation is outlined in Table 32-3. The most important part of the diagnostic process is obtaining adequate tissue for histologic and cytologic diagnosis and classification. This procedure is generally accomplished by open incisional biopsy under general anesthesia.

Staging and Clinical Grouping Pretreatment staging for RMS is performed to stratify the extent of the disease for the purpose of determining

Stage -

Sites

I

Orbit Head and neck (excluding parameningeal) Bladder-nonprostate Bladder-prostate Extremity Cranial parameningeal Other (includes truncal, retroperitoneal, perineal, biliary, intrathoracic) Bladder-prostate Extremity Cranial parameningeal Other (as in stage II) All

II

111

Iv

-,

History and physical examination (height, weight) Measurement of lesion (physical or imaging) Complete blood count, differential, platelets Urinalysis Electrolytes, creatinine, calcium, phosphorus Alkaline phosphatase, lactate dehydrogenase, bilirubin, serum glutamic-pyruvic transaminase Bone marrow biopsy or aspirate Chest radiograph Magnetic resonance imaging (MRI) or computed tomography (CT) of primary tumor CT of chest MRI or CT of head (for head tumors) Bone scan Cerebrospinal fluid cytology (for parameningeal tumors) Electrocardiogram or echocardiogram (selective)

the appropriate treatment regimen as well as to compare outcome. This classification is a modification of the TNM staging system and is based on primary tumor site, primary tumor size, clinical regional node status, and distant metastatic spread (Table 32-4) .58,74 Pretreatment size is determined by external measurement or by magnetic resonance imaging or computed tomography (CT), depending on the anatomic location. The staging is "clinical" and should be done by the responsible surgeon based on preoperative imaging and physical findings. Intraoperative or pathologic results do not affect the stage but do affect the clinical group. The IRS clinical grouping system is based on the pretreatment and operative outcome (Table 32-5). Its basic premise is that total tumor extirpation at the original site is the best hope for cure, and it stratifies patients

Tumor

Size

Nodes

TI or T2

a or b

No or N,

Mo

TI or T2

a

No or N,

Mo

TI or T2

a b

N1 NO. N,I N,

Mo

a or b

NO.NI, Nx

MI

il or T,

Metastasis

Tumor: T,, confined to anatomic site of origin: (a) 5 cm diameter in size, (b) >5 cm diameter in size; T, extension and/or fixation to surroundingtissue: (a) 5 cm diameter in size, (b) > 5 cm diameter in size. Regional nodes: No,regional nodes not clinically involved; N,, regional nodes clinically involved by neoplasm; N,, clinical status of regional nodes unknown (especially sites that preclude lymph node evaluation). Metastasis: M, no distant metastasis; M,, metastasis present.

528

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Group I: Localized disease, completely resected. (Regional nodes not involved-lymph node biopsy or sampling is highly advised [9602] or required [9803, 98021, except for head and neck lesions.) (a) Confined to muscle or organ of origin. (b) Contiguous involvement-infiltration outside the muscle or organ of origin, such as through fascia1 planes. Note: This includes both gross inspection and microscopic confirmation of complete resection. Any nodes that may be inadvertently taken with the specimen must be negative. If the latter are involved microscopically, the patient is placed in group Ilb or Ilc. Group II: Total gross resection with evidence of regional spread. (a) Grossly resected tumor with microscopic residual disease (surgeon believes that all the tumor has been removed, but the pathologist finds tumor at the margin, and additional resection to achieve a clean margin is not feasible [9602] or reasonable [9803, 98021). No evidence of gross residual tumor. No evidence of regional node involvement. Once radiotherapy and chemotherapy have been started, re-exploration and removal of the area of microscopic residual do not change the patient's group. (b) Regional disease with involved nodes, completely resected with microscopic residual. Note: Complete resection with microscopic confirmation of no residual disease makes this different from groups Ila and Ilc. Additionally, in contrast to group Ila, regional nodes (which are completely resected) are involved, but the most distal node is histologically negative. (c) Regional disease with involved nodes, grossly resected, but with evidence of microscopic residual or histologic involvement of the most distal regional node (from the primary site) in the dissection. Note [9602 only]: The presence of microscopic residual disease makes this group different from group Ilb, and nodal involvement makes this group different from group Ila. Group Ill: Incomplete resection with gross residual disease. (a) After biopsy only. (b) After gross or major resection of the primary tumor (>50%). Group IV: Distant metastatic disease present at onset (lung, liver, bone, bone marrow, brain, distant muscle and nodes). Note (9602 only]: The above excludes regional lymph nodes and adjacent organ infiltration, which places the patient in a more favorable grouping (see group 11). The presence of positive cytology in cerebrospinal fluid or pleural or abdominal fluids or implants on pleural or peritoneal surfaces or in the omentum are regarded as indications for placement in group IV.

i Numbers in brackets are the specific study number underthe IRS protocols.

according to tumor resectability. This has led, in the past, to aggressive and often mutilating procedures. This system does not take into account the biologic nature or natural history of the tumor, nor does it account for the experience and the aggressiveness of the operating surgeon. With the more frequent use of biopsy and neoadjuvant chemotherapy, there has been a "shift" from group I or I1 to group 111, with biopsy followed by neoadjuvant therapy. Group assignment is based on intraoperative findings and postoperative pathologic status and includes final pathologic verification of margins, residual tumor, node involvement, and cytologic examination of pleural and peritoneal fluid, when applicable. Both clinical grouping and pretreatment staging have been shown to correlate with outcome.4.27.74 Based on the findings from IRS-I through -IV, risk groups have been established for treatment in IRSV, which combines group, stage, and histology subtype to allocate patients to three different therapeutic protocols according to risk of recurrence (Table 32-6). Low-risk patients have an estimated %year failure-free survival (FFS) rate of 88%; intermediate-risk patients have an estimated %year FFS rate of 55% to ?6%, and high-risk patients have a 3-year FFS rate of less than 30%. Multidisciplinary treatment is recommended, as defined by histologic subtype, primary site, extent of disease at diagnosis, and response to treatment. The goal is to achieve local control with preservation of form and function."'

TREATMENT The approach to the treatment of RMS has been multimodal for more than 30 years. The advances in understanding the biology and treatment of this disease can

Risk Group Stage Clinical Group, Node Status, Site Low

I

Intermediate

I I II 111 IV

High

I, II; No; all favorable sites (orbit, head and neck, nonparameningeal, genitourinary, nonbladder-prostate) Ill; No, N,; orbit only I; No, N,; all other (unfavorable) sites; tumor =5 cm in widest diameter II; N;, all favorable sites (see above) Ill; No, N, N,; all favorable sites except orbit 11, Ill; No, N, N;, all other sites 11, Ill; No, N, N,; all other sites IV; No, N, N,; any site with metastatic disease, including tumor cells in cerebrospinal, pleural, or peritoneal fluid or omental implants

LI -

.-

No,regional nodes not clinically involved; N,, regional nodes clinically involved by neoplasm; N, clinical status of regional nodes unknown (especially sites that preclude lymph node evaluation).

CHAPTER

32

Rhabdomyosarcoma

529

demonstrated the benefits of PRE. In IRS-I and IRS-11, largely be attributed to the IRS (I-V). The surgical treat154 patients with extremity or trunk RMS were initially ment for RMS has become progressively less mutilating placed in clinical group IIa; then 41 patients underwent or surgically aggressive while maintaining the excellent successful PRE and were converted to clinical group I survival statistics of earlier studies. before the onset of adjuvant therapy. These patients were The surgical treatment of RMS is site specific and is compared with 113 patients who had microscopic residual discussed later by individual site. The general principles disease and did not undergo PRE and with 73 patients include complete wide excision of the primary tumor who were free of disease after the initial resection (cliniand surrounding uninvolved margins while preserving cal group I). Among the 41 PRE patients, the 3-year cosmesis and function. Kaplan-Meier survival estimate was 91%, compared with The initial biopsy is generally incisional except in small 74% for group IIa patients not undergoing PRE and 74% lesions, where excisional biopsy is possible. Some lesions for group I patients. This approach may be applicable to have a pseudocapsule that may allow the lesion to be tumors in other locations as well. PRE should be considshelled out, giving the surgeon the false notion that he or ered, even if the margins are apparently normal, if the she has removed the entire lesion. Many sites have gross or initial resection was not a "cancer" operation (i.e., maligmicroscopic residual tumor, and pretreatment re-excision is warranted if this can be done without m ~ t i l a t i o n . ~ ~ nancy was not suspected at the initial excision) ,21349 Biopsy of any lesion may involve reoperation and wide Second-look operations have been used for several excision. Longitudinal incisions are frequently better pediatric tumors to evaluate therapeutic response and to remove any residual tumor after completing initial therthan horizontal incisions on areas such as an extremity. A biopsy to confirm malignancy requires that the biopsy apy. The use of second-look operations was evaluated in IRS-I11 and shown to be beneficial in clinical group I1 tract be excised at the time of reoperation; if the biopsy RMS patient~.l~.~,l~7-llg The performance of a second-look site is inappropriately placed, this excision may require operation changed the response status in a significant much larger incisions or resections than necessary. number of patients; 12% of presumed complete-response Solid tumor biopsies are traditionally divided into patients were found to harbor residual tumor, and 74% excisional biopsies, in which the entire tumor is included of both partial- and no-response patients were recategoin the specimen, and incisional biopsies, in which only a rized as complete responders after operation. The surportion of the tumor is included. In an excisional biopsy, vival rate of these recategorized patients was similar to margins should be carefully marked to allow re-resection that of patients confirmed to be complete responders at should the biopsy reveal a positive margin on review. re-exploration.117,1 Ideally, excisional biopsies are planned to allow resections The general surgical principles learned from IRS-I that will leave behind only negative margins. If such an through -IV and thus considered in IRS-V include the excisional biopsy would result in too large a resection, following: (1) Patients with localized, completely resected incisional biopsy is more appropriate. disease (group I) generally have the best prognosis for If biopsy margins are not carefully marked on both 5-year FFS and overall survival. Patients with metastases the specimen and the operative field (usually by sutures at diagnosis (group IV) have the worst outlook, and or clips), the surgeon's ability to subsequently obtain negthose with group I1 and I11 disease have an intermediate ative margins is severely compromised. For example, an prognosis. Thus, it is preferable to try to remove all visible inappropriate approach to biopsy may lead to further tumor, if doing so is feasible without excessive morbidity. difficulties in the case of testicular masses. Any testicular (2) When a lesion has been resected, primary re-resecmass should be approached through an inguinal rather tion is indicated if the primary operation was not a cancer than a scrotal incision so that proximal control of the cord operation for malignancy. Any question about margin can be obtained and a wide local excision performed status warrants re-resection. Group I (totally resected) without seeding the scrotum with tumor. The proximal patients with embryonal RMS are not subjected to postspermatic cord should be examined for free margins. operative radiation therapy.l2"3) It is desirable to preserve Higher excision may be necessary if tumor is still present. organ function and thus spare such structures as the eye, Biopsy of the tumor through the scrotum may lead vagina, and bladder. Also, patients with tumor at or near to further scrotal resection and increased risk of local these sites have a good prognosis. Primary chemotherapy recurrence. followed by radiation therapy is the recommended Secondary excision after initial biopsy and neoadjuvant approach. Delayed excision of initially unresected tumor therapy has a better outcome than does partial or incommay improve the prognosis by changing a partial plete excision. There has been a shift of patients into response into a complete response after initial shrinkage clinical group 111, but chemotherapy followed by delayed of the tumor by chemotherapy, with or without radiation or second-look surgery allows a better prognosis with less therapy.l17 (4) There is a relationship between age at mutilating surgery. Biopsy of regional nodes, or sentinel diagnosis and likelihood of regional lymph node involvelymph node mapping, is warranted in selected sites, such ment in boys with nonmetastatic paratesticular RMS. as the extremity. Event-free survival in IRS-IV was better for boys younger In some patients with extremity or trunk RMS, initial than 10 years because the nodal relapse rate was lower tumor resection is thought to be complete, but histopathothan in those aged 10 years and older. We now recomlogic review reveals microscopic residual disease corremend performing a modified ipsilateral retroperitoneal sponding to clinical group IIa in the surgical margins. In lymph node dissection in older boys who have no clinical many of these patients, primary re-excision (PRE) is possible, achieving wider disease-free margins. Hays et a1.43 evidence of regional node involvement. If the nodes are

530

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MAIORTUMORS OF CHII.DHOOD

uninvolved, cyclophosphamide and radiation therapy VAC has been the gold standard for combination are withheld; if tumor is present in the nodes, cyclophoschemotherapy in the treatment of most cases of RMS. phamide and radiation therapy are given, in addition to consecutive-large " randomized trials have led to modifications of this combination tailored to specific subgroups vincristine and actinomycin D.120.121 Other considerations for IRS-V include a more aggresbased on clinical group and site of disease. In patients sive approach to evaluating lymph nodes. In the earlier with clinical group I embryonal tumors, results of IRSIII studies,g"57 lymph node involvement was thought to be showed equivalent survival for patients treated with VA rare at most sites, because the nodes were rarely evaluated. only versus VAC.2.5In IRS-IV, patients with clinical group I paratesticular or orbital disease were treated with VA More recent studies suggest that the incidence of involved alone for 2 years. In an IRSV pilot study, VA chemotherapy lymph nodes in patients with primary tumors of the alone was given to patients with "low-risk" disease, includextremity may be higher than initially s u ~ p e c t e d . ~ ~ Sentinel lymph node mapping, using a vital dye such as ing those with stage I, clinical group I or I1 (No)orbital, Lymphazurin blue along with radiolabeled technetium head and neck (nonparameningeal), or genitourinary sulfur colloid, can localize the regional node most likely tract (nonbladder-prostate) disease; those with stage " 11, clinical group I disease; and those with stage I, clinical to contain tumor ~ells.~"he surgeon removes the indicated sentinel node, and the pathologist can thoroughly group I11 (orbit only No) disea~e.2~3~2 When evidence of the efficacy of eto~osideand ifosinvestigate the presence or absence of tumor in that famide for RA4S was recognized,71 this was incorporated node. The sentinel node reflects the status of the nodal into a randomized treatment protocol in IRS-IV. basin. If the node is positive, the nodal basin is irradiated. Randomization of VAC versus VAI versus VIE was The utility of sentinel lymph node mapping is being evaldone for nonmetastatic RMS. Data from IRS-IV indicate uated in IRS-V. that the current standard combination of VAC, with For patients whose tumors are initially deemed unresectable, a second-look procedure should be considered cyclophosphamide at 2.2 g/m2 per dose with granulocyte after initial chemotherapy. Imaging studies have not been colony-stimulating factor, is equally efficacious with consistently reliable in determining the actual response regard to FFS and overall survival, as are VAI and VIE.'" Therapy for patients with intermediate-risk disease to treatment. In IRS-111, 75% of children with group I11 tumors and evidence of partial or no response on imagmay be improved by the introduction of new agents. ing studies either had a pathologically complete response Dose intensification using" known active chemotherapeutic agents should also be considered. Preliminary or were converted to such a response by resection of all remaining tumor. Most (but not all) patients who IRS-IV results have shown an improvement in FFS for intermediate-risk embryonal RMs, probably related showed a complete response on imaging studies were to an increased cyclophosphamide dose.2 Escalation confirmed as having such a response by secondary surgery. of cyclophosphamide from 0.9 g/m' in IRS-111 to Survival was better in those patients who converted to a 2.2 g/m2 in IRS-IV improved the FFS of patients with complete response. Secondary surgery is less beneficial embryonal RMS but not those with alveolar RMS or in children with stage IV disease. Second-look surgery is least useful for tumors in the head and neck but is approundifferentiated RMS.2 Data from IRS-I, IRS-11, and IRS-I11 in 1431 patients priate for tumors in the trunk and limbs. The trend indicate that there is no benefit to adding doxorubicin to toward improved survival in patients converted to a VAC in patients with group 111 and group IV disease, complete response by means of second-look operations has been enduring.~~7~**8 whether analyzed together or within group I11 and group N categories individually.25."%7o,Y'LThe addition of doxorubicin and cisplatin with or without etoposide to the VAC regimen did not improve the outcome for CHEMOTHERAPY patients with advanced disease in IRS-III.2"6"7() Before multimodal therapy, surgery alone for RMS resulted Patients with metastatic disease have a poor prognosis . .. despite aggressive therapy. Intensive, multiagent combiin survival rates of less than 20%. Local micrometastatic disease, nodal disease, or unrecognized or untreated disnations have been used in an attempt to improve survival. tant disease frequently led to early recurrence and subseThe International Society of Pediatric Oncology (SIOP) quent death mainly due to advanced metastatic disease. reported a 53% response rate to a combination of carboplatin, epirubicin, &d vincristine in previously untreated The development of adjuvant and later neoadjuvant patients with metastatic RMS.3" chemotherapy has led to a marked increase in survival. The use of methotrexate in front-line treatment regiThe IRS Group studies have shown progressively better mens offers the potential advantages of relative lack of survival rates with less mutilating surgery and less chemotoxici~y.24.2~.569,70083 additive myelosuppression and a different mechanism of Agents with known activity in the treatment of RMS action. In a phase I1 trial, Pappo et a1.81reported a 33% response rate to high-dose methotrexate.in patients with include vincristine (V), actinomycin D (A), doxorubicin, cyclophosphamide (C), ifosfamide (I), and etoposide (E). previously untreated, advanced-stage RMS. Melphalan and cisplatin were evaluated for their potenTopotecan, a campotothecin analogue that acts as an tial role in patients with locally extensive or metastatic disinhibitor of topoisomerase I, is being examined for its ease and did not improve outcome compared with other potential role in RMS (inhibition of topoisomerase I options in the randomized trials involving patients with inhibits DNA repletion). The IRS Group reported a 45% clinical group I11 or IV disease.2jJo0 response rate to topotecan used in a window setting in -

-

CHAPTER

newly diagnosed patients with nonparameningeal metastatic RMS.8'J11An IRSV pilot for metastatic RMS is currently evaluating topotecan in combination with cyclophosphamide in an up-front window before VAC and radiation therapy. It appears to be active in newly diagnosed patients with metastatic RMS and can be given in combination with VAC.$z Autologous bone marrow transplantation has been used in several of the childhood solid tumors. To date, it has not been of value in patients with metastatic RMS.51,54 In summary, the recommendations for IRS-V, which is presently ongoing, are as follows: Low-risk patients are those with localized embryonal RMS in favorable sites (stage I) or in unfavorable sites (stages I1 and 111) that has been grossly removed. Those with the best prognosis are placed in subgroup A and receive VA with or without radiation therapy. The others, placed in subgroup B, receive VAC with or without radiation therapy. Intermediate-risk patients are those with localized alveolar RMS or undifferentiated sarcoma (stages I to 111) or embryonal RMS (stages I1 and 111) with gross residual disease (group 111) or embryonal RMS with metastases (group IV) younger than 10 years at diagnosis. They are randomized to receive VAC or VAC alternating with vincristine and cyclophosphamide plus topotecan, along with radiation therapy. High-risk patients have embryonal RMS diagnosed at 10 years of age or older, or alveolar RMS or undifferentiated sarcoma at any age younger than 21 years, with metastases at diagnosis (group IV). They receive a trial of irinotecan34 over 6 weeks, followed by VAC. Irinotecan is continued at intervals for those who responded to it initially but is omitted for nonresponders. High-risk patients with cranial parameningeal tumors and meningeal impingement at diagnosis receive VAC without irinotecan.

RADIOTHERAPY Radiotherapy is tailored for specific sites and is based on extent of disease. In some sites, such as the head and neck or pelvis, tumors often cannot be completely removed surgically. Radiation therapy may be used in conjunction with chemotherapy to eradicate residual tumor cells. The guidelines for radiation doses have changed over successive IRS Group studies. The dosage is now tailored to the amount of residual disease (gross or microscopic) and the tumor response. In IRS-IV, radiation therapy was defined by clinical group. Patients with completely resected clinical group I, TNM stage I and I1 tumors received no radiotherapy. Patients with completely resected group I, stage I1 tumors and those with group I1 tumors received conventional external beam radiation to a total dose of 4140 cGv. Clinical group I11 patients were randomized to receive 5040 cGy external beam radiation or hyperfractionated radiotherapy to a dose of 5940 cGy. Based on IRS-IV, there is no indication that giving hyperfractionated radiotherapy with 59.4 Gy in two daily fractions of 1.1 Gy, with

32

Rhabdomyosarcoma

531

a 6-hour interfractional interval, results in a better localregional control rate among children with group I11 tumors than that obtained with 50.4 Gy in 1.8 fractions daily.29230 There is no evidence of a benefit in giving radiation to patients with completely resected, locailesi<ns (group I), provided the histologic subtype is embryonal RMS.lZ3 Graded doses of irradiation are appropriate for all other patients, based on the patient's group at the time of studv entry. Volumes to be irradiated include the wretreatment primary tumor and the regional lymph node area, if involved. Patients with group - IV disease receive radiation therapy to both the primary site and the sites of metastases, within the limits of bone marrow tolerance. An analysis of patients with group I1 disease in IRS-I through -IV showed improved outcome in IRS-I11 and -IV, ~ e r h a i due s to intensi6ed thera~v.I0" Local failure rates for patients with group I11 disease in IRS-I11 and -IV were reviewed in 2000 by the IRS Statistical Office. The rates have remained'stable or improved. In IRS-IV, local failure rates were 2% in orbit primary sites, 16% in cranial parameningeal sites, and 12% in other head or neck sites. Local failure rates were 7% in extremity sites, 19% in genitourinary sites, and 14% in other sites. Current IRS Group results suggest that most patients with cranial parameningeal sarcoma, including those with localized intracranial extension contiguous with the primary tumor at diagnosis, can be successfully managed with systemic chemotherapy and radiation therapy. Radiation therapy is directed to the primary tumor, including any extension, along with a 2-cm margin, including the adjacent meninges. Whole-brain irradiation and intrathecal anticancer agents are not necessary in the absence of diffuse meningeal involvement, such as multiple intracranial metastase~.~~~~~ A summary of the recommendations for radiation therapy in IRS-V include the following: Patients with completely excised embryonal RMS (group I) receive no radiation therapy. However, patients with completely excised (group I) alveolar RMS and undifferentiated sarcoma receive radiation therapy to the primary site.lZ3 Other patients receive radiation therapy as a function of group, histologic subtype, and status of regional lymph nodes or distant metastases. Patients with metastases receive radiation therapy to the primary tumor and to sites of metastases within the limits of bone marrow tolerance.92 x ,

MANAGEMENT BY SITE Head and Neck Head and neck lesions include superficial head and neck, orbit, parotid, buccal, laryngeal, and oropharyngeal locations. The multidisciplinary approach to therapy has allowed less aggressive surgical procedures while maintaining an excellent prognosis at this site. Wide excision is appropriate when feasible, but the possibility of achieving wide margins is restricted to small superficial lesions.47

532

PART

III

MATOR TUMORS OF CHILDHOOD

Tumors of the orbit have an excellent response to ~~~~~l~ residual mass effect on imaging s t u d i e ~ . l ~ "Other therapy because the tumor is usually confined to the bony studies suggested a good correlation between evidence orbit and there is a paucity of lymphatics. Abramson et al.1 of stable residual disease on CT and subsequent local demonstrated that radiation therapy plus chemotherapy relapse and death." This is being investigated further. is the most effective treatment for orbital RMS; this type of therapy ended the need for orbital exenteration. Survival of more than 90% of patients is standard with VA Genitourinary Sites chemotherapy and radiation therapy.25~32J14Metastatic The genitourinary sites include the bladder, prostate, spread to regional nodes is seen in less than 3% of patients? Cervical lymph node biopsy or sentinel lymph paratesticular areas, vagina, uterus, vulva, and, rarely, kidnode mapping does not appear to be warranted unless neys or ureter. RMS is the most common malignancy of nodes are clinically involved. Patients with nodal involvethe pelvic structures in children. Tumors in these locations ment should be treated with the IRS intermediateare considered in two different categories on account of risk protocol. Thus, except for small lid lesions, the role their different prognoses: bladder-prostate versus vulvoof surgery for orbital primary tumors is limited to biopsy vagina, uterus, and paratesticular. These sites accounted a10ne."'~.~2Jl~J~~Orbital exenteration has been used selecfor approximately 25% of cases in IRS-III.2Vn 6% of tively in recurrent disease. those patients with pelvic tumors in IRS-I and -11, the exact site of origin within the pelvis could not be defined. Nonorbital, nonparameningeal sites include superficial and deep tumors that do not impinge on the meninges. Tumors in the vagina and testicular areas have a good For some tumors, such as parotid, laryngeal, oropharynprognosis and are more commonly of embryonal histolgeal, and other deep tumors, surgery is limited to biopsy ogy, often with the botryoid (vaginal) or spindle cell followed by chemotherapy and radiation therapy for (paratesticular) variant. treatment regimen has led to tumor eradication.l1"his Bladder RMS and prostate RMS can be difficult to dissurvival rates of 83%.3,38 tinguish from each other because of their anatomic proxThe need for alkylating agents in orbital and nonorimity and the tumor's tendency to grow to a large size bital head and neck sites has been q ~ e s t i o n e d . ~ ~ " ~ l l ~ ~before l l 6 diagnosis. When this determination is possible, In IRS-111, patients with orbital and nonparameningeal however, it is evident that patients with bladder tumors head and neck tumors who received intensive VA have a better prognosis than those with tumors arising chemotherapy and radiation therapy had the same rate from the prostate.l15 The majority of tumors in these of survival (90%) as did patients in IRS-I1 who received areas are embryonal (71%) or botryoid (20%);2% are of those therapies in conjunction with alkylating agent~.2~,25 alveolar histology.75 The present recommendation for this low-risk group is In IRS-I11 it was found that children with tumors of the to receive VA with or without radiation therapy.27 bladder or prostate who received more intensive Parameningeal tumors are associated with a poor chemotherapy and earlier radiation therapy had a survival prognosis because of the propensity for extension and rate only slightly lower than that of patients with head the presence of abundant lymphatics.3~*0,5fi."6In addition, and neck tumors. This finding contrasts with that of IRS-II.24,25,699,0,87 parameningeal RMS often occurs in hidden sites, which frequently results in delayed diagnosis.32Jl4Jl6 Fifteen Bladder or prostate tumors commonly arise near the percent of patients with parameningeal RMS present area of the trigone and produce symptoms of bladder with metastatic disease.25 Bone erosion is a predictor outlet obstruction or hematuria. Diagnosis is usually made of local relapse." More intensive treatment of paraby cystoscopic evaluation and biopsy, as well as CT or magmeningeal RMS, including VAC chemotherapy, intrathecal netic resonance imaging. Previously, the initial managechemotherapy, and radiation therapy to the entire cranial ment of these tumors in children was usually anterior or neuraxis, has resulted in increased survival.86In patients total pelvic exenteration, followed by chemotherapy and receiving this intensified therapy, the tumor-freesurvival radiation; this treatment produced very good long-term rate increased from 33% to 57%, and the failure rate survival rates, approaching 85% in some series, but it also for local tumor control fell from 28% to 6%.86 The value necessitated a permanent urinary conduit and, in some of prophylactic radiation therapy to the central nervous cases, colostomy.87,90 Today, bladder salvage is an impor~ ~IRS-111, radiation system has been q u e ~ t i o n e d .In tant goal, and less aggressive surgical procedures are therapy and intrathecal chemotherapy were based on c ~ m m o n . Neoadjuvant ~ ~ ~ , ~ ~ chemotherapy and radiathe degree of meningeal involvement, and most patients tion have decreased the rate of exenterative cystectomy received less radiation therapy than that used in from greater than 50% to approximately 30%.44-4"n IRS-11. There was no decrease in progression-free survival IRSIII 50% of patients with bladder RMS received cisplatin among patients in IRS-I11 compared with those in in addition to vincristine-doxorubicin (Adriamycin)IRS-11.24.25 cyclophosphamide or VAC and irradiation. Of 171 children Craniofacial resection for anterior skull-based tumors with primary bladder lesions enrolled in IRSI through -111, of the nasal areas, paranasal sinuses, temporal fossa, and 40 underwent partial cystectomy after receiving neoadjuother such sites should be reserved for surgical teams vant chemotherapy and radiation. Relapse occurred in with expertise in its performance and for secondary pronine patients (seven locally). The Kaplan-Meier estimate cedures when tumor persists after initial chemotherapy of survival rate with a functioning bladder among all and radiation therapy. In some reports, no viable tumor children with bladder or prostate tumors in IRS-I11 was could be found in the resected specimens, despite a 60%. Long-term survival was in excess of 80%.44-46

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Rhabdomyosarcoma

533

Exenteration is no longer the primary treatment for testes and the entire cord, including the atraumatic clamp, RMS of the prostate. This site accounted for about 5% of together; (6) thoroughly irrigate the field. Patients with newly diagnosed cases in IRS-111. The mean age at the time spillage are considered clinical group IIa regardless of of diagnosis was 5.3 years. Most tumors were relatively the completeness of r e s e ~ t i o n . ~ ~ large, had embryonal histology, and were clinically localThe incidence of nodal metastatic disease for paratesized but unresectable without major loss of organ functicular RMS has been reported to be as high as 26% to tion. The 44 patients with group I11 tumors (gross residual 43%.37,77,86,120 During IRS-111, all patients were required disease) were treated according to the IRS-I11 protocol. to undergo ipsilateral retroperitoneal lymph node dissecForty-three of them underwent biopsy only, and one tion. During IRSIV, the retroperitoneal lymph nodes were evaluated with CT. In this study, only those patients with patient had subtotal resection as the initial procedure. The average number of surgical procedures per patient lymph node involvement on CT required surgical evaluation of the lymph nodes. This led to the "down-grouping" was two (range, one to five). Six of the 44 patients had no additional surgery. The second-look procedures performed of about 15% of patients from group I1 (lymph nodes positive) to group I (total resection, no nodal disease). in the other 38 patients included exenteration,14 prostatectomy,4 cystoscopic or perineal needle biopsy? lapaThis effect was higher in adolescents (>30%).This change rotomy with biopsy,6 and subtotal excision with bladder led to fewer patients receiving radiation to the retroperisalvage.%dditional surgery was required for four patients toneum, but also a poorer FFS in IRS-IV and a higher for evaluation of residual mass, postoperative fistula, relapse rate. For patients younger than 10 years, long-term ureteral stricture, or small bowel obstruction. Six patients survival rate did not differ between IRS-I11 and -IV and was excellent (IRS-111, 100%; IRS-IV, 98%). However, with relapse or residual disease underwent additional or treatment in about 30% of adolescents assigned to group I chemotherapy and late exenteration,~rostate~tomy,~ biopsy.? Four of the six were cured, one received treattumor status in IRS-IV failed; those patients required ment for a second malignancy, and the other had residual retreatment, with poor salvage. In IRS-IV, among disease after exenteration. Thus, 36 of the 44 patients patients given retroperitoneal lymph node radiation with group I11 tumors were cured (minimum follow-up, and intensive three-agent chemotherapy, including alky6 years; range, 6 to 11 years), compared with 23 of lating agents, survival at 3 years was 100%. Based on 47 patients in IRS-11. The bladder salvage rate for those these data, the IRS Group resumed recommending cured of their disease was also better (64% versus 57%). retroperitoneal lymph node dissection for all patients Conservative, delayed surgery, performed after intensive older than 10 years. chemotherapy with or without radiotherapy, yields a better This remains controversial, because SIOP no longer recommends retroperitoneal lymph node dissection for cure rate while maintaining a high rate of bladder salvage any patients. Olive et al.77found that chemotherapy was in children with group I11 prostatic RMS.65 effective in eradicating occult micrometastases; thus, they concluded that lymph node dissection was not necessary in completely resected paratesticular RMS treated with Paratesticular Sites multiagent chemotherapy. Paratesticular RMS represents 7% of all childhood RMS Retroperitoneal lymph node dissection is associated and 12% of childhood scrotal tum0rs.l2~Most paratesticuwith significant long-term complications. Heyn et al.48 lar RMS is embryonal, nonmetastatic, and highly curable found it to be associated with intestinal obstruction, loss with multimodal therapy including surgery, multiagent of ejaculatory function, and lower extremity lymphedema. chemotherapy, and, for patients with retroperitoneal There are risks associated with using the more intensive lymph node involvement or incompletely resected disease, chemotherapy protocol as well. Cyclophosphamide is an radiation therapy.80 N-phosphorylated cyclic derivative of nitrogen mustard. Most tumors present as a painless scrotal mass and are Side effects of cyclophosphamide include immunooften easily resected (group I). Survival rates exceed 90% suppression, pulmonary fibrosis, sterility, and testicular for group I and I1 patients.6o," Lesions adjacent to the atrophy in men."' Present recommendations are that all patients with testis or spermatic cord should be removed by orchiectomy and resection of the entire spermatic cord through paratesticular RMS should have thin-cut abdominal and an inguinal incision with proximal control of the sperpelvic CT scans with double contrast to evaluate for evimatic cord. The contralateral testis may be transposed to dence of nodal involvement. Patients aged 10 years and the adjacent thigh, temporarily, when scrotal radiotherapy older receive ipsilateral retroperitoneal nerve-sparing is required. Open scrotal biopsy or tumor spillage should template node dissection. Patients with group I1 disease receive intensified treatment (e.g.,VAC and retroperitoneal be avoided, because inguinal recurrence may follow; lymph node radiation).lQisease in children younger spillage or open biopsy requires scrotectomy with or withthan 10 years can be staged with abdominal thin-cut (5-mm out radiation. If biopsy is warranted before orchiectomy, slices) CT, reserving ipsilateral node d-issectionfor those the following steps should be followed: (1) achieve atraumatic high control of the spermatic cord; (2) mobilize with positive scans. Patients with group I disease should the testis and cord, carefully isolated from the operative receive VA chemotherapy without radiation. Inguinal field; (3) keep the biopsy site closed and the testes covnodes are rarely involved and are biopsied only if clinically ered while awaiting the frozen section report; (4) change positive or if the scrotum is invaded by tumor. Inguinal gowns and gloves and the instruments that were used for nodes are not considered regional; when they are positive, biopsy; (5) if the biopsy report is positive, remove the this places the patient in stage IV (clinical group IV).

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For tumors of the vagina, vulva, and uterus, the general principles followed in IRS-V include biopsy and staging, followed by chemotherapy as directed by stage and group Vulvovaginal and uterine RMS is the most common (i.e., risk category). Second- and third-look operations malignancy of the pediatric female genital system. This with biopsy a i d dystoscopy are common. Distal vaginal tumor generally presents in the first few years of life with lesions may be polypoid or localized and are amenable to vaginal bleeding, discharge, or a vaginal mass. If the tumor primary resection or delayed resection. Rarely is vaginecarises from the vulva, it consists of a firm nodule embedtomy or hysterectomy indicated, except for recurrent or ded in the labial folds, or it may be periclitoric in location. persistent-viable tumor. Lymph node involvement is very Diagnosis is made with incisional or excisional biopsy. rare. Oophorectomy is not done except for direct involveVaginal lesions generally have embryonal or botryoid with advanced or recurrent disease. ~~~~ embryonal histology and have an excellent p r o g n o ~ i s . ~ ment A primary chemotherapy approach with the gold stanVulvar lesions may have alveolar histology, but because dard of VAC, followed by local resectional therapy and most are localized, they also have a good prognosis. occasional use of radiotherapy when indicated, has proVaginal lesions usually arise from the anterior vaginal duced excellent results.lO Patients aged 1 to 9 years fared wall in the area of the embryonic vesicovaginal septum the best (5-year survival of 98%); patients outside of this (urogenital sinus). The bladder, prostatic utricle, prostate, age range benefited from the intensified therapy used and lower vagina all arise from the urogenital sinus. These in IRS-I11 or -IV (5-year survival of 67% in IRS-I and -11, are common sites for RMS in both sexes. versus 90% in IRS-111 and -IV).l0 Before 1972, pelvic exenteration was the accepted surgical approach for vaginal RMS. Beginning in 1972, the IRS Group began to enter patients in prospective clinical trials. The first eight patients with nonmetastatic vagiTrunk nal RMS underwent primary surgical intervention, Primary RMS of the trunk may occur in paraspinal sites, followed by postoperative chemotherapy with VAC. Three the thoracic or chest wall, the abdominal wall, intrapatients also received radiotherapy. Because vaginal RMS abdominal sites, or the pelvis or retroperitoneum. These appeared to be responsive to chemotherapy, IRS-I1 contumors tend to have a higher incidence of alveolar histolsisted of a primary chemotherapy regimen followed by ogy and a somewhat worse prognosis in some site^.^.^^ delayed surgical intervention with or without radiation. These lesions present differently, depending on site, and Fourteen of 20 patients (70%) eventually underwent surare discussed separately. gical resection." During IRS-111, these patients were given primary chemotherapy consisting of VAC plus doxorubicin and Paraspinal Sites cisplatin after initial biopsy (clinical group 111). Only 7 Paraspinal RMS presents as an enlarging mass in the of 23 patients (30%) underwent surgical resection after paravertebral muscle area. This is usually diagnosed by primary chemotherapy. Six of the seven patients had no incisional biopsy and must be distinguished from viable tumor in the resected specimen, and one had extraosseous Ewing's sarcoma, which is more common in maturing rhabdomyoblasts. The presence of rhabdomythis site in our experience. For all truncal tumors, the oblasts may not signify persistent active disease.4Wt M. D. biopsy should be performed in the long axis of the tumor Anderson Cancer Center, we continued chemotherapy (i.e., parallel to the ribs), to allow for wide local excision without resection when rhabdomyoblasts were found. No and rib resection as necessary. viable tumor or rhabdomyoblastswere found after further Most patients with paraspinal lesions require chemotherchemotherapy or subsequent biopsy in these patients. apy before resection, and many require postoperative Only six patients in IRSIII underwent radiotherapy." radiation therapy. Wide local excision is frequently done During IRS-IV, only 3 of 21 patients (14%) underwent in conjunction with a plastic surgeon, who can assist in surgical resection after primary chemotherapy. Three flap closure of the defect. In small children, it may be wise patients had only rhabdomyoblasts, and one patient who to eliminate radiation therapy close to the spine whenever underwent early second-look surgery had rhabdomyoblasts feasible. and a small amount of viable tumor. No patient in IRS-IV had a cystectomy, and all but one patient are still alive with no evidence of disease. Abdominal WaN Early IRS Group studies suggested that patients with This location is relatively rare (
Vulva, Vagina, and Uterus

CHAPTER

and -111, only 105 had primary tumors of the chest wall, pleura, lung, or heart. It has been suggested that these sites have a poor prognosis owing to histology, advanced stage at presentation, and difficulty of local resection. Early studies showed high rates of local and distant relapse." A review of IRS-I1 and -1118 included 84 patients with thoracic sarcomas: 76 chest wall tumors, 3 lung tumors, 4 pleural tumors, and 1 that arose from the heart. Sixty patients (71%) achieved a complete response. Thirty-nine patients had a local relapse, and 22 patients had a distant relapse. Forty-two percent of patients survived. Progression-free survival was not significantly associated with histology, site, clinical group, or IRS number. Overall survival was significantly associated with clinical group, size, and local or distant recurrence but not histology or IRS number by univariate analysis. In a multivariate analysis, only clinical group and local and distant recurrence showed statistical significance. Thus, if survival is to be improved, local tumor control with negative margins must be achieved. Clinical group I1 patients were treated with radiation therapy and had a better survival rate than did those in clinical group I (totally resected and thus no radiation therapy), indicating that the resection may have left microscopic or even gross residual disease. Either second-look surgery or consideration of local radiation therapy for possible residual disease in clinical group I may be indicated to improve survival." Specific surgical management of chest wall RMS includes initial biopsy (longitudinal to ribs) and staging. Following neoadjuvant chemotherapy, the tumor is resected to clear margins, and attached pleura or lung is removed as necessary. If needed, wide local resection can be followed by chest wall reconstruction, usually with a synthetic material covered by a myocutaneous flap. Frequently, tumor size reduction allows resection with primary closure.

Retroperitoneal and Pelvic Sites RMS of the retroperitoneum and pelvis usually presents as a large, bulky tumor whose exact site of origin is difficult to determine.'Vrequently, these tumors invade or involve vital organs or vessels; thus, only biopsy can be performed at the initial exploration. Early IRS Group studies indicated a poor prognosis for these sites.2" Blakely et al.14 reported on 94 patients with group 111 disease from IRS-111 and IRS-IV Pilot and found a 57% FFS rate at 4 years. They found that age younger than 10 years at diagnosis and embryonal histology were favorable -prognostic factors, as was the performance of a debulking procedure before instituting chemotherapy and radiation therapy.14 Recently Raney et al.gQeported on the results of 56 patients with localized retroperitoneal and pelvic RMS. Fifty-four of these patients had gross residual disease (clinical group 111) a t the completion of the initial diagnostic procedure. Two patients underwent grossly complete surgical excision with microscopic involved marginswithout Tgroup IIa) or with (group Cc) tumor-involved regional lymph nodes that were removed before beginning chemotherapy. Only 15 patients (27%) had 50% or more of the tumor removed before

32

Rhabdotnyosarcoma

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beginning chemotherapy and were classified as debulked; the other 41 patients were classified as having biopsy only. Among the 15 patients who underwent debulking of the tumor before chemotherapy or radiotherapy, there have been no treatment failures thus far. In contrast, 15 of the 41 patients who underwent biopsy only developed recurrent sarcoma. Thus, it appears that debulking may be of value when it can be achieved safely and with minimum morbidity. Otherwise, an alternative would be delayed primary excision after shrinkage with chemotherapy.

Biliary Sites Patients with biliary RMS do relatively well with chemotherapy and radiotherapy without aggressive surgiMost patients have the botryoid variant cal rese~tion.8~3104 of embryonal RMS, which responds well to chemotherapy. Although these tumors present with significant obstructive jaundice, biopsy followed by neoadjuvant chemotherapy commonly reduces the jaundice without the need for resection or internal or external biliary drainage. Surgical resection or bypass involves significant complications. Spunt et al.104 reported on 25 patients treated in IRS-I through -IV and found that total resection was rarely possible, external biliary drains were frequently associated with infection, and tumors responded well to combination chemotherapy without aggressive surgical intervention.

Perineal and Perianal Sites RMS of the perineum or anus is a rare sarcoma of childhood with a relatively poor prognosis. Blakely et al.I5 reported on 71 patients treated in IRS-I through -IV. The majority (64%) were at an advanced stage (clinical groups I11 and IV) at initial presentation, and 50% had positive regional lymph node involvement. The 5-year FFS for all patients was 45%, and the overall survival rate was 49%. Characteristics that were associated with significantly improved survival were primary tumor size less than 5 cm, lower (less advanced) clinical group and stage, negative lymph node status, and age younger than 10 years. When the extent of disease was controlled for multivariate analysis, only age younger than 10 years predicted an improved outcome. The 5-year overall survival rate for patients younger than 10 years was 71%, versus 20% for older patients (P < 0.001). Because of the high incidence of regional lymph node involvement, biopsy of clinically suspicious nodes should be done, and sentinel lymph node mapping for nonclinically suspicious nodes should be entertained.

Extremities Primary tumors of the extremity accounted for 19%of RMS in IRS-1117 and 20% in IRS-IV.74 Despite the intensive efforts of the IRS Group, the outcome of extremity RMS remains suboptimal compared with that of RMS in

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MAJORT ~ J M OOF RS CHII.DI~OOD

other sites. Improvements in survival have been seen with subsequent studies, but estimated 5-year survival is about 74% for patients without distant metastatic d i ~ e a s e . ~ Analysis of these studies suggests that the improvement is attributable to the intensification of therapy for patients with a poorer prognosis, while allowing a decrease in therapy for those with a good prognosis. Various prognostic factors have been suggested for extremity RMS in children. The elements of the Lawrence-GehanMstaging system used in IRS-IV are local tissue invasiveness, tumor size, presence of nodal and distant metastases, and site. BecaGse the extremities are relativelv unfavorable sites, no extremity tumors are classified as stage I by this system. A total of 139 patients were entered in IRS-IV with extremity RMS and were assigned a preoperative stage and a clinical group, as follows: stage I1 ( n = 34), stage 111 ( n = 73), stage IV ( n = 32); group I ( n = 31), group I1 ( n = 21), group I11 ( n = 54); group IV ( n = 33). Three-year FFS was 55%, and the overall survival rate was 70%. FFS was significantly worse for patients with advanced disease. Totally resected patients (group I) had a 3-year FFS of 91%.74 Initial treatment consists of biopsy, either incisional or excisional. This should be done in a longitudinal or axial direction to allow for wide local excision. If wide local excision can be accomplished without mutilation, this should be considered. The standard 2-cm margins are arbitrary and are not practical in children. There is little evidence that a clear margin of only a few millimeters involves a higher risk for r&urrence than do larger margins. Amputation is rarely indicated except for larger recurrent or persistent disease. Excision of the entire muscle from origin to insertion, as recommended in the past, is not necessary. The importance of complete resectibn is emphasized, because survival is markedly improved with total excision or microscopic residual only. Careful determination of margin status is extremely important, and reresection at initial or subsequent operation is warranted. Hays et a1.4Wemonstratedthat patients with node-negative extremity and trunk sarcomas who underwent re-excision for micrbscooic residual tumor had a survival rate that was significantly higher than those who did not have reexcision or were reported to have no residual tumor after initial resection. It is our policy to recommend re-excision for all patients referred i o our institution after previous resection, no matter what was previously reported. We have found residual and even gross disease in patients reported to have complete resection (probably because the surgeon was unaware that cancer was present). Lymph node involvement with extremity RMS in IRSI and -11 was only 12%,537,5"57 because few patients actually had lymph node biopsy. LaQuaglia et al." reported 40% incidence of positive nodes. In a review of IRS-IV, Andrassy et al.7 demonstrated that 39% of patients who underwent evaluation of their lymph nodes had histologic confirmation of disease. ~ e v i l l eet a1.,74 in a review of IRS-IV data, found that 50% of biopsied lymph nodes contained disease. Of the patients whose lymph nodes were clinically negative but were biopsied anyway, 17%were found to have microscopic disease. The finding of histologically positive lymph nodes is a statistically significant predictor of FFS. Although lymph node dissection has

a

not improved the survival rate, positive regional nodes should be irradiated to prevent local recurrence. We have used and recommended lymphatic mapping with sentinel node biopsy to evaluate the regional nodes.7K.74 If sentinel lymph node mapping is not available, aggressive sampling is warranted.

COMPLICATIONS Complications of treatment for RMS are varied and extensive. These include chemotherapy toxicity and death, radiation-related acute and long-term complications, and the standard surgical complications of biopsy and resection. Discussion of the specific complications and their treatment is beyond the scope of this chapter. Long-term follow-up of all patients is warranted for delayed complications and second m a l i g n a n c i e ~ . ~ ~

TREATMENT OF METASTATIC DISEASE Metastatic disease most commonly involves the lung (58%), bone (33%), regional lymph nodes (33%), liver (22%), and brain (20%).21 Of the patients enrolled in IRS-111,'" 14% were clinical group IV at the time of diagnosis. Primary sites more likely to have metastases include the extremities (23%), parameningeal sites (13%), and retroperitoneal, trunk, gastrointestinal, and intrathoracic sites. Primarv sites with a low incidence of metastases include the orbit (1.8%), nonparameningeal or nonorbital head and neck (4.5%), and genitourinary sites.g7 Metastatic disease is the single most important predictor of clinical outcome in patients with RMS. The 3-year FFS As menis only 25% in patients with metastatic di~ease.2"7~) tioned previously, regional node metastases vary with the site of the primary tumor (highest in the extremities) and also affect survival. The lung is the most common site of metastatic disease. Patients with only lung metastases appear to have a somewhat better prognosis than do those with metastases in multiple sites or metastases to bone or liver.9"atients with only lung metastases also have a greater incidence of favorable histology and a smaller number of extremity primary tumors." Because RMS is highly chemosensitiv6, resection of numerous metastases is not indicated. In our experience, an isolated single metastasis to the lung has a better prognosis than do multiple metastases. For this reason, it is worthwhile to biopsy a single metastasis to confirm histology. The better prognosis may well be related to the treatment of nonmetastatic lung lesions other than RMS. Persistent or recurrent diseaseafter chemotherapy may warrant resection both for diagnosis and possibly to decrease the tumor burden. Overall, there has been little improvement in the survival of patients with metastatic diskase. They are presently categohzed in stage IV, group IV and are considered high risk. Aggressive chemotherapy and radiation in an attempt to improve survival is being studied. During IRS-IV, 127 eligible patients were treated for metastatic disease with one of two regimens that incorporated a window of either ifosfamide and etoposide with vincristine, dactinomycin,

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Rhabdornyosarcoma

537

10. Arndt CA, et al: What constitutes optimal therapy for patients with rhabdornyosarcoma of the female genital tract? Cancer 2001;91:2454. 11. Asmar L, et al: Agreement among and within groups of pathologists in the classification of rhabdornyosarcoma and related childhood sarcomas: Report of an international study of four pathology classifications. Cancer 1994;74:2579. 12. Beech TR, et al: What comprises appropriate therapy for children/adolescents with rhabdomyosarcoma arising in the abdominal wall? A report from the Intergroup Rhabdornyosarcoma Study Group.J Pediatr Surg 1999;34:668. OUTCOME 13. Birch JM, et al: Excess risk of breast cancer in the mothers of children with soft tissue sarcomas. Br J Cancer 1984; The overall trend has been an increase in survival for each 49:325. subsequent IRS Group study. The survival rate depends 14. Blakely ML, et al: Does debulking improve survival rate in on clinical group, stage, and primary site. The overall advanced-stage retroperitoneal embryonal rhabdomyosar5-year survival rate in IRS-I11was 71%; it was 90% for clincoma? J Pediatr Surg 1999;5:736. ical group I, 80% for clinical group 11, 70% for clinical 15. Blakely ML, et al: Prognostic factors and surgical treatment group 111, and 30% for clinical group IV. The survival guidelines for children with rhabdornyosarcoma of the perrate by pretreatment staging classification was 80% for ineum or anus: A report of Intergroup Rhabdomyosarcoma stage I, 68% for stage 11, 49% for stage 111, and 21% for Studies I through IV, 1972 through 1997. J Pediatr Surg stage IV.lZ4 2003;38:347. 16. Breneman JC, et al: The management of pediatric geniOverall, FFS rates for the patients treated in IRS-IV did tourinary rhabdornyosarcoma. In Vogelzang NJ, et al (eds): not differ from those of similar patients treated in IRSIII; The Comprehensive Textbook of Genitourinary Oncology. the estimated 3-year FFS rate was 76% in IRS-111 and 77% Baltimore, Williams & Wilkins, 1996. in IRS-IV. Three-year FFS rates were improved for patients 17. BrenemanJC, et al: Prognostic factors and clinical outcomes with embryonal RMS treated in IRS-IV compared with in children and adolescents with metastatic rhabdomyosarIRSIII (83% versus 74%). The improvement seemed to be coma: A report from the Intergroup Rhabdomyosarcoma restricted to patients with stage I1 or stage 11-111, group 1-11 Study rV.J Clin Oncol2003;21:78. embryonal RMS. The sites of treatment failure were local 18. Burger RA, et al: Extent of surgery in rhabdornyosarcoma in 93 patients (51%),regional in 30 (17%),and distant in of urogenital structures. Eur Urol 1989;16:114. 58 (32%).Salvage therapy after relapse differed by group. 19. Cavazzana AO, et al: Spindle cell rhabdornyosarcoma. Am J Surg Path01 1992;16:229. Forty-one percent of patients with group 1-11 tumors were 20. Coene IMJH, et al: Rhabdornyosarcoma of the head and alive 3 years after relapse, compared with 22% of those with neck in children. Clin Otolaryngol 1992;17:291. group 111 tum0rs.2~ 21. Cofer BR, et al: Rhabdomyosarcoma. In Andrassy RI (ed): Pediatric Surgical oncology. Philadelphia, WB ~aunders, 1998. REFERENCES 22. Corpron CA, et al: Conservative management of uterine pediatric rhabdornyosarcoma: A report from the Intergroup 1. Abramson DH, et al: The treatment of orbital rhabdomyosarRhabdomyosarcoma Study I11 and IV Pilot. J Pediatr Surg coma with irradiation and chemotherapy. ~ ~ h t h a l m b l o g y 1995;30:942. 1979;86:1330. 23. Crist WM, et al: Soft tissue sarcomas arising in the retroperi2. Anderson GJ, et al: Rhabdornyosarcoma of the head and toneal space in children: A report from the Intergroup neck in children. Arch Otolaryngol Head Neck Surg 1990; Rhabdomyosarcoma Study. Cancer 1985;56:2125. 116:428. 24. Crist WM, et a1 (for the IRS Committee): Prognosis in chil3. Anderson JR, et al: Improved outcome for patients with embrydren with rhabdornyosarcoma: A report of IRS-I and IRS-11. onal histology but not alveolar histology rhabdomyosarcoma: J Clin Oncol 1990;8:443. Results from Intergroup Rhabdornyosarcoma Study IV 25. Crist WM, et al: Intergroup Rhabdornyosarcoma Study (IRS-IV). Proc Soc Clin Oncol 1998;17:526a. (IRS) 111.J Clin Oncol 1995;13:610. 4. Andrassy RJ: Rhabdornyosarcoma. Semin Pediatr Surg 26. Crist WM, et al: Preliminary results for patients with local/ 1997;6:17. regional tumors treated on the Intergroup Rhabdomyosar5. Andrassy RJ: Advances in the surgical management of sarcocoma Study-IV (1991-1997). Proc Am Soc Clin Oncol 1999; mas in children. Am J Surg 2002;184:484. 18:18. 6. Andrassy RJ, et al: Conservative surgical management of 27. Crist WM, et al: Intergroup Rhabdornyosarcoma Study-IV: vaginal and vulvar pediatric rhabdomyosarcoma: A report Results for patients with nonmetastatic disease.J Clin Oncol from the Intergroup Rhabdornyosarcoma Study-111. J Pediatr 2001;19:3091. Surg 1995;30:1034. 28. Dagher R, et al: Rhabdomyosarcoma: An overview. 7. Andrassy RJ, et al: Extremity sarcomas: An analysis of progOncologist 1999;4:34. nostic factors from the Intergroup Rhabdornyosarcoma 29. Donaldson S, et al: Hyperfractionated radiation in children Study (IRS) 111.J Pediatr Surg 1996;31:191. with rhabdomyosarcoma: Results of an Intergroup 8. Andrassy RJ, et al: Thoracic sarcomas in children. Ann Surg Rhabdornyosarcoma Pilot Study. Int J Radiat Oncol Biol 1998;227:170. Phys 1995;32:903. 9. Andrassy RJ, et al: Progress in the surgical management of 30. Donaldson SS, et al: Results from the Intergroup vaginal rhabdornyosarcoma: A 25-year review from the Rhabdornyosarcoma Study-IV randomized trial of hyperIntergroup Rhabdomyosarcoma Study Group. J Pediatr Surg fractionated radiation in children with rhabdomyosar1999;34:731. coma. Int J Radiat Oncol Biol Phys 2000;48:178.

and cyclophosphamide or vincristine, melphalan, and VAC. The estimated overall survival and FFS was 39% and 25%, respectively, at 3 years. Overall survival at 3 years was influenced by histology (47% for embryonal versus 34% for all others) and number of metastatic sites. By multivariate analysis, the presence of two or fewer metastatic sites was the only significant predictor.17

538

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31. Ferracini R, et al: Retrogenic expression of the MET protooncogene correlates with the in;asive phenotype of human rhabdomyosarcomas. Oncogene 1996;12:1697. 32. Fiorillo A, et al: Multidisciplinary treatment of primary orbital rhabdornyosarcoma: A single institution experience. Cancer 1991;67:560. 33. Frascella E, et al: Response of previously untreated metastatic rhabdomyosarcoma to combination chemotherapy with carboplatin, epirubicin, and vincristine. Eur J Cancer 1996;32A:821. 34. Furman W, et al: A phase I study of irinotecan (CPT-11) in children with relapsed solid tumors. Proc Am Soc Clin Oncol 1998;17:187a. 35. Gasparini M, et al: Questionable role of CNS radioprophylaxis in the therapeutic management of childhood rhabdomyosarcoma with meningeal extension. J Clin Oncol 1990;8:1854. 36. Gilles R, et al: Head and neck rhabdomyosarcomas in children: Value of clinical and CT findings in the detection of local regional relapses. Clin Radiol 1994;49:412. 37. Goldfarb B, et al: The role of retroperitoneal lymphadenectomy in localized paratesticular rhabdomyosarcoma. J Urol 1994;152:785. 38. Gross M, et al: Therapy of rhabdomyosarcoma of the larynx. Int J Pediatr Otorhinolaryngol 1988;15:93. 39. Grufferman A, et al: In utero x-ray exposure and risk of childhood rhabdomyosarcoma. paper-presented at the Fourth Annual Meeting of the Society for Epidemiologic Research, June 11, 1991, Buffalo, NY. 40. Grufferman S, et al: Parents' use of recreational drugs and risk of rhabdomyosarcoma in their children. Cancer Causes Control 1993;4:217. 41. Hamilton CR, et al: The management of paratesticular rhabdornyosarcoma. Clin Radiol 1989;40:314. 42. Hartley AN, et al: Patterns of cancer in the families of children with soft tissue sarcoma. Cancer 1993;72:923. 43. Hays DM, et al: Primary re-excision for patients with "microscopic residual" following initial excision of sarcomas of trunk and extremity sites. J Pediatr Surg 1989;24:5. 44. Hays DM, et al: Partial cystectomy in the management of rhabdomyosarcoma of the bladder: A report from the Intergroup Rhabdornyosarcoma Study. J Pediatr Surg 1990;25:719. 45. Hays DM, et al: Retention of functional bladders among patients with vesicle/prostatic sarcomas in the Intergroup Rhabdomyosarcoma Studies (IRS) (1978-1990) [abstract]. Med Pediatr Oncol 1991;19:423. 46. Hays DM, et al: Children with vesical rhabdomyosarcoma (RMS) treated by partial cystectomy, with neoadjuvant or adjuvant chemotherapy with or without radiotherapy. J Pediatr Hematol Oncol 1995;17:46. 47. Healy GB, et al: The role of surgery in rhabdomyosarcoma of the head and neck in children. Arch Otolaryngol Head Neck Surg 1991;117:1185. 48. Heyn R, et a1 (for the IRS Committee): Late effects of therapy in patients with paratesticular rhabdomyosarcoma. J Clin Oncol 1992;10:614. 49. Heyn R, et al: Preservation of the bladder in patients with rhabdornyosarcoma. J Clin Oncol 1997;15:69. 50. Horn RC, et al: Rhabdomyosarcoma: A clinicopathological study and classification of 39 cases. Cancer 1958;ll:181. 51. Horowitz ME, et al: Total-body irradiation and autologous bone marrow transplant in the treatment of high-risk Ewing's sarcoma and rhabdomyosarcoma.J Clin Oncol 1993;11:1911. 52. Kao GD, et al: The sequelae of chemoradiation therapy for head and neck cancer in children: Managing impaired growth, development and other side effects. Med Pediatr Oncol 1993;21:60.

53. Kilpatrick SE, et al: Relationship of DNA ploidy to histology and prognosis in rhabdomyosarcoma. Cancer 1994; 74:3227. 54. Koscielniak E, et al: Do patients with metastatic and recurrent rhabdomyosarcoma benefit from high-dose therapy with hematopoietic rescue? Report of the German/Austrian Pediatric Bone Marrow Transplantation Group. Bone Marrow Transplant 1997;19:227. 55. LaQuaglia MP, et al: Factors predictive of mortality in pediatric extremity rhabdomysarcoma. J Pediatr Surg 1990; 25:238. 56. Lawrence W Jr, et al: Lymphatic metastasis with childhood rhabdornyosarcoma. Cancer 1987;60:910. 57. Lawrence W Jr, et al: Surgical lessons from the Intergroup Rhabdomyosarcoma Study (IRS) pertaining to extremity tumors. World J Surg 1988;12:676. 58. Lawrence W Jr, et al: Pretreatment TNM staging of childhood rhabdomyosarcoma: A report of the Intergroup Rhabdornyosarcoma Study Group, Children's Cancer Study Group, Pediatric Oncology Group. Cancer 1997;80:1165. 59. Leader M, et al: Myoglobin: An evaluation of its role as a marker of rhabdomyosarcomas. Br J Cancer 1989;59:106. 60. Leuschner I, et al: Spindle cell variants of embryonal rhabdomyosarcoma in the paratesticular region: A report of the Inergroup Rhabdomyosarcoma Study. Am J Sur Pathol 1993;17:221. 61. Li FP, et al: Soft tissue sarcomas, breast cancer and other neoplasms: A familial syndrome? Ann Intern Med 1969; 71:747. 62. Li FP, et al: A cancer family syndrome in twenty-four kindreds. Cancer Res 1988;48:5358. 63. Li M, et al: Molecular genetics of Beckwith-Wiedemann syndrome. Curr Opin Pediatr 1997;9:623. 64. Lobe TE, et al: Neonatal rhabdomyosarcoma: The IRS experience. J Pediatr Surg 1994;29:1167. 65. Lobe TE, et al: The argument for conservative, delayed surgery in the management of prostatic rhabdomyosarcoma. J Pediatr Surg 1996;31:1084. 66. Malkin D, et al: Germ line p53 mutations in a familial syndrome of breast cancer, sarcomas, and other neoplasms. Science 1990;250:1233. 67. Mandell LR, et al: The influence of extensive bone erosion on local control in non-orbital rhabdomyosarcoma of the head and neck. Int J Radiat Oncol Biol Phys 1989;17:649. 68. Mandell LR, et al: Prognostic significance of regional lymph node involvement in childhood extremity rhabdomyosarcoma. Med Pediatr Oncol 1990;18:466. 69. Maurer HM, et al: The Intergroup Rhabdomyosarcoma Study-I: A final report. Cancer 1988;61:209. 70. Maurer HM, et al: The Intergroup Rhabdomyosarcoma Study-11. Cancer 1993;71:1904. 71. Miser JS, et al: Ifosfamide with mesna uroprotection and etoposide: An effective regimen in the treatment of recurrent sarcomas and other tumors of children and young adults. J Clin Oncol 1987;5:1191. 72. Morison IM, et al: Insulin-like growth factor 2 and overgrowth: Molecular biology and clinical implications. Mol Med Today 1998;4:110. 73. Neville HL, et al: Lymphatic mapping with sentinel node biopsy in pediatric patients. J Pediatr Surg 2000;35:961. 74. Neville HL, et al: Preoperative staging, prognostic factors, A prelimiand outcome for extremity rhabd~m~osa'rcoma: nary report from the Intergroup Rhabdornyosarcoma Study IV (1991-1997).J Pediatr Surg 2000;35:317. 75. Newton WA, et al: Pathology of rhabdomyosarcoma and related tumors. In Maurer HM, Ruyman FB, Pochedly C (eds): Rhabdomyosarcoma and Related Tumors in Children and Adolescents. Boca Raton, Fla, CRC Press, 1991.

CHAPTER

76. Newton WA, et al: Classification of rhabdomyosarcomas and related sarcomas: Pathologic aspects and proposal for a new classification. An Intergroup Rhabdomyosarcoma Study. Cancer 1995;76:1073. 77. Olive D, et al: Paraaortic lymphadenectomy is not necessary in the treatment of localized paratesticular rhabdomyosarcoma. Cancer 1984;54:1283. 78. Ortega JA: A therapeutic approach to childhood pelvic rhabdomyosarcoma without pelvic exenteration. J Pediatr Surg 1979;94:205. 79. Pack GT, et al: Rhabdomyosarcoma of the skeletal muscle: Report of 100 cases. Surgery 1952;32:1023. 80. Pappo AS, et al: Biology and therapy of pediatric rhabdomyosarcoma. J Clin Oncol 1995;13:2123. 81. Pappo AS, et al: A phase I1 trial of high-dose methotrexate in previously untreated children and adolescents with high-risk unresectable or metastatic rhabdomyosarcoma. J Pediatr Hematol Oncol 1997;19:438. 82. Pappo AS, et al: Up-front window trial of topotecan in previously untreated children and adolescents with metastatic rhabdornyosarcoma: An Intergroup Rhabdomyosarcoma Study (IRSG).J Clin Oncol 2001 ;19:213. 83. Pinkel D, et al: Rhabdomyosarcoma in children. JAMA 1961;175:293. 84. Pollono DG, et al: Rhabdomyosarcoma of extrahepatic biliary tree: Initial treatment with chemotherapy and conservative surgery. Med Pediatr Oncol 1998;30:290. 85. Raney RB Jr: Rhabdomyosarcoma and related tumors of the head and neck in childhood. In Maurer HM, Ruymann FB, Pochedly C (eds): Rhabdomyosarcoma and Related Tumors in Children and Adolescents. Boca Raton, Fla, CRC Press, 1991. 86. Raney RB Jr, et al: Paratesticular rhabdomyosarcoma in children. Cancer 1978;42:729. 87. Raney RB Jr, et a1 (for the IRS Committee): Primary chemotherapy with or without radiation therapy and/or surgery for children with localized sarcoma of the bladder, prostate, vagina, uterus and cervix: A comparison of the results in Intergroup Rhabdomyosarcoma Studies I and 11. Cancer 1980;66:2072. 88. Raney RB Jr, et a1 (for the IRS Committee): Soft-tissue sarcoma of the trunk in childhood: Results of the Intergroup Rhabdomyosarcoma Study (IRS), 1972-1976. Cancer 1982;49:2612. 89. Raney RB Jr, et al: Improved prognosis with intensive treatment of children with cranial soft tissue sarcomas arising in nonorbital parameningeal sites: A report from the Intergroup Rhabdomyosarcoma Study. Cancer 1987;59:147. 90. Raney RB Jr, et al: Sequelae of treatment in 109 patients followed from five to fifteen years after diagnosis of sarcoma of the bladder and prostate: A report from the Intergroup Rhabdomyosarcoma Study (IRS) Committee. Cancer 1993; 71:2387. 91. Raney RB Jr, et al: Results of treating localized cranial parameningeal sarcoma on Intergroup Rhabdomyosarcoma (RMS) Studies (1RS)-I1 through IV. Med Pediatric Oncol 2000;35:178. 92. Raney RB Jr, et al: The Intergroup Rhabdomyosarcoma Study Group (IRSG): Major lessons from the IRS-I through IRSIV studies as background for the current IRSIV treatment protocols. Sarcoma 2001;5:9. 93. Raney RB Jr, et al: Results of treatment of 56 patients with localized retroperitoneal and pelvic rhabdomyosarcoma: A report from the Intergroup Rhabdomyosarcoma Study-IV, 1991-1997. Pediatr Blood Cancer 2004;42:618. 94. Rich DC, et al: Second malignant neoplasms in children after treatment of soft tissue sarcoma. J Pediatr Surg 1997; 32:369.

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95. Rodeberg DA, et al: Surgical principles for children/ adolescents with newly diagnosed rhabdomyosarcoma: A report from the Soft Tissue Sarcoma Committee of the Children's Oncology Group. Sarcoma 2002;6:111. 96. Rodeberg DA, et al: Characteristics and outcomes of rhabdomyosarcoma patients with isolated lung metastases from IRSIV. J Pediatr Surg 2005;40:256. 97. Ruymann FB: Rhabdomyosarcoma in children and adolescents: A review. Hematol Oncol Clin North Am 1987;1:621. 98. Ruymann FB, et al: Congenital anomalies associated with rhabdomyosarcoma: A report from the Intergroup Rhabdomyosarcoam Study. Med Pediatr Oncol 1988;16:13. 99. Ruymann FB, et al: Epidemiology of soft tissue sarcomas. In Maurer HM, Ruymann FB, Pochedly C (eds): Rhabdomyosarcoma and Related Tumors in Children and Adolescents. Boca Raton, Fla, CRC Press, 1991. 100. Ruymann FB, et al: Comparison of two double chemotherapy regimens and conventional radiotherapy in metastatic rhabdomyosarcoma: Improved overall survival using ifosfamide/etoposide compared to vincristine/ melphalan in IRSGIV. Proc Am Soc Clin Oncol 1997; 16:521a. 101. Seymour-Dempsey K, et al: Neurofibromatosis: Implications for the general surgeon. J Am Coll Surg 2002;195:553. 102. Shapiro DN, et al: Relationship of tumor-cell ploidy to histologic subtype and treatment of outcome in children and adolescents with unresectable rhabdomyosarcoma. J Clin Oncol 1991;9:159. 103. Smith LM, et al: Which patients with rhabdomyosarcoma (RMS) and microscopic residual tumor (group 11) fail therapy? A report from the Intergroup Rhabdomyosarcoma Study Group (IRSG). Proc Am Soc Clin Oncol 2000; 19:577a. 104. Spunt SL, et al: Aggressive surgery is unwarranted for biliary tract rhabdomyosarcoma. J Pediatr Surg 2000;35:309. 105. Stobbe GC, et al: Embryonal rhabdomyosarcoma of the head and neck in children and adolescents. Cancer 1950; 3:826. 106. Stout AP: Rhabdomyosarcoma of the skeletal muscle. Ann Surg 1946;123:447. 107. Strong LC, et al: The Li-Fraumeni syndrome: From clinical epidemiology to molecular genetics. Am J Epidemiol 1992;135:190. 108. Tapscott SJ, et al: Deficiency in rhabdomyosarcomas of a factor required for MyoD activity and myogenesis. Science 1993;259:1450. 109. Tefft M, et al: Radiation therapy combined with systemic chemotherapy of rhabdomyosarcoma in children: Local control in patients enrolled into the Intergroup Rhabdomyosarcoma Study. Natl Cancer Inst Monogr 1981;56:75. 110. Turc C: Consistent chromosomal translocation in alveolar rhabdomyosarcoma. Cancer Genet Cytogenet 1986;19:361. 111. Vietti T, et al: Topotecan window in patients with rhabdomyosarcoma (RMS): An IRSG study. Proc Am Soc Clin Oncol 1997;16:510a. 112. Weintraub H, et al: The MyoD gene family: Nodal point during specification of the muscle cell lineage. Science 1991;251:761. 113. Wexler LH, et al: Pediatric soft tissue sarcomas. CA Cancer J Clin 44:211,1994. 114. Wharam M, et al: Management of drbital rhabdomyosarcoma. In Jacob C (ed): Cancers of the Head and Neck, Boston, Martinus Niijhoff, 1987. 115. Wiener ES: Rhabdomyosarcoma: New dimensions in management. Semin Pediatr Surg 1993;2:47. 116. Wiener ES: Head and neck rhabdomyosarcoma. Semin Pediatr Surg 1994;3:203.

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117. Wiener ES, et a1 (for the IRS Committee of CCSG, POG, UKCCSG): Second look operations in children in group 111 and IV rhabdomyosarcoma (RMS). SIOP XXII Meeting, October, 1990, Rome. Med Pediatr Oncol 1990;18:408. 118. Wiener ES, et a1 (for the IRS Committee of CCSG and POG): Complete response or not complete response? Second look operations are the answer in children with rhabdomyosarcoma. ASCO Annual Meeting, May 19-21, 1991, Houston, Texas Proc Am Soc Clin Oncol 1991;10:316. 119. Wiener ES, et al: Rhabdomyosarcoma in extremity and trunk sites. In Maurer HM, Ruymann FB, Pochedly C (eds): Rhabdomyosarcoma and Related Tumors in Children and Adolescents. Boca Raton, Fla, CRC Press, 1991. 120. Wiener ES, et al: Retroperitoneal node biopsy in paratesticular rhabdomyosarcoma. J Pediatr Surg 1994;29:171.

121. Wiener ES, et al: Controversies in the management of paratesticular rhabdomyosarcoma: Is staging retroperitoneal lymph node dissection necessary for adolescents with resected paratesticular rhabdomyosarcoma? Semin Pediatr Surg 2001;10:146. 122. Wiener ES, et al: What is optimal management for children or adolescents with localized paratesticular rhabdomyosarcoma? Results in IRSIII and I R W . J Pediatr Surg (in press). 123. Wolden SL, et al: Indications for radiotherapy and chemotherapy after complete resection in rhabdomyosarcoma: A report from the Intergroup Rhabdomyosarcoma Studies (IRS) I to 111.J Clin Oncol 1999;17:3468. 124. Young JL, et al: Cancer incidence, survival, and mortality for children younger than 15 years. Cancer 1986;58:598.

Other Soft Tissue Tumors Thorn E. Lobe

Soft tissue tumors, primarily sarcomas, are a complex group of childhood malignancies of varied histologic subtypes. The prognosis depends on the histology, age, site, extent of involvement, and a variety of other factors. This chapter focuses on those tumors classified as nonrhabdomyosarcoma soft tissue sarcomas and other soft tissue tumors of childhood. The discussion focuses on three areas: ( 1 ) classification and nomenclature, (2) current multimodal therapy, and (3) the surgical approach to problematic tumor types and sites. Soft tissue tumors in children constitute a diverse group of pathologic entities whose phenotypic variations parallel the multipotential nature of mesenchymal tissues. As noted in Table 33-1 ,sQhe phenotypic diversity is expressed by benign and malignant variants of each cell type. However, the terms benign and malignant do not necessarily match the potential clinical aggressiveness of these tumors. Some tumors in the benign group can be

easily treated by simple excision, such as hemangioma; others can recur and require extensive resection, such as desmoid-type fibromatosis. Similarly, the malignant group includes low-grade sarcomas, such as infantile fibrosarcoma, that have little propensity for metastasis, as well as high-grade sarcomas that often present with disseminated bone marrow disease. Some of these tumors are better considered reactive rather than neoplastic in nature; examples include nodular fasciitis and inflammatory myofibroblastic tumor. Pediatric sarcomas show striking differences in incidence compared with their adult counterparts. A prime example is malignant fibrous histiocytoma, which is often the most common sarcoma in adult series but is rare in children. Only the angiomatoid variant, a low-grade lesion of borderline malignant behavior, occurs with sufficient frequency to be seen by most pediatric pathologists. Similar differences in frequency exist for liposarcoma

Tissue Type

Benign

Sarcomatous

Fat Blood and lymphatic vessels

Lipoblastoma (relatively common) Hemangioma, lymphangioma, and variants (very common) Post-traumatic scar (common); fibromatosis and variants (common); nodular fasciitis (relatively common) Fibrous histiocytoma and variants (common) Rhabdomyoma (rare) Leiomyoma (rare) Neurofibroma (relatively common); neurilemmoma (relatively uncommon)

Liposarcoma (rare) Angiosarcoma (rare); hemangiopericytoma, infantile and adult variants (relatively rare) Fibrosarcoma, infantile and adult type (relatively rare)

Fibrous

Fibrohistiocytic Skeletal muscle Smooth muscle Peripheral nervous tissue

Osseous Chondrocytic

Pigmented villonodular synovitis and related lesions (relatively rare) Myositis ossificans (relatively common) Chondromas of soft tissue (rare)

Epithelial Melanocytic Myofibroblastic

? ? Inflammatory myofibroblastic tumor (relatively rare)

Malignant fibrous histiocytoma (rare) Rhabdomyosarcoma (common) Leiomyosarcoma (rare) Malignant peripheral nerve sheath tumors and variants; peripheral primitive neuroectodermal tumors (relatively common) Synovial sarcoma (relatively common) Extraosseous osteosarcoma (very rare?) Extraskeletal chondrosarcoma, myxoid vs mesenchymal (relatively rare) Epithelioid sarcoma (relatively rare) Clear cell sarcoma of tendons and aponeuroses Myofibrosarcoma (rare)

542

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MAJORTUMORS OF CHILDHOOD

and leiomyosarcoma. Conversely, rhabdomyosarcoma is by far the most common soft tissue malignancy in children but is rare in adults. In adults, rhabdomyosarcoma typically occurs as the pleomorphic variety, but the very existence of this cell type in children has been questioned." Synovial sarcoma and neural tumors have an increased occurrence in children. Surgeons must also be aware of the borderline "malignant" nature of many pediatric soft tissue tumors, a situation similar to that noted with epithelial surface tumors of the ovary. An example is the aforementioned angiomatoid malignant fibrous histiocytoma; the infrequency of metastases has led to the omission of the "malignant" qualifier by some investigators.35 Other borderline lesions include epithelioid hemangioendothelioma, spindle cell hemangioendothelioma, and dermatofibrosarcoma protuberans. Occasionally, however, these lesions present with metastases, and the histologic appearance is often not predictive of this capacity. Several examples of pediatric soft tissue tumors are relatively benign when they occur in infants and children younger than 5 years old but behave in a more typically aggressive fashion in older children. Infantile fibrosarcoma may appear high grade on histologic examination and form large, expansile extremity lesions on clinical presentation, yet the rarity of metastatic disease in these lesions is well known, and conservative therapy is advised.67 A similar lesion is infantile hemangiopericytoma, whose behavior is akin to a benign vascular lesion in infants but is potentially more malignant in older children and adolescents. Because of the inconsistencies in predicted behavior, the grading scheme for pediatric soft tissue sarcomas takes into account cytohistologic features used for adult sarcomas but employs the caveats of the childhood lesions (Table 33-2).8",88 For example, fibrosarcomas are

Grade 1 Myxoid and well-differentiated liposarcoma Deep-seated dermatoflibrosarcoma protuberans Well-differeniated or infantile (age <5yr) fibrosarcoma Well-differentiated or infantile (age <5yr) hemangiopericytoma Well-differentiated malignant peripheral nerve sheath tumor Angiomatoid malignant fibrous histiocytoma Grade 2 Sarcomas not specifically include in grades 1or 3; 4 5 % of tumor shows geographic necrosis or the mitotic index is <5 per 1 0 high-power fields Grade 3 Pleomorphic or round cell liposarcoma Mesenchymal chondrosarcoma Extraskeletal osteosarcoma Malignant triton tumor Alveolar soft part sarcoma Other sarcomas not specifically induced in grades 1or 2, in which >15% of tumor shows geographic necrosis or the mitotic index is >4 per 10 high-power fields

low grade (grade 1) when they occur in children younger than 5 years, regardless of features such as mitotic index, necrosis, or cytology. In older children, however, they are grade 2 or 3, depending on whether the mitotic index is low (<5per 10 high-power fields) or high (>4 per 10 highpower fields) or whether there is little (<15%)or abundant (>15%) geographic necrosis. Cytologic features such as pleomorphism and cellularity are used to distinguish ambiguous cases. This system should not be used with rhabdomyosarcoma or peripheral primitive neuroectoderma1 tumors (PNETs), which are always considered high grade and are best treated with a systematic approach using surgical resection, combination chemotherapy, and radiation. Fibromatoses are a heterogeneous group of lesions, some of which are potentially lethal entities requiring wide excision and careful follow-up for cure. These tumors all contain benign-appearing fibroblasts as major constituents, but they vary in their affected age range, histologic patterns, typical location, tendency toward multifocality or chondroid differentiation, and likelihood of recurrence with incomplete surgical margins. One entity, fibrous hamartoma of infancy, contains a mixture of fat, mature fibrous tissue, and immature fibrous tissue and is typically located in the subcutis of the back and shoulder; it usually does not recur. In contrast, infantile desmoidtype fibromatosis is a more homogeneous, diffusely infiltrating mass of mature fibroblasts and fat that may occur in locations not easily amenable to surgical excision; it leads to significant morbidity or mortality by invasion of adjacent anatomic structures. Infantile desmoid-type fibromatosis is distinguished from infantile fibrosarcoma by virtue of its lack of cellular pleomorphism or mitotic activity, and it does not metastasize. Older children and adolescents may also have desmoid-type musculoaponeurotic fibromatosis, with similar histology and behavior. Some pharmacologic agents have been found to be of therapeutic but large numbers of patients have not been tested in a prospective, randomized clinical trial. Another entity is infantile myofibromatosis, which .may occur as solitary or multicentric lesions; visceral involvement with the latter may prove lethal. Diagnosis of pediatric soft tissue tumors may be accomplished with routine histology or even fine-needle a~piration,~lQutit often requires a battery of special techniques that may include histochemistry, immunohistochemistry, electron microscopy, cytogenetics, flow cytometry, in situ hybridization, or reverse transcriptase polymerase chain reaction (RT-PCR). In general, because of their primitive, undifferentiated nature, round cell lesions require more extensive study, whereas spindle cell lesions are more likely to be diagnosed by routine histology if sufficient tissue is available. Paradoxically, round cell tumors usually yield better specimens on fine-needle aspiration cytology, whereas the more cohesive spindle cell lesions often give inadequate or insu'fficient samples by this technique. Close interaction among oncologists, surgeons, and pathologists is required to maximize diagnostic yield and utility. Occasional life-threatening situations may require an expedited diagnosis with less than adequate material. When time allows, however, a precise and accurate diagnosis is invaluable in clinical management.

CHAPTER

The time required for the turnaround of ancillary data ranges from 1 day or less for immunohistochemistry and RT-PCR to several days for electron microscopy to 2 weeks for cytogenetics. The availability and reliability of these techniques depend on the nature and amount of material submitted; fresh tissue is required for cytogenetics and RT-PCR, and special fixation is required for electron microscopy and possibly for immunohistochemistry. RT-PCR has the advantage of extreme sensitivity, so only a small specimen is required. Cytogenetics may give misleading results if the specimen is contaminated by normal host tissues, or no results if there is poor sample viability. Diagnostic features of the more common round and spindle cell sarcomas are listed in Table 33-3.86 The initial pathologic evaluation generally attempts to determine first whether the lesion is benign or malignant and second whether it is a round or spindle cell tumor. Then a differential diagnosis is constructed, and special studies are acquired as necessary to eliminate or confirm the diagnostic possibilities. The differential diagnosis of a completely undifferentiated round cell tumor includes a variety of lesions, with the most likely candidates being rhabdomyosarcoma, lymphoma, neuroblastoma, PNET, or soft tissue Ewing's tumbr. Immunohistochemical stains for desmin and muscle-specific actin (muscle markers), CD45 and other lymphoid markers, neuron-specific enolase and synaptophysin (neural markers), and vimentin and CD99 (Ewing's markers) are evaluated. The combination of results is usually of great utility in weighing the alternatives, but many caveats exist. For example, neuronspecific enolase is a sensitive neural markerbut is often positive in rhabdomyosarcoma, so its presence is more helpful in the absence of muscle markers. Similarly, CD99 is a very sensitive and relatively specific marker of PNET, but it is also commonly found in T-cell lymphomas. Neural markers may be present in both PNET and neuroblastoma, but the latter are CD99 negative. Finally, some tumors such as primitive ectomesenchymoma commonly display multipotential differentiation patterns with positivity for diagnostically disparate markers. In these confusing situations, it is wise to consider results from alternative methods such as electron microscopy and cytogenetics. L,

NONRHABDOMYOSARCOMATOUS SOFT TISSUE SARCOMA Malignant soft tissue sarcomas are derived from mesenchyma1 cells and account for 7% of all childhood tumors.74J21 These tumors encompass two major histologc subgroups: rhabdomyosarcoma and nonrhabdomyosarcomatous soft tissue sarcomas. Rhabdomyosarcoma (see Chapter 32) is the most common soft tissue sarcoma in children and accounts for more than half of all cases of childhood soft tissue sarcomas, with 250 newly diagnosed patients J2l encountered yearly in the United S t a t e ~ . ~ ~Nonrhabdomyosarcomatous soft tissue sarcomas (NRSTSs) are a heterogeneous group of malignancies; they account for 47% of all pediatric soft tissue sarcomas and for 3% of all pediatric cancers.74.75 The clinical behavior of these tumors has not been well defined.75,"J21Their rarity and

33

Other Soft Tissue Tumors

543

histologic heterogeneity have precluded careful study of their natural history and response to therapy. Therefore, much of the information regarding treatment of these tumors in pediatric patients has been derived from adult studies. Further, despite their aggressive pathologic appearance, some subtypes of pediatric NRSTS (e.g., infantile fibrosarcoma) have a relatively benign clinical course after treatment with surgery alone.23.75 NRSTS, like rhabdomyosarcoma, can arise in any part of the body. Two series totaling 322 pediatric patients indicated that the most common sites were the extremities, trunk, and abdomen and pel~is.~"~"omesites such are extremely rare. as the eye and orbit18and the In these series, synovial sarcoma, neurofibrosarcoma, malignant fibrous histiocytoma, and fibrosarcoma were ~ ~ ~ 9 have been the most frequent h i ~ t o l o g i e s . ~NRSTSs associated with Li-Fraumeni syndrome, and some tumors (e.g., malignant fibrous histiocytoma) can develop in previously irradiated sites.75Approximately 4% of patients with neurofibromatosis type 1 (NF-1) develop malignant peripheral nerve sheath tumors; 40% of these rare malignancies are seen in patients with NF-1.27Leiomyosarcoma can occur in children infected with human immunodeficiency virus (HN) and Epstein-Barr virus.70 Pediatric soft tissue sarcomas are increasingly being defined by both histologic appearance and underlying chromosomal abnormalities to determine their biologic behavior. Most sarcomas of this type have specific chromosomal translocations that create unique fusion genes. These fusion genes may have diagnostic, prognostic, and surveillance implications for the patient." Prognostic factors in children with NRSTS include whether the tumor can be resected, tumor size, histologic grade, tumor invasiveness, and the presence or absence of metastatic disease.84,98 In a review of 37 children with synovial sarcoma, the 5-year probability of survival was 80 f9% for patients with completely resected lesions, compared with 17 f 15% for those with unresected or metastatic lesions.84Of 154 children with NRSTS who were treated at a single institution, 31% with grade 1 or 2 lesions had treatment failure, and 73% with grade 3 disease developed recurrent disease. Similarly, 88% of those with large, invasive, grade 3 lesions failed therapy, compared with 2% of children with small, low-grade, noninvasive lesions.99 Unlike rhabdomyosarcoma, which is a highly chemosensitive tumor, the mainstay of treatment for NRSTS is complete surgical resection with or without adjuvant radiotherapy to prevent local recurrence. Several prospective adult trials of NRSTS failed to document a survival benefit of adjuvant chemotherapy.72J27 The only prospective pediatric trial addressing the value of adjuvant chemotherapy was conducted by the Pediatric Oncology Group (POG). In this trial, 75 children with completely resected lesions were assigned either to receive adjuvant chemotherapy with vincristine, dactinomycin, cyclophosphamide, anddoxorubicin or to be simply observed. The 3-year disease-free survival rates for these two groups did not differ (74% versus 76%). Subgroup analysis disclosed that patients with grade 3 lesions fared significantly worse than those with grade 1 or 2 disease (3-year event-free survival, 75% versus 91%; P = 0.018).88 Distant relapse accounted for more than

1 Tumor Round Cell Rhabdomyosarcoma PNET, Ewing's tumor Lymphoma Desmoplastic small cell tumor Langerhans cell histiocytosis Neuroblastoma

Spindle Cell Synovial sarcoma

1

Malignant peripheral nerve sheath tumor Fibrosarcoma, myofibrosarcoma

RT-PCR or Other Molecular Technique

lmmunohistochemistry

Electron Microscopy

Desmin, muscle actin, MyoD CD99, synaptophysin, vimentin, NSE CD45, CD45R0, CD20, CD3, CD43, CD30 Vimentin, cytokeratin desmin, Synaptophysin, NSE, CD57 S100, CDla, peanut lectin

Thick and thin filaments, Z bands, pools of glycogen, primitive cytoplasm, neurosecretory granules, primitive cytoplasm, lack of intercellular junctions Not diagnostic

Burkitt's: t(2;8), t(8;14), t(8;22) Anaplastic large cell: +(2;5) t(11;22)(p13;q12)

Burkitt's: c-myc;lgH: c-myc; Igk: c-myc;lgh ALK;ALM WT1;EWS

Birbeck granules

Not diagnostic

Not diagnostic

PAS stai,n for glycogen PAS stain for glycogen; absent reticulin Flow cytometry; consider extranodal Characteristic desmoplastic stroma Eosinophils frequent

NSE, synaptophysin, chromagranin (weak)

Processes with microtubules, neurosecretory granules, synaptic junctions

l p deletions, double minutes, homogeneous staining regions (nonspecific)

N-myc amplification (may be seen in alveolar rhabdomyosarcoma

Ganglionic differentiation; urinary catecholamines; CD99 negative

Cytokeratin, EMA

Epithelial differentiation process, Luse bodies, basal lamina, pseudomesaxons

t(X;18)

SSX1;SYT SSX2;SYT

None

Deletion of NF-I?

None

None

Beware confusion due t o neural invasion History of neurofibromatosis; origin within major nerve; coexisting neurofibroma Inflammatory variants described; consider inflammatory myofibroblastic tumor

S100, CD57, GFAP

Vimentin, smooth muscle actin

Lamellae of RER, terminal web, actin microfilaments, collagen granules, fibronexus junctions, pinocytotic vesicles

-

Cytogenetics t(1;13); t(2;13) (alveolar only) t(11;22), t(21;22)

I

PNET, primitive neuroectodermaltumor; RT-PCR, reverse transcriptase-polymerase chain reaction; NF-1, neurofibromatosis typel; NSE, neuron-specific enolase

Other

CHAPTER

80% of the failures in the high-grade group. These data suggest that a prospective trial of adjuvant chemotherapy in children with high-grade, completely resected NRSTS may be warranted if prospective trials of children with unresectable or metastatic N E T S identify active agents. The outcome for children with metastatic NRSTSs continues to be poor, with less than 20% of patients disease free at 3 year^.^^^^^ Surgical resection is the treatment of choice for most NRSTSs. The role of chemotherapy and radiation therapy is poorly defined. Evaluation o f the role of chemotherapy has been limited by the lack of randomized, controlled trials. The POG attempted to randomize patients after surgical resection of -NRSTS (clinical groups I and 11) to chemotherapy (vincristine, doxorubicin, cyclophosphamide, dactinomycin) or observation.96 Of the 81 eligible patients, only 30 accepted randomization. The ~ a t i e n t swho received chemotherapy (both randomized and nonrandomized) did worse; however, this is likely due to a greater number of highgrade tumors among the treated patients. The most active drugs against NRSTS include ifosfamide and doxorubicin.29 A prospective POG trial for children with unresectable or metastatic NRSTS compared VADRAC (vincristine, doxorubicin [Adriamycin]; cytoxan) with VADRAC plus dacarbazine (DTIC). DTIC conferred no additional benefit: the 4year overall and event-free 8.5% and 18.4 6.8%, survival estimates were 30.6 respectively.9Vdentification of new agents in phase I and I1 trials, intensification of known active agents and concomitant growth factor support, and administration of preoperative chemotherapy are strategies that may help improve the outcome for children with NRSTS. Children with metastatic disease, particularly those older than 10 years or those with bone or bone marrow involvement, tend to have a poor outcome and need new treatment options. The use of high-dose single, multiple, or combined chemotherapy-radiotherapy regimens with stem cell rescue has, for the most part, failed to improve the poor outcome, but this remains the cornerstone of today's clinical trials.5 Radiotherapy is generally administered for microscopic residual disease or histologic evidence of tumor extending close to the margin of resection and may be indicated for group I tumors larger than 5 cm. The efficacy of radiotherapy has not been proved, however, and the adverse effects of'radiation exposure in children, including effects on body growth and secondary cancers, make its use in small, totally resected tumors questionable. Spunt et al.l14 described 121 patients with group I and I1 NRSTSs treated at St. lude Children's Hos~ital.Radiation reduced the risk of local recurrence in group I1 patients but had no impact on event-free survival. Radiation did not impact local recurrence in patients with group I disease. Pediatric soft tissue sarcomas arising as second malignancies can be cured using the same strategies used for de novo pediatric ~arcomas.~l

+

+

d

-

-

Synovial Sarcoma Synovial sarcoma is one of the most common NRSTSs seen in pediatric patients; approximately 30% of synovial

33

Other Soft Tissue Tumors

545

sarcomas occur in patients younger than 20 years. There are few reports concerning synovial sarcoma in pediatric patients.38,6z,K*.84,107 As in adults, most of these sarcomas arise in the extremities, most commonly the lower extremity. Other common sites are the trunk and the head and neck. The 5-year event-free survival rate is approximately 70% for all pediatric patients; however, survival is approximately 80% for those with group I and I1 tumors and 0% to 58% for patients with group I11 and IV tumors. The outcome appears similar to that seen in adults. Because most reports include only adults or only children, and because different staging systems are used, direct comwarison is difficult. Local recurrences are common, with metastases primarily to lung but also to lymph nodes." Late relapses are common, and survival curves continue to fall off even at 10 and 15 years. The primary treatment for synovial sarcoma is surgical resection. There are many reports of response to chemotherapy, but no study has clearly shown that chemotherapy improves survival. The CWS-81 study treated patients initially with chemotherapy using combinations of vincristine, doxorubicin, cyclophosphamide or ifosfamide, and actinomycin D. In five patients with group 111and IV tumors, a complete response was seen in two and a partial response in three; complete resection and long-term survival were achieved in all five patients.63 The use of high-dose ifosfamide (14 to 18 g/m2) in 13 adult patients with metastatic disease resdted in a response in all patients treated. Most responses were partial or transient, but when combined with surgical Eesection of residual disease, disease-free status was noted in four patients at 3, 14, 21, and 42 months, respectively."J3These data suggest that chemotherapy may have a role in shrinking tumors to permit subsequent surgical resection, but the use of chemotherapy in an adjuvant setting is unproved for synovial sarcoma. The optimal treatment strategy for synovial sarcoma is thus subject to debate, and different strategies have been used for pediatric and adult patients. One retrospective analysis examined a large group of patients of all ages treated at a single institution over a 30-year period. The study included 271 patients ranging in age from 5 to 87 years; 255 had localized disease that was macroscopically resected in 215 cases and was deemed unresectable at diagnosis in 40 cases. Chemotherapy was administered to 41% of patients, corresponding to 76% of patients aged 16 years of younger and less than 20% of older patients; 28% of patients with macroscopically resected disease received chemotherapy on an adJuvant basis. The overall 5-year event-free survival rate for the study cohort was 37%, although this rate varied with age (66% for patients aged 16 years or younger, 40% for those 17 to 30 years, and 31% for those older than 30 years). Among patients with surgically resected tumors, the 5-year metastasis-free survival rate was 60% for those treated with chemotheraDv versus 48% for those who were not. The benefit associated with chemotherapy appeared greatest for patients aged 17 years or older who had tumors measuring greater than 5 cm (metastasis-free survival 47% with chemotherapy versus 27% without chemotherapy). In the subgroup of patients with measurable disease, the rate of tumor response to chemotherapy was approximately 48%. l i

546

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Although the authors await more convincing proof of the efficacy of adjuvant chemotherapy in the treatment of adult soft tissue sarcoma, they recommend that patients with high-risk synovial sarcoma (tumor size >5 cm) be the first to be considered for this type of treatment.40 Radiotherapy for synovial sarcoma is often used for microscopic residual disease or histologic evidence of tumor close to the resected margin. As with other NRSTSs, its efficacy has not been proved, and radiation's negative effects on growth in children and the risk of secondary cancers and other late effects make its use in small, totally resected tumors questionable.89 Genetic evaluation of synovial sarcoma tumor tissue shows a poorer outcome for tumors associated with the SYT-SSX fusion type.@This fusion type is more common in patients presenting with metastases than is SYT-SSX2; in patients with localized disease, SYT-SSXl is associated with a shorter overall survival time. Certain primary sites, such as synovial sarcoma of the hand, are rare. No clear guidelines exist with regard to their management. A functional limb-saving approach, without compromising the principles of cancer management, should be individualized in each case.51 Primary renal synovial sarcomas are now an accepted entity and are likely a subset of what was previously considered an adult variant of Wilms' tumor."

~~ results can be expected with be c ~ r a t i v e .Similar fibrosarcoma of the trachea.93

Hemangiopericytoma Only 5% to 10% of hemangiopericytomas occur in children and and many of these are infantile hemangiopericytoma, an entity with a more benign course than that seen in older patients. The infantile form is more likely to occur in the head and neck and has a low metastatic potential. Infants with incomplete removal of hemangiopericytoma often do well with no further therapy.6 Responses to chemotherapy have been reported.4xWongenital hemangiopericytoma generally does not metastasize and has a good prognosis, although some instances of metastases and death have been reported."pontaneous resolution has been reported after biopsy alone." This lesion can present in odd locations, such as a thyroglossal duct remnant," on rare occasions. This tumor can mimic a benign arteriovenous malformation that is sometimes still referred to as an "angioma."7Vt has also been reported to occur in association with trisomy 15 as a sole anomaly."'

Neurogenic Sarcoma Infantile Fibrosarcoma Infantile fibrosarcoma is the most common soft tissue sarcoma of infants, accounting for about half of fibrosarcomas in the pediatric population. These tumors usually present as a slowly enlarging mass that may have been present for months to years. Most occur on the extremities, but head and neck tumors are also common. The name infantile fibrosarcoma is a misnomer, because the improved prognosis it implies and the chromosomal changes associated with this tumor are also seen in children up to about 5 years of age. Younger children with fibrosarcoma also have a good prognosis, with a better than 90% long-term survival rate. Although childhood fibrosarcoma has a recurrence rate of about 50%, the metastatic potential is less than 10%.24,113 Infantile fibrosarcoma grows rapidly, infiltrates locally, but rarely metastasizes. Although complete surgical resection is curative, it is not always possible. Neoadjuvant chemotherapy causes many tumors to shrink sufficiently to allow resection. There does not seem to be a role for adjuvant chemotherapy or radiation after complete resection. Although recurrence is frequent, most cases can be managed with additional surgical excision. Overall survival is greater than 90%.37 Because of the typically benign course of infantile fibrosarcoma in children younger than 5 years, conservative surgical procedures are recommended to preserve function. Infantile fibrosarcoma is generally responsive to chemotherapy and in some instances can be successful as initial therapy.",H0 Spontaneous regression has also been .~~ fibrosarreported in infantile f i b r o ~ a r c o m aPulmonary coma is a rare malignant tumor in childhood. In the absence of metastasis, complete resection appears to

Neurogenic tumors (malignant peripheral nerve sheath tumors, neurofibrosarcomas, neurosarcomas, and malignant schwannomas) often present with pain or neurologic symptoms that have been present for prolonged periods before diagnosis. Neurogenic sarcomas may arise de novo or from a preexisting fibroma. In pediatric series, NF-1 was Less than 5% of present in 21% to 62% of patients.17~3'r~~ patients with NF-1 develop a sarcoma, however."2 Primary sarcomas of the central nervous system are rare in children. Their cell of origin is controversial, but the most widely accepted theory names the pluripotential primitive mesenchymal cells in the dura mater, the leptomeninges or their pial extensions into the brain and the spinal cord along the periadventitial spaces, the choroidea, and the stroma of the choroid plexus. The reported incidence of sarcomas at this site varies from 0.1% to 4.3%,owing to the inconsistent definitions from study to study. These tumors frequently arise in the supratentorial compartment in children. Dural attachment and central nervous system dissemination are often found. Metastasis outside the central nervous system is associated with a poor prognosis, although aggressive resection with postoperative radiation may offer a chance for long-term survival. Repeat craniotomy should be offered for recurrent local disease. Newer chemotherapy protocols may hold promise in the future.' These are very aggressive tumors, and radical surgery is the primary treatment. In patients with NF-1, the tumors present at an earlier age and recur and metastasize more quickly and more f r e q ~ e n t l y . ~ - ~ ~ . " W a l i g n a n t peripheral nerve sheath tumors are rare and usually fatal, with a high risk of local recurrence and distant metastasis.115

CHAPTER

Complete excision is the most important prognostic factor, with a 5-year disease-free survival rate of 67%. With microscopic residual tumor, the 5-year disease-free survival rate is 43%; this falls to 22% when the tumor is not completely resected because recurrence is inevitable, with most tumors metastasizing to the lungs.126 External beam radiation does not appear to impact survival, but brachytherapy (BRT) and intraoperative radiation are beneficial.lz6

Liposarcoma Although liposarcoma is one of the more common soft tissue sarcomas in adults, it is rare in children.19,"fi4J11 Gross total resection is the indicated treatment. Tumor shrinkage to allow for complete excision has been chemotherapy.39 Adjuvant achieved with radiation1"nd chemotherapy or radiation has been used in children with microscopic residual tumor, but its effectiveness has not been do~umented."f'~The 5-year survival rates in extremity liposarcoma in adults is dependent on histologic subtype and are as follows: for well-differentiated tumors, 100%; for myxoid tumors, 88%; for fibroblastic tumors, 58%; for pleomorphic tumors, 56%; and for lipoblastic tumors, 40%.20 The better prognosis in children with liposarcoma compared with adults may be related to the higher incidence of myxoid and welldifferentiated subtypes (70% to 85% of pediatric liposarcomas).

Desmoplastic Small Round Cell Tumor Desmoplastic small round cell tumor occurs primarily in young men who present with pain, ascites, abdominal distention or mass, nausea and vomiting, or signs of bowel or bladder obstruction. Presentation with widely disseminated metastases to liver, lungs, and lymph nodes is common.45 Although the precise tumor type may be difficult to determine, the RT-PCR method for formalin-fixed material has a 94% to 100% specificity for tumor type.43 Because of widespread dissemination at presentation, complete surgical resection is rarely possible. Response to chemotherapy, including high-dose chemotherapy and autologous stem cell rescue, has been docuLong-term survival remains dependent mented.1023624~"J~4 on the ability to resect all gross disease after neoadjuvant chemotherapy. Radiation therapy may be of benefit in treating microscopic residual disease. The use of radiofrequency for the ablation of unresectable hepatic metastasis in desmoplastic small round cell tumor may be e f f e ~ t i v e . ~ ~

Malignant Melanoma of Soft Parts Approximately 25% of these tumors occur in patients younger than 20 years. Most patients present with an enlarging mass in the extremities that has been present for a long time.25J0fi Local recurrence is common. Metastases occur to lung (59%), lymph nodes (53%), and bone (22%).

33

Other Soft Tissue Tumors

547

Treatment is surgical excision. The median overall survival duration is 49 months,l06 but patients with metastases at diagnosis generally survive less than 1 year. Local relapses and metastases can occur years after diagnosis and treatment. The role of adjuvant chemotherapy or radiation is uncertain for these tumors.44

Alveolar Soft Part Sarcoma Approximately 25% of alveolar soft part sarcomas are seen in patients younger than 20 years. This tumor is predominant in women (61%), especially in younger patients." Presentation consists of a painless enlarging mass of the extremity, with head and neck tumors also common in ~hildren.~6,~"toccurs in 0.8% to 1.8% of children. Mean length of survival is 20 years in patients age 0 to 9 years at diagnosis and 14 years in those age 10 to 19 years. Tumors greater than 5 cm in diameter have an increased risk of metastasis, which usually occurs early in the disease. Excision of metastasis can influence survival.83 Approximately 20% of patients have metastases at diagnosis. Metastases can sometimes occur many years after the initial diagnosis and affect the lung, bone, and brain. Treatment is primarily surgical, with complete excision being the best treatment. There is a low risk of local recurrence if adequate margins are obtained. In patients presenting with metastatic disease at diagnosis, the median survival duration is 3 years.66Younger patients have a longer survival time, but this is related primarily to a lower incidence of metastases at diagto the Soft-Tissue Sarcoma Italian nosis.66~*~ccording Cooperative Group, pediatric alveolar soft part sarcoma has a more favorable prognosis than its adult counterpart.16

SPECIAL DIAGNOSTIC AND SURGICAL CONSIDERATIONS New Imaging Modalities Magnetic resonance spectroscopy appears to be effective in assessing tumor response in childhood cancer and could potentially be used to tailor chemotherapy to the individual child's needs."* The prognostic significance of magnetic resonance spectroscopy has been studied in sarcomas of the extremity, where the aim was to determine whether pretreatment spectra might be useful in defining good- versus poor-risk tumors and to determine whether changes that occur early during the course of therapy can be useful to predict tumor response.sg Fluorodeoxyglucose positron emission tomography scans have been assessed for their diagnostic and therapeutic role in childhood sarcomas through a systematic review of the relevant literature and a meta-analysis. There is no apparent indication for the use of this modality in the standard treatment of sarcomas at present, although it may be used for the detection, grading, treatment, and evaluation of locally advanced sarcomas.'

548

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in certain situations, especially in the vicinity of major nerves or vessels, the margns may be only a few millimeters. The value of fine-needle aspiration is primarily to differIn this case, it is advisable to remove the adventitial sheath entiate a solid mass from a fluid-containing mass or an along with the specimen.55J02Although resection is the primary concern, dissection is often tailored to the individual abscess that may require drainage. In all other instances, patient, based on preoperative diagnostic imaging. at a minimum, a Tru-Cut needle biopsy is warranted.12,52,65~94,99~100 Although needle tract recurrences The skin from the previous biopsy site is completely ellipsed, and the flaps are raised. The deeper extent of the have been documented, these are extremely rare events and are more common among patients with carcinoma.lo8 dissection is usually initiated on one side 2 to 3 cm from the When the tissue obtained is insufficient to obtain a spetumor. Often the deep margins overlie the vessels or nerve. cific diagnosis or a discrepancy exists, an open biopsy is In this case, the adventitial sheath or ~erineuralsheath indicated. For extremity lesions, the incision should be adjacent to the tumor should be resected. to acquire a little placed longitudinally or parallel to the neurovascular more margin. If the vessel is grossly involved, resection of bundle. A transverse biopsy incision would contaminate the vessel with interposition of a vascular prosthesis can be multiple tissue compartments and thus preclude limb considered. If the Gmor abuts the bone; stripping of the An excisional biopsy of a lesion is periosteum, marginal resection of the bone, or resection of salvage ~urgery.~~99~10l undertaken only if the tumor is small (< 2.5 cm) or situa segment of the bone can be performed. In these ated such that an eventual wide local resection could be instances, the bony defect may be bridged by a vascularized done without risk of functional deformity.119 In all other fibula graft or allograft plus intramedullary nails. instances, an incisional biopsy is obtained and should be In the popliteal fossa and the elbow, compartmental carefully planned and placed, so that the tract can be resection of a tumor with satisfactory margins is almost completeiy excised at the time of definitive surgery. impossible because of the complex 'eurovascular anatomy, the loose connective tissue, and the close conIt has been shown repeatedly that when resection is 0 5 ~ ~tumors ~ are not fines of adjacent s t r ~ c t u r e s . g 0 ~ ~These planned for a benign tumor or when resection of a maligconfined by fascia1 boundaries and are considered extranant lesion is not carefully planned, the quality and compartmental. It is my policy to maintain limb function amount of tumor resection are inadequate. In these whenever feasible with resection of these lesions, albeit instances, residual tumor can be identified following priwith tenuous margins. Radiation therapy is added for mary re-excision in 30% to 49%of patients.12,14,47,gg,102,122,124 If primary radical resection is -not performed, local local control in the form of interstitial brachytherapy, recurrence rates of 50% to 90% have been external beam radiation, or a combination of both. observed.'"1"47~5ji~99~10'L~128 Therefore, whenever diagnostic Major ablative procedures such as amputation should be imaging, the operative notes, or pathologic examination considered when there is neurovascular involvement, for local recurrence, and in a skeletally immature child. suggests that there is residual tumor or that the tumor is A similar situation arises in lesions of the hand or foot, close to the specimen margin, it is recommended that which are relatively uncommon primary sites. The tight the patient undergo primary re-excision of the operative site whenever possib~e.12,~4,58,99,101,~~99~25 compartments interspersed with tendons and neurovasculai- bundles make resection with adequate margins difficult. Surgical procedures may include ray amputation of one or more digits, wide local excision of the EXTREMITY TUMORS al or use of a neurovascuarea, and s u ~ ~ l e m e n tradiation lar free transfer technique, especially in the case of Two major factors have contributed to reduced amputa, ~ the 8s~ lower ~ , ~extremity, ~ resection of the t h ~ m b . ~ ~ In tion rates in children with soft tissue sarcoma. First, amputation still has a role in the management of large, although amputation results in a high rate of local con124~125 invasive tumors or when combination thertrol, it fails to improve overall s ~ r v i v a l . 1 4 ~ 5 5 ~ 9 9 ~ ~ ~ 2 ~ ~ 2 2 ~ high-grade apy could result in a poor functional outcome. Second, limb salvage procedures with or without adjuvant radiation therapy have effectively decreased local recurAmputation may also be appropriate for pain control, rence rates to less than 10%.22,*1-42,77,9","2,124 Although especially in a weight-bearing limb, and for recurrent local disease. amputation may be logical in an elderly patient, it is not This combined-modality management has led to 90% the best choice for a growing child. Amputation in adult to 95% limb salvage in NRSTS, with local recurrence patients obviates the musculoskeletal deformity or the In recent vears. rates in the vicinity of 10%.12,99,101,122J24 risk of a second malignan~y.~~,94,"~~~~,~~2 , , The surgical principle is to obtain a wide local resecbetter understanding of tumor biology and improved tion with adequate margins, generally considered to be techniques for the delivery of radiation have emerged. e nthe d i size n g and site of the about 2 ~ m . l ~ ~ ~ ~ ~ W e pon Radiation therapy may be administered preoperatively, tumor, wide local resection may be obtained by means of intraoperatively, or postoperati~ely.'2~'".42~R1~122-123 a radical compartmental resection, resection of a muscle from insertion to origin, or radical wide local resection." Although wide margins are obtained in most directions, MANAGEMENT OF EXTREMITY LYMPH

Biopsy and Surgery

x x

NODE DRAINAGE The role of regional node dissection in soft tissue sarcoma has become clearer in recent years. In a collective

CHAPTER

33

Other Soft Tissue Tumors

549

involvement survived. The need for nodal assessment in review of more than 2500 cases of NRSTS, the incidence all patients with extremity rhabdomyosarcoma was conof nodal involvement was around 3.9%. In the same firmed in an analysis of Intergroup Rhabdomyosarcoma series, the authors detected a slightly increasing inciStudy-111.2 dence of lymph node metastasis with increasing tumor grade, ranging from 0% for grade 1 lesions to 12% for grade 3 lesions.69 In a review of NRSTS at St. Jude Children's Hospital, a similar range was noted.ll* In FUNCTIONAL OUTCOME FOLLOWING LIMB another review, 76 of 204 patients underwent either SALVAGE SURGERY lymph node dissection or biopsy of suspicious lesions; it Over the past two and a half decades, limb salvage surgery was positive for tumor in nine, and in seven of the nine with adjuvant irradiation has emerged as the optimal treatIt children the tumors were high-grade le~ions.~8~99J~lJ(Q ment and has been performed on a substantial number of is my practice to biopsy only suspicious nodes of highpatients. Although the outcome of this combined modalgrade lesions that are more than 5 cm in size, or if the ity addresses primarily cosmetic concerns, in young lymph nodes are present in the field of dissection of the children and particularly the skeletally immature, attenprimary tumor. tion should be given not only to quality of life but also to When lymph node involvement is suspected in associated local complications, including a stiff, painful, extremity tumors, it can be assessed by injection with isoshortened, or disfigured extremity or fractures associated sulfan blue dye into the lesion at the time of surgery. Children should with demineralization of bone.9.'14~56J2~ Uptake of the dye into the nodes draining the lesion can have active physical therapy to minimize contracture. be determined in this fashion (Fig. 33-1). Use of the Musculoskeletal Tumor Society functional Mandell et a1.68 evaluated 34 patients with extremity outcome evaluation has been detailed mostly in the adult rhabdomyosarcoma, 27 of whom underwent evaluation literature. Excellent to good results were obtained in of regional lymph node drainage. Thirteen patients 75% to 80% of patients, with more than 75% returning to (48%) demonstrated evidence of nodal involvement, full employment. A similar detailed study in the pediatric only one of whom survived. In contrast, there were literature is lacking. Complications noted in my experience 12 survivors among the 14 patients without nodal among long-term survivors after combined treatment involvement. Even when patients with distant metastasis include limb shortening requiring epiphysiodesis, flexion were excluded, 11 of the 12 patients with no nodal

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by means of absorbable mesh and to deliver at least a portion of the radiation therapy dose as brachytherapy. Brachytherapy increases local control and reduces the probability of late complications (especially altered bone and organ growth) in comparison to external beam radiation (Fig. 33-2). Low-energy radionuclides and remote afterloading technology allow the treatment of infants and very young children while reducing radiation exposure to patients, family, and medical personnel.'8

REFERENCES a

.

Afterloading catheters are placed for brachytherapy

in the patient with epithelioid sarcoma depicted in Figure 33-1. (Courtesy of Dr. Bhaskar Rao, St.Jude Children's Research Hospital,

Memphis, Tenn.)

deformity, fibrosis, chronic edema, fracture, and secondary osteosarcoma in 7 of 50 long-term survivors with extremity sarcoma. These patients have been followed for 12 to 104 months (median, 36 months).

SOFT TISSUE SARCOMA OF THE TRUNK When a chest wall resection is indicated, a standard thoracotomy incision is appropriate. The investing layer of the serratus anterior or pectoralis is incised at an appropriate distance from the tumor. Careful palpation should be used to gauge the extent of resection, which may include resection of the periosteum with placement of afterloading catheters for brachytherapy. However, if imaging studies or visualization at the time of surgery indicates infiltration of the intercostal muscles or intrathoracic extension, a formal chest wall resection is indicated. The intercostal muscles are divided at an appropriate point, after ligation of the intercostal vessels. Careful palpation of the intrathoracic extension determines the extent of resection and the number of ribs to be removed. The anterior and posterior extent of resection should be 2.5 to 5 cm. The superior and posterior extent is generally a rib above or below the primary lesion. Any adhesions between the pulmonary parenchyma and tumor are excised using an endoscopic linear stapler, so that the specimen can be removed en bloc. The resultant defect is closed by a double layer of mesh and neighboring muscle flaps or myocutaneous flaps. The abdominal wall is a rare primary tumor site. Accurate preoperative imaging can determine tumor resectability. The entire extent of the tumor is resected to obtain satisfactory margins. The deep margins should include resection of the peritoneum whenever possible. The peritoneal defect may be closed by an omental patch or absorbable mesh. Direct contact between the nonabsorbable mesh and the bowel should be avoided to reduce the risk of bowel fistula. It is my policy, especially in the case of lower abdominal wall lesions, to place the bowel loops away from the postoperative radiation field

1. Al-gahtany M, Shroft M, Bouffet E, et al: Primary central nervous system sarcomas in children: Clinical, radiological, and pathological features. Childs Nerv Syst 2003;19: 808-817. 2. Andrassy RJ, Corpron CA, Hays D, et al: Extremity sarcomas: An analysis of prognostic factors from the Intergroup Rhabdomyosarcoma Study 111. J Pediatr Surg 1996;31: 191-196. 3. Argani P, Ladanyi M: Recent advances in pediatric renal neoplasia. Adv Anat Path01 2003;10:243-260. 4. Atkinson JB, MahourJB, Isaacs H, et al: Hemangiopericytoma in infants and children: A report of six patients. Am J Surg 1984;148:372-374. 5. Atra A, Pinkerton R: High-dose chemotherapy in soft tissue sarcoma in children. Crit Rev Oncol Hematol 2002;41: 191-196. 6. Bailey PV, Webber TR, Tracy TF, et al: Congenital hemangiopericytoma: An unusual vascular neoplasm of infancy. Surgery 1993;114:936941. 7. Bastiaannet E, Groen H, Jager PL, et al: The value of F D G PET in the detection, grading and response to therapy of soft tissue and bone sarcomas: A systematic review and meta-analysis. Cancer Treat Rev 2004;30:83-101. 8. Bauernhofer T, Stoger H, Schmid M, et al: Sequential treatment of recurrent mesenteric desmoid tumor. Cancer 1996;77:1061-1065. 9. Bell RS, O'Sullivan B, Davis A, et al: Functional outcome in patients treated with surgery and irradiation for soft tissue tumours. J Surg Oncol 1 991 ;48:224231. 10. Bisogno G, Roganovich J, Sotti G, et al: Desmoplastic small round cell tumour in children and adolescents. Med Pediatr Oncol 2000;34:338-342. 11. Bisogno G, Sotti G, Nowicki Y, et al: Soft tissue sarcoma as a second malignant neoplasm in the pediatric age group. Cancer 2004;100:1758-1765. 12. Brennan MF: Management of soft tissue sarcoma. Aust N Z J Surg 1990;60:419-428. 13. Brennan MF: The enigma of local recurrence. Ann Surg Oncol 1997;4:1-12. 14. Brennan MF, Casper ES, Harrison L, et al: The role of multimodality therapy in soft-tissue sarcoma. Ann Surg 1991; 214:328-338. 15. Brien EW, Terek RM, Geer RJ, et al: Treatment of softtissue sarcomas of the hand. J Bone Joint Surg Am 1995;77:564571. 16. Casanova M, Ferrari A, Bisogno G, et al,: Alveolar soft part sarcoma in children and adolescents: A report from the Soft-Tissue Italian Cooperative Group. Ann Oncol 2000;ll:1445-1449. 17. Casanova M, Ferrari A, Spreafico F, et al: Malignant peripheral nerve sheath tumors in children: A single-institution twenty-year experience. J Pediatr Hematol Oncol 1999; 21509-513.

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18. Castillo BV, Kaufman L: Pediatric tumors of the eye and orbit. Pediatr Clin North Am 2003;50:1-20. 19. Castleberry RP, Kelly DR, Wilson ER, et al: Childhood liposarcoma: Report of a case and review of the literature. Cancer 1984;54:579-584. 20. Chang HR, Hajdu SI, Collin C, et al: The prognostic value of histologic subtypes in primary extremity liposarcoma. Cancer 1989;64:15141520. 21. Chen KT, Kassel SH, Medrano VA: Congenital hemangiopericytoma. J Surg Oncol 1986;31:127-129. 22. Cheng EY, Dusenbery KE, Winters MR, et al: Soft tissue sarcomas: Preoperative versus postoperative radiotherapy. J Surg Oncol 1996;61:90-99. 23. Chung EB, Enzinger FM: Infantile fibrosarcoma. Cancer 1976;38:729-739. 24. Chung EB, Enzinger FM: Infantile myofibromatosis. Cancer 1981;48:1807-1818. 25. Chung EB, Enzinger FM: Malignant melanoma of soft parts. Am J Surg Pathol 1983;7:405-413. 26. Cionini L, Marzano S, Olmi P: Soft tissue sarcomas: Experience with intraoperative brachytherapy in the conservative management. Ann Oncol 1992;3:S63866. 27. DeCou JM, Rao BN, Parham DM, et al: Malignant peripheral nerve sheath tumors: The St Jude Children's Research Hospital experience. Ann Surg Oncol 1995;2:524529. 28. Dehner LP, Hill DA, Deschryver K: Pathology of the breast in children, adolescents and young adults. Semin Diagn Pathol 1999;16:235-247. 29. Demetri GD, Elias AD: Results of single agent and combination chemotherapy for advanced stage soft tissue sarcomas: Implications for decision making in the clinic. Hematol Oncol Clin North Am 1995;9:765-783. 30. de Oliveira-Filho AG, Miranda ML, Diz FL, et al: Use of radiofrequency for ablation of unresectable hepatic metastasis in desmoplastic small round cell tumor. Med Pediatr Oncol 2003;41:476477. 31. Dominguez Malagon HR, Alfeiran Ruiz A, Chavarriaxicotencatl P, et al: Clinical and cellular effects of colchicine in fibromatosis. Cancer 1992;69:2478-2483. 32. Ducatman BS, Scheithouer BW, Peipgras DG, et al: Malignant peripheral nerve sheath tumors in childhood. J Neurooncol 1984;2:241-248. 33. Ducatman BS, Scheithouer BW, Peipgras DG, et al: Malignant peripheral nerve sheath tumors: A clinicopathologic study of 120 cases. Cancer 1986;57:2006-2021. 34. Enzinger FM: Hemangiopericytoma. In Weiss SW (ed): Soft Tissue Tumors, 2nd ed. St Louis, Mosby, 1988, pp 596613. 35. Enzinger FM, Weiss SW: Soft Tissue Tumors, 3rd ed. St Louis, Mosby, 1995. 36. Farhat F, Culine S, Lhomme C, et al: Desmoplastic small round cell tumors: Results of a four-drug chemotherapy regimen in five adult patients. Cancer 1996;7:1363-1366. 37. Ferguson WS: Advances in the adjuvant treatment of infantile fibrosarcoma. Expert Rev Anticancer Ther 2003;3: 185-191. 38. Ferrari A, Casanova M, Massimino M, et al: Synovial sarcoma: Report of a series of 25 consecutive children from a single institution. Med Pediatr Oncol 1999;32:32-37. 39. Ferrari A, Casanova M, Spreafico F, et al: Childhood liposarcoma: A single-institution twenty year experience. Pediatr Hematol Oncol 1999;16:415-421. 40. Ferrari A, Gronchi A, Casanova M, et al: Synovial sarcoma: A retrospective analysis of 271 patients of all ages treated at a single institution. Cancer 2004;101:627-634. 41. Fontanesi J, Pappo AS, Parham DM, et al: Role of irradiation in management of synovial sarcoma: St Jude Children's Research Hospital experience. Med Pediatr Oncol 1996;26:264267.

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42. Frezza G, Barbieri E, Ammendolia I, et al: Surgery and radiation therapy in the treatment of soft tissue sarcomas of extremities. Ann Oncol 1992;3:S93-S95. 43. Fritsch MK, Bridge JA, Schuster AE, et al: Performance characteristics of a reverse transcriptase-polymerase chain reaction assay for the detection of tumor-specific fusion transcripts from archival tissue. Pediatr Dev Pathol 2003;6:43-53. 44. Gandolfo N, Marinoli C, Cafiero F, et al: Malignant melanoma of soft tissues (clear cell sarcoma) of the foot: Is MRI able to perform a specific diagnosis? Report of one case and review of the radiological literature. Anticancer Res 2000;20:3993-3998. 45. Gerald WL, Ladanyi M, de Alava E, et al: Clinical, pathological, and molecular spectrum of tumors associated with t(ll:22)(p13:q12): Desmoplastic small round-cell tumor and its variants. J Clin Oncol 1998;16:30263036. 46. Gonzalez-Crussi F. Crawford SE. Sun CC: Intraabdominal desmoplastic small tumors with' divergent differentiation: Observations on three cases of childhood. Am J Surg Pathol 1990;14:633-642. 47. Goodlad JR, Fletcher CD, Smith MA: Surgical resection of primary soft-tissue sarcoma: Incidence of residual tumour in 95 patients needing re-excision after local resection. J Bone Joint Surg Br 1996;78:658-661. 48. Gross E, Rao BN, Bowman L, et al: Outcome of treatment for pediatric sarcoma of the foot: A retrospective review over a 20-year period. J Pediatr Surg 1997;32:1181-1184. 49. Gross E, Rao BN, Pappo AS, et al: Soft tissue sarcoma of the hand in children: Clinical outcome and management. J Pediatr Surg 1997;32:698-702. 50. Gupta A, Maddalozzo J, Win Htin T, et al: Spindle cell rhabdomyosarcoma of the tongue in an infant: A case report with emphasis on differential diagnosis of childhood skindle cell lesions. Pathol Res Pract 2004;200:537-543. 51. Hajai MM, Bal RK, Hagpal BM, et al: Synovial sarcoma of the hand. Indian Pediatr 1999;36:194197. 52. Heslin MJ, LewisJ, WoodruffJM, et al: Core needle biopsy for diagnosis of extremity soft tissue sarcoma. Ann Surg Oncol 1997;4:425-431. 53. Jaffe KA, Morris SG: Resection and reconstruction for softtissue sarcomas of the extremity. Orthop Clin North Am 1991;22:161-176. 54. Johnstone PA, Wexler LH, Venzon DJ, et al: Sarcomas of the hand and foot: Analysis of local control and functional result with combined modality therapy in extremity preservation. Int J Radiat Oncol Biol Phys 1994;29:735-745. 55. Karakousis CP, Proimakis C, Walsh DL: Primary soft tissue sarcoma of the extremities in adults. Br J Surg 1995;82: 1208-1212. 56. Karasek K, Constine LS, Rosier R: Sarcoma therapy: Functional outcome and relationship to treatment parameters. Int J Radiat Oncol Biol Phys 1992;24:651-656. 57. Kauffman SL, Stout AP: Hemangiopericytoma in children. Cancer 1960;13:695-710. 58. Keus RB, Rutgers EJ, Ho GH, et al: Limb-sparing therapy of extremity soft tissue sarcomas: Treatment outcome and long-term functional results. Eur J Cancer 1994;30A: 1459-1463. 59. Koutcher KA, Ballon D, Grahan M, et al: 31PNMR spectra of extremity sarcomas: Diversity of metabolic profiles and changes in response to chemotherapy. Magn Reson Med 1990;16:19-34. 60. Kurkchubasche AG, Halvorson EG, Forman EN, et al: The role of preoperative chemotherapy in the treatment of infantile fibrosarcoma. J Pediatr Surg 2000;35:880-883. 61. Kushner BH, LaQuaglia MP, Wollner N, et al: Desmoplastic small round cell tumor: Prolonged progression-free

552

62.

63. 64. 65. 66. 67. 68.

69. 70. 71. 72. 73.

74. 75.

76. 77.

78. 79. 80.

81.

82.

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MAJOR TUMORS OF CHILDHOOD

survival with aggressive multimodal therapy. J Clin Oncol 1996;14:1526-1531. Ladanyi M, Antonescu CR, Leung DH, et al: Impact of mTSSX fusion type on the clinical behavior of synovial sarcoma: A multi-institutional retrospective study of 243 patients. Cancer Res 2002;62:135-140. Ladenstein R, Treuner J, Koscielniak E, et al: Synovial sarcoma in childhood and adolescents: Report of the German CWS-81 study. Cancer 1993;71:3647-3655. LaQuaglia MP, Spiro SA, Ghavimi F, et al: Liposarcoma in patients younger than or equal to 22 years of age. Cancer 1999;72:31143119. Lawrence W, Neifield JP: Soft tissue sarcomas. Curr Probl Surg 1989;2:753-827. Lieberman PH, Brennan MF, Kimmel M, et al: Alveolar soft-part sarcoma: A clinico-pathologic study of half a century. Cancer 1989;63:1-13. Madden NP, Spicer RD, Allibone EB, et al: Spontaneous regression of neonatal fibrosarcoma. Br J Cancer Suppl 1992;18:S72-S75. Mandell L, Ghavimi F, LaQuaglia M, et al: Prognostic significance of regional lymph node involvement in childhood extremity rhabdomyosarcoma. Med Pediatr Oncol 1990;18:46&471. Mazeron JJ, Suit HD: Lymph nodes as sites of metastasis from sarcomas of soft tissue. Cancer 1987;60:1800-1808. McClain KL, Leach CT, Jenson HB, et al: Association of Epstein-Barr virus with leiomyosarcomas in children with AIDS. N Engl J Med 1995;332:12. Meis JM, Enzinger FM, Martz KL, et al: Malignant peripheral nerve sheath tumors (malignant schwannoma) in children. Am J Surg Pathol 1992;16:694707. Merens WC, Bramwell VH: Adjuvant chemotherapy for soft tissue sarcomas. Hematol Oncol Clin North Am 1995; 9:801-815. Meterissian SH, Reilly JA, Murphy A, et al: Soft-tissue sarcomas of the shoulder girdle: Factors influencing local recurrence, distant metastases, and survival. Ann Surg Oncol 1995;2:530-536. Miller RW, Young JL, Novakovic B: Childhood cancer. Cancer 1995;75:395-405. Miser JS, Triche TJ, Kinsella TJ, et al: Other soft tissue sarcomas of childhood. In Pizzo PA, Poplack DG (eds): Principles and Practice of Pediatric Oncology. Philadelphia, Lippincott-Raven, 1997, pp 865-888. Mounayer C, Benndorf G, Bisdorff A, et al: Facial infantile hemangiopericytoma resembling an arteriovenous malformation. J Neuroradiol 2004;31:227-230. Nag S, Olson T, Ruymann F, e t al: High-dose-rate brachytherapy in childhood sarcomas: A local control strategy preserving bone growth and function. Med Pediatr Oncol 1995;25:463-469. Nag S, Tippin DB: Brachytherapy for pediatric tumors. Brachytherapy 2003;2:131-138. Neifeld J, Maurer H, Dillon P, et al: Non-rhabdomyosarcoma soft tissue sarcomas (NRSTS) in children. Society of Surgical Oncology, 1994. Newton WA Jr, Soule EH, Hamoudi AB, et al: Histopathology of childhood sarcomas, Intergroup Rhabdomyosarcoma Studies I and 11: Clinicopathologic correlation. J Clin Oncol 1988;6:67-75. Nielsen OS, Cummings B, O'Sullivan B, et al: Preoperative and postoperative irradiation of soft tissue sarcomas: Effect of radiation field size. Int J Radiat Oncol Biol Phys 1991;21:1595-1599. Okeu MF, Despa S, Choroszy M, et al: Synovial sarcoma in children and adolescents: Thirty three years of experience with multimodal therapy. Med Pediatr Oncol 2001;37:90-96.

83. Ordonez NG: Alveolor soft part sarcoma: A review and update. Adv Academ Pathol 1999;6:125-139. 84. Pappo AS, Fontanesi J, Luo X, et al: Synovial sarcoma in children and adolescents: The St Jude Children's Research Hospital experience. J Clin Oncol 1994;12: 2360-2366. 85. Pappo AS, Parham D, Cain A, et al: Alveolar soft part sarcoma in children and adolescents: Clinical features and outcomes in 11 patients. Med Pediatr Oncol 1996;2681-84. 86. Pappo AS, Parham D, Lobe TE: Soft tissue sarcomas in children. Semin Surg Oncol 1999;16:121-143. 87. Pappo AS, Shapiro DN, Crist WM, et al: Biology and therapy of pediatric rhabdomyosarcoma. J Clin Oncol 1995;13:2123-2139. 88. Parham DM, Webber BL, Jenkins JJ 111, et al: Nonrhabdomyosarcomatous soft tissue sarcomas of childhood: Formulation of a simplified system for grading. Mod Pathol 1995;8:705-710. 89. Paulino AC: Late effects of radiotherapy for pediatric extremity sarcomas. Int J Radiat Oncol Biol Phys 2004;60:265-274. 90. Philippe PG, Rao BN, Rogers DA, et al: Sarcomas of the flexor fossae in children: Is amputation necessary? J Pediatr Surg 1992;27:964967. 91. Picard E, Udassin R, Ramu N, et al: Pulmonary fibrosarcoma in childhood: Fiber-optic bronchoscopic diagnosis and review of the literature. Pediatr Pulmonol 1999;27:347-350. 92. Pitcher ME, Thomas JM: Functional compartmental resection for soft tissue sarcomas. Eur J Surg Oncol 1994; 20:441-445. 93. Postovsky S, Peleg H, Ben-Itzhak 0 , et al: Fibrosarcoma of the trachea in a child: Case report and review of the literature. Am J Otolaryngol 1999;20:332-335. 94. Pratt CB, Kun LE: Soft Tissue Sarcomas of Children. Boston, Kluwer, 1993. 95. Pratt CB, Maurer HM, Salzberg A, et al: Treatment of unresectable or metastatic pediatric soft tissue sarcomas with surgery, irradiation and chemotherapy: A Pediatric Oncology Group study. Med Pediatr Oncol 1998;4: 201-209. 96. Pratt CB, Pappo AS, Gieser P: Role of adjuvant chemotherapy in the treatment of surgically resected pediatric nonrhabdomyosarcomatous soft tissue sarcomas: A Pediatric Oncology Group Study. J Clin Oncol 1999; 17:1219-1226. 97. Raney RB, Kollath J, Anderson.J, et al: Late effects of therapy for patients with primary orbital rhabdomyosarcoma: A report from the Intergroup Rhabdomyosarcoma Study (IRS-III), 19841991. Med Pediatr Oncol 1997;29:425. 98. Rao BN: Malignant lesions of the chest and chest wall in childhood. Chest Surg Clin North Am 1993;3:461-475. 99. Rao BN: Nonrhabdomyosarcoma in children: Prognostic factors influencing survival. Semin Surg Oncol 1993;9: 524531. 100. Rao BN: Present day concepts of thoracoscopy as a modality in pediatric cancer management. Int Surg 1997;82: 123-126. 101. Rao BN, Etcubanas EE, Green AA: Present-day concepts in the management of sarcomas in children. Cancer Invest 1989;7:349-356. 102. Rao BN, Santana VM, Parham D, et al: Pediatric nonrhabdomyosarcomas of the extremities: Influence of size, invasiveness, and grade on outcome. Arch Surg 1991;126: 1490-1495. 103. Rosen G, Forscher C, Lowenbraun S, et al: Synovial sarcoma: Uniform response of metastasis to high dose ifosfamide. Cancer 1994;73:2506-2511.

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104. Rosoff PM, Bayliff S: Successful clinical response to irinotecan in desmoplastic round blue cell tumor. Med Pediatr Oncol 1999;33:500-503. 105. Rydholm A, Gustafson P, Rooser B: Limb-sparing surgery without radiotherapy based on anatomic location of soft tissue sarcoma. J Clin Oncol 1991;9:1757-1765. 106. Sara AS, Evans HL, Benjamin RS: Malignant melanoma of soft parts (clear cell sarcoma): A study of 17 cases, with emphasis on prognostic factors. Cancer 1990;65:367-374. 107. Schmidt D, Thum P, Harms D, et al: Synovial sarcoma in children and adolescents: A report from the Gel Pediatric Tumor Registry. Cancer 1991;67:1667-1672. 108. Schwartz HS, Spengler DM: Needle tract recurrences after closed biopsy for sarcoma: Three cases and review of the literature. Ann Surg Oncol 1997;4:228-236. 109. Serpell JW, Ball AB, Robinson MH, et al: Factors influencing local recurrence and survival in patients with soft tissue sarcoma of the upper limb. Br J Surg 1991;78:1368-1372. 110. Shetty AK, YLILC, Gardner RV, et al: Role of chemotherapy in the treatment of infantile fibrosarcoma. Med Pediatr Oncol 1999;33:425-427. 111. Shmookler BM, Enzinger FM: Liposarcoma occurring in children: An analysis of 17 cases and review of the literature. Cancer 1983;52:567-574. 112. Sorensen SA, MulvihillJ, Nielsen A: Long-term follow-up of von Recklinghausen neurofibromatosis: Survival and malignant neoplasms. N Engl J Med 1986;314:1010-1015. 113. Soule EH, Pritchard DJ: Fibrosarcoma in infants and children. Cancer 1977;40:1711-1721. 114. Spunt SL, Poquette CA, Hurt YS, et al: Prognostic factors for children and adolescents with surgically resected nonrhabdomyosarcomatous soft-tissue sarcoma: An analysis of 121 patients treated at St Jude Children's Research Hospital. J Clin Oncol 1999;17:3697-3707. 115. Stark AM, Buhl R, Hugo HH, et al: Malignant peripheral nerve sheath tumors: Report of 8 cases and review of the literature. Acta Neurochir 2001;143:357-364. 116. Taylor SR, Nunez C: Fine-needle aspiration biopsy in a pediatric population: Report of 64 consecutive cases. Cancer 1984;54:1449-1453.

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117. Vadlamani I, Ma E, Brink DS, et al: Trisomy 15 in a case of pediatric hemangiopericytoma and review of the literature. Cancer Genet Cytogenet 2002;138:116-119. 118. Vaiday SJ, Payne GS, Leach MO, et al: Potential role of magnetic resonance spectroscopy in assessment of tumour response in childhood cancer. Eur J Cancer 2003;39:728-735. 119. Valle AA, Kraybill WG: Management of soft tissue sarcomas of the extremity in adults. J Surg Oncol 1996;63: 271-279. 120. Wall JE, Kaste SC, Greenwald CA, et al: Fractures in children treated with radiotherapy for soft tissue sarcoma. Orthopedics 1996;19:657-664. 121. Wexler LH, Helman LJ: Rhabdomyosarcoma and the undifferentiated sarcomas. In Pizzo PA, Poplack DG (eds): Principles and Practice of Pediatric Oncology. Philadelphia, Lippincott-Raven, 1997, pp 799-829. 122. Wiklund T, Huuhtanen R, Blomqvist C, et al: The importance of a multidisciplinary group in the treatment of soft tissue sarcomas. Eur J Cancer 1996;32A:269-273. 123. Willett CG, Suit HD, Tepper JE, et al: Intraoperative electron beam radiation therapy for retroperitoneal soft tissue sarcoma. Cancer 1991;68:278-283. 124. Williard WC, Collin C, Casper ES, et al: The changing role of amputation for soft tissue sarcoma of the extremity in adults. Surg Gynecol Obstet 1992;175:389-396. 125. Wilson AN, Davis A, Bell RS, et al: Local control of soft tissue sarcoma of the extremity: The experience of a multidisciplinary sarcoma group with definitive surgery and radiotherapy. Eur J Cancer 1994;30A:746-751. 126. Wong WW, Hirose T, Scheithauer BW, et al: Malignant peripheral nerve sheath tumor: Analysis of treatment outcome. Int J Radiat Oncol Biol Phys 1998;42:351-360. 127. Zalupski MM, Baker LH: Systemic adjuvant chemotherapy for soft tissue sarcomas. Hematol Oncol Clin North Am 1995;9:787-800. 128. Zornig C, Peiper M, Schroder S: Re-excision of soft tissue sarcoma after inadequate initial operation. Br J Surg 1995;82:278-279.

Teratomas and Other Germ Cell Tumors -

Richard G . Azizkhan

Pediatric germ cell tumors (GCTs) are a heterogeneous group of rare neoplasms. They occur at a rate of 2.4 cases per million children and account for approximately 1% of cancers diagnosed in children younger than 15 years.195 These neoplasms occur in both gonadal and extragonadal sites, with extragonadal and testicular tumors predominating in children younger than 3 years and gonadal tumors predominating during and after puberty. GCTs exhibit a broad spectrum of clinical presentation and histopathologic features and carry varying risks for malignancy, depending on the type of lesion. Irrespective of such differences, lesions are presumed to originate from the primordial germ cell. Clinical and pathologic variations stem from differences in the stage of germ cell development at tumorigenesis, gender, and oncogenic influences.36 Early in embryogenesis, germ cells begin to undergo a directed migration along the midline dorsal mesentery of the hindgut and are eventually incorporated into embryonic gonadal tissue. When this migratory process is perturbed, nests of germ cells may be deposited in abnormal locations. Thus, GCTs are found in the sacrococcygeal area, the mediastinum, the retroperitoneum, the pineal area of the brain, and the ovary and testis. Malignant transformation can occur at any of these sites. The broad spectrum of GCTs and tissue types in different anatomic locations reflects the totipotential nature of germ cells, with specific tumor types associated with the degree of cell differentiation. Most GCTs are associated with a number of biologic markers that are useful in identifying and managing these tumors and assessing their recurrence. Treatment depends on multiple factors, including specific pathology, anatomic location, tumor stage, histology, and resectability. Optimal outcomes are achieved with complete surgical resection, accurate histologic examination, and the selective use of chemotherapy. Of particular importance, the introduction of cisplatinum chemotherapy in the late 1970s led to a dramatic improvement in both survival and salvage rates for recurrent and metastatic disease.46 Current survival rates for low-stage extragonadal sites and for both low- and high-stage gonadal sites vary from

90% to loo%, depending on location. Survival for higherstage extragonadal lesions approximates 75%.'48 This chapter focuses on the most common extragonadal GCT, the teratoma, and on the malignant extragonadal GCTs typically seen by pediatric surgeons. Tumors of the ovaries and testes and intracranial tumors are discussed here only briefly but are covered in more detail in Chapters 36, 37, and 41, respectively.

EMBRYOLOGY Primordial germ cells originate near the allantois of the embryonic yolk sac endoderm and become evident by the fourth week of gestation. By the fifth week, these cells migrate through the mesentery to the gonadal ridgew and eventually become the gonads. This migration appears to be mediated by the c-kit receptor and stem cell factor. The latter is expressed in an increasing gradient from the yolk sac to the gonadal ridge, along which germ cells appear to migrate.'08J71Migration of cells cephalad to the gonadal ridges is complete by 6 weeks' gestation. At this stage, the ridges extend from the cervical to the lower lumbar levels on either side of the developing vertebral column.'j7 In animal models, the absence of c-kit receptor expression in primordial germ cells is associated with failure of migration and proliferation into the gonad.36 The prevailing hypothesis is that extragonadal GCTs arise from aberrant migration or the deposition of germ cells l l s migrate into along the path of m i g r a t i ~ n . ~ ~ emay areas that are not within the normal pathway (e.g., pineal and sacrococcygeal regions) or may remain outside the coalescence of gonadal tissue.

HISTOPATHOLOGIC CLASSIFICATION AND STAGING Although there is slight variation among the published classifications, GCTs are generally considered to consist of seven main histologic types: dysgerminorna (or seminoma),

CHAPTER

Stage I: Localized disease, with complete resection at any site (coccygectomy for sacrococcygeal site); negative tumor margins; tumor markers positive or negative Stage II: Microscopic residual disease; capsular invasion; negative lymph nodes or microscopic lymph node involvement; tumor markers positive or negative Stage Ill: Gross residual disease; gross lymph node involvement; cytologic evidence of tumor cells in ascites or pleural fluid; tumor markers positive or negative Stage IV: Distant metastases involving lungs, liver, brain, bone, distant nodes, or other sites. Adapted from staging systems of the Children's Oncology Group and the National Cancer Institute.

yolk sac (endodermal sinus) tumor, embryonal carcinoma, polyembryoma, choriocarcinoma, teratoma, and mixed GCT. Most malignant GCTs occur in pure form, but in 10% of cases, two or more tumor types are combined.'6l In order of frequency, the most common are teratoma, endodermal sinus tumor, germinoma, and mixed GCT. Choriocarcinoma, embryonal carcinoma, and polyembryoma are rarely seen. The existence of multiple tumor types and sites of origin precludes the development of a homogeneous staging system comparable to that for other organ-specific malignancies. The Children's Oncology Group and the National Cancer Institute have, however, adopted a general staging system for malignant extragonadal GCTs (Table 341). (For staging systems for female and male gonadal tumors, see Chapters 36 and 37.)

MAJOR BIOLOGIC MARKERS Alpha Fetoprotein Over the past several decades, a number of biologic markers used in the diagnosis and management of GCTs

I!

Mean

SD

34

555

Teratomas a n d O t h e r Germ Cell Tumors

have been the subject of intensive investigation,'5 and the clinical importance of these markers has become well established. Most GCTs secrete either alpha fetoprotein (AFP) or P-human chorionic gonadotropin (P-HCG); optimally, both markers should be measured before surgical excision of a suspected tumor to establish a baseline so that the impact oftherapy can be determined. AFP, which was first identified as a serum marker of liver tumors, is the predominant serum-binding fetal protein. The fetal and neonatal liver secretes AFP in large quantities, with newborn levels of 50,000 ng/mL being normal; higher levels are noted in premature infants. AFP reaches its peak concentration at 12 to 14 weeks' gestation and gradually drops to a normal adult level of 10 ng/dL by 8 months to 1 year of age."' Interpretation of AFP levels must thus be viewed within the context of the wide variability in normal levels during the first year of life. These levels become clinicallv relevant when thev are significantly elevated over the normal range for any particular age (Fig. 341). Elevated serum AFP levels or positive immunohistochemical staining of GCTs for AFP indicates the presence of malignant c&mponents, specifically yolk sac or embryonal carcinoma. Operative excision alone usually returns serum AFP levels to normal: its serum half-life is 5 to 7 davs.109 In most cases, treatment regimens are closely linked to the behavior of AFP, and postoperative monitoring is useful to detect tumor recurrence before it is clinically. apparent. If metastasis or residual tumor is susuected because AFP levels do not fall as expected, an extensive search should be undertaken using diagnostic imaging and possibly surgery. Elevations of AFP are not, however, always indicative of tumor progression. Chemotherapy-induced tumor lysis can cause abrupt though transient AFP elevation.187 Disorders associated with abnormal hepatic function, such as benign liver conditions, hepatic and gastrointestinal malignancies, viral hepatitis, cholestasis secondary to anesthesia, or drug-induced hepatic cholestasis, can also conditions ther lead to persistently high AFP l e v e l ~ . ~ " ~ " ~ ~ W associated with AFP elevation include hypothyroidism, ataxia telangiectasia, and hereditary tyrosinemia.194 Although these disorders are readily distinguishable from -

A

7

Premature Newborn Newborn -2 wks

134,734 541,444

48,406 %34,718

2 wks -1 mo

33,113 532,503

2 mos

9,452 i12,610

3 rnos 323 +278

4 mos 88 587

74 +56

5 mos 46.5 i19.0

6 mos 12.5 +9.8

7 moss

8 rnos

9.7 i7.1

+5.5

1

1 Declining serum alpha fetoprotein levels in normal infants. (Adapted from Wu JT, Sudar K: Serum alpha fetoprotein (AFP) levels in normal infants. Pediatr Res 1981;15:50.)

556

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MAJORTUMORS OF CHILDHOOD

GCTs, they should be considered when interpreting an elevated AFP level.

P-Human Chorionic Gonadotropin 0-HCG is a glycoprotein presumed to be produced by placental syncytiotrophoblasts. It is composed of a and p subunits, and the latter can be reliably assayed. P-HCG elevation suggests the presence of syncytiotrophoblasts as seen in choriocarcinoma, seminoma or dysgerminoma, . ~contrast ~ to the and occasionally embryonal c a r ~ i n o m aIn long half-life of AFP, the P subunit of HCG has a half-life ranging from only 24 to 36 hours.106 Its decline is rapid, and its sustained disappearance indicates complete tumor removal. Monitoring P-HCG levels helps assess the progress of patients with P-HCGsecreting tumors. As with AFP, a sudden elevation of serum P-HCG can occur after cell lysis secondary to chemotherapy.187 Also, rising levels of this marker may be associated with an increase in luteinizing hormone after bilateral orchiectomy or oophorectomy; this occurs because of immunologic cross-reactivity between the a subunit of luteinizing hormone and that of HCG.GOAlthough a number of other neoplasms (e.g., multiple myeloma and malignancies of the pancreas, gastrointestinal tract, breast, lung, and bladder) are associated with modest serum P-HCG elevation, these disorders are seen primarily in adults.

not require additional chemotherapy. Although it appears that tumor marker levels and the rate of half-life marker clearance are of prognostic importance, mild to moderate elevations during the later phases of chemotherapy may be less reliable indicators of persistent disease.

OTHER MARKERS

Elevated levels of serum lactate dehydrogenase (LDH), a glycolytic liver enzyme, have been observed in patients with GCTs and may be a prognostic indicator.90 LDH is a nonspecific marker thought to correlate with tumor growth and regression, although it shows no particular association with any GCT In patients with dysgerminoma, increased serum LDH isoenzyme 1 does, however, correlate with tumor burden and is useful in surgical management.I60 Spurious increases in LDH are seen with viral illnesses, liver diseases, and during and after chemotherapy."' Placental alkaline phosphatase (PLAP) is a reliable marker of GCT differentia ti or^,^^ and immunohistochemical staining for PLAP is useful for determining the origin of histologically undifferentiated GCTs.106 PLAP is elevated in the sera of virtually all patients with advanced seminoma and in 30% of patients with stage I semin0ma.103.l~~ It may also be useful in the analysis of other tumors of uncertain histogenesis, particularly if the differential diagnosis lies between seminoma and lymphoma.2" Two recent studies indicate that the concentration of Observations and Caveats s-kit (the soluble isoform of c-kit) in cerebrospinal fluid Over the past decade, investigators have made important may be a useful clinical marker for central nervous system observations that have stimulated debate regarding the germinomas, particularly for detecting recurrence 01-subAnother study indicates interpretation of AFP and HCG serum levels. Of particuarachnoid dis~emination.'2gJ~~ that combined CD117 (c-kit) and CD30 (Ki-1 antigen) lar relevance, a study conducted by Trigo et al.lsOindicated that the lack of elevated tumor markers is not always a reliimmunohistochemistrv, mav, be a valuable tool for d&tinguishing seminoma from embryonal carcinoma.l13 able indicator of the absence of recurrent disease. The authors suggested that although tumor marker assessment Vascular endothelial growth factor protein expression should be included in treatment follow-up, early detection is higher in testicular GCTs than in normal testes and correlates with microvessel count and svstemic metastases.58 of recurrence should not rely on this assessment alone. The prognostic significance of the prolonged half-life The epidermal growth factor receptor is a useful marker clearance of AFP or HCG has been the focus of a number to identify the syncytiotrophoblastic cells in testicular GCTs.81 of studies, with findings reflecting a lack of consensus or, at Investigators continue to look for biologic and the very least, a degree of confusion. Christensen et al.S4 questioned the concept of a fixed half-life for HCG, sugimmunohistochemical markers that will help differentiate gesting that a half-life delay following the later stages of GCT types and stratify patient^.^^",^"^^^,'?^,^^ Although chemotherapy may not always indicate persistent disease. many interesting observations have been made, further This delay has been attributed to a biphasic pattern of study in larger patient populations is required to validate the findings. Moreover, it is important to keep in mind half-life clearance, with a slower component occurring later in chemotherapy. Findings of other clinicians~?5J~~that most studies have been conducted in adult populasuggest that the rate of marker decline early in chemothertions rather than in children. apy is of prognostic value across risk groups. Bosl and Head26 reported that pretreatment risk status and posttreatment marker clearance are independent and equal prognostic variables, with prolonged half-life clearance being an important variable in both previously untreated New cytogenetic technologies have improved our underand treated patients. In contrast, Morris and Bosll30 standing of the genetics and molecular mechanisms reported six cases in which stable, modest elevations in involved in the development of GCTs. Genetic alterserum markers were present after treatment, even though ations may be associated with clinical outcome and are there were no radiographic or clinical indications of perthe subject of intense study. Flow cytometry has detersistent disease. Patients were closely monitored but did mined that pediatric GCTs have varied DNA ploidy and

APTER

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Teratomas and Other Germ Cell Tumors

557

are thus unlike adult GCTs, which tend to have aneuploid DNA.168 Most teratomas in children younger than 4 years are diploid, have normal karyotypes, and behave in a benign fashion regardless of site of Malignant GCTs in this age group are almost always yolk sac tumors and are generally diploid or tetraploid.14jJ70 The most common cytogenetic abnormalities involve chromosomes 1, 3, and 6. Studies have demonstrated deletion of lp36 in 80% to 100% of infantile malignant GCTs arising from testicular and extragonadal sites.145J70 A small minority of these tumors show evidence of c-myc or n-myc amplification, proto-oncogenes that may have prognostic s i g n i f i ~ a n c e . ' ~ ~ In older children and adolescents, cytogenetic analysis of central nervous system teratomas has shown a high frequency of sex chromosome abnormalities, most commonly increased copies of the X c h r o m o ~ o m e . ~ * J ~ ~ Although isochromosome 12p or i(12p) is quite common in all types of adult GCTs, it is infrequently seen in childhood GCTs. Having three or more copies of this isochromosome has been associated with treatment failure and is considered to be of prognostic i m p ~ r t a n c e . ~ ~ This abnormality has been described in pineal germinomas but has not been seen in pineal t e r a t ~ m a s . ~ ~ J ~ ~ J ~ ~ Sacrococcygeal teratoma in an infant at 30 weeks' Isochromosome 12p has also been identified in ovarian gestation. The tumor was successfully resected, and the patient is now tumors in both adolescents and a d ~ l t s . ~ a young adult. -

TERATOMAS

1

Disfiguring cleft palate defects are found in newborns with massive cranial and nasopharyngeal t e r a t o m a ~ . ~ ~ , ~ ~ Teratomas are the most frequently occurring GCT. These Teratomas can present as solid, cystic, or mixed solid neoplasms arise in both gonadal and extragonadal locaand cystic lesions. By definition, these lesions are comtions, and location is thought to correspond to the posed of representative tissues from each of the three embryonic resting sites of primordial totipotential germ germ layers of the embryonic disk (ectoderm, endoderm, cells. Teratoma presentation correlates with both age and mesoderm) and usually contain tissues foreign to the and anatomic site. Teratomas occurring in infancy and anatomic site of origin.40 One germ cell layer may preearly childhood are generally extragonadal, whereas dominate, and occasionally a teratoma can be monoderthose presenting in older children more commonly mal. Most teratomas that are present at birth consist of occur in the ovary or testis.164 More than half of terectodermal and mesodermal components. Epidermal atomas are observed at birth; they present in many locaand dermal structures such as hair and sebaceous and tions but are most common in the sacrococcygeal area sweat glands are frequently present, as are fairly well(Fig. 342). In prepubertal children, approximately 75% developed teeth. Pancreatic, adrenal, and thyroid tissue of teratomas occur in the sacrococcygeal area, and the diagnosis is generally made during the first year of life. Although more than one third of teratomas of the testis are recognized in the first year of life, these lesions are rarely diagnosed in the neonatal period?gJ76 The sacrococcyx is also the most common extragonadal location irrespective of age (45% to 65%) (Table 342). Cervicofacial Incidence (%) Site tumors and tumors of the intracranial cavity are seen less 45-65 Sacrococcygeal region frequently. Teratomas presenting in the mediastinum, 10-12 Anterior mediastinum heart, retroperitoneum, and liver are rare. Excluding 10-35 Gonadal (ovary and testis) testicular teratomas, 75% to 80% of teratomas occur in 3-5 Retroperitoneum females. Approximately 20% of tumors contain malig3-6 Cervical area nant components, the most common being endodermal 3-5 Presacral area 2-4 sinus tumor. Central nervous system
,

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The most important predictor of tumor recurrence in is also observed. Virtually all teratomas have mesodermal pediatric immature teratomas is the presence of microcomponents, including fat, cartilage, bone, and muscle. scopic foci of yolk sac tumor." Because of their size, they Endodermal components commonly seen include intesmay be missed by the pathologic sampling process. Such tinal epithelium and cystic structures lined by squamous, oversights may account for metachronous metastases cuboidal, or flattened epithelium.36 Mature and immature after resection of the immature teratoma metastasis. neuroepithelial and glial tissue is also frequently seen. In general, prognosis depends on the patient's age, Tumor tissue shows varying levels of maturity, and tumors the resectability of the tumor, and the presence of metasare classified histologically as either mature or immature tases or metastatic potential. (Fig. 343). Most pediatric teratomas are mature, exhibiting the absence of coexisting malignant cells with little or no tendency to undergo malignant degeneration. Mature teratomas of the gonads are encapsulated, multicystic, or Fetus in Fetu solid tumors, whereas extragonadal teratomas do not have The relationship between fetus in fetu and teratoma ~ ~ , ~ ~ , a~mature ~ clearly defined external c a p s ~ l e s . Although remains controversial and vague, with no clear distincteratoma may be benign from a histologic standpoint, it is ~ ~ in, fetu ~ ~is ,character~ ~ , ~ ~ tion between the t ~ o . ~ , Fetus important to note that it may be fatal if the airway is comized by organized vertebral, musculoskeletal, and organ promised or if vital structures such as the brain or heart structures that may resemble a fetus (Fig. 344). It has are involved. Moreover, depending on location and size, been detected both pre- and postnatally, with an abdomeven benign tumors may be inoperable and incompatible inal retroperitoneal mass being the most common cliniwith extrauterine life. nt is that fetus in fetu is a rare cal ~ i t e . ~ W u r r e thought Immature teratomas are usually larger and more solid form of highly differentiated teratoma. According to the than mature lesions. They differ histologically in that varWorld Health Organization classification, it is presently ious immature tissues, usually neuroepithelium, are prescategorized as a mature teratoma.I6l ent in lesions. A number of authors have devised and modified grading systems for immature teratoma~.l37J~~ Such systems generally consider the degree of immaturity of the tumor as well as the presence and quantity of Sacrococcygeal Teratoma its neuroepithelial components. Although grading has prognostic significance only for immature teratomas of Clinical Presentation and Diagnosis the adult 0vary,3~in the management of adolescents, it Sacrococcygeal teratoma (SCT) is the predominant terprovides clinicians with a useful indication of which atoma as well as the most common neoplasm of the fetus tumors may have a propensity for malignant transformaand newborn. The tumor has an estimated incidence of tion and therefore require close surveillance. Grading 1 in 20,000 to 40,000 live births and a female predominance systems are not as useful in the fetus or newborn because embryonic or immature elements may be appropriate Regardless of tumor for the stage of de~elopment.~2J84 grade in these patients, immature teratomas are associated with a favorable prognosis, and only in rare cases does immature neuroglial tissue metastasize to adjacent lymph nodes, lungs, and other distant organs from an immature primary site. 17,43,6"179

( 1 Histology of sacrococcygeal teratoma with hematoxylineosin stain demonstrating mature cystic epithelial elements, along with a dense central focus of immature neuroepithelial tissue.

Retroperitoneal fetus in fetu removed ti-om a 9-month-old female. This anencephalic tumor had extremities, a spine, and primitive facial structures.

CHAPTER

ranging from 2:l to 4:1.10,39,117J" Most SCTs are histologically benign; however, approximately 17% exhibit malignant histologic or clinical feature^.^.'^ Most cases of SCT occur sporadically, although 10% of patients have a family history of twinning. Ten percent to 20% of patients with SCT have coexisting anomalies such as tracheoesophageal fistula, imperforate anus, anorectal stenosis, spina bifida, genitourinary malformations, meningomyelocele, and anencephaly.l0,"~142,1"Jgl Also, many patients have significant structural abnormalities of juxtaposed organs resulting from displacement by a large teratoma. A classification system developed by Altman et aL3 divides SCTs into four distinct anatomic types that differ in the degree of intra- and extrapelvic extension. Type I (46.7%) is predominantly external, with minimal presacral extension. Type I1 (34.7%) arises externally and has a significant intrapelvic component. Type I11 (8.8%) is primarily pelvic and abdominal but is apparent externally. Type IV (9.8%) is presacral and has no external manifestation (Fig. 345). These authors observed that the incidence of malignant components correlates not only with anatomic type (8% in type I versus 38% in type IV) but also with age at diagnosis and gender; however, the size of the tumor is ~nrelated."~"he rate of malignancy of tumors found in older infants (older than 6 months) and in children is significantly higher than that of the visible exophytic tumors seen in neonates. Malignant change particularly appears to be more frequent in males,3j30,57 l~~ those with solid versus complex or cystic ~ u r n 0 r s . The most common malignant elements identified within sacrococcygeal lesions are yolk sac tumor and embryonal carcin~ma.~~ Many larger SCTs manifest in utero and can be diagnosed prenatally. To date, more than 60 such cases have Although the diagnosis is usually made been rep0rted.2~3~~' between 22 and 34 weeks' gestation, it has been made as early as 13 weeks. Uterine size larger than expected for gestational date (polyhydramnios or tumor enlargement) is the most common obstetric indication for performing a maternal-fetal ultrasound (US) examination.

I a Sacrococcygeal teratoma classification scheme. (From Altman RP, Randolph JG, Lilly JR: Sacrococcygeal teratoma: American Academy of Pediatrics Surgical Section Survey-1973. J Pediatr Surg 1974;9:389.)

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Teratomas a n d O t h e r Germ Cell Tumors

559

US may reveal an external mass arising from the sacral area of the fetus (Fig. 346A). This mass is composed of solid and cystic areas, with foci of calcification sometimes apparent. Most prenatally diagnosed SCTs are extremely vascular and can be s e e n on color-flow Doppler ~tudies.2~ Lumbosacral myelomeningocele is the most likely entity to be confused with SCT. This type of myelomeningocele and cystic SCT have similar findings on sonography. Because both are associated with elevated maternal levels of AFP, these levels are not helpful in distinguishing the two entities. Other critical information iained from sonography includes the possible presence of abdominal or pelvic extension, evidence of bowel or urinary tract obstruction, assessment of the integrity of the fetal'spine, and documentation of fetal lower extremity function.163 Imaging of the fetal brain is helpful in establishing the diagnosis because most fetuses with lumbosacral myelom~ningocelehave cranial signs such as ArnoldChiari malf0rmation.2~When there is doubt, fetal MRI can be extremely valuable in clarifying fetal anatomy and making a definitive diagnosis (Fig. 346B). Other soft tissue tumors that may mimic SCT include neuroblastoma, hemangioma, leiomyoma, and lipoma." Tumors can grow at an unpredictable rate to tremendous dimensions and may extend retroperitoneally, displacing pelvic or abdominal structures. Large tumors can cause placentomegaly, nonimmune fetal hydrops, and ~ , ' ~ conditions ~ are thought the mirror ~ y n d r o m e . ~These to result from a hyperdynamic state induced by lowresistance vessels in the teratoma.7 Without fetal intervention, high-output cardiac failure and hydrops resulting" in fetal demise are almost certain. Thus, in a select subset of fetuses that meet stringent criteria, restoring more normal fetal physiology may be achieved by surgical debulking of the SCT in u t e r ~ . ~ ~ ~ e o n a t adeath l mG occur due to obstetric com~lications from tumor rupture, preterm labor, or d y s t o ~ i a . ~ ~ , ~ ? ~ Impending preterm labor from polyhydramnios or uterine distention from tumor mass may require treatment by amnioreduction or cyst aspiration. ~ 6 t o c i aand tumor u

'

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A

B

Fetal imaging of a fetus with a sacrococcygeal teratoma. A, Prenatal maternal-fetal ultrasonograpy depicting a fetus with a sacrococcygeal teratoma (SCT). B, Maternal-fetal magnetic resonance image depicting a sizable sacrococcygeal teratoma in a 20-week fetus. (Courtesy of Dr. Timothy Crombleholme.)

rupture can be avoided by planned cesarean section delivery for infants with tumors larger than 5 cm.16" Antenatal diagnosis carries a significantly less favorable prognosis than does diagnosis at birth, and prognostic factors outlined in the current SCT classification system are not applicable to fetal cases."Z4 Whereas the mortality rate for SCT diagnosed in neonates is 5% at most, that for fetal SCT is close to 50%.24,5"54 Results of most clinical series indicate that hydrops or polyhydramnios and placentomegaly portend a fatal outcome. The indication for maternal-fetal US is also a predictive factor.Z4 If SCT is an incidental finding on routine prenatal sonography, the prognosis is favorable at any gestational age. Many of these lesions are predominantly cystic and relatively avascular and can be managed postnatally with surgical resection. If US is performed owing to maternal indications, the outcome is much less favorable. Additionally, prematurity from polyhydramnios or cesarean section performed before 30 to 32 weeks' gestation results in increased mortality.'" In light of these factors, antenatal diagnosis requires referral to a high-risk obstetric center with immediately available neonatal intensive care and pediatric surgical and anesthesia expertise. Postnatally, the diagnosis is determined by clinical findings on physical examination, serum AFP and PHCG levels,-and a number of radiographic imaging studies. Ninety percent of SCTs are noted at delivery, with a protruding caudal mass extending from the coccygeal region. Though uncommon, these tumors are easily recognized, and a reliable diagnosis can generally be made by physical examination alone. Intrapelvic components can be diagnosed by a rectal digital examination. SCTs seen at birth are predominantly benign, and many are c, functionally asymptomatic. Intrapelvic variants may have a delayed postnatal prese n t a t i ~ n . " . They ~ ~ ~ ~are ~ . ~typically noted in infants and

-

u

s

children between 4 months and 4 years of age. In contrast to the SCTs seen in neonates, these tumors are located in the pelvis and have no external component. More than one third are associated with malignancy. Clinical presentation may include constipation, anal stenosis, symptoms related to the tumor compressing the bladder or rectum, and a palpable mass. Presacral tumors are associated with sacral defects and anorectal malformations (Currarino's triad) (Fig. 347).

,

1 Abdominal radiograph in a 9-month-old female with Currarino's triad. A pelvic mass is seen displacing the intestine cephalad. A scimitar-shaped sacrum can also be visualized.

CHAPTER

Radiographs of the pelvis identify any sacral defects or tumor calcifications. Computed tomography (CT) with intravenous and rectal contrast material defines the intrapelvic extent of the tumor, identifies any nodal or distant metastases, and demonstrates possible urinary tract displacement or obstruction. CT also identifies liver metastasis and periaortic lymph node enlargement. MRI is useful when spinal involvement is suspected or if the diagnosis is in doubt. A chest radiograph is useful for revealing obvious pulmonary metastases, but because chest CT is more reliable in picking up smaller metastatic lesions, it should be performed when there is a high index of suspicion. The frequency of malignancy appears to correlate with age at diagnosis.3 Approximately 8% of SCTs noted at birth are malignant. After 2 months of age, the frequency of malignant transformation rises sharply. By 6 months, 40% to 80% of SCTs are malignant, with the most common type of malignancy being yolk sac tumor. Because presacral (type IV) SCTs are often diagnosed at an older age, they have an increased rate of malignancy.

Operative Treatment The treatment of choice for infants with SCT is complete surgical resection. With the exception of emergencies

Hegar dilator

34

Teratornas a n d O t h e r Germ Cell Tumors

561

related to tumor rupture or hemorrhage that adversely affect the neonate's hemodynamic status, operative intervention can be undertaken on an elective basis early in the newborn period. The anatomic location of the tumor determines the operative approach. Tumors with extensive intrapelvic extension or a dominant abdominal component (type I11 or IV) are initially approached through the abdomen. A posterior sacral approach is sufficient for most type I and I1 tumors (Fig. 348). Operative goals include (1) complete and prompt tumor excision, (2) resection of the coccyx to prevent tumor recurrence, (3) reconstruction of the muscles of anorectal continence, and (4) restoration of a normal A significant delay in perineal and gluteal appearan~e.695~ performing surgery may result in serious complications, including pressure necrosis, tumor hemorrhage, and malignant degeneration. Initial control of the middle sacral and hypogastric arteries may be required to safely remove tumors in these fragile infants. Surgery is performed in a temperaturecontrolled environment, and infants are protected from heat loss with appropriate measures. The urinary bladder is catheterized, and the procedure is generally performed with the patient in a pronejackknife position, cushioned in a sterile foam ring (see Fig. 348A). After skin preparation and sterile draping, a frown-shaped

Teratoma

Operative treatment of sacrococcygeal teratoma. A, Prone positioning of the infant. It is helpful to place a Hegar dilator partially into the rectum to facilitate its identification during the tumor resection. B, A "frown" or inverted V posterior incision facilitates access to the tumor and the coccyx, which is being divided. C, Middle sacral vessels after division of the coccyx. Once these vessels are ligated and divided, the tumor can be dissected from the rectum and separated from the gluteal and levator muscles. D, Tumor has been removed, and underlying rectum and pelvic muscles can be visualized. E, Anatomic reconstruction of the anorectal muscles is performed. Final closure of the incision.

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or inverted V incision is made superior to the tumor (see Fig. 348B). This incision provides excellent exposure and keeps the subsequent wound closure some distance from the anal orifice. To delineate the rectum, the surgeon's finger or a Hegar dilator may be inserted 3 cm into the anal canal. After raising skin flaps off the tumor, the attenuated retrorectal muscles are carefully identified and preserved. The mass is mobilized close to its capsule, and hemostasis is secured with electrocautery and suturing of vessels. To retard heat loss, warm gauze pads are placed over the exposed dissection and the tumor mass. The main blood supply to the tumor usually arises from a primitive middle sacral artery or from branches of the hypogastric artery. After division of the coccyx from the sacrum, the vessels can be observed exiting the presacral space ventral to the coccyx (see Fig. 348C). For patients with extremely large or vascular lesions in which excessive fluid shifts or hemorrhage may result in operative mortality, surgeons occasionally use extracorporeal membrane oxygenation in conjunction with hypothermia and hypoperfusion to facilitate better control of bleeding during resection. ' I h Because failure to remove the coccyx is associated with a recurrence rate as high as 37%,70the coccyx is excised in continuity with the tumor. The tumor is dissected free from the rectal wall, and the anorectal muscles are reconstructed (see Fig. 348D and E). The levator muscles are attached superiorly, providing support to the rectum and positioning the anus in the normal location. A closed suction drain may be placed below the subcutaneous flaps. The wound is then closed in layers with interrupted absorbable sutures (see Fig. 348F). A urinary catheter is left in position for several days. To maintain wound cleanliness, the patient is kept prone for several days postoperatively. Premature newborns with large teratomas are challenging to manage. Owing to lung immaturity, increased tumor vascularity, and poor tolerance of blood loss, the surgical risks are high." In these patients, devascularization and staged resection may be considered to avoid excessive blood loss. A fetus with a large SCT presents an even greater management challenge. As mentioned earlier, fetal hydrops and placentomegaly are associated with fetal demise. The most serious complication of excision is intraoperative hemorrhage, and the major cause of mortality is hemorrhagic shock. One successful preoperative strategy for stabilizing patients with vascular tumors and significant bleeding is to tightly wrap the teratoma with an elastic bandage. As a salvage approach for acute life-threatening hemorrhage, Teitelbaum et a1.177reported performing an emergent laparotomy and temporarily cross-clamping the distal abdominal aorta. As with any surgical procedure, wound complications can occur. Resection of teratomas with significant intrapelvic and intraperitoneal extension may be associated with temporary or persistent urinary retention in the postoperative period, but these symptoms generally resolve. Although patients with small tumors invariably have normal anorectal continence, 30% to 40% of premature infants with large SCTs and in whom the levator

and gluteal muscles are severely attenuated have fecal incontinence. Long-term bowel management strategies allow most patients to achieve socially acceptable bowel function.

Long- Term Outcome Research over the past several decades indicates that age at diagnosis is the dominant prognostic factor for SCT. Fetuses diagnosed with SCT after 30 weeks' gestation tend to have better outcomes than those diagnosed earlier.54z104J57 Postnatally, when the diagnosis is made before 2 months of age or excision is performed before 4 months of age, Additionally, cystic the malignancy rate is 5% to 10%.44,1X9 tumors, which are generally mature, carry a better prognosis. Complications related to hemorrhage, vascular steal, and malignancy are seen more frequently in patients with solid tumors. The long-term outcome in newborns with SCT is generally excellent. The Pediatric Onoclogy GroupChildren's Cancer Group study reported 80% event-free survival and 100% survival with complete resection alone in immature teratomas, even when microscopic foci of yolk sac tumor were present.Iy0 Nevertheless, because all SCTs have a risk of local or distant recurrence, close follow-up at 3-month intervals for 3 to 4 years is essential. According to findings reported by Rescorla et al.,IsO a Children's Cancer Group study noted an 11% tumor recurrence rate with mature teratoma and a 4% recurrence rate with immature teratoma. Although 43% to 50% of these recurrences were malignant, the chemosensitivity of yolk sac (endodermal sinus) tumor resulted in a high survival rate. Serum AFP levels are monitored, and physical examinations are performed. Special attention is given to rectal examination because it may detect a presacral recurrence. When AFP levels do not fall appropriately, abdominal US is performed. When there is an index of suspicion, abdominopelvic CT or MRI is carried out, as well as lung CT. A recurrent tumor may be benign, but it should be re-excised to minimize the longterm risk of malignant transformation.

Adjuvant Therapy Detection of malignant elements warrants adjuvant multiagent chemotherapy. The most active antineoplastic drugs include cisplatin, etoposide, and bleomycin. Current reports indicate impressive survival rates in patients with both locally advanced and metastatic disease after the administration of intensive chemotherapy."@,'4" Even with malignant transformation of SCT, Misra et a1.lZR reported survival rates of 88% with local disease and 75% with distant metastases. Moreover, it appears that stage, extent of metastasis, and extension into bone have no prognostic significance when children are treated with platinum-based regimens.ZY For patients in whom the primary malignant tumor is unresectable, a multiagent chemotherapy course is administered to facilitate subsequent resection. If a good tumor response is indicated by a diminishing serum AFP level and by CT and chest radiography, resection is undertaken after several cycles of chemotherapy.

CHAPTER

In patients with localized malignant recurrence, complete resection remains the cornerstone of salvage treatment. This is done in conjunction with adjuvant chemotherapy. Chemotherapy is also effective in the treatment of metastatic foci in the lungs and liver. However, to ensure the removal of any malignant elements, residual lesions must be excised. Though uncommon, radiation therapy may have a role in controlling unresectable disease in selected patients.

Head and Neck Teratoma Head and neck teratomas account for 5% of all neonatal teratomas. These rare neoplasms may occur in the brain, orbit, oropharynx, nasopharynx, or cervical region.

Intracranial Teratoma

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into contemporary research trials in an effort to reduce the long-term morbidity associated with radiotherapy, particularly in very young children. Additionally, both chemotherapy and radiotherapy have been used to sal2.~2~ vage failures by these respective m o d a l i t i e ~ . ~ , ~Some authors maintain that adding chemotherapy to the treatment protocol of children with germinoma may not enhance the already high survival rates but may lead to less radiation-induced morbidity by allowing reduced radiation volumes and doses or by delaying radiation future therapy in very young patients.*~~76~'~Wptimally, approaches for managing germinoma will combine minimal radiation doses and field sizes with less aggressive chemotherapeutic regimens. In contrast, high-risk patients with nongerminoma GCTs may benefit from a more aggressive approach including more intensive chemotherapy, radiation, and surgery. Considering the rarity of intracranial teratomas and the lengthy interval between treatment and the development of related side effects, evidence based on prospective randomized studies is a long-term goal.

Intracranial teratomas (covered in depth in Chapter 41) present in a bimodal age pattern. They account for nearly 50% of all brain tumors in early infancy, and a Cervicofacial Teratoma high prevalence is seen in the teenage years (ages 12 to Cervical teratomas are extremely rare neoplasms. 16) as well. In neonates, intracranial teratomas have an Although most of these tumors are histologically benign, equal sex predilection; in older children, they occur more they frequently cause significant airway and esophageal commonly in boys ( 2 1 ) . The pineal gland is the most obstruction in the perinatal period and are thus potentially common site of origin, although teratomas are also found fatal. Primary tumor sites include the tongue, nasopharynx, in the hypothalamus, ventricles, and suprasellar and cerepalate, sinus, mandible, tonsil, anterior neck, and thyroid bellar regions. Whereas intracranial teratomas occurring gland. As with SCTs, cervicofacial teratomas are predomiin neonates are generally benign, those seen in older chilnantly congenital in origin. Males and females are equally dren and teenagers are almost always malignant. All histoaffected. logic types have been observed, but intracranial Prenatal US is a reliable and essential diagnostic tool teratomas are broadly classified into two groups: nearly for detecting these lesions in utero, thereby allowing for 50% are classified as germinomas, and the remaining careful arrangement of the time, mode, and place of are considered nongerminoma GCTs. In many instances, delivery. When large cervical teratomas are detected prehowever, the tumor shows a mixed histologic pattern. The natally, findings generally reveal multiloculated irregular most common presenting finding in infants is increased masses with both solid and cystic components (Fig. 349).j2 intracranial pressure related to obstructive hydrocephalus. Older children and teenagers present with severe headaches, seizures, lethargy, visual disturbances, and vomiting. Boys with tumors that produce PHCG sometimes &th precocious puberty. The diagnosis is supported by skull radiographs and CT or MRI revealing either midline or paraxial supratentorial lesions that are often calcified. Resection is the treatment of choice, but many neonatal intracranial teratomas are not resectable. Palliative shunting to alleviate intracranial pressure and relieve hydrocephalus clearly has a short-term benefit but does not necessarily prolong survival in patients with malignant teratomas. Moreover, in some infants, shunting is associated with the spread of tumor to extracranial sites. Both chemotherapy and radiotherapy have been incorporated into contemporary treatment regimens. In children with germinoma, treatment with radiotherapy - . has yielded an excellent 5-year survival of 80% to 90%.1"7"1" In patients with nongerminoma GCTs, however, treatment with surgery and radiotherapy has yielded to 33% 5-vear s ~ r v i v a l . ~ ~ J ~ ~ a Door outcome. with 0% . I Prenatal ultrasonography depicting a barge cervical Although the role of chemotherapy in these patients has teratoma. not yet been well established, it has been incorporated -

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To delineate anatomy more clearly, fetal MRI is the diagnostic study of choice. Among cases detected prenatally, lymphatic malformation (cystic hygroma) is the most likely entity to be mistaken for cervical teratoma. Similarities in size, sonographic findings, clinical characteristics, location, and gestational age at presentation can make this distinction difficult.16 Other lesions to be considered in the differential diagnosis include large branchial cleft cyst and congenital thyroid goiter. Because less than 30% of cervical teratomas are associated with elevated serum AFP levels, this assay is not particularly helpful in the differential diagnosis of fetal cervical masses.21 Approximately one third of prenatally diagnosed cases are complicated by maternal polyhydramnios, which is thought to be due to esophageal obstruction or interference with fetal swallowing. There is a high incidence of preterm labor and delivery that may be secondary to increased uterine size resulting from polyhydramnios or tumor. Cervical teratomas are generally large and bulky, often Tumor measuring 5 to 12 cm in diameter (Fig. 3410) .16,167 masses greater than the size of the fetal head have been reported,l"g5.140 as has involvement of the oral floor, protrusion into the oral cavity (epignathus), and extension .~~ lesions may cause into the superior r n e d i a s t i n ~ mMassive dystocia, requiring a cesarean section to deliver the baby. Various anomalies occurring in association with cervical teratomas have been reported. These include craniofa,~ cia1 and central nervous system a n o m a l i e ~ hypoplastic left ventricle, trisomy 13, and one case each of chondrodystrophia fetalis and imperforate anus. Mandibular hypoplasia has also been seen as a direct result of mass effect on the develaping mandible.Z1 Up to 50% of cervicofacial teratomas contain calcificaand these are often seen best on postnatal tion~,~ZJO~ plain radiographs.74.172 When calcifications are present in a partially cystic and solid neck mass, they are virtually diagnostic of cervical teratoma.72 A postnatal CT scan is particularly useful in delineating the anatomic extent and precise involvement of the neoplasm.

1 Large cervical teratoma in a 34week premature baby. This infant had significant airway obstruction at birth and was successfully intubated in the delivery room.

As shown by Azizkhan et airway obstruction at birth is life threatening and is associated with a high mortality rate. In patients with massive fetal neck masses, this is generally associated with a delay in obtaining an airway and an inability to ventilate effectively. Delay can result in hypoxia and acidosis, and a delay longer than 5 minutes can result in anoxic injury. In light of these concerns, most cervicofacial teratomas are definitively treated after delivery, which should take place at a tertiary care center with an expert perinatal team that includes a pediatric surgeon. Optimally, if a cesarean section is performed, maternal-fetal placental circulation should be maintained while an airway is secured. This is done by employing an EXIT (ex utero intrapartum treatment) procedure. This method allows time to perform procedures such as direct laryngoscopy, bronchoscopy, tracheostomy, surfactant administration, and cyst decompression, which may be required to secure the airway.Z1Because precipitous airway obstruction may occur due to hemorrhage orotracheal intubation is indicated into the t~mor,l~,~2,89 in all patients, regardless of the presence or absence of symptoms. . l ~ ~ either had acute airway In some s e r i e ~ , l l ~infants obstruction or lost a previously secure orotracheal airway within a few hours or days after delivery. Because early resection after stabilization is the most effective method of achieving total airway control, it is the treatment of choice. Delaying surgery can have other serious ramifications, including retention of secretions,atelectasis,or pneumonia due to interference with swallowing.l6~65Resection also removes the risk of malignant degeneration, which occurs at much higher frequencies (>go%) in cases of cervical teratomas that are not diagnosed or treated until late adolescence or adulthood.2' To minimize operative morbidity, dissection of the teratoma should begin in areas distant to important regional nerves. Cervical teratomas often have a pseudocapsule, facilitating gentle elevation of the tumor out of the neck. If the tumor arises from the thyroid gland, the involved thyroid lobe is excised in continuity with the teratoma. Any enlarged lymph nodes should be excised with the tumor, because glial metastases may be present. After excision, a drain is left in place for 24 to 48 hours. Because these tumors are often large, envelopment of vital anatomic structures in the neck is common. In some cases, complete tumor excision with acceptable functional and cosmetic results may be achieved only by staged procedures.8 In contrast to the high incidence of malignancy (>60%) in adults, malignant cervicofacial teratomas with metastases are comparatively uncommon in neonates, with a 20% incidence reported by Azizkhan et a1.8 Despite the existence of poorly differentiated or undifferentiated tissue in the primary tumor, many infants remain free from recurrence following complete resection of a cervical teratoma. Such cases suggest that malignant biologc behavior is uncommon in this population.l6~45,~ Reported findings show a number of consistent histologic patterns.8 Neuroectodermal elements and immature neural tissue are the most commonly observed tissues in metastatic foci. In approximately one third of cases, the metastases are more differentiated but are confined to

CHAPTER

regional nodes. Patients with isolated regional node metastases who are treated with excision of the primary tumor generally survive free of disease. This supports the concept that the presence of metastases containing only differentiated tumor usually correlates with a good prognosis. There are currently no chemotherapy guidelines for neonates with malignant cervical teratomas. Based on results of their series, however, Azizkhan et a1.8 recommended that this modality be reserved for infants with disseminated disease (that has not differentiated) and those who have invasive tumors and residual disease after resection. Although cervical teratoma is generally a benign tumor, the possibility of malignant transformation mandates close surveillance for tumor recurrence. Serum AFP levels should be monitored at 3-month intervals in infancy and annually thereafter, with a rising level alerting the clinician to the possibility of tumor recurrence. As discussed earlier in this chapter, serum AFP levels must be interpreted with caution and viewed within the framework of their natural half-life. Imagng studies twice a year for the first 3 years of life are also recommended for surveillance. Because the thyroid and parathyroid glands may be removed or affected by tumor excision, the risk of temporary or permanent hypothyroidism must be con~idered.~ If encountered, these complications must be monitored and managed appropriately.

Mediastinal Teratoma Mediastinal teratomas account for approximately 20% of all mediastinal pediatric neoplasms. They are the second most common extragonadal site of teratomas and affect boys and girls equally. Though uncommon, other malignant mediastinal GCTs with various histologic patterns also arise. Mediastinal teratomas more frequently arise in the anterior mediastinum but are also observed within the pericardium or heart and, rarely, in the posterior mediastinum. Less than 50% of childhood mediastinal teratomas occur in neonates. Although adolescents and young adults are frequently asymptomatic, infants and children usually have symptoms that are related to compression of the lung or bronchi; they may range from acute respiratory distress to a chronic cough, chest pain, or wheezing. Anterior mediastinal and pericardial tumors are associated with superior vena cava syndrome. Some boys with mediastinal teratomas may present with precocious puberty associated with a benign or malignant P-HCGsecreting neoplasm. Because such neoplasms are associated with Klinefelter's syndrome, chromosomal karyotyping should be performed. More than 30 cases have been diagnosed prenatally. Accompanying polyhydramnios, fetal hydrops, and a number of other serious conditions have resulted in fatal outcomes. It is thought that open fetal surgery may have a role in a select subset of patients, although the two attempts to date have been unsuccessful. A postnatal chest radiograph may reveal a mediastinal mass; in approximately one third of cases, this mass is calcified. US of the chest shows a mass with cystic and solid components and

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may be useful in distinguishing the mass from the pericardium and heart. CT often clarifies the extent of the tumor and its relationship to surrounding anatomic structures. The differential diagnosis includes thymoma, thymic cyst, lymphatic malformation, mediastinal nonHodgkin's lymphoma, esophageal duplication, and bronchogenic cyst. When there is an index of suspicion, bone scintigraphy may be performed to detect osseous metastases. Serum levels of AFP, P-HCG, LDH, and PLAP may be ele~ated.~2 An overall malignancy rate of 15% has been reported in the pediatric age g r o ~ p . ~AOnumber of studies have shown that both mature and immature mediastinal teratomas occurring in newborns and infants behave in a in these age benign fashion if resected.3~J~7~~7Wutcomes groups have been shown to be more favorable than those in adolescents and adults. Complete surgical removal is the treatment of choice for both benign and malignant lesions. Because anterior mediastinal masses frequently compress the airway, anesthesia management is critical. Once spontaneous respiration has been eliminated by intravenous paralytic agents, patients may lose their ability to be ventilated, even with a properly positioned endotracheal tube. A sternotomy or thoracotomy provides excellent operative exposure. Care should be taken to avoid injury to the phrenic nerves. Histologic study reveals immature cellular elements in approximately 20% of mediastinal tumors in young children. Although this carries almost no increased risk of maliznancv in these children, the presence of immature " tissue is asiociated with high'mor(a1ity from progressive tumor in older teenagers and young adults. Thus, they should be treated with adjuvant chemotherapy. In cases in which malignant tumor has infiltrated into vital structures, resection may not be possible, and chemotherapy may be required to make the teratoma amenable to subsequent resection. Because cure of malignancy is unusual with resection alone, all patients undergo adjuvant postoperative chemotherapy to prevent disease recurrence and progression. Although results from cooperative multiagent chemotherapy trials have not been as impressive as those with sacrococcygeal lesions, they have been quite favorable. In a recent series,22 18 of 36 patients underwent biopsy followed by chemotherapy and then tumor resection. Tumor size remained stable or increased in 6 patients and decreased a mean of 57% in 12. The overall 4year survival rate for children treated with a regimen of etoposide, bleomycin, and cisplatin was 71%; the eventfree survival rate was 69%. The authors suggested that boys aged 15 years or older may be a high-risk subgroup for mortality from tumor progression.

Cardiac Teratoma Although a teratoma may arise in the heart, this occurs only rarely and almost exclusively in girls. Cardiac teratomas typically present with signs and symptoms of congestive heart failure, confined to the right side of the heart. The diagnosis is suspected on echocardiography, which reveals the presence of a multicystic intracardiac mass.

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Arrhythmias and an intraventricular block may be observed on an electrocardiogram. Associated congenital heart defects such as atrial septal defect and ventricular septal defect are frequently seen. To avoid the occurrence of complete outflow obstruction or a fatal arrhythmia, prompt resection is essential. Malignant teratomas (25%) require treatment with chemotherapy. For patients with benign, resectable cardiac teratomas, cardiac transplantation offers a reasonable therapeutic alternative.

RetroperitonealTeratoma The retroperitoneum is the third most common extragonadal site, accounting for 5% of all teratomas.us Most tumors are observed in early infancy, with 50% identified in the first year of life and 75% occurring by age 5. Girls are more dommonlv affected (21) . , than bovi. Patients usually present with a large palpable abdominal mass that may cause symptoms of alimentary tract compression. The differential diagnosis includes a number of other tumors seen in early childhood (e.g., neuroblastoma and Wilms' tumor), as well as cystic retroperitoneal lymphatic malformations, omental cyst, and fetus in fetu. Plain abdominal radiographs may .reveal displacement of bowel and calcification within the tumor. When calcification is present, the pattern is more distinct and noticeably different from the diffuse stippled calcification seen in neuroblastoma. CT or MRI of the abdomen helm differentiate this neoplasm from more common childhood tumors. Laparotomy for complete tumor resection is the therapy of choice.~ecausemost of these tumors are benign, this approach is usually successful. Approximately 20% of retroperitoneal teratomas are malignant at diagnosis, and 30% to 40% may have immature tissues. Benign glial implants have occasionally been observed, in&caiing a maturation process of these metastatic foci. Because malignant recurrence has been reported in patients with benign teratomas containing immature components, both malignant lesions and those containing high-grade immature elements should be treated with postoperative chemotherapy. '"5

Other Rare Extragonadal Teratomas Gastric Teratoma Gastric teratomas are exceedingly rare. These lesions may present as a palpable epigastric mass, with symptoms of gastric outlet obstruction or upper gastrointestinal bleeding occurring in infancy. These neoplasms are usually large and are often multicystic. Plain radiographs of the abdomen often show calcification. An upper gastrointestinal contrast study defines the stomach and tumor relationship. Upper endoscopy may reveal an extrinsic mass that compresses the gastric lumen or evidence of erosion by the tumor. Histologic examination reveals that these lesions are composed of mature tissues, frequently containing immature neuroglial elements. Resection of the tumor is the treatment of choice. The prognosis for this teratoma is generally fa~orable.47.Y1.~~2

Vaginal Teratoma These rare lesions present in the first year of life, often in the neonatal period. Examination may reveal minor bleeding from an easily visible vagnal mass. Most lesions are yolk sac tumors. A chest radiograph is performed to rule out lung metastases, and CT delineates the extent of the lesion. If the tumor is localized, management entails local resection of the tumor by partial vagmectomy and lowdose multiagent chemotherapy. Involvement of the uterus requires a hysterectomy. Preliminary adjuvant chemotherapy may limit the extent of the required resection.164

Gonadal Teratomas Ovarian Teratoma Teratomas are the most common pediatric ovarian tumor, accounting for more than 50% of all ovarian neoplasms and 25% of all childhood teratomas. Most ovarian teratomas present between 5 and 16 years of age and are unusual in the first 2 to 3 years of life. Pain is the most common presenting symptom, observed in more than 50% of patients. Acute abdominal pain from torsion of the tumor is reported in 25% of patients. Because most tumors are large (10 to 15 cm), the identification of an asymptomatic abdominal mass is another common presentation. Intra-abdominal and pelvic calcifications resembling teeth are seen in approximately half of abdominal radiographs. Tumors occur equally on the right and left ovaries and are bilateral in 5% to 10% of cases. Although abdominopelvic US shows a mass composed of cystic and solid components as well as the structure of the contralateral ovary, CT is the optimal imaging study for preoperative staging. Serum AFP and HCG levels should be obtained. If elevated, they may be indicative of malignant potential. Simple or salpingo-oophorectomy is the treatment of choice for benign tumors with an intact capsule and mature elements on histologic examination. At the time of surgery, any ascitic fluid is collected for cytologic analysis. If ascitic fluid is absent, peritoneal washings are obtained and evaluated for the presence of tumor cells. All peritoneal surfaces, including the underside of the diaphragm, are inspected for peritoneal implants. If they are observed, biopsy specimens are obtained. An infracolic omentectomy should be performed if the omentum has gross tumor. Gonad-sparing resection of benign cystic ovarian teratomas has been advocated by some surgeons. However, long-term follow-up is limited, and this approach remains controversial.l~s The management of immature ovarian teratomas with extraovarian peritoneal involvement is complex. Fortunately, most patients have mature glial implants. They do not require chemotherapy and hive an excellent prognosis.155 Tumors with a higher histologic grade (grades I1 and 111) have a risk of malignancy and require adjuvant multiagent chemotherapy. Treatment with current chemotherapeutic regimens has resulted in a survival rate approaching 90%.Y7 (For a more detailed discussion, refer to Chapter 36.)

CHAPTER

Testicular Teratoma Testicular teratomas are the most common testicular neoplasms in childhood. They present bimodally in terms of age, with infants younger than 2 years and teenagers and young adults most commonly affected. Infants usually present with a nontender scrota1 mass. In 15% of patients, a hydrocele may also be present. Preoperative serum AFP and HCG levels are obtained. A chest radiograph and an abdominal CT scan are obtained to evaluate for nodal and visceral metastases. Tumors are staged by virtue of their resectability and the presence of nodal and distant metastases. In stage I disease (80% of cases), treatment consists of a transinguinal radical orchiectomy and includes excision of the spermatic cord at the internal ring. Radical orchiectomy alone in stage I disease in infants is associated with greater than 90% 5-year survival. Most malignant tumors in infants are yolk sac tumors that rarely metastasize to retroperitoneal lymph nodes. . ~ e t r o ~ e r i t o n e alymph l node -dissection is thus not required for infants with stage I disease who are younger than 2 years and have a normal preoperative abdominal CT scan. If elevated serum tumor markers do not return to normal after resection (20% of cases), the teratoma is restaged, ., retroperitoneal lymph node dissection is subsequently perfdrmed, and adjuvant chemotherapy is administered. Retro~eritonealnode dissection is usuallv performed unilaterally, using nerve-sparing techniques to prevent retrograde ejaculation. Suspicious contralatera1 lymph nodes should be biopsied. The frequency of relapse following lymphadenectomy is 10% to 15%, with disease usually recurring in the lungs or mediastinum. Most patients with metastatic disease benefit from multiagent chemotherapy. (For a more detailed discussion, refer to Chapter 3'7.) A

YOLK SAC TUMOR Yolk sac tumors are the most common malignant GCT affecting children from infancy to adolescence. In neonates and young children, these neoplasms are found primarily in extragonadal sites, particularly the sacrococcygeal area. However, they are also common in the testes of infants and young boys,'" with yolk sac tumor being the predominant pediatric malignant GCT involving the testis. In older children and adolescents, the ovary is the most common location. Less common primary sites include the mediastinum, retroperitoneuk, pineal area, and vagina. In adolescents, these tumors rarely occur in pure form in extragonadal sites but are seen as a component of mixed malignant G C T S . ~Pediatric ~ , ~ ~ yolk sac tumor is cytogeneticdly and biologically distinctfrom its adult counterpart. Examination of pediatric tumor tissue has shown deletions in chromosomes 1 ( l p ) and 6 (6q), but no evidence of the i(12p) deletion observed in adult GCTs. 43 Grossly, yolk sac tumors appear as pale gray to yellow friable, mucoid tissue with foci of cystic areas and necrosis."J7 One relatively recent and credible theory suggests that these neoplasms originate from the primary yolk

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sac,l36 a structure that develops early in embryogenesis. The yolk sac consists of multipotential primitive endoderm tissue capable of differentiating into the primitive gut and its derivatives, including the liver, thus leading to variable histologic patterns. The pseudopapillary (festoon) and microcystic (reticular) patterns are the most common and widely recognized. Both usually display perivascular sheaths of cells referred to as endodermal sinus structures or Schiller-Duval bodies. Most welldifferentiated yolk sac tumors also contain intra- and extracellular hyaline deposits that are resistant to periodic acid-~chiffdiastase staining and positive for AFP. However, in that the microcystic pattern is less differentiated, it is often associated with eosinophilic globules and strands that infrequently stain positively for AFP. Occasionally, endodermal sinus tumors are more solid and can be difficult to distinguish from embryonal carcinoma. Some tumors may have a hepatoid- pattern that resembles fetal liver 'cells.7" Variations in histologic pattern do not appear to correlate with outcome, which has improved considerably with multiagent chemotherapy. ~ e v ~ r t h e l e sass ,evidenced by the Pediatric Oncology Study (19'71-1984), 7 h e o n a t a l SCTs may recur as yolk sac tumors, which are associated with a worse -prognosis owing to their invasive nature. -

EMBRYONAL CARCINOMA Though far less common than yolk sac tumors, embryonal carcinoma also presents in the first year of life. It rarely occurs in pure form in children; more often, it is a component of a mixed malignant GCT. The major histologic pattern is epithelial, comprising large nests of cells with varying amounts of central necrosis. However, pseudotubular and papillary patterns, which may be confused with those of volk sac tumors. are also common. Cells are AFP negative, and tumors generally lack the eosinophilic hyaline globules characteristic of some yolk sac tumors. In contrast to other GCTs, embryonal carcinoma is positive for cytokeratin by immunohistochemical staining.36

GERMINOMA The term germinoma is currently used to refer to a group of neoplasms with common histologic characteristics. Formerly, a lesion was termed a seminoma if found in the testis, a dysgemzinoma in the ovary, and a germinoma in an extragonadal site. These tumors are thought to arise f r ~ m t o t i ~ o t e n t igerm a l cells present at the indifferentiated stage of gonadal development. They are commonly seen in the ovary, anterior mediastinum, and pineal region and are the most common pure malignant GCT occurring in the ovary and central ;ervous system in children.49J7"In children, germinomas account for 10% of all ovarian tumors and approximately !5% of GCTs in all locations. These tumors are rarely seen in infants and small children and occur most often in prepubertal girls and young women, with 44% of cases presenting before age 20 years.73 Germinoma is the predominant malignancy found in dysgenetic gonads and undescended testes.

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On gross examination, germinomas appear solid, encapsulated, gray-pink or tan in color, with occasional small foci of hemorrhage and necrosis and a rubbery consistency. Tumor cells are arranged in nests separated by bands of fibrous tissue associated with variable degrees of lymphocytic infiltration. The cells are large, with clear to slightly eosinophilic cytoplasm, distinct cell membranes, and large round nuclei having one or two h with giant prominent n u ~ l e o l i . ~ W t h o u ggranulomas cells as well as syncytiotrophoblasts may be present, they alter tumor prognosis only when associated with cytotrophoblasts in foci of choriocarcinoma. Germinoma cells strongly stain for PLAP, whereas syncytiotrophoblasts stain for P-HCG. As noted by Scully et al.,lMgerminomas are also immunoreactive for vimentin and, in some cases, LDH, neuron-specific enolase, Leu-'7, cytokeratin, desmin, and glial fibrillary acidic protein. In one study,183c-kit localization was found in 92% of germinomas.

to extraovarian spread of tumor at presentation.lV2 The histologic tumor appearance is characterized by a preponderance of embryoid structures that resemble normal early embryos in various stages of development. These structures are composed of yolk sac, embryonal, and hepatic elements, as well as chorionic elements such as syncytiotrophoblastic giant cells. Mature and immature teratomatous elements, predominantly of endodermal derivation, are usually present as well.1" In many cases, elevated serum levels of AFP and P-HCG have been noted. Histologically, both the yolk sac and the hepatic elements are immunoreactive for AFP and alphal-antitrypsin. Syncytiotrophoblastic elements are immunoreactive for HCG.l02,133",47,173

GONADOBLASTOMA Gonadoblastoma is a relatively rare tumor composed of aerm cells intermixed with stromal c e l l s . ~ ~ " .is~con~~8~t sidered a precursor to the development of a malignant GCT. Gonadoblastoma is most commonly found in dysgenetic gonads of phenotypic females wh&have at least a .~~ are generally fragment of the Y c h r o m ~ s o m ePatients older adolescents or in the third decade of life and have a history of primary amenorrhea. They may exhibit a lack of secondary sexual characteristics and the presence of elevated gonadotropin levels and streak gonad~:~(),l"-lg0 These tumors are often quite small, soft to firm, gray-tan to brown, and slightly Ibbulated. Microscopic Features include the proliferation of both germ cells and gonadal sex cord cells. Germ cells show positivity for PLM.36 Most gonadoblastomas behave in a benign fashion, although there is a 30% risk of overgrowth of a malignant germ cell elernent.18Warying malignant elements may be present; germinoma is the most common, occurring in ~ ~malignant ~~!) potential approximately 50%of c a s e ~ . I ~The of this tumor is determined by the underlying malignant component. Gonadectomy is recommended for young patients with mixed gonadal dysgenesis because of the increased frequency of gonadoblastoma arid germinoma and the virilizing effects of residual testicular tissue.1"'

-

Choriocarcinoma is a rare, highly malignant tumor seen primarily in females. This tumor typically occurs as a component of a malignant mixed GCT. As with yolk sac tumors and embryonal carcinoma, this lesion can occur during the first year of life, either as a metastasis secondary or as a primary tumor to a placental chorio~arcinoma",~~ arising from locations such as the liver, lung, brain, kidney, or maxilla."".l" The most common site is the pineal region.5(i,~(i(i I~ presents in both prepubertal children and young adolescents, occurring primarily in the gonads and less frequently in the mediastinum. Pure choriocarcinoma in young infants almost always represents disseminated metastasis from maternal or placental gestational trophoblastic tumor.i"55 On gross examination, pure choriocarcinoma is characteristically solid, hemorrhagic, and friable. Microscopically, both cytotrophoblasts and syncytiotrophoblasts are present. Cytotrophoblasts typically appear as closely packed nests of relatively uniform, medium-sized cells with clear cytoplasm, distinct cell margins, and vesicular nuclei, whereas syncytiotrophoblasts represent giant multinucleated syncytial trophoblastic cells." Both cell types are typically immunoreactive for cytokeratin. The syncytiotrophoblastic cells are also immunoreactive for HCG, human placental lactogen, and pregnancy-specific Dl-glycoprotein. In addition, immunoreactivity for PLAP, epithelial membrane antigen, neuron-specific enolase, alphal-antitrypsin, and carcinoembryonic antigen is seen in some tumors.161

POLYEMBRYOMA Polyembryomas are exceedingly rare malignant tumors of the ovary, with fewer than 10 cases reported during the last 4 decades.'" They are often reported in combination with other neoplastic components.l8.l02Patients are typically children or young women who present with clinical symptoms and signs indicative of the presence of a large pelvic mass. Rarely, patients have symptoms related

MIXED GERM CELL TUMORS GCTs often comprise two or more pure histologic types. .Benign throughhossibly malignan; GCTs such as immature teratomas may coexist with frankly malignant GCTs, and 10% to 40% of patients with malignant tumors have Of these patients, 40% are diagmixed hi~tology.l~",~"~12~ nosed before-puberty.~" The most common histolog~c component of mixed GCTs is dysgerminoma (germinoma), although immature teratoma, endodermal sinus tumor, and embryonal carcinoma may be detected in varying proportions.36 Also, mixed GCTs account for 8% to 10% of malignant primitive GCTs of the o ~ a r y . l ~ ) ~ - l ~ ~ The occurrence of these tumors underscores the importance of careful gross examination and judicious tumor tissue sampling.- he prognosis of patiknts with mixed GCTs is generally thought to depend on the tumor's most malignant element, but some investigators have > .

CHAPTER

reported that a minor component of a highly malignant element affects the prognosis less adversely than does a major component.IO5

TREATMENT OVERVIEW AND FUTURE PERSPECTIVES Advances in surgical treatment, together with the use of platinum-containing multiagent chemotherapy regimens, have resulted in a dramatic improvement in the outcome for children with malignant GCTs. International studies using integrated multimodal treatment strategies are reporting impressive survival rates, ranging from 75% to 90%.1".fi5121,149,178,193Although chemotherapy protocols in these studies differ somewhat, the standard chemotherapy regimen in the United States for children with malignant extragonadal GCTs includes a combination of cisplatin, etoposide, and bleomycin (PEB). This protocol has, however, been associated with a high risk of late effects, particularly the nephrotoxicity and ototoxicity Growing concern about these effects has of ci~platin.".~~ spurred investigations into alternative protocols with less deleterious long-term effects. In the United Kingdom, the combination of carboplatin, etoposide, and bleomycin UEB) has undergone clinical investigation in children younger than 16 years. Authors have reported comparable event-free survival with less ototoxicity and renal impairment than PEB.HgCorroborating these findings, a recent prospective study conducted in the United States concluded that carboplatin could be substituted for cisplatin without sacrificing response or survival; overall survival and In event-free survival were 91% and 87%, respe~tive1y.l~~ contrast, adult studies that substituted standarddose carboplatin for cisplatin in combination with etoposide alonegor with etoposide and lowdose bleomycinx8 demonstrated inferior event-free and overall survival in patients with malignant GCTs. To date, no randomized comparison of PEB versusJEB has been conducted in children. Because pediatric extragonadal GCTs are rare and treatment is effective, the number of relapsed patients is small, ranging from 20% to 30%. Children with recurrent malignancy following resection may be salvageable with the standard PEB regimen. For patients with cisplatinrefractory or poorly responding tumors, a further dose escalation of cisplatin under protection with amifostine is being evaluated in the United States, with results regarding toxicity still pending. Results from German protocols suggest that locoregional hyperthermia offers an attractive alternative, in that cisplatin is a good thermosensitizer and hyperthermia may thus overcome cisplatinum resistance.l* Additionally, authors anticipate that locoregional hyperthermia will result in fewer systemic side effects than cisplatin dose escalation. Although ifosfamide is not used as a first-line therapy, it has been incorporated into various treatment strategies and, in for adults with relapsed or refractory disease115~l2.fi combination with cisplatin and etoposide (ICE), has been There used in a small number of pediatric patient~.l22J2~ is, however, increasing concern about the nephrotoxicity of this drug combination in children. Another area of ongoing research, particularly for high-risk GCTs in

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older adolescents and young adults, is high-dose chemotherapy with peripheral blood stem cell transplant.23 Outcomes of this approach have not yet been clearly established. In a further effort to minimize the late toxic effects of treatment, the Pediatric Oncology Group and the Children's Cancer Group cooperatively developed a classification scheme that allows for less intense and more individualized treatment approaches. Based on the results of their studies, patients are stratified into three distinct risk groups: Low risk-patients with stage I malignant gonadal and extragonadal GCTs, including stage I immature teratomas Intermediate risk-patients with stage I1 to IV gonadal and stage I1 extragonadal GCTs High risk-patients with stage I11 and IV extragonadal GCTs The Children's Oncology Group is currently developing risk-specific treatment strategies based on this new scheme. Under consideration is observation without adjuvant chemotherapy after surgical resection for all patients with stage I tumors."J1g To ensure that recurrent disease is detected early, strict guidelines for the evaluation and follow-up of these patients will be mandated. For patients with intermediate-risk tumors, consideration is being given to a modified standard PEB treatment that decreases the length of therapy. For children with high-risk extragonadal GCTs, the previously cited investigation using high-dose PEB in combination with amifostine is ongoing.

REFERENCES 1. Ablin A, Krailo M, Ramsey N, et al: Results of treatment of malignant germ cell tumors in 93 children: A report from the Children's Cancer Study Group. J Clin Oncol 1991;9:1782. 2. Alpers CE, Harrison MR: Fetus in fetu associated with an undescended testis. Pediatr Path01 1985;4:37. 3. Altman RP, Randolph JG, Lilly JR: Sacrococcygeal teratoma: American Academy of Pediatrics Surgical Section Survey-1973. J Pediatr Surg 1974;9:389. 4. Atkin NB, Baker MC: Abnormal chromosomes including small metacentrics in 14 ovarian cancers. Cancer Genet Cytogenet 1987;26:355. 5. Aubry F, Satie AP, Rioux-Leclercq N, et al: MACE-A4, a germ cell specific marker, is expressed differentially in testicular tumors. Cancer 2001;92:2778. 6. Azizkhan RG: Neonatal tumors. In Carachi R, Azmy A, Grosfeld JL (eds): The Surgery of Childhood Tumors. New York, Oxford University Press, 1999, ch 8. 7. Azizkhan RG, Caty MG: Teratomas in childhood. Curr Opin Pediatr 1996;8:287. 8. Azizkhan RG, Haase GM, Applebaum H, et al: Diagnosis, management, and outcome of cervicofacial teratomas in neonates: A Children's Cancer Group study. J Pediatr Surg 1995;30:312. 9. Bajorin DF, Sarosdy MF, Pfister DG, et al: Randomized trial of etoposide and cisplatin versus etoposide and carboplatin in patients with good-risk germ cell tumors: A multiinstitutional study. J Clin Oncol 1993;11:598.

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177. Teitelbaum D, Teich S, Cassidy S, et al: Highly vascularized sacrococcygeal teratoma: Description of this atypical variant and its operative management. J Pediatr Surg 1994;29:98. 178. Toner GC, Stockler MR, Boyer . MI, - et al: Comparison of two standard chemotherapy regimens for good prognosis germ cell tumors: A randomized trial. Lancet 2001:357:739. 179. Touran T, Applebaum H, Frost DB, et ;I: Congenital metastatic cervical teratoma: Diagnostic and management considerations. J Pediatr Surg 1989;24:21. 180. Trigo JM, Tabernero JM, Paz-Ares L, et al: Tumor markers at the time of recurrence in patients with germ cell tumors. Cancer 2000;88:162. 181. Troche V, Hernandez E: Neoplasia arising in dysgenetic gonads: A review. Obstet Gynecol Surv 1986;41:74. 182. Tsukahara Y, Fukuta T, Yamada T, et al: Retroperitoneal giant tumor formed by migrating polyembryoma with numerous embryoid bodies from an ovarian mixed germ cell tumor. Gynecol Obstet Invest 1991;31:58. 183. Tsuura Y, Hiraki H, Watanabe K, et al: Preferential localization of c-kit product in tissue mast cells, basal cells of skin, epithelial cells of breast, small cell lung carcinoma and seminoma/dysgerminoma in human: Immunohistochemical study on formalin-fixed, paraffin-embedded tissues. Virchows Arch 1994;424:135. 184. Valdiserri RO, Yunis EJ: Sacrococcygeal teratomas: A review of 68 cases. Cancer 1981;48:217. 185. Verp MS, Simpson JL: Abnormal sexual differentiation and neoplasia. Cancer Genet Cytogenet 1987; 25:191. 186. Vilain E, Jaubert F, Fellous M, et al: Pathology of 46,XY pure gonadal dysgenesis: Absence of testis differentiation associated with mutations in the testis-determining factor. Differentiation 1993;52:151.

187. Vogelzang NJ, Lange PH, Goldman A, et al: Acute changes of alpha-fetoprotein and human chorionic gonadotropin during induction chemotherapy of germ cell tumors. Cancer Res 1982;42:4855. 188. von Eyben FE, Madsen EL, Blaabjerg 0 , et al: Serum lactate dehydrogenase isoenzyme 1 and relapse in patients with nonseminomatous testicular germ cell tumors clinical stage I. Acta Oncol 2001;40:536. 189. Waldhausen JA, Kolman JW, Vellios F, et al: Sacrococcygeal teratoma. Pediatr Surg 1963;54:933. 190. Warner Bh, Monsaert RP, Stumpf PG, et al: 46,XYgonadal dysgenesis: Is oncogenesis related to H-Y phenotype or breast development? Hum Genet 1985;69:79. 191. Werb P, Scurry J, Ostor A, et al: Survey of congenital tumors in perinatal necropsies. Pathology 1992;24:247. 192. Wessalowski R, Kruck H, Pape H, et al: Hyperthermia for the treatment of patients with malignant germ cell tumors: A phase 1/11 study in ten children and adolescents with recurrent or refractory tumors. Cancer 1998;82:793. 193. Wollner N, Ghavimi F, Wachtel A, et al: Germ cell tumors in children: Gonadal and extragonadal. Med Pediatr Oncol 1991;19:228. 194. Wu JT, Book L, Sudar K: Serum alpha fetoprotein (AFP) levels in normal infants. Pediatr Res 1981;15:50. 195. Young JLJr, Ries LG, Silverberg E, et al: Cancer incidence, survival and mortality for children younger than age 15 years. Cancer 1986;58(2 Suppl):598. 196. Young R, Scully R: Germ cell tumors: Nonseminomatous Tumors, Occult Tumors, Effects of Chemotherapy in Testicular Tumors. Chicago: ASCP Press, 1990, p 37. 197. Yu IT, Griffin CA, Phillips PC, et al: Numerical sex chromosomal abnormalities in pineal teratomas by cytogenetic analysis and fluorescence in situ hybridization. Lab Invest 1995;72:419.

Hodgkin's Disease and ~ o n r ~ o d ~ l uLymphoma n's Michael t? La Ouaglia and WendyT. Su

HODGKIN'S DISEASE

Incidence and Epidemiology

Hodgkin's disease was first described by Hodgkin in 1832, based on anatomic observation. The original paper was entitled "On Some Morbid Appearance of the Absorbent Glands and Spleen."44~ f t e r t h edevelopment of microscopic histology, Sternberg in 1898 and Reed in 1902 were the first to characterize the histopathology.l"JJ21 They emphasized the unique appearance of a multinucleated giant cell with prominent nucleoli, which distinguished it from tuberculosis. The first reports of radiotherapy for Hodgkin's disease were published in 1902 and 1903.98The radiotherapeutic principles required for curative treatment of Hodgkin's disease were reported by Gilbert.33Petersg4in Toronto subsequently published a series of patients who survived disease-free 20 years after treatment. Staging laparotomy was developed in the late 1960s to map out patterns of metastatic spread and for research.34Kaplan et al.1"51J0htStanford University laid the foundation for modern supervoltage treatment of Hodgkin's disease. Use of a derivative of nitrogen mustard to treat patients with lymphosarcoma and Hodgkin's disease was published in 1946,Shnd the results of multiagent treatment with MOPP (Mustargen [mechlorethamine], Oncovin [vincristine], procarbazine, prednisone) were reported in 1967.22As survival improved, it was noted that more patients developed adverse side effects, such as secondary malignancy and infertility. The non-cross-resistant ABVD regimen (Adriamycin [doxorubicin] , bleomycin, vinblastine, dacarbazine) was developed in the 1970s, with less risk of secondary acute myelo~enousleukemia and infertility. In the 1980s more investigators began to recognize the long-term sequelae of standard-dose radiotherapy and chemotherapy, especially in the pediatric population. A combined-modality regimen was applied to a subset of patients initially selected with staging laparotomy and later by diagnostic imaging in the 1990s. Risk-adaptive trials and tailored therapy were the main investigational efforts of that decade, with the aim of finding the optimal combination therapy with maximal efficacy and minimal toxicity.

Hodgkin's disease (HD) is characterized by a bimodal age distribution. The first peak is from 15 years to the late 20s, and the second peak occurs in those older than 50 years. Three forms of HD have been recognized by epidemiologic studies. The childhood form occurs in those younger than 14 years, the young adult form occurs in those 15 to 34 years old, and the older adult form occurs in those between 55 and 74 years. Children and adolescents account for 15% of all HD patients, and HD is twice as common in teenagers as it is in those younger than 10 years. HD accounts for 5% of all pediatric malignancies, with an incidence of about 6 cases per 1 million. Histologic subtypes also vary with age. Mixed cellularity HD is more common in young children, whereas nodular sclerosing HD is more frequently observed in adolescents. The cause of HD is multifactorial, but there is an association with Epstein-Barr virus (EBV) exposure that is most frequently seen in children younger than 10 years. The viral infection appears to precede tumor cell expansion, and EBV may act alone or in conjunction with other carcinogens. Until recently, the origin of Reed-Sternberg cells was elusive. Advances in immunohistology and molecular biology have revealed the clonal nature of these cells. Reed-Sternberg, lymphocytic, and histiocytic cells seen in HD appear to derive from a single transformed B cell that has undergone monoclonal expansion. Immunophenotyping of HD cells has demonstrated B-cell antigens. HD is also characterized by many cytokineproducing and -responding cells, which are responsible for the nonspecific signs and symptoms seen with this tumor.

Clinical Presentation Painless cervical or supraclavicular lymphadenopathy is the most common presenting symptom of HD (80%). Enlarged nodes primary to the axilla or groin are relatively 575

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than 38°C (100.4OF). Pruritus is also commonly observed among HD patients but does not carry as much prognostic value. The immune profiles of HD patients are altered, and the disease is characterized by generalized immune deficiency, ineffective host autoimmune response, and cutaneous anergy.123

.

Thoracic computed tomography scan showing tumor in the mediastinum (avow) in a patient with stage IIB Hodgkin's disease. These studies should be obtained before surgery to identify tracheobronchial obstruction. uncommon (30%), and primary inguinal involvement is encountered in less than 5% of cases. The lyrnphadenopathy is usually firm, rubbery, and nontender. More than two thirds of patients have mediastinal involvement at presentation, and good posteroanterior chest radiographs are essential to evaluate the mediastinum and to rule out airway obstruction before any invasive procedures. When a mediastinal mass is identified by plain radiographs, it is also advisable to obtain a thoracic computed tomography (CT) scan with intravenous contrast material to evaluate the airway and obtain further anatomic information (Figs. 35-1 and 35-2). Clinicians should always assume that airway compression by tumor is a possibility before the institution of general anesthesia. The superior vena caval syndrome, with facial swelling, distended neck veins, and plethoric complexion above the neck, is highly suggestive of superior vena cava obstruction by mediastinal tumor. Approximately one third of patients present with systemic symptoms (substage B symptoms; see later), which may include loss of more than 10% of body weight in the past 6 months, drenching night sweats, or fever greater

The workup of patients with suspected HD should begin with a careful history and physical examination. All nodal groups should be evaluated, and enlarged lymph nodes measured. The lymphatic tissue composing Waldeyer's ring (adenoids and tonsils) should also be examined. The diagnosis of HD requires lymph node biopsy for histologic evaluation. The presence of Reed-Sternberg cells is pathognomonic of HD (Fig. 35-3). There are four histologic subtypes defined by the Rye classificationlymphocyte predominance, nodular sclerosing, mixed cellularity, and lymphocyte depletion-each with a unique immunophenotypic profile.40Nodular sclerosing is the most common subtype seen in children (>65%), followed by mixed cellularity and lymphocyte predominance. The lymphocyte-predominance subtype carries the best prognosis historically. However, since the develop ment of highly effective multiagent and multidisciplinary treatment regimens, all histologic subtypes have become responsive to therapy. Laboratory studies should include a complete blood cell count with differential, erythrocyte sedimentation rate, baseline hepatic and renal function tests, and electrolytes. The serum copper and lactate dehydrogenase (LDH) levels at diagnosis have been correlated with tumor burden, but there are no specific tumor markers.

Staging Staging of HD can be either clinical or pathologic. Clinical staging is based on the well-established Ann Arbor

.

The same patient in Figure 35-1 after chemotherapy. The nodular mediastinal mass has resolved (avow), but there is homogeneous thymic enlargement. This rebound thymic hyperplasia can be confused with disease persistence or recurrence.

.

.

A histopathologic section from a patient with nodular

sclerosing Hodgkin's disease. The arrow identifies a Reed-Sternbergcell.

CHAPTER

1 Stage

111

IV

Criteria lnvolvement of a single lymph node region (I) or a single extralymphatic organ or site (IE) lnvolvement of two or more lymph node regions on the same side of the diaphragm (11) or localized involvement of an extralymphatic organ or site and one or more lymph node regions on the same side of the diaphragm (IIE) Involvement of lymph node regions on both sides of the diaphragm (Ill); this may include splenic involvement (IIIS) or localized involvement of an extralymphatic organ (IIIE) or site (IIIES) Disseminated involvement of one or more organs or sites with or without associated lymph node involvement

I

staging system (Table 35-1) and requires information obtained from the history, physical examination, and diagnostic imaging studies. The substage classifications A, B, and E are based on defined clinical features. Substage A indicates asymptomatic disease. Substage B symptoms are strictly defined as more than 10% weight loss over 6 months, drenching night sweats, and fever greater than 38°C for 3 days. Substage E denotes minimal extralymphatic disease. Radiographic imaging is an integral component of clinical staging. Chest radiographs often reveal the presence of a mediastinal mass, and the ratio of its maximal diameter to that of the thoracic cavity on a posteroanterior view is prognostically important. A ratio greater than 1:3 places the patient in the subcategory of bulky mediastinal disease, which is associated with a worse prognosis and requires systemic chemotherapy for adequate treatment. CT of the chest and abdomen permits a more accurate assessment of disease extent. If high cervical nodes are involved, CT of the neck is also obtained to evalute Waldeyer's ring. CT of the chest provides the best information regarding the extent of mediastinal disease and also evaluates the pulmonary parenchyma, pleura, pericardium, and chest wall. Both intravenous and oral contrast agents should be administered for CT evaluation of infradiaphragmatic disease, to better distinguish lymphadenopathy from other structures. CT scanning is of limited usefulness in children because of the small quantity of retroperitoneal fat and the frequency of benign lymphadenopathy in this age group. Under these circumstances, CT scanning is inaccurate in detecting splenic or periaortic nodal involvementl4 and has a reported accuracy of 71% to 74% when compared with laparotomy. Magnetic resonance imaging (MRI) provides a more accurate evaluation of infradiaphragmatic disease compared with CT, with better visualization of fat-encased retroperitoneal nodes. Lymphangiography is technically difficult and is rarely performed in children. Gallium 67 scans are less specific and do not differentiate inflammatory changes from malignancy, but persistent activity may indicate residual disease. Positron emission tomography has recently been shown to detect disease

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not identified on CT scans in adults, although data are limited in children.30 Pathologic staging theoretically requires surgical staging, including splenectomy, unless metastatic disease is found in bone, marrow, liver, or lung biopsies. However, modern HD therapy almost always includes systemic chemotherapy, so the results of pathologic staging do not affect treatment. Therefore, surgical staging with splenectomy is almost never done today. The only exception, which is very rare, is the treatment of localized HD in an adolescent male with radiotherapy alone.

Surgery All patients with HD require a biopsy, usually of involved lymph nodes, to establish the diagnosis and histologic subtype. Frozen sections are inadequate for diagnostic purposes, and permanent hematoxylin-eosin sections must always be obtained. In addition, it is important to procure tissue for more detailed studies, such as immunohistochemistry, immunophenotyping, and cytogenetics. Biopsies should be taken from the most easily accessible site. In patients with only mediastinal involvement, biopsy samples can be obtained via mediastinoscopy, Chamberlain procedure, or thoraco~copy.~~ Retroperitoneal lymphadenopathy is often accessible through laparoscopic biopsy. Fine-needle aspiration cytology is inadequate to detect sparse Reed-Sternberg cells, and 20% of interventional radiologic procedures for HD diagnosis were falsely negative in one study.% Excisional lymph node biopsy or incisional biopsy of massively enlarged or matted nodes is essential to make an accurate diagnosis. Every attempt should be made to provide a specimen that preserves cytoarchitecture without crush or cautery artifact. The role of surgical staging has changed with the paradigm shifts in the treatment of HD. Staging laparotomy was initially devised by radiation oncologists to define the pathologic extent of disease and direct accurate supervoltage radiation fields, because all involved nodal sites required irradiation if cure was to be achieved. Low-stage HD presenting in the neck often followed a predictable route of progression that could be defined by sampling retroperitoneal lymph nodes and removing the spleen. If the disease had extended beyond reasonable radiation portals, chemotherapy would be necessary. The historical purpose of laparotomy-splenectomy in HD was to document the anatomic distribution of disease and thus determine nodal echelons requiring radiotherapy. It was not designed as a therapeutic maneuver. With the wide application of chemotherapy in all stages of HD,2"62 surgical staging has become irrelevant because the additional information it provides does not alter treatment. As noted earlier, the exception is the rare male adolescent with localized disease who might be treated by radiation alone. Traditionally, surgical staging requires laparotomy, splenectomy, bilobar liver needle and wedge biopsies, and thorough sampling of multiple lymph node sites

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(splenic hilum, porta hepatis, suprapancreatic, bilateral effectiveness of both MOPP and ABVD and the fact that para-aortic, and mesenteric) . Bilateral oophoropexies their toxicities do not overlap, trials combining the two are also performed in girls. Staging performed laparoregimens were done, with good preliminary results.10 7 , ~ 2 9regimens are given in an outpatient setting and have scopically may reduce postoperative m 0 r b i d i t y , ~ ~ 0 ~ ~ ~ 6 ~ ~ ~These including the risk of postoperative bowel 0bstruction.2~ easily manageable acute toxicities. However, their sigHowever, the susceptibility to infection caused by nificant long-term toxicity prompted the design of splenectomy is not altered. alternating regimens of MOPP-ABVD to avoid reaching cumulative doses associated with toxicitv. The current trend is the application of "tailored therChemotherapy apy" based on disease response. This approach aims to Effective chemotherapy regimens for HD contain drugs limit the cumulative dose, thus minimizing toxicity while that are individually effective and that have different maintaining efficacy. Results of response-based therapy mechanisms of action so that multiple homeostatic funcwere recently reported by the Pediatric Oncology Group.114 For advanced-stage HD, early responders received only tions in the tumor cell are attacked and drug resistance is minimized (Table 35-2). The agents should have three cycles of ABVE-PC (Adriamycin, bleomycin, vinnonoverlapping toxicities so that a full dose of each drug cristine, etoposide, prednisone, cydlophospha&ide) vercan be given. The MOPP regimen fulfills these requiresus five cycles, followed by 25 Gy of radiation. The 2-year ments and was the first multidrug regimen found to be event-free survival was 90.8% for early responders and effective against HD. In a long-term study of 188 patients 87.7% for slow responders. Low-stage patients received from the National Cancer Institute treated with MOPP, either two or four cycles of ABVE (for early and slow the complete remission rate was 89%, and 54% of patients responders, respectively), followed by radiotherapy, with remained disease free at 10 years.67The mean age at diagno difference in outcome. New trials are under way to nosis for this group was 32 years and ranged from 12 to evaluate the use of dose- and time-intensive delivery. 69 years. In this study, 95% of patients had stage I11 or IV disease, and 89% had B symptoms. Maintenance therapy Radiation Therapy did not affect the remission rate and does not seem to be necessary in HD. Historically, the application of radiation therapy was ABVD was the second regimen used in the treatment based on the concept of contiguous lymph node basin of HD." It was developed for the treatment of patients involvement. Ideally, a 4 to 8-MeV linear accelerator is failing MOPP therapy and contains individually effective used for treatment. Orthovoltage techniques are condrugs with nonoverlapping toxicities. In view of the traindicated, and cobalt 60 is associated with significant radiation scatter, which should be avoided in children. The risk of recurrence is 10% or less if doses of 3500 to 4400 cGy are used. Thus, clinically involved areas are usually given 4000 to 4400 cGy, whereas prophylactic treatment of subclinical areas can be accomplished with 3000 to 4000 cGv. The combination of chemothera~v 1 Regimen Agents and radiotherapy can be effective, with local control rates Doxorubicin (Adriamycin), bleomycin, vinblastine, of 97%. However, the long-term toxicity prompted trials dacarbazine in the 1980s with protocols incorporating six cycles of ABVE (DBVE) Doxorubicin (Adriamycin), bleomycin, vincristine, chemotherapy and lowerdose (1500 to 2500 cGy), limitedetoposide field radiotherapy. This resulted in excellent disease control Vincristine, doxorubicin (Adriamycin),methotrexate, and decreased musculoskeletal deformity.25.87 prednisone The application of risk-adapted therapy using combinaOPPA f COPP Vincristine (Oncovin), prednisone, procarbazine, tion chemotherapy has achieved excellent disease-free (females)lo7 doxorubicin (Adriamycin), cyclophosphamide, survival and overall survival. Recent studies have shown vincristine (Oncovin), prednisone, procarbazine that the addition of low-dose involved-field radiation OEPA f COPP Vincristine (Oncovin), etoposide, prednisone, (males)lo7 doxorubicin (Adriamycin), cyclophosphamide, im~rovesevent-free survival but does not affect overall vincristine (Oncovin), prednisone, procarbazine survival in patients with a complete response to chemoCyclophosphamide, vincristine (Oncovin), therapy.84Currently, the standard of care for the majority prednisone, procarbazine, doxorubicin of children and adolescents with HD is risk-adapted (Adriamycin), bleomycin, vinblastine combined-modality therapy using lowdose, involved-held BEACOPP Bleomycin, etoposide, doxorubicin radiation in conjunction with multiagent chemotherapy. (advanced (Adriamycin),cyclophosphamide, vincristine /

x ,

stage)S4 COPP CHOP ABVE-PC (DBVE-PC)"

(Oncovin), prednisone, procarbazine Cyclophosphamide, vincristine (Oncovin), prednisone, procarbazine Cyclophosphamide, doxorubicin (Adriamycin), vincristine (Oncovin), prednisone Doxorubicin (Adriamycin), bleomycin, vincristine, etoposide, prednisone, cyclophosphamide

Complications Treatment Toxicity Late effects of treatment include surgical complications, soft tissue and bone growth abnormalities, cardiopulmonary effects, endocrine sequelae, and secondary

CHAPTER

malignancies. An alteration in the proportion of sitting to standing height has been noted in patients receiving radiation to the axial skeleton.97 Boys seem to be more severely affected than girls. There is also shortening of the clavicles, reduced interclavicular distance, fibrosis of the soft tissues in the neck, and thinning of hair in the posterior cervical region. Growth disturbance is not significant in children with bone ages of 14 to 15 years at the time of treatment. Significant radiation-induced pulmonary injury can occur, depending on the volume included in the radiation field, the dose, and the daily fraction size. Symptomatic pulmonary injury occurs in 3.6% of patients receiving high-dose mantle therapy. Bleomycin also may cause severe pulmonary dysfunction. Radiation injury to the myocardium is also related to dose, fraction size, and volume irradiated. Approximately 13% of children receiving high-dose mantle therapy develop cardiac injury. The coronary arteries and great vessels can be affected as well. Doxorubicin is also known to cause cardiac injury, and Raynaud's syndrome has been reported in patients receiving vinblastine and bleomycin. Endocrine effects include hypothyroidism, sterility, and other alterations in fertility. Using thyroid-stimulating hormone as a marker for hypothyroidism, between 4% and 79% of patients develop this complication.19Thyroid abnormalities depend on the dose given to the neck; 17% of patients receiving less than 26 Gy develop thyroid abnormalities, whereas 78% of those receiving 26 Gy or more become hypothyroid. Gonadal dysfunction (both ovarian and testicular) has been documented after HD therapy.lll Pelvic irradiation carries a high likelihood of ablating ovarian function. Ovarian transposition, whereby the ovaries are moved away from the radiation field, can preserve ovarian function and fertility.31 The ovaries can be moved to the midline behind the uterus or to both flanks. A small clip should be placed on the peritoneum in the area where the ovaries were moved for identification by the radiotherapist. Sterility is a much greater problem in males, and gonadal dysfunction may exist at the time of diagnosis in 30% to 40% of patients.l5288J27 Pretreatment storage of sperm in older patients should be considered.

Secondary Malignancies Second malignancies include acute nonlymphocytic leukemia, non-Hodgkin's lymphoma, thyroid cancers (usually differentiated), breast cancer (in irradiated p a t i e n t ~ ) , ~ , l ~ , ~ " 7 " ~ bone % n d or soft tissue sarcomas. Patients who underwent prior splenectomy also have a risk of developing leukemia. The MOPP regimen involves a higher risk of secondary malignancy compared with the ABVD regimen. Children who require retreatment also have higher risk of secondary malignancy as a direct dose effect." The incidence of secondary leukemia in patients primarily treated with MOPP may be 5% to 7%; this increases to 10% if MOPP is given with radiotherapy. The risk of leukemia decreases after 10 years, whereas the risk of non-Hodgkin's lymphoma increases with time, underlying the importance of continual monitoring. Solid tumors may develop in as many as 4% of patients.

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Complications of Laparotomy Complications specific to staging laparotomy can be divided into three groups: (1) early postsurgical complications (<6 weeks after operation), (2) late complications (>6 months after surgery), and (3) septic complications related to splenectomy. Hays et a1.42,4~eviewedthe experience of the Intergroup Hodgkin's Disease in Childhood Study, consisting of 234 staging laparotomies; in the initial report, 55% of children were followed for at least 2 years, and in the updated summary, the median follow-up was 5 years. In the first 6 weeks after laparotomy, three pulmonary and three abdominal complications were noted, for an overall incidence of 2.6%. These included one case of right ureteral obstruction secondary to scar, which required operative lysis; one intestinal obstruction from adhesions, requiring reoperation; one superficial wound infection; and three cases of atelectasispneumonia. There were no postoperative deaths. Five late surgical complications occurred (2.1%) . There were four cases of bowel obstruction requiring adhesiolysis, and in one of these an intestinal perforation secondary to volvulus of a bowel segment around an adhesive band required repair. In the filfth patient, a right oophorectomy was necessary because of torsion and secondary necrosis. This ovary had been moved to the flank during staging laparotomy to avoid the major radiation portals. Thus, the combined incidence of early and late surgical complications specific for laparotomy was 4.7%, including clinically significant atelectasis. Schneeberger and GirvanH2reported on 39 children with HD who underwent staging laparotomy. No operative deaths were reported, and there were no minor complications such as atelectasis. There were five (12.8%) cases of small bowel obstruction, and four were managed nonoperatively with nasogastric suction. One patient required re-exploration 11 years after staging laparotomy because of a small bowel volvulus around adhesions. Donaldson ~ that the rate of significant, nonand K a ~ l a n 2reported lethal complications in the immediate postoperative period after staging laparotomy in children was approximately 1%. Significant complications in this study included wound infection and dehiscence, subphrenic abscess, pulmonary infection, retroperitoneal hematoma, pancreatitis, and significant postoperative bleeding. Complications such as mild postoperative atelectasis were not included. Late complications such as adhesive bowel obstruction have been reported in 3% to 12% of patients in other series and may occur even if abdominal radiation is not given."O

Complications of Splenectomy Increased susceptibility to infection after splenectomy was first noted by King and Shumackefiqn 1952, and multiple confirmatory reports have been published since then.2R119 The incidence of postsplenectomy sepsis is increased in younger children, especially those younger than 10 years. In interpreting data from patients undergoing splenectomy in the setting of HD, it should be remembered that the disease process itself and chemotherapeutic agents are immunosuppressive.

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Serious questions about the use of splenectonly in children with HD were raised following the report of Chilcote et a1.16 in 1976. This was a retrospective study of 200 children aged 19 years or younger treated for HD at collaborating institutions of the Children's Cancer Study Group. In this study, 20 episodes of sepsis were noted in 18 patients, and the interval from splenectomy to infection varied from 8 days to 3 years. The median age of patients developing sepsis was 10 years. All but three of these patients had received or were receiving chemotherapy, and all but two had received radiation therapy. Organisms included pneumococci, Haemophilus influenzae, streptococci, and meningococci. Ten of the children who developed sepsis died; and most of them had a fulminant course. Significantly, only two contributing institutions used prophylactic antibiotics at the time, and neither reported serious infections. The overall follow-up interval was not stated. Subsequent analysis of postsplenectomy sepsis rates by the Intergroup Hodgkin's Disease in Childhood Study showed that this was less of a problem with the use of vaccination and prophylactic antibiotics.42 In the first report from this group, with 55% of patients followed 2 years or more, only two disease-free patients developed documented sepsis. An additional two children developed sepsis in the setting of chemotherapy given for relapse. There were also three cases of possible sepsis, but blood cultures were negative. Most important, no deaths were noted in this group. Significantly, 83% of these children received pneumococcal vaccination before splenectomy, and 74% were given prophylactic antibiotics. In an u ~ d a t eof this series, with a median follow-up of 5.5 years, the total number of documented cases of sepsis had risen to five, but no deaths were reported. In two patients, pneumococcus was isolated from the blood, and in the remaining three, H. injluenzae was found. Of the five children who developed sepsis, four had received pneumococcal vaccine, but only three had been vaccinated preoperatively. Four of the five children had antibiotics discontinued or interrupted before the development of sepsis. Age at diagnosis ranged from 4 to 14 years, with a median of 9 years in the group developing sepsis. An additional five patients became gravely ill and were thought to have sepsis because of a good response to antibiotics; blood cultures in these children were negative, and there was no mortality. With a mean follow-up-of more than 5 years, there were five (2.1%) confirmed cases and five suspected cases of sepsis, and the lethality from this complication was zero. The defect in humoral immunity caused by splenectomy is permanent, however, and additional cases of postsplenectomy infection can be expected in HD surg vivors undergoing staging l a p a r ~ t o m y . ~ ~ W s ai nsepsis incidence of 0.38% per year derived from the Intergroup Hodgkin's Disease in Childhood Study (2.1% incidence in 5.5 years), it was estimated that almost 20% of splenectomized HD patients would develop this complication over a 50-year period." The incidence of sepsis is reduced in adults and falls with age, so this is probably an overestimate. The cumulative risk of sepsis over a lifetime is not known.

Treatment of Metastatic Disease and Relapse The salvage therapy for patients with refractory or recurrent disease depends on the initial therapeutic regimen. Fifty percent to 80% of patients treated initially with radiation alone can be cured with chemotherapy or combined-modality therapy. With the use of combined-modality therapy for early-stage disease and a risk-adapted approach for advanced-stage disease, nearly 90% of patients with Hodgkin's lymphoma are cured with initial therapy. However, in patients who have primary refractory or relapsed disease, highdose therapy and autologous stem cell transplantation constitute the best curative option. The use of peripheral blood progenitor cells has decreased transplant-related mortality to less than 3%, but long-term p r e gression-free survival has shown minimal improvement.77-79

Prognostic Factors The current treatment approach to HD is risk-adapted therapy. Risk features at the time of diagnosis include the presence of B symptoms, age, stage, nodal bulk, and number of involved nodal regions. Patients with localized nodal involvement and the absence of B symptoms have a favorable clinical presentation. Those with B symptoms, bulky mediastinal or peripheral lymphadenopathy, extranodal extension of disease, and advanced disease (stage IIIB to IV) have an unfavorable clinical presentation. Patients with an unfavorable clinical presentation are treated with standard non-cross-resistant chemotherapy on a conventional schedule, followed by consolidation therapy of low-dose, involved-field radiation. Alternatively, abbreviated, dose-intensive multiagent chemotherapy followed by consolidating radiation is being evaluated. Early response to therapy is correlated with better prognosis and reflects tumor bulk and biology.12

Outcome The application of risk-adapted therapy consisting of chemotherapy alone has resulted in 5-year survival of greater than 90% and disease-free survival of greater than 85%. The goal of optimal therapy is to preserve the high survival rate, decrease the relapse rate, and minimize late adverse effects.

NON-HODGKIN'S LYMPHOMA The non-Hodgkin's lymphomas are divided into Burkitt's and Burkitt's-like lymphomas, lymphoblastic lymphomas, diffuse large B-cell lymphomas, and anaplastic large cell lymphomas. The anatomic distribution of these neoplasms can be at least partially understood by reference to normal B-cell and T-cell ontogeny.

Incidence and Epidemiology There are 750 to 800 new cases of non-Hodgkin's lymphoma each year in the United States.93 Burkitt's and

CHAPTER

Burkitt's-like lymphomas have a fivefold higher incidence in males than in females in patients younger than 20 years (3.2 versus 0.7 cases per million). The overall incidence of Burkitt's lymphoma rises after 5 years of age and falls again after age 15. In contrast, the incidence of diffuse large cell lymphoma rises steadily with age and has a male-female ratio of 1.4. Lymphoblastic lymphomas occur at similar frequencies in those younger than 20 years and have a male-female ratio of 2.5.

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small, noncleaved cell lymphomas. Burkitt's lymphoma is a subset of these undifferentiated lymphomas. Because B cells develop in the bone marrow and then migrate to secondary lymphoid organs (lymph nodes, spleen, Peyer's patches, liver), one would expect clinical localization of the developing neoplasm in those anatomic sites. As a corollary, B-cell lymphoma should not occur in the anterior mediastinum in the region of the thymus because normal B cells are not thymic dependent. Usually, but not always, this anatomic distribution is consistent with clinical observations. In the United States, Burkitt's lymphoma has a predilection for the abdomen (in western Biology equatorial Africa, it usually arises in the mandible, but abdominal lymphoma is al& noted in up to 20% of these Lymphocyte Ontogeny and Differentiation patients). Burkitt's lymphoma of the tonsil and testis (as a site of relapse) has also been reported, but Burkitt's lymAlthough a detailed discussion of lymphoid cell developphoma of the anterior mediastinum is extremely rare.53j.57 ment is beyond the scope of this chapter, a short review A simplified schema for the differentiation of T cells of this subject may help in understanding the various is depicted in Figure 35-5. Because thymic residence is a histologic subgroups and their unique clinical behavior. necessary part of T-cell development, most lymphomas Basic to our current understanding of the normal and presenting in the anterior mediastinum originate from pathologic immune system is the idea that there are func~ ~ T-cell ~ J ~ ~lineage. Fifty percent to 70% of patients with tionally separate B-cell and Tcell c o m p a r t m e n t ~ . ~ ~the lymphoblastic lymphoma ( T cell) present with an A second important notion is that mature lymphocytes are intrathoracic tumor, usually an anterior mediastinal not end-stage cells but can undergo transformation to an mass; an abdominal presentation is uncommon. There is effector cell type in the presence of antigen. Lymphoid for T-cell-dependent or B-cella general development can be conceptualized as progressing dependent anatomic areas of the lymphoid system to be through a differentiation path from a stem cell to an actiinvolved by lymphomas that also express surface markers vated cell. This is followed by transformation to an effector specific for their respective T or B lymphocytes. Of interest phenotype when the proper stimulus is provided. A simis the observation that removal of the thymus prevents plified scheme for B-cell differentiation is illustrated in T lymphomas in mice, whereas removal of the bursa of Figure 35-4. B cells originate in the bone marrow from Fabricius prevents B lymphomas in ~ h i c k e n s . Y ' ~ l ~ ~ totipotential stem cells that differentiate through many intermediate cell types to eventually become antibodyproducing plasma 'cells. Malignant .transformation can Cytogenetic and Molecular Biologic Findings occur at any point along the differentiation path, thus In 1976, a characteristic chromosomal translocation involvproducing some readily recognizable clinical syndromes ing chromosomes 8 and 14 was discovered in Burkitt's or histopathologic subtypes. Of interest to the pediatric lymphoma.lg"t was subsequently shown that the c-myc surgeon is that B cells, at the developmental stage when proto-oncogene was translocated from chromosome 8 to immunoglobulin M (IgM) surface immunoglobulin is the immunoglobulin heavy-chain locus on chromosome detectable (see Fig. 35-4), can undergo malignant trans14.124 Finally, it was determined that in a minority of formation into undifferentiated lymphoma. Because of Burkitt's lymphomas, the 8;14 translocation was replaced their light microscopic appearance, these are also called by an 8;22 or 2;8 translocation.YThis still involved the c-myc gene on chromosome 8. The difference in this minority of cases was that instead of an immunoglobulin heavy-chain locus, the K light-chain locus on chromosome 2 or the h light-chain locus on chromosome 22 was involved. Thus, ahroto-oncogene was always juxtaposed to an immunoglobulin constant region coding sequence. Because Burkitt's lymphomas are of B-cell origin, it was thought that these cytogenetic abnormalities involving known proto-oncogene and immunoglobulin coding sequences were not coincidental and had pathophysiologc significance. It was subsequently shown that the translocated c-myc allele becomes activated by its proximity to the may result in an immunoglobulin coding region."his inappropriate expression of c-myc RNA and protein in Pre-B Cells Mature 13Cell B lymphocytes at this stage of differentiation.% Act~vatedmature B Cell In contrast to the extensive cytogenetic data in small, S~mpl~fied d~agramof the B-cell d~fferentiat~on pathnoncleaved cell tumors, most lymphoblastic lymphomas do not manifest specific, nonrandom r n u t a t i ~ n sA. ~small ~ way Und~fferent~ated lymphoma developsjust after cells express surface percentage of lymphoblastic tumors of T-cell origin have ~mmunoglobuhnM

.

582

PART

III

MAJOR TUMORS OF CHII.DHOOD

CD2, CD7, CD38, CD71

Stage I

.

CD1, CD2, CD4, CD7, CD8, CD38

1

Stage I1

1

1

CD2, CD3, TCR, CD418, CD5, CD38

Stage Ill

Simplified diagram of T-cell differentiation. Lymphoblastic lymphomas usually express the enzyme terminal deoxynucleotide transferase. T cells must traverse the thymus during differentiation.

translocations, most often involving chromosome 14 (14qll) in a region occupied by the T cc and 8 receptor gene (T-cell receptor) or chromosome 7 near TP.Z1 This is analogous to the involvement of immunoglobulin gene coding regions in &cell lymphomas. Information from cytogenetic and molecular biologic analysis has provided important insights into the molecular mechanisms of malignant degeneration of lymphoid cells.

Lymphoma Subtypes and Histopathology This brief description of immune system ontogeny serves as a basis for understanding the three major subcategories of childhood non-~odgkin'slymph om^: (1) undifferentiated, which are also called small, noncleaved cell lymphomas; (2) lymphoblastic; and (3) large cell (diffuse large B-cell and anaplastic large cell). All three are considered high grade in contrast to other subtypes observed in adult patients. The exceptions to this rule are certain large cell lymphomas with a follicular-center cell type, which are considered intermediate in grade but are rare in childhood and adolescence. The undifferentiated lymphomas are primarily abdominal in origin and develop from B-cell precursors. Malignant degeneration occurs before cleavage of the nucleus during differentiation. They can be divided into Burkitt's and non-Burkitt's categories based on their appearance under light microscopy. Burkitt's lymphoma is characterized by medium-sized nuclei that are approximately the same size as interspersed benign histiocytes, which provides a convenient method of measurement and confers a "starry-sky" L

L

appearance (Fig. 35-6). There are usually two to five prominent basophilic nucleoli. A high nuclear-to-cytoplasmic ratio is observed. Non-Burkitt's varieties often show frequent, single, large nucleoli and more variation in nucleolar size and shape. A later age at presentation and an increased incidence of peripheral lymph node or bone marrow involvement have been associated with non-Burkitt's small, noncleaved cell lymphomas. No cytogenetic, immunohistochemical, or molecular biologic markers distinguish the two. Small, noncleaved cell lymphomas express surface immunoglobulin of the IgM class

.

Histopathologic section from a Burkitt's lymphoma showing multiple prominent nucleoli.

CHAPTER

.

35

Hodgkin's Disease and Non-Hodgkin's Lynlphoma

583

.

Representative section from a lymphoblastic lymphoma. The dark-staining cells are normal lymphocytes.

Representative section from a diffuse large cell lymphoma. Several macrophages (arrow)are seen ingesting tumor cells.

and surface antigens detected by the monoclonal antibodies CD19 and CD2O.logThey do not contain the enzyme terminal deoxynucleotide transferase, which is always found in lymphoblastic lymphomas. Small, noncleaved cell lymphoma must be distinguished from small cell nodular lymphomas that occur in adults and have a more indolent course. Lymphoblastic lymphomas are located predominantly in the anterior mediastinum and are characterized by diffuse effacement of nodal architecture. A lobular appearance may be observed because of extension of tumor cells along normal tissue planes. Cytologically, the nuclei are smaller than those of the interspersed histiocytes, and the nucleoli are inconspicuous (Fig. 35-7). Again, the starry-sky pattern can be appreciated, and the nuclear-to-cytoplasmic ratio is higher than that seen in small, noncleaved cell lymphomas. In about half the cases, the nuclear membrane is convoluted or cleaved. The enzyme terminal deoxynucleotide transferase is invariably found, and most lymphoblastic lymphomas express Tcell markers, including CD7 or CD5.65 Large cell lymphomas (diffuse large cell lymphomas) are usually high grade. As noted previously, the follicularcenter cell type is technically intermediate in grade but shows aggressive biologic behavior. The normal nodal architecture is effaced by cells with large nuclei and scant cytoplasm (Fig. 35-8). The nuclei are larger than those of invading histiocytes. These cells are large and cleaved and have cleaved nuclei, whereas nucleoli are inconspicuous. Another cell type consisting of large, cleaved cells with a narrow rim of cytoplasm and prominent, pyknotic nucleoli may also be present. The two cell types may coexist in the same tumor. A study done by the Pediatric Oncology Group categorized large cell lymphomas into two subtypes.85 The first was a large cell, cleaved or uncleaved lymphoma arising in germinal centers of lymphoid follicles and of B-cell origin. The second type of large cell lymphoma was described as immunoblastic, and most of these originated from T-cell precursors. A plasmacytoid variant of the immunoblastic large cell lymphoma is thought to be of B-cell origin. A variant of large cell lymphoma expresses the Ki-1 antigen, which

is also found on Reed-Sternberg cells and is of T-cell 0rigin.4,104.113 It should be emphasized that all childhood nonHodgkin's lymphomas are diffuse and fast growing. This contrasts with the nodular and often indolent forms of lymphoma observed in adults. Thus, childhood lymphoma should be treated as a systemic disease from the time of diagnosis, with the early institution of multiagent chemotherapy. It is estimated that the growth fraction of childhood lymphoma approaches 100% in some cases and that uncorrected doubling times that do not take into account spontaneous cell death (apoptosis) are as low as 12 hours to several days. Measured doubling times that account for cell death have been reported to average approximately 3 days for small, noncleaved cell tumors injected subcutaneously into mice. It is estimated that the cell death rate for African Burkitt's lymphoma is 70% of all progeny cells. Undifferentiated B-cell tumors of childhood have the highest growth fractions, with up to 27% of cells in S phase by flow c y t ~ m e t r y . ~ ~ , ~ ~

Clinical Presentation Undifferentiated Lymphoma In the United States, children with non-Hodgkin's lymphoma present with a small number of defined syndromes that generally correlate with cell type. More than 90% of patients with small, noncleaved cell lymphoma present with a palpable abdominal tum0r.7.1~'The tumor can cause abdominal pain, distention, change in bowel habits, nausea, vomiting, intestinal obstruction, intussusception, intestinal bleeding, ascites, or bowel perforation. Commonly, the lymphoma presents as a right iliac fossa mass and can be confused with appendicitis or an appendiceal abscess. These patients may have enlarged inguinal or iliac lymph nodes. Patients with extensive intra-abdominal involvement may have fatigue, malaise, and weight loss. An example of an extensive abdominal Burkitt's lymphoma almost totally replacing the liver is illustrated in Figure 35-9. Interestingly, Burkitt's lymphoma in equatorial Africa,

584

.

PART

-

III

M q l o ~TUMORS OF CHILDHOOD

Abdominal computed tomography scan of a patient

Thoracic computed tomography scan of a patient with lymphoblastic lymphoma and a large anterior mediastinal mass (arrow).The airway is displaced but not compressed.

with Burkitt's lymphoma showing almost total hepatic replacement with tumor. The diagnosis was made by bone marrow aspiration.

although usually presenting as a diffuse jaw tumor, also involves the abdomen in more than 50% of patients. In the United States, other sites of involvement at presentation include bone marrow, pleural effusions, cerebrospinal fluid, central nervous system, peripheral nodes, kidneys, and pharynx.j7J" The ovary is a common site of presentation in both the United States and Africa.80 For practical purposes, patients with abdominal nonHodgkin's lymphomas can be divided into two groups. In the first group, the disease process is localized anatomically within the abdomen. In this case, the tumor often involves the bowel wall, and many of these children present with acute abdominal symptoms suggesting appendicitis or intussusception. The majority can undergo complete gross tumor resection, often with a simple bowel resection and reanastomosis, with little consequent morbidity. In the second group, there is extensive intraabdominal tumor, and presentation with an abdominal mass without acute symptoms is more likely. The mesenteric root and retroperitoneum are heavily involved, and attempts at complete excision are associated with a higher complication rate.

Lymphoblastic Lymphoma Fifty percent to 70% of patients with lymphoblastic lymphoma present with an anterior mediastinal mass or intrathoracic tumor (or both). Figure 35-10 shows a thoracic CT scan of a patient with mediastinal lymphoblastic lymphoma. These tumors may be distinguishable from the middle mediastinal mass associated with HD, but this is often not feasible, especially with extensive mediastinal masses. Fifty percent to 80% of patients have supradiaphragmatic lymphadenopathy, including cervical, supraclavicular, and axillary regions. Abdominal involvement is uncommon and, when observed, usually includes hepatosplenomegaly. Bone marrow infiltration is common in this situation, making the distinction from acute

lymphoblastic leukemia difficult. In these cases, survival may be better after treatment with a lymphoblastic leukemia-type regimen. Pleural effusions are often observed, and patients may complain of dyspnea, chest pain, or dysphagia. Vena caval syndrome with facial, chest, and upper extremity edema and dilated cutaneous veins over the upper torso and shoulders, or airway compression with severe dyspnea or orthopnea (or both), may require the urgent institution of chemotherapy or radiation.','" The central nervous system is rarely involved at diagnosis.

Large Cell Lymphoma The anatomic distribution of primary sites in large cell lymphoma is similar to that observed for small, noncleaved cell tumors. Unusual sites of presentation are possible, however, such as B-cell large cell lymphomas that arise in the anterior mediastinum. Ki-1-positive (anaplastic, usually derived from T cells) large cell lymphomas often involve the skin, central nervous system, lymph nodes, lung, testis, and muscle in addition to the gastrointestinal tract. Lung, facial, and intracerebral primary tumors are more likely to be large cell lymphomas.R6s106J08 A progressively enlarging mass is the most common mode of presentation.

Post-Transplant Lymphoproliferative Disease Post-transplant lymphoproliferative disease (PTLD) occurs as a complication of allogeneic transplantation and can be progrkssive, with a fatal outcome. 1tcan occur after both solid organ and bone marrow transplants. The probability of PTLD is increased after T-cell-depleted bone marrow grafts, after transplants from unrelated donors, in who develop @aft-versus-hostdisease, and particularly in patients treated with aggressive immunosuppressive regimens, including those that contain antithymocyte globulin. PTLD that occurs after bone marrow transplantation arises from transformation

CHAPTER

35

Hodgkin's Disease a n d Non-Hodgkin's Lymphoma

585

chemotherapy. Many patients also require surgical interof the donor B cells by EBV. These patients often present vention because of abdominal com~licationssuch as with gastrointestinal disturbance such as nausea and intussusception or bleeding or to obtain diagnostic tissue. vomiting or derangement in hepatic function. For tumors The pediatric surgeon must be aware that childhood arising in the gastrointestinal tract, endoscopic biopsy lymphoma is a systemic disease, and the operative procemay establish the diagnosis. Multiple biopsies are usually dure should not delay the institution of chemothkrapy. required to identifj the transformed cells. Liver lesions can The Ann Arbor staging system for HD is not relevant be biopsied laparoscopically or percutaneo~sly.~,~~~~~~9s,~2~-~2'L Treatment of PTLD consists of stopping immunosupto non-Hodgkin's lymphomas, and a number of groups pression and administering an anti-CD20 monoclonal have attempted to develop more appropriate classifications.k82 Presently, no clinical staging schema is entirely antibody (rituximab). In addition, various targeted cellular satisfactory, and it may be more important to assess the strategies directed against EBV-transformed cells have been tumor volume at presentation rather than trying to fit a developed, including reinfusion of donor lymphocytes at diffuse systemic process into a limited number of staging low dose. There is no role for surgical resection. categories. The most widely used system for non-Hodgkin's lymphoma staging in childhood is that from St. Jude's Children's Research Hospital (Table 35-3). The Children's Diagnosis Oncology Group divides non-Hodgkin's lymphomas into The evaluation of a patient presenting with possible nontwo categories: limited and extensive. Limited disease Hodgkin's lymphoma includes an extensive history and corresponds to stages I and I1 in the St. Jude's system, physical examination. This is followed by a complete and extensive correlates with stages I11 and IV.81 blood count; liver function tests, including LDH, serum electrolytes, blood urea nitrogen, creatinine, and uric acid level; chest radiograph; bone marrow aspirations; Treatment and lumbar puncture with cytospin for cytology. A four-site bone marrow aspiration and two-site bone marrow biopsy Surgery frequently identify marrow involvement, which has Magrath et a1.,70 basing their conclusions on an extensive serious implications for outcome. A gallium-67 scan and experience with patients in Uganda with abdominal CT scan of the chest and abdomen with oral and intraBurkitt's lymphoma, suggested that surgical reduction of venous contrast material can provide valuable informatumor bulk has a favorable impact on survival. In retrotion concerning tumor location and extent. Gallium is spect, there are several problems with this conclusion. taken up by neoplastic lymphoid cells (in particular, small, First, extent of disease at diagnosis was not evaluated for noncleaved cells) and provides a good total-body screen its predictive effect on outcome. Subsequent studies have for disease. Bone scans can identify suspected skeletal shown that the most important predictor of survival is involvement. MRI may play a role, especially in the evalextent of disease. Second, only 9 of the 68 patients (13%) uation of epidural disease, but is probably not absolutely actually underwent total resection (defined as >90% necessary. The role of positron emission tomography resection). The vast majority had biopsy alone (63%) or remains investigational. subtotal resection (24%). This observation strongly suggests a biologic selection for the patients undergoing total resection. In addition, the patients received single-agent Staging chemotherapy (cyclophosphamide), whereas the standard Staging laparotomy is not performed in non-Hodgkin's is currently a multiagent, histopathology-specific protocol. Finally, the reported surgical mortality rate in this lymphoma because all patients require systemic

Stage

Lymphoblastic

Single extra-abdominal tumor Resected intra-abdominal (>go%)tumor Multiple extra-abdominal sites except BM and CNS Unresected intra-abdominal tumor or non-stage IV epidural disease Intra-abdominal and extra-abdominal tumor except BM

I II lllA lllB

Single extrathoracic tumor Multiple extrathoracic tumors except BM and CNS Single thymic tumor Mediastinal tumor with pleural effusion

IVA

IVA

BM without abdominal or CNS involvement

IVB

IVB IVC

BM and abdominal tumor without CNS involvement CNS disease (cells in cerebrospinal fluid, cranial nerve palsy)

IVC IVD

Mediastinal tumor with extrathoracic extension except BM or CNS BM and intrathoracic tumor without CNS or other extrathoracic involvement EM and extrathoracic tumor without CNS involvement Bone marrow and CNS disease

Stage I IR II lllA

--Undifferentiated

*Tumor burden is assessed at diagnosis, which is the main determinant of outcome. BM, bone marrow; CNS, central nervous system.

586

PART

I11

M q l o ~TUMORS OF C H I L U I ~ ~ O U

series was 10%, which seems excessive under the present circumstances. Kemeny et al." evaluated the role of surgery for treatment of the primary tumor and for treatment of complications in patients with American Burkitt's lymphoma. They suggested that complete resection has an advantage but pointed out that extent of disease was not analyzed as an independent variable. A role for surgical intervention in the supportive therapy of non-~odgkin'slymphoma was also suggested. As noted, small, noncleaved cell tumors in particular have high growth fractions. As a consequence, renal shutdown caused by urate nephropathy is a real danger and could be complicated by mechanical ureteral obstruction by a retroperitoneal mass. In addition, the tumor lysis syndrome may occur, especially during induction chemotherapy of small, noncleaved cell lymp h o m a ~ . I Final13 ~ ~ ~ ~ "multiple gastrointestinal complications, including bleeding, obstruction, or perforation, can occur. The authors pointed out that surgery can provide vascular access for dialysis or hydration, ureteral stenting in the h c e of obstruction, and definitive operations for intestinal complications. Initial surgical management should include incisional biopsy for diagnosis, followed by intense, multiagent chemotherapy, except for small, easily resectable lesions.52 Data regarding the role of surgery in abdominal Burkitt's lymphoma indicate that the extent of disease is a more significant predictive variable than is completeness of surgical resection."? Major surgical procedures in patients with extensive abdominal disease are u~llikelvto result in complete excision and may be associated with an increased complication rate, resulting in a delay in instituting chemotherapy. ' I 5 Similarly, the surgical committee of the Children's Cancer Group (CCG) evaluated the role of surgical therapy in 68 patients with non-Hodgkin's lymphoma in the CCG-551 study.(i0Variables analyzed included (1) extent of disease at diagnosis; (2) completeness of surgical resection (complete gross resection); (3) radiation therapy to the prima~ysite; and (4) sex, age, and race. Laparotomy was performed in 67 children (99%), with complete gross resection accomplished in 28 (42%).Age at diagnosis, sex, and race had no effect on event-free survival. Tumor burden was the most important prognostic factor. Complete resection was also a significant predictor of event-free survival but was not as important as tumor burden. Of the 10 reported surgical complications, 8 occurred in the group with extensive disease and incomplete resection. These data support a role for complete surgical resection in the setting of localized disease, especially when confined to the bowel. Resections performed in these circumstances positively af'fect outcome by reducing tumor cell burden and preventing certain comBecause extensive plications, such as bowel perforati~n.'~ r e t r ~ ~ e r i t o n edissection, al with the possibility of significant hemorrhagic or septic con~plications,is avoided, chemotherapy can be initiated promptly. Attempts at resection of massive retroperitoneal masses or-large hepatic lymphomas are associated with an increased complication rate and serve to postpone essential chemotherapy. This is particularly deleterious because undifferentiated lymphomas grow so rapidly. In patients

presenting with extensive abdominal disease, diagnosis can often be made by bone marrow aspiration because at least 20% of all patients have obvious marrow involvement (symptoms, positive bone scan), and an additional 20% have microscopic involvement that is unsuspected clinically. Additional sources of diagnostic tissue include ascites and pleural effusions, peripheral lymph nodes, or localized bone lesions, which can sometimes be biopsied by needle. Tumor may invade the bowel wall and undergo subsequent necrosis, resulting in free perforation and peritonitis or severe hemorrhage. Often, Burkitt's lymphoma is localized to the right lower quadrant in the region of Peyer's patches, and symptoms may mimic acute appendicitis. I11 this situation, resection of the ileocecal segment and adjacent mesentery often results in complete gross resection. Patients with large mediastinal masses need careful preoperative evaluation; preoperative airway assessment by clinical and radiographic examination is crucial. Plain chest radiographs and CT scans indicate the degree of airway compression. Because cervical, supraclavicular, and axillary lymph node involvement approaches 50%, diagnostic biopsies performed at these sites under local anesthesia avoid the dangers associated with a general anesthetic and airway manipulation. Aspiration of malignant pleural effusions may also provide diagnostic material.

-

Technique of anterior mediastinotomy, or the

Chamberlain procedure. This is a useft11approach when the diagnosis of lymphoma cannot be made using less invasive techniques, such as lymph node biopsy, bone marrow aspiration, or thoracentesis.

CHAPTER

If intrathoracic biopsy is required, the anesthetic technique may be modified so that patients can be safely intubated. Postoperative extubation is usually not feasible, however, until the tumor has been treated, and arrangements should be made for patient transfer to an intensive care environment.ZYFigure 35-11 depicts the technique for mediastinotomy, or the Chamberlain procedure. This approach can be useful in patients with large mediastinal masses but without more accessible nodal involvement. It can be performed on either side, depending on the CT findings, and thoracostomy drainage is almost never necessary. At present, there is no defined role for resection of mediastinal lymphomas, and operative removal is not indicated. Rarely, patients with mediastinal lymphoblastic lymphoma present with a malignant pericardial effusion and incipient tamponade. If clinical signs are apparent, including tachycardia, tachypnea, neck vein distention, pulsus paradoxus, and muffled heart tones, an emergency echocardiogram must be done. A large pericardial effusion can almost always be drained by catheter pericardi~centesis.~~ Minimally invasive techniques that allow much more thorough thoracic or abdominal exploration without the attendant morbidity of large incisions may have a role in the diagnosis, staging, and treatment of childhood non-Hodgkin's lymphomas. This role remains undefined by prospective or randomized studies; however, trials by both the Pediatric Oncology Group and the CCG are under way to determine their eventual role in this disease process. Laparoscopy may be the optimal method for managing lymphoproliferative disease in the following settings: for the differential diagnosis of hepatic or splenic focal lesions; when percutaneous needle biopsy fails or genetic analysis is needed for a therapeutic decision; for the primary diagnosis and abdominal staging of patients with diffuse retroperitoneal lymphadenopathy in the absence of peripheral lymphadenopathy; for cases of abdominal restaging after concurrent chemoradiotherapy, and in cases of suspected relapse when percutaneous biopsy is not technically possible; and for patients with lymphoproliferative disease when splenectomy is req~ired.110,116,~~.'2" Significant bone marrow infiltration can cause severe thrombocytopenia; therefore, a complete blood count with platelet count should be available preoperatively. The production of serum clotting factors may also be affected by hepatic infiltration, and a full coagulation screen should be performed in preparation for surgery. Surgical intervention in non-Hodgkin's lymphoma should obtain sufficient biopsy material when other sources are unavailable. If adequate diagnostic material can be obtained from bone marrow aspirates, a more invasive procedure may not be required. Laparotomy is indicated when acute abdominal symptoms are present or when sufficient diagnostic tissue cannot be obtained from other sources. Similarly, a thoracic or mediastinal procedure such as the Chamberlain procedure should be designed and carried out with minimal surgical trauma and prompt institution of systemic chemotherapy. An adequate workup to rule out life-threatening metabolic or hematologic problems and to establish airway

35

Hodgkin's Disease and Non-Hodgkin's Lymphoma

587

integrity should be done before operation. The surgeon is obligated to verify that tissue samples are sent in an appropriate condition for immunohistochemistry, immunophenotyping, and cytogenetics. Children with localized abdominal disease, especially if it involves an intestinal segment, should undergo complete gross resection if this can be accomplished with speed and minimal morbidity. Patients with extensive infiltration of tumor throughout the small bowel mesentery or retroperitoneum or those with massive parenchymal involvement are best treated by adequate tissue biopsy through the smallest possible incision and prompt initiation of appropriate multiagent chemotherapy. Mediastinal or cervical primary tumors should undergo initial diagnostic biopsy, and complete tumor resection must be avoided. Laparoscopic and thoracoscopic approaches may prove useful in the diagnosis and treatment of non-Hodgkin's lymphomas. These techniques minimize tissue trauma, which may prove useful because systemic treatment can be initiated with little delay. Studies to evaluate the role of minimal-access surgery in patients with solid tumors are being undertaken by cooperative groups.

Chemotherapy Non-Hodgkin's lymphomas in childhood are disseminated at diagnosis. This concept is supported by the finding that patients with completely excised, localized disease almost always relapse in distant sites (e.g., bone marrow, cerebrospinal fluid) .">l3l Effective therapy must therefore be systemic, and chemotherapy is the primary treatment modality. Historically, only 20% to 30% of patients with non-Hodgkin's lymphoma survived for 5 years until in 1975, the pioneering work of Wollner et a1.28,13"1M when the LSA2-L2 regimen, adapted from the treatment of acute lymphoblastic leukemia, resulted in a 73% salvage reported rate. At about the same time, Ziegler et a1.7i~ix successful treatment of these patients using the COMP (cyclophosphamide, Oncovin [vincristine], methotrexate, prednisone) regimen. The Children's Cancer Study Group began a randomized trial comparing these two high-dose chemotherapy regimens for non-Hodgkin's lymphoma in 1977 (CCG551),9 with patients being randomized at diagnosis. The results suggested that therapy for non-Hodgkin's lymphoma in children should be modified to take into account the specific histopathologic subtype. A short summary of this trial is illustrative. Overall disease-free survival was 60% at 2 years for patients in CCG551. Patients with nonlocalized disease and lymphoblastic histopathologic findings had a disease-free survival of 76% at 2 years if treated with LSA2L2, whereas similar patients treated with COMP had only a 26% survival (P=0.00002). Conversely, in patients with nonlocalized, undifferentiated (small, noncleaved cell) tumors, disease-free survival was 57% for COMP, compared to 28% for LSA2-L2 (Y = 0.02). Lymphoblastic tumors did significantly better when treated with LSA2L2, whereas COMP was more effective for undifferentiated lymphomas. Chemotherapy is the primary treatment modality for all stages and histopathologic subtypes of non-Hodgkin's lymphoma. Given the high growth fractions encountered,

588

PART

III

MAJORTUMORS OF CHII.DHOOD

Lymphoblastic Lymphoma Stage I, II Vincristine, doxorubicin, cyclophosphamide, prednisone, mercaptopurine, meth~trexate~~

Small Noncleaved Lymphoma

Stage Ill, IV BFM-NHL 90: prednisone, dexamethasone, vincristine, daunorubicin, doxorubicin, L-asparaginase, cyclophosphamide, cytarabine, rnethotrexate, 6-mercaptopurine, 6-thioguanine, CNS irradiation3' CHOP + MTX (NCI-POB-7704): LMTB1: LSA2L2 regimen supplemented cyclophosphamide, doxorubicin, by 1 0 courses of high-dose rnethotrexatego vincristine, and prednisone, alternating with infusional methotrexateG9 COMP: cyclophosphamide, vincristine, rnethotrexate, prednisone3

especially with undifferentiated non-Hodgkin's lymphoma, it is crucial that chemotherapy be initiated as expeditiously as possible. Chemotherapeutic protocols for non-Hodgkin's lymphoma continue to evolve, and some of these regimens are listed in Table 35-4. Many lymphomas with localized gross disease still receive COMP chemotherapy. Mediastinal Tcell tumors are treated with regimens similar or identical to those used for lymphoblastic lymphoma, and LSA2-L2 is no longer widely used. Small, noncleaved cell lymphomas, including Burkitt's, are treated with regimens that are dose intense but shorter in duration. The use of supportive granulocytecolony stimulating factor has been associated with a reduction in hospital readmission for febrile neutr~penia."-~"glAn anti-CD20 monoclonal antibody has been used for refractory or recurrent B-cell lymphomas.118 There are no reported trials in childhood lymphomas.

Radiation Therapy In the treatment of localized non-Hodgkin's lymphoma, radiation therapy has been shown to add toxicity with no therapeutic benefit.26.8Vonversely, external beam radiation cannot be used to treat diffuse involvement at multiple anatomic sites. At present, radiotherapy should be reserved for specific emergent situations, such as mediastinal involvement with airway obstruction or massive testicular involvement. Routine central nervous system prophylaxis is readily accomplished with intrathecal methotrexate and cytosine a r a b i n ~ s i d eA . ~number ~ of recent studies continue to show a favorable outcome for non-Hodgkin's lymphoma patients treated with chemotherapy without radiotherapy.37,63,101

Stage I, II COMP French LMB-89: high-dose cyclophosphamide, vincristine, prednisone, doxor~bicin~~

Stage Ill, IV French LMB-89

CHOP NHL-BFM 90 CHOP + MIX (NCI-POB-7704) NHL-BFM 90: prednisone, NCI-89-C-0041F: dexamethasone, vincristine, cyclophospharnide, doxorubicin, cyclophosphavincristine, doxorubicin, mide, ifosfamide, etoposide, and methotrexate cytarabine, methotrexatelo' (Codox-M),alternating with cytarabine, etoposide, and ifosfamide (IVAC)2

have extremely high growth fractions and rapid cellular turnover rates. This results in a large turnover of tumor cells, either because they outgrow their blood supply or undergo cell death and lysis for other reasons. Depending on the size of the tumor, this places a tremendous metabolic load on the kidneys, composed of phosphates, potassium, purines, and protein. Patients may present with elevated serum uric acid, lactate, and potassium levels. This syndrome may be further aggravated during the initial massive cell lysis caused by chemotherapy. The result is the tumor lysis syndrome, which can result in hyperuricemic nephropathy and renal shutdown.41 Obviously, the metabolic and hematologic status of the patient should be determined before surgery. A full serum electrolyte screen, as well as determinations of serum creatinine and blood urea nitrogen, is mandatory before surgical intervention, and preoperative hemodialysis may be required to control electrolyte disturbances. All patients should be treated with allopurinol and undergo alkaline diuresis before chemotherapy. Ancillary roles for surgery include the establishment of vascular access for chemotherapy and, if necessary, hemodialysis. Decompression of the urinary tract may also be required in cases of ureteral obstruction by a large abdominal tumor. Cystoscopic placement of ureteral catheters (doub1e-J) can result in marked improvement in urine output and renal function. This technique is preferable to percutaneous puncture both for patient comfort and to avoid infectious complications from percutaneous catheters when the granulocyte counts fall after chemotherapy.

Prognostic Factors Complications As previously noted, childhood non-Hodgkin's lymphomas, especially the small, noncleaved cell subtype,

Clinical outcome depends on tumor burden at the time of diagnosis. This is reflected by the clinical stage, but no current staging system correlates linearly ~ . ~ ~ of serum parameters with tumor b ~ r d e n .A~ number

CHAPTER

can be used to estimate tumor amount, as these substances are secreted or shed from malignant cells. These include LDH, interleukin-2 receptor, P2-microglobulin, uric acid, lactic acid, and p0lyamines.2~~~~J2~ Determination of serum LDH levels is readily available and easy to obtain. LDH levels greater than 250 mg/U/L suggest significant tumor burden, whereas levels greater than 500 are associated with a significantly worse prognosis.

Summary Non-Hodgkin's lymphoma is a heterogeneous group of lymphoid malignancies that can be systematized by reference to normal lymphoid ontogeny. Most abdominal tumors are of the undifferentiated histopathologic subtype (also called small, noncleaved cell), with Burkitt's lymphoma included in this group. Present data support complete resection of abdominal lymphomas only when this can be accomplished with minimal morbidity and without delaying the initiation of chemotherapy. Most mediastinal lymphomas are of T-cell orgin, and resection should not be performed. Surgical intervention may also be required to treat complications, such as massive tumor lysis, bowel perforation, gastrointestinal hemorrhage, or urinary tract obstruction.

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94. 95.

96. 97. 98. 99.

100. 101.

102.

103. 104. 105.

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Ovarian Tumors Claire L. Templeman and Mary E. Fallat

INCIDENCE

ovarian tumors in children and adolescents ranged from Primary cysts and tumors of the ovaries are uncommon in 10% to 40%.48,53,190 children. The majority of these masses are not malignant.'j4 Gynecologic malignant conditions account for approximately 2% of all types of cancer in children, and 60% to EPIDEMIOLOGY 70% of these lesions arise in the ovary.l" Recently the A few syndromes or diseases have been associated with North American Association of Central Cancer Registries ovarian pathology. The Peutz-Jeghers syndrome has been released data from 1992 to 1997 regarding more than 1.6 million women and children diagnosed with cancer.233 associated with granulosa cell tumors, ovarian cystadenoThis report revealed that 1.2% of ovarian cancer cases mas, and sex cord-stromal tumors with annular t~bules.l6~ ~ granulosa cell tumors have been detected occurred in females between birth and age 19 ~ e a r s . 2 ~ Juvenile with Ollier's disease (multiple enchondromatosis)l' Lindfors117analyzed several large series of ovarian tumors and Maffucci's syndrome (enchondromatosis and in children and estimated that the annual incidence of hemangiomas) .Z0l The Sertoli-Leydig cell tumor has been combined benign and malignant lesions was 2.6 cases per associated with Ollier's disease,%nd fibrosarcoma has 100,000 girls younger than 15 years. been linked with Maffucci's syndrome.% Sclerosing stroAge distribution has an influence on the relative frema1 tumors have been associated with the Chkdiak-Higashi quency of specific types of ovarian lesions. Lack et al.112 syndrome (oculocutaneous albinism, pyogenic infections, reviewed 157 primary ovarian tumors from a 50-year and leukocyte granule abnormalities that result in defiexperience at the Boston Children's Hospital. The incicient phagocytosis).97The presence of ovarian cysts had dence of mature cystic teratomas was relatively static been noted in various dysmorphic syndromes, including beyond 5 years of age, the incidence of granulosa cell those with craniofacial, laryngeal, and digital malformatumors dropped after 9 years of age, the peak incidence tions.lz6 The McCune-Albright syndrome (triad of cafe au of yolk sac tumors occurred between 10 and 14 years of lait macules, polyostotic fibrous dysplasia, and autonoage and then dropped dramatically, and surface epithemous endocrine hyperactivity) is generally characterized lial tumors were not seen in girls younger than 10 years. by gonadotropin-independent sexual precocity due to The concept that the highest incidence of malignant recurrent ovarian follicle formation and cyclic estradiol conditions occurs in the youngest patients has been secretion.2Z4Fibromas are often associated with the basal reassessed. Newer diagnostic imaging techniques have cell nevus syndrome. increased the detection of all gonadal masses, and the Nulliparity is associated with a 1.5 to 3.2 times greater frequency of ovarian cancer has decreased. A 43year review risk of the development of ovarian cancer than is parity. published in 1992 by Gribbon et al.77noted that malignant Women who have never used oral contraceptives have a ovarian tumors are more frequent (70%) in the second risk 1.4 to 2.5 times greater than that of women who have decade of life. used them. Other potential but more controversial risk Previous surveys reported a 55% to 67% incidence of malignant ovarian lesions.78,"QAn 11-year experience of factors include exposure to ovulation-inducing drugs without successful pregnancy and diets high in meat and 91 cases from the Children's Hospital of Philadelphia animal fats, dairy products, and lactose. Prior tuba1 ligapublished in 1993 detected only a 21% incidence of tion and hysterectomy may reduce the risk of ovarian malignant tumors.Z6 Ninety-seven percent of the patients can~er.130,18~ younger than 8 years had benign lesions, compared with Approximately 5% to 10% of women with breast and 33% in older age groups. Imai et al.96 reported a 20% incidence of malignancy among 114 ovarian tumors colovarian cancer have a genetic predisposition. High percentages of hereditary breast and ovarian cancers arise lected from a large hospital network in Japan. Several from mutations in the tumor suppressor genes BRCAl other series reported that the occurrence of malignant

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and BRCA2. Approximately 70% of familial ovarian canBoth neoplastic and non-neoplastic ovarian lesions cer cases are caused by BRCAl mutations and 20% by demonstrate endocrine activity in approximately 10% of BRCA2. These mutations are inherited in an autosomal cases.26,19"~~~ Ovarian cysts of the simple, follicular, or dominant fashion. If a woman is a carrier of one of these luteal type may secrete estrogen and can cause precocious gene mutations, she has a lifetime risk of developing isosexual development. The lesions usually function ovarian cancer as high as 60%."2130 autonomously, and the girls have suppressed gonadotropin Genetic testing of adolescents is ~ontroversial.*~~~~222 concentrations. As a result, they can be distinguished from KodishIo7formulated the argument that physicians should patients with central precocious puberty (with accelerated respect the "rule of earliest onset" and defer testing until skeletal maturation) or premature thelarche (isolated the age when the onset of disease becomes possible. breast development) by estrogen withdrawal and vaginal bleeding after cyst involution or removal. Precocious Although it may seem premature to address these issues in adolescence, some mature young women at risk for pseudopuberty may occur due to the production of breast or ovarian cancer may inquire about the efficacy human chorionic gonadotropin in girls with germ cell of future surgical or medical interventions. In most cases, tumors, including dysgerminomas, yolk sac tumors, and choriocarcinomas. Precocious puberty is most common surgical intervention is not indicated until age 35 years or older or completion of childbearing. The use of oral with the sex cord-stromal tumors, such as juvenile granulosa cell tumors or some Sertoli-Leydig cell tumors, which contraceptives has been shown to reduce the risk of ovarcause elevated levels of circulating estrogen. ian cancer in the general population. Whether the use of these agents in young women with BRCA mutations is Virilization due to androgen excess can occur with beneficial remains to be determined.130 Sertoli-Leydig cell tumors, and masculinization is occaThe American Society of Human Genetics and the sionally seen in older girls with dysgerminomas that conAmerican College of Medical Genetics issued a joint tain syncytial trophoblastic giant cells. Yolk sac tumors, report on the genetic testing of children and adolescents steroid cell tumors, and polycystic ovaries can be associin 1995.1° If the primary goal of genetic testing is to proated with virilization. mote the well-being of the child, testing is acceptable only if there are medical benefits, such as preventive measures and therapy. Currently, the benefits of prophyDIAGNOSIS lactic surgery or increased surveillance in adolescent patients have not been evaluated or tested, and there is Laboratory Tests no conclusive evidence that BRCA testing has a medical benefit in individuals younger than 18years. An alternative Many ovarian neoplasms are associated with the secretion view proposed by Elger and Harding""~ that some of specific tumor markers or hormones. These are outmature adolescents may obtain significant psychological lined in Tables 361 and 362 and are discussed further in the sections on individual tumors. relief from knowing their mutation status and may be capable of using this information for reproductive and health decisions.

Tumor Markers

CLINICAL PRESENTATION Ovarian lesions can present with variable signs and symptoms. Most often, the clinical presentation does not differentiate a benign tumor from a malignant one. Abdominal pain is the most common ~ymptorn.2"g6~190 With cysts and other non-neoplastic conditions, the pain can be acute in onset, with a crescendo pattern of severity because of torsion, rupture, or hemorrhage. The clinical picture may mimic appendicitis.3" A more chronic, insidious pattern of pain, increasing girth, and marked distention over several weeks to months may occur. Secondary symptoms include anorexia, nausea, vomiting, and urinary frequency and urgency. A palpable abdominal mass with or without tenderness is the most frequent finding on physical examination and is detected in more than 60% of patients with ovarian tumors.26Jg0 These tumors are usually mobile and palpable above the pelvic brim. Bimanual palpation between the lower abdomen and rectum may be helpful in detecting smaller lesions. Vaginal examination is usually reserved for sexually active patients, although vaginal inspection is of value in all patients. An increasing number of ovarian lesions are discovered incidentally by abdominal radiographs or ultrasonography (US) done for other reasons.

Germ cell tumors are associated with various biologic markers that are useful in identifying and managing this group

Histologic Subtype

CA-125 CA-19.9 AFP

Endometrioma Epithelial Borderline Carcinoma Germ cell* Dysgerminoma Yolk sac Immature teratoma Choriocarcinoma Embryonal Endodermal sinus Sertoli-Leydig

PHCG -LDH

+

+

+ + + .

+ +

+

+

+

+ +

*The markers indicated are elevated in pure tumors; mixed tumors may secrete several markers. AFP, alpha fetoprotein; HCG, P-humanchorionic gonadotropin; LDH, lactate dehydrogenase.

CHAPTER

Histologic Subtype

Estradiol

Ovarian cyst Simple Follicular Luteal Sex cord-stromal Juvenile granulosa Sertoli-Leydig Luteinized thecoma Sex cord tumor with annular tubules Steroid cell tumor Gonadoblastoma Choriocarcinoma

Testosterone

36

Ovarian Tumors

Urinary 17-Ketosteroid

595

Gonadotropins

?

1' T

7‘*

1‘ TI ? 1‘

1 1

tt

7' * T T

'T‘*

t ?

1‘

1 1‘

--

*Indicates rarer variants of the tumor. tFunctioning Sertoli cells predominate *FunctioningLeydig cells predominate.

of tumors.48 Protein markers, including alpha fetoprotein (AFP), Phuman chorionic gonadotropin (PHCG), and lactate dehydrogenase (LDH), are the most readily available. They are measured with serum assays or immunohistochemical staining of paraffin-fixed or frozen tumor.

Alpha Fetoprotein The association of AFP with germ cell tumors was first described by Abelev et a1.l ~ e c a u s ethe fetal yolk sac is the source of AFP early in human embryogenesis, elevations of the marker occur with yolk sac tumors.207 This is also true with hepatoblastoma, hepatocellular carcinoma, and teratocarcinoma.200 The elevation reflects the presence of fetal tissue from which normal progenitor cells arise. There is wide variability in normal levels of AFP from birth through the first year of life,230and AFP is significantly elevated in premature and normal newborns (Table 363). Its usefulness in the diagnosis of yolk sac

tumor or embryonal carcinoma in the first month of life is limited.66.71 Its value in tumor identification begins when the AFP level is significantly elevated over the normal range at any particular age. The normal serum half-life of AFP is 5 to 7 days. Its decline after removal of an AFP-producing tumor signifies a response to treatment. The goal of any treatment is to return AFP to normal levels. Tumor recurrence is marked by a sudden elevation of the AFP level.

j3-Human Chorionic Gonadotropin PHCG is a glycoprotein produced by placental syncytiotrophoblasts. It comprises two subunits, a and P; the latter can be reliably assayed.214 PHCG elevation in a patient with a germ cell tumor suggests the presence of syncytiotrophoblasts, as seen in seminoma, dysgerminoma, choriocarcinoma, and occasionally embryonal ~ a r c i n 0 m a . l ~ ~ Elevations above 100 ng/mL are unusual and suggest the Unlike the much longer diagnosis of chorio~arcinoma.'~ half-life of AFP, the 0 subunit has a half-life of 20 to ~ rapid disappearance implies complete 30 h o ~ r s . l 5Its removal of a tumor.

Serum Lactate Dehydrogenase Age Premature Newborn Newborn-2 wk 2 w k - l mo 2 mo 3 mo 4 mo 5 mo 6 mo 7 mo 8 mo

Number of Samples

Mean f SD (ng/mL)

11 55 16 12 40 5 31 6 9 5 3

134,734 f 41,444 48,406 f 34,718 33,113 f 32,503 9 4 5 2 f 12,610 323 f278 88 f87 74 56 46.5 f 1 9 12.5 f 9.8 9.7 7.1 8.5 5.5

+

+ +

From Wu JT, Book L, Sudar K: Serum alpha-fetoprotein(AFP) levels in normal infants. Pediatr Res 1981;15:50.

Serum LDH is a nonspecific marker that is widely distributed in human tissues and is therefore of limited value in establishing tumor type or response to treatment. However, elevated LDH may indicate increased cell turnover and has been used as a nonspecific indicator of malignancy.I45It is most useful as a prognostic marker for lymphoid tumors and neuroblastoma. The gene for this isoenzyme is located on 12p, and nonrandom structural changes in chromosome 12 have been seen in all histologic subtypes of germ cell tumors.

Cancer Genetics Ovarian germ cell tumors are associated with sex chromosome abnormalities. Although a few case studies

596

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M . 4 1 0 ~TUMORS OF CHILDHOOD

suggest otherwise, a large study examining 456 first- or second-degree female relatives of 78 patients with ovarian germ cell tumors did not identify an increased risk for o c ~ u r r e n c e . 1 8 ~ 1 ~ ~ ~ ~ ~ ~ The application of new cytogenetic technologies has increased our understanding of the genetics and molecular mechanisms involved in the development of germ cell tumors. Nonrandom changes in molecular structure have commonly been reported in chromosomes 1 and 12, as well as in others.fl7.8J" For example, the chromosomal aberration of trisomy 12 has been identified in many stromal tumors.l4%n isochromosome is a chromosome in which both arms are derived from one of the two arms by breakage at the centromere and subsequent duplication. Isochromosome 12p [i(12p)] has been identified in all types of germ cell tumors,lgJ72,191 including testicular germ cell tumors in men.aJ72.1g"he presence of three or more copies of i(12p) has been associated with treatment failure.88Nonrandom endodermal sinus tumors in children involve the deletion of segments of chromosome l p and 6q. Deletion of the terminal portion of l p has been identified in other tumors, indicating that it may be a locus of one or more tumor suppressor genes not yet characterized. Isochromosome 12p has been identified in ovarian tumors in adolescents and adults.'? Endodermal sinus tumors in children may show cytogenetic differences from adults with no evidence of i(l2p), but with deletions involving l p , 3q, and 6q.lj3 The c-myc oncogene has been found in a few endodermal sinus tumors, and the current Children's Oncology Group protocol will begin to correlate amplification with survival and response to therapy.31Further studies are required to

- A

determine the significance of these findings. Many germ cell tumors in children express Pglycoprotein, a membranebound protein that can decrease the response to chemotherapy; this may explain why these tumors are frequently resistant to treatment.""'

Imaging Techniques Various radiographic studies play an important role in the clinical evaluation of pediatric ovarian lesions. Prenatal US can usually differentiate ovarian lesions from intestinal duplication, hydronephrosis, duodenal atresia, choledochal cyst, urachal remnants, hydrometrocolpos, and intestinal obstruction (Fig. 361). Mesenteric and omental cysts are more difficult to distinguish from simple ovarian cysts, because the ovary is an abdominal rather than a pelvic organ in an infant. US is the diagnostic study of choice for the initial evaluation of potential ovarian pathology in all age groups. Adequate urinary bladder distention is mandatory to displace gas-filled intestinal loops out of the pelvis and to ensure adequate sound wave transmission through the ovaries. Ovarian volume changes with age from less than 0.7 c m q n girls younger than 2 years to 1.8 to 5.7 cm3 in postpubertal patients.'" Morphologic characteristics also change. In children younger than 8 years, the ovaries are generally solid, ovoid structures with a homogeneous echogenic texture. During and after puberty, the ultrasonographic spectrum of the gonad undergoes cystic changes that parallel ovulatory follicle activity in the organ. Ovarian cysts are generally anechoic, thin-walled masses

and B, Two views of an ultrasonogram of a fetus in the third trimester. A large, complex ovarian cyst containi~ internal septdtion , and solid components can be seen. An ovarian neoplasm was identified during surgery after birth. (Courtesy Thieme, MD, Pre!natal Diagnosis Center, University of Colorado School of Medicine.)

debiris. A.

CHAPTER

with through transmission. With torsion, fluid debris or septation may be present.18Wost benign tumors are complex masses that are hypoechoic with peripheral echogenic mural nodules, which may exhibit acoustic shadowing. Malignant tumors are often larger than 10 cm in diameter and appear as complex soft tissue masses with ill-defined, irregular borders and central necrosis, thick septations, or papillary projections on US. Doppler color-flow imaging and transvaginal US are also valuable in postpubertal patients to determine morphologic characteristics of ovarian lesions.'2J6~~"j Computed tomography (CT) and magnetic resonance imaging (MRI) are useful when the origin of the pelvic mass cannot be established by US or when assessment of the full extent of a noncystic lesion is necessary. The characteristic finding of a benign tumor on CT is a fluid-filled mass with fat and calcification^.^ Focal solid components arising from the tumor wall are common (Fig. 36-2). Malignant lesions are large and predominantly solid with occasional cystic areas as well as fine or coarse calcifications. Direct extension of tumors to adjacent pelvic structures or to the liver and lungs can also be demonstrated by CT, which provides more accurate staging of disease than US. Adnexal torsion in association with any tumor has a distinct appearance on CT, which is demonstrated by dynamic scanning after the administration of contrast medium. The appearance is generally characterized by lack of enhancement of mural nodules, which indicates interruption of blood flow, and demonstration of thick, engorged blood vessels that drape around the tumor and indicate markedly congested veins distal to the site of torsion. MRI is well suited for imaging pelvic lesions because it is not influenced by extensive subcutaneous fat and offers superb soft tissue contrast resolution." The technique is especially valuable in determining whether a mass is ovarian or uterine in origin, and it has a specific signal behavior and a distinct appearance that enable the

Ovarian Tumors

597

detection of dermoid cysts, endometrioma, and endometrial implants.lo6Jg4The ability of MRI to delineate the extent of disease in endometriosis after laparoscopic biopsy may be useful for monitoring treatment response.60 The character of cystic fluid, either simple hemorrhagic or complex, can be assessed by MRI." The long imaging times required may cause peristalsis and respiratory motion to obscure peritoneal and intestinal surfaces, and sedation may be needed in small children. Ovarian torsion with hemorrhagic infarction can be detected on MRI by the finding of a high-intensity rim at the periphery of the mass on the T1-weighted image.lo4

DISEASE CLASSIFICATION AND STAGING Ovarian lesions are generally divided into non-neoplastic and neoplastic entities; the former category includes several functioning cysts, and the latter includes benign and malignant tumors. The clinical system presented here is modified from the most recent version of the World Health Organization's proposal for the international histologic classification of diseases and its adaptation for oncology (Tables 36-4 and 36-5) .Is4 Non-neoplastic and neoplastic lesions may arise from surface epithelium, germ cell components, or support stroma. Neoplastic lesions are listed based on the tissue of origin. Proper management of ovarian neoplasms requires accurate staging of the initial extent of disease. In malignant cases, recent advances in therapy have resulted in increased survival rates and preservation of fertility. Surgcal staging with histologic confirmation must be done to s u p plement the clinical assessment of disease status. Precise staging is based on clinical examination, surgical exploration, tissue histology, and fluid cytology, as reaffirmed by the Cancer Committee of the International Federation of Gynecology and Obstetrics (FIGO) (Table 36-6).62 Because ovarian neoplasms are relatively uncommon, evaluation and treatment protocols developed from multiinstitutional collaborative studies have been most valuable.

.

,

Computed tomography scan of a large, calcified abdominal mass. The Inass has a large cystic component, with solid, thickened walls that are somewhat eccentric in appearance. The tumor was a thin-walled fibrous cyst with extensive hemorrhagic infarction throughout the entire cyst wall. Histology was consistent with a benign cystic teratorna.

36

Massive edema Fibromatosis Endometriosis Cyst, unclassified (simple cyst) Inflammatory lesions

598

PART

III

M ~ \ J O TUMORS R OF CHII.DHOOD

1. Surface epithelial-stromal tumors 1.1. Serous tumors 1.2. Mucinous tumors 1.3. Endometrioid tumors 1.4. Clear cell tumors 1.5. Transitional cell tumors 1.6. Squamous cell tumors 1.7. Mixed epithelial tumors 1.8. Undifferentiated and unclassified tumors 2. Sex cord-stromal tumors 2.1. Granulosa-stromal cell tumors 2.1.1. Granulosa cell tumor group 2.1.1.1. Adult 2.1.1.2. Juvenile 2.1.2. Tumors in thecoma-fibroma group 2.2. Sertoli-stromal cell tumors 2.3. Sex cord-stromal tumors of mixed or unclassified cell types 2.3.1. Sex cord tumor with annular tubules 2.3.2. Gynandroblastoma 2.4. Steroid cell tumors 3. Germ cell tumors 3.1. Primitive germ cell tumors

4.

5. 6.

7. 8. 9.

Uniform surgical guidelines that incorporate standard approaches to these lesions have been formulated, although the approach to ovarian neoplasms has become more conservative with time.20"2°Y Preoperative assessment should try to exclude obvious malignancy by the collection of serum tumor markers and carefully performed pelvic US to determine whether the ovarian mass is complex in nature.

Stromal and germ cell tumors have been assessed in studies from the Children's Cancer Group (CCG), the Pediatric Oncology Group (POG), and the Gynecologic Oncology Group (GOG)."343wJ67 In children, the intergroup POG 9048/9049 and CCG 8882/8891 studies used a system that incorporated both surgical and pathologic findings. This concept has been preserved by the Children's Oncology Group (COG) (Table 36-7).31

Stage

Extent of Disease

-. --Primary tumor cannot be assessed No evidence of primary tumor Tumor confined to ovaries Tumor limited to one ovary, capsule intact No tumor on ovarian surface No malignant cells in ascites or peritoneal washings Tumor limited to both ovaries, capsule intact No tumor on ovarian surface No malignant cells in ascites or peritoneal washings Tumor limited to one or both ovaries, with any of the following: Capsule ruptured, tumor on ovarian surface, malignant cells in ascites or peritoneal washings Tumor involves one or both ovaries with pelvic extension Extension to or implants on uterus or tubes or both No malignant cells in ascites or peritoneal washings Extension to other pelvic organs No malignant cells in ascites or peritoneal washings IIA or IIB with positive malignant cells in ascites or peritoneal washings Tumor involves one or both ovaries with microscopically confirmed peritoneal metastasis outside the pelvis or regional lymph nodes metastasis Microscopic peritoneal metastasis beyond the pelvis Macroscopic peritoneal metastasis beyond the pelvis 2 cm or less in greatest dimension Peritoneal metastasis beyond the pelvis more than 2 cm in greatest dimension or regional lymph nodes metastasis Distant metastasis beyond the peritoneal cavity ,

II IIA

IIC 111

3.1.1. Dysgerminoma 3.1.2. Yolk sac tumor (endodermal sinus tumor) 3.1.3. Embryonal carcinoma 3.1.4. Polyembryoma 3.1.5. Nongestational choriocarcinoma 3.1.6. Mixed germ cell tumors (specify components) 3.2. Biphasic or triphasic teratomas 3.2.1. Immature 3.2.2. Mature 3.3. Monodermal teratomas Germ cell sex cord-stromal tumors 4.1. Gonadoblastoma 4.2. Mixed germ cell-sex cord-stromal tumor of nongonadoblastoma type Tumors of rete ovarii Miscellaneous tumors 6.1. Small cell carcinomas, hypercalcemic type 6.2. Gestational choriocarcinomas 6.3. Soft tissue tumors not specific to ovary Tumorlike conditions Lymphoid and hematopoietic tumors Secondary tumors

CHAPTER

Stage -

Extent of Disease

I

Limited to ovary (peritoneal evaluation should be negative); no clinical, radiographic, or histologic evidence of disease beyond the ovaries (Note: The presence of gliomatosis peritonei does not change stage I disease to a higher stage) Microscopic residual; peritoneal evaluation negative (Note: The presence of gliomatosis peritonei does not change stage II disease to a higher stage) Lymph node involvement (metastatic nodule); gross residual or biopsy only; contiguous visceral involvement (omentum, intestine, bladder); peritoneal evaluation positive for malignancy Distant metastases, including liver

II

111

IV

Elevated tumor markers and a complex mass on US strongly suggest a malignancy, and an abdominal and pelvic CT scan should be obtained. For potentially malignant lesions, an adequate abdominal incision is used, and violation of the tumor capsule is avoided. Alternatively, if tumor markers are negative and the mass is thought to be benign (e.g., a mature cystic teratoma) a laparo~copic approach can be considered (Fig. 36-3). Initial resection in pediatric patients should virtually always be conservative. Pelvic washings, unilateral ovarian cystectomy, intraoperative frozen section, and careful visual inspection of the contralateral ovary are appropriate in the initial management of benign lesions or tumors of low malignant potential. Pelvic washings are part of the staging system for ovarian tumors and should be performed immediately on entry into the abdomen (via either laparoscopy or laparotomy) in an attempt to avoid

A

36

Ovarian T u m o r s

599

contamination in the event of intraoperative tumor rupture. Because the final pathology will not be known until either frozen section or histologic evaluation of paraffin-embedded tissue, peritoneal washings should be performed in all patients with complex adnexal masses in case of an unsuspected malignancy. If there is no evidence of free fluid upon entering the abdomen, lactated Ringer's solution can be used to irrigate the pelvis and paracolic gutters, then aspirated and sent as washings. Malignant germ cell and stromal tumors are almost never bilateral in early-stage disease, so unilateral salpingooophorectomy with a staging procedure is adequate firstline management. Excellent responses have been reported with chemotherapy, even in children with extensive tumors, and maintenance of childbearing capability is possible with this approach. In bilateral or more advanced disease, the current success of in vitro fertilization techniques has prompted the consideration of uterus-sparing procedures during the initial operation.'4,"'2 The expected biologic behavior of the tumor and its response to adjuvant therapy generally dictate the ultimate extent of surgery required. The value of laparoscopic examination in the assessment of pelvic disease is well established (see Fig. 36-3). Elsheikh et a1.57reported a series of 54 patients between 14 and 20 years of age with ovarian masses managed laparoscopically. Final path~lo~gy included mature cystic teratomas in 22 patients, 12 cases of endornetriosis, 8 serous and 5 mucinous cystadenomas, 3 borderline tumors, and 3 cases of fibroma-thecoma. Hiloury et al.x"performed laparoscopy in 28 children with pathologic conditions of the adnexa. Several nonovarian lesions were detected among the 25 children who had laparoscopy for diagnostic purposes. In addition, the histologic nature of an ovarian tumor was confirmed in four children, and diagnostic aspiration was performed on nine functional cysts. Pelvic adhesions prevented successful laparoscopy in one case, and one postoperative complication necessitated secondary laparotomy.

B

A, 1,aparoscopic view o f an abdominal mass, originally palpated during a routine well-child examination. W o r k u p included a computed tomogl.aphy scan o f the abdomen and pelvis, which disclosed a large cystic mass in the left ovary. B, T h e Harn~onicScalpel was used to make an incision over t h e central aspect or waist o f the mass, enabling cyst dissection. T h e ovary was preserved.

600

PART

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MAIORTUMORS OF CHILDHOOD

two of these cysts (5 and 10 cm in diameter) had undergone adnexal torsion and left no identifiable ovarian tissue. In a series of 28 patients with early sexual development, 12 had isolated premature thelarche, 4 presented with vaginal bleeding, and 7 had true central precocious puberty. In these groups, no ovarian cysts were larger than 2 cm in diameter." Girls with premature thelarche often had detectable ovarian microcysts. The remaining five patients with precocious pseudopuberty had larger ovarian cysts. Although two lesions regressed spontaneously, three others required surgical excision of luteinized follicular cysts. Ovarian cysts have beet1 recognized prenatally with some frequency with the increased use of maternal US.'" The precise cause of fetal ovarian cysts remains unclear, but they may be due to either production of fetal Solliclestimulating hormone, maternal estrogen, or placental chorionic gonadotropin or stimulation of an immature Non-neoplastic Ovarian Tumors hypothalamus-pituitary-ovarian axis. A postnatal decrease Ovarian cysts are known to arise from mature follicles. in hormonal stimulation often leads to a self-limited Autopsy studies of prepubertal girls have documented process. Ovarian cysts noted in the prenatal and peririatal periactive follicular growth at all ages and normal oocytes, granulosa cells, and cysts in various stages of inv01ution.l~~J~~ ods can be expected to spontaneously regress during the By convention, physiologic follicles are differentiated from first year of life, and in utero therapy is notjustified."J2" pathologic ovarian cysts or1 the basis of size: any lesion Cesarean section should be performed for obstetric indilarger than 2 cm in diameter is no longer considered a cations only, even when a large cyst is s u ~ p e c t e d . ~ ~ . ' ~ ~ mature follicle. These lesions may occasionally be complicated by torsion, Non-neoplastic cysts are benign and generally asympintestinal obstruction, or perforation and cyst rupture.s.178 tomatic, although they represent approximately 35% Bagolan et a l . l b n d Giorlandino et al.jOconfirmed that of all surgically treated ovarian lesions in children and patients with echogenic cysts with fluid debris, retracting adolescent^.'^ Although surgical intervention is rarely clot, or septation should undergo surgical intervention indicated, these lesions occasionally have clinical manibecause such findings were associated with torsion and festations, based on size or associated functional activity, hemorrhage.'xVn this age group, torsion is often a prenatal event, and viable ovarian tissue may not be identified, that warrant differentiation from true ovarian neoplasms. even with the most expeditious neonatal surgical interWhen an operation is necessary, a conservative approach vention (Fig. 36-4)."23 Cysts that develop in utero are should be undertaken. In most cases, it is possible to remove the cyst and preserve the adjacent normal ovarian most often lined by luteinized cells, whereas those in tissue. older children are more often lined by granulosa cells.154 Most authors now advocate increasingly conservative measures for neonatal ovarian lesions. Small, asymptomatic The American Association of Gynecologic Laparoscopists reviewed more than 13,000procedures performed for persistent ovarian masses." Stage I ovarian cancer was detected in 0.4% of cases. Although these results are encouraging in adult women, there is concern about the difficulty of establishing the true nature of an ovarian tumor by gross examination in children, because experience with such an evaluation is so infrequent. Nevertheless, techniques are being established to avoid tumor spillage that may expand the use of this method. In addition, experienced surgeons are beginning to perform more extensive staging procedures and lymph node dissections using the l a p a r o ~ c o p e . ~ ~

FoNicular Cysts

Follicular cysts represent about 50% of the non-neoplastic ovarian lesions.z4They are unilateral, unilocular, and histologically benign and often have a thin, yellowish, clear liquid content. These lesions are now known to be quite common in neonates and infants. Cohen et al.3" detected cysts in 84% of all imaged ovaries in 77 patients from birth to 24 months of age. The prevalence was similar in each .%monthage bracket. Parallel findings were noted in premenarchal girls between 2 and 12 years of age." Cysts were detected in 68% of patients; again, a generally equal distribution was noted across the age spectrum. The presence of cysts in the premenarchal ovary of an otherwise healthy child does not necessarily suggest endocrinologic or other disease. Occasionally, ovarian cysts persist and enlarge and are capable of secreting estrogen, thereby leading to precocious isosexual de~elopment."~ The size of an ovaEian lesion has been a major factor in determining clinical management. Millar et al.I2' found 17 cysts larger than 2 cm in diameter in 99 prepubertal girls during a 5-year period. Seven were treated by observation alone, without adverse outcome. Benign follicular or luteinized cysts were excised in the other 10 girls;

This newborn female infant had a prenatal diagnosis of an intra-abdominal cystic mass. Postnatal imaging showed a lowattenuation cystic structurc with a curvilinear calcification along one wall. Laparotomy disclosed a torsed ovarian cyst and ovary, attached by only a small residual stalk. The fallopian tube was preserved. Pathology showed a thin-walled cyst containing dystrophic calcifications.

CHAPTER

cysts are generally observed for regression with serial US. Cysts 5 cm in diameter or larger and those with a long adnexal pedicle are more likely to undergo torsion and should be excised with ovarian preservation2hr aspiUS-guided cyst aspiration is associated with rated."12".17.1 minimal recurrence and few complications.43,52 Smaller simple cysts should be observed unless they become symptomatic, recur, or fail to regress after several months of obser~ation."~ In prepubertal children, the occurrence of acute symptoms and endocrine activity are more problematic. Warner et a1."8 described the outcome of 92 patients with large ovarian cysts. Ninety percent of the cysts clinically regressed or completely resolved. Acute, severe abdominal pain was the indication for operative intervention in 17 of the 23 surgically treated patients. Cyst size and US characteristics did not accurately predict outcome. Laparotomy was recommended if symptoms did not resolve within 24 hours, a large mass was associated with intra-abdominal complications, or there was evidence of a neoplasm on imaging studies. Surgical intervention was also recommended for any cyst that increased in size or failed to regress on follow-up US. As many as 75% of girls with juvenile hypothyroidism have multicystic ovaries and may show varying degrees of sexual precocity and galactorrhea due to increased secretion of pituitary gonadotropins and prolactin.lM Multiple follicular cysts should also be distinguished from polycystic ovary syndrome, which is the most common cause of delayed puberty and heavy anovulatory bleeding in adolescent fernales.l7O In one randomized study of postmenarchal patients, cysts 5 cm in diameter or larger and those with a complex appearance on imaging studies were followed for a short time with serial pelvic US. High regression rates were seen with those followed expectantly.192 Exploratory laparotomy or laparoscopy was recommended for patients with cysts that had not resolved or had increased in size within 2 to 3 monthslY2and for cysts associated with acute or severe chronic abdominal pain or intra-abdominalcomplications. In non-neoplastic ovarian cysts, surgical preservation of as much normal ovarian tissue as possible is a high priority. A plane of dissection can usually be established between the normal gonadal tissue and the cyst after injecting saline with a fine-bore needle beneath the visceral peritoneum. If the surgical manipulation necessary to completely remove the lesion would threaten significant viable ovarian tissue, the cyst should be unroofed and debulked, and the cyst wall excised to the extent possible, while protecting the ovary. Unilateral oophorectomy is indicated only if there is a reasonable certainty that no viable gonadal tissue can be salvaged. The ipsilateral fallopian tube should be spared because fertilization is still possible from the contralateral normal ovary.

Corpus Luteum Cysts True functioning corpus luteum cysts develop only in adolescents who are actively ovulating. Although these cysts may be bilateral and become quite large, they usually regress spontaneously with the cyclic decline in serum progesterone. The gross appearance of the external surface is often bright yellow, although it may take on a

36

Ovarian Tumors

601

hemorrhagic appearance when filled with bloody fluid. The cyst lining is composed of luteinized granulosa and theca cells and is capable of actively producing estrogen and progesterone. These cysts may cause acute pelvic pain if they rupture or undergo torsion. Failure of the corpus luteum to involute may cause menstrual irregularity and dysfunctional uterine bleeding. Surgcal goals for corpus luteum cysts parallel those for other follicular lesions. Surgical intervention is indicated in the presence of cyst accident or persistence, demonstrated by repeat pelvic US performed 4 to 6 weeks after the initial assessment. Hassons%as able to treat 17 of 19 patients who had corpus luteum cysts with laparoscopic aspiration, fenestration, or cyst wall excision. Clinical symptoms resolved in all but one patient. Cyst recurrence was rare.

Parovarian Cysts Parovarian cysts are usually small and rarely symptomatic. They do not arise from ovarian tissue but are usually considered with this group of lesions because of their proximity to the gonad. These cysts originate from the epoophoron and are located in the leaves of the mesosalpinx. Parovarian cysts cannot be distinguished from ovarian follicular cysts using any radiographic imaging technique. During an operation, their gross features are virtually identical to those of follicular lesions, but they can usually be accurately identified because of their anatomic position. When surgical treatment is required, both standard open and minimally invasive techniques have been used.8"179 Large parovarian cysts (>3cm) should be completely enucleated from the mesosalpinx in such a way that the fallopian tube and ovary are not damaged.42 Those less than 3 cm may be treated with puncture and bipolar coagulation of the cyst wa11.G

Endometriosis Endometriosis is a disorder in which the endometrial glands and stroma are implanted on the peritoneal surfaces of extrauterine sites. The proposed mechanisms for the pathogenesis of this disease include menstrual flow obstruction with retrograde menstruation, mechanical transplantation and implantation of endometrial elements, The interval between and coelomic metapla~ia.~~~105~144 the onset of menarche and the diagnosis of endometriosis may be as short as 1 month, and the incidence of disease in teenage grls may be far higher than previously anticipated or described.165 Extensive disease is uncommon in young adolescents unless it is associated with an obstructive mullerian anomaly.I7" The incidence of endometriosis reportedly ranges from 1% in younger girls to 47% in older girls.73,89,124 Typical symptoms include a pattern of chronic cyclic or Early diagnosis is acyclic pelvic pain and dy~men0rrhea.l:~ critical so that treatment can preclude the development of extensive intraperitoneal inflammation, as indicated by extensive adhesions and endometriomas. Early lesions on the peritoneal surfaces appear as small petechiae that penetrate the surface less than 1 mm. More recently it has been recognized that endometriosis may have an atyp ical appearance, including vesicular lesions, white plaques, powder burns, and adhesions.*16

602

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I1 I

MAJORTUMORS OF CHILDHOOD

The revised American Fertility Society classification of endometriosis is widely accepted as the staging system for the disease and was developed as a prognostic tool for patients with infertility.' However, the four stages do not correlate with pain symptoms; rather, they are associated with depth of disease.Io8For patients with pelvic pain and a suspected diagnosis of endometriosis, medical therapy with nonsteroidal anti-inflammatory drugs or oral contraceptives should be considered. Both medications act to suppress prostaglandins, which are known to be important in the pathophysiology of dysmenorrhea. These drugs along with gonadotropin hormone antagonists, used for a &month period, are the most commonly used medications. Currently, laparoscopy with biopsy of any suspicious lesions is the accepted diagnostic procedure, although endometriomas are well visualized on US. A histologic diagnosis of endometriosis may be important, because minimal disease at a younger age has been shown in some cases to progress to more extensive disease with age.109 If the surgeon is experienced with the management of endometriosis ablation, excision of all visible lesions is superior to placebo in the management of pelvic pain in patients with endometriosis.lg~

Histologic Type

0-4 Yr

5-9 Yr

10-14 Yr

G e r m cell Sex cord-stromal C o m m o n epithelial Miscellaneous

48 40 6 6

59 17 4 20

68 5 13 14

15-19 Yr All Ages 47 12 34 6

62.2 9.7 19.3 8.7

From DeprestJ, Moerman P, Corneillie P, et al: Ovarian borderline mucinous tumor in a premenarchal girl: Review on ovarian epithelial cancer in young girls. Gynecol Oncol 1992:45:219.

teenagers. Neoplasms that are rare in children include endometrioid and clear cell tumors, which are usually malignant; Brenner tumors, which are usually benign; disseminated malignant lymphoma; and metastatic lesions to the ovary.

Surface Epithelial-Stromal Tumors

Epithelial tumors account for 70% of all ovarian neoplasms, but they are not common in children. In one recent series, Simple Cysts they accounted for only 16% of all surgically resected Most authors consider simple cysts to be follicular in origin. ovarian masses.134Norris and JensenI4' reported that 67 of Anatomically, they are generally small, unilocular, thin 353 ovarian tumors (19%) in children were epithelial in walled, and similar to follicular lesions. They are always origin, and 12% were malignant. The tumors are usually histologically benign and hormonally inactive. Large symp Twenty percent of serous tumors serous or mucin0us.~~2 tomatic lesions should be managed in a manner similar to are bilateral, and very few are malignant.ll'J" Mucinous that of follicular cysts. Laparoscopic inspection with finetumors are usually unilateral, and 10% are malignant.112 needle aspiration, fenestration, and biopsy with or withDeprest et a1.47calculated a 16% malignancy rate for ovarout cyst lining excision was evaluated in 1990.83Only 1 of ian epithelial neoplasms derived from a collected series 56 functional simple or parovarian cysts recurred after that reported more than 1700 pediatric patients with varilaparoscopic management. ous types of ovarian tumors. Ovarian carcinoma is different in children than in adults. The proportion of mucinous tumors was 40% in children, compared with 12% in adults; in children, 30% were of borderline malignant potential, Neoplastic Ovarian Tumors compared with the adult rate of less than 10% for these Most neoplastic ovarian tumors develop from cell lines more favorable lesions. derived from one of three sources: the germinal epitheSerum CA-125 is a useful tumor marker in malignant lium covering the urogenital ridge, the underlying stromal epithelial ovarian tumors. However, in premenopausal elements of the urogenital ridge, or the germ cells that patients, CA-125 may also be raised in several benign arise from the yolk sac. Cells from each of these lineages gynecologic conditions, including endometriosis, pelvic may develop into an ovarian neoplasm by dedifferentiation, inflammatory disease, fibroids, and pregnancy. Immunoproliferation, and eventually malignant tran~formation.~g0 scintigraphy, currently used in the research setting, may Malignant ovarian tumors probably arise from their benign be useful in the future as a supplement to conventional counterparts as a consequence of either direct or indirect diagnostic methods. This technique, which localizes CA-125 hormonal stimulation. Histologically and biologically interusing a monoclonal antibody,I5lmay also prove useful for mediate forms between benign and malignant epithelial localizing active disease after chemotherapy and monilesions have been identified and designate tumors of low toring for the presence of recurrent disease.101 malignant potential. Epithelial tumors are staged using the FIG0 sy~tem.~Z Age influences the relative frequency of the various Stage IA tumors may be treated with unilateral salpingotypes of ovarian neoplasms. In adults, most tumors are oophorectomy. The opposite ovary should be examined derived from the epithelial line, and adenocarcinomas preexternally and a biopsy taken of any surface abnormalities. dominate. In children, germ cell tumors are most common Most young patients with stage IB tumors (tumors and represent approximately 60% of Epithelial limited to both ovaries) may be adequately treated by bilesions account for only about 15% of tumors in the lateral gonadectomy; however, the uterus should be preyounger age group (Table 3&8).3"47Although germ cell ovarian served to allow future in vitro fertilizati~n.I~.~~"n tumors predominate in each age group, the peak incicancer of a more advanced stage, maximum cytoreducdence of sex cord-stromal tumors occurs in the first 4 years tion is important and has been associated with an of life, and epithelial tumors are more common in older improved outcome.*17Total abdominal hysterectomy and

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bilateral salpingo-oophorectomy are usually appropriate. Omentectomy and resection of as much gross intraperitoneal disease as possible should be accomplished. Adjuvant chemotherapy after appropriate surgical excision has been beneficial in cases of advanced ovarian carcinoma. Six cycles of carboplatin and cyclophosphamide has yielded 60% to 70% clinical response rates, with 5-year survival rates of 10% to 20%.14Wore recent trials using combined cisplatin and paclitaxel are promising. Radiation therapy, second-look surgery, and secondary cytoreduction may be useful in cases of advanced cancer, but their current role remains controversial.

Miscellaneous Tumors Small cell carcinoma of the ovary is an extremely rare condition, with a very poor pr0gnosis.6~These tumors are very aggressive and are the most common undifferentiated ovarian carcinoma in young patients. They have been encountered in patients aged 9 to 44 years, with a mean age of 23 years.l"".'8Varaendocrine hypercalcemia occurs in two thirds of cases, but patients rarely have clinical manifestations of this abnormality. Serum parathormone levels are normal. Virtually all tumors are unilateral, although only 40% have been detected at stage IA. The gross appearance of the tumor

A

36

Ovarian Tumors

603

is a fleshy white to pale tan color; extensive areas of hemorrhage or necrosis are common. Small cell carcinomas have an uncertain histogenesis, and electron microscopy is often needed to make the final diagnosis. Only one third of patients with stage IA tumors survive long term, and survival of patients with more widespread disease is rare.fl2 Unilateral salpingo-oophorectomy has been associated with long-term survival in some patients with stage IA tumors. Metachronous appearance of tumor in a contralatera1 conserved ovary has been encountered, and bilateral adnexectomy may be a more appropriate surgical option. Despite various treatment modalities, including resection, radiation therapy, and intensive chemotherapy, the average life expectancy remains low, at 18 months.'6"

Tumors of Low Malignant Potential Ovarian epithelial tumors of low malignant potential differ from epithelial cancer in two major ways: they occur in younger patients, and they have a better prognosis than ovarian cancer. They have been described for all subtypes of ovarian cancer.47The serous and mucinous tumors are by far the most common and resemble their benign counterparts. These borderline tumors are differentiated from standard adenocarcinoma in that they lack stromal invasion by neoplastic epithelial elements (Fig. 36-5). Up to

B A, Ovanan tumor from a 17-year-old glrl wlth masslve b~lateralovarlan les~onsThe opened specimen shows a cavlty filled w ~ t hclear fluid, and the wall 1s hned by numerow nodule? and paplllary protuberances B, Hlstologc sectlon of the leslon qhows serous p a p lllary tumor of low malignant potentla1 (hernatoxylineosrn staln, x40) C,Hlgher-power photom~crographof a \ectlon of the leslon shows that the paplllae are fibrovascular cores hned by strat~fiedeplthellal cells wthout stromdl Invasion (henlatoxylrneosln stam, x400)

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because they result in systemic hormonal effects. They 50% of these tumors are bilateral, and they demonstrate account for 13% of ovarian tumors encountered in the a characteristic indolent clinical course. However, recurBoston Children's Hospital series112and 17% in another rences may occur as long as 10 to 15 years after surgery series of ovarian neoplasms in children.'" Before 9 years for the primary tumor, and they may take the form of of age, most sex cord-stromal tumors are feminizing; invasive cancer.38 In a recent adult series, long-term survival among after 9 years of age, there is a predominance of virilizing neoplasms.154 women with mucinous and serous borderline tumors was compared. Overall 10-year survival for women with serous ovarian borderline tumors and carcinomas was Granulosa-Theca Cell Tumors 96% and 30.4%, respectively. For patients with mucinous Granulosa-theca cell tumors are the most common type borderline tumors and carcinomas, it was 94% and 64%, of sex cord-stromal neoplasms and the most common respectively.I87 In adults, 91% of borderline mucinous t,y ~ of e functioning. ovarian neoplasm. The iuvenile arantumors present as stage I disease, with a 5-year survival ulosa cell tumor is a specific subclassification of these rate of 98%. Serous tumors have a similar outcome. The lesions; 44% occur in the first decade of life, and 97% extensive review by Massad et a1.'22 noted an overall surare seen by 30 years of age.'Q Isosexual pseudoprecovival of 98% for stage I tumors, 94% for stage 11, and 79% cious puberty is the presenting sign in the majority of for stages 111and IV. In children, Morris et a1.l" noted that premenarchal girls who have this tumor (Fig. 36-6).164 75% of the patients presented with stage I disease, and Most patients have elevated serum and urinary estrogen overall survival was 100%. The combined 10-year survival levels, whereas gonadotropin levels are low. This profile rate for all stages was 73%. assists in differentiating children with these tumors from Surgery is the primary method of therapy. Unilateral others with true sexual precocity, gonadotropin-secreting salpingo-oophorectomy is adequate for all low-stage lesions, or feminizing adrenal tumors. Levels of serum tumors and has been standard treatment; however, inhibin, a glycoprotein produced by ovarian granulosa recent studies have shown that ovarian cystectomy can be performed in young patients with careful folIow-~p.~~3cells, may be a useful tumor marker.Il4J40 MiillerianThese patients require close surveillance, with pelvic inhibiting substance levels are elevated in some granuexaminations, CA-125 serum samples, and US every 3 losa-theca cell tumors, which suggests a potential role as a prognostic marker.80 to 6 months, because patients managed with ovarian Clinical findings include premature thelarche, vaginal cystectomy have a higher risk of recurrence than those et a1.133 reported discharge or bleeding, labial enlargement, development managed more aggres~ively.2~Worice recurrence rates of 36.3%, 15.1%, and 5.7% after cysof pubic or axillary hair, increased somatic growth, and tectomy, oophorectomy, and hysterectomy with bilateral advanced bone age. Clitoral enlargement is a rare manifestation of virilization and tumor androgen production. oophorectomy, respectively. Despite the difference in recurrence risk, there was no demonstrated impact on Postpubertal girls may present with an abdominal mass, relatively nonspecific symptoms of abdominal pain, or overall survival; all patients were salvaged with further increased girth. Tumor rupture with hernoperitoneum, surgery. Conservative treatment should therefore be conalthough rare, is a dramatic event that necessitates surgery. sidered in young patients who wish to preserve their fertilAmenorrhea and other menstrual irregularities may occur. ity and will comply with follow-up. Routine contralateral Clinical emergencies can occur in young infants who have wedge biopsy is unnecessary1" if the ovary appears a rapid onset of pleural effusion and ascites that causes normal on US.'" Bilateral tumors require bilateral oophorocystectomy severe abdominal distention and respiratory d i s t r e s ~ . ~ ~ In addition to differences in clinical presentation, or salpingo-oophorectomy. Uterus-sparing procedures juvenile granulosa cell tumors demonstrate a pattern of are probably not appropriate for advanced-stage disease. histologic features and biologic behavior that are distinct The pathologic features that identify poor prognosis are from the adult counterpart.- he juvenile variety is usustill being elucidated," and currently there are no clear ally a relatively large lesion that averages 12.5 cm in candidates. At present, surgery remains the most effective diameter.2g At laparotomy, it appears as a yellow-tan or therapy for these patients; the place of adjuvant therapy ~ ~ ~individual treatment gray solid neoplasm with cystic areas that often contain has yet to be e ~ t a b l i s h e d . 1 "No strategy has led to consistently superior outcomes, but hemorrhagic fluid. In contrast to adult-type tumors, the the favorable biology of this tumor minimizes the imporjuvenile type has abundant eosinophilic or luteinized tance of the limited clinical benefit achieved from adjuvant cytoplasm, with atypical nuclei and a higher mitotic rate. therapy. DNA content and cell-cycle kinetics analyzed by flow cytometry do not necessarily correlate with the prognosis in children, as they often do in adults.lYY Sex Cord-Stromal Tumors Although the adult form is generally an indolent, slowSex cord-stromal tumors probably arise from uncommitgrowing lesion of relatively low malignant potential, the biologe behavior of the juvenile tumor is more aggressive and ted mesenchymal stem cells that reside below the surface correlates well with tumor size, disease stage, presence of epithelium of the urogenital ridge.'" This totipotential tissue may differentiate into several different cell lines, rupture, and degree of nuclear atypia and mitotic activity. including granulosa-theca cells in the ovary and LeydigThe lesion was unilateral in 122 of 125 cases reviewed by Sertoli cells in the testicular interstitium. Sex cord-stromal the adult tumor recurs, it is usually Young et al.23-f tumors are referred to as functioning ovarian tumors more than 5 years after diagnosis. Malignant granulosa L

L,

2 .

L,

CHAPTER

36

Ovarian Tumors

605

A, Three-year-old girl demonstrating isosexual pseudoprecocious puberty. B, Surgery revealed a benign juvenile granulosa cell tumor. Unilateral salpingo-oophorectomy was performed to remove the tumor.

cell tumors in young patients tend to recur much more quickly. Granulosa cell tumors are staged similarly to other ovarian lesions (see Table 36-6). In children, these tumors are associated with a favorable prognosis because more than 90% of patients present with stage I disease. Overall survival is- approximately 95% for stage IA patients and 80% for stage IC patients. Virtually all patients with stage I1 or greater disease die regardless of analyzed a series of 39juvenile treatment. Plantaz et al.15Y granulosa cell tumors from several centers in France. Patients' median age was 6 years; 52% developed precocious pseudopuberty, and 10% had endocrine dysfunction after puberty. Tumor rupture caused a surgical emergency in three cases. Four of the five deaths within 6 months were in girls with stage I11 or IV disease. Because of the low rate of bilateral occurrence and the favorable prognosis of stage I tumors, unilateral oophorectomy or salpingo-oophorectomy is adequate initial therapy when preservation of fertility is desired. Because of the poor prognosis for children with advanced-stage disease, aggressive multidisciplinary therapy is indicated, although the benefits remain unclear. Hysterectomy with bilateral salpingo-oophorectomy and 3000 cGv whole-abdominal radiation, with a boost to areas of residual disease, have been used in girls with stage I11 tumors that ruptured or had macroscopic chemotherapy, includtumor e~tension.~~Wultiple-drug ing methotrexate, actinomycin D, cyclophosphamide,

bleomycin, and the vinca alkaloids, has been used with some response. However, most patients subsequently relapsed and died. Currently, specific chemotherapeutic regimens must be considered investigational in those few patients with advanced malignant disease.

Fibromas and Thecomas Fibromas and thecomas account for 14% of sex cordstromal tumors in pediatric patients.ll' Although they are extremely uncommon in females younger than 20 years, fibromas are usually associated with the basal cell nevus syndrome and are frequently bilateral, multicentric, and calcified. Most ovarian thecomas occur in menopausal women; however, two variants of this lesion have been reported in the second decade of life. Calcified thecomas invariably cause amenorrhea or other If these tumors menstrual irregularities and hir~utism.""~ contain a substantial number of lutein cells, they are appropriately called luteinized thecomas, which can occur in younger girls and may be associated with androgenic manifestations. On gross examination, fibromas are Grm, solid masses with a whorled, trabeculated appearance on cross section. The lipid content of thecomas results in a pale yellow to orange color. These lesions are benign, and unilateral oophorectomy is adequate treatment. In the case of bilateral fibromas, all gross tumor tissue should be removed, with particular attention to sparing normal-appearing

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ovarian tissue." Tumor recurrence is rare and is managed by reoperation. Virilizing symptoms usually resolve after resection of the tumor.

Sclerosing Stromal Tumors Sclerosing stromal tumors have recently been recognized as entities distinct from fibromas and thecomas. These tumors occur in girls, with 30% of documented cases presenting in the first 2 decades of life. Estrogen secretion has occasionally been reported, whereas androgen manifestations are quite rare. The typical presentation includes the presence of a pelvic mass and pelvic pain in a young patient with a history of menstrual irregularity. This lesion has also been associated with the ChidiakHigashi syndrome.g7 Sclerosing stromal tumors are unilateral, usually larger than 5 cm in diameter, and benign. At laparotomy, these tumors are well-circumscribed, firm, whitish yellow masses with clearly demarcated areas of edema and cyst formation. Histologically, the tumor is characterized by a pseudolobulated pattern, with cellular foci clearly demarcated from the edematous and collagenized areas.91 Gross tumor removal is generally adequate treatment.

Sertoli-Leydig Cell Tumors Sertoli-Leydig cell tumors account for less than 0.5%of all ovarian tumors but constitute between 10% and 30% of the sex cord-stromal neoplasms.ll*Although most of these tumors are masculinizing, some are nonfunctional or even associated with estrogenic effects. Therefore, the older terms arrhenoblastoma and androblastoma are no longer favored. One third of cases occur in patients younger than 20 years. These tumors are almost always unilateral and present as stage IA at diagnosis. Survival is excellent, with tumor-related deaths in only 5% of affected individuals.154 Similar to granulosa cell tumors, the gross appearance of Sertoli-Leydig cell tumors varies widely, but these lesions are less often filled with hemorrhagic fluid and rarely have a unilocular, thin-walled, cystic appearance. Current classifications now recognize five histologic patterns based on the degree of differentiation and the presence of heterologous, endodermal, or mesenchymal elements. Tumor stage and histologic appearance are important prognostic factors. Sertoli-Leydig cell tumors with heterologous elements are more common in younger patients and may be difficult to distinguish from immature teratomas.Is4There are two phases of the masculinizing effects of androgen overproduction. Initially, defeminization takes place with amenorrhea, breast atrophy, and loss of female body habitus. This may be followed or overlapped by masculinization characterized by hirsutism, clitoral hypertrophy, and voice deepening. In prepubertal girls, masculinization and accelerated somatic growth predominate. Postpubertal girls usually have menstrual irregularities, acne, body habitus masculinization, and hirsutism. The virilizing effects are caused by testosterone accumulation resulting from a deficiency in catabolizing enzymes. Gonadotropin levels are low, and excretion of urinary 17-ketosteroid and pregnanetriol is normal. Because the testosterone level is often directly related to tumor tissue

volume. this hormone is a biolo~ic " marker for monitoring disease behavior.49 Tumor markers most likely to be elevated are AFP and CA-125.11%DH may be elevated or normal. The hormonal profile of these lesions assists in differentiating them from exogenous androgen sources, adrenal tumors, true hermaphroditism, and polycystic ovaries. Similar to granulosa cell tumors, the Sertoli-Leydig cell lesions mav be associated with multi~leenchondromas caused by nonhereditary mesodermal dysplasia (Ollier's disease) .223 Surgical therapy should be conservative for patients with low-stage disease. Unilateral oophorectomy b r adnexectomy is adequate and preserves later childbearing capacity. If tumors are bilateral, are poorly differentiated, have ruptured, or demonstrate aggressive behavior, a more aggressive approach similar to that used for granulosa Gershenson et a1." looked at cell tumors is nece~sary.~O the response of these tumors when treated with surgery and chemotherapy if poor prognostic indicators werk present at initial diagnosis. Following completion of four cycles of bleomycin-etoposide-cisplatin chemotherapy, 50% of patients remained disease free at 28 months, with an overall resDonse rate of 83%. Limited data are available regarding preserved ovarian function following chemotherapy. Oral contraceptives and gonadotropinreleasing hormone agonists may provide some ovarian protection both during and after chemotherapy.28

Sex Cord Tumors with Annular Tubules Sex cord tumors with annular tubules are rare but distinct variants of sex cord-stromal tumors. They have the potential for bidirectional differentiation into granulosa or Sertoli cells."2 These lesions are observed in patients with Peutz-Jeghers syndrome. When associated with this syndrome, the lesions are small, multifocal, and usually bilateral. The tumors are often calcified and are invariably noted incidentally during autopsy or in an ovary removed for reasons unrelated to neoplasia. Although patients with these tumors occasionally have menstrual irregularities suggesting hyperestrinism, surgical therapy is rarely indicated. When these tumors occur in the absence of PeutzJeghers syndrome, the clinical difference is significant. Such lesions occur in older patients with a mean age of 34 years, although cases have been reported in patients from 6 to 76 years old. In younger patients, the tumor is unilateral and almost always larger than 5 cm in diameter; 20% are malignant. Even with aggressive therapy, 50% of patients with these tumors die.234

Steroid Cell Tumors Steroid cell tumor is now the preferred name for lesions previously called lipid cell tumors. This term is more appropriate because of the morphologic features of the tumor and its propensity to secrete steroid hormones, and because many such lesions contain little or no lipids. The group is subclassified into three major categories according to the cells of origin: (1) Stromal luteoma is a small steroid cell tumor contained in the ovary arising from the stromal lutein cell. (2) Leydig cell tumor contains

CHAPTER

the classic intracytoplasmic Reinke's crystals and arises from histologically similar precursor cells found in the ovarian hilus. (3) Steroid cell tumors not otherwise specified account for approximately 60% of cases and typically occur in younger patients. The first and second categories of lesion are usually encountered in postmenopausal women and are only rarely reported in patients in the first 3 decades of life. Most cases in the third category and in prepubertal children have been associated with androgenic, heterosexual pseudoprecocity.82 The tumors are rarely estrogenic, but isosexual pseudoprecocious puberty has been reported.45The androgenic tumors show elevated testosterone and androstenedione levels, increased urinary 17-ketosteroid excretion, and decreased gonadotropin levels. These lesions are well-demarcated, solid masses with a bright yellow to brownish appearance on gross examination; fossae of hemorrhage and necrosis may occasionally be observed. In older patients, malignant steroid cell tumors not otherwise specified may occur in 25% of patients and require aggressive surgery because adjuvant . ~children, ~ these lesions are virtherapy is not e f f e c t i ~ eIn tually always benign and at a low stage. Unilateral salpingooophorectomy is adequate treatment, but close follow-up is essential. Most of the hormonal symptoms should progressively resolve after tumor removal, although younger children may develop true precocious puberty after tumor removal because chronic androgen exposure appears to induce an early maturation of the hypothalam~s.~8'

Germ CeN Tumors

36

Ovarian Tumors

607

here; later they are discussed as a group with regard to overall management decisions.

Germinoma The term germinoma encompasses a group of tumors with common histologic characteristics. It is the primary malignant tumor found in dysgenetic gonads. This tumor mav be referred to as a seminoma if found in the testis, a dysgerminoma in the ovary, and a germinoma in an extragonadal site. Germinomas are believed to arise from the totipotential germ cells that were present at the undifferentiated stage of gonadal development.220 Germinomas represent the most frequent ovarian malignant neoplasm seen in both children and adults.'" They account ibr approximately 10% of all benign and malignant ovarian tumors.44 Germinomas are most often seen in prepubertal girls and young women, with 44% of cases occurring before 20 years of age and 87% by 30 years.Vhe typical patient is genotypically and phenotypically normal. These often bulky tumors may reach massive proportions and lead to abddminal pain. and symptoms o f pelvic pressure or symptoms related to obstruction of the gastrointestinal or urinary tract. Occasionally, girls with these tumors present with an acute abdomen as a result of torsion, rupture, or hemorrhage into the tumor (Fig. 3&7).25 Ascites may be present. Because germinomas are endocrinologically inert, the presence of remote endocrine effects suggests that the tumor is a mixed germ cell tumor. In true cell tumors, LDH is elevated in 95% of patients, but other markers are negative.lO2 In the mixed form of these tumors, markers may be positive or negative, depending on which germ cell component is present. On gross examination, these tumors appear bulky, encapsulated, solid, and yellowish in color (see Fig. 367); they can be bilateral in 5% to 30% of cases.2"46~"0 Germinomas have a rather uniform microscopic appearance consisting of large, round cells that have vesicular nuclei and clear to eosinophilic cytoplasm. These cells resemble primordial germ cells. Lymphoid infiltrates may be present. The management of germ cell tumors begins with surgical excision. Conservative surgery with a unilateral ~alpingeoophorectomy,thorough-inspection of the contralateral ovary with biopsy of suspicious lesions, and careful staging (as outlined in the section on surgcal approach) is mandatory. Surgery alone is adequate for stage IA disease, although the older literature disputed this.75 These tumors are very radiosensitive, but the cost of . ~ chil~ cure may be too high if fertility is c ~ m p r o m i s e dIn dren, other long-term effects such as growth abnormalities or secondary tumors must also be considered. Radiation has been abandoned in favor of effective multiagent chemotherapeutic programs that include platinum, etoposide, and bleomycin, which is now standard therapy.31,76,225

The path of descent of the primordial germ cells is imperfect; as a result, some of the cells occasionally miss their destination and can be deposited anywhere along this migration route. Germ cells have been found in the pineal area of the brain, mediastinum, retroperitoneum, sacrococcygeal area, and ovary and testis. If malignant transformation occurs at any of these sites, a gonadal or extragonadal neoplasm will develop. Because these nests of cells are totipotential in nature, a wide variety of tumors is seen. The specific type of tumor depends on the degree of differentiation that has occurred; this has been characterized bv Telium.20" If no differentiation occurs, a germinoma develops; with differentiation, embryonal carcinomas occur; and with extraembryonic differentiation, choriocarcinomas or endodermal sinus tumors develop. If embryonal differentiation occurs, the teratoma-the most mature of these tumor types-is seen. Germ cell tumors are rare in children and adolescents, but when they occur, the gonad is the most frequent site. A summary of 13 reviews encompassing 1491 cases of benign and malignant germ cell tumors in children noted that 41% were gonadal in location,2 and 71% of these l stromal ovarian tumors prewere ovarian. ~ G t h e l i a and vail in adults; germ cell tumors predominate in children. Several large series of ovarian neoplasms report an inciEndodermal Sinus Tumors dence of germ cell tumors ranging from 48% to 62%.92,96,142 Endodermal sinus or yolk sac tumors are aggressively This g o u p of tumors develops from the same totipotential malignant neoplasms that, either alone or as a component primordial germ cell, but each neoplasm has different of a mixed germ cell tumor, are the second most common behavioral characteristics, which are presented individually

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A, This encapsulated mass from a 5-year-old girl with acute abdominal pain proved to be a dysgerminoma. The child's contralateral tube and ovary are seen to the left of the tumor. A small portion of the ipsilateral tube and uterus were in the surgical specimen but uninvolved with tumor. B, The cut surface of the tumor is characterized by lobules divided by thin, fibrous septae. C, Micrograph of a dysgerminoma demonstrating polygonal, clear tumor cells divided into small lobules by fibrous septae that contain scattered lymphocytes. (A, B see colm plate.)

histologic subtype of malignant ovarian germ cell tumors In neonates and young in children and ad01escents.l~~ children, the primary location of these tumors is the sacrococcygeal area. In older children and adolescents, it is found most frequently in the ovary. The origin of this and many particular tumor has been debated,177.204.'05 microscopic patterns of this tumor have been described. Nogales141 suggested that this tumor originates from the

primary yolk sac, a structure that develops very early in embryogenesis and consists of multipotential primitive endoderm. This tissue is capable of differentiating epithelial somatic tissues as well as secondary yolk sac tissue (a terminal, temporary structure with limited differentiating capacity) and mesenchyma. Yolk sac tumors with pure endodermal sinus subtypes are less mature than the differentiated glandular or hepatoid subtypes.175

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These rapidly growing tumors are the second most are common germ cell tumor in ~hildren.~Vymptoms generally present for less than a month and are related to the presence of an intra-abdominal mass. Seventy-five percent of patients present with abdominal pain and increased abdominal girth.160 Elevation of the biologic marker AFP is the hallmark of this tumor. The gross appearance of these tumors during surgery is pale yellow-tan and slimy, with foci of cystic areas and necrosis.2 The tumors are soft and friable when handled. Most tumors show a distinct histologic subtype, with differentiation toward vitelline or yolk sac structures.111 Microscopically, the most common papillary pattern has the so-called endodermal sinus structures (SchillerDuval bodies) or perivascular sheaths of cells. Most welldifferentiated yolk sac tumors also contain extracellular and intracellular droplets that are resistant to periodic acid-Sciff diastase staining and positive for AFP.

Embryonal Carcinomas A relatively uncommon isolated germ cell tumor is embryonal carcinoma, which may resemble an anaplastic carcinoma with extensive necrosis. Embryonal carcinoma is more often found in association with other germ cell tumors and is referred to as a mixed germ cell tumor. One subtype of this tumor, the polyembryoma, is capable of producing both AFP and P-HCG, resulting in clinical endocrinopathies such as menstrual irregularities and isosexual precocious puberty. The histologic appearance is characterized by bodies that resemble tiny embryos.206 The workup and surgical approach to this tumor are similar to those for endodermal sinus tumor. Isolated, unilateral disease is managed by unilateral salpingooophorectomy. Advanced local disease necessitates panhysterectomy for local control; multiagent chemotherapy and radiation therapy are also indicated.

Choriocarcinomas Choriocarcinomas are rare, endocrinologically active, highly malignant germ cell tumors that occur in girls and women. Estrogen is produced both by the tumor and by the ovary itself in response to the release of gonadotropin by the neoplastic chorionic tissue. The P-HCG level is elevated, and AFP is normal. The clinical presentation is influenced by the age of the patient. Premenarchal girls present with signs of isosexual precocity and evidence of a rapidly growing neoplasm. These usually large, solid tumors generally adhere to surrounding tissues, and distant metastatic disease is associated with this tumor. The child may become cachectic and die quickly despite surgical excision and multidisciplinary therapy. In adolescents, the tumor also develops rapidly, but hormone production leads to menstrual disturbances and may initially simulate pregnancy. A gestational form of this tumor can arise in the placenta during pregnancy.33 Operative excision can be a formidable task because the tumor may be friable and quite vascular, and it often If the lesion is localized, invades contiguous structures.~

36

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609

surgery is limited to unilateral salpingo-oophorectomy; however, this is rarely the case. A more extensive extirpative procedure is usually required that involves removing the tumor, the opposite ovary, the uterus, and as much metastatic tissue as possible. Grossly, these tumors appear nodular with a friable consistency. The tumor is purple with variegated areas of dark brown and yellow secondary to hemorrhage and necrosis. Microscopic evaluation of these tumors reveals cytotrophoblasts and syncytiotrophoblasts, with evidence of extensive necrosis and hemorrhage. Metastatic implants are friable and have a similar gross and microscopic appearance as the primary lesion. Multiagent chemotherapy is the treatment regimen of choice.

Teratomas Teratomas are a group of neoplasms composed of tissue elements that are foreign to the organ or anatomic site where they are found.74 Classically, these tumors are defined as being composed of tissue derived from the three germ layers: ectoderm, mesoderm, and endoderm. All three germ layers do not have to be present in each tumor, but some embryonic tissues must be found in an abnormal location. These tissues show elements of disorganization as well as various levels of maturation. As such, teratomas are histologically classified as mature and immature tumors and those with malignant components.119 The development of a somatic malignancy within a teratoma is a rare event in childhood and is thought to occur within differentiated teratomatous elements rather than from totipotent embryonal ~ e 1 l s . l ~ ~

Mature Teratomas: Most teratomas in children are of the mature type. The majority of mature ovarian teratomas have entered but have not completed meiosis, suggesting that they arise from germ cells arrested in meiosis I.lj4 There is little or no tendency for malignant degeneration of preexisting benign elements or the coexistence of malignant cells in a benign teratoma." In neonates, mature teratomas are found most commonly in the sacrococcygeal area, followed by the head and neck.98.119,203 The ovary becomes an important site later in childhood, especially during adolescence. Ovarian teratomas are predominantly cystic in nature.36 Overall, benign cystic ieratomas are the most common ovarian neoplasms in children92 and can be bilateral in as many as 10% of patients.XJg3 Symptoms of mature teratomas can be acute or chronic. Acute symptoms that mimic appendicitis are seen when torsion, hemorrhage, or rupture of the mass occurs. Gradual onset of symptoms may be related to the presence of an intra-abdominal adnexal mass, which mav cause pressure on adjacent organs. Occasionally, a ruptured teratoma may lead to a chronic inflammatory response with the development of a m a s of intestine and omentum adhering to the anterior abdominal wall; this condition is associated with pelvic adenopathy, which mimics a malignant tumor.55 On examination, findings are primarily related to the mass itself. These tumors are located in the abdomen in infants and young children. They are found in the

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.

A, Plain abdominal radiograph of a 16-year-old girl with a unilateral ovarian teratoma; the pelvic mass contains toothlike calcifications. B, The patient presented to the emergency room with a several-day history of abdominal pain and was found to have a ruptured benign ovarian teratoma with torsion. Upon detorsion, the cyst was removed and the ovary preserved. Six months after surgery, the patient has evidence of two normal ovaries on ultrasonography.

pelvis of adolescents, although large tumors may be palpated in the abdomen, and there may be associated tenderness. Plain abdominal radiographs demonstrate calcifications in up to 67% of cases (Fig. 368).4US is a commonly used diagnostic test. The positive predictive ability of US approaches 100% when two or more characteristic findings, such as shadowing echodensity and regionally bright echodensity, are present.'" MRI may be more useful than CT in the diagnosis of mature cystic teratoma due to its ability to clearly define soft tissue components.212 Conservative ovarian surgery in childhood and adolescence is important for the development of normal puberty and future fertility. This must be balanced with complete removal of the mature cystic teratoma (Fig. 36-9). Traditional management of children with mature cystic teratomas has been oophorectomy via laparotomy. However, laparoscopic removal, either by cystectomy or oophorectomy, is a safe alternative when done by an experienced laparoscopist (see Fig. 363).209Campo and Garcea,'7 in a randomized, controlled trial, demonstrated that the use of an endobag when removing a mature cystic teratoma laparoscopically decreased the occurrence of spillage from 46% to 3.7% of cases. Simple aspiration of a giant, predominantly cystic lesion as a means of "removal" should be avoided, because a malignant component may be present. Every effort should be made to spare the ovary, even when the mass is very large or bilateral, in an attempt to preserve hormonal and reproductive functions (see Figs. 368 and 369).Io0If this is not possible, the gonad and tumor alone should be removed, leaving the fallopian tube in place unless it is necrotic from torsion. In adults, the reported incidence of recurrent mature cystic teratomas following cystectomy is 3% to 4%8,29

and usually occurs in patients younger than 40 years8 Also, in younger patients with multiple or bilateral mature cystic teratomas, there is a 2% to 3% incidence of the s u b sequent development of germ cell In the absence of specific literature investigating recurrence in children, recommendations for postoperative surveillance are empirical. Given the sensitivity of US in the detection of mature cystic teratomas, annual imagng in prepubertal and young adolescents followed by annual pelvic examinations in older adolescents seems appropriate. Miliary, intraperitoneal glial implants (i.e., grade 0), are occasionally encountered in association with mature teratomas." These implants are never suspected before surgery. They appear as white or gray nodules, usually 1 to 3 mm in diameter, and are usually confined to the omentum, pelvic peritoneum, or adjacent or adherent to the tumor itself. Several explanations have been offered for the development of these implants.lM The most widely accepted theory is that implantation occurs through a defect in the capsule of the primary tumor, permitting penetration by teratomatous elements under pressure. If the components near the d e f e ~ histologically mature, the metastatic implants will also be ~ ~ l a t u r e . In 11 of 12 cases reported by Robboy and S ~ u l l y , l ~ ~ the capsule of the primary tumor was torn or had omentum or adnexal structures adhering to the mass. Implants can have a disturbing appearance, but no specific treatment is necessary when they are well differentiated, and their presence does not change management of the primary tumor. However, if adjacent components are immature, the lesions may progress and require adjuvant therapy. Immature Teratomas: Immature teratomas are germ cell neoplasms composed of tissue derived from the three

CHAPTER

C

36

Ovarian Tumors

611

D

A, Large ovarian dermoid tumor in a 14year-old girl with acute severe abdominal pain upon awakening. The fallopian tube is seen below the tumor. B, After tumor excision, the surface where the cyst was peeled away from the ovary can be seen. C, Ovarian tissue (left) and fallopian tube (right) remaining after cyst removal. D,Opened gross specimen of an ovarian dermoid showing multiple tooth- and jawlike calcifications. (A, B, C, SSP rolorplatr.)

germ cell layers. These teratomas are clinically distinct from benign or malignant teratomas because they also contain immature, neuroepithelial elements (Fig. 36-10). Immature teratomas can coexist with the more macure solid or cystic benign teratomas or with malignant teratomas, in which case treatment is determined by the malignant component. Immature teratomas are graded by the degree of immaturity of the tumor and the presence and quantity of neuroepithelial components. The grade of the primary tumor is significant and is one of the major determinants of the likelihood of extraovarian metastasis. The current grading system was developed by Thurlbeck and Scully2" and modified by Norris et al.14" and Ihara et al.Y4 Grade I. Limited to ovary (peritoneal evaluation should be negative). No clinical, radiographic, or histologic evidence of disease beyond the ovaries. (The presence of gliomatosis peritonei does not change grade I disease to a higher grade.)

Grade 11. Microscopic residual; peritoneal evaluation negative. (The presence of gliomatosis peritonei does not change grade I1 disease to a higher grade.) Grade 111. Lymph node involvement (metastatic nodule); gross residual or biopsy only; contiguous visceral involvement (omentum, intestine, bladder); peritoneal evaluation positive for malignancy. Grade IV.Distant metastases, including liver. Multidisciplinary therapy has improved the prognosis of immature teratomas. In a study published in 1976 by Norris et a1.,I43survival was 82% for patients with grade I tumors, 62% for grade 11, and 30% for grade I11 with the use of combination therapy. The experience of the M. D. Anderson Cancer Center published in 1986 disclosed that 15 of 16 patients managed initially with surgery alone had recurrence of the tumor, but 10 of 11 who received subsequent chemotherapy were salvaged.68 Eighteen of 21 patients who received combination vincristine, actinomycin D, cyclophosphamide (VAC) chemotherapy survived.

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MAJORTUMORS OF CHILDHOOD A, Characteristic gross appearance of an immature teratoma in a 5-year-old girl who presented with a left ovarian mass. The tumor is a solid and cystic globoid mass with a smooth, shiny surface. B, Cut section of an immature teratoma shows a variegated, solid, cystic appearance with focal areas of hemorrhage.

Based on improvement in survival, current management of immature teratomas must balance survival with the maintenance of childbearing capacity.l2l In 1989 Koulos et reviewed 25 cases accrued from the Connecticut Tumor Registry and found that 18 of 23 patients with stage I disease were effectively treated with preservation of the opposite adnexa, with or without adjuvant chemotherapy. They concluded that it might be reasonable to withhold chemotherapy from patients with stage I, grade I and I1 immature teratomas who were initially treated with conservative surgery if the patient can be followed closely for possible recurrence. In cases of recurrence, rescue can be achieved with salvage therapy. Kawai et al.l0\greed that unilateral salpingo-oophorectomy alone is adequate for stage I immature teratoma if the tumor has a histologic grade of I; however, chemotherapy with VAC or VAC with cisplatin is required for grade I1 or 111 tumors. In their study, 18 of 19 patients were disease free at a mean follow-up of 62 months. A similar conclusion was reached by Bonazzi et al.I%ased on a 10-year prospective study of 32 patients with ovarian immature teratoma. Patients with stage I or 11, grade I or I1 tumors can be managed with fertility-sparing surgery without chemotherapy, whereas patients with stage I11 or grade 111 (regardless of stage) or with relapse are most effectively treated with platinum-based chemotherapy. In their study, all 32 patients were disease free with a median survival of 47 months. Immature teratomas are rarely bilateral,40 and biopsy of the unaffected ovary is unnecessary if it looks normal.G8 To preserve future childbearing potential in children,

unilateral salpingo-oophorectomy for stage I, grade I disPlatinum-based chemotherapy is ease is adequate.*l~l2~ required for grade I1 or I11 tumors. For tumors of stage I1 or higher, attempts should be made to preserve reproductive capability whenever possible, along with the addition of chemotherapy. It is also suggested that postinduction surgery should be used for grade I1 or 111 and stage I1 or higher tumors, with termination of chemotherapy if no tumors of grade I or higher are identified.68 Monodermal Teratomas: A monodermal teratoma is an ovarian tumor composed exclusively or almost exclusively of ectoderm or mesoderm or endoderm, for example, neuroectoderm."

Gonadoblastomas Gonadoblastoma, a tumor first described by ScullyI80 in 1953, is relatively rare and occurs most commonly in patients with dysgenetic gonads. Most patients are virilized or nonvirilized phenotypic females. In the only l 74 cases and large series reported, S ~ u l l y ' ~reviewed found that 89% were chromatin negative and the most common karyotype was 46XY or 45X/46XY. Troche and Hernandez,Z1"n a literature review o l 140 cases of neoplasms arising in dysgenetic gonads, found that 80% had these karyotypes. Patients are usually older adolescents or in the third decade of life with a history of primary amenorrhea. Androgen production by the tumor causes virilization. When a workup for amenorrhea or

CHAPTER

virilization is undertaken, an abnormal karyotype with a Y chromosome or chromosome fragment can be found in ~ ~ often small tumors as many as 90% of ~ a t i e n t s . 2These may then be identified during examination or exploration. They may also be found incidentally during excision of These tumors gonadal streaks or dysgenetic g0nads.I~~s22~ become invasive early, and gonadectomy is recommended as soon as 46XY gonadal dysgenesis is diagnosed.13g,1s1~213 Gonadoblastomas are composed of germ cells and sex cord derivatives that are similar to granulosa and Sertoli cells, although immunohistochemical and ultrastructural findings are more supportive of Sertoli-like differentiation.I6%utein or Leydig-like stromal cells occur in two thirds of cases and probably reflect a stromal reacThese tumors are tion to gonadotropin ~timulation.~68 considered precursors to germ cell tumors in dysgenetic or streak gonads because they may coexist with dysgerminomas and other germ cell tumors in more than half of patienha3 The tumor may be difficult to identify on gross examination because of overgrowth by the malignant component and other changes, including calcification, fibrosis, or both. In fact, calcification may be the only remnant of the gonadoblastoma, and the presence of calcification in a dysgerminoma should raise the suspicion of an underlying gonadoblastoma. The malignant potential of this tumor is determined by the underlying malignant component and should be treated accordingly. The outcome for patients may be enhanced because abnormal sexual development prompts early evaluation and subsequent diagnosis of the tumor. The prognosis of nongerminomatous germ cell tumors has improved with the advent of bleomycin, etoposide, and cisplatin protocols, and survival rates of 70% to 90% have been reported.154

Mixed Germ CeN Tumors Germ cell tumors in children are often composed of more than one pure histologic type. Benign but questionably malignant tumors (immature teratomas) and frankly malignant tumors (germinomas, choriocarcinomas, endodermal sinus tumors, embryonal carcinomas) may be present. Management of mixed tumors is geared toward the most malignant component.

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Benign lesions require only tumor resection via ovarian cystectomy or unilateral oophorectomy. Benign tumors, frankly malignant tumors, and those with mixed histologic characteristics often cannot be distinguished based on gross appearance alone. If in doubt, staging is recommended, because the treatment and prognosis of malignancies depend on accurate staging. The current intergroup COG protocol includes thorough inspection, palpation, and biopsy of any suspicious peritoneal and liver nodules (including the subphrenic spaces).31 Both ovaries are inspected. If a tumor is found in an ovary, it should be removed by unilateral oophorectomy. The opposite ovary should be inspected, and nodules or suspicious areas should be biopsied and removed. If a contralateral tumor is found, bilateral salpingooophorectomy is done. Ascitic fluid is collected for cytologic evaluation. If no fluid is present, peritoneal washings using lactated Ringer's solution must be obtained. Biopsy of suspicious omental lesions should be done. Omentectomy is performed for tumors involving the omentum. Retroperitoneal lymph nodes are palpated, and suspicious or enlarged nodes are biopsied, including debulking of all obvious retroperitoneal lymphatic spread and removal of any large, bulky areas of metastatic tissue in the peritoneum. If tumor invasion has occurred to the extent that a safe, nonmutilating procedure cannot be done, attempts to surgcally excise the tumor may be delayed until the effectiveness of chemotherapy can be determined. At week 12 of treatment, postinduction surgery is performed on patients with persistently elevated tumor markers or clinical evidence of gross residual intraabdominal disease on physical examination or imaging studies. Postinduction surgery includes biopsy or resection of obvious disease, sampling of the lymph nodes, and biopsy of the kidney to assess cisplatin toxicity.

CHEMOTHERAPY FOR OVARIAN GERM CELL TUMORS

Forty years ago, no effective therapy for germ cell tumors existed. Based on the early success of managing testicular germ cell tumors using multiagent platinum-based chemotherapy, ovarian tumor treatment evolved along similar lines. The addition of chemotherapy reduced the risk of recurrent disease for adult patients with comSURGICAL GUIDELINES FOR OVARIAN pletely resected ovarian germ cell tumors.~2~nitially, GERM CELL TUMORS adjuvant VAC was added to surgical e x c i s i o n . ~ ~ ~ e c a u s e it was effective on testicular germ cell tumors, cisplatin The goal of surgery is to completely evaluate the extent was added to more recent treatment protocols, and the of disease, safely and completely resect the tumor, and regimen of cisplatin, etoposide, and bleomycin (PEB) spare all uninvolved reproductive organs. Preservation of became the preferred protocol. An 8-year study from the reproductive potential is a high priority during surgery GOG that closed in 1992 evaluated PEB and found that for ovarian lesions in children. An increasinag number 91 of 93 patients were free of recurrent germ cell tumors of laparoscopic procedures are being performed for the with a median follow-up of 38.6 months.Z8 evaluation of pelvic masses, and data demonstrate that Historically, several chemotherapeutic regimens were the benefits of a faster recovery time and a shorter hospi~ ~ in children, and the best results were achieved with tal stay seen in adults are also applicable to ~ h i l d r e n . 2 ~ ~ 9 2tried PEB.116J20 In a pilot study, Pinkerton et a1.l" demonstrated If a suspected ovarian malignancy is detected at the time the effectiveness of substituting cisplatin with carboof laparoscopy, complete surgical staging and resection by platin, a less toxic drug; carboplatin was then combined conventional laparotomy are currently recommended.

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with bleomycin and etoposide. Eight of eight patients with ovarian germ cell tumors survived with this regimen. Using a platinum-based regimen, only 1 of 17 girls with resected ovarian nonseminomatous germ cell tumors in FIG0 stage IA relapsed in an analysis of European trials by Gobel et al.72 In 1991 the CCG exverience of 93 children with malignant germ cell tumors included 30 ovarian tumo~-s.~ By study design, immature teratomas and dysgerminomas were not included. Using a cisplatin-based regimen, the 4year event-free survival rate was 63%. Tumor size affected prognosis. If the tumor was larger than 16 cm in diameter, the outcome was worse. Patients in whom complete tumor resection could not be done during the original procedure were more likely to have subsequent adverse events than were those in whom the tumor was completely removed (P = 0.08). In 1994 Nair et a1.I" reported their findings in 107 children with germ cell tumors, including 43 girls with ovarian tumors. Of these, 22 received multiagent chemotherapy. A complete response was seen in 6 of 11 patients treated with platinum, vinblastine, and bleomycin, compared with 10 of 11 patients who responded completely to treatment with PEB (with etoposide replacing vinblastine). The risk of chemotherapy-related complications is low relative to the effectiveness of the PEB regimen.227 There is currently a phase I11 study of reduced therapy in the treatment of children with low- and intermediaterisk extracranial germ cell tumors through the COG (COGAGCT0132) that was activated November 3,2003.31 Based on data from the last POGCCG intergroup study, patients with malignant germ cell tumors can be stratified into three riskgroups (low, intermediate, and high) " " , defined by stage and p r h a b site. Based on preliminary data from POG 9048/CCG 8891, patients with stage - I ovarian and extragonadal immature teratomas with malignant elements appear to do well following complete surgical resection.ll In the current study, all patients with stage I tumors will be categorized in the low-risk category and treated with surgery followed by close observation and monitoring. The intermediate-risk group will consist of patients with stage I1 to I11 gonadal tumors. Such patients have been shown to have a 3-year event-free surThese vival of about 90% with standard-dose PEB.31,167 patients will be treated with a modified PEB regimen consisting of three cycles of compressed PEB every 21 days. Saxman et a1.l7+eported that long-term survival was equivalent for men with germ cell cancer who were treated with either three or four cycles of PEB. Patients who are partial responders may then have surgical resection of residual tumor. Therapy is discontinued upon pathologic complete response and normal markers, or it is continued for an additional three cycles in children who remain partial responders. Patients with recurring germ cell tumors may be salvaged with high-dose chemotherapy with autologous stem cell transplantation.

UNCLASSIFIED BENIGN TUMORS Although the ovary is highly vascularized, hemangiomas are extremely rare; a review found only 40 published ir is relatively cases of these t u m o r ~ . ~ V h eoccurrence

evenly distributed between infancy and postmenopausal age groups. The lesions are usually quite small, asymptomatic, and discovered incidentally. Bilateral occurrence is rare, and the tumors are almost alwavs cavernous. Benign-appearing ultrasonographic features have been described.148When the tumors are large, associated symp toms include abdominal pain, distention, and bloody ascites. Torsion or rupture may cause an acute surgical emergency. No malignant tumors of this type have been described, and oophorectomy or adnexectomy is curative if needed. Primary ovarian leiomyomas are also extremely rare, although they have been reported in teenage girls.174 Most reported cases are clinically silent; however, the lesion may be large enough to cause increased abdominal girth and pelvic pain. Tumor markers are normal, and imaging studies are generally unable to differentiate this benign solid tumor from a malignant process. Unilateral salpingo-oophorectomy is curative. The ovarian myxoma is a rare benign tumor characterized by conspicuous vascularity and mesenchymal proliferation that requires only a conservative surgical procedure.54

UNCLASSlFlED MALIGNANT TUMORS Primary ovarian sarcomas are a heterogeneous group of aggressive tumors associated with poor survival. Most cases occur in older women; however, a review of 151 cases described 10 of 29 patients with rhabdomyosarcoma who were younger than 20 years.Is6These patients presented with nonspecific symptoms of abdominal discomfort or swelling, with occasional urinary or gastrointestinal complaints secondary to mass effect. Accurate staging is critical. Hysterectomy with bilateral salpingo-oophorectomy and debulking of as much diseased intra-abdominal tissue as possible have been done. Radiation therapy is administered for residual pelvic disease, and several chemotherapeutic regimens have been used. In contrast to other rhabdomyosarcomas, the outcome for patients with ovarian lesions has generally been poor, perhaps because of the advanced stage of disease at diagnosis. Nevertheless, the most recent chemotherapeutic regimens used in cooperative group studies have been highly effective, and it is reasonable to assume that more conservative surgical resection will provide adequate treatment for these rare tumors. Genuine stromal sarcomas and low-grade endometrial stromal sarcomas of the ovary have been occasionally reported in the second decade of life. These lesions are believed to arise from ovarian endometriosis, coelomic mesenchyma, or neometaplasia of stromal cells. Lesions are usually discovered because of nonspecific pelvic discomfort, although early infiltration into adjacent tissues may cause intestinal or ureteric obstruction. Tumor infiltration may not be grossly apparent, so initial surgical resection should be aggressive, with total hysterectomy and bilateral salpingo-oophorectomy. Progesterone administration may provide effective adjunctive therapy, although this has to be continued indefinitely because stromal sarcomas can reappear and spread dramatically when the medication is stopped. Radiation therapy has

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been used for local residual disease, although recurrence is common. The role of chemotherapy for these tumors has not been defined. Cases of genuine ovarian fibrosarcoma in children are extremely rare. Patients present with pelvic pain and a palpable mass. Fibrosarcoma has been associated with Maffucci's syndrome." Although the outcome is uniformly poor in older patients, survival of younger patients who have undergone aggressive surgical resection, including hysterectomy and bilateral salpingo-oophorectomy, has been reported. Success with subsequent radiation or chemotherapy has not been reported. Primary leiomyosarcoma of the ovary is extremely rare in children. These tumors may arise de novo from any of the smooth muscle sites in the ovary or may represent malignant degeneration of leiomyoma, a benign counterpart.'" As with most of these rare tumors, presenting symptoms are nonspecific, and discovery may occur in an advanced stage of disease. Aggressive surgical therapy is recommended because no adjuvant therapy has proved beneficial.

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revealed a characteristic appearance and was effective in detecting ovarian involvement in these patients." Survival was based on aggressive systemic multiagent chemotherapy and not on the degree of surgical resection of the ovarian lesion. Routine pelvic radiation therapy was of no benefit. Reports have noted granulocytic sarcoma of the ovary occurring in patients with acute or relapsed acute myelogenous leukemia.2" Although aggressive systemic cheme therapy is critical to survival, an ovarian mass should be investigated immediately to determine its nature (i.e., benign or malignant and exact cell type). In this instance, surgical resection of the ovary and any other involved gynecologic organs or pelvic tissue must be done. Radiation therapy has been used for residual disease in the pelvis. Although the ultimate outcome of granulocytic sarcomas is probably dependent on the effectiveness of chemotherapy, local measures of tumor control cannot be overlooked when this tumor is detected.

SUMMARY

The diagnosis and management of ovarian lesions in infants and children remain challenging because of the SECONDARY TUMORS wide variety of possible pathologies, some of which are extremely rare. Non-neoplastic lesions are being detected Although secondary ovarian malignancy is rare, the more commonly as imaging techniques continue to ovaries are a potential metastatic site for a wide variety of improve. Neoplastic lesions are more readily diagnosed childhood malignancies (Table 369) .12"238 Distinguishing and completely characterized with advances in biochemiprimary neoplasms from secondary neoplasms is imporcal, immunohistologic, and cytogenetic technology. tant to prevent inappropriate therapy or adverse sequelae. Because of the relative rarity of ovarian tumors in Metastatic spread to the ovary occurs through four main children, clinical approaches may be based on experipathways: (1) hematogenous spread, (2) lymphatic ence with similar adult lesions. However, it is critical to spread, (3) transcoelomic dissemination with surface recognize the differences exhibited by the juvenile forms implantation, and (4) direct spread.lz3 Highly malignant of many of these entities, which often present at a less tumors that have a predilection for the pelvic region are intra-abdominal desmoplastic small round cell tum0rs.2~~ advanced stage and have a more favorable natural history and response to therapy. Preservation of reproductive and Pais et al.l47 reviewed 23 cases of ovarian involvement endocrine function is of paramount importance in the in patients with relapsing leukemia. Abdominal pain was treatment of ovarian lesions in infants and children. the most common symptom, and a mass could usually be Careful observation or nonoperative therapies may be palpated. Although most patients in whom leukemia appropriate for many non-neoplastic conditions. Most treatment failed had systemic and not local disease, US benign neoplasms are adequately managed with conservative surgical approaches. Even frankly malignant tumors increasin~lvvield to multidisci~linarv thera~v.

Colorectal Breast Gastric carcinoma Carcinoid tumors (liver, lung) Malignant melanoma Burkitt's lymphoma Rhabdomyosarcoma Wilms' tumor Neuroblastoma Retinoblastoma Ewing's sarcoma Rhabdoid tumor of the kidney Medulloblastoma Osteogenic sarcoma Chondrosarcoma Leukemia

useful in specific cases to increase local control, but, given the paucity of cases, a survival advantage has not been demonstrated. ACKNOWLEDGMENTS The authors would like to thank Drs. Catheryn Yashar and Alexandra Cheerva for their kind review of the chapter.

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159. Plantaz D, Flamant F, Vassal G, et al: Juvenile granulosa cell tumor in children: A clinical study of 39 cases [abstract]. Med Pediatr Oncol 1991;19:396. 160. Pliskow S: Endodermal sinus tumor of the ovary: Review of 10 cases. South Med J 1993;86:187-189. 161. Podczaski E, Kaminski PF, Pees RC, et al: Peutz-Jeghers syndrome with ovarian sex cord tumor with annular tubules and cervical adenoma malignum. Gynecol Oncol 1991;42:7478. 162. Powell JL, Johnson NA, Bailey CL, et al: Management of advanced juvenile granulosa cell tumor of the ovary. Gynecol Oncol 1993;48:119-123. 163. PowellJL, McAfee RD, McCoy RC, et al: Uterine and ovarian conservation in advanced small cell carcinoma of the ovary. Obstet Gynecol 1998;91:846848. 164. Raafat F, Klys H, Rylance G: Juvenile granulosa cell tumor. Pediatr Pathol 1990;10:617-623. 165. Ranney B: Etiology, prevention and inhibition of endometriosis. Clin Obstet Gynecol 1980;23:875-883. 166. Robboy SJ, Scully RE: Ovarian teratoma with glial implants on the peritoneum: An analysis of 12 cases. Hum Pathol 1970;1:643-653. 167. Rogers PC, Olson TA, Cullen JW, et al: Treatment of children and adolescents with stage I1 testicular and stages I and I1 ovarian malignant germ cell tumors: A Pediatric Intergroup study-Pediatric Oncology Group 9048 and Children's Cancer Group 8891. J Clin Oncol 2004;22: 3563-3569. 168. Roth LM, Eglen DE: Gonadoblastoma: Immunohistochemical and ultrastructural observations. Int J Gynecol Pathol 1989;8:72-81. 169. Rottem S, Levit N, Thaler I, et al: Classification of ovarian lesions by high frequency transvaginal sonography. J Clin Ultrasound 1990;18:359-363. 170. Rotterdam ESHRE/ASRM, Sponsored PCOS Consensus Workshop Group: Revised 2003 consensus on diagnosis criteria and long-term health risks related to polycystic ovary syndrome. Fertil Steril 2004;81:19-25. 171. Sakala EP, Leon ZA, Rouse GA: Management of antenatally diagnosed fetal ovarian cysts. Obstet Gynecol Surv 1991;46:407-414. 172. Samaniego F, Rodriquez E, Houldsworth J, et al: Cytogenetic and molecuiar analysis of human male germ cell tumors: Chromosome 12 abnormalities and gene amplification. Genes Chromosomes Cancer 1990;4:239-300. 173. SanfilippoJS, Wakim NG, Schikler K, et al: Endometriosis in association with uterine anomaly. Am J Obstet Gynecol 1986;154:39-43. 174. SanMarco L, Londero F, Stefanutti V, et al: Ovarian leiomyoma. Clin Exp Obstet Gynecol 1991;18:145-148. 175. Sasaki H, Furusato M, Kiyokawa T, et al: Prognostic significance of histopathological subtypes in state I pure yolk sac tumors of the ovary. Br J Cancer 1994;69:529-536. 176. Saxman SB, Finch D, Gonin R, et al: Long term follow-up of a phase I11 study of three versus four cycles of bleomycin, etoposide, and cisplatin in favorable-prognosis germ-cell tumors: The Indiana University experience. 1 Clin Oncol 1998;16:702-706. 177. >chiller W: Mesonephroma ovarii. Am J Cancer 1939;35: 1-21. 178. Scholz PM, Key L, Filston HC: Large ovarian cyst causing cecal perforation in a newborn infant. J Pediatr Surg 1982;17:91-92. 179. Schwobel MG, Stauffer UG: Surgical treatment of ovarian tumors in childhood. Prog Pediatr Surg 1991;26:112-123. 180. Scully RE: Gonadoblastoma: A gonadal tumor related to the dysgerminoma (seminoma) and capable of sex-hormone production. Cancer 1953;6:455-463.

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181. Scully RE: Gonadoblastoma: A review of 74 cases. Cancer 1970;25:1340-1356. 182. Scully RE: Weekly clinicopathological exercises: Case 221982. N Engl J Med 1982;306:1348-1355. 183. Scully RE: Small cell carcinoma of hypercalcemic type. Int J Gynecol Pathol 1993;2:148-152. 184. Scully RE, Young RH, Clement PB: Atlas of Tumor Pathology, Tumors of the Ovary, Maldeveloped Gonads, Fallopian Tube and Broad Ligaments, 3rd ser, fascicle 23. Washington, DC, American Registry of Pathology, Armed Forces Institute of Pathology, 1998. 185. Seeber B, Driscoll D: Hereditary breast and ovarian cancer syndrome: Should we test adolescents? J Pediatr Adolesc Gynecol 2004;17:161-167. 186. Shakfeh SM, Woodruff JD: Primary ovarian sarcomas: Report of 46 cases and review of the literature. Obstet Gynecol Surv 1987;42:331-349. 187. Sherman ME, Mink PJ, Curtis R, et al: Survival among women with borderline ovarian tumors and ovarian carcinoma: A population-based analysis. Cancer 2004;lOO: 1045-1052. 188. Shulman LP, Muram D, Marina N, et al: Lack of heritability in ovarian germ cell malignancies. Am J Obstet Gynecol 1994;170:1803-1808. 189. Siegel MJ, Surratt JT: Pediatric gynecologic imaging. Obstet Gynecol Clin North Am 1992;19:103-126. 190. Skinner MA, Schlatter MG, Heifetz SA, et al: Ovarian neoplasms in children. Arch Surg 1993;128:849-854. 191. Speleman F, DePotter C, Dal Cin P, et al: i(12p) in a malignant ovarian tumor. Cancer Genet Cytogenet 1990;45: 49-53. 192. Steinkampf MP, Hammond KR, Blackwell RE: Hormonal treatment of functional ovarian cysts: A randomized, prospective study. Fertil Steril 1990;54:775-777. 193. Stern JK, Buscema J, Rosenshein NB, et al: Spontaneous rupture of benign cystic teratomas. Obstet Gynecol 1981; 57:363-366. 194. Stevens SK, Hricak H, Stern JL: Ovarian lesions: Detection and characterization with gadolinium-enhanced MR imaging at 1.5Tl. Radiology 1991;181:481-488. 195. Stickland JL: Ovarian cysts in neonates, children and adolescents. Curr Opin Obstet Gynecol 2002;14:459-465. 196. Suiijkerbuijk RF, van de Veen Y, van Echten J, et al: Demonstration of the genuine i(12p) character of the standard marker chromosome of testicular germ cell tumors and identification of further chromosome 12 aberrations by competitive in situ hybridization. Am J Hum Genet 1991;489:269-401. 197. SurrattJT, Siegel MJ: Imaging of pediatric ovarian masses. Radiographics 1991;11:533-548. 198. Sutton CJ, Ewen SP, Whitelaw N, et al: Prospective, randomized, double-blind, controlled trial of laser laparoscopy in the treatment of pelvic pain associated with minimal, mild, and moderate endometriosis. Fertil Steril 1994;62:696-700. 199. Swanson SA, Norris HJ, Kelsten ML, et al: DNA content of juvenile granulosa tumors determined by flow cytometry. Int J Gynecol Pathol 1990;9:101-109. 200. Talerman A, Haije WG, Baggerman L: Serum alpha-feto protein (AFP) in patients with germ cell tumors of the gonads and extragonadal sites: Correlation between endodermal sinus (yolk sac) tumor and raised serum AFP. Cancer 1980;46:380-385. 201. Tanaka Y, Sasaki Y, Nishihira H, et al: Ovarian juvenile granulosa cell tumor associated with Maffucci's syndrome. Am J Clin Pathol 1992;97:523-527. 202. Tangir J, Zelterman D, Wenging M, et al: Reproductive function after conservative surgery and chemotherapy for malignant germ cell tumors of the ovary. Obstet Gynecol 2003;101:251-257.

203. Tapper D, Lack E: Teratomas in infancy and childhood, a 54 year experience at the Children's Hospital Medical Center. Ann Surg 1983;198:398-410. 204. Teilum G: Endodermal sinus tumor of the ovary and testis. Cancer 1959;12:1092-1105. 205. Teilum G: Classification of endodermal sinus tumor (meloblastoma vitellinum) and so-called embryonal carcinoma of the ovary. Acta Pathnl Microbiol Scand 1965;64: 407-429. 206. Teilum G: Special Tumors of Ovary and Testis, 2nd ed. Copenhagen, Munksgaard, 1976. 207. Teilum G, Albrechtsen R, Norgaard-Pedersen B: The histogenetic-embryologicbasis for reappearance of AFP in endodermal sinus tumors (yolk sac tumors) and teratomas. Acta Pathol Microbiol Scand 1975;83:80-86. 208. Templeman C, Blenshevsky A, Fallat ME, et al: Noninflammatory ovarian masses in girls and young women. Obstet Gynecol 2000;96:229-233. 209. Templeman CL, Hertweck SP, Scheetz JP, et al: The management of mature cystic teratomas in children and adolescents: A retrospective analysis. Hum Reprod 2000;15: 2669-2672. 210. Templeman CL, Reynolds AM, Hertweck SP, et al: Laparoscopic management of neonatal ovarian cysts.J Am Assoc Gynecol Laparosc 2000;7:401-404. 211. Thurlbeck W, Scully RE: Solid teratoma of the ovary: A clinico-pathologic analysis of 9 cases. Cancer 1960;13: 801-811. 212. Togashi K: Ovarian cancer: The clinical role of US, CT, and MRI. Eur Radio1 2003;13(Suppl 4):L87-L104. 213. Troche V, Hernandez E: Neoplasia arising in dysgenetic gonads: A review. Obstet Gynecol Surv 1986;41: 7479. 214. VaitukaitisJK, Braunstein GC, Ross GT: A radioimmunoassay which specifically measures human chorionic gonadotropin in the presence of human luteinizing hormone. Am J Obstet Gynecol 1972;113:751-758. 215. Van Voorhis BJ, SchwaigerJ, Syrop CH, et al: Early diagnosis of ovarian torsion by color Doppler ultrasonography. Fertil Steril 1992;58:215-217. 216. Vercellini P, Bocciolone L, Vendola N, et al: Peritoneal endometriosis: Morphologic appearance in women with chronic pelvic pain. J Reprod Med 1991;36:533-536. 217. Vergote IB: Surgery for gynecologic malignancies. Curr Opin Oncol 1993;5:877-884. 218. Warner BW, Kuhn JC, Barr LL: Conservative management of large ovarian cysts in children: The value of serial pelvic ultrasonography. Surgery 1992;112:749-755. 219. Weinblatt M, Kochen J: An unusual family cancer syndrome manifested in young siblings. Cancer 1991;68: 1068-1070. 220. Weinblatt ME, Ortega JA: Treatment of children with dysgerminoma of the ovary. Cancer 1982;49:2608-2611. 221. Weinstein RS, Kuszak JR, Kluskens LF: P-glycoproteins in pathology: The multidrug resistance gene family in humans. Hum Pathol 1990;21:34-48. 222. Wertz DC, Fanos JH, Reilly PR: Genetic testing for children and adolescents: Who decides? JAMA 1994;272: 875-881. 223. Weyl-Ben Arush M, Oslander L: Ollier's disease associated with ovarian Sertoli-Leydig cell tumor and breast adenoma. Am J Pediatr Hematol Oncol 1991;13:49-51. 224. Wierman ME, Beardsworth DE, Mansfield MJ, et al: Puberty without gonadotropins: A unique mechanism of sexual development. N Engl J Med 1985;312:65-72. 225. Williams SD, Birch R, Einhorn LH, et al: Treatment of disseminated germ cell tumors with cisplatin, bleomycin, and either vinblastine or etoposide. N Engl J Med 1987;316:1435-1440.

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226. Williams SD, Blessing JA, Liao SY, et al: Adjuvant therapy of ovarian germ cell tumors with cisplatin, etoposide, and bleomycin: A trial of the Gynecologic Oncology Group. J Clin Oncol 1994;12:701-706. 227. Williams SD, Blessing J, Slayton R, et al: Ovarian germ cell tumors: Adjuvant trials of the Gynecologic Oncology Group [abstract 5841. Proc Am Soc Clin Oncol 1989; 8:150. 228. Williams SD, Gershenson DM, Horowitz CJ, et al: Ovarian germ cell and stromal tumors. In Hoskins W, Perez CA, Young RC (eds): Principles and Practice of Gynecologic Oncology. Philadelphia, JB Lippincott, 1992, p p 715-730. 229. Wilson E, Vuitch F, Carr B: Laparoscopic removal of dysgenetic gonads containing a gonadoblastoma in a patient with Swyer syndrome. Obstet Gynecol 1992;79: 842-844. 230. Wu JT, Book L, Sudar K: Serum a-fetoprotein (AFP) levels in normal infants. Pediatr Res 1981;15:50-52. 231. Yamamoto K, Akiyama H, Maruyama T, et al: Granulocytic sarcoma of the ovary in patients with acute myelogenous leukemia. Am J Hematol 1991;38:223-225. 232. Yanai-Inbar ISR: Relation of ovarian dermoid cysts and immature teratomas: An analysis of 350 cases of immature teratoma and 10 cases of dermoid cyst with microscopic

233. 234. 235. 236. 237.

238. 239.

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foci of immature tissue. Int J Gynecol Pathol 1987;6: 203-212. Young JL Jr, Wu XC, Roffers SD, et al: Ovarian cancer in children and young adults in the United States 1992-1997. Cancer 2003;97(10 Suppl):26942700. Young RH: Ovarian tumors other than those of surface epithelial-stromal type. Hum Pathol 1991;22: 763-775. Young RH, Clement PB, Scully RE: Calcified thecomas in young women: A report of fou; cases. IntJ Gynecol Pathol 1988;7:343-350. Young RH, Dickersin GR, Scully RE: Juvenile granulosa cell tumor of the ovary: A clinicopathological analysis of 125 cases. Am J Surg Pathol 1984;8:575-596. Young RH, Eichhorn JH, Dickersin GR, et al: Ovarian involvement by the intraabdominal desmoplastic small round cell tumor with divergent differentiation: A report of three cases. Hum Pathol 1992;23:454464. Young RH, Kozakewich HPW, Scully RE: Metastatic ovarian tumoFs in children: A report of 14 cases and review of the literature. Int J Gynecol Pathol 1993;12:8-19. Zanetta GRS, Rota S, Chiari S, et al: Behaviour of borderline tumors with particular interest to persistence, recurrence, and progression to invasive carcinoma: A prospective study. J Clin Oncol 2001;19:2658-2664.

Testicular Tumors Hsi-Yang Wu and Eugene Wiener

Testicular tumors in prepubertal boys differ from those in postpubertal men in both pathology and tendency for metastasis. This difference allows testis-sparing procedures to be applied more liberally in younger patients but requires careful evaluation of pubertal development in older patients. The peak incidence for testicular tumors is 2 to 4 years of age.13 These tumors represent 1% of all pediatric solid tumors and are rare in the African American and Asian populations. Testis tumors that arise later in life are associated with a history of cryptorchidism and mixed gonadal dysgenesis. The risk of malignancy arising from an undescended testis after puberty is 1% in inguinal testes and 5% in abdominal testes.The most common pathology in a testis that remains undescended is seminoma, whereas a testis that has been surgically placed in the scrotum is more likely to have embryonal or teratocarcinoma pathology. Orchiopexy does not reduce the incidence of testicular cancer.' Because prepubertal testis biopsies rarely detect tumors in undescended testes, the pathologic finding of normal testicular parenchyma does not preclude the later development of tumor.

CLINICAL PRESENTATION A nontender, solid scrotal mass is the usual presenting sign of a testicular tumor. Often a history of trauma is volunteered, but this likely alerted the boy or his parents to a previously unrecognized painless, enlarged testis, rather than being the cause. The differential diagnosis includes testicular torsion and epididymitis, but in the absence of pain, dysuria, and inflammation, tumor is more likely. However, it is not unusual for a patient with a tumor to be mistakenly operated on for suspected torsion. Physical examination should differentiate between epididymal swelling (spermatocele or epididymitis) and testicular swelling (orchitis or tumor). There may be an associated hydrocele. Transillumination does not rule out the presence of a tumor, because a tumor and a hydrocele can coexist. Stromal testicular tumors can present with precocious puberty (Leydig cell) or gynecomastia (Sertoli cell).

DIAGNOSIS Imaging If the testis cannot be palpated owing to a tense hydrocele or if the examination is unclear, scrotal ultrasonography is belpful in determining the architecture and echogenicity of the testis. The normal testis has a homogeneous texture, whereas a tumor has a heterogeneous texture in comparison to the normal testicular parenchyma next to it. If there are cystic areas in the involved testis, a teratoma or epidermoid cyst is the likely diagnosis, and testis-sparing surgery should be considered. The presence of multiple small calcifications (microlithiasis) is of unclear significance. It has been found in association with testis tumor in adult men. If microlithiasis is found in the contralateral (presumably normal) testis, follow-up imaging is warranted owing to the possibility of the later formation of a testis tumor. l 1 A metastatic evaluation is performed after the diagnosis of a malignant tumor is established. A chest computed tomography (CT) scan should be obtained because metastases from yolk sac tumors are more likely to occur in the lung than the retroperitoneum. A CT scan of the abdomen and pelvis to look for retroperitoneal nodal involvement is performed postoperatively.

Tumor Markers Serum alpha fetoprotein (AFP) and P-human chorionic gonadotropin (P-HCG) levels should be obtained preoperatively in all patients with suspected testis tumor. Although elevated levels are occasionally useful in making the diagnosis, they are most beneficial in followup for recurrence. AFP (a marker for yolk sac tumors) is normally elevated in newborns until 8 months of age27 and in patients with liver dysfunction, so serial determinations after orchiectomy are needed. The half-life of AFP is 5 days, so the level should be normal 25 days after orchiectomy if the entire tumor was removed. P-HCG is occasionally elevated in seminoma and more commonly in choriocarcinoma, both of which are rare

CHAPTER

37

Testicular T ~ ~ m o r s

623

entering puberty, teratoma should be treated as it is in adult patients, with radical inguinal orchiectomy, owing to its more malignant behavior. If the AFP level is elevated relative to age-adjusted levels, Percentage Tumor Type --.one should assume that yolk sac elements are present and Yolk sac 62 not perform testis-sparing surgery. Scrota1 ultrasonography 23 Teratoma showing internal calcifications and a heterogeneous 4 Gonadal stromal mass in the testis, in association with a normal AFP level, 3 Epidermoid cyst suggests a teratoma. The testis is approached through an 3 Juvenile granulosa inguinal incision, and after vascular control has been 3 Sertoli cell obtained at the level of the internal inguinal ring, the 1 Leydig cell 1 Gonadoblastoma teratoma can be shelled out from the testis; a frozen section can confirm the patholocgy.ylEven when the teratoma significantly compresses normal testicular parenchyma, postoperative ultrasound studies usually show good in the prepubertal population. Its half-life is 1 day, so it recovery of testicular tissue, with presumably preserved should return to normal by 1 week postoperatively. function.I4 There are two different approaches to the use of frozen sections. The classic approach is to obtain a frozen section STAGING AND CLASSIFICATION to confirm teratoma pathology and that there are no maturation changes in the neighboring parenchyma.Z0 Table 37-1 lists the distribution of pathologies in the Others have suggested that the combination of ultrasound 2002 American Academy of Pediatrics Testis Tumor findings and normal AFP level should be sufficient to Registry.") The predominance of yolk sac tumors may make the diagnosis of teratoma preoperatively. They also reflect a reporting bias; in many single-institution studies teratomas are more common, but they are often not recommend that any patient with pubertal development reported to registries because they are benign.1,14,2"26 should be excluded from testis-sparing surgery.14.':4Most Table 37-2 shows the staging system for testis tumor used prepubertal boys with teratomas have good gonadal preservation after testis-sparing surgery. by the Children's Oncology Group (COG).

TREATMENT BY TUMOR TYPE Germ Cell Tumor Teratoma Teratomas are derived from ectoderm, mesoderm, and endoderm and therefore can have solid and cystic components. Epidermoid cysts can be considered monophasic teratomas, in that they are derived only from ectoderm. Before puberty, teratoma can be managed with a testissparing approach")^"^?^ because it is always benign, even shows immature el em en^.^ In patients when the path~lo~gy

Stage

Description

I

Limited to testis, completely resected by high inguinal orchiectomy; no clinical, radiographic, or histologic evidence of disease beyond the testes; patients with normal or unknown tumor markers at diagnosis must have a negative ipsilateral retroperitoneal node sampling to confirm stage I disease if radiographic studies demonstrate lymph nodes >2 cm Transscrotal biopsy, microscopic disease in scrotum or high in spermatic cord (25 cm from proximal end) Retroperitoneal lymph node involvement, but no visceral or extra-abdominal involvement; lymph nodes >4 cm by computed tomography or >2 cm and <4 cm with biopsy proof Distant metastases, including liver

II Ill

IV

Sixty percent of prepubertal testis tumors are germ cell tumors. The yolk sac tumor in children manifests a different pattern of metastasis than in adults. In children, hematogenous metastases to the lung occur in 20% of cases, whereas spread to the retroperitoneal nodes occurs in only 4% to 6% of cases; in adults, spread is usually to the retroperitoneal nodes. Most yolk sac tumors present during the first 2 years of life. The yolk sac tumor is managed with radical inguinal orchiectomy. The pathology reveals Schiller-Duval bodies. If the patient is stage I (no chest metastasis or retroperitoneal adenopathy, with appropriate drop in AFP), no chemotherapy is necessary.ZO The recommended surveillance program is shown in Figure 37-1. Patients with stage I1 disease (transscrotal orchiectomy, microscopic disease, or persistently elevated AFP) receive platinum-based chemotherapy (cisplatin, etoposide, bleomycin) and no radiation therapy. Whether children who have undergone transscrotal orchiectomy also require hemiscrotectomy is controversia1,22 because it now appears that local therapy does not change the outcome if chemotherapy is given in adults, although no similar study has been performed in children.' The current COG protocol no longer requires hemiscrotectomy in this situation. Patients with stage I1 disease with persistent retroperitoneal mass or persistent elevated serum AFP levels after chemotherapy should have retroperitoneal lymph node dissection (RPLND). If viable tumor is found, the chemotherapy regimen is changed. Those with stage I11 (>2 cm retroperitoneal lymph node) Y disease (metastasis) receive chemotherapy, and stage J

624

PART

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M i \ j o ~TIIMORS OF CHILDHOOD Surgery (testis sparing or inguinal orchiectomy)

s

Stage I yolk sac

Surveillance

,

All studies negative

1

Observe

Stage Il-IV yolk sac

Teratoma

Platinum-based chemotherapy,

Observe

Markers remain elevated . - R ' estage

Markers and nodes resolved

Surveillance

/

.

-

Algorithm for

surveillance of germ cell tumors. CT, computed tomography. (Adapted from POG 9048/ CCSG 8891.)

with CT

Partial or no response

Retroperitoneal lymph node dissection

No viable tumor K '

Surveillance

I

w Residual tumor Salvage chemotherapy

Surveillance protocol: Markers every month x 1 year, then every 2 months x 1 year. Chest radiograph every 2 months x 1 year, then every 3 months x 1 year. CT every 3 months x 1 year, then every 6 months x 1 year.

followed by RPLND for any residual mass. The overall survival for all stages approaches 100%. The rare extragonadal germ cell tumor (retroperitoneal and abdominal) is best treated with initial biopsy (complete resection if possible), chemotherapy, and re-resection of residual tumor. Event freesurvival is 83% at 6 years.4

They can present with ~gynecomastia.Follow-up CT scans of the retroperitoneum are necessary for at least 2 years because the pathology does not always predict outcome. Although these tumors are usually benign, the frequency of patients with retroperitoneal node involvement is not known, because the entire experience with malignant behavior in prepubertal patients is limited to a few case reports.Z5

Gonadal Stromal Tumor Leydig cell tumors are the most common gonadal stroma1 tumors of adults and children.2Vhe classic triad of findings in Leydig cell tumors is precocious puberty ( l o % ) , unilateral testis mass (go%), and elevated 17ketosteroid. Unlike precocious puberty induced by a pituitary lesion (high luteinizing hormone [LH] , folliclestimulating hormone [FSH], and testosterone levels), Leydig cell tumors have low LH and FSH and high testosterone levels. The precocious puberty may not resolve after resection, but this does not necessarily indicate the presence of residual tumor. Nodules induced by congenital adrenal hyperplasia tend to be bilateral (80%) and also have low LH and FSH and high testosterone. These nodules are suppressed with dexamethasone or adrenocorticotropic hormone administration and regress when treated with glucocorticoids. The Reinke crystal, which is pathognomonic for Leydig cell tumors in adults, is rarely found in children. Leydig cell tumors can also be managed using a testis-sparing approach, similar to teratoma, because they are benign in children.12,*4,25 Sertoli cell tumors are rare in children, usually benign, and safely treated with testis-sparing procedures.17~24.Zj

Gonadoblastoma Gonadoblastoma is classically encountered in patients with mixed gonadal dysgenesis (45,X/46,XY) or intersex with dysgenetic gonads in association with a Y chromosome in the karyotype. The tumors are small, bilateral in 33% of cases, malignant in lo%, and usually present after puberty. The pathology includes germ cells and stroma cells. Although it is a low-grade malignancy, the nonpalpable gonad is managed with early gonadectomy because it can degenerate into seminoma later in life. Previously, it was recommended that both gonads be removed in patients with mixed gonadal dysgenesis.Vhe management of these tumors has become more complicated with the realization that neonatal testosterone imprints the brain; therefore, bilateral gonadectomy and rearing as a female may not correspond with the eventual gender role. If it is elected to leave a gonad in the scrotum, one suggestion is to perform annual scrota1 examinations and ultrasonography until patients complete puberty, and to perform testis biopsies looking for testicular carcinoma in situ at the beginning and end of puberty.'"

CHAPTER

Secondary Tumor Secondary tumors of the testis are usually due to lymphoma or leukemia and appear hypoechoic on ultrasonography. Although it was once common practice to biopsy the testes of patients who were completing chemotherapy for lymphoma and leukemia, no survival advantage has been shown, so this is no longer routinely performed.lC If a patient has an enlarged testis after treatment for lymphoma or leukemia, a biopsy of the affected testis should be taken, and testicular radiation given. Additional chemotherapy should also be given, because the presence of tumor in a sanctuary site such as the testis suggests residual disease elsewhere. Paratesticular rhabdomyosarcoma is discussed in detail in Chapter 32.

TECHNIQUE Testis-sparing surgery is generally performed through an inguinal incision. The testis is delivered into the incision, and a Penrose drain is placed around the cord at the level of the internal inguinal ring to occlude the vessels. The tunica vaginalis of the testis is opened directly over the mass. Sometimes intraoperative ultrasonography is

, -

Right modified nervesparing retroperitoneal lymph

node dissection template. (From Marshall FF [ed]: Textbook of Operative Urology. Philadelphia, WB Saunders, 1996, pp 368-369.)

37

Testicular Tumors

625

helpful in localizing the tumor if it is deep in the parenchyma. The edge of the knife blade is used to shell out the tumor; this preserves the neighboring parenchyma, which the pathologist needs to examine to ensure that pubertal maturation has not occurred. Hemostasis is accomplished with finely controlled bipolar cautery. The tunica vaginalis is closed with absorbable suture and replaced in the scrotum. A radical orchiectomy is performed by high ligation of all cord structures at the level of the internal ring. If the mass is too large to mobilize from the scrotum, the inguinal incision should be lengthened to the superior aspect of the scrotum to avoid tumor rupture. RPLND can be performed through a transabdominal, thoracoabdominal, or laparoscopic approach. The procedures are based on the dissections originally designed for adult testicular tumors.10 The most common sites for lymph node metastases in instances of right-sided tumors are the interaortocaval and paracaval nodes, whereas left-sided tumors tend to spread to the para-aortic and interaortocaval nodes. The boundaries of the dissection depend on the initial stage of the tumor. If the tumor is stage 11, a modified unilateral template may be used (Figs. 37-2 and 37-3). If the tumor is stage I11 or IV, a bilateral dissection is required (Fig. 37-4). The nodal packets

, . Left modified nerve-sparing retroperitoneal lymph node dissection template. (From Marshall FF [ed]: Textbook of Operative Urology. Philadelphia, WB Saunders, 1996, pp 368-369.)

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for testis tumors. Leydig cells tend to be more resistant to chemotherapy, and androgen replacement is usually not necessary.lg

SUMMARY Testis-sparing surgery should be considered when the preoperative evaluation suggests that the pathology will be a non-germ cell tumor in a prepubertal boy. If yolk sac pathology is suspected based on an elevated AFP level, radical orchiectomy and treatment based on postoperative staging result in excellent survival outcomes.

REFERENCES

, Template for full bilateral retroperitoneal lymph node dissection. (From Marshall FF [ed]: Textbook of Operative Urology. Philadelphia, WB Saunders, 1996, pp 368-369.)

are split over the great vessels, and the sympathetic ganglia are preserved as they course over the iliac veins to preserve ejaculation. Laparoscopic RPLND achieves a similar dissection using five transabdominal ports. Because the experience in adult patients has been limited to stage I and small residual masses in stage I1 tumors,"I8 the use of laparoscopic RPLND in children should probably be limited to small stage I1 tumors.

COMPLICATIONS Infertility and testicular failure are two long-term complications of treatment. Whereas adult patients with testis tumors have the option of pretreatment sperm banking, this is not possible for prepubertal boys. Survivors of childhood male genital tumors are only 0.45 times as likely as controls to be fertile.5 If the sympathetic nerves are sacrificed during RPLND, loss of ejaculation will occur. Alkylating agents such as cyclophosphamide tend to affect sperm count the most but are not routinely used

1. Andrassy RJ, Copron C, Ritchey M: Testicular tumors. In O'Neill JA, Rowe MI, Grosfeld JL, et a1 (eds): Pediatric Surgery, 5th ed. Philadelphia, WB Saunders, 1998, p 542. 2. Batata MA, Whitmore WF, Chu FCH, et al: Cryptorchidism and testicular cancer. J Urol 1980;124:382. 3. Bhayani SB, Ong A, Oh WK, et al: Laparoscopic retroperitoneal lymph node dissection for clinical stage I nonseminomatous germ cell testicular cancer: A long-term update. Urology 2003;62:324. 4. Billmire D, Vinocur C, Rescorla F, et al: Malignant retroperitoneal and abdominal germ cell tumors: An intergroup study. J Pediatr Surg 2003;38:315. 5. Byrne.J, Fears TR, Gail MH, et al: Effects of treatment on fertility in long-term survivors of testicular cancer. N Engl J Med 1987;3178:1315. 6. Campbell HE: Incidence of malignant growth of the undescended testicle: A critical and statistical study. Arch Surg 1942;44:353. 7. Capelouto CC, Clark PE, Ransil BJ, et al: A review of scrotal violation in testicular cancer: Is adjuvant local therapy necessary?J Urol 1995;153:981. 8. CarneylA, Thompson DP, Tohnson CL, et al: Teratomas in children: ~ l i n i c a and i pa
CHAPTER

17. Nonomura K, Koyama T, Kakizaki H, et al: Testicular-sparing surgery for the prepubertal testicular tumor: Experience of two cases with large cell calcifying Sertoli cell tumors. Eur Urol2001;40:699. 18. Palese MA, Su LM, Kavoussi LR: Laparoscopic retroperitoneal lymph node dissection after chemotherapy. Urology 2002;60:130. 19. Relander T, Cavallin-Stahl E, Ganvicz S, et al: Gonadal and sexual function in men treated for childhood cancer. Med Pediatr Oncol 2000;34:52. 20. Ross JH, Rybicki L, Kay R: Clinical behavior and a contemporary management algorithm for prepubertal testis tumors: A summary of the prepubertal testis tumor registry. J Urol 2002;168:1675. 21. Rushton HG, Belman AB, Sesterhenn I, et al: Testicular sparing surgery for prepubertal teratoma of the testis: A clinical and pathological study. J Urol 1990;144:726.

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22. Schlatter M, Rescorla F, Giller R, et al: Excellent outcome in patients with stage I germ cell tumors of the testes: A study of the Children's Cancer Group/Pediatric Oncology Group. J Pediatr Surg 2003;38:319. 23. Shukla AR, Woodard C, Carr MC, et al: Experience with testis sparing surgery for testicular teratoma. J Urol 2004;171:161. 24. Sugita Y, Clarnette TD, Cooke-Yarborough C, et al: Testicular and paratesticular tumours in children: 30 years' experience. Aust N Z J Surg 1999;69:505. 25. ThomasJC, RossJH, Kay R: Stromal testis tumors in children: A report from the Prepubertal Testis Tumor Registry. J Urol 2001;166:2338. 26. Walsh C, Rushton HG: Diagnosis and management of teratomas and epidermoid cysts. Urol Clin North Am 2000; 27:509. 27. Wu JT, Book L, Sudar K: Serum alpha fetoprotein (AFP) levels in normal infants. Pediatr Res 1981;15:50.

Adrenal Tumors Stanley. T Lau and Michael G. Caty

ANATOMY Translated from its Latin root, adrenal means "near the kidney." The bilateral adrenal glands are found anteromedially in relation to the superior pole of the kidneys, covered by perirenal fat and enclosed by Gerota's fascia. In adults, the glands weigh approximately 5 g each. The right gland abuts the inferior vena cava and liver and lies on the posterior extension of the diaphragm, and the left gland lies next to the splenic vessels and the tail of the pancreas. Although the blood supply to the adrenal glands is variable, it comes from three general sources: the inferior phrenic artery superiorly, the aorta medially, and the renal arteries inferiorly. The venous drainage does not parallel the arterial supply; instead, a single large adrenal vein provides the majority of the venous drainage for each gland. The right adrenal vein empties into the inferior vena cava, and the left adrenal vein joins the left renal vein. The adrenal lymphatics arise from one plexus beneath the capsule and from a second plexus in the medulla. The right adrenal lymph vessels drain into the periaortic lymph nodes near the diaphragmatic crus, and the left adrenal lymphatics empty into lymph nodes near the takeoff of the left renal artery. The innervation of the adrenal glands arises from the celiac plexus and the greater thoracic splanchnic nerves. The preganglionic sympathetic fibers enter the hilum and end in ganglia within the medulla. The two distinct regions of the adrenal gland are the cortex and the medulla. These regions not only are distinct on gross examination but also are different embryologically, structurally, and functionally. The adrenal medulla is derived from ectodermal cells from the neural crest. These early cells form the chromocell system and the neuronal system, which accounts for the possible development of two distinct medullary neoplasms: pheochromocytoma and neuroblastoma. The preganglionic sympathetic neural cells innervate the secretory chromaffin cells, which synthesize norepinephrine and epinephrine. The cortex comprises the outer portion of the adrenal gland and secretes sex hormones, mineralocorticoids, and glucocorticoids. It is divided into three separate zones with separate synthetic functions. The zona glomerulosa is the outermost cortical zone and produces aldosterone

and related mineralocorticoids. The zona fasciculata lies beneath the zona glomerulosa and secretes cortisol and the adrenal sex hormones. The inner zona reticularis maintains cholesterol stores as a precursor for steroidogenesis and secretes cortisol, androgens, and estrogens.

EMBRYOLOGY The primordium of the adrenal cortex becomes visible as early as the fourth week of gestation and is clearly seen by the sixth week. On prenatal ultrasonography (US), the adrenal glands may be visible as early as 20 weeks' gestation and are identifiable in the majority of fetuses by 30 weeks' gestation." During the fourth to sixth weeks of gestation, the mesodermal cells ofthe posterior abdominal wall at the adrenogenital ridge become more columnar and invade the mesenchyma beneath the epithelial surface, ultimately forming the fetal adrenal cortex. Another proliferation of epithelial cells subsequently forms a cap over these primitive cortical cells, becoming the zona glomerulosa of the definitive cortex. The ectodermal chromaffin cells of the adrenal medulla arise from the neural crest as early as the fifth week, with primitive cells from the thoracic ganglia from the 6th to 12th segments invading the gland and forming the medulla. Differentiation of these primitive medullary cells into chromaffin cells begins at the third month of gestation, ultimately leading to the cells' production of epinephrine and norepinephrine. The fetal zone of the adrenal cortex begins to appear around the sixth week of gestation. This zone continues to enlarge and occupy the majority of the gland. In fact, because of the large size of the fetal cortical zone, the fetal adrenal gland is four times the size of the kidney during the fourth month of gestation. This fetal cortex subsequently decreases in size, disappearing in the first year of life. During fetal development, ectopic rests of medullary and cortical tissue may remain and persist after birth. Extraadrenal medullary rests are usually found along the aorta and its branches. The organ of Zuckerkandl is an example of a chromaffin mass at the origin of the inferior mesenteric artery. Most extra-adrenal chromaffin rests involute after birth; the chromaffin cells in the medulla differentiate.

CHAPTER

Extra-adrenal cortical rests are common in children and are found in the kidney or liver or along the migratory path of the gonads, in hernia sacs, or in the gonads themselves. Approximately 50% of newborns have adrenocortical rests, but these rests typically atrophy and disappear within a few weeks after birth.30

PHYSIOLOGY Adrenal Medullary Function The adrenal medulla synthesizes and releases catecholamines-dopamine, epinephrine, and norepinephrine. Catecholamine synthesis begins with tyrosine, a nonessential amino acid. Tyrosine hydroxylase converts tyrosine into dihydroxyphenylalanine (DOPA) and is the rate-limiting step in the synthetic pathway. DOPA decarboxylase converts DOPA into dopamine. Phenylamine R-hydroxylase converts dopamine into norepinephrine. Finally, phenylethylamine N-methyltransferase converts norepinephrine into epinephrine. The chromaffin cells within the medulla contain cytoplasmic granules that store the catecholamines. Preganglionic sympathetic nerve endings release acetylcholine, which causes calcium-dependent exocytosis of these cytoplasmic storage granules and release of the catecholamines. Regulation of adrenal medullary catecholamine release is accomplished through inhibitory feedback mechanisms involving norepinephrine. Norepinephrine inhibits acetylcholine release from the presynaptic a2receptors and also inhibits tyrosine hydroxylase activity when present in high concentrations.

Adrenal Cortical Function The adrenal cortex synthesizes three types of hormones: glucocorticoids, mineralocorticoids, and sex hormones. Regulation of these hormones is accomplished by the hypothalamic-pituitary-adrenal axis. The hypothalamus p;bduces cor&otropin-releasing hormone (CRH); this is transported to the anterior pituitary gland, where it stimulates the release of adrenocorticotropic hormone (ACTH). ACTH then stimulates the production of adrenal hormones from the adrenal cortex. The physiologic diurnal variation in CRH release leads to a cyclic variation in ACTH and the hormones regulated by it. Serum concentrations peak shortly before-or at the time of awakening and decline throughout the remainder of the day. Both cortisol and ACTH inhibit CRH release, creating a negative feedback loop. Adrenocortical production of glucocorticoids begins with a cholesterol substrate and is regulated by ACTH. The majority of serum cortisol is bound by cortisol-binding protein (90%) and albumin (6%),leaving only a small percentage (4%) free and physiologically active. As with most steroids, the unbound cortisol fraction is lipophilic and therefore readily crosses the plasma membrane of target cells. specific receptors then bind with cortisol and act in the cell nucleus to regulate messenger RNA synthesis.

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Cortisol affects metabolism primarily by opposing insulin. It causes hyperglycemia by increasing the proteolysis necessary for gluconeogenesis and inducing hepatic gluconeogenic enzymes. Cortisol also decreases the use of glucose by peripheral tissues; it inhibits glucose uptake into fat cells and decreases the amount of insulin bound by insulin-sensitive tissues. Cortisol also decreases inflammation and immune function, affecting wound healing. Cortisol lowers both the lymphocytic and the granulocytic cellular immune response by decreasing the lymphocyte response to antigenic stimulation and impairing chemotaxis and phagocytosis of leukocytes. These two immune functions are an important part of early wound healing; thus, wounds have decreased tensile strength and impaired healing in the setting of excess cortisol. Aldosterone, a mineralocorticoid, is synthesized in the zona glomerulosa and metabolized primarily by the liver. The renin-angiotensin system controls the majority of aldosterone regulation, with ACTH playing only a small role. The macula densa of the renal juxtaglomerular apparatus releases renin in response to a drop in renal perfusion or hyponatremia. Renin converts angiotensinogen, which is produced by the liver, to angiotensin I. Angiotensin-converting enzyme, found in the lung, converts angiotensin I to angiotensin 11. Angiotensin I1 stimulates the synthesis of aldosterone by directly acting on the cells of the adrenal zona glomerulosa; it also acts as a vasoconstrictor. By increasing the renal retention of sodium, aldosterone increases blood pressure and corrects hyponatremia, thus reducing the release of renin. The serum potassium concentration also provides a small amount of aldosterone regulation. Hyperkalemia leads to increased aldosterone production by directly acting on the zona glomerulosa cells, as well as increasing renin release from the juxtaglomerular cells. Aldosterone promotes an increased renal excretion of potassium, thus lowering aldosterone production and providing another feedback mechanism. Adrenal androgens are synthesized in the zona reticularis and are regulated primarily by ACTH. These hormones are released in a cyclic manner, correlating with the release of cortisol and ACTH. The adrenal androgens are only weakly active but are converted by peripheral tissues into more active forms such as testosterone and dihydrotestosterone. Metabolism of these hormones occurs in the liver.

IMAGING OF THE ADRENAL GLAND In children, imaging of the adrenal glands is necessary when an intra-abdominal mass is detected or when there are secondary signs of a hyperfunctioning adrenal gland. Imaging of the abdomen and retroperitoneum identifies the organ of origin, detects metastatic disease, and demonstrates bilaterality. Nuclear medicine studies can be used to localize tumors to their adrenal origin and demonstrate extra-adrenal tumors. The use of specific radiopharmaceuticals allows one to predict the cell type of an adrenal tumor.

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Plain abdominal radiographs have minimal clinical MIBG with one of two iodine isotopes at the meta posiutility in the assessment of an adrenal mass. Small function of the benzoic ring. The iodine isotope 1311 has a tional adrenal masses will not be visualized, and although half-life of 8.2 days and emits high-energy radiation. The large masses, such as neuroblastoma, will demonstrate iodine isotope n31has a shorter half-life and emits lowercalcifications and mass effect, they are often palpable energy radiation.15 Patients undergoing MIBG scanning and more readily diagnosed by physical examination. should be given a saturated solution of potassium iodide The initial screening examination to evaluate an to block thyroid uptake of the free iodine isotope. abdominal mass is often abdominal US. US offers the Scintigraphy is performed at 24 and 48 hours. MIBG advantages of correlating imaging with physical examinascanning i s valuable for the detection of extra-adrenal and metastatic pheochrornocytoma. It also confirms the tion findings and avoiding ionizing radiation. The goals of abdominal US are to identify the organ of origin, adrenal location of a pheochrornocytoma in patients define the character and size of the mass, and determine with positive urine or serum catecholamine tests: its vascularity. It may be difficult to identify the adrenal Positron emission tomography (PET) may be a useful imaging study for pheochrornocytoma in the near gland as the organ of origin for large masses, owing to future. PET sc-inning uses short-lived positron-emitting compression from adjacent organs such as the kidney. The normal adrenal gland is easily visualized by US agents to identify specific areas of uplake in the body. during the first week of life. The adrenal soon involutes, Because of the increased metabolism of tumors, labeled glucose can be used to identify malignant tissue. The and the distinction between the cortex and the medulla is lost. Adrenal hemorrhage may manifest as an adrenal host common form of labeled~gluco~e in use for PET mass in newborns. Affected newborns may have predisscanning is [18F]-fluorodeoxyglucose (FDG). Resolution posing factors such as asphyxia or a difficult delivery. The of pheochromocytoma and distinction between benign appearance of the adrenal gland following adrenal hemand malignant pheochrornocytoma are not optimal orrhage is varied. The adrenal gland may be echogenic, with FDG PET, however. A more useful agent may be hypoechoic, or a mixture of the two.41 Adrenal hemor6-[18F]-fluorodopamine (DA). The similarity between rhage may be confused with neuroblastoma. Patients with norepinephrine and DA allows selective uptake by symOne study found that FDG PET normal urinary catecholamine levels and the appropriate pathoadrenal ti~sue.~2 demonstrated metastases better than MIBG scanning risk factors for adrenal hemorrhage can be observed and did.37 PET scanning results in lower radioactivity expoundergo repeat US. Differentiation of adrenal adenoma sure than standard scintigraphy. When specific agents and carcinoma by US is difficult; in addition, both resemble an adrenal pheochromocytoma. An ultrasonographic charsuch as DA become generally available, it may prove to acteristic that suggests malignancy is central necrosis from be the imaging method of choice. rapid growth. Biochemical testing and the use of computed Another useful radiopharmaceutical is 1311-iodomethyl1-19-norcholesterol (NP-59). This cholesterol analogue tomography (CT), magnetic resonance imaging (MRI),and nuclear medicine studies narrow the diagnostic possibilities. is taken up as cholesterol into the steroid pathways of the When US identifies a solid mass in the retroperitoneum, adrenal cortex. It is used to identify the adrenal cortex planar imaging is performed to identify the organ of origin and can differentiate adenomas from adrenocortical and define resectability. The two immediate choices in hyperplasia. children are CT and MRI. Although CT is an accurate method of diagnosing adrenal lesions, it is less accurate in younger children owing to the absence of retroperitoneal LESIONS OF THE ADRENAL MEDULLA fat. Other disadvantages of CT are the need for intravenous contrast material and exposure to ionizing radiation. Pheochromocytoma Simultaneous scanning of the chest to rule out pulmonary In 1886 Frankel of Freiburg, Germany, published the metastases in patients suspected of having adrenal carcinoma is a benefit of CT. Imaging of adrenal lesions with first description of bilateral pheochromocytomas found MRI offers the advantage of multiplanar imaging. Coronal during the postmortem examination of an 18-year-old imaging is a useful modality to distinguish adrenal woman who had presented with symptoms of anxiety, masses from the adjacent kidney and vice ver~a.2~~"~38palpitations, and headache.44 In 1912 Pick named the Pheochromocytomas demonstrate low or intermediate tumor for its predominant cell type, the pheochromosignal intensity on T1-weighted images and enhance with cyte, but it was not until 1922 that Labbe et al. first gadolinium-diethylenetriaminepentaace tic acid (DTPA).*0 described a clear relationship between pheochromocyThe unique cellular properties of tumors of the adrenal toma and paroxysmal hypertension. In 1927 Mayo performed the first successful removal of a pheochromogland allow imaging with radiopharmaceuticals. The seleccytoma in a patient with paroxysmal hypertension who tive uptake of specific compounds allows the identification underwent surgical exploration without a preoperative of adrenal and extra-adrenal locations of pheochromocytoma and the location of adrenal adenomas. diagnosis. In 1929 Pincoffs made the first 'correct preopThe adrenal gland and pheochrornocytoma cells erative diagnosis, and the successful operation was contain transporter systems for norepinephrine. performed by Shipley.14 Since that time, the behavior of Metaiodobenzylguanidine (MIBG), which is structurally pheochromocytomas has become better understood, similar to norepinephrine, is taken up by the norepiparticularly with respect to children. nephrine transporter system into intracytoplasmic Pheochromocytoma is an uncommon tumor of childvesicles. Radionuclide imaging is achieved by labeling hood, and there are several characteristics that distinguish

CHAPTER

Incidence Familial pattern (%) Bilateral (%) Extra-adrenal site (%) Malignant (%)

Pediatric

Adult

1:500,000 10 24-70 30 3

1:50,000 2-3 10 10 10

it from its adult counterpart. The incidence of pheochromocytoma in childhood is 10% of the adult incidence, occurring in approximately 1 in 500,000 chiidren compared with 1 in 50,000 adults.34Approximately 10% of childhood pheochromocytomas are familial, which is about four times the frequency in adults. Whereas only 7% of pheochromocytomas are bilateral in adults, the reported incidence of bilateral pheochromocytomas in children ranges from 24% to as high as 70%. Extra-adrenal pheochromocytomas are approximately twice as prevalent . ~ ~ 38-1). in children compared with a d ~ l t s l l(Table Pheochromocytomas originate from medullary chromaffin cells, which produce the catecholamines that cause the symptoms of the tumor. These cells migrate along the aorta, usually remaining near the branches off the aorta.

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can also be measured by radioenzyme assay. However, patients must remain supine and calm during the blood draws, which can be difficult in children. Patients with normal plasma catecholamine levels during a hypertensive episode probably do not have pheochromocytoma, but levels greater than 2000 pg/mL are diagnostic of pheochre mocytoma. Plasma catecholamine levels between 500 and 1000 pg/mL are suspicious for a pheochromocytoma, and further testing is After obtaining the chemical diagnosis of pheochromocytoma, the tumor must be localized. Although large masses such as a neuroblastoma can be seen on plain abdominal films, most adrenal masses cannot be visualized without the use of other imaging methods. Almost all pheochromocytomas occur in the abdomen or pelvis, and although the adrenal gland is the most common site, up to 43% of children may have multifocal disease."?he initial study in infants and children is often US, which can be useful in distinguishing between solid and cystic masses but may not visualize small adrenal lesions. CT and MRI offer the advantage of much better resolution and sensitivity, particularly MRI (Fig. 38-1). Another useful

Symptoms In children with pheochromocytoma, the average age at presentation is 11 years, although the tumor can occur at any age. Over half the children present with headaches, fever, palpitations, thirst, polyuria, sweating, nausea, and weight loss, but the most common presentation is sustained hypertension.4.34.36 In children, most causes of hypertension are secondary, with renal abnormalities being most common (78%),followed by renal artery disease (12%), and coarctation of the aorta (2%).23 Pheochromocytoma accounts for 0.5% of children with hypertension and must be considered once other causes are eliminated. In children with pheochromocytoma, hypertension is sustained in up to 70% to 90% of cases, with only a small minority presenting with paroxysmal hypertension. In contrast, up to 50% of adults with pheochromocytorna have paroxysmal h y p e r t e n ~ i o n . ~ ~

Diagnosis The diagnosis of pheochromocytorna relies on elevated levels of blood and urinary catecholamines and their metabolites. A 24hour urine measurement of catecholamines, metanephrine, and vanillylmandelic acid is the best diagnostic test.l8,4Wrinary metanephrine levels are increased in about 95% of patients, and urinary vanillylmandelic acid and catecholamine levels are increased in approximately 90% of p a t i e n t ~ ~ q h eisr ealso a linear relationship between the amount of vanillylmandelic acid and the size of the pheochromocytoma.l~henormal 24hour urinary secretion is less than 100 mg for free catecholamines, less than 7 mg for vanillylmandelic acid, and less than 1.3 mg for metanephrine. Plasma catecholamines

B

- A, Computed tomography of the abdomen in a 10-year-old girl with a left adrenal mass associated with hypertension. B, Magnetic resonance image demonstrates a left adrenal pheochrome cytoma. No other masses were noted. No contrast agent was required.

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imaging technique is '-1-labeled MIBG scanning; this radioisotope accumulates where norepinephrine is taken up and allows detection of the tumor. This can be particularly useful in localizing extra-adrenal pheochromocytomas, but this location is rare in the pediatric population. The head and neck may be a more common site of these tumors in children compared with adults, followed by the retroperitoneum.4'

Treatment The treatment of pheochromocytoma is surgical excision, but medical management is an essential part of the preoperative preparation. The high levels of catecholamines increase the risk of sudden and severe intraoperative hypertension, as well as profound hypotension once the tumor is removed and catecholamine release has ceased. In fact, these complications accounted for the high mortality rate associated with surgical resection in the past.36 Improvements in preoperative and intraoperative management have reduced the operative mortality from 24% to 45% in the past to less than 10% today.9 Preoperative use of a-adrenergic blockers such as phenoxybenzamine and phentolamine minimizes the effects of epinephrine and norepinephrine by blocking the a-adrenergc recep tors. These agents should be used at least 3 to 7 days before the procedure to minimize the intraoperative risks. P-Adrenergic blockade with agents such as proprano101 and labetalol may be used once an a-adrenergic blockade is achieved, particularly if a resting tachycardia develops. If these agents are used, it is crucial that a-blockade be established first. Patients with pheochromocytomas tend to be slightly hypovolemic at baseline, with an average 15% reduction in plasma volume. As the pharmacologic blockade is established preoperatively, it may be necessary to administer intravenous fluid replacement. This volume re-expansion also helps minimize intraoperative blood pressure fluctuations and cardiac arrhythmias. Despite good preoperative normalization of blood pressure, the anesthesiologst must be prepared for sudden fluctuations. The times of significant intraoperative risk are during anesthetic induction and intubation, during surgical manipulation of the tumor, and immediately following ligation of the tumor's venous drainage.7 An arterial catheter and a central venous line are crucial for monitoring intraoperative blood pressure and fluid status. The anesthesiologist must also be prepared to use fastacting agents to raise or lower blood pressure as needed. Sodium nitroprusside and nitroglycerin are useful agents, as are vasopressors and intravenous fluids. Cardiac arrhythmias can be managed with the use of propranolol, esmolol, and lidocaine. The traditional operative approach uses a transabdominal incision, usually subcostal. Through this incision, both adrenal glands can be visualized, as well as the periaortic sympathetic ganglia, the small bowel mesentery, and the pelvis. More than 95% of pediatric pheochromocytomas are located in the abdomen, and this approach reveals the majority of tumors. The surgeon must make a conscious effort to minimize direct manipulation of the tumor during dissection. Early control and ligation of

the adrenal vein limit the release of catecholamines as the tumor is removed. The surgeon can expose the right adrenal gland by reflecting the transverse colon inferiorly and mobilizing the duodenum medially. This exposes the upper portion of the right kidney as well as the right adrenal gland. Reflecting the liver superiorly and rolling the lateral border of the inferior vena cava medially expose the adrenal gland further. There is a greater risk of hemorrhage on the right side than on the left, owing to the shorter length of the right adrenal vein and the greater risk of tearing this vessel. The surgeon can expose the left adrenal gland by incising the peritoneum lateral to the splenic flexure and mobilizing the colon in a medial direction. The perirenal fascia can then be incised, exposing the left adrenal gland. Alternatively, the surgeon can divide the gastrocolic ligament, mobilizing the stomach superiorly and the transverse colon inferiorly. The posterior peritoneum along the inferior pancreatic border can then be incised, allowing mobilization of the pancreatic tail and exposure of the adrenal vein. An adrenal pheochromocytoma is typically encapsulated, and although there may be small amounts of normal adrenal tissue, the entire adrenal gland should be removed. It is rarely necessary to perform a nephrectomy because the tumor is usually not adherent to the kidney. As previously mentioned, once the adrenal vein is ligated and the tumor is removed, the patient may become hypotensive due to the removal of the catecholamine excess. In fact, it may be several days before the blood pressure normalizes. If hypertension returns postoperatively, one should suspect a second pheochromocytoma. All patients should undergo follow-up to confirm normalization of catecholamine levels. Long-term follow-up is indicated because of the possibility of a metachronous occurrence of a multifocal p h e o c h r o m o ~ y t o m a . ~ ~ ~

Associated Disorders Familial pheochromocytomas may occur in the setting of several syndromes. The most common syndromes are multiple endocrine neoplasia type 2 (MEN-2) and von Hippel-Lindau disease. There is a smaller incidence of familial pheochromocytomas in patients with neurofibromatosis type 1 and in patients without any other abnormalities. MEN-2 is an autosomal dominant disorder caused by a mutation of the RETproto-oncogene on chromosome 10. These patients are at risk for medullary thyroid carcinoma, and up to 50% will develop adrenal pheochromocytoma. These tumors are almost always bilateral and are almost never malignant. Patients with MEN-2A are also at risk for hyperparathyroidism, and patients with MEN-2B may have a marfanoid habitus or mucosal ganglioneuromas. A mutation of the von Hippel-Lindau gene on chromosome 3 leads to von Hippel-Lindau disease. This condition is characterized by retinal angiomas, hemangioblastomas of the central nervous system, renal cysts, renal cell carcinoma, pancreatic cysts, and pheochromocytomas. These pheochromocytomas are often multifocal and are frequently extra-adrenal (Fig. 38-2).

CHAPTER

A

-

38

Adrenal T u m o r s

633

B

-

A, Relatively small extra-adrenal pheochromocytoma that arose from a paraspinal sympathetic ganglion i n a 13-year-old girl who experienced paroxysmal hypertension and severe headache while horseback riding. B, T h e operative field after tumor excision shows the vena cava and aortic bifurcation. A vessel loop is around the ureter.

Malignancy Histologic examination of a pheochromocytoma cannot accurately determine malignancy, which has been reported to occur in up to 10% of children with this tumor.4 The diagnosis of a malignant pheochromocytoma often relates to the tumor's clinical behavior. A malignant pheochromocytoma may have local infiltration or distant metastasis, which most commonly occurs in bone, liver, lymph nodes, lung, and central nervous system. Synchronous or metachronous pheochromocytomas may present anywhere along the sympathetic chain. Although surgical resection remains the treatment of choice, longterm palliation may be obtained through a multimodal approach including local excision, radiation, and chemotherapy."

Age less than 3.5 years at the time of diagnosis and symptom duration of less than 6 months before diagnosis are favorable prognostic indicators in adrenocortical carcinoma. Early detection is essential in these children, because a delay in diagnosis adversely affects clinical outcome.so Adrenocortical tumors are associated with several congenital anomalies, including hemihypertrophy; other tumors associated with hemihypertrophy include nephre blastoma and hepatoblastoma. Patients with BeckwithWiedemann syndrome (exomphalos, macroglossia, and gigantism) also have a higher than expected incidence of adrenocortical carcinoma.Y1Most adrenocortical tumors, however, occur s p ~ r a d i c a l l y . ~ ~

Cushing's Syndrome

In 1932 Cushing first described the syndrome that bears his name in a patient with a pituitary adenoma. Since LESIONS OF THE ADRENAL CORTEX that time, the understanding of the pathophysiology and cause has expanded considerably. Adrenocortical neoplasms are rare in the pediatric popEndogenous Cushing's syndrome is a rare condition ulation, accounting for less than 0.2% of all pediatric in the pediatric population. In general, the incidence of .~ tumors and 6% of all adrenal tumors in ~ h i l d r e n The spontaneous Cushing's syndrome is approximately 5 per incidence of these neoplasms has been reported to be million population; it occurs primarily in young adult approximately 25 cases per year in the United States, of which about 75% are adrenocortical ~arcinomas.3"~~women, with a female-male ratio of 9:l. Ten percent of cases occur in children and adolescent^.^^ Adrenocortical tumors occur more frequently in girls, The typical manifestation of Cushing's syndrome in chilwith a male-female ratio of approximately 1:2 to 1:3.z6Like dren is generalized obesity and long bone growth pheochromocytomas, adrenocortical neoplasms behave retardation.Z4Other symptoms include hypertension, weakdifferently in children than in adults. Approximately ness, thin skin with striae and easy bruising, acne, menstrual 85% to 95% of these tumors are hormonally active in irregularity, osteoporosis, and glucose intolerance. Unlike children, compared with less than 50% in adult^.^,'^ in adults with Cushing's syndrome, muscle weakness, sleep Further, whereas there are clear pathologic criteria for disturbances, and mental changes such as emotional labilmalignancy in the adult population, these guidelines do ity, irritability, or depression are rare in children.Y4 not always hold true in the pediatric population. Because CRH is secreted by the hypothalamus and is the the clinical behavior of these tumors does not always most potent stimulator of ACTH release from the antecorrelate with the pathologic appearance, the diagnosis rior pituitary. ACTH then stimulates the production of of malignancy should be based on clinical behavior.

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glucocorticoids, mineralocorticoids, and sex hormones from the adrenal cortex. Cushing's syndrome can be divided into ACTH-dependent and ACTH-independent types. In the former condition, the inappropriately high ACTH levels stimulate the adrenal cortex to produce excessive cortisol. In the ACTH-independent type, abnormal adrenal tissue produces excessive cortisol irrespective of ACTH levels. Cushing's disease refers to Cushing's syndrome caused by pituitary tumors that lead to excessive ACTH production. Typically, these tumors are microadenomas and are less than 1 cm in diameter; however, large, invasive pituitary adenomas may develop. These tumors lead to bilateral adrenocortical hyperplasia, with a corresponding glucocorticoid excess. As the age of the patient increases, there is a greater likelihood of a pituitary cause of the syndrome. In patients younger than 6 years, the most likely cause of endogenous Cushing's syndrome is an adrenal tumor.

Although adrenocortical carcinomas represent only 0.2% of all childhood malignancies and 6% of adrenal cancers, approximately 60% to 80% of pediatric Cushing's syndrome cases are caused by adrenocortical carcinomas." The clinical diagnosis of hypercortisolism must be confirmed biochemically to diagnose Cushing's syndrome. In addition, the specific source of the syndrome must be localized (Fig. 38-3). Because the normal circadian rhythm of cortisol secretion is lost in Cushing's syndrome, random serum cortisol levels are of limited value. Screening with morning and evening serum cortisol levels to assess diurnal variation has a low sensitivity. Instead, the 24hour urinary free cortisol level is the best way to diagnose hypercortisolism, with a sensitivity of approximately %%.I6 In children, this value must be corrected for size. A normal value is less than 70 pg/m2 per day; this is elevated with Cushing's syndrome. Another useful test is the 24hour urinary 17-hydroxysteroid excretion; this is an indirect measure of cortisol secretion and

Diagnostic Studies to Localize Hypercortisolism

el 00 pglday

Repeat test

>5 pg/mL

<5 pgImL

JI

\Ir

ACTH-independent causes

ACTH-dependent causes

dexamethasone Ratio < 2 (No suppression)

Ratio >2 (Suppression)

No mass or nodules

Dominant mass

v Ectopic ACTH-secretion

.

.

Cushing's disease Adenocarcinoma

Algorithm to localize the cause of hypercortisolism in children with suspected Gushing's syndrome. ACTH, adrenocorticotropic hormone; CT, computed tomography.

CHAPTER

is elevated with hypercortisolism. Once it is corrected for creatinine excretion, the normal value is between 2 and 7 mg per gram of creatinine per day. Another useful screening test is the overnight 1-mg dexamethasone suppression test (or 0.3 mg/m2 in children). After the administration of dexamethasone, a morning cortisol level above 5 pg/dL indicates unsuppressed cortisol secretion consistent with Cushing's syndrome. Once the diagnosis of Cushing's syndrome has been established, the next step is to determine the underlying cause of the hypercortisolism. As shown in Figure 38-3, measurement of the ACTH level can distinguish between ACTH-dependent and ACTH-independent causes. If the ACTH level is greater than 5 pg/mL, the source is ACTH dependent; if the level is less than 5 pg/mL, it is ACTH independent. ACTHdependent causes of hypercortisolism include both pituitary and ectopic ACTH-secreting neoplasms. Although ectopic production of ACTH is rare in children, Wilms' tumors and tumors of the thymus, pancreas, or neural tissue can produce ACTH. Most patients with ACTH-secreting tumors have Cushing's disease (Cushing's syndrome caused by a pituitary tumor). Although a highdose dexamethasone suppression test or an inferior petrosal sinus sampling can distinguish a pituitary source from an ectopic source, MRI can also show a pituitary tumor. An ectopic tumor producing CRH is another ACTHdependent source of Cushing's syndrome, but this condition has not been reported in children.3J" In both adults and children, the treatment of choice for Cushing's disease is a transsphenoidal resection of the pituitary adenoma. In patients with no postoperative improvement or with recurrence, some response may be obtained with pituitary irradiation using cobalt 60. If an ectopic ACTH-secreting tumor is indicated by the workup, the patient must undergo screening for medullary carcinoma of the thyroid (serum calcitonin levels) and screening for pheochromocytoma (24hour urine measurement of catecholamines, metanephrine, and vanillylmandelic acid). Other ectopic locations such as a bronchial, thymic, or intestinal carcinoid tumor may be seen on CT of the chest and abdomen. Ectopic ACTH-producing tumors should be resected if possible. If resection is not possible, bilateral adrenalectomy can offer an effective treatment of Cushing's syndrome. ACTH-independent causes of Cushing's syndrome include adrenal neoplasms and nodular adrenal hyperplasia. ACTH-independent Cushing's syndrome is relatively more frequent in children than in adults.l"n children, an adrenocortical tumor most frequently occurs in the setting of a virilizing syndrome, and the majority of children present with virilizing symptoms. Approximately 33% of these patients have Cushing's syndrome; less than 10% present with isolated Cushing's syndrome without any virilizing signs.28.3" Nodular adrenal hyperplasia is a rare condition that occurs in children and young adults. This disease usually presents in the first 2 decades of life, predominantly in girls. Although this entity can occur sporadically, many cases are familial and appear in an autosomal dominant fashion.lVhe adrenal glands contain multiple nodules approximately 3 to 5 mm in size. Histologic examination

38

Adrenal Tumors

635

reveals lymphocytic infiltration of the cortex, suggesting an autoimmune cause of the disorder. The treatment of this cause of Cushing's syndrome is bilateral adrenalectomy.16 This procedure is associated with significant morbidity rates and requires permanent postoperative mineralocorticoid and glucocorticoid replacement.

Sex Hormone-ProducingTumors An adrenocortical lesion may lead to either a virilizing or a feminizing tumor. As previously mentioned, most adrenocortical tumors in children are hormonally active. Virilization with or without hypercortisolism is the most These virilizing tumors common pre~entation.22~2~~~0~45 may be more difficult to recognize in boys than in girls. Boys may present with precocious puberty, including penile enlargement, acne, and premature development of pubic, axillary, and facial hair. Girls may develop clitoral hypertrophy, hirsutism, and acne (Fig. 38-4). The treatment of choice is adrenalectomy. Although feminizing adrenocortical tumors are rare in children, they are usually malignant. In the normal adrenal gland, very small amounts of estrogens may be secreted. With adrenocortical tumors, however, overproduction of estrogens, particularly estradiol, may occur. In girls, these tumors present with precocious isosexual development, including early breast enlargement, accelerated growth, and advanced bone age. In boys, these tumors cause bilateral gynecomastia, accelerated growth rate, and delayed pubertal development; there is also an absence of spermatogenesis.

Treatment of Adrenocortical Tumors Surgical resection is the mainstay of treatment for adrenocortical tumors. The treatment of choice for a benign adrenal adenoma is adrenalectomy. Adrenocortical carcinomas, however, require a wide excision with adequate abdominal exploration for metastatic disease. In either case, postoperative steroid replacement is typically required until the contralateral gland can recover from its suppression. CT or MRI can help distinguish between adrenal hyperplasia and an adrenal tumor. An NP-59 scintiscan may aid in the evaluation of an adrenal lesion. Adrenal adenomas usually have an increased uptake of NP-59, whereas adrenocbrtical carcinomas typically do not take up the isotope. Bilateral uptake of NP-59 indicates bilateral adrenal hyperplasia, which can be the result of ACTH oversecretion. The most common sites of metastatic adrenocortical carcinomas are the lung, liver, lymph nodes, contralatera1 adrenal gland, bones, kidneys, and brain. If complete resecGon is not possible, tumor debulking may be of some benefit. Medical therapy with mitotane may also play a role in treating patients with unresectable disease. Mitotane acts as an adrenolytic agent by altering mitochondria1 function, blocking adrenal steroid hydroxylation, and altering the extra-adrenal metabolism of cortisol and androgens. The success of chemotherapy

636

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III

MATORTUMORS OF CHII.DHOOD

A, This 3-year-old girl presented with a large right upper quadrant mass. B, She was noted to have pubic hair. C, The mass was a virilizing adrenocortical carcinoma. Despite complete excision and treatment with chemotherapy, the child developed metastases and eventually succumbed.

has not been clearly shown, however, and complete surgical resection is the only treatment that makes a significant difference in terms of sunival.31

HYPERALDOSTERONISM Overproduction of aldosterone, or hyperaldosteronisrn, may be due to either adrenal dysfunction or overproduction of renin. Primary hyperaldosteronism refers to adrenal dysfunction, such as an aldosterone-secreting tumor or bilateral adrenal hyperplasia. Secondary hyperaldosteronism refers to an overproduction of renin, which can be caused by cirrhosis, congestive heart failure, a renin-producing juxtaglomerular cell tumor, or renovascular abnormalities such as renal artery stenosis. The symptoms of hyperaldosteronisrn include headaches, fatigue, weakness, lethargy, poor weight gain, polyuria, polydipsia, and nocturia. Hypertension develops as a result of increased sodium and water reabsorption. Weakness occurs due to hypokalemia, which is the most common laboratory finding, although metabolic alkalosis may be observed from the loss of hydrogen ions in the urine. The biochemical diagnosis of hyperaldosteronisrn is demonstrated by excessive aldosterone secretion in the setting of suppressed renin secretion. Once the diagnosis of primary hyperaldosteronism has been established,

patients with aldosterone-secreting adrenal tumors must be distinguished from those with the more common condition of bilateral adrenocortical hyperplasia. In patients with bilateral adrenocortical hyperplasia, dexamethasone administration normalizes the abnormally high aldosterone level and low renin level.43 In the pediatric population, the incidence of aldosteronoma, or an adrenal adenoma causing primary hyperaldosteronism, is extremely low. There are only a handful of reported cases in the literature. As previously mentioned, the more common cause of primary hyperaldosteronism is bilateral cortical hyperp1asia.l An aldosteronoma is best treated by unilateral adrenalectomy. Patients with bilateral adrenocortical hyperplasia do not respond well to surgical treatment and are best managed with medical therapy using spironolactone and a m i l ~ r i d e Adrenal .~~ insufficiency resulting from bilateral adrenalectomy is more difficult to manage than hyperaldosteronism.

ADDISON'S DISEASE Insufficient production of steroid hormones (either glucorticoids or mineralocorticoids) can lead to Addison's disease. Children with Addison's disease present with a variety of symptoms, including weakness, anorexia, weight loss, fatigue, nausea, vomiting, and diarrhea.

CHAPTER

If the child has an elevated ACTH level, hyperpigmentation will develop, because melanocytes are stimulated by ACTH. Seizures may also occur in the setting of the hypoglycemia, which occurs with adrenal crisis. There are manv causes of adrenal insufficiencv in children. Congenital adrenal hypoplasia can result from either an autosomal recessive disorder or an X-linked disorder that occurs in boys. Errors in steroid metabolism can also lead to adrenal insufficiency. The most common group of inborn errors involves defects in glucocorticoid synthesis and is collectively known as congenital adrenal hyperplasia. Acquired lesions involving the hypothalamus or pituitary can also lead to adrenal insufficiency through a reduction in CRH or ACTH secretion. Destruction of the adrenal glands can also lead to adrenal insufficiency. Conditions causing adrenal demise include hemorrhage, infection, adrenoleukodystrophy, and autoimmune diseases. In older patients, overwhelming infection can lead to adrenal hemorrhage. Tuberculosis used to be a common cause of infectious adrenal destruction; however, the incidence of this condition has fallen in modern times. One of the more common causes of acute adrenal insufficiency is cessation of chronic exogenous glucocorticoid administration. In newborns, adrenal hemorrhage is not an uncommon event. In fact, the adrenal gland is the second most common source of hemo~eritoneum in the newborn period." The pathogenesis of adrenal hemorrhage in newborns is not fully understood. Associated factors include traumatic delivery, asphyxia, maternal hypotension, over~3~ whelming infection, or hemorrhagic d i s o r d e r ~ . l ~The incidence of adrenal hemorrhage is almost 2 cases per 1000 live births,gObut as the sensitivity of imaging technology improves, this number may increase. Adrenal hemorrhage occurs three to four times more frequently in the right adrenal gland than the left and is bilateral in 8% to 10% of patients.I"his bias toward the right side may be due to the direct drainage of the right adrenal gland into the inferior vena cava, making the right gland more susceptible to changes in venous pressure. The left gland remains somewhat protected by its drainage into the left renal vein. The fetal cortex contributes to fetal and neonatal adrenal hemorrhage due to both its size and its later involution. The large size of the fetal cortex makes the adrenal glands relatively large, increasing the vulnerability to trauma. The physiologic involution of the fetal cortex may occur quite rapidly, tearing the unsupported central adrenal gland vessels.39 On prenatal US, adrenal hemorrhage appears as an echogenic mass. This mass becomes increasingly hypoechoic and usually involutes on subsequent sonograms. The lesion may completely resolve, leaving only residual calcifications. However, the lesion mav not resolve, and surgical resection may 'be necessary t& differentiate the mass from a cystic neuroblastoma. The treatment of Addison's disease is replacement of the deficient steroid hormone. This may be accomplished with a mineralocorticoid such as fludrocortisone or a glucocorticoid such as hydrocortisone or prednisone. During periods of acute stress, such as infection or operation, increased doses of glucocorticoids are needed.

38

Adrenal Tumors

637

INCIDENTAL ADRENAL MASS The incidental discovery of adrenal lesions on imaging studies performed for other reasons has been increasing in both children and adults, perhaps due to the increased frequency of imaging studies being performed and the increased sensitivity of those imaging modalities. In adults, the current recommendation is to remove all hormonally active tumors regardless of size. In the case of nonfunctional adrenal masses, it is considered the safe to observe a mass less than 4 cm in ~ize.2~~~.2"n pediatric population, however, there are no clear guidelines about incidental, nonfunctional adrenal masses. Owing to the higher incidence of both functional tumors and malignant tumors in the pediatric adrenal gland, many surgeons recommend adrenalectomy in this setting.2"

ADRENALECTOMY The objective of adrenal surgery is to attain complete tumor resection, resulting in normalization of endocrine function and cure of malignancy. Perioperative planning includes correction of potential electrolyte abnormalities, establishing alpha and beta blockade in the case of pheochromocytoma, and performing localizing studies to guide the surgical approach. The surgical approach is based on the probable histology of the adrenal mass, the presence of bilaterality, and the surgeon's preference. The introduction of laparoscopic adrenal resection has provided an attractive alternative for the resection of many adrenal masses in children. Traditional approaches to adrenal resection have included anterior, posterior, and thoracoabdominal approaches. The anterior approach to adrenalectomy permits resection of either the left or the right adrenal gland. It also allows bilateral resection through a single incision. During the anterior approach to right adrenalectomy, the duodenum is mobilized by the Kocher maneuver (Fig. 38-5). Gerota's fascia is opened, and the right lobe of the liver is retracted in a cephalad direction. The most important element of the procedure is the dissection between the medial border of the adrenal mass and the lateral wall of the inferior vena cava. This plane is developed in a cephalad direction until the relatively short right adrenal vein is identified entering the vena cava. Multiple veins may be present and should be identified to prevent accidental avulsion. During the anterior approach to the left adrenal gland, the initial maneuver is to mobilize the splenic flexure of the colon. The pancreas and spleen are retracted superiorly, and Gerota's fascia is opened. The left adrenal vein enters the renal vein superiorly and can be ligated in this plane. Several arteries enter the medial surface of the adrenal gland from the lateral side of the aorta; these arteries need to be divided before adrenal removal. The posterior approach to the adrenal gland is accomplished most commonly through the bed of the 11 th rib. This strategy avoids intraperitoneal dissection, eliminates postoperative adhesions, and decreases postoperative ileus. The posterior approach is not useful for bilateral adrenal lesions,

638

PART

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M A ~ OTUMORS R OF CHII.DHOOD

cava / ,\

-

Adrenal tumor

.

Transabdominal approach to tnrnors of the adrenal glands. A, The right adrenal gland is exposed by reflecting the transverse mesocolon inferiorly, mobilizing the duodenum rnedially with a Kocher maneuver, and incising the posterior fascia to expose the diaphragm, adrenal gland, and superior pole of the right kidney. B, The left adrenal gland is exposed by dividing the gastrocolic ligament and elevating the stomach. The colon is retracted inferiorly, and the pancreas is elevated, exposing the adrenal gland and left adrenal vein that enters the renal vein.

malignancies, or large vascular tumors. The thoracoabdominal approach to adrenalectomy is best applied to very large unilateral lesions. Although this approach provides optimal exposure of large vascular tumors, postoperative pain and impairment of ventilation limit its application. The first laparoscopic adrenalectomy was reported in an adult in 1991.'2 Since then, a number of studies involving laparoscopic adrenalectomy in children have 2~ the feasibility and been p ~ b l i s h e d , ' ~ ,demonstrating safety of this approach. Most commonly, laparoscopic adrenalectomy is performed with the patient in the lateral position. A kidney rest elevates the flank opposite the adrenal lesion. Four or five trocars are placed in a subcostal position on the side of the adrenal gland to be resected. Exposure is improved on the right side by dividing the right triangular ligament of the liver. Division of the lienocolic ligament on the left improves exposure of the left adrenal gland. When possible, the adrenal vein is

ligated with clips at the initial point of dissection. The adrenal specimen should be removed in a specimen bag because of the potential for malignancy. Most adrenal lesions in children are small and benign, making laparoscopic resection an appropriate choice in the majority of cases. Although no absolute contraindications to lapare scopic resection exist, an open approach should be considered in patients with large tumors, malignancies with potential lymph node involvement, and highly vascular pheochromocytomas.

REFERENCES, 1. Aganvala S, Mitra DK, Bhatnagar V, et al: Aldosteronoma in childhood: A review of clinical features and management. J Pediatr Surg 1994;29:1388-1391. 2. Arnaldi G, Masini AM, Giachetti G, et al: Adrenal incidentaloma. BrazJ Med Biol Res 2000;33:1177-1189.

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3. Bickler SW, McMahon TJ, Campbell JR, et al: Preoperative diagnostic evaluation of children with Gushing's syndrome. J Pediatr Surg 1994;29:671-676. 4. Caty MG, Coran AG, Geagan M, Thompson NW: Current diagnosis and treatment of pheochrornocytoma in children: Experience with 22 consecutive tumors in 14 patients. Arch Surg 1990;125:978-981. 5. Chudler RM, Kay R: Adrenocortical carcinoma in children. Urol Clin North Am 1989;16:469-479. 6. Ciftci AO, Senocak ME, Tanyel FC, et al: Adrenocortical tumors in children. J Pediatr Surg 2001;36:549-554. 7. Ein SH, Pullerits J, Creighton R, Balfe JW: Pediatric pheochrornocytoma: A 3Gyear review. Pediatr Surg Int 1997; 2:595-598. 8. Ein SH, Weitzman S, Thorner P, et al: Pediatric malignant pheochrornocytoma. J Pediatr Surg 1994;29:1197-1201. 9. Ellis D, Gartner JC: The intraoperative medical management of childhood pheochrornocytoma. J Pediatr Surg 1980;15:655-659. 10. Farndon JR, Davidson HA, Johnston ID, Well SA Jr: VMA excretion in patients with pheochrornocytoma. Ann Surg 1980;191:259-263. 11. Fonkalsrud EW: Pheochromocytoma in childhood. Prog Pediatr Surg 1991;26:103-111. 12. Gagner M, LaCroix A, Bolte E: Laparoscopic adrenalectomy in Cushing's syndrome and pheochrornocytoma. N Engl J Med 1992;327:1033. 13. Grumbach MM, Biller BM, Braunstein GD, et al: Management of the clinically inapparent adrenal mass ("incidentaloma"). Ann Intern Med 2003;138:424429. 14. Hume DM: Pheochromocytoma in the adult and in the child. Am J Surg 1960;99:458-496. 15. Ilias I, Pacak K: Current approaches and recommended algorithm for the diagnostic localization of pheochromocytoma. J Clin Endocrinol Metab 2004;89:479-491. 16. Jones KL: The Cushing syndromes. Pediatr Clin North Am 1990;37:1313-1332. 17. Kadamba P, Habib Z, Rossi L: Experience with laparoscopic adrenalectomy in children. J Pediatr Surg 2004;39:764767. 18. Kaufman BH, Telander RL, vanHeerden JA, et al: Pheochromocytoma in the pediatric age group: Current status. J Pediatr Surg 1983;18:879-884. 19. Khuri FJ, Alton DJ, Hardy BE, et al: Adrenal hemorrhage in neonates: Report of 5 cases and review of the literature. J Urol 1980;124:684687. 20. Krestin GP, Steinbrich W, Friedmann G, et al: Adrenal masses: Evaluation with fast gradient-echo MR imaging and Gd-DTPA-enhanced dynamic studies. Radiology 1989; 171:675-680. 21. Lack EE, Mulvihill JJ, Travis WD, Kozakewich HP: Adrenal cortical neoplasms in the pediatric and adolescent age group: Clinicopathologic study of 30 cases with emphasis on epidemiological and prognostic factors. Pathol Annu 1992; 27(Pt 1):l-53. 22. Lee PD, Winter RJ, Green OC: Virilizing adrenocortical tumors in childhood: Eight cases and a review of the literature. Pediatrics 1985;76:437-444. 23. Londe S: Causes of hypertension in the young. Pediatr Clin North Am 1978;25:55-65. 24. Magiakou MA, Mastorakos G, Oldfield EH, et al: Cushing's syndrome in children and adolescents: Presentation, diagnosis, and therapy. N Engl J Med 1994;331:629-636.

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25. Masiakos PT, Gerstle JT, Cheang T, et al: Is surgery necessary for incidentally discovered adrenal masses in children? J Pediatr Surg 2004;39:754758. 26. Mayer SK, Oligny LL, Deal C, et al: Childhood adrenocortical tumors: Case series and reevaluation of prognosisa 24year experience. J Pediatr Surg 1997;32:911-915. 27. Meyer JS: Retroperitoneal MR imaging in children. Magn Reson Imaging Clin North Am 1996;4:657-678. 28. Michalkiewicz E, Sandrini R, Figueiredo B, et al: Clinical and outcome characteristics of children with adrenocortical tumors: A report from the International Pediatric Adrenocortical Tumor Registry. J Clin Oncol 2004;22: 838-845. 29. Miller KA, Albanese C, Harrison M, et al: Experience with laparoscopic adrenalectomy in pediatric patients. J Pediatr Surg 2002;37:979-982. 30. Nadler EP, Barksdale EM: Adrenal masses in the newborn. Semin Pediatr Surg 2000;9:156-164. 31. Ng L, Libertino JM: Adrenocortical carcinoma: Diagnosis, evaluation and treatment. J Urol 2003;169:5-11. 32. Pacak K, Eisenhofer G, Carrasquillo JA, et al: Diagnostic localization of pheochrornocytoma: The coming of age of positron emission tomography. Ann N Y Acad Sci 2002; 970:170-176. 33. Petrus LV, Hall TR, Boechat MI, et al: The pediatric patient with suspected adrenal neoplasm: Which radiological test to use? Med Pediatr Oncol 1992;20:53-57. 34. Reddy VS, O'Neill JA Jr, Holcomb GW 111, et al: Twentyfive-year surgical experience with pheochrornocytoma in children. Am Surg 2000;66:1085-1091. 35. Ribeiro RC, Michalkiewicz EL, Figueiredo BC, et al: Adrenocortical tumors in children. Braz J Med Biol Res 2000;33:1225-1234. 36. Ross JH: Pheochromocytoma: Special considerations in children. Urol Clin North Am 2000;27:393-402. 37. Shulkin BL, Thompson NW, Shapiro B, et al: Pheochromocytomas: Imaging with 2-[fluorine-18lfluoro2-deoxy-D-glucosePET. Radiology 1999;212:35-41. 38. Siege1 MJ: MR imaging of the pediatric abdomen. Magn Reson Imaging Clin North Am 1995;3:161-182. 39. Skandalakis J, et al: The suprarenal glands. In Skandalakis J, Gray S: Embryology for Surgeons, 2nd ed. Baltimore, Williams & Wilkins, 1994. 40. Stewart JN, Flageole H, Kavan P: A surgical approach to adrenocortical tumors in children: The mainstay of treatment. J Pediatr Surg 2004;39:759-763. 41. Teele R: Abdominal masses. In Share J, Teele R: Ultrasonography of Infants and Children. Philadelphia, WB Saunders, 1991. 42. Tekautz TM, Pratt CB, Jenkins JJ, Spunt SL: Pediatric extraadrenal paraganglioma. J Pediatr Surg 2003;38: 1317-1321. 43. Telander RL, Zimmerman D, Kaufman BH, vanHeerden JA: Pediatric endocrine surgery. Surg Clin North Am 1985;65:1551-1587. 44. Welbourn RB: Early surgical history of phaeochromocytoma. Br J Surg 1987;4:594596. 45. Wieneke JA, Thompson LD, Heffess CS: Adrenal cortical neoplasms in the pediatric population: A clinicopathologic and immunophenotypic analysis of 83 patients. Am J Surg Pathol 2003:27:867-881.

Tumors of the Lung Stephen J. Shochat

The majority of pulmonary neoplasms in children are due to metastatic disease; however, primary pulmonary tumors of the lung do occur in the pediatric age group. The approximate ratio of primary pulmonary tumors to metastatic neoplasms and non-neoplastic lesions of the lung is 1:5:60.'"15 Although primary pulmonary tumors are rare in children, the majority of these tumors are malignant. In a review of 383 primary pulmonary neoplasms in children by Hancock et al.>9 76% were malignant and 24% were benign. This incidence is similar to that previously reported by Hartman and Shochat.31 Table 39-1 demonstrates the variety of primary pulmonary neoplasms seen in children. This chapter addresses the more common benign and malignant pri-

mass starting as a focus of organized pneumonia with a tendency for local invasion. Extension of the tumor beyond the confines of the lung is common. At least four deaths have been reported due to tracheal obstruction or involvement of the mediastinum by massive lesions. Treatment consists of a conservative pulmonary resection with removal of all gross disease if possible. Primary hilar adenopathy may be present, and local invasion with disregard for tissue planes mimics malignancy. A frequent problem is identifying the benign nature of these masses.

Type of Tumor

BENIGN TUMORS

Plasma Cell Granuloma (Inflammatory Pseudotumor) Plasma cell granuloma has also been called inflammatory myofibroblastic tumor, fibroxanthoma, histiocytoma, and fibrohistiocytoma. This lesion, which is seen frequently in adults, occurs rarely in children younger than 10 years (approximately 8% of cases). However, plasma cell granuloma is the most common benign tumor in children and accounts for slightly more than 50% of all benign lesions and approximately 20% of all primary lung tumors.31These tumors usually present as peripheral pulmonary masses but occasionally present as polypoid endobronchial turn or^.^^^ The pathogenesis of plasma cell granuloma is not well understood, but an antecedent pulmonary infection has been reported in approximately 30% of cases. The mean age at presentation in children is 7 years, and 35% of the children Many children are between 1 and 15 years of age.2,5,81 are asymptomatic at the time of presentation, but fever, cough, pain, hemoptysis, pneumonitis, and dysphagia may be present. The natural history is that of a slow-growing

Benign (n = 92) Plasma cell granuloma Hamartoma Neurogenic tumor Leiomyoma Mucous gland adenoma Myoblastoma Benign teratoma Malignant (n = 291) Bronchial "adenoma" Bronchioalveolar carcinoma Pulmonary blastoma Fibrosarcoma Rhabdomyosarcoma Leiomyosarcoma Sarcoma Hemangiopericytoma Plasmacytoma Lymphoma Teratoma Mesenchymoma Myxosarcoma

No. of Patients (%) * 48 (52.2) 22 (23.9) 9 (9.8) 6 (6.5) 3 (3.3) 3 (3.3) l(1.1) 1 1 8 (40.5) 49 (16.8) 45 (15.5) 2 8 (9.6) 1 7 (5.8) 11(3.8) 6 (2.1) 4 (1.4) 4 (1.4) 3 (1.0) 3 (1.0) , 2 (1.7) l(0.3)

*Percent of benign or malignanttumors. Modified from Hancock BJ, DiLorenzo M, Youssef S, et al: Childhood primary pulmonary neoplasms.J Pediatr Surg 1993;28:1133.

CHAPTER

However, the diagnosis can usually be confirmed by frozen section. Malignant fibrous histiocytoma of the lung, an extremely rare tumor in children, can mimic plasma cell granuloma and must be considered in the differential diagnosis.53 Recurrences following resection are rare but have been reported. Nonsteroidal anti-inflammatory drugs have been used to treat large inoperable lesions, with encouraging re~ults.~2

Hamartoma Pulmonary hamartoma is the second most frequent benign lesion seen in children. These lesions usually present as parenchymal lesions and can be quite large. Approximately one quarter are calcified, and "popcornlike" calcification is pathognomonic.21 Two endobronchial lesions have been reported. Four tumors occurring in the neonatal period were quite large and were associated with significant respiratory distress; all were fatal. An interesting triad is the combination of pulmonary hamartoma, extra-adrenal paraganglioma, and gastric smooth muscle tumors; the majority of these patients are young women. Conservative pulmonary resection is the treatment of choice; however, lobectomy or even pneumonectomy may be required, especially for large lesions and endobronchial lesions when sleeve resection is not possible.

MALIGNANT TUMORS Bronchial Adenoma The most frequently encountered malignant primary pulmonary tumor is bronchial adenoma. These tumors are a heterogeneous group of primary endobronchial lesions. Although adenoma implies a benign process, all varieties of bronchial adenomas occasionally display malignant behavior. There are three histologic types: carcinoid tumor (most common), mucoepidermoid carcinoma, and adenoid cystic carcinoma. Carcinoid tumors account for 80% to 85% of all bronchial adenomas in children. The presenting symptoms are usually due to incomplete bronchial obstruction, with cough, recurrent pneumonitis, and hemoptysis. Owing to diagnostic difficulties, symptoms are often present for months; occasionally, children with wheezing have been treated for asthma, delaying diagnosis as long as 4 to 5 years. Metastatic lesions are reported in approximately 6% of cases, and recurrences occur in 2%. There is a single report of a child with a carcinoid tumor and metastatic disease who developed the classic carcinoid ~yndrome.~3 Bronchial adenomas of all histologic types are associated with an excellent prognosis in children, even in the presence of local invasion.68 The management of bronchial adenomas is somewhat controversial because most are visible endoscopically. Biopsy in these lesions may be hazardous because of the risk of hemorrhage, and endoscopic resection is not recommended. Bronchography or computed tomography

39

Tumors of the Lung

641

(CT) may be helpful to determine the degree of bronchiectasis distal to the obstruction, because the degree of pulmonary destruction may influence surgical the rap^.^ However, Tagge et a1.7Vescribed a technique for pulmonary salvage despite significant distal atelectasis. Conservative pulmonary resection with removal of the involved lymphatics is the treatment of choice. Sleeve segmental bronchial resection is possible in children and ~,~~ is the treatment of choice when f e a ~ i b l e . zAdenoid cystic carcinomas (cylindroma) have a tendency to spread submucosally, and late local recurrence or dissemination has been reported. In addition to en bloc resection with hilar lymphadenectomy, a frozen section examination of the bronchial margins should be carried out in children with this lesion.

Bronchogenic Carcinoma Although bronchogenic carcinoma is rare in children, this tumor was the second most common malignant lesion reported by Hancock et al.29 Interestingly, squamous cell carcinoma was rare, with the majority of tumors being either undifferentiated or adenocarcinomas. The term bronchioalveolar carcinoma has been used These tumors are associated with both in most ca~es.~5 cystic adenomatoid malformations and intrapulmonary bronchogenic cysts (Table 39-2).* Only rare survivors have been reported, and mortality exceeds 90%. The majority of children present with disseminated disease, and the average survival is only 7 months. Localized lesions can be treated by complete resection, followed by adjuvant therapy. Mucoepidermoid carcinoma of the bronchus has also been described in children as young as 4 years (Fig. 39-1) .66

Pulmonary Blastoma Pulmonarv blastoma is a rare malignant tumor that " occurs primarily in adults and arises from mesenchymal blastema. This tumor is an aggressive lesion, with metastatic disease at presentation in approximately 20% of cases.l7.29 They may arise from the lung, pleura, and mediastinum.56 Occasionally, these tumors may arise in an extralobar sequestration or in a previous lung cyst (Table 39-3).t The majority of cases occur in the right hemithorax (Fig. 39-2). Frequent sites of metastases are the liver, brain, and spinal cord. Local recurrences are frequent, and the mortality rate is approximately 40%.6,29 he majority of children present before 4 years of age, and symptoms include persistent cough, chest pain, episodes of pneumonia that are refractory to antibiotics, and hemoptysis. Diagnosis is achieved by CT of the chest, bronchoscopy, and biopsy. Because most of these tumors are located peripherally, resection is usually possible by segmental or lobar resection. The use of multimodal

'See references 7, 19, 22, 27, 37, 40, 45, 51, 58, 59, 73. t See references 1, 11, 23, 36, 47, 57, 64, 65, 71, 74, 80, 84.

642

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MAIORTUMORS OF CHILDHOOD

Year of Publication

Author Prichard58 Hurleys7 Benjamin7

Type of Lung Cyst

Age at Diagnosis (yr)

Comments

CCAM type 1 CCAM type 1 CCAM type 1

30

Died of metastatic disease

CCAM type 1 CCAM type 1 CCAM type 1 CCAM type 1 Bronchogenic (intrapulmonary) Bronchogenic (intrapulmonary) CCAM type 1 0.5, 13,18 30,36 CCAM type 1

BAC diagnosed in same lobe with segmental resection 1 9 yr earlier; died at 2 3 yr

Incomplete resection of CCAM in neonatal period Lobectomy for recurrent infection; BAC was finding Abnormal CXR noted 10 yr earlier; presented with dyspnea, BAC was incidental finding, 3 x 1mm Long-standing history of cyst infections

1BAC in a recurrent cyst; 1other patient with a typical adenomatous hyperplasia (both patients underwent segmental resection) Abnormality seen on CXR from 1 0 yr earlier

I BAC, bronchioalveolar carcinoma; CCAM, congenital cystic adenomatoid malformation; CXR, chest radiograph. Adapted from LaBerge JM, Puligandla P, Flageole H: Asymptomatic congenital lung malformations. Semin Pediatr Surg 2005;14:16.

neoadjuvant chemotherapy and radiation following surgical resection has shown promising results in a few patients with extensive disease and dis~emination.56~67 Chemotherapeutic agents that have been used include actinomycin D, vincristine, cyclophosphamide alternating with courses of doxorubicin, and cisplatin. Histologic evaluation of the tumor shows an exclusive mesenchymal composition, including primitive tubules, immature blastema, and spindle cell stroma. Some demonstrate

'

elements of embryonal rhabdomyosarcoma arising within a multicyctic lesion.

Rhabdomyosarcoma Rhabdomyosarcomas of the lung are rare and account for only 0.5% of all childhood rhabdomyosarcomas (see Chapter 32).9 Many of the lesions are endobronchial in origin (Fig. 39-3); however, several cases apparently originated in congenital cystic anomalies. (see Table 39-3).* This is an important issue because 4% of benign tumors and 8.6% of malignant tumors enumerated in Table 39-1 were associated with previously that develdocumented cystic malformations.~~umors oped in these malformations included 11 sarcomas, 9 pulmonary blastomas, 3 bronchogenic carcinomas, and 2 mesenchymomas.

Comments

-

.

Anteroposterior view of a right upper lobe lesion in a 4year-old girl. The tumor was resected by right upper lobectomy and was shown to be a mucoepidermoid carcinoma. (Courtesy of Jay I,. Grosfeld, MD.)

Although children with primary lung tumors represent a heterogeneous group of patients, analysis of the reported cases suggests that evaluation and treatment are similar in the majority of patients. Many children are asymptomatic, especially those with benign tumors; however, cough, recurrent pneumonitis, and symptcims of atypical bronchial asthma may be the initial presentation. Radiographic findings usually indicate a solitary mass

' See references 4, 8, 10, 16, 33, 41, 49, 52, 54, 67, 79, 86

CHAPTER

Author Stephanopoul~s~~ Ueda79 Martinez47 Valderramaso Sumner74 Weinbera83 Krous41 Weinblatt84 Holland-Moritz36 Moralesso Williams86 Allan4 Shariff67 Hedlund33 CairolilO Domizio20 Senac65 Murphy52 Bogerss Calabriall M~Dermott~~ Paupe57 Seballos64 Tagge75 Adiriml D'Agostino16 Federici23 Ozcan54 Papagiannopoulos55 Stocker71

Year

39

Tumors of the Lung

T y ~ eof Lung Cyst

Type of Malimancy

"Cystic hamartoma" CCAM "Polycystic disease" Extralobar sequestration Peripheral cyst Congenital lung cyst Bronchogenic cyst (intrapulmonary) "Cystic lung disease" "Pneumatocele" Congenital cyst CCAM "Congenital origin of cysts not confirmed" CCAM type 1 "Cystic hamartoma" CCAM "Congenital cyst"

Myxosarcoma RMS Pulmonary blastoma Pulmonary blastoma Pulmonary blastoma Mixed mesenchymal sarcoma Embryonal RMS Pulmonary blastoma PPB Pulmonary blastoma Embryonal RMS RMS RMS RMS RMS Malignant mesenchymoma PPB Embryonal RMS RMS Pulmonary blastoma Embryonal RMS Pulmonary blastoma Pulmonary blastoma PPB Pulmonary blastoma Embryonal RMS PPB Embryonal RMS PPB PPB

Bronchogenic cyst, CCAM (2) Lobar emphysema "Pneumatoceles" Congenital cyst Cystic lung lesion CCAM Bilateral pneumatocele CCAM type 1 CCAM type 2 CCAM type 1 CCAM CCAM type 4 CCAM type 4

Age at Diagnosis Imo)

CCAM, congenital cystic adenomatoid malformation; CPAM congenital pulmonary airway malformation; PPB, pleuropulmonaryblastoma; RMS, rhabdomyosarcoma Adapted from LaBerge JM, Puligandla P, Flageole H: Asymptomatic congenital lung malformations.Semin Pediatr Surg 2005;14:16.

A , . -

643

B

A, Computed tomography scan of the chest shows a cystic lesion in the right hemithorax. B, The tumor was resected (Iobectomy), and the histology showed findings consistent with a pleuropulmonary blastoma. (Courtesy of Jay L. Grosfeld, MD.)

644

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MAJORTUMORS OF CHILDHOOD

0-• Patient with complete atelectasis of the left lung and obstruction of the left main bronchus secondary to rhabdomyosarcoma.

lesion or evidence of airway obstruction with resultant atelectasis and pneumonitis. Because many of these tumors can be visualized by bronchoscopy, a bronchoscopic examination should be performed. Flexible bronchoscopic techniques may be helpful for diagnosis, but the use of rigid bronchoscopy with modern magnification, along with general anesthesia, is necessary if endoscopic biopsy is contemplated. Preparation for emergency thoracotomy should be made at the time of bronchoscopy in the event of life-threatening hemorrhage. Bronchoscopic removal of some isolated lesions may be attempted, but owing to the high incidence of recurrence and the possibility of severe hemorrhage, this technique should be used selectively. Conservative surgical resection is the procedure of choice for benign pulmonary tumors to achieve histologic diagnosis and preserve maximum functioning lung tissue. Thoracoscopic resection is an option in these children.35CT and magnetic resonance imaging should be performed in children with large space-occupying lesions to determine resectability. Fine-needle aspiration for cytology or core needle biopsy may be performed as the initial procedure for diagnosis in selected cases. Treatment of malignant lesions varies, depending on location and histology. Sleeve resections should be considered for bronchial adenomas. Resection of involved lymphatics should be considered with malignant lesions. Combined-modality therapy with adjuvant chemotherapy and possibly radiation therapy may be

helpful in children with large primary malignancies or dissemination. An important consideration is the association of primary lung tumors with congenittal cystic pulmonary malformations. These lesions may be asymptomatic and be discovered incidentally. In some instances, the natural history of the lung cyst is unknown, and a few may regre~s.~2 Although some authors recommend simple observation, most pediatric surgeons argue against prolonged observation of cystic lesions because of an increased risk of infection, pneumothorax, sudden cyst enlargement with potential respiratory compromise, and If patients with associated malignan~y.1,11~42~~7.~~~~~~65~75 asymptomatic cystic malformations are observed without resection, they should be followed closely and evaluated frequently.

TREATMENT OF METASTATIC DISEASE Pulmonary metastases occur much more frequently than primary tumors in children, and the surgical approach depends on the histology of the primary tumor and the response of the primary site to combined-modality therapy. Pulmonary metastases should not be considered for resection until the primary tumor is eradicated without evidence of recurrence and other sites of metastatic disease are ruled out. Tumors most frequently considered

CHAPTER

Author

No. of Patients

Martini48 spa no^^^ TelanderT7 GiritskyP5 Rosenberg60 Burgers9 SchalleF3 Goorin26 Carter12

22 29 28 12 18 12 17 32 43

39

Tumors of the Lung

Average Interval to Relapse (mo) (Range)

No. of Procedures (No. of Lesions)

Disease-Free Survival, No. (%)

Median Follow-up for Survivors/ (mo) (Range)

10 (2-25) 15.7 (430) 9/6 (2-34) 9 (1-21)

59 (113) 52 (124) 60 (173) 19

33 (15-234) 36 (9-234) 25 (6-48) 17 (9-39)

-

-

7 (32) 11(37) 13 (46) 6 (50) 7 (39) 5 (42) 7 (41) 9 (28) 4 (10)

13 (2-20) -

12.5 (459) 13 (1-83)

9 34 26 (>63)

-

645

(36-72) (12-192) 55 (19-101) 69 (59-80)

From LaQuaglia MP: The surgical managementof metastases in pediatric cancer. Semin Pediatr Surg 1993;2:75.

for pulmonary metastasectomy are osteosarcoma, soft tissue sarcoma, and Wilms' tumor.3g

Osteosarcoma Children with osteosarcoma should be considered for resection of pulmonary metastases once the primary lesion is controlled. The overall disease-free survival is approximately 40% in children who develop metachronous pulmonary metastases. Multiple factors, such as number of pulmonary nodules and time of recurrence, play an important role in children with osteosarcoma 2 1 ~ ~et a1.61showed that and pulmonary m e t a s t a s e ~ . ~Roth patients with fewer than four pulmonary nodules had an improved survival over those with more than four lesions. According to Goorin et a1.,26 a complete resection of all pulmonary lesions is an important determinant of outcome, and penetration through the parietal pleura is associated with an adverse outcome. Although somewhat controversial, the outlook seems to be somewhat improved, even in patients presenting with pulmonary metastases, if complete resection of all metastatic lesions can be accomplished.46 Harris et al.30 reported a 68% survival rate in 17 patients with fewer than eight pulmonary nodules at presentation following chemotherapy, resection of the primary tumor, and pulmonary metastasectomy. The data in Table 39-4 suggest that an aggressive attempt at surgical resection of pulmonary metastases is indicated in osteosarcoma, possibly irrespective of the number of lesions or the interval to the development of metastases.

Soft Tissue Sarcoma The usefulness of resecting pulmonary metastases in patients with soft tissue sarcoma depends on the histologic subtype. Rarely is pulmonary resection of metastatic lesions required in rhabdomyosarcoma, and resection of pulmonary metastasis in Ewing's sarcoma has not been found to be efficacious." The remaining

sarcomas should be considered for resection if complete excision is possible and the patient's primary tumor is under control. The time to development of pulmonary metastases, number of lesions, and tumor doubling time are all significant prognostic factors in soft tissue sarcomas. Historically, approximately 10% to 20% of these patients can be salvaged by resection of pulmonary meta~tases.~~

Wilms' Tumor Rarely is pulmonary resection of metastatic disease required in children with Wilms' tumor. In a review of the National Wilms' Tumor Study by Green et a1.,28 no advantage of pulmonary resection was found compared with chemotherapy and radiation therapy alone. In an attempt to avoid pulmonary radiation, deKraker et a1.18 suggested a protocol using primary pulmonary resection after chemotherapy for pulmonary metastases. The overall results were not encouraging, and few patients ultimately required resection of pulmonary metastases following chemotherapy. Because the results of chemotherapy and whole-lung irradiation are excellent for children with Wilms' tumor and pulmonary metastases, pulmonary resection of metastases should be reserved for only selected cases (see Chapter 27).

Comments Operation for pulmonary metastases in children depends on the histology of the primary tumor, the extent of the metastatic disease, and whether the metastatic disease is responsive to chemotherapy. The surgical approach varies, depending on the disease process and the age of the patient. No difference ir. survival has been demonstrated with sequential lateral thoracotomy versus sternotomy, but the latter is preferable in older patients with osteosarcoma. Complete resection of all metastatic disease is an imporiant consideration, and the use of automatic stapling devices can be helpful. Wedge resection is

646

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usually possible in children with osteosarcoma. However, formal lobectomy or segmentectomy may be required to remove all tumor completely, especially when the primary tumor is not responsive to chemotherapy or radiation.6 Muscle-sparing techniques are available in those children requiring posterolateral thoracotomies, and thoracoscopy may be appropriate in certain cases.55 However, port site recurrences have been reported following thoracoscopic resection of pulmonary metastatic disea~e.~z.~~

REFERENCES 1. Adirim AD, King R, Klein BL: Radiologic case of the month: Congenital cystic adenomatoid malformation of the lung and pulmonary blastoma. Arch Pediatr Adolesc Med 1997;151:1053. 2. Agrons GA, Rosado-de-Christenson ML, Kirejczyk WM, et al: Pulmonary inflammatory pscudotumor: Radiologic features. Radiology 1998;206:51. 3. Ahel V, Zubovic I, Rozmanic V. Bronchial adenoid cystic carcinoma with saccular bronchiectasis as a cause of recurrent pneumonia in children. Pediatr Pulmonol 1992: 12:160. 4. Allan BT, Day DL, Dehner LP: Primary pulmonary rhabdomyosarcoma of the lung in children: Report of two cases presenting with spontaneous pneumothorax. Cancer 1987;59:1005. 5. Bahadoni M, Liebow AA: Plasma cell granulomas of the lung. Cancer 1973;31:191. 6. Ballantine TVN, Wiseman NE, Filler RM: Assessment of pulmonary wedge resection for the treatment of lung metastases. J Pediatr Surg 1975;10:671. 7. Benjamin DR, Cahill JL: Bronchioalveolar carcinoma of the lung and congenital cystic adenomatoid malformation. Am J Clin Pathol 1991;95:889. 8. Bogers AJ, Hazebroek FW, Molenaar J, et al: Surgical treatment of congenital bronchopulmonary disease in children. Eur J Cardiothorac Surg 1993;7:117. 9. Burgers JM, Brear K, van Dobbenburgh OA, et al: Role of metastasectomy without chemotherapy in the management of osteosarcoma in children. Cancer 1980; 45: 1664. 10. Cairoli G, Bertana S, Giuntoli M, et al: Cystic adenomatoid malformation of the lung: Experience in four operated cases. Pediatr Med Chir 1990;12:681. 11. Calabria R, Srikanth MS, Chamberlin K, et al: Management of pulmonary blastoma in children. Am Surg 1993; 59:192. 12. Carter SR, Grimer RJ, Sneath RS, et al: Results of thoracotomy in osteogenic sarcoma with pulmonary metastases. Thorax 1991;46:727. 13. Crisei KL, Greenberg SB, Wolfson BJ: Cardiopulmonary and thoracic tumors of childhood. Radiol Clin North Am 1997;35:1341. 14. Crist WM, Raney RB, Newton W, et al: Intrathoracic soft tissue sarcomas in children. Cancer 1982;50:598. 15. Cohen MC, Kaschula ROC: Primary pulmonary tumors in childhood: A review of 31 years' experience and the literature. Pediatr Pulmonol 1992;40:222. 16. D'Agostino S, Bonoldi E, Dante S, et al: Embryonal rhabdomyosarcoma of the lung arising in cystic adenomatoid malformation: Case report and review of the literature. J Pediatr Surg 1997;32:1381.

17. Dehner LP: Pleuropulmonary blastoma is the pulmonary blastoma of childhood. Semin Diagn Pathol 1994; 11:144. 18. deKraker J, Lemerle J, Voute PA, et al: Wilms' tumor with pulmonary metastases at diagnosis: The significance of primary chemotherapy. J Clin Oncol 1990;8:1187. 19. De Perrot M, Pache JC, Spiliopoulous A: Carcinoma arising in congenital lung cysts. Thorac Cardiovasc Surg 2001;49:184. 20. Domizio P, Liesner RL, Dicks-Mireaux C, et al: Malignant mesenchymoma associated with a congenital lung cyst in a child: Case report and review of the literature. Pediatr Path01 1990;10:785. 21. Eggli KD, Newman B: Nodules, masses and pseudomasses in the pediatric lung. Radiol Clin North Am 1993; 31:651. 22. Endo T, Inoue M, Waatanabe N, et al: Two operative cases of pulmonary blastoma. Kyobu Geka 1982;35:219. 23. Federici S, Domenichelli V, Tani G: Pleuropulmonary blastoma in congenital cystic adenomatoid malformation: Report of a case. Eur J Pediatr Surg 2001;11:196. 24. Gaissert HA, Mathisen Dl, Grillo HC, et al: Tracheobronchial sleeve resection in children and adolescents. J Pediatr Surg 1994;29:192. 25. Giritsky AS, Etcubawas E, Mark JBD: Pulmonary resection in children with metastatic osteogenic sarcoma. J Thorac Cardiovas Surg 1978;75:354. 26. Goorin AM, DeCorey MJ, Lack EE, et al: Prognostic significance of complete surgical resection of pulmonary metastases in patients with osteogenic sarcoma: Analyses of 32 patients. J Clin Oncol 1984;2:425. 27. Granata C, Gambini C, Balducci T, et al: Bronchioalveolar carcinoma arising in a cystic adenomatoid malformation in a child: A case report and review on malignancies originating in congenital adenomatoid malformations. Pediatr Pulmonol 1998;25:62. 28. Green DM, Breslow N, Ii Y, et al: The role of surgical excision in the management of relapsed Wilms' tumor patients with pulmonary metastases: A report from the National Wilms' Tumor Study. J Pediatr Surg 1991;26:728. 29. Hancock BJ, DiLorenzo M, Youssef S, et al: Childhood primary pulmonary neoplasms. J Pediatr Surg 1993; 28:1133. 30. Harris M, Gieser P, Goorin AM, et al: Treatment of metastatic osteosarcoma at diagnosis: A Pediatric Oncology Group study. J Clin Oncol 1998;11:3641. 31. Hartman GE, Shochat SJ: Primary pulmonary neoplasms of childhood: A review. Ann Thorac Surg 1983;36:108. 32. Hawkins DS, Arndt CA: Pattern of disease recurrence and prognostic factors in patients with osteosarcoma treated with contemporary chemotherapy. Cancer 2003; 98:2447. 33. Hedlund GL, Bisset GS 111, Bove KE: Malignant neoplasms arising in cystic hamartomas of the lung in childhood. Radiology 1989;173:77. 34. Heij HA, Vos A, deKraker.1, et al: Prognostic factors in surgery for pulmonary metastases in children. Surgery 1994; 115:687. 35. Holcomb GW 111, Tomita SS, Haase GM, et al: Minimally invasive surgery in children with cancer. Cancer 1995; 76:121. 36. Holland-Moritz RM, Heyn RM: Pulmonary'blastoma associated with cystic lesions in children. Med Pediatr Oncol 1984;12:85. 37. Hurley P, Corbishsley C, Pepper J: Bronchoalveolar carcinoma arising in longstanding lung cysts. Thorax 1985; 40:960.

CHAPTER

38. Jalal A, Jeyasingham K: Bronchoplasty for malignant and benign conditions: A retrospective study of 44 cases. Eur J Cardiothorac Surg 2000;17:370. 39. Karnak I, Senocak ME, Kutluk T, et al: Pulmonary metastases in children: An analysis of surgical spectrum. Eur J Pediatr Surg 2002;12:15. 40.Kaslovsky RA, Purdy S, Dangman BC, et al: Bronchioalveolar carcinoma in a child with congenital cystic adenomatoid malformation. Chest 1997;112:548. 41. Krous HF, Harper PE, Perlman M: Congenital cystic adenomatoid malformation in bilateral renal agenesis: Its mitigation of Potter's syndrome. Arch Pathol Lab Med 1980;104:368. 42. LaBerge JM, Puligandla P, Flageole H: Asymptomatic congenital lung malformations. Semin Pediatr Surg 2005; 14:16. 43. Lack EE, Harris GBC, Eraklis AT, et al: Primary bronchial tumors in childhood: A clinicopathologic study of six cases. Cancer 1983;51:492. 44. LaQuaglia MP: The surgical management of metastases in pediatric cancer. Semin Pediatr Surg 1993;2:75. 45. MacSweeney F, Papagiannopoulos K, Goldstraw P, et al: Assessment o f the'expanded classification of congenital cystic adenomatoid malformations and their relationship to malignant transformation. Am J Surg Pathol 2003; 27:1139. 46. Marina NM, Pratt CB, Rao BN, et al: Improved prognosis of children with osteosarcoma metastatic to the ling(s) at the time of diagnosis. Cancer 1992;70:2722. 47. Martinez JC, Pecero FC, Gutierrez de la Pena C, et al: Pulmonary blastoma: Report of a case. J Pediatr Surg 1978;13:93. 48. Martini N, Havos AG, Mike V, et al: Multiple pulmonary resections in the treatment of osteogenic sarcoma. Ann Thorac Surg 1971;12:271. 49. McDermott VG. MacKenzie S. Hendrv GM: Case reDort: Primary intrathoracic rhabdokyosarcbma: A rare c'hildhood malignancy. Br J Radio1 1993;66:937. 50. Morales L, Julia V, Tardio E, et al: Pulmonary blastoma at the site of a congenital pulmonary cyst. Chir Pediatr 1986; 27:53. 51. Morresi A, Wockel W, Karg 0 : Adenomatoid cystic lung abnormality in adults with associated bronchioalveolar carcinoma. Pathologe 1995;16:292. 52. MurphyJ, Blair GK, Fraser GC, et al: Rhabdomyosarcoma arising within congenital pulmonary cysts: Report of three cases. J Pediatr Surg 1992;27:1364. 53. Nistal M, Jimenez-Hefferman JA, Hardisson D, et al: Malignant fibrous histiocytoma of the lung in a child. Eur J Pediatr 1997;156:107. 54. Ozcan C, Celik A, Ural Z, et al: Primary pulmonary rhabdomyosarcoma arising within cystic adenomatoid malformation: A case report and review of the literature. J Pediatr Surg 2001;36: 1062. 55. Papagiannopolous KA, Sheppard M, Bush AP, et al: Pleuropulmonary blastoma: Is prophylactic resection of congenital lung cysts effective? Ann Thorac Surg 2001; 72:604. 56. Parsons SK, Fishman SJ, Hoorntje LE, et al: Aggressive multimodal treatment of pleuropulmonary blastoma. Ann Thorac Surg 2001:72:939. 57. Paupe A, Martelli H, Lenclen R, et al: Pneumothorax revealing pneumoblastoma in an infant. Arch Pediatr 1994;1:919. 58. Prichard MG. Brown PI. Sterrett GF: Bronchioalveolar carcinoma arising in longstanding lung cysts. Thorax 1984;39:545. 4 ,

39

Tumors of the Lung

647

59. Ribet ME, Copin MC, Soots JG, et al: Bronchalveolar carcinoma and cystic adenomatoid malformation. Ann Thorac Surg 1995;60:1126. 60. Rosenberg SA, Flye MW, Conkle D, et al: Treatment of osteogenic sarcoma. 11. Aggressive resection of pulmonary metastases. Cancer Treat Rep 1979;63:753. 61. Roth JA, Putnam JB, Wesley MN, et al: Differing determinants of prognosis following resection of pulmonary metastases from osteogenic and soft tissue sarcoma patients. Cancer 1985;55:1361. 62. Sartorelli KH, Patrick D, Meagher DP Jr: Port-site recurrence after thoracoscopic resection of pulmonary metastasis owing to osteogenic sarcoma. J Pediatr Surg 1996;31:1443. 63. Schaller RTJr, Haas J, SchallerJ, et al: Improved survival in children with osteosarcoma following resection of pulmonary metastases. J Pediatr Surg 1982;17:546. 64. Seballos RM, Klein RL: Pulmonary blastoma in children: Report of two cases and review of the literature. J Pediatr Surg 1994;29:1553. 65. Senac MO Jr, Wood BP, Isaacs H, et al: Pulmonary blastoma, a rare childhood malignancy. Radiology 1991;179:743. 66. Seo IS, Warren M, Mirkin LD, et al: Mucoepidermoid carcinoma of the bronchus in a four year old child. Cancer 1984;53:1600. 67. Shariff S, Thomas JA, Shetty N, et al: Primary pulmonary rhabdomyosarcoma in a child with a review of the literature. J Surg Oncol 1988;38:261. 68. SogaJ, YakuwaY Bronchopulmonary carcinoids: An analysis of 1875 reported cases with special reference to a comparison between typical carcinoids and atypical varieties. Ann Thorac Cardiovasc Surg 1999;5:211. 69. Spanos PK, Payne WS, Ivins JC, Pritchard DJ: Pulmonary resection for metastatic osteogenic sarcoma. J Bone Joint Surg Am 1976;58:624. 70. Stephanopoulos C, Catsaras H: Myxosarcoma complicating a cystic hamartoma of the lung. Thorax 1963;18:144. 71. StockerJT: Congenital pulmonary ainvay malformationsa new name for and an expanded classification of congenital cystic adenomatoid malformation of the lung. Histopathology 2002;41(Suppl):S424. 72. Su W, KO A, O'Connell TX, et al: Treatment of pseudotumors with nonsteroidal anti-inflammatory drugs: J Pediatr Surg 2000;35:1635. 73. Sudou M, Sugi K, Murakami T: Bronchioalveolar carcinoma arising from a congenital cystic adenomatoid malformation in an adolescent: The first case in the Orient. J Thorac Cardiovasc Surg 2003;126:902. 74. Sumner TE, Phelps CR, Crowe JE, et al: Pulmonary blastoma in a child. AJR Am J Roentgen01 1979; 133:147. 75. Tagge EP, Mulvihill D, Chandler JC, et al: Childhood pleuropulmonary blastoma: Caution against nonoperative management of congenital lung cysts3 Pediatr ~ u r g1996; 31:187. 76. Tagge EP, Yanis E, Chopy KJ, et al: Obstructing endobronchial fibrous histiocytoma: Potential for lung salvage. J Pediatr Surg 1991;26:1067. 77. Telander RL, Pairolero PC, Pritchard DJ, et al: Resection of pulmonary metastatic osteogenic sarcoma in children. Surgery 1978;84:335H. 78. Thompson RC Jr, Cheng EY, Clohisy 'DR, et al: Results of treatment for metastatic osteosarcoma with neoadjuvant chemotherapy and surgery. Clin Orthop 2002;397:240. 79. Ueda K, Gmppo R, Unger F, et al: Rhabdomyosarcoma of lung arising in congenital cystic adenomatoid malformation. Cancer 1977;40:383.

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80. Valderrama E, Salija G, Shende A, et al: Pulmonary blastoma: Report of two cases in children. Am J Surg Pathol 1978;2:415. 81. Verbeke JIML, Verberne AAPH, Den Hollander JC, Robben SGF: Inflammatory myofibroblastic tumor of the lung manifesting as progressive atelectasis. Pediatr Radiol 1999;29:816. 82. Vujanic GM, Dojcinov D: Inflammatory pseudotumor of the lung in children. Pediatr Hematol Oncol 1991;8:121. 83. Weinberg AG, Currarino G, Moore GC, Votteler TP: Mesenchymal neoplasia and congenital pulmonary cysts. Pediatr Radiol 1980;9:179.

84. Weinblatt ME, Siege1 SE, Isaacs H: Pulmonary blastoma associated with cystic lung disease. Cancer 1982; 49:669. 85. Wille GA, Gregory R, Guernsey JM: Tumor implantation at port site of video-assisted thoracoscopic resection of pulmonary metastasis. West J Med 1997;166:65. 86. Williams RA: Embryonal rhabdomysosarcoma occurring in cystic adenomatoid malformation. Pediatr Pathol 1986; 5:118. 87. Zaidi A, Zamvar V, Macbeth F, et al: Pulmonary blastoma: Medium-term results from a regional center. Ann Thorac Surg 2002;73:1572.

Bone Tumors Saminathan S. Nathan and John H. Healey

Bone tumors are rare. In the United States there were GENERAL CONSIDERATIONS 166,487 cases of breast cancer and 164,753 c a ~ e s 2of ~ prostate cancer in 2000. By comparison, there were only Pathophysiology 2,051 of all types of bone sarcomas that year. A large proThe main aim of this section is to illustrate the specific portion of these tumors occur in the pediatric population. issues of the pathophysiology of bone tumors that distinIn one published database 26.8% of all bone sarcomas guish them from tumors of soft tissue. occurred in the pediatric age group. There are no popu" Bone tumors should be approached initially from the lation-based benign bone registries so it would be imposstandpoint of being benign or malignant. Whereas tradisible to guess at the true incidence of benign bone tional approaches regarding the treatment of most tumors. Most databases of this nature derive from tertinonskeletal benign lesions have been one of benign ary referral institutions, and so benign conditions, which neglect if these lesions are not perceived to be causing are often asymptomatic, would be grossly underrepreproblems, the management of benign bone lesions is sented. Nevertheless, one study has shown that up to complicated by a potential c o m p r o m ~ eof skeletal struc43% of children have a bone lesion during skeletal develtural integrity. Cortical deficiency weakens bones and opment.18 This implies that the overwhelming majority can mandate treatment to prevent fracture. The pruof lesions are benign. dent, if rare, consideration is-one of syndromic presentsThe pediatric surgeon will often be called into the mantion and malignant transformation. Many of these agement of the patient with bone tumors for a number of principles are applicable to malignant lesions as well. reasons. The very young child on follow-up for an unreHowever, malignant lesions have at their cornerstone of lated condition may manifest with a bone lesion secondary consideration their im~licationon survival, which will be to osteomyelitis or leukemia. The older child with a elaborated. Metastatic lesions to bone are not common metastatic osteogenic sarcoma may require the expertise in the pediatric age group. Their pathophysiologic impliof the pediatric thoracic surgeon for the resection of pulcations tend to be structural or diagnostic. monary nodules. The teenager with a pathologic fracture In the pediatric age group benign lesions far outnumthrough a unicameral bone cyst or nonossifylng fibroma ber primary malignant lesions, which in turn outnumber may present first to the pediatric surgeon on call in the metastatic lesions. Owing to the protean manner in which pediatric emergency department. benign lesions behave, some are not evident in the physiThe diagnosis of these rare groups of conditions is readcian's office. Conclusions about their natural history and ily attained through a careful clinical evaluation. In that malignant potential are therefore difficult to ascertain.67 regard, the utility of plain radiographs can never be overThis is obviously not the problem with malignant and stated. They facilitate the initial workup of these patients metastatic lesions. In this section we discuss pathologc and allow them to be referred to specialized centers with conditions of the bone that occur most commonly in the multidisciplinary expertise. Although the subsequent pediatric age group. In the pediatric population the imaging modalities are important, the radiographs form a commonly occurring benign lesions are the unicameral key part of surgical planning. bone cyst, aneurysmal bone cyst, enchondroma, osteoIt is with the pediatric surgeon in mind that this chapchondroma, nonossifylng fibroma, and osteoid osteoma. ter is written. Lengthy discourse on the pathology is The common malignant bone tumors are osteogenic saravoided, and several excellent references e~ist.62,~~,~2~,~35 coma and Ewing's family tumor (Table 40-1). Here we Instead, the format adopted is a practical approach to the highlight specifiE features of each tumor. For a more thormanagement of these conditions. Where prudent, insights ough understanding of pathology the reader is directed to and controversies are highlighted to spur interest into any one of a number of fine books on the s~bject.62,6~,"~,~35 specific areas.

650

PART

III

MAJOR TUMORS OF CHILDHOOD

Benign Tumors

Malignant Tumors

Tumor-like Conditions

Birth to 5 years

Eosinophilic granuloma

5 t o 1 5 years

Unicameral bone cyst Osteochondroma Aneurysmal bone cyst Osteoid osteoma Enchondroma Nonossifying fibroma Chondromyxoid fibroma Chondroblastoma Unicameral bone cyst Osteochondroma Osteoid osteoma Aneurysmal bone cyst Nonossifying fibroma Giant cell tumor Enchondroma Chondroblastoma Chondromyxoid fibroma

Leukemia Metastatic neuroblastoma Ewing's sarcoma Osteogenic sarcoma

Osteomyelitis Nonaccidental injury Fibrous dysplasia Osteomyelitis Osteofibrous dysplasia Stress fracture

Osteogenic sarcoma Ewing's sarcoma

Fibrous dysplasia Stress fracture

1 5 to 2 0 years

1

By consideringthefactors age, frequency, and location in the long bones (see Fig. 40-3), a diagnosis can be arilved in the majority of cases. The possibility of trauma should always be borne in mind and in the noncommunicativechild youngerthan 5 years old, nonaccidental injury may be the cause.

Benign Lesions The typical benign lesion in the pediatric age group (Table 40-2) is determined incidentally. These lesions rarely cause any symptoms and are often diagnosed when a parent notices a lump or deformity (e.g., osteochondroma) or a radiograph is obtained for an unrelated

Tumors Benign Osteochondroma Aneurysmal bone cyst Osteoid osteoma Nonossifying fibroma Enchondroma Giant cell tumor Chondroblastoma Chondromyxoid fibroma Unicameral bone cyst Malignant Osteogenic sarcoma Ewing's sarcoma

All Bone Tumors (%)

Bone Tumors in the First Two Decades (%)

7.86 2.60 2.99 1.13 3.02 5.10 1.07 0.41 Unknown

4.69 1.96 1.94 0.99 0.98 0.80 0.66 0.14 Unknown

14.9 4.6

7.53 3.50

In usingthis table a number of caveats need to be remembered. Most benign lesions are often asymptomatic, and only symptomatic ones will present. Of these, most will be managed at the primary care setting. Malignant lesions will, however, usually present to a referral center. Hence in terms of population incidence these figures are unreliable. In relative terms, however, they have some utility in indicatingtheirprevalence. Unicameral bone cysts are left in this list as a reminder of their frequency.

condition (e.g., nonossifying fibroma). In these cases there are two main surgical indications: diagnosis through a biopsy and surgical stabilization of bones that have fractured or are likely to fracture, especially through a precarious location. For example, a bone cyst in the neck of a femur should be seriously considered for surgical stabilization because a fracture through this area may result in avascular necrosis of the femoral head. The biopsy itself cannot be undertaken lightly because it can weaken the bone, mandating surgical or external splinting. This is pertinent because benign lesions are often asymptomatic whereas the biopsy itself incurs morbidity. The challenge is in improving the yield from biopsy in terms of distinguishing malignant from benign disease.

Size of the Tumor Size is an important consideration. For example, cartilaginous tumors larger than 4 cm in a heterogeneous group of patients with cartilaginous rib lesions were found to have increased likelihood of malignant behavior.62 Because of their aggressive malignant potential large cartilaginous tumors should be resected widely despite their relatively bland histologic appearance (Fig. 40-1). Large tumors can also grow into neighboring compartments and cause mechanical compromise to joints. Although this is less critical in joints of the upper limb, it is more important in the spine and in the lower.limbs, where they cause mechanical impingement and pain. The disruption of a tubular bone that results from the growth of a lesion results in weakening of the bone. Thus, lesions that involve more than 50% of the cross-section of a bone should be treated from a mechanical standpoint.45~462.5" These lesions are at increased risk of fracture and, on the

CHAPTER

40

Bone Tumors

651

of the growth plate, caused disordered linear growth of the long bone.135 These cases are often familial and rarely compromised by their condition.Joints of the upper limb often have high tolerance for the resultant deformity. In the occasional case, however, especially in the lower limb, degenerative arthritis develops necessitating premature surgery.

Multiplicity of Bone Tumors

B

A

-

A, Chondrosarcoma in the proximal humerus of a 13-year-old boy. This is an exceedingly rare diagnosis in this age group. B, A proximal humeral resection with allograft reconstruction was performed. In children, the available prostheses may be too large and hence bulk allografts may be the only choice. o

1

1

Multiple bone lesions are often syndromic and may confer a higher incidence of malignant degeneration.67-128-135 Multiple osteochondromas occur in multiple hereditary exostoses-an autosomal dominant condition caused by abnormalities of the EXTI, EXT2, and EXT? genes on chromosomes 8, 11 and 19.30,74,142Patients with this condition have an increased incidence of malignant degeneration into chondrosarcomas of 10% to 27.6%. By comparison, isolated osteochondromas have a malignant degeneration rate of about l%.62,67l1z8Because only symptomatic lesions will present to the physician, the true incidence of malignant degeneration in isolated lesions is probably impossible to ascertain with certainty. Multiple enchondromatoses is a sporadic condition that confkrs an increased incidence of malignant transformation of up to 50% in the involved bones.67 Limb-length inequality and malalignment are also common. OllierS dzsease, as this condition is termed, has another counterpart

chance that they may be malignant, could result in a potential limb-sparing operation being deferred for an amputation.

Fracture Through a Benign Lesion The fractured benign lesion is typified by the unicameral bone cyst. These lesions may appear aggressive, but a careful history and physical examination with appropriate imaging modalities will usually establish their benign nature (Fig. 40-2). Unicameral bone cysts that fracture have been known to resolve spontaneously. However, the vast majority of them will continue to fracture through a child's lifetime and prove to be disabling.g8 In general, they should be treated surgically, especially if they are symptomatic. The timing of surgery is critical. An early biopsy would show callus formation that would be difficult to distinguish from a malignant process. Therefore, these lesions should be observed during fracture healing for about a month, following which a biopsy and a definitive procedure are performed.

A I

Location in Relation to the Physis Location in relation to the physes is an important consideration distinguishing tumor assessment and management of children versus adults (Fig. 40-3). The term diaphyseak aclaszs was coined to highlight a condition in which multiple osteochondromas, a condition primarily

- , I

t3 A, Large unicameral bone cyst of the proximal

humerus that had fractured. The aggressive appearance may lead one to suspect a malignant process, but a careful evaluation of the margins of this lesion and absence of periosteal reaction reaffirms the management decision of observation before surgery. B, This cyst was curetted and packed with an allograft 1 month after the fracture. Treatment with an intramedullary fibular graft provided stabilization, and supplemental bone graft healed the lesion.

652

PART

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MAJORTUMORS OF CHILDHOOD

Benian lesions

Malignant lesions

Osteogenic sarcoma

Ewing's sarcoma

osteoblastoma , The location of lesions in relation to the physis gives a clue to the diagnosis. In most cases the diagnosis can be made on radiographs, leaving further imaging to plan for surgery. 1 1

classically affecting one limb anlage. A variant, MafSucci's syndrome, describes widespread enchondromas associated with hemangiomas of the hand. The occurrence of multiple nonossifylng fibromas, associated with mental retardaendocrine disorders. cardiovascular Lon, cafe-au~laits~ots, malformations, 'and ocular abnormaliiies has been termed Jafie-Campanacci syndrome but has no malignant implications.67~94

the outset.73 However, of the truly benign lesions that do metastasize, they tend to be in atypical lesions and have had surgical manipulation that may have embolized tumor cells. When followed, some of these metastatic lesions, primarily in the lung, may remain dormant and not progress. The possibility, therefore, is that they represent a transport phenomenon more akin to a mechanical embolism and not true metastasis, which would require a number of mutations before finally seeding.62~~~

Site of lnvolvement The site of benign cartilaginous lesions has important Malignant Lesions implications on malignant potential. Peripheral lesions in the hand rarely turn malignant, whereas those toward Epidemiology the axial skeleton have important malignant potential even if they appear benign histologi~ally.62,67~86,94,128,135The main histologic types of bone tumors are osteogenic Lesions in bones about weight-bearing joints should be sarcoma, Ewing's family tumor, chondrosarcoma,and other regarded with special care. In the pediatric group these sarcomas. They affect children at a rate of 6:3:2:1.2s,128 lesions are usually chondroblastomas. They grow epiphyOsteogenic sarcomas (also known as osteosarcomas) seally and in so doing can cause weakening of the s u b are malignant bone-forming tumors of the bone. They chondral bone and ultimately an intra-articular extension occur at any age but most frequently present in middle or fracture that may even mimic osteochondral defects. teenage years in the extremity. There are various subIn the case of sarcomas, a relatively conservative resection types with varying implications on survival. In general, in this context would have to be deferred to an extrathe subtypes perform similarly except perhaps for telanarticular resection. giectatic osteogenic sarcomas, which bear special mention. In the pre-chemotherapy era this was regarded as the tumor with the poorest prognosis.91 Presently, howMetastatic Potential The lytic nature of these ever, it has the best progno~is.~S A unique feature of benign bone tumors is that there sarcomas weakens bone, resulting in the highest rate of is a small incidence of metastasis in these lesions. pathologic fracture. Increasingly, rarer forms of osteogenic Accordingly 1.7% of chondroblastomas and 3% of giant sarcoma are described. Two variants of note are the small cell do metastasize. It is controversial cell sarcoma and giant cell rich osteogenic sarcoma. The if some of these lesions were, in fact, malignant from former can be confused with Ewing's family tumor and as

CHAPTER

40

Bone Tumors

653

such is often treated by similar chemotherapy protocols.9O,ll6The latter can be confused in the appropriate setting with giant cell tumors of the bone, which is a benipn " condition.l2J3,41 Ewing's sarcoma occurs at a younger age (see Table 40-1) and may affect any bone, particularly the femur, pelvis, and humerus. It is the most common cancer in the pelvis, ribs, foot. and fibula. It was once considered to be distinct from peripheral neuroectodermal tumors but has been shown to be genetically identical to this entity. It is presently considered to be in the same family of neoplasms also known as Ewing's family t ~ m o r s . ~ 2 , l ~ ~ Chondrosarcoma is less prevalent in the pediatric age group. It is more widely distributed in the body compared with its occurrence in adults.

Genetics There have been few consistent " ~ e n e t i cor svndromic associations with osteogenic sarcoma. Patients with the Li-Fraumeni syndrome77 have a TP53 germline mutation78,81on 9p21 and are predisposed to osteogenic sarcoma, breast cancer, and leukemia (Fig. 40-4). Two to 3 percent of patients with osteogenic sarcoma will be the proband for Li-Fraumeni families.lz4 Another germline mutation of 13q14, hereditary retinoblastoma, predisposes to osteogenic sarcomas.ll Children who received radiation therapy for retinoblastoma, Hodgkin's and nonHodgkin's lymphoma, Ewing's family tumor, and other cancers are at 5% to 10% risk of developing osteogenic sarcoma. Patients with an RB gene deletion and a history of alkylating agent exposure from a prior malignancy are predisposed to this complication as well.lZ7 About 5% of all osteogenic sarcomas occur as postradiation sarcomas.65 Ewing's family tumor is a malignancy associated with a number of translocations. The 11 to 22 translocation resulting in an EWSFLIl fusion transcript is the most common variant, and type 1 is associated with the best prognosis.15 Other translocations include type 2 EWSFLI1, EWSERG from a 21,22 translocation, and EWSETVl from a 7,22 translocation. These rarer variants have not been as well studied but appear to confer a poorer prognosis.15 Further additive mutations involving cell-cycle genes reduce the prognosis of these tumors further. Ewing's family tumor is the most common solid tumor to metastasize to the brain.32

A, Osteogenic sarcoma in the left scapula of a female patient with Li-Fraumeni syndrome. This patient had a family history of osteogenic sarcoma in a firstdegree relative. At the time of staging for the osteogenic sarcoma in the scapula a lesion in the breast was discovered on CT of the chest. This was subsequently found to be an adenocarcinoma. B, The patient underwent a scapular replacement. A latissimus dorsi flap was used for skin cover.

Diagnosis and Staging Bone tumors are diagnosed based on the well-recognized triad of history, physical examination, and investigation. After a clinical diagnosis it is imperative that imaging and staging procedures are done before biopsy. Preoperative imaging allows for planning of the definitive procedure and hence placement of the biopsy incision. In addition, changes that would occur in the lesion after biopsy would be difficult to distinguish from changes due to tumor growth on imaging. Furthermore, changes in the lung after general anesthesia (e.g., atelectasis) are difficult to distinguish from metastatic deposits.

Clinical Evaluation Although it is not possible to be comprehensive in this section, the history and physical examination are important parts of the assessment of a patient w~tha bone tumor. Patient demographics and tumor location narrow the differential diagnosis and focus the workup efficiently. The patient's age is important (see Table 40-2). Most malignancies occur in the second decade of life.62,67,128J35 Among children, subtle variation occurs in the prevalence of disease with respect to age (see Table 40-1).

654

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MATORTUMORS OF CHILDHOOD

diaphyseal lesions are typical of Ewing's family tumor, Demographically, it is exceedingly rare for patients of fibrous dysplasia, or enchondromas. African descent to have Ewing's family tumor.135 Pain at rest is an important sign that occurs in tumors and in other organic conditions such as infection and Laboratory Evaluation bone infarction. It distinguishes these conditions from The main blood parameters of importance are lactate mechanical pain, which occurs with activity. Most malignant Lactate dehydrogenase and alkaline pho~phatase.50,7"~23 tumors will present as pain. Pain relieved by nonsteroidal dehydrogenase levels have been used as a surrogate for anti-inflammatory drugs (NSAIDs) is pathognomonic of tumor load and have been correlated with survival in . ~ ~ can occur at any age and is charosteoid o ~ t e o m aThis the case of Ewing's family tumor.jOSerum alkaline phosacterized by painful scoliosis when it occurs in the spine. phatase elevation is characteristic of osteogenic sarcoma A family history of malignancy should be discerned and is correlated with poor survival in this ~ondition.7~J2" especially in possible sentinel cases of the Li-Fraumeni syndrome.77,78181 Such patients should have systemic Glucose intolerance is associated with chondrosarcoma of workups to rule out other sites of involvement in the the bone.48.85Erythrocyte sedimentation rates, C-reactive protein, and white blood cell and differential counts form of radioisotope bone scans or positron emission should be sought to rule out infection. tomographic scans. As described earlier, the surgeon should be alert to any dysmorphism that the patient may have. Cutaneous Preoperative Planning stigmata are evident in patients with neurofibromatosis, Magnetic resonance imaging (MRI) of the lesion offers an fibrous dysplasia, and Jaffe-Campanacci syndrome.94 Limb discrepancies are seen in patients with multiple assessment of compartmentalization of the tumor. A comenchondromatoses and multiple hereditary e x o s t o ~ e s . ~ ~partment is an abstract concept and refers to any plane that Infection should be a differential diagnosis in almost offers a fascia1 or cortical bone bamer to contiguous every case seen. Tumor epidemiology is very telling. For spread. It has implications on the extent of surgery, which example, childhood leukemia is nearly 10 times as comby definition must be outside the compartment to be radimon as Ewing's family tumor and so rare manifestations cal (see later) .37 Also by forming a baseline assessment one is able to make an assessment of response to chemotherapy of leukemia are more common than routine presentain the case of neoadjuvant treatment.6O It has secondary tions of Ewing's family tumor. importance in providing the actual diagnosis. In specific The nature of bony reconstruction also requires that examples it is useful in histologic diagnosis. The aneurysthe method chosen be matched with the demands of the mal bone cyst shows fluid-fluid levels on an MR image. patient. As such, an idea of the patient's expectation should be sought at this time. Pigmented villonodular synovitis is hypointense (dark) on TI- and T2-weighted imagng owing to hemosiderin deposition. Cartilaginous lesions are hyperintense (light) on Radiology T2-weighted imaging. Mineralized and dense fibrous tissue The minimal radiologic assessment at the first visit should are dark on T1- and T2-weighted imagi11g.~,96 be two orthogonal radiographic views of the area in question. Radiographs remain the most specific diagnostic Staging imaging tests and are the only ones that give the "gestalt" Staging studies are meant to assess the degree of spread of overall assessment of skeletal biology and mechanics. of the disease. In the case of bone tumors two systems are By analyzing the location of the tumor (see Fig. 40-3) as used: the Enneking system or Surgical Staging System well as whether it is benign or malignant, the diagnosis (SSS)39as adopted by the Musculoskeletal Tumor Society can be arrived at in the majority of cases.@Jj7J~8,l3j Benign lesions are well circumscribed, with a good scleand the American Joint Committee on Cancer (AJCC) rotic border, and have no soft tissue edema. Malignant system, which at the time of writing is in its sixth revision.j3 In the case of Ewing's family tumor a different classificalesions have lucent or variegated matrices and permeative tion from Enneking is used.36 borders. Edema is often apparent as the presence of In the SSS, tumors are designated GO, G1, and G2 for fat lines. benign, low-grade, and high-grade lesions. Benign The often-quoted eponymous phrases are not specific lesions (GO) are classified as latent, active, or aggressive to specific malignancies. Codman's triangle refers to the lifting and ossification of periosteum at the periphery of designated by Arabic numerals 1, 2, and 3, respectively. Malignant lesions are designated I if low grade and I1 an osteogenic sarcoma. The sunburst appearance is due to if high grade. The further designation A or B denotes the ossification of fibers and vessels subperiosteally as the intracompartmental or extracompartmental disease. tumor expands out of the cortex. Onion skinningrefers to Stage III disease is metastatic disease. Therefore, in this the periodic ossification and expansion of periosteum classification, grade, compartmentalization, and metasfrom the cortex. Any of these conditions can be seen in tases are the fundamental prognostic factors. tumors or infections that are sufficiently fast growing. In the AJCC system, I and I1 similarly designate In the diagram, epiphyseal lesions are typical of chondroblastoma or giant cell tumors; physeal lesions are low- and high-grade lesions. A and B designate tumors typical of osteochondromas; metaphyseal lesions are smaller or larger than 8 cm, respectively. I11 denotes multicentric disease, and l%' denotes metastatic disease. typical of osteogenic sarcomas, unicameral bone cysts, IVA denotes pulmonary metastases, and IVB denotes aneurysmal bone cysts, and nonossifylng fibromas; and

CHAPTER

extrapulmonary metastases. Therefore, this classification considers grade, size, multicentricity, and metastases as prognostic factors. In the Enneking staging system of Ewing's family tumor, stage I tumors are solitary intraosseous lesions, stage I1 are solitary lesions with extraosseous extension, stage I11 are multicentric lesions, and stage N are metastatic. It is unclear how to stage patients who have independent sites of bone marrow involvement versus those who have circulating tumor cells identified by light microscopy (i.e., Enneking stage I11 or N ) . Modern pathology analysis extends these concepts to include immunohistochemistry or reverse transcriptase polymerase chain reaction (RT-PCR) of recombinant gene products. The modalities used for staging are bone scans and computed tomography (CT) of the chest.3g Positron emission tomographic scans are presently being evaluated but have fundamental utility in the management of recurrent or metastatic disease.I6 In the case of Ewing's family tumor, bone marrow biopsies are done in an attempt to capture cases that are multicentric at presentation. The utility of this approach is being evaluated.40

a A and B, An aneurysmal bone cyst of the right proximal fibula in a 17-year-old boy. C, In this instance a primary wide resection was done because the bone was expendable and it prevented contamination of the common peroneal nerve (arrow). -

1

1

40

Bone Tumors

655

Biopsy The biopsy is a critical procedure that can complicate management severely if not performed appropriately. Misplaced incisions continue to be important causes of resectable tumors being rendered nonamenable to limb salvage surg e ~ ~ .A " ,good ~ ~ pathologist comfortable in handling bony tissue is critical to this process. In the appropriate case, extra tissue may be needed for cytogenetic studies. Ewing's family tumors are particularly fragile, and biopsy specimens should be handled carefully to allow for processing.

Presurgical Considerations As a general rule, all imaging and staging should be completed before biopsy. The lesion that warrants biopsy should be given consideration for a primary wide excision. This approach is typically applicable to small lesions less than 3 cm, lesions in expendable bones (e.g., distal phalanx), distal ulna lesions, and proximal fibula lesions, where there is a risk of common peroneal nerve contamination (Fig. 40-5).

656

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III

M A ~ O TUMORS R OF CHILDHOOD

The lesion should preferably be sampled in the instituin the treatment of benign conditions. Up to 10% risk of tion where the definitive procedure is to be done by the malignant transformation occurs when benign lesions are irradiated.l9,62,~,67,l27,128,135 definitive surgeon. It has been shown repeatedly that when this was not adhered to the results were comprorni~ed.8Y,~~ Both chemotherapy and radiation therapy can be used Consideration should be given to needle biopsies in the in the neoadjuvant (preoperative) or adjuvant (postoperacase of lesions in the pelvis or about the spine where the tive) setting in the treatment of malignant conditions. The exposure necessary for an open biopsy may be extensive neoadjuvant approach has the advantage of "shrinking" and oblige the commitment to a definitive procedure. the tumor and provides a more discernible margin, theoA pathologist familiar with processing bone tissue should retically improving local control of the disease. In the case be on hand to evaluate the biopsy. If tumor tissue can be cut of chemotherapy, before the era of modular prosthesis, with a knife, then it can be cut with a microtome. Frozenthe neoadjuvant route was necessary while the custom section analysis is required primarily to ascertain the adeprostheses were manufactured. This technique has been quacy and representativeness of the specimen and secondshown to be as efficacious as primary surgery. Even so, arily for the definitive diagnosis. the one randomized trial of preoperative and postoperaAntibiotics should be withheld before the biopsy to tive chemotherapy versus only postoperative chemotherimprove the yield of microbiologic assessment. The biopsy apy failed to show any difference in survival. Therefore, may be done with use of a tourniquet to prevent bleeding in selected cases it is reasonable and may be prudent to and dissemination of the tumor locally. When the tourniperform surgery first.92 quet is applied, simple elevation should be used for exsanguination. Compressive exsanguination should be Chemotherapy avoided because this could rupture the tumor. At all times Historically, before the era of chemotherapy, survival the limb should be protected from fracturing because in osteogenic sarcomas was less than 20%. Between 1972 this would cause extensive local dissemination of disease. and 1981 the development of chemotherapy protocols for osteogenic sarcoma revolutionized treatment and Surgical Considerations the present 5-year disease free survival rates are 60% to 76%.6,55,64,87,92,106 The planned incision for the definitive surgery should be marked. This should generally follow extensile expoAt present the standard approach to the treatment of sures and be longitudinal along the line of the definitive osteogenic sarcoma has been neoadjuvant therapy to treat unrecognized microscopic disease, followed by definitive incision. The incision should be placed directly over the lesion. Flaps and dissection should be avoided. resection and then adjuvant chemotherapy. This approach The incision is developed directly into the tumor. If there has been more traditional than empirical. Still the availabilis a soft tissue component of the tumor, then this alone needs ity of comparison tissue at the time of definitive resection be sampled. If a bone biopsy is necessary, then the edges of has been an important tool in prognostication. the biopsy specimen should be rounded to minimize a stress Chemotherapy-associated necrosis in resected speciriser. Frozen section analysis will confirm the adequacy of mens has been graded. Grade I necrosis is necrosis the biopsy. In the meantime, a culture is taken, the tourniamounting to less than 50% of a tumor. Grade I1 necrosis quet is released, and antibiotics are given. Absolute hemoamounts to necrosis of 50% to 90% of a tumor. Grade I11 stasis is needed at the conclusion of the procedure to necrosis is necrosis in more than 90% of a tumor, and minimize spread of tumor cells in the hematoma. grade IV necrosis is necrosis in virtually the entire tumor. This has further been grouped with grades I and I1 necroThe wound is closed in layers. If a drain is necessary, this should be brought out in the line of the incision so sis being referred to as standard response and grades I11 and IV necrosis being designated good response. Good that it can be excised at the time of definitive surgery. response in post-resection specimens is an important indicator of good prognosis in osteogenic sarcoma as Postsurgical Considerations well as Ewing's family tumor patient~.~2J~3 The patient should be limited to protected weight bearIt should be remembered that historically 20% of ing at least until some healing of the biopsy or ossification patients had been cured by surgery alone and even now of the tumor as a response to neoadjuvant chemotherapy up to 24% to 40% are not cured of their disease. This occurs. This typically takes up to 6 weeks. means that 44% to 64% of patients have no change in Fractures through osteogenic sarcomas have traditioncure. Nevertheless, even they benefit from chemotherapy ally precluded limb salvage surgery. Recent studies have by enjoying longer survival, better local disease control, shown that limb salvage may still be possible in selected and higher limb salvage rates.% The typical agents used can be classified as cell cycleSpecial surgical consideration is needed in these cases. specific and cell cycle-nonspecific agents. Cell cyclespecific agents include methotrexate and, doxorubicin. These interfere with cell division and hence affect cells that are actively proliferating. In any cell population there Adjuvant Therapy are quiescent cells. These cells would not be affected by cell This section concentrates on the use of radiation and cycle-specific agents. For this purpose the cell cyclechemotherapy. In general, these modalities are not used nonspecific agents are used. Cisplatin and alkylating

CHAPTER

agents (e.g., cyclophosphamide and ifosfamide) directly damage the DNA of a cell and so even quiescent cells are affected. This Goldie-Coldman model of chemotherapeutic administration is the most commonly used in the treatment of osteogenic sarcomas and Ewing's family tumors.51 Multiple-agent chemotherapy has been adopted by a number of working groups in the treatment of osteogenic sarcoma. In Europe the Cooperative Osteosarcoma Study group (COSS) reports an actuarial 10-year survival of 64%.14The Rizzoli Institute reports an 8-year disease-free survival rate of 59%.43Hence, it appears that in its present form multimodality treatment with multiple-agent chemotherapy and surgical resection appears to have stagnated in the past 20 years. Novel approaches and agents are continually being developed. The traditional agents cisplatin, doxorubicin, and high doses of methotrexate have been combined with ifosfamide in a number of centers. Preliminary results are promising. The Rizzoli Institute, as part of thk Italian Sarcoma Group/Scandinavian Sarcoma Group, reports that the combination is associated with a 5-year overall survival of 87% and a 5-year disease-free survival of 73%, improving on their earlier result^.^,^^ Ifosfamide has been used in this manner at our center with variable results. Chemotherapy-associated necrosis has not been dramatic. nor has this been associated with an increased survival benefit in our patients. Chemotherapy as the sole agent in the treatment of osteogenic sarcoma has been reported to have inferior results.'j8 The complications with this approach include increased local recurrence and metastases. Cure was convincingly achieved in only 10% of patients. Recently, it has been discovered that bisphosphonates may have important anticancer properties and these agents are being investigated clinically in some centers.70 The optimal route of delivery for chemotherapeutic agents continues to be developed. In a recent study, the use of neoadjuvant intra-arterial cisplatin and intravenous doxorubicin, followed by surgical resection of the tumor and completion of chemotherapy, conferred an 84% 10-year event-free survival rate. Necrosis was monitored preoperatively by angiography, and surgery was performed only after 90% or greater reduction in neovascularitv was achieved. After resection and assessment of necrosis, adjuvant chemotherapy was tailored according to the chemotherapeutic response seen in the resection specimen. This state of the art represents a culmination of a number of techniques that h e been developed in the field and represents the necessary multidisciplinary approach in these conditions.137

40

Bone Tumors

657

effective but has been reported to have a higher rate of local recurrence than surgery alone. When used alone, doses up to 6600 cGy may be necessary to produce local control.lZ2 In contrast, 3000 to 4000 cGy in divided doses is given in this condition when surgery is combined with radiation therapy.89 Because of its propensity to cause and 2 ~the ~~ premature physeal closure and bone n e c r o s i ~ ~ additional concern of radiation sarcoma developing in these genetically altered patients in whom alkylating ~ , role " , ~of" ~ radiation ~~ agents have been ~ s e d , ~ ~ , ~the therapy in local control in some institutions has been limited to the treatment of spine and pelvic lesions. In these settings the treatment may be used solely or intraoperatively in conjunction with surgery (Fig. 40-6). In the ireatment of extremity lesions a purely surgical approach may be desirable, reserving irradiation for when margins of resection are compromised or when the response to preoperative chemotherapy has been incompIete.89,108,143 Although not studied specifically in the pediatric age group, radiation therapy has been shown to increase wound complications in the perioperative period, which is another factor to consider if the patient is to have chemotherapy.lo2 Thus, in general this modality is best used judiciously. 1 n - ~ a n ~ e r h ahistiocytosis, ns low-dose radiation therapy amounting to less than 1000 rads effects good local control of disease while avoiding the skeletal side effects of radiation therapy.ll5

Surgery In bone tumors, resection and reconstruction are two aspects of management that have largely complementary but occasionally conflicting goals (e.g., cryotherapy is good for extending the margins of resection of a tumor

Radiation Therapy Radiation therapy has been used in both the neoadjuvant and adjuvant setting in the treatment of Ewing's family tumor. Osteogenic sarcoma does not respond well to radiation therapy, and its use in this tumor has been limited to only very select situations.34.75 Regimens for treatment of Ewing's family tumor differ according to site and center. Radiation is generally

Intraoperative radiation therapy in a 19-month-old girl who underwent a wide resection with nodal clearance for a rhabdomyosarcoma of the pelvis.

658

PART

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MAJORTUMORS OF CHILDHOOD

but results in weakening of the bone). Therefore, while the goals of resection are generally quite clear (i.e., cure), the goals of reconstruction are often compromised, especially in malignant conditions. In benign conditions, reconstruction tends to have to be more restorative of function. In this section we present a general list of considerations that will be elaborated on in the section on specific considerations.

Minimally lnvasive Options The minimally invasive option is reserved for benign conditions. It is born of two management philosophiesthe desire to effect local control and the hesitation to cause more morbidity than the primary lesion. Whichever modality is chosen, it is imperative that a histologic diagnosis be obtained a priori.

Radiofrequency Ablation Radiofrequency ablation employs high-intensity heat in proximity to a lesion to effect thermal necrosis. It has wide utility in the ablation of various solid tumors. In bone tumors it has principally been used in the ablation of osteoid osteomas. This condition is a painful condition marked by increased night pain and is promptly relieved by the use of NSAIDs. Otherwise it is relatively benign. It can be found most commonly in the proximal femur. In these locations, surgical ablation in the form of a resection can incur high morbidity. Hence an option such as radiofrequency ablation is ideal, although it incurs a 10% to 15% recurrence rate"2lo7 compared with surgery, which has a near 0% recurrence rate.2Vt has limited utility in the spine owing to the indiscriminate high heat generated.

Injection This technique is principally used in the treatment of unicameral bone cysts. Clinically apparent bone cysts have a tendency to recurrent fracture and need to be treated." However, they have no malignant potential ~ ,controversial ~~ and have been known to r e g r e s ~ .It~ is if corticosteroid injection is a necessary element of treatment-it has been shown that simple decompression of a cyst is sufficient to induce a regression.126 Cure rates of up to 50% are reported, with a median injection rate of three and a range of one to up to nine injecEach of these sessions requires the child to ti0ns.22,~~ be under anesthesia. Therefore, it has not been widely received. As alluded to earlier, various forms of decompression have been advocated in the literature with varying success. One approach involves the injection of bone marrow.s5.71,79,1°9,144Cure rates of up to 50% to 70% may be achieved. However, with this technique repeated injections may be necessary, incurring multiple inductions of anesthesia and donor site morbidity. Curettage, widely regarded to be the gold standard, has a recurrence rate of 5% to 50%.98Thus there is no clearly superior modality in the treatment of this condition.

NSAlD Treatment Although not a surgical modality, NSAID treatment has been used in the treatment of osteoid osteomas in selected individuals. In patients who have lesions in the spine or in the acetabular area, surgical or radiofrequency ablation could result in disordered growth, necessitating spinal fusions or corrective hip surgery. In these instances, NSAID treatment associated with a predictable amelioration of symptoms may be attempted. This can be continued as long as there are no gastric or renal side effects. Cure rates of up to 45% are possible but require protracted ingestion of NSAIDs for about 30 months.66

Resection Surgical decisions are based on the concept of compartments in relation to a tumor (Fig. 40-7). The compartment is bound by a barrier, which naturally limits the expansion of a tumor. When first described it was useful in teaching the principles of wide resection or a resection with a margin of healthy tissue: if a resection was performed outside a compartment it resulted in a margin that was free of maligThis idea was useful in drawing paralnant inv~lvement.~~ lels to conventional cancer surgery of the time. We realize now that this theory is flawed at many levels. For example, most osteogenic sarcomas present with tumors that have breached the cortex and so their distinction from a "contained osteogenic sarcoma is moot. In the lower limb a tumor that has involved the rectus femoris has involved a compartment extending from the anterior inferior iliac spine of the pelvis to the tibia1 tubercle. Clearly it would not be practical in this setting to perform a hindquarter amputation. Finally, especially in the region of the linea aspera, there are numerous perforating vessels, which go through the lateral intermuscular septum---clearly these do not form a continuous barrier to tumor spread. Still, the concept of compartmentalization is useful when one describes the surgical procedures as intralesional, marginal, wide, and radical." Although not often used in the context of amputations, these principles are applicable as well. Intralesional procedures, as the name implies, are procedures that leave macroscopic residual tissue. A biopsy or injection of a lesion is an intralesional procedure. A marginal procedure stops at the level of the extent of maximal expansion of a tumor. Curettage is a marginal procedure. A wide procedure goes beyond the reactive zone of the tumor. When first described, the "reactive zone" referred to the zone of reaction around the tumor marked by inflammatory change (i.e., hyperemia and This assessment was made predominantly at the time of surgery. With the advent of more sophisticated imaging modalities it can now be demonstrated that this "zone" may extend further than previously appreciated. Therefore, it appears that the description of a reactive zone is rather more abstract than real. As a general rule, resecting a tumor beyond its capsule where vessel tortuosity and edema is seen is a wide resection and hence this appreciation, while strongly influenced by newer imaging, remains largely surgical. Most malignant tumors are resected widely. A radical resection is an excision of the compartment in

CHAPTER

Resections

40

Bone Tumors

659

Amputations Radical

Radical

Wide Radical

Wide Marginal Marginal lntralesional lntralesional

Surgical margins in relation to the compartments involved. At left are the resections, and at right are the amputations. These classifications are largely academic because in the strictest terms most of the resections except radical resections and only wide or radical amputations are performed. Radical resections involve the compartment bearing the tumor and hence in this case would amount to removing the tibia (arrows). Marginal amputations may be resorted to in the spine and pelvis whereupon local adjuvants assume significant roles in disease control (see Fig. 40-6). Intralesional amputations are obviously not therapeutic applications in tumor surgery but are included here for completeness. Of interest, intercalary amputations in the pediatric population can be problematic when the remnant stump elongates through appositional growth. To avoid this complication it may be necessary to resort to a through-joint (e.g., through-knee) amputation.

which a tumor resides. An above-knee amputation for a tibia1 lesion is a radical resection. There are a number of surgical adjuvants that may be employed. This can be in the form of heat (e.g., argon beam coagulator) or cold (e.g., liquid nitrogen cryotherapy).80ta8In addition, chemical measures may be employed (e.g., phenol, polymethylmethacrylate ~ e m e n t ) . * In ~ , the l~~ occasional case, specialized forms of radiation (e.g., brachytherapy, intraoperative radiation therapy) may be used especially in the pelvis (see Fig. 40-6). The purpose of these surgical adjuvants is to extend the margins of resection beyond what can be mechanically removed by the surgeon. These improve local control of the tumor.

Benign Lesions It is useful at this juncture to recall the staging system for benign lesions. This is classified as benign, active, and aggressive. It is evident in these entities that even within this group specific nuances of the condition warrant special considerations. In benign bony conditions the procedures available are curettage, high-speed burring of lesional walls, , ~ ~ to adjuvant procedures, and wide r e s e c t i ~ n .It~is~helpful describe these procedures from most to least aggressive. In benign conditions, wide resection may occasionally be resorted to when the involved bone is expendable (e.g., rib or terminal phalanx of the little toe) or at the

end of a bone (e.g., distal ulna or proximal fibula). In these situations, reconstruction provides little value and can, in fact, be the source of considerable morbidity. Additionally, it may be resorted to in the context of a recalcitrant recurrent benign or aggressive lesion. Typical lesions that are resected in this manner are giant cell tumors, aneurysmal bone cysts, or fibrous dysplasia. Marginal excision is typified conceptually by the technique used to excise a soft tissue lipoma. Such a procedure is not technically feasible in most bony lesions. Osteochondromas and periosteal chondromas may be removed in such a fashion. Intralesional procedures are more commonly performed in benign tumors. This typically involves curettage of a lesion with high-speed burring of the wall. By and large this is the typical procedure for most latent or active benign bony conditions (e.g., unicameral bone cyst). The use of heat, cold (Fig. 40-8), or chemical modalities serves to extend this margin of clearance further and is typically used in active or aggressive tumors (e.g., giant cell tumor, chondroblastoma).

Malignant Lesions The sine qua non of the resection of malignant bone lesion is that at minimum a wide resection must be performed. In certain situations, however, this may not be possible

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Cryosurgery in a patient with chondrosarcoma. Liquid nitrogen is poured into a funnel that directs the agent into the lesion while avoiding contact with the surrounding skin. The effect of freezing extends the margins of necrosis beyond that which can be felt by the surgeon, effectively extending the surgical margins from an intralesional or marginal excision to a wide resection.

A

'

(e.g., a tumor that has expanded into the spinal canal or a t;mor that has invaded-into the ~ e l v i ccaGtv). ,, In these instances, the results tend to be suboptimal. With newer imaging modalities it is now often possible to perform a physeal-sparing procedure in growing children (Fig. 40-9). Although it used to be believed that the physis is an effective barrier to tumor spread, it has been shown that up to 80% of tumors abutting the physis have Physeal-sparing procedures in fact breached it.38,69,99,118 must therefore be carefully balanced with the response to chemotherapy to determine if this is feasible. As a variation on this theme it is occasionally possible to save the epiphysis and hence the neighboringjoint by performing a distraction procedure through the growth plate. This effectively increases the margin of normal tissue proximal to a tumor. A resection may then be performed through this now-lengthened segment.z4 Another approach to retaining a joint would be to perform a Van Nes rotationplasty (Fig. 40-10).133This procedure, generally undertaken for high-grade tumors about the kiee, involves wide extra-articular resections whereupon the distal leg and foot are joined to the proximal remaining femur. In the process, the sciatic nerve is resection of the femoral arterv retained and a segmental " with a true femoral-popliteal arterial anastomosis is performed. The foot is rotated with the heel pointing anteriorly. Of practical interest the distal segment is rotated externally, bringing the sciatic nerve and vessels anteromedially. This should be documented in the surgical note to facilitate further surgical procedures as may be necessary. The ankle, therefGre, finctions as a kneejoint. This procedure has poor acceptance among patients owing to their cosmetic abhorrence but is highly functional and durable.Z0 A similar Winkelmann procedure may be performed where the proximal tibia-is brought to.the hip. In children it is remarkable to note the plasticity and remodeling of these disparate bones, which in time will accommodate each other in a stable f a s h i ~ n . l ~ ~ . l ~ ~

B

A, Ewing's sarcoma of the tibia in an 11-year-oldboy. The lesion extended to 1 cm from the growth plate. It responded well to chemotherapy with virtually no remaining soft tissue involvement. A physeal-sparing resection was done along a resection plane (double-headed arrow) carefully performed under image intensifier guidance. B, The use of a pin fixator in this regard is extremely advantageous because it allows stabilization of the small proximal tibial segment that precludes routine pin fixation. The remaining gap was reconstructed with a proximal tibial allograft (thick arrow) and vascularized fibular graft (broken arrow) harvested with a paddle of skin, which provided skin cover of the construct.

Radical procedures and amputations have received poor support because they are regarded as being disfiguring. Studies have shown that patients with limb salvage procedures do better in terms of function and cost savings."J04 Although this appears true at face value, in-depth analysis shows that these studies are too heterogeneous to allow any firm conclusions. With the aid of modern prosthesis, patients with amputations are able to achieve very high levels of activity. Furthermore, complications are three to four times higher in limb salvage compared with limb ablative surgery. Although most series have not shown a significant survival benefit between amputation and limb-sparing surgery, these studies are underpowered or include cases of amputation being salvage procequestion that needs to be d ~ r e s . ~ ~ ,The ~ z , "primary ~ answered is whether there is any survival and functional benefit in two-site and stage-controlled groups with respect to amputation or wide resection. This would require a case-controlled study with amputation and wide resection arms, and it is a safe assumption that this will never be done. There is still a role for amputations, especially when the tumor is in the distal extremity, adjuvant therapies are ineffective, or reconstruction is too problematic because of nerve, vessel, or soft tissue problems.

CHAPTER

40

,)

Bone Tumors

661

\

Tumor

Above knee amputation\

Acetabular remodelling in Winkelrnann procedure

Van Nes rotationplasty\

/

Winkelrnann rotationplasty

A, Osteogenic sarcoma (arrow) with large soft tissue extension in an 8-year-old child. The small size of the child and high level of activity precluded endoprosthetic reconstruction. B, A Van Nes rotationplasty was performed. C, Variants of the rotationplasty are compared with the above-knee amputation. The bottom panel illustrates how the proximal tibia remodels and accommodates the acetabulum in the Winkelmann procedure.

Local recurrence in malignant lesions is a poor prognostic factor and is associated with a 90% fatality rate. It is generally a reflection of compromised local control, although in one study good chemotherapy response was associated with a low local recurrence rate.47Specifically, in this series when intralesional procedures had been performed for osteogenic sarcoma, standard responders were three times as likely to get a local recurrence as good responders. However, even among good responders, local recurrence was 14 times more likely if a intralesional procedure had been done as opposed to a wide resection. This underscores the need both for good surgical margins and effective chemotherapy.

Reconstruction In most instances after the resection of benign lesions, small defects arise. These are easily dealt with through the use of various gap fillers. With malignant lesions, large creative solutions are needed. It becomes difficult to determine which lesions are best treated by which technique because of the relative paucity of cases and the high-risk nature of these procedures. In this section we will highlight the various modalities available and the pertinent qualifiers for each modality.

Benign Lesions Following the resection of these lesions one is usually left with a small defect. In latent and perhaps active

conditions there is a low rate of local recurrence. Thus the aim here is the reconstitution of bone. The modalities that have been tried are bone graft and bone graft s u b stitutes. In general, autografts tend to have better incorporation rates but incur the risk of donor site morbidity or-worse--donor site tumor implantation. Allografts have a low risk of disease transmission and immunologic r e ~ p o n s e . l ~Synthetic J~~ grafts tend not to incorporate as well.aJ32 In the more aggressive lesions the risk of recurrence increases. In these situations bone substitutes could be resorbed by the disease process and increase the delay before subsequent radiologic imaging is able to distinguish between postoperative change and recurrence. In this setting, bone cement becomes a good alternative.a0J03 Furthermore, radiopaque cement acts as a contrast agent. Recurrence at the margin of the cemented defect can readily be identified and treated.

Malignant Lesions The solutions that have been tried to solve the complex bone, joint, and soft tissue defects left after tumor resections form a veritable cornucopia of techniques, spanning all of orthopedic and plastic surgery. It is impossible to reiterate all these solutions here. Instead, we present a list of principal solutions pertinent to the specific reconstructive option. The paramount requirement of all solutions is as a spacefiller and skin closure. Without these two requirements

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chemotherapy cannot resume and the patient will not survive. Most solutions will provide space-filling ability if there is adequate skin for closure. If skin closure is not possible a local flap or vascularized pedicular graft may be necessary. In some instances, especially with intercalary resections, the ability to provide intercalary stability with overlying skin closure can be provided by a vascularized fibular graft with a skin paddle. The skin paddle affords the additional advantage of monitoring the viability of the flap. Rotationplasties and their variants are remarkably functional solutions to the problem but have poor acceptance among patients because of their appearance. Similarly, amputations are often an instant solution to the problem, although even here the occasional exception exists.104 Joint reconstruction is a challenging endeavor. Biologic solutions include the use of bulk allograft (Fig. 40-11). They have the advantage of becoming incorporated by the body. The disadvantages82are high fracture rates of 19%, nonunion rates of 17%, and infection rates of 11%.

Osteoarticular allografts also become arthritic (16%) with time. Theoretically, however, with good incorporation of the allograft one would be able to perform a conventional less constrained joint replacement (Fig. 40-12). The endoprosthetic solution tends to be easier but is less resilient, suffering from wear and loosening with time.flJ"J4With advancements in technology, better designs will allow for longer-lasting implants (Fig. 40-13). The allograft prosthetic composite is another approach that appears to capitalize on the lasting nature of allografts and their soft tissue capsular attachments and the simplicity of prosthetics (Fig. 40-14). In very young children the available endoprostheses may be too large, and this may be a relative indication for the use of bulk allografts instead (see Fig. 40-1). Downsized pediatric implants are incapable of holding up in adults and are destined for failure and revision (Fig. 40-15). Prosthetic reconstruction has the distinct advantage of allowing immediate weight bearing, which is very important in patients who may have a reduced life expectancy. In truth, the various modalities are complementary rather than independent.

C

.

-

A, Ewing's sarcoma of the proximal tibia in an 11-year-old. Band C, This was widely resected and reconstructed with an osteoarticular tibia1 allograft. A gastrocnemius flap was raised to provide soft tissue cover to the construct. A

#

B • A, Resection and reconstruction of Ewing's sarcoma of the pelvis. B, Degenerative changes developed in his hip 2 years later and required hip replacement surgery. d

l

CHAPTER

A

Bone Tumors

A

.

- AI A, Osteogenic sarcoma in a 16-year-old girl. B, An endoprosthetic device was placed in the patient after resection of the lesion. C, With growth of the child, it becomes occasionally necessary to swap implants with devices that can provide further extensibility. prox.imal hum era1 losite was

663

Growth is a complex problem in the management of these patients. In the year that patients receive chemotherapy growth is often stunted. After this, however, the child resumes growth. There are various means to predict this growth.Xg% a rule of thumb, the distal femur grows 1 cm a year and the proximal tibia grows 7 mm a year. Girls generally stop growing at 14 years and boys at 16 years. Therefore, a 10-year-old boy who had an extra-articular resection would have potentially 10 cm of growth to accommodate. In general, a 2-cm length discrepancy is considered compensable and does not require treatment. Thus, in this example an additional 8-cm correction is needed. The modalities available include contralateral epiphysiodeses. This method ablates the growth plate of the contralateral knee. The procedure needs to be timed accurately and tends to be really only practical in the older child approaching the last few centimeters of growth. Bone transport is another option. This yields good results but the child must remain in the apparatus for long periods of time. At an elongation rate of 1 mm/day, the child with an 8-cm defect must remain in the apparatus at minimum for 3 months for the elongation and a further 3 months for consolidation of the regenerate (Fig. 40-16). This duration is commonly doubled when distraction osteogenesis is done during chemotherapy. Even in healthy individuals the risk of pin tract infection during the procedure is greater than 9076." In the patient with malignant disease who is to receive chemotherapy this would be an important consideration.Io5In addition, the regenerate tends to be weak and is prone to fracture (Fig. 40-17). Patients on chemotherapy are prone to osteoporosis and are already at risk for fracture. The extensible prosthesis is a marvel of modern science that is presently ;ndergoing "teething" issues.111.112,1m-134 The manual designs require repeated surgical procedures to periodically lengthen the limb to keep pace with L.

B

r: -

A, 0,steogeiiic s; humerus of a l&year-old boy. B, A resection with allograft and PIrostlused to reconstruct the defect

40

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Ewing's sarcoma of the tibia. The patient underwent wide resection and a planned bone transport procedure. The middle ring ( a m ) is secured to a segment of bone that has been osteotomized. This segment of bone is allowed 5 days for a provisional callus to form. By progressively advancing the ring distally at a rate of 1 mm/day, the segment of bone is transported to fill the defect while at the same time remaining connected to the proximal tibia. This regenerate is weak and requires an equivalent amount of time to consolidate. For example, an 80-mm defect would require 5 days to form provisional callus, 80 days to lengthen, and 80 days to consolidate befire removal of the frame. This ungainly device needs to be tolerated by the patient for the duration of the limblengthening procedure.

As such there are many solutions to the problem but no perfect one. Therefore, it is apparent that the surgeon dealing with this condition must be able to perform or at least facilitate all of these procedures. Any one of these procedures is applicable to the individual case, and they remain complementary to each other.

A

.

B

- A# A, Osteogenic sarcoma of the proximal femur in a 14year-old girl. B, A wide resection and bipolar hemiarthroplasty with proximal femoral replacement was performed. Of note, the femoral head matched the acetabulum so an additional bipolar component was not added.

normal growth (see Fig. 40-13C). The Stanmore implants have been used for nearly 20 years and have a 23% revision rate.'" Survivorship analysis, however, shows a nearzero survivorship at 10 years.lZ9 Self-extending designs work through electromagnetic couplers or heating coils that allow motors or heat release springs to extend the implant. The Phenix device is presently undergoing evaluation in the United States.138 Preliminary results show a complication rate of up to 44%, necessitating revision. The Repiphysis system uses an external electromagnetic field to provide controlled released of a spring held in place by a locking mechanism. This device is associated with a implant revision rate of 44%.49 In general, the stems in these devices are too narrow and mechanically insufficient and fixation techniques remain inadequate. As such, all these designs have poor longevity but reduce immediate surgical complications (e.g., infection). They are well tolerated by patients and families.

SPECIFIC CONSIDERATIONS In this section specific issues are highlighted that pertain to characteristics of the individual case and the way they may affect management. A discussive rather than a didactic style is used to facilitate familiarity with the problems and to unify the concepts as presented in the section on general considerations. Features specific to respective diagnoses are covered in the section on pathophysiology.

Diagnosis In the very young child, below 5 years of age, the patient who presents with a lesion in the bone is likely to have one of only a few diagnoses (see Table 40-1). The main considerations in this group are infection and localized manifestations of systemic malignancies (i.e., leukemias). Consideration should be given to metastatic disease, which in this group is often neuroblastoma. In the group between 5 and 10 years of age, Ewing's family tumor needs to be considered. In the second decade, with increased activity of the child and increased use of radiographs in assessing incidental trauma, many of the benign conditions are diagnosed. In addition, osteogenic sarcoma and Ewing's family tumor become prevalent.

CHAPTER

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665

Site The implications of site of disease in relation to pathology and pathophysiology have been alluded to earlier. Here the focus is on the implications of site of involvement to the reconstruction of a defect.

Upper Limbs

A

B

A, A patient presented with osteogenic sarcoma of the proximal humerus that was resected and reconstructed with a vascularized fibular graft shoulder arthrodesis at 6 years of age. He developed a shortened humerus at maturity, which was lengthened. B, Post lengthening, the regenerate was protected with a plate and hypertrophied with time.

Growth Issues of linear growth have been touched on earlier. In the treatment of conditions of the bone adjacent to a physis the potential for future growth should be considered. This is more prudent in the benign case when conceivably nonsurgical management can be offered without dire consequences. Thus in the typical case of the unicameral bone cyst adjacent to the growth plate it may be prudent not to subject the physis to curettage, accepting that this may increase recurrence rates. In the case of a chondroblastoma, which tends to be more aggressive, however, growth plate damage may be unavoidable and a local adjuvant may be indicated (e.g., cryosurgery). By contrast in malignant conditions, sacrificing the growth plate with the aim of achieving good surgical margins is an acceptable concession (see Fig. 40-13).

In general terms, load-bearing requirements in the upper limbs differ considerably from those in the lower limb. In the upper limb the prehensile functions of feeding and personal hygiene are considered fundamental in terms of goals of surgery. In the lower limb, weight bearing is paramount. With that in mind the upper limb tends to be more forgiving in terms of reconstructive durability but more demanding in terms of mobility. The following discussion is more applicable to large segmental bony defects. Cavitary lesions are managed with appropriate bone fillers (see bone graft and bone graft substitutes, earlier). In the shoulder, good function can be achieved by ~~~~~~~~~ periscapular resections and r e c o n s t r ~ c t i o n s . 2The options for reconstruction here involve suspensory arthroplasties or scapular replacements (see Fig. 40-4). Abduction is limited, but otherwise prehensile function remains good. Humeral resections generally perform well but, owing to the indicated pathologic processes, tend to be applicable only to lower grade lesions. Replacements with osteoarticular allografts (see Fig. 40-1) or allograft prosthetic composites (see Fig. 40-13) afford good replacement of function. In lower-grade lesions, in which the deltoid and rotator cuff may be retained, abduction is often acceptable. The elbow has limited options because of the poor soft tissue coverage in this area.l*OJ31J36Osteoarticular allografts and endoprosthesis provide reasonable flexion and extension and pronation and supination. Forearm bone resections are highly specialized affairs involving intercalary bone resections and replacement with vascularized fibular grafts. In the event of wrist disruption, this may have to be fused. Involvement of various nerves in the forearm may necessitate tendon transfers. Cross circulation in the palm is an important sign to document in the event of the need to sacrifice the radial or ulnar artery. Lesions occurring distally in the hand rarely require treatment if benign and often require varying forms of amputation if malignant.

Lower Limbs In the lower limb, pelvic resections are classified into type I resections above the acetabulum, type I1 resections in the periacetabular area, and type 111 resections below the acetabulum.1~21JOOComplications in this type of surgery are very high, mainly because the internal iliac supply to the posterior gluteal flap is often disrupted in the process of resection and because the duration of the procedures is long. In addition, because of the limited bone available afterward, reconstructive options become challenging.

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In type I resections, the need is for a strut to span the remaining hemipelvis to the sacrum. Allografts or autogenous fibular grafts are usually used in this context. This is occasionally not possible and a defect is left. In these cases patients are able to function reasonably well. In type I1 resections, replacement of the joint becomes necessary. This can be achieved through a custom prosthesis, an allograft-prosthetic composite (see Fig. 40-12), or an arthrodesis. Type I11 resections are usually stable and can be left with a defect. Combination defects especially after type 1-11 resections are especially challenging. The options include allograft prosthetic composites and saddle prostheses. Occasionally, hindquarter amputations are still necessary. In proximal femoral lesions, articular involvement may necessitate type 11-like extra-articular pelvic resections and reconstructions. Contained proximal femoral lesions are treated with prostheses or allograft prosthetic composites. Intercalary femoral and tibial resections are generally managed with allografts or vascularized fibular autografts or combinations of these. Bone transport is another viable option but, as mentioned, takes a protracted course and has a high complication rate. Recent work suggests that pin fixators are safe even if the patient is to undergo chemotherapy. Resections about the knee are generally treated with Bulk osteoarticular endoprosthetic re~onstmction.~~~~~3o~~~~~ allografts have been used and provide reasonable function (see Fig. 40-11). These invariably become arthritic with time.8' But at that point a more traditional joint replacement may be performed. Arthrodeses have generally fallen out of favor, although they remain good alternatives with reasonable function in the appropriate setting.lo4 In the ankle, variable resections of the fibula may be performed with reasonable expectation of function. In general, with tibial resections, arthrodesis needs to be performed.27,2"lo4 In the foot, as with the hand, various types of amputations are generally recommended.

and surgical induction of remission by removal of all macroscopic disease. These are multidisciplinary efforts that should be reserved for specialized centers. Patients may have to undergo segmental pulmonary resections together with resections of their tumors and reconstructic& thereof. The patient who develops metastases after a remission has a very variable prognosis, ranging from 0% to 26% in ~ ' these ~ ~ ~ patients, although the princivarious s e r i e ~ . In ples of management are similar, the expectation is different. Surgical induction of remission is still a very effective method in these patients and the main determinant of survival.44This entails bilateral thoracotomies and segmental resections of solitary bony metastases as needed.S12l Ironically, owing to the poor prognosis, limb salvage surgery is relatively indicated. This, however, needs to be balanced with the duration of recuperation from surgery during which the child will not be on chemotherapy. The surgeon should select the operation with the fastest most predictable recovery. For example, this would drive the decision to use a cemented prosthesis rather than the uncemented i m ~ l a n tthat would be used in localized disease in children. Timing of surgery can be complex. Pulmonary metastasis occurring at presentation of the primary lesion should be resected in a staged manner during recovery from the primary resection. A lesion that develops during consolidation chemotherapy should be resected after completion of a round of chemotherapy. Metastasis that develops after chemotherapy should be aggressively resected, with consideration given to staged bilateral thoracotomies if this occurs early. In these patients the issues df management may not necessarily be curative. The surgeon needs to be able to balance the procedures that may be offered with the expected prognosis of the child. Two actual cases illustrate this point.

Case 1 Metastatic Disease The implications of aggressiveness in the case of benign lesions and compartmentalization in the case of malignancies have been touched on previously. Here the discussion is confined to metastatic osteogenic sarcoma and Ewing's family tumor. Patients with metastatic osteogenic sarcoma may present in two settings: the patient with metastasis at the outset and the patient who has developed metastasis despite having had a remission. It has been shown that patients who present with early unilateral pulmonary metastasis within 2 years of diagnosis have a high incidence of contralateral disease and should undergo staged Late unilateral pulmonary bilateral thora~otomies.l2~ metastasis tends not to be associated with contralateral disease. Patients with metastasis at the outset have been shown to have a survival of 11% to 36%.9,93Management of this group requires the aggressive implementation of chemotherapy to treat unrecognized microscopic disease

A patient with advanced osteogenic sarcoma of the tibia fungating through the skin presents for the first time with multiple metastases to the lungs and regional lymph nodes. Note that in the AJCC staging system this patient has stage IVB disease. This patient underwent an amputation before chemotherapy. A few questions arise, the foremost being why a limb salvage procedure was not performed in this case. Limb salvage in this case would have required either an allograft or vascularized fibular graft and hardware to be placed into the defect. This would have incurred a significant risk of skin breakdown and infection, requiring a free muscle flap. In the meantime the metastatic disease would have progressed and the patient might have died. When a thoracotomy for this patient is done to resect.the pulmonary metastases, it should be planned with consideration that a free latissimus flap may be needed and so the muscle should not be compromised. A second question may be posed as to the use of neoadjuvant therapy in this setting. Here, the patient would

CHAPTER

have been immunocompromised in the presence of an infected wound. Hence in this situation the most prudent approach was an amputation.

Case 2 A patient with a history of osteogenic sarcoma of the left distal femur that has been resected and reconstructed and is 2 years out from chemotherapy now presents with metastasis in the right distal femur and proximal tibia. This patient underwent resection and reconstruction with an endoprosthesis. An amputation would not have been curative in this case because it is assumed that other sites of metastases must exist. Yet a surgical induction of remission was necessary because the patient developed metastases soon after chemotherapy and thus may have developed resistance to the chemotherapeutic agents. These two cases illustrate the many levels of complexity that underlie the management of these patients. Only through a careful consideration of all factors can the most appropriate line of management be offered.

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11. Berg HL, Weiland AJ: Multiple osteogenic sarcoma following bilateral retinoblastoma: A case report. J Bone Joint Surg Am 1978;60:251-253. 12. Bertoni F, Bacchini P, Staals EL: Malignancy in giant cell tumor. Skeletal Radio1 2003;32:143-146. 13. Bertoni F, Bacchini P, Staals EL: Malignancy in giant cell tumor of bone. Cancer 2003;97:2520-2529. 14. Bielack SS, Kempf-Bielack B, Delling G, et al: Prognostic factors in high-grade osteosarcoma of the extremities or trunk: An analysis of 1,702 patients treated on neoadjuvant cooperative osteosarcoma study group protocols. J Clin Oncol 2002;20:776-790. 15. Bonin G, Scamps C , Turc-Carel C, Lipinski M: Chimeric EWS-FLI1 transcript in a Ewing cell line with a complex t(11;22;14) translocation. Cancer Res 1993;53:3655-3657. 16. Brenner W, Bohuslavizki KH, Eary JF: PET imaging of osteosarcoma. J Nucl Med 2003;44:930-942. 17. Brownlow HC, Simpson AH: Comwlications of distraction osteogenesis: A changing pattern.'Am J Orthop 2002;31: 31-36. 18. Caffey J: On fibrous defects in cortical walls of growing tubular bones: Their radiologic appearance, structure, prevalence, natural course, and diagnostic significance. Adv Pediatr 1955;7:13-51. 19. Cahan WG, Woodard HQ, Higinbotham NL, et al: Sarcoma arising in irradiated bone: Report of eleven cases: 1948. Cancer 1998;82:8-34. 20. Cammisa FP Jr, Glasser DB, Otis JC, et al: The Van Nes tibia1 rotationplasty: A functionally viable reconstructive procedure in children who have a tumor of the distal end of the femur. J Bone Joint Surg Am 1990;72:1541-1547. 21. Campanacci M, Capanna R: Pelvic resections: The Rizzoli Institute experience. Orthop Clin North Am 1991; 22:65-86. 22. Campanacci M, De Sessa L, Trentani C: Scaglietti's method for conservative treatment of simple bonecysts with local injections of methylprednisolone acetate. Ital J Orthop Traumatol 1977;3:27-36. 23. Campanacci M, Ruggieri P, Gasbarrini A, et al: Osteoid osteoma: Direct visual identification and intralesional excision of the nidus with minimal removal of bone. J Bone Joint Surg Br 1999;81:814820. 24. Canadell J, Forriol F, Cara JA: Removal of metaphyseal bone tumours with preservation of the epiphysis: Physeal distraction before excision. J Bone Joint Surg Br 1994; 76:127-132. 25. Capanna R, Sudanese A, Baldini N, Campanacci M: Phenol as an adjuvant in the control of local recurrence of benign neoplasms of bone treated by curettage. Ital J Orthop Traumatol 1985;11:381-388. 26. Capanna R, van Horn JR, Biagini R, et al: The TikhoffLinberg procedure for bone tumors of the proximal humerus: The classical "extensive" technique versus a modified "transglenoid" resection. Arch Orthop Trauma Surg 1990;109:63-67. 27. Casadei R, Ruggieri P, Giuseppe T, et al: Ankle resection arthrodesis in patients with bone tumors. Foot Ankle Int 1994;15:242-249. 28. Centers for Disease Control and Prevention, National Cancer Institute, and North American Association of Central Cancer Registries: United States Cancer Statistics: 2000 Incidence. 2000. 29. Chou LB, Malawer MM: Analysis of surgical treatment of 33 foot and ankle tumors. Foot Ankle Int 1994;15: 175-181. 30. Cook A, Raskind W, Blanton SH, et al: Genetic heterogeneity in families with hereditary multiple exostoses. Am J Hum Genet 1993;53:71-79.

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31. Damien CJ, Parsons JR: Bone graft and bone graft substitutes: A review of current technology and applications. J Appl Biomater 1991;2:187-208. 32. de Alava E, Antonescu CR, Panizo A, et al: Prognostic impact of P53 status in Ewing sarcoma. cancer 2000;89:783-792. 33. de Berg JC, Pattynama PM, Obermann WR, et al: Percutaneous computed-tomography-guided thermocoagulation for osteoid osteomas. Lancet 1995;346:350-351. 34. de Moor NG: Osteosarcoma: A review of 72 cases treated by megavoltage radiation therapy, with or without surgery. S Afr J Surg 1975;13:137-146. 35. Docquier PL, Delloye C: Treatment of simple bone cysts with aspiration and a single bone marrow injection. J Pediatr Orthop 2003;23:766773. 36. Enneking WF: Musculoskeletal Tumor Surgery. New York: Churchill Livingstone, 1983, vol2, p 1351. 37. Enneking, WF. Musculoskeletal Tumor Surgery. New York: Churchill Livingstone, 1983,vol 1, pp 89-122. 38. Enneking WF, Kagan A. Transepiphyseal extension of osteosarcoma: Incidence, mechanism, and implications. Cancer 1978;41:15261537. 39. Enneking WF, Spanier SS, Goodman MA: A system for the surgical staging of musculoskeletal sarcoma. Clin Orthop Relat Res 1980;(153):106120. 40. Fagnou C, Michon J, Peter M, et al: Presence of tumor cells in bone marrow but not in blood is associated with adverse prognosis in patients with Ewing's tumor. SociCtC Fran~aised'oncologie Pediatrique. J Clin Oncol 1998; 16:1707-1711. 41. Fain JS, Unni KK, Beabout JW, Rock MG: Nonepiphyseal giant cell tumor of the long bones: Clinical, radiologic, and pathologic study. Cancer 1993;71:35143519. 42. Ferrari S, Bacci G, Picci P, et al: Long-term follow-up and post-relapse survival in patients with non-metastatic osteosarcoma of the extremity treated with neoadjuvant chemotherapy. Ann Oncol 1997;8:765-771. 43. Ferrari S. Bertoni F. Mercuri M. et al: Predictive factors of disease-free survival for non-metastatic osteosarcoma of the extremity: An analysis of 300 patients treated at the Rizzoli Institute. Ann Oncol 2001;12:1145-1150. 44. Ferrari S, Briccoli A, Mercuri M, et al: Postrelapse survival in osteosarcoma of the extremities: Prognostic factors for long-term survival.J Clin Oncol 2003;21:710-715. 45. Fidler M: Prophylactic internal fixation of secondary neoplastic deposits in long bones. BMJ 1973;1:341-343. 46. Fidler M: Incidence of fracture through metastases in long bones. Acta Orthop Scand 1981;52:623-627. 47. Gherlinzoni F, Picci P, Bacci G, Campanacci D: Limb sparing versus amputation in osteosarcoma: Correlation between local control, surgical margins and tumor necrosis: Istituto Rizzoli experience. Ann Oncol 1992;3(Supp1 2): S23-S27. 48. Ghosh L, Huvos AG, Mike V: The pancreatic islets in chondrosarcoma: A qualitative and quantitative study in humans. Am J Pathol 1973;71:23-32. 49. Gitelis S, Nee1 MD, Wilkins RM, et al: The use of a closed expandable prosthesis for pediatric sarcomas. Chir Organi Mov 2003;88:327-333. 50. Glaubiger DL, Makuch R, Schwarz J, et al: Determination of prognostic factors and their influence on therapeutic results in patients with Ewing's sarcoma. Cancer 1980;45:2213-2219. 51. Goldie JH, Coldman AJ, Gudauskas GA: Rationale for the use of alternating non-cross-resistant chemotherapy. Cancer Treat Rep 1982;66:439-449. 52. GoldweinJW: Effects of radiation therapy on skeletal growth in childhood. Clin Orthop Relat Res 1991;(262):101-107.

53. Greene FL: AJCC Cancer Staging Manual, 6th ed. New York, Springer-Verlag, 2002. 54. Grimer RJ, Carter SR, Pynsent PB: The cost-effectiveness of limb salvage for bone tumours. J Bone Joint Surg Br 1997; 79:558-561. 55. Grimer RJ, Taminiau AM, Cannon SR: Surgical outcomes in osteosarcoma. J Bone Joint Surg Br 2002;84:395-400. 56. Haas A, Ritter SA: Benign giant-cell tumor of femur with embolic metastasis in prepuce of penis. Am J Surg 1955; 89:573-578. 57. Ham SJ, Schraffordt KH, Veth RP, et al: Limb salvage surgery for primary bone sarcoma of the lower extremities: Long-term consequences of endoprosthetic reconstructions. Ann Surg Oncol 1998;5:423-436. 58. Harrington KD: The role of surgery in the management of pathologic fractures. Orthop Clin North Am 1977; 85341. 59. Hasegawa T, Hirose T, Sakamoto R, et al: Mechanism of pain in osteoid osteomas: An immunohistochemical study. Histopathology 1993;22:487-491. 60. Hogeboom WR, Hoekstra HJ, Mooyaart EL, et al: Magnetic resonance imaging (MRI) in evaluating in vivo response to neoadjuvant chemotherapy for osteosarcomas of the extremities. Eur J Surg Oncol 1989;15:424430. 61. Huvos AG: "Benign" metastasis in giant cell tumor of bone. Hum Pathol 1981;12:1151. 62. Huvos AG: Bone Tumors-Diagnosis, Treatment & Prognosis, 2nd ed. Philadelphia, WB Saunders, 1991. 63. Huvos AG, Rosen G, Bretsky SS, Butler A: Telangiectatic osteogenic sarcoma: A clinicopathologicstudy of 124 patients. Cancer 1982;49:1679-1689. 64. Huvos AG, Rosen G, Marcove RC: Primary osteogenic sarcoma: Pathologic aspects in 20 patients after treatment with chemotherapy en bloc resection, and prosthetic bone replacement. Arch Pathol Lab Med 1977;101:1418. 65. Huvos AG, Woodard HQ, Cahan WG, et al: Postradiation osteogenic sarcoma of bone and soft tissues: A clinicopathologic study of 66 patients. Cancer 1985;55:12441255. 66. Ilyas I, Younge DA: Medical management of osteoid osteoma. Can J Surg 2002;45:435-437. 67. Jaffe HL: Tumors and Tumorous Conditions of the Bones and Joints. Philadelphia, Lea & Febiger, 1958. 68. Jaffe N, Carrasco H, Raymond K, et al: Can cure in patients with osteosarcoma be achieved exclusively with chemotherapy and abrogation of surgery? Cancer 2002;95:2202-2210. 69. Jesus-Garcia R, Seixas MT, Costa SR, et al: Epiphyseal plate involvement in osteosarcoma. Clin Orthop Relat Res 2000;(373):32-38. 70. Klenner T, Wingen F, Keppler BK, et al: Anticancer-agentlinked phosphonates with antiosteolytic and antineoplastic properties: A promising perspective in the treatment of bone-related malignancies? J Cancer Res Clin Oncol 1990;116:341-350. 71. Kose N, Gokturk E, Turgut A, et al: Percutaneous autolcgous bone marrow grafting for simple bone cysts. Bull Hosp Jt Dis 1999;58:105-110. 72. Kyriakos M, Land VJ,Penning HL, Parker SG: Metastatic chondroblastoma: Report of a fatal case with a review of the literature on atypical, aggressive, and malignant chondroblastoma. Cancer 1985;55:1770-1789. 73. Ladanyi M, Traganos F, Huvos AG: Benign metastasizing giant cell tumors of bone: A DNA flow cytometric study. Cancer 1989;64:1521-1526. 74. Le Merrer M, Legeai-Mallet L, Jeannin PM, et al: A gene for hereditary multiple exostoses maps to chromosome 19p. Hum Mol Genet 1994;3:717-722. 75. Lee ES: Osteosarcoma: A reconnaissance. Clin Radio1 1975; 26:5-25.

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76. Levine AM, Rosenberg SA: Alkaline phosphatase levels in osteosarcoma tissue are related to prognosis. Cancer 1979;44:2291-2293. 77. Li FP, Fraumeni JF Jr: Soft-tissue sarcomas, breast cancer, and other neoplasms: A familial syndrome? Ann Intern Med 1969;71:747-752. 78. Li FP, Garber JE, Friend SH, et al: Recommendations on predictive testing for germ line p53 mutations among cancerprone individuals. J Natl Cancer Inst 1992;84:1156-1160. 79. Lokiec F, Ezra E, Khermosh 0 , Wientroub S: Simple bone cysts treated by percutaneous autologous marrow grafting: A preliminary report. J Bone Joint Surg Br 1996;78:934937. 80. Malawer MM, Dunham W: Cryosurgery and acrylic cementation as surgical adjuncts in the treatment of aggressive (benign) bone tumors: Analysis of 25 patients below the age of 21. Clin Orthop Relat Res 1991;(262):42-57. 81. Malkin D,Jolly KW, Barbier N, et al: Germline mutations of the p53 tumor-suppressor gene in children and young adults with second malignant neoplasms. N Engl J Med 1992;326:1309-1315. 82. Mankin HJ, Gebhardt MC, Jennings LC, et al: Long-term results of allograft replacement in the management of bone tumors. Clin Orthop Relat Res 1996;(324):86-97. 83. Mankin HJ, Lange TA, Spanier SS: The hazards of biopsy in patients with malignant primary bone and soft-tissue tumors. J Bone Joint Surg Am 1982;64:1121-1127. 84. Mankin HJ, Mankin CJ, Simon MA: The hazards of the biopsy, revisited. Members of the Musculoskeletal Tumor Society. J Bone Joint Surg Am 1996;78:656663. 85. Marcove RC, Francis KC: Chondrosarcoma and altered carbohydrate metabolism. N Engl J Med 1963;268: 1399-1400. 86. Marcove RC, Huvos AG: Cartilaginous tumors of the ribs. Cancer 1971;27:794801. 87. Marcove RC, Mike V, HajekJV, et al: Osteogenic sarcoma under the age of twenty-one: A review of one hundred and forty-five operative cases. J Bone Joint Surg Am 1970;52:411-423. 88. Marcove RC, Miller TR: Treatment of primary and metastatic bone tumors by cryosurgery. JAMA 1969;207: 1890-1894. 89. Marcove RC, Rosen G: Radical en bloc excision of Ewing's sarcoma. Clin Orthop Relat Res 1980;(153):86-91. 90. Martin SE, Dwyer A, Kissane JM, Costa J: Small-cell osteosarcoma. Cancer 1982;50:990-996. 91. Matsuno T, Unni KK, McLeod RA, Dahlin DC: Telangiectatic osteogenic sarcoma. Cancer 1976;38:25382547. 92. Meyers PA, Heller G, Healey J , et al: Chemotherapy for nonmetastatic osteogenic sarcoma: The Memorial SloanKettering experience. J Clin Oncol 1992;10:5-15. 93. Meyers PA, Heller G, Healey JH, et al: Osteogenic sarcoma with clinically detectable metastasis at initial presentation. J Clin Oncol 1993;11:449-453. 94. Mirra JM, Gold RH, Rand F: Disseminated nonossifylng fibromas in association with cafe-au-lait spots (JaffeCampanacci syndrome). Clin Orthop 1982;(168):192-205. 95. Moseley CF: A straight-line graph for leg-length discrepancies. J Bone Joint Surg Am 1977;59:174179. 96. Moser RP Jr, Madewell JE: An approach to primary bone tumors. Radiol Clin North Am 1987;25:1049-1093. 97. MouldJ, Adam NM: The problem of avascular necrosis of bone in patients treated for Hodgkin's disease. Clin Radiol 1983;34:231-236. 98. Neer CS, Francis KC,Johnston AD, Kiernan HAJr: Current concepts on the treatment of solitary unicameral bone cyst. Clin Orthop Relat Res 1973;(97):40-51. 99. Norton KI, Hermann G, Abdelwahab IF, et al: Epiphyseal involvement in osteosarcoma. Radiology 1991;180:813-816.

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100. O'Connor MI, Sim FH: Salvage of the limb in the treatment of malignant pelvic tumors. J Bone Joint Surg Am 1989;71:481-494. 101. O'Connor MI, Sim FH, Chao EY Limb salvage for neoplasms of the shoulder girdle: Intermediate reconstructive and functional results. J Bone Joint Surg Am 1996;78: 1872-1888. 102. Peat BG, Bell RS, Davis A, et al: Wound-healing complications after soft-tissue sarcoma surgery. Plast Keconstr Surg 1994;93:980-987. 103. Persson BM, Wouters HW:Curettage and acrylic cementation in surgery of giant cell tumors of bone.Clin Orthop Relat Res 1976;(120):125-133. 104. Renard AJ, Veth RP, Schreuder HW, et al: Function and complications after ablative and limb-salvage therapy in lower extremity sarcoma of bone. J Surg Oncol 2000;73: 198-205. 105. Rod1 R, Gosheger G, Leidinger B, et al: Correction of leglength discrepancy after hip transposition. Clin Orthop Relat Res 2003;(416):271-277. 106. Rosen G, Nirenberg A, Caparros B, et al: Osteogenic sarcoma: Eight-percent, three-year, disease-free survival with combination chemotherapy (T-7). Natl Cancer Inst Monogr 1981;(56):213-220. 107. Rosenthal DI, Hornicek FJ, Wolfe MW, et al: Percutaneous radiofrequency coagulation of osteoid osteoma compared with operative treatment. J Bone Joint Surg Am 1998;80:815-821. 108. Rosito P, Mancini AF, Rondelli R, et al: Italian Cooperative Study for the treatment of children and young adults with localized Ewing sarcoma of bone: A preliminary report of 6 years of experience. Cancer 1999;86:421-428. 109. Rougraff BT, Kling TJ: Treatment of active unicameral bone cysts with percutaneous injection of demineralized bone matrix and autogenous bone marrow. J Bone Joint Surg Am 2002;84:921-929. 110. Scaglietti 0 , Marchetti PG, Bartolozzi P: The effects of methylprednisolone acetate in the treatment of bone cysts: Results of three years follow-up.J Bone Joint Surg Br 1979;61:200-204. 111. Schiller C, Windhager R, Fellinger EJ, et al: Extendable tumour endoprostheses for the leg in children. J Bone Joint Surg Br 1995;77:608-614. 112. Schindler OS, Cannon SR, Briggs TW, et al: Use of extendable total femoral replacements in children with malignant bone tumors. Clin Orthop Relat Res 1998;(357): 157-170. 113. Scully SP, Ghert MA, Zurakowski D, et al: Pathologic fracture in osteosarcoma: Prognostic importance and treatment implications. J Bone Joint Surg Am 2002;84:49-57. 114. Scully SP, Temple HT, O'Keefe RJ, et al: The surgical treatment of patients with osteosarcoma who sustain a pathologic fracture. Clin Orthop Relat Res 1996;(324):227-232. 115. Selch MT, Parker KG: Radiation therapy in the management of Langerhans cell histiocytosis. Med Pediatr Oncol 1990;18:97-102. 116. Sim FH, Unni KK, Beabout JW, Dahlin DC: Osteosarcoma with small cells simulating Ewing's tumor. J Bone Joint Surg Am 1979;61:207-215. 117. Simon MA, Aschliman MA, Thomas N, Mankin HI: Limbsalvage treatment versus amputation for osteosar~omaof t Am 1986; the distal end of the femur. J Bone ~ o i n Surg 68:1331-1337. 118. Simon MA, Bos GD: Epiphyseal extension of metaphyseal osteosarcoma in skeletally immature individuals. J Bone Joint Surg Am 1980;62:195-204. 119. Solomon L: Bone growth in diaphysial aclasis. J Bone Joint Surg Br 1961;43:700-716.

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120. SperlingJW, Pritchard DJ, Morrey BF: Total elbow arthroplasty after resection of tumors at the elbow. Clin Orthop Relat Res 1999;(367):256-261. 121. Su WT, Chewning J, Abramson S, et al: Surgical management and outcome of osteosarcoma patients with unilateral pulmonary metastases. J Pediatr Surg 2004;39:41&423. 122. Suit HD: Role of therapeutic radiology in cancer of bone. Cancer 1975;35:930-935. 123. Thorpe WP, Reilly JJ, Rosenberg SA: Prognostic significance of alkaline phosphatase measurements in patients with osteogenic sarcoma receiving chemotherapy. Cancer 1979;43:2178-2181. 124. Topchida J,Yamaguchi T, Dayton SH, et al: Prevalence and spectrum of germline mutations of the p53 gene among patients with sarcoma. N Engl J Med 1992;326:1301-1308. 125. Tomford WW: Bone allografts: Past, present and future. Cell Tissue Bank 2000;1:105-109. 126. Tsuchiya H, Abdel-Wanis ME, Uehara K, et al: Cannulation of simple bone cysts. J Bone Joint Surg Br 2002;84:245-248. 127. Tucker MA, D'Angio GJ, Boice JD Jr, et al: Bone sarcomas linked to radiotherapy and chemotherapy in children. N Engl J Med 1987;317:588-593. 128. Unni KK: Dahlin's Bone Tumors-General Aspects and Data on 11,087 Cases, 5th ed. Philadelphia, LippincottRaven, 1996. 129. Unwin PS, Blunn GW: Advances in the design of extendible replacements: An analysis of 597 replacements. In: Proceedings of the Musculoskeletal Tumor Society, Long Beach, CA: Musculosketal Tumor Society, 2004, p 51. 130. Unwin PS, Walker PS: Extendible endoprostheses for the skeletally immature. Clin Orthop Relat Res 1996;(322): 179-193. 131. Urbaniak JR, Aitken M: Clinical use of bone allografts in the elbow. Orthop Clin North Am 1987;18:311-321. 132. Vaccaro AR, Chiba K, Heller JG, et al: Bone grafting alternatives in spinal surgery. Spine J 2002;2:206-215. 133. Van Nes CP: Rotation-plasty for congenital defects of the femur: Making use of the shortened limb to control the knee joint of a prosthesis.J Bone Joint Surg Br 1950;32:12-16.

134. Verkerke GJ, Schraffordt KH, Veth RP, et al: An extendable modular endoprosthetic system for bone tumour management in the leg. J Biomed Eng 1990;12:91-96. 135. Vigorita VJ: Orthopaedic Pathology. Philadelphia, Lippincott Williams & Wilkins, 1999. 136. Weber KL, Lin PP, Yasko AW: Complex segmental elbow reconstruction after tumor resection. Clin Orthop Relat Res 2003;(415):31-44. 137. Wilkins RM, Cullen JW, Odom L, et al: Superior survival in treatment of primary nonmetastatic pediatric osteosarcoma of the extremity. Ann Surg Oncol 2003;lO: 498-507. 138. Wilkins RM, Soubeiran A: The Phenix expandable prosthesis: Early American experience. Clin Orthop Relat Res 2001;(382):51-58. 139. Winkelmann WW: Hip rotationplasty for malignant tumors of the proximal part of the femur. J Bone Joint Surg Am 1986;68:362-369. 140. Winkelmann WW: Type-B-IIIa hip rotationplasty: An alternative operation for the treatment of malignant tumors of the femur in early childhood. J Bone Joint Surg Am 2000;82:814828. 141. Wittig JC, BickelsJ, Kellar-Graney KL, et al: Osteosarcoma of the proximal humerus: Long-term results with limbsparing surgery. Clin Orthop Relat Res 2002;397:156-176. 142. Wu YQ Heutink P, de Vries BB, et al: Assignment of a second locus for multiple exostoses to the pericentromeric region of chromosome 11. Hum Mol Genet 1994;3: 167-171. 143. Wunder JS, Paulian G, Huvos AG, et al: The histological response to chemotherapy as a predictor of the oncological outcome of operative treatment of Ewing sarcoma. J Bone Joint Surg Am 1998;80:1020-1033. 144. Yandow SM, Lundeen GA, Scott SM, Coffin C: Autogenic bone marrow injections as a treatment for simple bone cyst. J Pediatr Orthop 1998;18:616-620. 145. Zeegen EN, Aponte-Tinao LA, Hornicek FJ, et al: Survivorship analysis of 141 modular metallic endoprostheses at early followup. Clin Orthop Relat Res 2004; 420:239-250.

Brain Tumors Phillip B. Storm and Leslie N. Sutton

Except for injuries, neoplasms are the most common cause neuroblastomas, melanotic neuroectodermal tumors in of death in children younger than the age of 15 years. infancy, and atypical teratoid/rhabdoid tumors (ATRT). Tumors of the central nervous system arethe most common solid neoplasms found in children, account for 20% of cancer deaths, and are second only to leukemia in CLINICAL FEATURES ,22,~~ 1700 pedioverall cancer f r e q u e n ~ y . ~ ~Approximately atric brain tumors are diagnosed each year, for an inciThe signs and symptoms of brain tumors in children vary dence of 3.1/100,000 children at risk.lo considerably based on tumor type and location and on the Important factors in diagnosing brain tumors are locaage of the child. In the absence of a seizure or a focal tion, age, and cell type. Location is probably the most neurologic deficit, such as a sixth nerve paresis causing important factor radiographically, with age being the double vision, the vast majority of the symptoms are nonsecond most important. The brain is divided into two comspecific and easily attributable to many more common partments by thk tentorium. Above the tentorium (supraand less serious causes. Common symptoms are headache, tentorial) are the cerebral hemispheres, the basal ganglia, nausea, vomiting, lethargy, subtle changes in personality, and the thalamus. Below the tentorium (infratentorial) and worsening school performance. This constellation of are the pineal gland, the tectum, the pons, the medulla, symptoms is often attributed to gastrointestinal problems, and the cerebellum. UnL~keadult tumors,which tend to be depress'\on,school anxiety, mig.raines, sinusitis, or a presupratentorial, pediatric tumors are evenly split between scription for glasses. Even a long-standing seizure disorder supratentorial and infi-atentorial. There is an interesting ultimately may be caused by a supratentorial brain tumor. division of location based on age. In children younger Infants typically present with a failure to thrive, decreased than 2 years of age, the tumors are typically supratentorial, intake, macrocephaly, or lethargy. whereas children between the ages of 3 and 15 predominately have infratentorial tumors (Table 41-1).15,2° The is usually poor in children who present with brain tumors when younger than the age of 1 year,8 with choroid plexus papilloma being the exception. Age Tumor Histology The development of immunohistochemical techniques has allowed pediatric tumors to be classified by 0-2 Teratoma Primitive neuroectodermal tumor histology. Tumors can arise from any of a number of cell Astrocytorna (high grade) types in the brain. The brain is composed of neurons and Choroid plexus papilloma glial cells. The glial cells far outnumber the neurons and 2-15 Supratentorial tumors (50%) provide a nourishing and supportive role. The three main Astrocytoma (low grade) glial cells are astrocytes, oligodendrocytes, and ependymal Craniopharyngioma cells, and the neoplasms they give rise to are gliomas. More Hypothalamic glioma specifically they form astrocytomas, oligodendrogliomas, Primitive neuroectodermal tumor and ependymomas, respectively. Tumors involving both Ependymorna neuronal and glial cells are called ganglion cell tumors and Choroid plexus papilloma consist of gangliogliomas, desmoplastic infantile ganglilnfratentorial tumors (50%) Primitive neuroectodermal tumor: medulloblastoma ogliomas, and gangliocytomas. Another mixed neuronal Cerebellar astrocytorna and glial tumor is a dysembryoplastic neuroepithelial Ependymoma tumor (DNET). Lastly are the embryonal tumors or Brainstem glioma primitive neuroectodermal tumors (PNETs). Embryonal tumors include medulloblastoma, m e d ~ l l o e ~ i t h e ~ o m a ,

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Pediatric patients with brain tumors are typically between the ages of 2 and 14years with a few days to weeks of headache, nausea/vomiting, gait ataxia, and/or diplopia, who have an enhancing midline posterior fossa tumor on magnetic resonance imaging (MRI) with associated hydrocephalus. In fact, it is the resultant hydrocephalus that is responsible for this constellation of symptoms rather than the tumor itself. Headaches are common in children with viral infections, but frequent, daily, morning headaches should raise the clinical suspicion for a mass lesion, especially in the absence of fever or other sequela of a viral infection. Patients with elevated intracranial pressure often have an exacerbation of their symptoms in the morning because lying in the recumbent position overnight raises intracranial pressure compared with being upright. Furthermore, sleeping results in hypoventilation, which results in an increase in Pco~,causing an even greater increase in the intracranial pressure. The elevated intracranial pressure can also cause the cerebellar tonsils to herniate into the foramen of magnum and result in occipital headaches and neck pain. There are two instances in which tumors cause nausea and vomiting. One is the elevation of intracranial pressure, and the other is direct irritation/infiltration of the vomiting center. The vomiting center (area postrema) is located on the floor of the fourth ventricle and is vulnerable from compression from large posterior fossa tumors or from direct invasion of intrinsic brainstem tumors causing vomiting. Because an intrinsic tumor in the medulla can cause vomiting in the absence of other neurologic findings, persistent vomiting should raise the possibility of a posterior fossa tumor and not be attributed to gastrointestinal diseases such as reflux without a detailed history and neurologic examination. Ataxia is often described by the parents as clumsiness, "walking like he is drunk," walking with the head tilted to one side, or falling to one side. The visual complaints resulting from posterior fossa tumors are most frequently diplopia, difficulty looking up (sunsetting eyes-Parinaud's syndrome), and occasionally decreased visual acuity. Again, these findings are a result of the hydrocephalus. Decreased visual acuity can occur because of papilledema. Loss of vision is more common in supratentorial tumors because of optic nerve atrophy from direct compression. Patients with posterior fossa tumors are usually diagnosed by MRI because their other symptoms occur long before they develop visual loss; thus, a lack of visual signs or symptoms does not exclude a tumor. Visual loss is still seen in some patients with posterior fossa tumors because of poor access to medical care. Even though the "typical" pediatric brain tumor is in the posterior fossa there are many supratentorial tumors, especially in patients younger than 2 years old. Children younger than 2 years of age often present with a failure to thrive, hemiparesis, seizures, or a full bulging anterior fontanelle with an enlarged head circumference.l*,35,43 Children who are older than age 2 years with supratentorial tumors present similarly to adult patients with brain tumors, with headaches and/or seizures. Patients who present with sudden onset of severe headache and/or rapidly declining mental status usually have hemorrhaged into their lesion. Occasionally, obstructive hydrocephalus can cause a rapid decline, but because of the

relative slow rate of growth of the tumor they present before the cerebrospinal fluid (CSF) pathways are completely obstructed. Less common signs and symptoms arise from endocrine abnormalities such as weight gain, weight loss, diabetes insipidus, short stature, truncal obesity, and delayed puberty; and galactorrhea is from tumors affecting the hypothalamic-pituitary axis. Because of the proximity of these tumors to the optic nerves and chiasm they often cause decreased vision as well as visual field cuts, most of which are asymptomatic.

RADIOGRAPHIC EVALUATION Patients suspected of having a brain tumor need to be evaluated with MRI with and without gadolinium enhancement. Even though MRI is the gold standard for evaluating tumors, patients presenting to an emergency department with clinical signs and symptoms of a brain tumor need head computed tomography (CT) without instillation of a contrast medium. CT is excellent in evaluating hydrocephalus and hemorrhage, the two main causes of a rapid neurologic decline. Furthermore, CT can be done in minutes and frequently does not require sedation, gives excellent detail and information, and is considerably less expensive. If the patient's condition is rapidly deteriorating, a contrast agent-enhanced head CT needs to be performed to better characterize the lesion for the radiologist and the neurosurgeon if the patient requires emergent surgical intervention. If the patient's condition is stable, the contrast agent can be omitted and MRI with and without gadolinium can be done, the timing of which is dictated by the clinical signs and symptoms. MRI provides much better brain resolution and provides images in the sagittal, axial, and coronal planes and, with newer imaging sequences and spectroscopy, may even point to a specific histologic diagnosis.62 This is far superior to the axial-only images that are obtained with CT. Furthermore, it is difficult to evaluate the lower brainstem with CT because of the bony artifact from the skull base. A limitation of MRI is that it does not show intratumoral calcifications very well and occasionally patients require both studies to aid in the proper diagnosis. The addition of gadolinium provides more information about the tumor. The blood-brain barrier is made up of tight junctions in the endothelial cells lining the brain capillaries, which prevent most blood contents from entering the brain, including gadolinium. Certain brain tumors cause breakdown of the blood-brain barrier and permit the gadolinium to enter the tumor and then appear bright on an enhanced T1-weighted image. In general, especially in the adult population, contrast medium enhancement in an intra-axial lesion means a more aggressive brain tumor and a poorer prognosis. This is not as consistent in pediatric tumors. There are enhancing pediatric brain tumors that are not aggressive and are curable with a total resection. In general, tumors that do not enhance are less aggressive. When looking at MRIs the important factors to consider are (1) the location of the tumor (e.g., supratentorial, infratentorial, pineal region, suprasellar), (2) whether it

CHAPTER

is intra-axial (within the brain tissue) or extra-axial (outside brain tissue), (3) the age of the patient, (4) whether it enhances, and (5) if it is single or multiple. By systematically looking at the scans and considering these factors, the differential diagnosis can be narrowed considerably and can be extremely helpful in preoperative planning. If there are multiple lesions in the brain, or the location and enhancement suggest a tumor type that metastasizes or tends to cause "drop mets" to the spine, then a spinal MRI with and without enhancement is performed. It is preferable to obtain the spinal MRI preoperatively but this is often dictated by the patient's clinical examination. All patients with brain tumors receive a postoperative MRI within 48 hours to evaluate the extent of resection and rule out hydrocephalus, bleeding, or ischemia. The timing is important because after 48 hours expected postoperative changes/"scarringn can enhance and make it difficult to distinguish scarring from residual tumor. If the patient did not get a preoperative MRI evaluation of the spine and the histiologic diagnosis is consistent with tumors that produce "drop mets," then the study should be done 2 weeks after surgery for staging of the tumor.

SURGICAL INTERVENTION The goal of surgical intervention is to safely debulk as much tumor as possible, to obtain a histologic diagnosis, and to reestablish normal CSF pathways or divert CSF. The location of the tumor often determines how aggressively the tumor is debulked. In fact, some tumors because of their location and their ability to be diagnosed with MRI are not sampled. For example, a pontine glioma, which is an intrinsic astrocytoma of the brainstem, cannot be debulked safely and has a characteristic finding on MRI. These patients are referred to the neuro-oncologist for management without needing a tissue diagnosis. Pineal region tumors are another example of a lesion that may be diagnosed without surgical intervention. Patients with a pineal lesion need to have serum beta-human chorionic gonadotropin (FhCG), alpha-fetoprotein (AFP), and placental alkaline phosphate (PLAP) levels obtained. If these are negative, then CSF markers are needed. If the markers are positive, then a diagnosis of pineal germ cell tumor is made. The treatment is stereotactic radiation without the need for a tissue diagnosis, and the cure rate approaches 100%for a germinoma. Most tumors, however, require surgical intervention consisting of either a stereotactic biopsy or an open craniotomy. The most important tool for preoperative planning is MRI. Tumors that are diffuse, intrinsic tumors of the thalamus or basal ganglia typically undergo stereotactic biopsy. This procedure involves rigidly fixing an MRIcompatible frame to the patient's skull. The patient then has an MRI, and the X, Y, and Z coordinates are determined. These coordinates are used to position the frame and arc so that the tip of the needle is exactly where these three points intersect in the brain. The advantages of a stereotactic biopsy are that the surgical procedure is done quickly, diagnosis is possible in areas of the brain that carry an unacceptable morbidity and mortality with an open craniotomy, and the patient is discharged on

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postoperative day 1. The disadvantages are that the pathologist is only given a small amount of tissue; if bleeding is encountered at the time of surgery it may not be recognized until the patient deteriorates neurologically after the procedure; and if the diagnosis requires the neurosurgeon to operate, the patient needs a second operative procedure and the tissue in that area may not be representative of the true grade of the tumor. The majority of pediatric tumors are treated with a craniotomy/craniectomy for open biopsy with an attempt at maximal microsurgical tumor resection, because prognosis of many tumors is strongly influenced by the amount l of postsurgical residual t ~ r n o r . ~ V e r e b r ahemispheric tumors are approached by craniotomy. Preoperative planning consists of an MRI coupled with a frameless stereotactic navigation study. The navigation study allows the neurosurgeon to view the tumor in the operating room in the sagittal, axial, and coronal planes and can be used to plan the incision and find the tumor. The limitation of this technology is that it is not a real time study and as the brain is retracted, cysts or CSF spaces are drained, the brain shifts position, and the accuracy is compromised. Intraoperative ultrasound is extremely helpful in finding lesions when brain shifting has decreased the accuracy of the intraoperative navigation system. Intraoperative MRI aims at correcting the limitation of the navigation systems by providing a real-time image; however, intraoperative MRI is severely limited by the resolution because the magnet is considerably weaker than those used for conventional MRI. This is exciting technology and as the resolution improves it will be used on all tumor cases and be an invaluable tool to the tumor surgeon. Functional MRI techniques can localize speech and motor cortex in relation to the tumor and aid in selecting the safest site to incise the cortex if these areas of eloquent cortex are involved by the tumor.48Functional MRI requires a cooperative, nonsedated patient. which in the pediatric population can be challenging. Electrophysiologc recording and stimulation are sometimes helpful in locating the motor strip. Even though these advances have substantially aided the neurosurgeon there is still no substitute for an outstanding understanding of the three-dimensional anatomy of the brain. When choosing a route, anatomic planes such as the interhemispheric fissure, the Sylvian fissure, and the cranial base are used if possible to avoid resecting normal brain. If there is no plane, the approach is usually through the least amount of brain tissue, with the obvious exception of areas of eloquent cortex such as language and motor. Tumors of the midline (hypothalamus, thalamus, basal ganglia, and brainstem) were once considered inoperable. Microsurgical techniques and innovative instrumentation, however, now make these tumors approachable. At the same time, advances in chemotherapy and singledose and fractionated radiosurgery oEfer alternatives, and it is unclear at this time which strategy or combination of strategies is best for a particular tumor. Pineal region tumors may be approached via a posterior fossa route, retracting the cerebellum from the underside of the tentorium, or by a supratentorial route between the hemispheres and through the posterior corpus callosum,

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or through the tentorium itself. The relationship of the pineal tumor to the tentorium dictates the approach. Tumors of the cerebellum and lower brainstem are approached by a posterior fossa craniotomy or craniectomy. Midline tumors of the fourth ventricle usually present as obstructive hydrocephalus. Although some neurosurgeons prefer to place a shunt before tumor resection, most n o w favor giving the child corticosteroids and placing a ventriculostomy at the time of the craniectomy, which is either removed or converted to a shunt if needed in the postoperative period. Between 20% to 40% of children will ultimately require a shunt." The patient is placed in the prone position, and the bone overlying the cerebellum is removed, occasionally including the posterior ring of C1. After opening the dura, the cerebellar vermis is vertically incised, providing access to the cavity of the fourth ventricle. The tumor is removed with bipolar cautery, suction, or the ultrasonic aspirator. Laterally placed tumors of the cerebellopontine angle are reached by retracting the cerebellum medially, and working around the cranial nerves, using electrophysiologic monitoring of cranial nerves V, VII, VIII, IX, X, XI, and XI1 as required. Tumors of the brainstem may be debulked, if they are dorsally exophytic and have low-grade histology. The dura is closed and covered with DuraGen, a collagen product that augments dura, but replacement of bone is not required. Postoperative problems include acute hydrocephalus and pseudomeningoceles, aseptic meningitis, mutism, pseudobulbar palsy,eg cranial nerve or brainstem dysfunction, gastrointestinal hem~rrhage,"~) and spinal instability.58 Patients with swallowing dysfunction and aspiration may require tracheostomy and feeding gastrostomy.

TUMOR TYPES Cerebellar Astrocytomas These tumors are usually histologically benign and curable with total surgical resection. The average age at presentation is 9 years, and patients present with pernicious vomiting, intermittent morning headache, and disturbances of balance, often over a period of months. The classic CT appearance7] is of a low-intensity cystic cerebellar mass in proximity to the vermis with a brilliantly enhancing "mural nodule." About one fourth will be entirely solid, however. MRI is helpful in defining the surgical anatomy, particularly the relationship of the tumor to the brainstem, and the nature of the cyst wall. Cerebellar astrocytomas are typically of low signal intensity on T1-weighted MRI sequences, are of increased intensity on T2-weighted sequences, and show enhancement of the solid component with intravenous gadolinium (Fig. 41-1). Obstructive hydrocephalus is common. Histologically, the tumors are composed of benignappearing astrocytes. Subtypes are the juvenile pilocytic form (60%) and the fibrillary form (30%).A "diffuse" form has also been described, which may carry a poorer prognosis." Detailed examination may reveal cellular pleomorphism and tumor extension to the subarachnoid space, but these tumors rarely disseminate. Malignant tumors

1 A 2-year-old girl presented after several days of vomiting and lethargy. A sagittal T1-weighted MR image with gadolinium shows a large posterior fossa tumor based in the cerebellum (small arrow). The patient has hydrocephalus (large nrrozu showing a dilated third ventricle). She also has herniation of the cerebellar tonsils through the foramen magnum (arrozuheczd).At surgery a diagnosis of cerebellar astrocytoma was made.

are rare and usually follow radiation therapy given for a previously benign tumor.j7 Treatment is complete surgical excision. This may be accomplished in a high percentage of cases in which there is no brainstem involvement. These tumors rarely recur after radiographically confirmed complete excision, and no adjuvant therapy is indicated.' Therefore, if there is residual tumor on the postoperative scan, reoperation for total excision is recommended. Radiation therapy may be considered for multiply recurrent lesions or in cases in which brainstem involvement precludes complete removal, but even in these cases residual tumor may remain indolent for years without specific therapy. Regular postoperative surveillance scanning is appropriate when there is suspicion for residual tumor. Recurrence is treated with reoperation if this is feasible.

Primitive NeuroectodermalTumor and Medulloblastoma A posterior fossa PNET is termed a medullohlastoma. Medulloblastoma is the most common malignant brain tumor of childhood. Histologically, the classic medulloblastoma is composed of densely packed cells with hyperchromatic nuclei and little cytopla'sm, giving the histologic slides a blue color when stained with hematoxylin and eosin. When the lesion is located in the posterior fossa, the tumor is termed medullohlastoma or posterior fossa PNET Tumors with identical histology can occur in the cerebral hemispheres and are termed supratentorial PMTs. Children with medulloblastomas typically

CHAPTER

present with headache, vomiting, and lethargy of relatively short duration, and the mean age at diagnosis is younger than that for cerebellar astrocytomas. Infants may present with failure to thrive. Supratentorial PNETs present with increased intracranial pressure and focal neurologic signs depending on location. On a CT scan, medulloblastomas typically appear as wellmarginated homogeneously dense masses filling the fourth ventricle causing obstructive hydrocephalus; however, unlike ependymomas, they lack calcifications. They usually enhance brilliantly with contrast medium instillation. MRI shows variable signal characteristics. The images are often slightly hypointense on T1 weighting, becoming brighter on fluid-attenuated inversion recovery (FLAIR) sequences, and may be bright or dark on T2-weighted studies. They usually enhance on MRI (Fig. 41-2). MRI of the spine is indicated either preoperatively or postoperatively to evaluate for spinal metastases ("drop mets"). Treatment begins with biopsy and surgical excision. These tumors are not curable with surgery alone; and in cases with metastases at diagnosis or extensive brainstem involvement, the major mass should be debulked but no attempt should be made to resect tumor from vital areas. After the operation, radiation therapy is usually administered to the entire brain and spinal canal, with a boost to the tumor bed. Younger children suffer significant cognitive problems as a result of whole-brain irradiation in an age- and dose-dependent fashion." Because chemotherapy has proven effective in both newly diagnosed and recent trials have recurrent medulloblastornas,~4~~0~40~~3 attempted to reduce, eliminate, or delay radiation and replace it with chemotherapy, particularl; in the younger age groups.lZ In determining the best treatment, staging

An 8-year-old boy presented after several weeks of morning headaches and vomiting. An axial T1-weighted MR image with gadolinium shows a heterogeneously enhancing lesion occupying the fourth ventricle (arrows). The lesion does not "ooze" out of the lateral CSF pathways (foramen of Luschka) like an ependymoma. The pathologic diagnosis was medulloblastoma. -

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criteria are important to define risk groups. In the past, the Chang system was used, which used the surgeon's estimate of the tumor size at operation and the extent of metastatic disease based on postoperative imaging.9 In most centers today, patients are assigned to a high-risk group based on younger age, postoperative residual disease, and presence of disseminated disease.s1,39,40 The rate of progression-free survival ranges from more than 70% at 5 years in groups with favorable risk factors7 to less than 30% in certain high-risk groups.14 Recent reports suggest that intensive adjuvant chemotherapy results in improved survival in high-risk patients comparable to low-risk patients treated with radiation alone.40 Patients require long-term supportive care, which is best done in the setting of a multidisciplinary pediatric neurooncology clinic. Surveillance scanning is of unproven value, because patients with tumors that recur after primary therapy almost invariably die of their disease.64 Late sequelae of therapy include pituitary dysfunction," growth retardation,47 cardiomyopathy,28 cognitive delay,4~sychosocial adjustment and family problems, and radiation-induced meningiomas, astrocytomas, and sarc0mas.2~

Ependymomas Ependymomas occur in the region of the fourth ventricle or cerebellopontine angle (Fig. 41-3), spinal cord, or supratentorial compartment. Most are histologically

. ,

41

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1

An 18-month-old boy presented after 3 days of

-

-

headaches and vomiting and 2 days , of gait ataxia: On the day of admission he was unresponsive at home. Emergent MRI revealed a large posterior fossa tumor. An axial T2-weighted MR image shows a tumor occupying the fourth ventricle and "oozing" out of the foramen of Luschka into the cerebellar pontine angle and encasing all of the posterior fossa cranial nerves (arrows). The patient was found to have an ependymoma.

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to ventricular obstruction and are usually treated with benign, but, despite this, they rank among the worst of either a ventriculoperitoneal shunt or endoscopic all pediatric brain tumors. They have a tendency to recur third ventriculostomy. These are usually extremely indoin the local tumor bed but may also disseminate throughlent, and treatment of the tumor itself is required only if out the neuraxis. The median age at diagnosis is between it progressively enlarges. 3 and 5 years,Z3 but tumors in infants and adults are not uncommon. When they arise in the posterior fossa (75% of cases), symptoms are similar to those of other tumors in this location. Cranial nerve and brainstem dysfunction Hypothalamic/Chiasmatic Astrocytomas suggest involvement of these structures. Vomiting may Suprasellar astrocytomas are usually low-grade neoplasms, arise without hydrocephalus, which suggests infiltration which may occur in association with neurofibromatosis of the region of the obex, which is characteristic of type 1 or as isolated tumors. The etiology of these tumors ependymomas. When they arise in the supratentorial is not well understood, but the association with neuroficompartment in children, they are often extremely large bromatosis type 1, which is localized to chromosome 17q, and, despite their presumed ependymal origin, may suggests a molecular genetics basis. These tumors may demonstrate no connection with the ventricle. present as primarily visual abnormalities (visual field cuts CT typically shows an isodense mass with flecks of calcior asymmetrical loss of visual acuity in association with fication and an inhomogeneous pattern of enhancement. optic atrophy) or as hypothalamic dysfunction (precoPosterior fossa lesions may extend through the foramina of cious puberty, growth failure, obesity, or the diencephalic Luschka into the cerebellopontine angle. On TI-weighted MRI, ependyrnomas are usually isointense to hypointense syndrome, which consists of failure of weight gain and loss and are hyperintense on TP/proton-weighted images.55 of subcutaneous tissue). Often visual and hypothalamic complaints coexist. They often enhance inhomogeneously. Imaging studies usually cannot distinguish hypothaTreatment is primarily surgical. Prognosis is strongly dependent on extent of surgical resection as determined lamic tumors from those arising from the visual apparaby postoperative imaging. The 5-year progression-free tus. The tumors typically do not calcify, which helps survival after complete resection is 60% to 80%, comdistinguish them from craniopharyngiomas, and appear as solid hypodense lesions on CT or T1-weighted MRI pared with less than 30% after incomplete resection.Z6 sequences with contrast agent enhancement. Extension Radical surgical resection may result in permanent neuroto the intraorbital optic nerves or along the optic radialogic damage and may not be possible in some cases. tions is diagnostic and rules out craniopharyngiomas, Unless the tumor has disseminated at diagnosis, postopergerminomas, or other tumors (Fig. 41-4). ative radiation is usually confined to the operative bed Treatment is controversial. Traditionally, treatment has with a generous margin. Adjuvant chemotherapy was been surgical biopsy, followed by radiation therapy. thought to be of little or no benefit,36but recent studies . ~ ~ ~ ~ ~Recently, chemotherapy with dactinomycin and vincristine, show improved outcomes with c h e m ~ t h e r a p yTrials of radiosurgery for unresectable tumors are under way in several centers.

Brainstem Gliomas It is now recognized that there are several types of brainstem gliomas, with very different outcome~.~"he most common variety is the dqfuse intm'nsicpontineglioma, which is not amenable to surgical resection. These tumors typically present as cranial neuropathies rather than hydrocephalus. Patients are young children with bilateral sixth nerve palsies, facial weakness, and ataxia. The diagnosis is established by MRI, which shows a swollen pons with diffuse signal abnormality (see Fig. 41-3). Surgery is not indicated. Radiation therapy provides symptomatic relief, but most children die within a year.37 Ceruicomedullary astrocytomas are considered to be rostral extensions of intrinsic spinal cord tumors and carry a favorable prognosis. Signs and symptoms may include vomiting, torticollis, slowly evolving motor weakness, or symptoms of hydrocephalus. MRI shows an enlarged upper cervical spinal cord, with a rostral extension presenting in the cisterna magna. These tumors are often amenable to aggressive surgical resection; and if the histology is benign, adjuvant radiation therapy is deferred. Tectal gliomas are now recognized to be a not infrequent cause of hydrotypically present as symptoms referable cephalus.4"hey

.

A

A 14month-old boy presented with a 1-week history

of lethargy and a 2-day history of vomiting. Sagittal TI-weighted MR image with gadolinium shows a large enhancing suprasellar and frontal tumor arising from the optic chiasm and hypothalamus (arrows). The diagnosis of a hypothalamic astrocytoma was confirmed at surgery.

CHAPTER

or other combinations, has shown promise, especially in infants and young children in whom radiation therapy is damaging to the brain.4,i Radical surgical resection as primary therapy has also been reported.'j8

Craniopharyngioma Craniopharyngiomas are histologically benign masses believed to arise from embryonic rests derived from the hypophyseal-pharyngeal duct. Symptoms arise from optic chiasm or nerve compression, hypopituitarism, hypothalamic dysfunction, or increased intracranial pressure in association with hydrocephalus. They also occur in adults, but the childhood form represents a distinct entity, characterized by large size and extensive calcification. There are two varieties of craniopharyngioma, the adamantinomatous and the papillary types. The most common variety in children is the adamantinomatous type. Histologically, they typically are composed of a squamous epithelial cyst wall, with cystic fluid composed of cholesterol crystals, and calcifications. They are usually inseparable from the pituitary gland and may have an interdigitating gliotic interface with the hypothalamus above. This makes complete surgical removal uncertain, because small rests of tumor may reside in the brain, and is also the explanation for hypothalamic dysfunction that may be seen after surgical excision. Radiographically, CT reveals either a rim-enhancing cystic mass with basal calcifications or an entirely solid tumor. MRI shows the sagittal anatomy well but may miss the calcifications (Fig. 41-5) .24 In some instances, imaging

A n 11-year-old boy presented with a several-month history o f headaches and lethargy and extreme thirst and high urine T1-weighted MR image shows a n output. Sagitral - with gadolinium enhancing intrasellar lesion enlarging the sella turcica (large amow). T h e tumor occupies the third ventricle and has a cystic component (small amou~s).T h e patient also has obstructive hydrocephalus with dilated lateral ventricles and a thinned corpus callosum (arrowheads). .

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cannot distinguish a craniopharyngioma from a hypothalamic glioma. Treatment is complete surgical excision via craniotomy, which is possible in a high percentage of cases.27 In cases in which complete resection is not possible, or when tumor recurs, radiation therapy is a useful adjunct.'j6Posttreatment problems include panhypopituitarism, obesity, visual problems, emotional lability," and pseudoaneurysms of the carotid artery60 Long-term survival is in the range of 90% at 10 but local recurrences are not uncommon. Recurrences are treated by reoperationF7 instillation of colloidal 32P into cysts, or radiosurgery.

Low-Grade Supratentorial Astrocytomas Low-grade astrocytomas and gangliogliomas of the cortical regions and temporal lobes often present as intractable seizures. CT may show masses of low density, which may or may not enhance with contrast medium instillation. MRI usually shows a mass of decreased signal on T1-weighted images and increased signal on T2 weighting. Complete resection is the goal of surgery, but this may be difficult owing to problems in defining the tumor margins and proximity to eloquent areas. Adjuncts to aid in this include language and motor mapping using implantable grids or intraoperative electrophysiologic monitoring techniques,2 functional MRI techniques, and imagedirected tumor resection.29 Tumors of the temporal lobe are often treated by formal temporal lobectomy to decrease the likelihood of seizures. Seizure mapping techniques have also been employed with cortical tumors, but simple removal of the tumor usually provides good seizure control,41and the value of these strategies is uncertain. The outcome of low-grade astrocytomas,g9 gangliogliomasm (Fig. 41-6), and DNETs (Fig. 41-7) that are

1

A 9-year-old boy presented with intractable seizures Axial TI-weighted M R image with gadolinium shows a minimally enhancing lesion i n the left temporal lobe (amoru).A ganglioglioma was completely resected, and the patient is s e i ~ u r efree.

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the pineal carry a good prognosis after irradiation, although in cases with disseminated disease whole-brain and spinal irradiation will be required." Treatment with chemotherapy alone is advocated in some centers. The other malignant germ cell tumors are usually fatal.% Pineoblastomas are treated like PNETs in other locations. Pineocytomas may be simply observed if totally resected or given focal radiation for residual tumor.

Rhabdoid/Atypical Teratoid Tumors

A 14year-old boy presented with left-sided headaches for months and a seizure. Axial T2-weighted image shows a hyperintense mesial temporal lobe lesion involving the cortex (arrow). The lesion was hypointense on TI-weighted images and did not enhance. The diagnosis was dysembryoplastic neuroepithelial tumor (DNET).

completely resected is favorable, although surveillance scanning is warranted. About 70% of children will be longterm survivors. Recurrent tumors can be treated by reoperation or reoperation followed by radiation

Pineal Region Tumors Tumors of the pineal region encompass a wide variety of histologic types. They can be divided into germ cell tumors (teratoma, germinoma, choriocarcinoma, embryonal cell carcinoma, yolk sac tumor), pineal parenchymal tumws ( pineocytoma, pineoblastoma) , tumors of surrounding structures (astrocytomas, meningiomas), and other benign conditions (cysts, vascular malformations). The older term pinealoma is no longer used. Patients present with signs and symptoms of hydrocephalus, upgaze paresis, and rarely precocious puberty. MRI confirms the presence of a tumor and excludes other possibilities but is nonspecific regarding the histologic type. Specific germ cell tumors may secrete "tumor markers," which may be measured in CSF obtained from lumbar puncture or ventriculostomy or blood. Elevated P-hCG (>50.0 IU/L) is seen in choriocarcinomas, elevated AFP (>25.0 IU/L) is seen in endodermal sinus tumors and embryonal cell carcinomas, and PLAP is elevated in germinomas. In the past, surgery in the pineal region was considered prohibitively dangerous and tumors were often treated without histologic confirmation. This region is now readily approachable using the supracerebellar/ infratentorial or interhemispheric-transcallosal routes with minimal morbidity, and in most centers biopsy is performed. As in the suprasellar region, pure germinomas of

These tumors have only recently been defined. They are highly malignant tumors with histologic resemblance to rhabdoid tumors of the kidney. They typically occur in the posterior fossa in young children and infants but may be located in the spine or supratentorial space. In the past, many of these were probably misclassified as PNETs but are distinguished by larger cells with pink cytoplasm that show immunohistochemical staining for smooth muscle actin, vimentin, and epithelial membrane antigen. Chromosomal analysis reveals monosomy 22 in a high percentage of cases.5 Treatment is surgical excision, chemotherapy, and irradiation in older children, but virtually all the patients in reported cases have died.

Malignant Supratentorial Astrocytomas Anaplastic astrocytomas and glioblastoma multiforme account for only about 6% of childhood tumors, which is a smaller incidence than that in adults. Clinical signs and symptoms reflect location. Imaging features are similar to those seen in adults, and the masses are often large, with enhancing rings and necrotic centers. ~isseminatgn occurs in about Treatment is maximal resection followed by radiation therapy, but the prognosis remains poor. Although more extensive resection confers better outcome, this may reflect the fact that more favorable tumors are more amenable to aggressive surgery. Chemotherapy prolongs life in children with high-grade astrocytomas, but overall 5-year progression-free survival is only 33%.17Trials of high-dose chemotherapy with autologous marrow rescue are ongoing.16

Choroid Plexus Tumors Tumors of the choroid plexus are divided into the benign choroid plexus papilloma and the malignant choroid plexus carcinoma. In children, they tend to arise in the trigone of the lateral ventricle, and they often present in infancy by producing hydrocephalus. The radiographic appearance is an intraventricular, homogeneously enhancing, lobulated mass. Carcinomas are typically larger and may disseminate. The vascular supply is the choroidal arteries, which may be seen with high-resolution MRI. Treatment is surgcal excision, which is curative for papillomas. The procedure is hazardous, because these tumors may be extremely vascular and the patients are typically small. Carcinomas are particularly difficult to remove

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CHAPTER

because of extreme vascularity. This has prompted some to recommend biopsy, followed by chemotherapy, and later resection." Prolonged survival and even cure are possible after complete removal of malignant choroid plexus tumors.

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the TP53 suppressor gene.g In neuroblastoma, amplification of N-MYC correlates with tumor growth and aggressiveness. The continued collaboration between neurosurgeons, oncologists, radiologists, and molecular biologists is imperative to improving the fight against pediatric brain tumors.

Meningiomas Meningeal tumors are uncommon in childhood, accounting for about 2% of tumors. They may be associated with neurofibromatosis. Meningiomas occur in the orbit, sphenoid wing, or virtually any portion of the intracranial compartment and need not have a dural attachment. Radiographically, they typically enhance and may be extremely large. Treatment is surgical resection, which is curative if complete removal can be accomplished. Irradiation is of benefit in recurrences or when complete removal is not possible.44

Metastases Metastatic brain tumors are uncommon in children. Primary tumors that may metastasize to brain include Wilms' tumor, osteogenic sarcoma, and embryonal rhabdomyosarcoma. Presentation is often abrupt, often with catastrophic neurologic symptoms due to hemorrhage.

TUMOR GENETICS Despite rapid developments in imaging, navigational systems, and surgical instruments and techniques, many tumors, especially high-grade lesions, are still incurable with surgery alone and in conjunction with chemotherapy and radiation therapy. The future in treating brain tumors lies in better biologic and molecular understanding of the tumors. Such techniques have given us better understanding of neurofibromatosis type 2, which is associated with the development of meningiomas and acoustic neuromas in children. The gene locus was identified on chromosome 22,51 the same chromosome that has been identified in pediatric meningiomas in patients without neurofibromatosis type 2.4 The genetic abnormalities result in a loss of a tumor-suppressor gene. Monosomy 22 has been associated with rhabdoid and atypical teratoid tumors.~eurofibromatosis type 1 is associated with childhood gliomas, particularly of the hypothalamus, brainstem, and optic chiasm. The gene locus is at 17q11.2, which encodes for the protein neurofibromin. Neurofibromin is an "off switch" for the RAS oncogene. Tissue from astrocytomas frequently has abnormalities of chromosome 17, which are primarily in the short arm (p). The short arm of chromosome 1'7 is where the TP53 tumor suppressor gene is located. The possibility exists that mutation of a "control gene" leads to development of the brain tumor, and if one copy of the gene is already dysfunctional, as in neurofibromatosis type 1, the likelihood of a tumor arising is increased. Abnormalities of chromosome 17 are also found in medulloblastoma,6 but some work suggests that the locus is distinct from

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18. Freeman CR, Farmer JP, Montes J: Low-grade astrocytomas in children: Evolving management strategies. Int J Radiat Oncol Biol Phys 1998;41:979. 19. Geyer JR, Sposto R, Jennings M, et al: Children's Cancer Group. Multiagent chemotherapy and deferred radiotherapy in infants with malignant brain tumors: a report from the Children's Cancer Group. J Clin Oncol 2005;23:7621. 20. Giuffre R: Biological aspects of brain tumors in infancy and childhood. Childs Nerv Syst 1989;5:55. 21. Gjerris F, Klinken L: Long-term prognosis in children with benign cerebellar astrocytoma. J Neurosurg 1978; 49:179. 22. Gold EB, Leviton A, Lopez R, et al: Parental smoking and risk of childhood brain tumors. Am J Epidemiol 1993; 137:620. 23. Goldwein JW, Leahy JM, Packer RJ, et al: Intracranial ependymomas in children. Int J Radiat Oncol Biol Phys 1990;19:1497. 24. Harwood-Nash DC: Neuroimaging of childhood craniopharyngioma. Pediatr Neurosurg 1994;21(Suppl 1):2. 25. Hawkins MM, Draper GJ, Kingston JE: Incidence of second primary tumours among childhood cancer survivors. Br J Cancer 1987;56:339. 26. Healey EA, Barnes PD, Kupsky WJ, et al: The prognostic significance of postoperative residual tumor in ependymoma. Neurosurgery 1991;28:666. 27. Hoffman HJ, De Silva M, Humphreys RP, et al: Aggressive surgical management of craniopharyngiomas in children. J Neurosurg 1992;76:47. 28. Jakacki RI, GoldweinJW, Larsen RL, et al: Cardiac dysfunction following spinal irradiation during childhood. J Clin Oncol 1993;11:1033. 29. Kelly PJ: Image-directed tumor resection. Neurosurg Clin North Am 1990;1:81. 30. Krischer JP, Ragab AH, Kun L, et al: Nitrogen mustard, vincristine, procarbazine, and prednisone as adjuvant chemothera~v in the treatment of medulloblastoma. l A Pediatric Oncology Group study. J Neurosurg 1991; 74:905. 31. Laurent JP, Chang CH, Cohen ME: A classification system for primitive neuroectodermal tumors (medulloblastoma) of the posterior fossa. Cancer 1985;56:1807. 32. Laws ER Jr, Taylor WF, Clifton MB, Okazaki H: Neurosurgical management of low-grade astrocytoma of the cerebral hemispheres. J Neurosurg 1984;61:665. 33. Lee M, Wisoff JH, Abbott R, et al: Management of hydrocephalus in children with medulloblastoma: Prognostic factors for shunting. Pediatr Neurosurg 1994;20:240. 34. Legido A, Packer RJ, Sutton LN, et al: Suprasellar germinomas in childhood: A reappraisal. Cancer 1989;63:340. 35. Loftus CM, Copeland BR, Carmel PW: Cystic supratentorial gliomas: Natural history and evaluation of modes of surgical therapy. Neurosurgery 1985;17:19. 36. Nazar GB, Hoffman HJ, Becker LE, et al: Infratentorial ependymomas in childhood: Prognostic factors and treatment. J Neurosurg 1990;72:408. 37. Packer RJ, Allen JC, Goldwein JL, et al: Hyperfractionated radiotherapy for children with brainstem gliomas: A pilot study using 7,200 cGy. Ann Neurol 1990;27:167. 38. Packer RJ, Sutton LN, Atkins TE, et al: A prospective study of cognitive function in children receiving whole-brain radiotherapy and chemotherapy: 2-year results.J Neurosurg 1989;70:707. 39. Packer RJ, Sutton LN, D'Angio G, et al: Management of children with primitive neuroectodermal tumors of the posterior fossa/medulloblastoma. Pediatr Neurosci 1985;12:272. i

40. Packer RJ, Sutton LN, Elterman R, et al: Outcome for children with medulloblastoma treated with radiation and cisplatin, CCNU, and vincristine chemotherapy. J Neurosurg 1994;81:690. 41. Packer RJ, Sutton LN, Pate1 KM, et al: Seizure control following tumor surgery for childhood cortical low-grade gliomas. J Neurosurg 1994;80:998. 42. Packer RJ, Sutton LN, Rorke LB, et al: Intracranial embryonal cell carcinoma. Cancer 1984;54:520. 43. Palma L, Russo A, Mercuri S: Cystic cerebral astrocytomas in infancy and childhood: Long-term results. Childs Brain 1983;10:79. 44. Perilongo G, Sutton LN, Goldwein JW, et al: Childhood meningiomas: Experience in the modern imaging era. Pediatr Neurosurg 1992;18:16. 45. Petronio J, Edwards MS, Prados M, et al: Management of chiasmal and hypothalamic gliomas of infancy and childhood with chemotherapy. J Neurosurg 1991;74:701. 46. Pollack IF, Pang D, Albright AL: The long-term outcome in children with late-onset aqueductal stenosis resulting from benign intrinsic tectal tumors. J Neurosurg 1994;80:681. 47. Probert JC, Parker BR, Kaplan HS: Growth retardation in children after megavoltage irradiation of the spine. Cancer 1973;32:634. 48. Puce A, Constable RT, Luby MId,et al: Functional magnetic resonance imaging of sensory and motor cortex: Comparison with electrophysiological localization. J Neurosurg 1995; 83:262. 49. Radcliffe J, Bunin GR, Sutton LN, et al: Cognitive deficits in long-term survivors of childhood medulloblastoma and other noncortical tumors: Age-dependent effects of whole brain radiation. Int J Dev Neurosci 1994;12:327. 50. Ross AJ 3rd, Siege1 KR, Bell W, et al: Massive gastrointestinal hemorrhage in children with posterior fossa tumors. J Pediatr Surg 1987;22:633. 51. Rouleau GA, Wertelecki W, HainesJL, et al: Genetic linkage of bilateral acoustic neurofibromatosis to a DNA marker on chromosome 22. Nature 1987;329:246. 52. Sandri A, Massimino M, Mastrodicasa L, et al: Treatment with oral etoposide for childhood recurrent ependymomas. J Pediatr Hematol Oncol 2005;27:486. 53. Scott RM, Hetelekidis S, Barnes PD, et al: Surgery, radiation, and combination therapy in the treatment of childhood craniopharyngioma-a 20-year experience. Pediatr Neurosurg 1994;21(Suppl 1):75. 54. Shiminski-Maher T: Patient/family preparation and education for complications and late sequelae of craniopharyngiomas. Pediatr Neurosurg 1994;21(Suppl 1):114. 55. Spoto GP, Press GA, Hesselink JR, Solomon M: Intracranial ependymoma and subependymoma: MR manifestations. AJR Am J Roentgen01 1990;154:837. 56. St. Clair SK, Humphreys RP, Pillary RK, et al: Current management of choroid carcinoma in children. Pediatr Neurosurg 1991;17:225. 57. Steinberg GK, Shuer LM, Conley FK, Hanbery JW: Evolution and outcome in malignant astroglial neoplasms of the cerebellum. J Neurosurg 1985;62:9. 58. Steinbok P, Boyd M, Cochrane D: Cervical spinal deformity following craniotomy and upper cervical laminectomy for posterior fossa tumors in children. Childs Nerv Syst 1989;5:25. 59. Sutton LN: Current management of low-grade astrocytomas of childhood. Pediatr Neurosci 1987;13:98. 60. Sutton LN, Gusnard D, Bruce DA, et al: Fusiform dilatations of the carotid artery following radical surgery of childhood craniopharyngiomas. J Neurosurg 1991;74:695. 61. Sutton LN, Packer RJ, Rorke LB, et al: Cerebral gangliogliomas during childhood. Neurosurgery 1983;13:124.

CHAPTER

62. Sutton LN, Wang Z, Gusnard D, et al: Proton magnetic resonance spectroscopy of pediatric brain tumors. Neurosurgery 1992;31:195. 63. Tait DM, Thomton-Jones H, Bloom HJ, et al: Adjuvant chemotherapy for medulloblastoma: The first multi-centre control trial of the International Society of Paediatric Oncology (SIOP I). Eur J Cancer 1990;26:464. 64. Torres CF, Rebsamen S, Silber JH, et al: Surveillance scanning of children with medulloblastoma. N Engl J Med 1994; 330:892. 65. Vertosick FT Jr, Selker RG: Brain stem and spinal metastases of supratentorial glioblastoma multiforme: A clinical 1990;27:516. series. Ne~~ros~irgery 66. Weiss M, Sutton I,, Marcia1 V, et al: The role of radiation therapy in the management of childhood craniopharyngioma. IntJ Radiat Oncol Biol Phys 1989;17:1313.

41

Brain Tumors

681

67. Wisoff JH: Surgical management of recurrent craniopharyngiomas. Pediatr Neurosurg 1994;21(Suppl 1):108. 68. Wisoff J H , Abbott R, Epstein F: Surgical management of exophytic chiasmatic-hypothalamic tumors of childhood. J Neurosurg 1990;73:661. 69. Wisoff JH, Epstein FJ: Pseudobulbar palsy after posterior fossa operation in children. Neurosurgery 1984;15:707. 70. YoungJL Jr, Percy CL, Asire AJ, et al: Cancer incidence and mortality in the United States, 1973-77. Natl Cancer Inst Monogr 1981;(57):1. 71. Zimmerman RA, Bilaniuk I,T, Bruno I>, Rosenstock J: Computed tomography of cerebellar astrocytoma. AJR Am J Roentgenol 1978;130:929.

Principles of Transplantation Jorge Reyes, Noriko Murase, andThomas E. Starzl

Histocompatibility matching, immunosuppression, tissue preservation, and techniques of implantation have been considered to be the generic struts of both organ and bone marrow cell transplantation. However, neither kind of transplantation could have emerged as a clinical service were it not for the induction by the graft itself of various degrees on donor-specific nonreactivity (tolerance). Without this fifth factor, no transplant recipient could survive for long if the amount of immunosuppression given to obtain initial engraftment had to be continued.

THE ENIGMA OF ACQUIRED TOLERANCE The variable acquired tolerance on which transplantation depends has been one of the most enigmatic and controversial issues in all of biology. This was caused, in part, by the unexpected achievement of organ engraftment at an early time-a decade before successful bone marrow transplantation and in ostensible violation of the very principles that would shape the impending revolution in general immunology. As a consequence, clinical organ transplantation was developed empirically rather than as a branch of classic immunology. This occurred in four distinct phases, each lasting more than a decade. Only at the end was it possible to explain organ engraftment and thereby eliminate the mystique of transplantation.

of bone marrow transplantation had to await discovery of the human leukocyte antigens (HLA). When this was accompli~hed,"2~,~~ the successfully treated human bone marrow recipients of 1968 were oversized versions of the tolerant chimeric mice. By the time of the clinical bone marrow transplant breakthrough of 1968, kidney transplantation22.23fi42,48x4g,64 already was an established clinical service, albeit a flawed 0ne.65 In addition, the first long survivals had been recorded after liver72 and heart transplantation5; these were followed in 1968-1969 by the first prolonged survival of a lung18 and a pancreas recipient" (Table 42-1). All of the organ transplant successes had been accomplished in the ostensible absence of leukocyte chimerism, without HLA matching and with no evidence of GVHD. By going

Phase 1: 1953-1968 Phase 1 began between 1953-1956with the demonstration that neonatal mice8*%ndirradiated adult micex develop donor-specific tolerance after successful engraftment o f donor hematolymphopoietic cells. The key observation was that the mice bearing donor cells (donor leukocyte chimerism) could now accept skin grafts from the original donor strain but from no other strain (Fig. 42-1). The chimeric neonatal mice and the irradiated adult mice were analogues of today's bone marrow transplantation into imm;ne deficient and cvtoablated humans, respectively. But because a good histocompatibility match was required for avoidance of graft-versus-host disease (GVHD) and of rejection," clinical application

-

A

The mouse models of acquired tolerance described

between 1953 and 1956. White cells (leukocytes) were isolated from the spleen or bone marrow of adult donor mice (up@ Lrft) and injected into the bloodstream of newborn mice (uppcr right) or of irradiated adult mice (middle right). Under both circumstances, the recipient immune system was too weak to reject the foreign cells (dark shaded). With engraftment of the injected cells (i.e., donor leukocyte chimerism), the recipient mice now could freely accept tissues and organs from the leukocyte donor but from no other donor (bottom 4).

686

Organ

PART

IV

City

TRANSPLANTATION

Date

Physician/ Surgeon Reference

Merrill/ Murray Liver Denver July 23, 1967 Starzl Barnard Heart Cape Town Jan. 2 , 1 9 6 8 Ghent Nov. 14, 1968 Derom Lung Pancreas Minneapolis June 3, 1969 Lillehei Kidney

Boston

Jan. 24, 1959

42, 4 8 72 5 18 34

beyond the leukocyte chimerism boundaries established by the mouse tolerance models, organ transplantation had entered unmapped territory.

"Pseudotolerant" Organ Recipients Two unexplained features of the alloimmune response had made it feasible to forge ahead precociously with organ tran~plantation.~~ The first was that organ rejection is highly reversible. The second was that an organ allograft, if protected by nonspecific immunosuppression, could induce its own acceptance. "Self-induced engraftment" was observed for the first time in 1959 in two fraternal twin kidney recipients, first in Boston by Joseph Murray48 and then in Paris by Jean Hamburger.22 These were the first successful transplantations in the world of an organ allograft, in any species. Both patients had been conditioned with 450 R sublethal total-body irradiation before transplantation. The renal allografts functioned for more than 2 decades without a need for maintenance drug therapy, which was, in fact, not yet available. A similar drug-free state was next occasionally observed after kidney transplantation (and more frequently after liver replacement) in mongrel dogs who were treated with a single immunosuppressive agent: Gmercaptopurine (6-MP) ,"Jfl a~athioprine,j036~ prednisone,fl3 or antilymphocyte globulin (ALG).70 After treatment was stopped, rejection in some animals never developed (Fig. 42-2A). Such results were exceedingly rare; less than 1% of the canine kidney experiments done under 6-MP and azathioprine up to the summer of 1962. However, the possibility that an organ could be inherently tolerogenic was crystallized by the human experience summarized in the title of a report in 1963 of a series of live donor kidney recipients treated in Denver: "The Reversal of Rejection in Human Renal Homografts with Subsequent " ~ ~ recipients Development of Homograft T ~ l e r a n c e . The had been given azathioprine before as well as after renal transplantation, adding large doses of prednisone to treat rejections that were monitored by serial testing of serum creatinine (Fig. 42-3A). Rejection occurred in almost every case, and 25% of the grafts were lost to uncontrolled acute rejection. However, the 1-year survival of 46 allografts obtained from familial donors over a 16-month period in 1962-1963was an unprecedented 75%. The development of partial tolerance in many of the survivors was inferred from the rapidly declining need

for treatment after rejection reversal (see Fig. 42-3A). Nine (19%) of the 46 allografts functioned for the next 4 decades, each depicted in Figure 42-4 as a horizontal bar. Moreover, all immunosuppression eventually was stopped in seven of the nine patients without rejection for periods ranging from 6 to 40 years (the solid portion of the bars). Eight of the nine patients are still alive and bear the longest surviving organ allografts in the world.92 What was the connection between the tolerant mouse models, the irradiated fraternal twin kidney recipients in Boston and Paris, the ultimate drug-free canine organ recipients (see Fig. 42-2A), and the unique cluster of "pseudotolerant" human kidney recipients in Denver (Fig. 42-4)? The mystery deepened with the demonstration in 1966 in France,I6 England,NJz," and the United States74 that the liver can be transplanted in about 20% of outbred pigs without any treatment at all (see Fig. 42-2B). None of the animal or human organ recipients, whether off or on maintenance immunosuppression, was thought to have donor leukocyte chimerism.

B

.

A, Caine recipient of an orthotopic liver homograft, 5 years later. The operation was on March 23, 1964. The dog was treated for only 120 days with a~athioprineand died of old age after 13 years. B, A spontaneously tolerant pig recipient described by Calne.12 -

1

CHAPTER

42

Principles of Transplantation

687

, A, Empirically developed immunosuppression used for kidney transplant recipients in 1962-1963. Note the reversal of rejection with the addition of prednisone to azathioprine. More than a third of a century later it was realized that the timing of drug administration had been in accord with the tolcrogcnic principles of immunosuppression (see text). B, Treatment revisions in immunosuppression made at the University of Colorado in December, 1963, that unwittingly violated principles of tolerogenic immunosuppression. Pretreatment was de-emphasized or eliminated, and high doses of prednisone were given prophylactically instead of as needed. Although the frequency of acute rejection was reduced, the drug-tree tolerance shown in Figure 4'2-4 was no longer seen. -

A

False Premises of Phase 1

been developed with azathioprine and prednisone (see Fig. 42-3B). The principal change was the use of large prophylactic doses of prednisone from the time of operation, instead of the administration of corticosteroids only when needed. In a second modification, the pretreatment was de-emphasized (see Fig. 42-3B). The incidence of acute rejection was greatly reduced after these changes. However, no cluster of drug-free kidney recipients like that shown in Figure 4 2 4 was ever seen again, anywhere in the world. More than 35 years passed before the long-term immunologic consequences of the modifications were realized.

Thus, organ transplantation became disconnected at a very early time from the scientific anchor of leukocyte chimerism that had been established by the mouse models and was soon to be exemplified by human bone marrow transplantation. The resulting intellectual separation of the two kinds of transplantation (Fig. 42-5) was an unchallenged legacy of phase 1, passed on from generation to generation ever since. There was another dark legacy of phase 1. This was a modified version of the treatment strategy that had

Nine (19%) of the 46 live donor kidney recipients treated at the University of Colorado over an 18-month period beginning in the autumn of 1962. The solid portion of the horizontal bars depicts the time off immunosuppression. Note that the current serum creatinine concentration (CR) is normal in all but one patient. *Murdered: kidney allograft normal at autopsy.

Recipient 1

[

~mrnunosuppression

No ~rnmunosuppression

Donor

CR

I Sister 4 . 5

2

1 Brother 4 . 5

3

[

Mother 4 . 5 Mother 4 . 5

4 5

1

1

w

--

Sister

6

7

8 9

Mother 2.5-3 c1.5

1 Gr. Aunt 4.5

< 9

1

1

I

0

10 20 30 Years post transplantation

I

I

40

Father

4.5

Uncle

4.5

688

PART

IV

TRANSPI.ANTATION Solid Organ

Bone Marrow

.

-

A

The developmental tree of

bone marrow (right) and organ transplantation (left) after it was demonstrated that rejection is an immunologic response. GVHD, graftversus-host disease.

Tissue match

Phase 2: 1969-1979 Throughout the succeeding phase 2 that began in 1969, immunosuppression for organ transplantation was based on azathioprine and prophylactic high-dose prednisone in about 15% of to which ALG was added after 196670,71 centers. Phase 2 was a bleak period. In the view of critics, the heavy mortality, and particularly the devastating morbidity caused by corticosteroid dependence, made organ transplantation (even of kidneys) as much a disease as

A

a treatment. Most of the liver and heart transplant programs that had been established in an initial burst of optimism after the first successful cases closed down. But in the few remaining centers, patients like the one shown in Figure 42-6 bore witness to what some day would be accomplished on a grand scale. Four years old at the time of her liver replacement for biliary atresia and a hepatoma in 1969, she is the longest surviving recipient of an extrarenal organ.

B

Four-year-old at the time of liver rep1acement for biliary atresia and a hepatoma but now in her 35th post-transplant year. She is the longest surviving recipient of an extrarenal organ. a

.

A

CHAPTER

42

Principles of Transplantation

689

Phase 3: 1980-1991

or a role of leukocyte chimerism. Although it was known that organs contain large numbers of passenger leukocytes, In fact, what had appeared to be the sunset of extrarenal these donor cells were largely replaced in the successfully organ transplantation was only the dawn of phase 3, which began with the clinical introduction of ~yclosporine,~~~~~,~~,~8 transplanted allograft by recipient leukocytes as shown in Figure 42-8A. followed a decade later by that of t a c r o l i m ~ s . 2 0 ~ ~ ~ ~~~~ ~ 2 The missing donor cells were thought to The use of these drugs was associated with stepwise have undergone immune destruction with selective improvements with all organs, but their impact was most sparing of the specialized parenchymal cells. As for conclusively demonstrated with liver and heart transplanbone marrow transplantation (see Fig. 42-8B), the ideal result had been perceived as complete replacement of tation. The results with liver transplantation shown in recipient immune cells (i.e., total hematolymphopoietic Figure 42-7 using azathioprine-, cyclosporine-, and chimerism). tacrolimus-based immunosuppression were presented at the meeting of the American Surgical Association in April 1994.10"~ then, intestinal transplantation under The Discovery of Microchimerism tacrolimus-based immunosuppression had become a Ser~Ce.104,10.5 A flaw in this historical dogma began to be exposed in the early 1990s. The first puzzling observation in Seattle56 As the new agents became available, they were simply and Helsinki107 was the invariable presence of a small incorporated into the modified formula of heavy proresidual population of recipient hematolymphopoietic phylactic immunosuppression that had been inherited cells in patients previously thought to have complete from phases 1 and 2. Used in a variety of multiple-agent bone marrow replacement (see Fig. 42-8D). This was combinations from the time of surgery, the better drugs followed in 1992 by the discovery of donor leukocyte fueled the golden age of transplantation of the 1980s microchimerism in long-surviving human organ recipand early 1990s. Acute rejection had become almost a ients. Now it was evident that organ engraftment (see "non" problem. However, the unresolved issues now were Fig. 42-86) and bone marrow cell engraftment (see chronic rejection, risks of long-term immunosuppression Fig. 42-8D) were mirror-image versions of leukocyte (e.g., infections and de novo malignancies), and drug chimerism, differing in the reversed proportion of donor toxicity (e.g., the nephrotoxicity of cyclosporine and and recipient cells. tacrolimus) . The discovery of microchimerism in organ recipients was made with a very simple clinical With the use of sensitive detection techniques, donor hematolymPhase 4: 1992-Present phopoietic cells of different lineages (including dendritic cells) were found in the blood, lymph nodes, skin, or It was clear that relief from the burden of lifetime other tissues of 30 of 30 liver or kidney recipients who immunosuppression would require elucidation of the had borne functioning allografts for up to 30 years. The mechanisms of alloengraftment and of acquired tolerance. An intensified search for the engraftment mechanisms donor leukocytes obviously were progeny of donor has dominated the current phase 4, which began in the precursor or pluripotent hematolymphopoietic stem cells that had migrated from the graft into the recipient early 1990s. after surviving a double immune reaction that presumably had occurred just after transplantation, years or The Historical Dogma decades earlier.35,45,57,94 It was concluded that organ engraftment had been Until this time, organ engraftment had been attributed the result of "responses of co-existing donor and recipito mechanisms that did not involve either the presence ent cells, each to the other, causing reciprocal clonal exhaustion, followed by peripheral clonal deleti~n."R"~~ The host response (the upright curve in Fig. 42-9) was the dominant one in most cases of organ transplantation but with the occasional exception of GVHD. In the conventionally treated bone marrow recipient, host cytoablation simply transferred immune dominance from the host to the graft (the inverted curve in Fig. 42-9), A CYA (n=1835) AZA (n=168) explaining the high risk of GVHD. All of the major differences between the two kinds of transplantation were caused by the recipient cytoablation. After an estrangement of more than a third of a century, the intellectual o 1 i i i i separation of bone marrow and organ transplantation Time after transplantation (years) was ended (Fig. 42-10). V

-

A

.

Patient survival: results with orthotopic liver trans-

plantation at the Universities of Colorado (1963-1980) and Pittsburgh (1981-1993), in periods defined by azathioprine (AZA)-, cyclosporine (CYA)., and tacrolimus (TAC)-basedimmune suppression. Stepwise improvements associated with the advent of these drugs also were made with other kinds of organs.

Immune Regulation by Antigen Migration and Localization But how was the exhaustion-deletion of the double immune reaction shown in Figure 42-9 maintained after its

690

PART

IV

TKANSPLANTATION

Single response (organ)

n

Proliferation of host

HVG (rejection)

Single response (bone marrow)

I \

Defenseless recipient

d

Double response (organ)

Double response (bone marrow)

lmmunosuppress~on

HVG (rejection)

2

HVG

2

.

Old ( A and B) and new views (Cand D)of transplantation recipients A, The early conceptualization of immune mechanisms in organ transplantation in terms of a unidirectional host-versus-graft (HVG) response. Although this readily explained organ rejection, i t limited possible explanations of organ engraftment. B, Mirror image of A depicting the early understanding of successful bone marrow transplantation as a complete replacement of the recipient immune system by that of the donor, with the potential complication of an unopposed lethal unidirectional graft-versus-host (GVH) response, that is, rejection of the recipient by the graft. C, Our current view of bidirectional and reciprocally modulating imrnune responses of coexisting immune competent cell populations. Because of variable reciprocal induction of deletiorial tolerance, organ engraftnlent was feasible despite a usually dominant HVG reaction. The bone silhouette in the graft represents passenger leukocytes of bone marrow origin. I), Our currently conceived mirror image of Cafter successful bone marrow transplantation. Recipient's cytoablation has caused a reversal of the size proportions of the donor and recipient populations of immune cells.

-.

---

'-, -,,-__-,,-*'-------------,GVH ----- -- -Donor

---_-- --__

1 Time after organ transplantation

-*Failure

<:onternporaneous HVG

(upright rurvc.s)and GVH (irzuntcd run~~.s) responses after transplantation. In contrast to the usually dominant HVG reaction of organ transplantation, the GVH reaction usually is dominant after bone marrow cell transplantation to the irradiated or otherwise immunodepressed recipient. Therapeutic failure with either type of transplantahon implies the inability to control one, the other, or both of the contemporaneous responses with a protective umbrella of immunosuppression. (Starzl TE, Zinkernagel R: Antigen localization and migration in immunity and tolerance. N Engl J Med 1998;339:19051913.)

CHAPTER

a

.

A

Unification of organ and bone marrow transplantation

(See text).

acute induction by the first wave of migratory leukocytes? Rolf Zinkernagel, in Zurich (Fig. 42-1l ) , had addressed this question during the 1990s in experimental studies of the nonresponsiveness that may develop to intracellular microorganisms such as tubercle bacillus and ~ 0 9analogies -~~1 between the noncytopathic v i r ~ s e s . ~ ~ ~The syndromes caused by such infectious agents and the events following transplantation were described in 1998 in a joint

42

Principles of Transplantation

691

review with Zinkernagel in the New England Journal of Medi~ine.~~ The analogies between transplantation and infection had been obscured by the characteristic double immune reaction of transplantation and by the complicating factor of immunosuppression. Now, these analogies were obvious. The antidonor resDonse induced bv the initiallv selective migration of the graft's leukocytes to host lymis comparable to the phoid organs (Fig. 42-12, left)17j",44,51 response induced by a spreading intracellular pathogen. The migration patterns of the donor leukocytes were the same whether these cells emigrated from an organ or were delivered as a bone marrow cell infusion. Cells that survived the antidonor response that they had induced begin within a few days to move on (see Fig. 42-12, right) to protected nonlymphoid niches where their presence may be detected no longer by the immune system (immune ignorance4.27,",31.8y). This was a survival tactic of noncytopathic microorganisms. The migration of donor leukocytes is shown schematically in Figure 42-13, left by centrifugal arrows: first by hekatogeious routes to lymphoid organs and, afte; a few weeks, on to nonlymphoid sites (outer circle). A subsequent reverse migration of donor cells from protected nonlvm~hoid niches back to host lvm~hoid I organs is deiictid by the inwardly directed dashed arrows in Figure 42-13, right. The retrograde migration is a twoedged sword. On one hand, these cells may sustain the clonal exhaustion-deletion induced at the outset, usuallv requiring an umbrella of maintenance immunosuppression. But on the other hand, these cells can perpetuate alloimmunity in the same way as surviving residual microorganisms perpetuate protective immunity. Not surprisingly, therefore, an alternative consequence of microchimerism may be the high panel reactive antibody (connoting sensitization to HLA antigens) that commonly develops after unsuccessful transplantation.'k6I i

Therapeutic Implications

-.

Rolf Zinkernagel (1944). Swiss physician-immunologist whose discovery (with Peter Doherty) of the mechanisms of the adaptive immune response to noncytopathic microorganisms earned the Nobel prize in 1996.

How could the new insight be exploited clinically? The window of opportunity for the donor leukocyte-induced clonal deletion that corresponds with collapse of the antigraft response (Fig. 42-14, left) is open only for the It was apparent first few post-transplant weeks.4"47~97~'.5 that the window could be closed by excessive postoperative immunosuppression (see Fig. 42-14, middle). With later reduction of the initial overimmunosuppression, recovery of the inefficiently deleted clone would be expected, leading to the delayed acute rejection, or the chronic rejection, that was being seen in the transplant clinics. Even in the best-case scenario, the patients would be predestined to lifetime dependence on immunosuppression. However, too little immunosuppression would result in uncontrolled rejection (see Fig. 42-14, right). The problem faced by clinicians was how to find just the right amount of post-transplant immunosuppression. In 2001, it was suggested that this dilemma could be addressed by successively applying two historically rooted therapeutic principles: recipient pretreatment, followed by minimalistic With pretreatment, post-transplant imm~nosuppression.~) the recipients, immune responsiveness would be reduced

692

PART

IV

TRANSPLANTATION 1 Initial preferential migration of passenger leukocytes from organ allografts (here a liver) to host lymphoid organs (left), where they induce a donor-specific immune response. After about 30 days, many of the surviving cells move on to nonlymphoid sites (right). 0

Jon Coulter. MA, CMI

before exposure to donor antigen, thereby lowering the anticipated donor-specific response into a more readily deletable range (Fig. 42-15). Clonal deletion by the kidneys' passenger leukocytes undoubtedly is what had been accomplished after sublethal irradiation alone in the ground-breaking fraternal twin (i.e., sublethal total body irradiation or myelotoxic drugs) cases of 1959.22,48In fact, radical pretreatment by recipient cytoablation ultimately

became the essential therapeutic step for conventional bone marrow transplantation. Because of the high risk of GVHD, this approach was too dangerous and too restrictive to be practical for organ transplantation. However, less drastic lymphoid depletion by ALG or other measures (so-called nonmyeloablative conditioning) had been repeatedly shown since the 1960s to be effective without causing GVHD71 (see Fig. 42-15).

.

The migration routes of passenger leukocytes of transplanted organs are similar to those of infused bone marrow cells. Left, Selective migration at first to host lymphoid organs. After 15 to 30 days, surviving leukocytes begin to secondarily move to nonlymphoid sites. Right, Establishment of reverse traffic by which the exhaustiondeletion induced at the outset can be maintained. .

A

CHAPTER

Too much treatment

Tolerogenic immunosuppression

Too little treatment

42

Principles of Transplantation

693

Prednisone Tacrolimus Irreversible

s~

e Tx

Time

E -

Tx

rejection

Time

,

J

/

Tx

Time

with pretreatment

, , A r e t r e a t m e nand t minimal

The effect of post-transplant immunosuppression on the seminal mechanism of clonal exhaustion deletion. Left, Just the right amount. Middle, Too much. Right, Too little. See text. 0

-

1

After pretreatment with one of today's potent antilymphoid antibody preparations, the preemp&velyweakened clonal activation could proceed efficiently to clonal deletion under minimalistic short- and long-term maintenance therapy (Fig. 42-16). In July 2001, we instituted the adult organ recipients. The d ~ u b i e - ~ r i n c istrategy ~le pretreatment was with a single infusion of 5 mg/kg of thymoglobulin. Beginning in 2002, a single Campath dose of 30 mg was substituted for thymoglobulin in most adult cases. After either kind of lymphoid depletion, treatment after transplantation was given with a conservative daily dose of a single drug (usually tacrolimus), adding other agents onlyin the event of breakthrough rejection and for as brief a period as possible. The strategy was extended to infants and children for intestinal transplantation in 2002 and for all kidney transplantations after April 2003. After 4 to 8 months, weaning from monotherapy to less than daily doses was begun in adults whose graft function was stable: every other day, then three times per week, twice a week, and in many cases to once a week by 1 year (Fig. 42-17). The strategy has been used for the

1 V)

1. Irradiation

2. Thoracic duct drainage

$ C

3. Other drugs

g

4. Antilymphoid antibodies

I

immunosuppression

, - 1 Conversion of rejection (thick dark arrow) to an immune response that can be exhausted and deleted by combination of pretreatment and minimalistic post-transplant immunosuppression. treatment of more than 1000 adult kidney, liver, intestine, pancreas, and lung recipients.40,5g,glThis experience has demonstrated that the quality of life of transplant recipients can be improved. For the first time, children are being considered for spaced weaning.

ORGAN PRESERVATION Procurement The breakthroughs of the early 1960s that made transplantation clinically practical were so unexpected that almost no formal preparation had been made to preserve the transplanted organs. Cardiac surgeons had used hypothermia for open-heart operations from 1950 onward and knew that ischemic damage below the level of aortic cross-clamping could be reduced by cooling the subdiaphagmatic organs." In an early report, Lillehei and colleagues"%mmersed intestines in iced saline before autotransplantation. In Boston, Sicular and MooreGO reported greatly slowed enzyme degradation in cold slices of liver. Despite this awareness, kidneys were routinely transplanted until 1963with no protection from warm ischemia during organ transfer. The only attempt to cool kidney allografts until then was by the potentially dangerous practice Off immune-

a,

z C

suppression

Daily multitherapy

'

E

Pretreatment

Daily mono-

I Tx

1 Rather than producing rejection (thick dark arrow), the donor-specific immune response to allografts may be exhausted and deleted, as depicted by the fall of the initially ascending continuous thin line, when recipient immune responsiveness is weakened in advance of transplantation (the pretreatment principle).

2 a week

.

4

- '

Diagram of 2 %-year follow-up.

6

694

PART

IV

TKANSPLANTATION

.

-

First technique of in situ cooling by

1

extracorporeal hypothermic perfusion. The catheters were inserted into the aorta and vena cava by way of the femoral vessels as soon as possible after death. Temperature control was provided with a heat exchanger. Cross-clamping of the thoracic aorta limited perfusion to the lower part of the body. This method of cadaveric organ procurement was used from 1962 to 1969, before the acceptance of brain death criteria. The preliminary stages of this approach provided the basis for subsequent in situ infusion techniques.

Pump

(used by thoracic surgeons for open-heart surgery) of immersing the live donor in a bathtub of ice water (totalbody hypt&ermia) .6Thiscumbersome method of cooling was quickly replaced by infusion of chilled solutions into the renal artery after donor nephrectomy,G7 exploiting a principle of core (transvascular) cooling that had been standardized several years earlier for experimental liver transplantation."' Core cooling in situ, the first critical step in the preservation of all cadaveric whole organs, is done todaywith variations of the technique described in 1963 by Marchioro and coworker^,^' which permits in situ cooling to be undertaken" (Fig. 42-18). Ackerman and Snelll and Merkcl and associates41popularized in situ cooling of cadaveric kidneys with simple infusion of cold electrolyte solutions into the donor femoral artery or distal aorta. Procurement techniques were e v e n t u a ~ l ~ ~ e r f e c t e d that allowed removal of all thoracic and abdominal organs, including the liver, without jeopardizing any of the individual organs (Fig. 42-19).79 Modifications of this flexible ~ r o c e d u r ehave been made for unstable donors and even for donors whose hearts have stopped beating.80 During the 5 years between 1980 and 1985, such techniques had become interchangeable in all parts of the world, setting the stage for reliable organ sharing. After the chilled organs are removed, subsequent preservation is possible with prototype strategies: simple refrigeration or continuous perfusion (see later).

\

Preservationfluid

)

through splenic v.

n fluid minal

Extended Preservation Continuous Vascular Perfusion Efforts to continuously perfuse isolated organs have proved to be difficult. For renal allografts, Ackerman and Barnard2 used a normothermic perfusate primed with

1 Principle of in situ cooling used for multiple organ procurement. With limited preliminary dissection of the aorta and of the great splanchnic veins (in this case the splenic vein), cold infusates can be used to chill organs in situ. In this case, the kidneys and liver were being removed. Note the aortic cross-clamp above the celiac axis.

CHAPTER

blood that was oxygenated within a hyperbaric chamber. Brettschneider and colleagues~0modified the apparatus and were able to preserve canine livers for 2 days, an unprecedented feat at the time. When Belzer and associates~liminatedthe hemoglobin and hyperbaric chamber components, their asanguinous hypothermic perfusion technique was immediately accepted for clinical renal transplantation but then slowly abandoned in most centers when it was learned that the quality of 2-day preservation was not markedly better than that of simpler and less expensive infusion and slush methods (see later). However, refinement of perfusion techniques may someday permit true organ banking.

Static Preservation With these "slush techniques," special solutions, such as those described by Collins and co~orkers,~%ere instilled into the renal vascular system of kidneys or the vascular system of other organs after their preliminary chilling and separation. The original Collins solution or modifications of it were used for nearly 2 decades before they were replaced with the University of Wisconsin (UW) solution that was developed by the team of Folkert Belzer. Although it was first used for the liver,7.2"I0' the UW solution provides superior preservation of kidneys and other organ~.'"I("~The UW preservation permitted longer and safer preservation of kidneys (2 days) and livers (18 hours), a higher rate of graft survival, and a lower rate of primary nonfunction. With the UW solution, national organ sharing was made economical and practical.

42

Principles of Transplantation

695

Match

Partial mismatch

a

Total mismatch

a The nullification effect of'sirn~~l~aneous host-versusgraft (HVG) and graft-versus-host (GWI) reactions when organs are transplanted to recipients whose imrnutie system has not been cytoablated. The reciprocal induction of tolerance, each to the other, of the coexisting cell populations is the explanation for- the poor correlation of HLA matching with outcome afier organ iransplantation.

TISSUE TYPING

Antigen Matching

identical to that of parent-offspring (one haplotype matched) grafts. The inescapable conclusion is that more The first prospective antigen matching trials were begun effective timing and dosage of immunosuppressive therin 1964 by Terasaki and associatesg7in collaboration with apy rather than refinements in tissue matching and organ the University of Colorado kidney transplantation team. sharing will be the primary method of improving the Although the value of this serologic technology was results of whole-organ transplantation. demonstrable when the kidney donor was a highly compatible family member (the "perfect match") ,75 lesser degrees of matching correIated poorIy with renal transplantation outcome.88The reasons for this paradox were Crossmatching inexplicable until the discovery of recipient chimerism None of the immunosuppressive measures available today (Fig. 42-20). However, the belief that matching should be can prevent immediate destruction of kidneys and other a prime determinant of success resulted in its use as an kinds of organ grafts in what has been called hyperacute overriding factor for the allocation of cadaver kidneys in rejection. This complication was first seen with the transthe United States. plantation of kidneys from ABO-incompatible donors The propriety of this kidney allocation policy has been when they were placed in recipients with antidonor repeatedly challenged on ethical as well as scientific isoagglutinins.69 After the description by Terasaki and grounds for nearly a third of a century. Those in favor of associatesg%f hyperacute kidney rejection by a recipient perpetuating the role of graded HLA matches cite multiwith antidonor lymphocytotoxic antibodies, Kissmeyercenter case compilations in the United States and Europe Nielsen and colleagues28 and others7~.7"1O0,"'Rconfirmed showing a small gain in allograft survival with histocompatthe association of hyperacute rejection with these antiible kidneys, whereas many of the individual contributing centers see no such trend in their own experien~e.~g,",.",~~graft antibodies. Although hyperacute rejection can usually be avoided with the lymphocytotoxic crossmatch In a compelling study, Terasaki and associatesg8reported originally recommended by Terasaki and associates, the that early survival and the subsequent half-life of kidneys from randomly matched, living unrelated donors was precise pathogenesis of such rejection remains poorly

696

PART

IV

TRANSPI.ANTATION

understood more than 30 years after its recognition as a complement activation syndrome.73.7" 15.

FUTURE PROSPECTS The revisions in timing and dose control that encourage the seminal mechanisms of clonal exhaustion-deletion and immune ignorance should make it possible to systematically reduce exposure to the risks of chronic immunosuppression. Our prediction is that conlpletely drug free tolerance will be largely, but not exclusively, limited to recipients of HLA-matched organs. But variable partial tolerance will be more regularly attainable in most of the others, not so much by developing better drugs as by the mechanism-based use of drugs we already have in hand. Xenotransplantation will have to be developed within the same immunologic framework. Here, the problem in principle is to create a better interspecies tissue match by transgenic modification. Although the a-1,3GT gene responsible for hyperacute rejection of pig organs by higher primates has been knocked out in pigs,54 it is not yet known what further changes have to be made before porcine organs can be used clinically. Where stem cell biology will fit remains unknown. But it also will have to conform to the same immunologic rules.

16. 17. 18. 19.

20.

21. 22.

23.

REFERENCES

24.

1. Ackermann JR, Snell MR: Cadaveric renal transplantation. Br J Urol 1963;40:515. 2. Ackermann JR, Barnard CN: Successful storage of kidneys. Br J Surg 1966;53:525-532. 3. Bach FH: Bone-marrow transplantation in a patient with the Wiskott-Aldrich syndrome. Lancet 1968;2:13641366. 4. Barker CF, Billingham RE: The role of afferent lymphatics in the rejection of skin homografts. J Exp Med 1968;128: 197-221. 5. Barnard CN: What we have learned about heart transplants. J Thorac Cardiovasc Surg 1968;56:457-468. 6. Belzer FO, Ashby BS, Dunphy JE: 24hour and 72-hour preservation of canine kidneys. Lancet 1967;2:536538. 7. Belzer FO, Southard JH: Principles of solid-organ preservation by cold storage. Transplantation 1988;45:673-676. 8. Billingham RE, Brent I,, Medawar PB: "Actively acquired tolerance" of foreign cells. Nature 1953;172:603-606. 9. Billingham R, Brent L, Medawar P: Quantitative studies on tissue transplantation immunity: 111. Actively acquired tolerance. Philos Trans R Soc Lond (Biol) 1956;239:357-412. 10. Brettschneider L, Daloze PM, Huguet C, et al: The use of combined preservation techniques for extended storage of orthotopic liver homografts. Surg Gynecol Obstet 1968;126:263-274. 11. Calne RY, White HJO, Yoffa DE, et al: Prolonged survival of liver transplants in the pig. BMJ 1967;4:645-648. 12. Calne RY, Sells RA, Pena JR, et al: Induction of immunological tolerance by porcine liver allografts. Nature 1969;223: 472-474. 13. Calne RY, White DJG, Thiru S, et al: Cyclosporin A in patients receiving renal allografts from cadaver donors. Lancet 1978;2:1323-1327. 14. Calne RY, Rolles K, White DJG, et al: Cyclosporin A initially as the only immunosuppressant in 34 recipients of cadaveric

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organs; 32 kidneys, 2 pancreases, and 2 livers. Lancet 1979;2:10531036. Collins GM, Bravo-Shugaman M, Terasaki PI: Kidney preservation for transportation: Initial perfusion and 30 hours ice storage. Lancet 1969;2:1219-1224. Cordier G, Garnier H, ClotJP, et al: La greffe de foie orthotopique chez le porc. Mem Acad Chir (Paris) 1966;92: 799-807. Demetris AJ, Qian S, Sun H, et al: Early events in liver allograft rejection. Am J Path01 1991;138:609-618. Derom F, Barbier F, Ringoir S, et al: Ten-month survival after lung homotransplantation in man. J Thorac Cardiovasc Surg 1971;61:835-846. Ferguson R: For the Transplant Infttrmation Share Group (TISG): A multicenter experience with sequential ALG/ cyclosporine therapy in renal transplantation. Clin Transpl 1988;2:285. FungJ, Todo S, Tzakis A, et a]: Conversion of liver allograft recipients from cyclosporine to FKfi06-based immunosuppression: Benefits and pitfalls. Transplant Proc 1991; 23:1421. Gatti RA, Meuwissen HI, Allen HD, et al: Immunological reconstitution of sex-linked lymphopenic immunolo~ical deficiency. Lancet 1968;2:1366-1369. Hamburger J, Vaysse J, Crosnier J, et al: Transplantation of a kidney between nonmonozygotic twins after irradiation of the receiver: Good function at the fourth month. Presse Med 1959;67:1771-1775. Hamburger J, Vaysse J, Crosnier J , et al: Renal homotransplantation in man after radiation of the recipient. Am J Med 1962;32:854871. Hoffman B, Sollinger H, Kalayoglu M, Belzer FO: Use of UW solution for kidney transplantation. Transplantation 1988;46:338-339. Inman B, Halloran B, Melk A, et al: Microchimerisrn in sensitized renal patients. Transplantation 1999;67:1381-1383. Kalayoglu M, Sollinger HW, Stratta RI, et al: Extended preservation of the liver for clinical transplantation. Lancet 1988;1:617-619. Karrer U, Althage A, Oderlnatt B, et al: On the key role of secondary lymphoid organs in antiviral immune responses studied in alymphoplastic (aly/aly) and spleenless (Hoxll(-)/-) mutant mice. J Exp Med 1997;185: 2157-2170. Kissmeyer-Nielsen F, Olsen S, Peterson VP, Fjeldborg 0 : Hyperacute rejection of kidney allografts, associated with preexisting humoral antibodies against donor cells. Lancet 1966;2:622. Kuss R, Legrain M, Mathe G, et al: Homologous human kidney transplantation: Experience with six patients. Postgrad Med J 1962;38:528-531. Lafferty KJ, Prowse SJ, Simeonovic CJ: Immunobiology of tissue transplantation: A return to the passenger leukocyte concept. Ann Rev Immunol 1983;1:143-173. Lakkis FG, Arakelov A, Konieczny BT, Inoue Y Immunologic ignorance of vascularized organ transplants in the absence of secondary lymphoid tissue. Nature Med 2000;6:686-688. Larsen CP, Morris PJ, Austyn JM: Migration of dendritic leukocytes from cardiac allografts into host spleens: A novel route for initiation of rejection. J Exp Med 1990;171: 307-314. Lillehei RC, Goott B, Miller FA: The physiological response of the small bowel of the dog to ischemia including prolonged in vitro preservation of the bowel with successful replacement and survival. Ann Surg 1959;150:543-560. Lillehei RC, Simmons RL, Najarian JS, et al: Pancreaticoduodenal allotransplantation: Experimental and clinical observations. Ann Surg 1970;172:405-436.

CHAPTER

35. Lu L, Rudert WA, Qian S, et al: Growth of donorderived dendritic cells from the bone marrow of murine liver allograft recipients in response to granulocyte/macrophage colonystimulating factor. J Exp Med 1995;182:379-387. 36. Main JM, Prehn RT: Successful skin homografts after the administration of high dosage X radiation and homologous bone marrow. J Natl Cancer Inst 1955;15:1023-1029. 37. Marchioro TL, Waddell WR, Starzl TE: Use of extracorporeal cadaver perfusion for preparation of organ homografts. Surg Forum 1963;14:174176. 38. Matas AJ, Sutherland DER, Najarian JS: The impact of HLA matching on graft survival. Transplantation 1992;54: 568-569. 39. Mathe G, Amiel JL, Schwarzenberg L, et al: Haematopoietic chimera in man after allogeneic (homologous) bonemarrow transplantation. BMJ 1963;2:1633-1635. 40. McCurry K, Iacono A, Zeevi A, et al: Early outcomes in human lung transplantation utilizing thymoglobulin or campath 1H for recipient pretreatment followed by posttransplant tacrolimus near-monotherapy.J Thorac Cardiovasc Surg, 2005;2:528-537. 41. Merkel FK, Jonasson 0 , Bergang: Procurement of cadaver donor organs: Evisceration technique. Transplant Proc 1972;4:585-589. 42. Merrill JP, Murray JE, Harrison JH, et al: Successful homotransplantation of the kidney between non-identical twins. N Engl J Med 1960;262:1251-1260. 43. Moskophidis D, Lechner F, Pircher H, Zinkernagel RM: Virus persistence in acutely infected immunocompetent mice by exhaustion of antiviral cytotoxic effector T cells. Nature 1993;362:758-761. 44. Murase N, Demetris AJ, Woo J, et al: Lymphocyte traffic and graft-versus-host disease after fully allogeneic small bowel transplantation. Transplant Proc 1991;23:3246-3247. 45. Murase N, Starzl TE, Ye Q et al: Multilineage hematopoietic reconstitution of supralethallyirradiated rats by syngeneic whole organ transplantation: with particular reference to the liver. Transplantation 1996;61:1-4. 46. Murase N, Demetris A, Woo J, et al: Graft versus host disease (GVHD) after BN to LEW compared to LEW to BN rat intestinal transplantation under FK 506. Transplantation 1993;55:1-7. 47. Murase N, Starzl TE, Tanabe M, et al: Variable chimerism, graft versus host disease, and tolerance after different kinds of cell and whole organ transplantation from Lewis to Brown-Norway rats. Transplantation 1995;60:158-171. 48. MurrayJE, Merrill JP, Dammin GJ, et al: Study of transplantation immunity after total body irradiation: Clinical and experimental investigation. Surgery 1960;48:272-284. 49. MurrayJE, Merrill JP, Harrison JH, et al: Prolonged survival of human-kidney homografts by immunosuppressive drug therapy. N Engl J Med 1963;268:1315-1323. 50. Murray JE, Sheil AGR, Moseley R, et al: Analysis of mechanism of immunosuppressive drugs in renal homotransplantation. Ann Surg 1964;160:449-473. 51. Nemlander A, Soots A, von Willebrand E, et al: Redistribution of renal allograft-responding leukocytes during rejection: 11. Kinetics and specificity. J Exp Med 1982;156:1087-1100. 52. Peacock J H , Terblanche J: Orthotopic homotransplantation of the liver in the pig. In Read AE (ed): The Liver. London, Butterworth, 1967, p 333. 53. Phelps CJ, Koike C, Vaught TD, et al: Production of al,3-galactosyltransferase-deficientpigs. Science 2003;299: 41 1-414. 54. Pierce JC, Varco RL: Induction of tolerance to a canine renal homotransplant with 6-mercaptopurine. Lancet 1962;1:781-782.

42

Principles of Transplantation

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55. Przepiorka D, Thomas ED, Durham DM, Fisher L: Use of a probe to repeat sequence of the Y chromosome for detection of host cells in peripheral blood of bone marrow transplant recipients. Am J Clin Path01 1991;95:201-206. 56. Sakamoto T, Ye Q, Lu L, et al: Donor hematopoietic progenitor cells in non-myeloablated rat recipients of allogeneic bone marrow and liver grafts. Transplantation 1999; 675333-840. 57. Owens JC, Prevedel AE, Swan H: Prolonged experimental occlusion of thoracic aorta during hypothermia. Arch Surg 1955;70:95-97. 58. Salvatierra 0Jr: Optimal use of organs for transplantation. N Engl J Med 1988;318:1329-1331. 59. Shapiro R, Jordan M, Basu A, et al: Kidney transplantation under a tolerogenic regimen of recipient pre-treatment and low-dose postoperative immunosuppression, with subsequent weaning. Ann Surg 2003;238:520-527. 60. Sicular A, Moore FD: The postmortem survival of tissues. J Surg Res 1961;1:16. 61. SivaSai KS, Jendrisak M, Duffj BF, et al: Chimerism in peripheral blood of sensitized patients waiting for renal transplantation: Clinical implications. Transplantation 2000;69:538-544. 62. Starzl TE, Kaupp HA Jr, Brock DR, et al: Reconstructive problems in canine liver homotransplantation with special reference to the postoperative role of hepatic venous flow. Surg Gynecol Obstet 1960;111:733-743. 63. Starzl TE, Brittain RS, Stonnington OG, et al: Renal transplantation in identical twins. Arch Surg 1963;86:600-607. 64. Starzl TE, Marchioro TL, Waddell WR: The reversal of rejection in human renal homografts with subsequent development of homograft tolerance. Surg Gynecol Obstet 1963;117:385-395. 65. Starzl TE: Experience in Renal Transplantation. Philadelphia, WB Saunders, 1964. 66. Starzl TE: Host-graft adaptation. In Starzl TE: Experience in Renal Transplantation. Philadelphia, WB Saunders, 1964, pp 164170. 67. Starzl TE: Donor nephrectomy. In Starzl TE: Experience in Renal Transplantation. Philadelphia, WB Saunders, 1964, pp 68-82. 68. Starzl TE: The role of cadaveric donors in homotransplantation. In Starzl TE: Experience in Renal Transplantation. Philadelphia, WB Saunders, 1964, pp 5458. 69. Starzl TE: Patterns of permissible donor-recipient tissue transfer in relation to ABO blood groups. In Starzl TE: Experience in Renal Transplantation. Philadelphia, WB Saunders, 1964, pp 37-46. 70. Starzl TE, Marchioro TL, Porter KA, et al: The use of heterologous antilymphoid agents in canine renal and liver homotransplantation and in human renal homotransplantation. Surg Gynecol Obstet 1967;124:301-318. 71. Starzl TE, Porter KA, Iwasaki Y, et al: The use of antilymphocyte globulin in human renal homotransplantation. In Wolstenholme GEW, O'Connor M (eds): Antilymphocytic Serum. London, J & A Churchill, 1967, pp 4-34. 72. Starzl TE, Groth CG, Brettschneider L, et al: Orthotopic homotransplantation of the human liver. Ann Surg 1968; 168:392-415. 73. Starzl TE, Lerner RA, Dixon FJ, et al: Shwartzman reaction after human renal transplantation. N Engl J Med 1968;278: 642-648. 74. Starzl TE: Rejection in unmodified animals. In Starzl TE: Experience in Renal Transplantation. Philadelphia, WB Saunders, 1964, p 184. 75. Starzl TE, Porter KA, Andres G, et a]: Long-term survival after renal transplantation in humans: With special reference to histocompatibility matching, thymectomy, homograft

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77. 78. 79. 80. 81. 82. 83. 84. 85. 86. 87. 88. 89. 90. 91. 92. 93. 94. 95.

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glomerulonephritis, heterologous ALG, and recipient malignancy. Ann Surg 1970;172:437-472. Starzl TE, Boehmig HJ, Amemiya H, et al: Clotting changes, including disseminated intravascular coagulation, during rapid renal-homograft rejection. N Engl J Med 1970;283:383-390. Starzl TE, Weil R 111, Iwatsuki S, et al: The use of cyclosporin A and prednisone in cadaver kidney transplantation. Surg Gynecol Obstet 1980;151:17-26. Starzl TE, Klintmalm GBG, Porter KA, et al: Liver transplantation with use of cyclosporin A and prednisone. N Engl J Med 1981;305:266-269. Starzl TE, Hakala TR, Shaw BWJr, et al: Aflexible procedure for multiple cadaveric organ procurement. Surg Gynecol Obstet 1984;158:223-230. Starzl TE, Miller C, Broznick B, Makowka L: An improved technique for multiple organ harvesting. Surg Gynecol Obstet 1987;165:343-348. Starzl TE, Todo S, Fung J, et al: FK 506 for human liver, kidney and pancreas transplantation. Lancet 1989;2: 1000-1004. Starzl TE, Fung J, Jordan M, et al: Kidney transplantation under FK 506. JAMA 1990;264:63-67. Starzl TE, Demetris AJ, Murase N, et al: Cell migration, chimerism, and graft acceptance. Lancet 1992;339:1579-1582. Starzl TE, Demetris AJ, Trucco M, et al: Systemic chimerism in human female recipients of male livers. Lancet 1992;340: 876-877. Starzl TE, Demetris AJ, Trucco M, et al: Cell migration and chimerism after whole-organ transplantation: The basis of graft acceptance. Hepatology 1993;17:1127-1152. Starzl TE, Demetris AJ, Trucco M, et al: Chimerism after liver transplantation for type IV glycogen storage disease and type I Gaucher's disease. N Engl J Med 1993;328:745-749. Starzl TE, Demetris AJ, Trucco M, et al: Chimerism and donor-specific nonreactivity 27 to 29 years after kidney allotransplantation. Transplantation 1993;55:1272-1277. Starzl TE, Eliasziw M, Gjertson M, et al: HLA and cross reactive antigen group (CREG) matching for cadaver kidney allocation. Transplantation 1997;64:983-991. Starzl TE, Zinkernagel R: Antigen localization and migration in immunity and tolerance. N Engl J Med 1998;339: 1905-1913. Starzl TE, Zinkernagel R: Transplantation tolerance from a historical perspective. Nature Rev Immunol 2001;1:233-239. Starzl TE, Murase N, Abu-Elmagd K, et al: Tolerogenic immunosuppression for organ transplantation. Lancet 2003;361:1502-1510. Starzl TE, Murase N, Demetris AJ, et al: Lessons of organinduced tolerance learned from historical clinical experience. Transplantation 2004;77:926-929. Takemoto S Terasaki PI, Cecka JM, et al: Survival of nationally shared HLA-matched kidney transplants from cadaveric donors. N Engl J Med 1992;327:834839. Taniguchi H, Toyoshima T, Fukao K, Nakauchi H: Presence of hematopoietic stem cells in the adult liver. Nat Med 1996;2:198-203. Terakura M, Murase N, Demetris AJ, et al: Lymphoid/ non-lymphoid compartmentalization of donor leukocyte

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chimerism in rat recipients of heart allografts, with or without adjunct bone marrow. Transplantation 1998;66: 350-357. Terasaki PI, Marchioro TL, Starzl TE: Sero-typing of human lymphocyte antigens: Preliminary trials on longterm kidney homograft survivors. In Russel PS, Winn HJ, Amos DB (eds): Histocompatibility Testing. Washington, DC, National Academy of Science-National Research Council, 1965. Terasaki PI, Vredevoe DL, Mickey MR, et al: Serotyping for homotransplantation: VII. Selection of kidney donors for thirty-two recipients. Ann N Y Acad Sci 1966;129:500. Terasaki PI, Cecka JM, Gjertson DW, Takemoto S: High survival rates of kidney transplants from spousal and living unrelated donors. N Engl J Med 1995;333:333-336. Thomas ED, Storb R, Clift RA, et al: Bone marrow transplantation. N Engl J Med 1975;292:832, 895-902 (2 parts). Ting A: The lymphocytotoxic crossmatch test in clinical renal transplantation. Transplantation 1983;35:403-407. Todo S, Nery J, Yanaga K, et al: Extended preservation of human liver grafts with UW solution. J A M 1989;261: 71 1-714. Todo S, FungJ, Starzl TE, et al: Liver, kidney, and thoracic organ transplantation under FK 506. Ann Surg 1990; 212:295-305. Todo S, FungJ, Starzl TE, et al: Single center experience with primary orthotopic liver transplantation under FK.506 immunosuppression. Ann Surg 1994;220:297-309. Todo S, Tzakis A, Reyes J, et al: Small intestinal transplantation in humans with or without colon. Transplantation 1994;57:840-848. Todo S, Reyes J, Furukawa H, et al: Outcome analysis of 71 clinical intestinal transplantations. Ann Surg 1995;222: 270-282. Ueda Y, Todo S, Imventarza 0,et al: The UW solution for canine kidney preservation: Its specific effect on renal hemodynamics and microvasculature. Transplantation 1989;48:913-918. Wessman M, Popp S, Ruutu T, et al: Detection of residual host cells after bone marrow transplantation using non-isotopic in situ hybridization and karyotype analysis. Bone Marrow Transplant 1993;11:279-284. Williams GM, et al: Studies in hyperacute and chronic renal homograft rejection in man. Surgery 1967;62:204. Zinkernagel RM, Ehl S, Aichele P, et al: Antigen localization regulates immune responses in a dose- and timedependent fashion: A geographical view of immune reactivity. Immunol Rev 1997;156:199-209. Zinkernagel RM, Hengartner H: Antiviral immunity. Immunol Today 1997;18:258-260. Zinkernagel RM, Bachmann MF, Kundig TM, et al: On immunologic memory. Annu Rev Immunol 1996;14: 333-367. Zukoski CF, Callaway JM: Adult tolerance induced by 6-methyl mercaptopurine to canine renal homografts. Nature (London) 1963;198:706707. Zukoski CF, Callaway JM, Rhea WG Jr: Tolerance to a canine renal homograft induced by prednisolone. Surg Forum 1963;14:208-210.

Renal Transplantation John C. Magee and Darrell A. Campbell, Jr.

Transplantation is the preferred treatment option for children with end-stage renal disease (ESRD) because it provides the best opportunity for health, growth, and development. Progress continues in pediatric transplantation, and currently patient and graft survival for pediatric renal recipients is excellent. The improvement in outcomes reflects better pretransplant care, a growing understanding of immunosuppression management in pediatric recipients, improvements in donor selection, and refinements in surgical technique and perioperative management. Several single-center experiences have documented the excellent results possible, even in small Children.34,4",47,57 Although single-center expertise provides great insight into many issues in transplantation, it is generally agreed that larger registry type data provide the most meaningful reflection of the state of transplantation as practiced across the country. One leading source of such information is the North American Pediatric Renal Transplant Cooperative Study (NAPRTCS), which was initiated in 1987.6,59,80 Additionally, national data in the United States are collected through the Organ Procurement Transplant Network (OPTN) and regularly analyzed by the Scientific Registry of Transplant Recipients (SRTR).14,*'j

END-STAGE RENAL DISEASE IN CHILDREN According to the United States Renal Data System (USRDS), 1216 individuals aged 19 or younger began treatment for ESRD in 2OO2.9The incidence of ESRD in this age group is 14.5 per million individuals per year. Because ESRD is much more uncommon in children than adults, this rate is well below the overall national incidence of ESRD of 333 per million per year. The etiology of renal disease in the pediatric transplant population is summarized in Table 43-1. According to these NAPRTCS data, the five most common diagnoses are obstructive uropathy, renal aplasia/hypoplasia/ dysplasia, focal segmental glomerulo sclerosis (FSGS), reflux nephropathy, and chronic glomerulonephritis. These diagnoses account for just over half the transplants performed. The causes of renal failure in children are distinctly different from those in the adult population;

specifically, congenital abnormalities and obstructive uropathy are some of the leading causes for renal transplantation in children. Additionally, FSGS is the most common acquired renal disease and is much more common in the pediatric age range compared with the adult population.

Disease Obstructive uropathy Aplasia/hypoplasia/dysplasia Focal segmental glomerulosclerosis Reflux nephropathy Chronic glomerulonephritis Medullary cystic disease Hemolytic-uremic syndrome Polycystic disease Prune belly syndrome Congenital nephrotic syndrome Familial nephritis Cystinosis Idiopathic crescentic glomerulonephritis Membranoproliferative glomerulonephritis type I Pyelo/interstitial nephritis Systemic lupus erythematosus nephritis Renal infarct Henoch-Schonleinnephritis Berger's (IgA) nephritis Membranoproliferative glomerulonephritis type II Wilms' tumor Denys-Drash syndrome Oxalosis Wegener's granulomatosis Membranous nephropathy Other systemic immunologic disease Sickle cell nephropathy Diabetic glomerulonephritis Other Unknown

% 16.1

From North American Pediatric Renal Transplant Cooperative Study (NAPRTCS)2004 annual report. Available at www.naprtcs.org.

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Within the pediatric population, the prevalence of causes varies by age, sex, and race. Congenital causes are more prevalent in younger children, whereas acquired diseases tend to become manifest in older children. Overall, 60% of the recipients are male, and males represent the majority of the recipients with obstructive uropathy (86%), aplasia/hypoplasia/dysplasia (62%), and FSGS (58%). Reflux nephropathy, chronic glomerulonephritis, and lupus nephritis are more prevalent in female recipients, with females accounting for 55%, 59%, and 81%, respectively. With regard to recipient race, for black children, FSGS was the most prevalent diagnosis (23%), followed by obstructive uropathy ( 16%), aplasia/hypoplasia/ dysplasia (14%), chronic glomerulonephritis (4%),and lupus nephritis (4%). In white recipients, obstructive uropathy was the most prevalent etiology (17%),followed by aplasia/hypoplasia/dysplasia (17%),FSGS (9%),reflux nephropathy (6%),and medullary cystic disease (4%).

History and physical examination Laboratory tests: Hematologic (complete blood cell count with platelets; prothrombin time/partial thromboplastin time) Biochemistry (renal function, electrolytes, liver function) Serologic studies (hepatitis B and C, herpesvirus, cytomegalovirus, Epstein-Barr virus, varicella-zoster, human immunodeficiency virus) ABO blood typing Tissue typing (human leukocyte antigen typing; alloantibody screening) Urinalysis Chest radiograph Electrocardiogram Psychosocial assessment As needed evaluations: Voiding cystourethrogram Vascular imaging

RECIPIENT EVALUATION Any child with ESRD should be considered a candidate for renal transplantation. Absolute contraindications are rare and include untreated malignancy or systemic sepsis. Relative contraindications include severe systemic disease that would severely shorten the patient's lifespan or a social situation that makes follow-up with post-transplant care and immunosuppression regimen absolutely impossible. At times the decision whether to perform a transplant in a given child with a poor quality of life or significant impairment can be extremely difficult for all involved. ~ h k r eis often no readily apparent correct answer. In such situations, a thorough discussion considering what are the expectations and goals for that particular child is helpful. &l children with progressive chronic renal insufficiency should be evaluated by a multidisciplinary pediatric transplant team, including a pediatric nephrologist, a transplant surgeon, social worker, and nutritionist. In addition,many teams include pediatric urologists and clinical psychologists, with other experts included as indicated. It is optimal if a child can be fully evaluated before initiating dialysis. This can facilitate evaluation of any potential living donor and prepare all involved for transplant. Ideally, this early evaluation can allow preemptive transplantation, obviating the need for dialysis. With respect to infant size, renal transplantation can be successfully in infants as small as 6.0 kg, although we and others97 believe 10.0 kg is ideal if this can be accomplished without compromising the health of the child. Our standard evaluation of process is summarized in Table 43-2. Every effort should be made to optimize the medical management of the child with ESRD, including management of bone disease, optimization of nutrition, and completing childhood immunizations. Several aspects of the evaluation of the pediatric recipient are unique l One is from adult watients and deserve s ~ e c i aattention. the evaluation and management of bladder function. Many patients will have lower-pole anomalies and may or may not have a bladder suitable for transplantation. ~ a children k ~ will have also undergone urologic procedures. Expertise in such issues, or a close working u

collaboration with pediatric urology, is essential. Nutrition is also of paramount importance in the pediatric population to optimize growth and development. Finally, it is important to evaluate and optimize issues related to the psychologic state of the child and caregivers. Adequate social support is vital for all involved. The stress of a chronically ill child undergoing a complex procedure places a great strain on all, and the need for ongoing education and reassurance is significant. In older children it is important to ensure they are actively involved in the process. Issues in the adolescent population can be particularly challenging, because the risk of noncompliance is held to be greatest in this group, both before and after transplantation. In addition to these factors, several other issues require special attention. One is the potential need to evaluate the patient's vasculature. As renal replacement therapy has improved, it is now possible to hemodialyze smaller and smaller children, including neonates. Unfortunately, these therapies require the use of indwelling catheters, which has been linked to increased rates of iliac vein and vena cava thrombosis. The lack of adequate venous outflow can make transplantation difficult and limit the standard surgical options. Thomas and coworkers summarized their experience with these venous thromboses and suggested a screening algorithm utilizing radiographic imaging for patients at risk, focusing on young children with a history of femoral vein catheterization or history of any intra-abdominal process associated with inflammation.92 The potential need for native nephrectomy is often an issue addressed during the evaluation process. Native nephrectomy is much more common in'the pediatric population compared with the adult transplant population. Nationally, 23% of pediatric recipients have had all native renal tissue removed before transplantation.7' Potential indications for native nephrectomy include recurrent severe infections due to reflux nephropathy, uncontrolled hypertension, and congenital nephrotic syndrome. The indication for patients with nephrotic

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syndrome arises from the fact that frequently these children are prothrombotic due to the significant proteinuria. Children with polycystic kidney disease may require native nephrectomies owing to issues related to bleeding, recurrent infections, or pain. Occasionally, native nephrectomy can be warranted if the native kidneys are so enlarged that the transplanted kidney would be compromised. Some contend that massive polyuria in small infants is an indication for nephrectomy, arguing that postoperative fluid management is made easier, thus decreasing the risk of graft hypoperfusion. Although this has appeal on a superficial level, careful attention to postoperative management can often avoid this as the sole indication for nephrectomy. Additionally, there are those who believe that children with FSGS should undergo native nephrectomy, suggesting it simplifies the diagnosis of recurrent disease, because any proteinuria reflects disease in the graft rather than persistent proteinuria from the native kidneys. In such situations, an initial attempt at "medical nephrectomy" with nonsteroidal therapy is worth consideration. In addition to a rational consideration of the indications for native nephrectomy, the timing of the nephrectomy is important. In children already on renal replacement therapy, if bilateral native nephrectomies are indicated, it may be safer and easier to accomplish this weeks before transplantation. In children not on renal replacement therapy, the issue is more complex. We prefer not to perform bilateral nephrectomies at the time of transplantation because this is a major procedure to combine with renal transplantation. Additionally, even in small infants, we perform the transplant via a retroperitoneal approach, which does not provide access to the contralateral native kidney. For children requiring bilateral native nephrectomy, and who are not yet on renal replacement therapy, many will have sufficient renal reserve to tolerate a unilateral left nephrectomy before transplantation and still not require dialysis. In this situation, at the time of the transplantation procedure we proceed with a standard retroperitoneal incision and extend the incision slightly cephalad, allowing us to perform a right native nephrectomy. In cases where unilateral native nephrectomy would require initiation of renal replacement therapy before transplantation, we have typically removed the ipsilateral native kidney at the time of the transplant procedure. The remaining contralateral native kidney can be removed several months after transplantation if still indicated. In consideringwhen to perform the transplant, any child currently on renal replacement therapy should undergo transplantation as soon as a suitable living donor is identified or a deceased donor organ becomes available. In children not yet on dialysis, transplantation should be done before the onset of symptoms of uremia. It is important to be aware of the impact of ESRD on growth and development. In patients with FSGS or lupus nephritis, transplantation is typically delayed until the disease is quiescent, which may preclude preemptive transplantation. In most other situations, preemptive transplantation allows the children to avoid the need for dialysis with no real disadvantage.Z4 Unfortunately, at present only 33% of children who receive a living donor transplant receive preemptive transplant and only 13% of deceased donor recipients are transplanted before initiation of dialy~is.~

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UROLOGIC ISSUES The high incidence of urologic issues in the pediatric ESRD population requires careful evaluation of bladder function before transplantation. In addition to dysplasia and bladder outlet obstruction, bladder function may be abnormal due to neuropathy, acquired voiding dysfunction, or acquired bladder pathology. Any previous surgical bladder augmentation will impair normal bladder function. A history of urinary incontinence, frequent urinary tract infections, previous urologic procedures, and the need for bladder catheterization should prompt further investigation. In patients with suspected bladder dysfunction, a voiding cystourethrogram (VCUG) should be obtained with urodynamic measurements. A pressure of less than 30 cm H 2 0 during the filling portion of the VCUG generally indicates the bladder will be suitable. The timing of any surgical intervention warrants careful consideration. In some patients with anuria/oliguria, the bladder may not be functional, although it is often too early to tell if it will eventually become suitable. Once bladder augmentation is performed, the patient will need to continue catheterizing long term because the bladder will that preserve native not be functional. ~rologic~rocedures renal function for many years are clearly prudent, but interventions before transplantation should be planned by carefully considering the risks and benefits of the procedure and being mindful of the impact on subsequent transplantation and the long-term management.

DIALYSIS ACCESS For children who do not undergo preemptive transplantation or who initially present with ESRD, establishment of adequate dialysis access is of paramount importance. Proper dialysis access is necessary for adequate dialysis, which is directly linked to the quality of life and health of the patient. Both hemodialysis and peritoneal dialysis are suitable options. According to USRDS data, at the end of 2002,61%of patients aged 19 years and younger were on hemodialysis, whereas 39% were on peritoneal dialysis.96 The choice of hemodialysis or peritoneal dialysis is best made on an individual basis, considering the patient and family's preferences and skill levels, as well as the treatment options available at the local site. With respect to hemodialysis, all attempts should be made to create a primary arterial venous fistula. For patients without adequate veins, a polytetra fluoroethylene graft is required. A native fistula is clearly preferred because of superior patency rates, although this option does require the presence of suitable veins. Additionally, a native fistula requires several weeks to mature following the procedure before it can be accessed. For patients in need of urgent hemodialysis with no access, the only option is a temporary catheter. Approximately three fourths of all pediatric patients have a temporary catheter as their access at time of initiation of dialysis." The use of these catheters is associated with increased risks of infection and poor clearance with dialysis. Additionally, these catheters can lead to central venous stenosis and thrombosis, which can make future permanent upper extremity vascular access

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more difficult to achieve. Accordingly, the jugular vein is preferred over the subclavian vein for catheter placement. Peritoneal dialysis is performed after placement of a Tenckhoff catheter. A double-cuffed peritoneal dialysis catheter is inserted via an open surgical procedure under general anesthesia. The loop of the catheter is placed in the pelvis. During the procedure it is important to ascertain that fluid can run freely through the catheter into the abdomen and drain freely as well. The use of double-cuffed catheters and orienting the catheter so that the exit site is oriented with the catheter pointing downward are associated with a lower incidence of infection.61

History and physical examination Laboratory tests: Hematologic (complete blood cell count with platelets; prothrombin time/partial thromboplastin time) Biochemistry (renal function, electrolytes, liver function) Serologic studies (hepatitis B and C, herpesvirus, cytomegalovirus, Epstein-Barr virus, human immunodeficiency virus) ABO blood typing Tissue typing (human leukocyte antigen typing) Urinalysis Chest radiograph Electrocardiogram Psychosocial assessment Helical CT scan

DONOR SELECTION Living donor transplantation is the preferred option for all patients with ESRD. Living donor transplantation offers the best outcomes after transplantation, compared with deceased donor transplantation. In addition, living donor transplantation can be performed as soon as a suitable donor is identified, avoiding the need for waiting on the transplant list for a deceased donor. Living donors may be either genetically related or unrelated to the potential recipient. The results from both types of living donors are equivalent, and both are superior to outcomes from deceased donors. Although there is no need for the living donor to be genetically related, nearly all donors share a significant relationship with the intended recipient. Potential living donors should undergo a full evaluation by a transplant center experienced in this process. The donor must be willing, be in good health, and have two normal kidneys. In addition, the donor and recipient must be ABO compatible. Although there is a growing interest in strategies to cross this barrier, such efforts are still in their early stages and the experience in In addition, the the pediatric population is limited.66,83 recipient should have a negative lymphocytotoxic crossmatch with the potential donor. Crossmatching is done to determine that the recipient does not have preformed antibodies directed against the recipient's human leukocyte antigens (HLA), which would likely cause hyperacute rejection and rapid graft loss. The onset of this process is immediate and nearly impossible to reverse. Strategies to manipulate anti-donor antibody activity are being investigated and include intravenous immunoglobulin and plasmapheresis. The most common causes of anti-HLA antibodies in the recipient are blood transfusions, previous transplantation, and pregnancy.

Evaluation of the Potential Living Donor Evaluation of potential living kidney donors should proceed independent of the recipient's evaluation, placing donor safety as the highest priority. Our standard evaluation of process is summarized in Table 43-3. Although HLA matching has traditionally played an important role in choosing which living donor to evaluate, current immunosuppression has minimized the impact of matching, and we believe the best potential living donor is the

individual who is most motivated. Lacking that distinction, and all else equal, we would choose the donor with the best HLA match. It is also important to consider other issues unique to each donor, including psychosocial concerns such as the need to care for other children, the need to care for the recipient, and what options would be least disruptive to the family unit. When discussing the situation with the family, it is important to consider other siblings who may also need renal transplantation in the future because this can play a role in deciding which donor donates to which recipient. The use of live donors younger than 18years of age is very rare, and this practice is not enco~raged.~~,44 Living kidney donation appears to be safe and has now been in practice for 50 years. The risk of operative mortality appears to be 3 in 10,000.50After the procedure, living kidney donors appear to do well over the long term as well. The introduction of laparoscopic donor nephrectomy has been a significant step forward for the individuals who consider kidney donation. The laparoscopic procedure is associated with quicker recovery and appears as safe as open donor nephrectomy.Y"l00 Although there was some concern that laparoscopic donation might result in inferior outcomes compared with open donor nephrectomy, particularly in small infants, this concern has not been substantiated at centers that have examined this issue.41,g"egardless of the approach utilized, however, the surgical team performing the donor nephrectomy should be experts at that approach.

Evaluation of the Deceased Donor For children who do not have a suitable living donor, deceased donor transplantation is the only option. Deceased donors can be individuals who have either suffered brain death or whose heart has irreversibly stopped beating. The latter group has often been referred to as "non-heartbeating donors." In the United States, organ allocation is governed by policies established by the OPTN. These policies undergo constant refinement as data support more rational and fair allocation strategies. At present, deceased donor kidneys are allocated both on a national and a local level. After a potential deceased

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donor is identified, the blood type, HLA type, and other relevant donor factors are entered into the national database maintained by the United Network for Organ Sharing (UNOS). If an ABO-compatible, HLA-identical recipient is identified, that individual would be offered this kidney. These zero antigen mismatch kidneys are shared on a national level. Although there is some benefit to this strategy, such an approach is also often associated with an increase in the cold ischemic time owing to the need to transport the kidney to the recipient's center. In cases in which no zero antigen mismatch recipient is identified, the kidneys are usually transplanted locally. Allocation of these kidneys is guided by a point system that factors in the degree of the HLA match at the DR locus and recipient waiting time. Additional points are given to recipients with a high level of anti-HLA antibodies because these individuals face considerable difficulty in finding a suitable kidney donor. Based on data that pediatric patients do poorly while on dialysis, the allocation strategy was adjusted to give additional points to pediatric patients based on their age. Further priority with respect to allocation is given to pediatric candidates who have not been transplanted within age-specific time goals after listing: candidates birth to 5 years old listed for 6 months; candidates 6 to 10 years old listed for 12 months; and candidates 11 to 17years old listed for 18 months. In total, these allocation policies result in pediatric candidates waiting for shorter times on transplant lists than adult candidates. Nonetheless, many children wait longer than intended. In late 2004, a further revision to the allocation policy was adopted whereby kidneys from all deceased donors younger than 35 years of age will be preferentially offered to pediatric candidates. The overall number of deceased donors each year has remained relatively stable. The criteria for donor acceptability, however, have expanded. Donors are now much older than those previously utilized, and a significant percentage of donors have a history of hypertension or other medical comorbidities, which may impact the quality of the organs donated. In attempts to improve utilization of kidney donors in the higher risk groups, a subset of such donors have been defined as extended criteria donors (ECD), and the kidneys are allocated based on principles designed to facilitate utilization of such 0rgans.~"69 The ECD criteria include any deceased donor older than the age of 60 years or older than the age of 50 years with two of the following: a history of hypertension, a terminal pre-donation serum creatinine value greater than or equal to 1.5 mg/dL, or death resulting from a cerebrovascular accident (stroke).The relative risk of graft failure for such kidneys is greater than 1.7 times the risk of a reference group of ideal deceased donors. Whereas accepting ECD kidneys will benefit many adult transplant candidates, the allocation priorities already provided to pediatric candidates obviate the need for utilizing such kidneys in children. Consequently, most children should not be listed for ECD kidneys. Driven by the severe shortage of donor organs, interest in Donation after Cardiac Death (DCD) has had a resurgence. DCD, formerly known as "non-heartbeating organ donation," has the potential to significantly increase the number of available organs. Patients meeting

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the strict criteria for brain death make up a relatively small fraction of all patients who die in hospitals. Most patients who die ne;er progress to brain death before cardiac arrest. Patients who sustain a severe and unrecoverable neurologic injury but do not meet the criteria for brain death may be eligible for organ donation if a determination to withdraw intensive care unit (ICU) support is made jointly by the legal next-of-kin and the physicians caring for the patient. DCD is an option that can allow such patients and their families to pursue organ donation. DCD accounted for only 3.3% of all deceased donor kidneys transplanted in 2002, a slight increase from 1.2% in 1994.6' Although the initial results using DCD kidneys have been good,there is often a higher risk of delayed graft function.12J5 In considering which organ to accept for a given pediatric recipient, the transplant surgeon must balance the desire to obtain the "perfect kidney" (e.g., quality of the donor, degree of HLA matching) with the benefit of rendering the patient free of dialysis. Refinements in organ allocation have made this process more straightforward. The pediatric recipient will, hopefully, require many years of function from the graft and, consequently, this limits enthusiasm for accepting older or marginal donors. Generally. , ECD or DCD donors should not be used in the pediatric population. Additionally, the use of kidneys from smaller pediatric deceased donors is associated with Doorer outcomes and kidnevs from such donors are rarely appropriate for pediatric candidates. An important exception might be the highly sensitized recipient who has waited for a long period of time and has had no suitable offers. In such a situation, the decision needs to be made on a case-by-case basis, weighing the various risks and benefits of the options available. ,

Preoperative Preparation Deceased donor transplant recipients are admitted to the hospital once a suitable kidney is accepted. We currently still admit our pediatric living donor recipients, although these patients could be potentially admitted on the day of their procedure if their dialysis regimen was stable or if they were not on dialysis. On admission, the need for a dialysis is assessed. It is also important to ask about any intervening health issues since the patient's last office visit, as well as examining for any evidence of ongoing infection.

Anesthesia Close coordination with the anesthesia team is vital to the conduct of any operation, although this is particularly important in kidney transplantation in small infants. Maintaining adequate volume status is critical. Because a kidney from an adult donor is typically used, blood flow to the graft often equals the entire cardiac output in the recipient, and thus hypotension can be particularly problematic. Many children have an obligate polyuria

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that can cause hypovolemia if not carefully monitored. After reperfusion, the new kidney can also sequester several hundred milliliters of blood, further aggravating hypovolemia.

Operative Procedure The child is taken to the operating room and general anesthesia induced. Adequate intravenous access is established. In children larger than 20.0 kg we typically do not place a central venous line if adequate peripheral access can be established. For smaller children we find central venous access useful, both for fluid administration as well as for monitoring central venous pressure. In these smaller children we also place an arterial line as well to permit constant blood pressure monitoring. The child is placed in the supine position and a Foley catheter is inserted into the bladder. We connect the urinary catheter to a three-way irrigation system using dilute povidone-iodine (Betadine) in saline. In other centers an antibiotic solution may be preferred. This arrangement allows the bladder to be filled and drained outside of the operative field as necessary. The abdomen is then prepped and draped. The child's temperature should be monitored closely, especially with small children who may become hypothermic with either fluid resuscitation or the perfusion of the cold kidney. The operating room temperature should be maintained and warming blankets used. In addition to routine anesthetic monitoring, a constant focus of attention must be the volume status of the recipient. It is vital that the arterial blood pressure and central venous pressure are adequate when the kidney is reperfused. For infants and small children, the central venous pressure is usually maintained in the range of 12.0 to 18.0 cm H 2 0 by administration of either crystalloid and/or colloid as necessary. Near completion of the vascular anastomoses, we typically give 0.5 mg/kg of mannitol intravenously. We do not routinely employ a loop diuretic.

Operative Techniques SmaN Children ( ~ 2 0 . 0 kg) In years past many have performed kidney transplants intra-abdominally in infants and small children via a midline incision. Since 1998 we have used a retroperitoneal approach similar to that used in adults. In small children, placing the kidney on the right side is preferable, because this gives the easiest access to the vena cava. A curvilinear skin incision is made in the right lower quadrant. The abdominal wall musculature is divided, and the preperitoneal space is entered. Attempts are made to stay outside the peritoneum during the course of the dissection. We use a fixed retractor for exposure. The spermatic cord is mobilized and preserved in males, whereas the round ligament is routinely divided in females. The dissection is carried medially until the common iliac vessels, the distal aorta, and vena cava are visualized. If a native nephrectomy is necessary on the

right side, this can be performed at this point as well, tracing the ureter up to the kidney. The exact site of the vascular anastomosis depends on the size of the kidney as well as the size of the child. Generally in small children the renal vein is anastomosed to the vena cava and the renal artery is anastomosed to either the distal aorta or the common iliac artery. The lymphatics overlying these vessels are divided between silk ties to hopefully minimize the risk of a lymphocele developing postoperatively. When an aortic anastomosis is planned, it is mobilized from below the inferior mesenteric artery to the bifurcation. Lumbar branches are controlled with Pott's ties rather than ligated. In the case of an aortic anastomosis, both the right and left common iliac arteries are controlled just distal to the aortic bifurcation. The vena cava is mobilized to allow placement of a side-biting vascular clamp, which can require ligation of some lumbar veins. Vessel loops are frequently used to help gently control the vessels during the dissection. Once the recipient's vessels have been exposed, the donor kidney is brought into the operative field. The kidney should be inspected for any evidence of unsuspected pathology, and the renal vessels are examined. After preparing the kidney, thoughtful consideration needs to be given for the fit of the kidney in the recipient's body cavity. Particular attention needs to be focused on the length of the renal vessels as well as their orientation. It is important to consider the final resting position of the kidney after it is perfused, the retractor is removed, and the wound closed. The venous anastomosis is performed first. The vena cava or iliac vein is controlled with a side-biting clamp. A longitudinal venotomy is made along the anterolateral or lateral aspect of the vein. The renal vein is cut to length, again after considering the lie of the kidney, and mindful that a redundant renal vein may predispose to thrombosis. We place and tie two corner sutures of 5-0 Prolene. The anastomosis is then performed in a running manner, making sure it is widely patent. An end-to-side arterial anastomosis is then performed, between the donor artery and the recipient's distal aorta or common iliac artery. The recipient vessels are controlled using gentle spring clips or occasionally a small vascular clamp. A longitudinal arteriotomy is made, mindful of the final orientation of the renal artery. We enlarge the arteriotomy using a 4.0 mm aortic punch. The renal artery is then sewn end-to-side using a running 6-0 Prolene suture. We typically perform the procedure with loupe magnification, which allows for more precise suture placement. If two renal arteries are present, they can either be implanted separately or they can be syndactylized before reimplantation. When the vessels are syndactylized, it is important to consider if this will allow the vessels to lie in good position at the end of the procedure, since syndactylization will fix both vessels relatively firmly in two dimensions. This can limit the options of where the anastomosis can be suitably performed or lead to kinking of one or both of the donor arteries if the final resting position of the kidney is not properly anticipated. Before completion of the arterial anastomosis it is worthwhile to discuss the hemodynamic state of the patient with the anesthesia team. Intraoperative assessment of the

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vascular volume by direct assessment of the vena cava is The retractor is removed, and the fascia is closed in one possible. Mannitol is also given at this time. Because of or two layers with a running suture. The skin is closed the size of the adult kidney volume, and given the normal using a running absorbable suture. The urinary catheter pediatric blood volume, the kidney can be both slow is flushed with saline to remove any clots that might to perfuse as well as sequester a significant volume of obstruct the catheter, and the catheter is then connected blood. The anesthesiologist must be ready to give volume to a urimeter. For small infants, the volume resuscitation replacement promptly as indicated. At this point the required to ensure excellent renal perfusion, combined clamp is removed from the vein and any bleeding with the size of the kidney contributing to a decrease in assessed. Next, during gentle occlusion of the renal respiratory excursion, may make ventilatory support in artery with vascular pickups, the clamps are removed the immediate postoperative period necessary. If the from the recipient's vessel, restoring distal blood flow. patient's oxygen saturation and pulmonary mechanics After a few seconds, flow is established to the kidney. are satisfactory, the patient can be extubated in the operIn small children we occasionally will briefly re-clamp ating room. the recipient's vessels distal to the arterial anastomosis to provide preferential blood flow to the kidney. The Larger Children (>20.0 kg) operative field is carefully examined for any bleeding The technique for renal transplantation in larger sites that should be controlled. The color and turgor of children is similar to that in the adults. We prefer to the graft are assessed. The renal artery should have a good put the kidney on the right side when possible. An incipulse, and a thrill can usually be appreciated as well. sion is made in the right lower quadrant, extending Both the lower and upper poles should be assessed for up from a fingerbreadth or two above the pubis to just perfusion. The renal vein should be full but not tense, lateral of the rectus sheath. The preperitoneal space with a turgor similar to the vena cava. The lie of the kidney is again developed, and the iliac vessels are mobilized. is again examined. Again we divide the lymphatics over these vessels Attention is then directed to performance of the between silk ties in hopes of minimizing the risk of ureteroneocystostomy. We generally perform the ureteral ~~~ anastomosis as an extravesical u r e t e r o n e o c y ~ t o s t o m y , ~ ~postoperative development of lymphocele. As in smaller although others prefer the transvesical Politanochildren, the placement of the arterial and venous anasLeadbetter a p p r o a ~ h . ~The ? , ~Foley ~ catheter is clamped, tomoses depends on the size of the child and the renal and the bladder is filled. A site on the dome of the vessels. The venous anastomosis can be done to the vena bladder is selected where the ureter will sit without any cava, the common iliac, or the external iliac vein. The angulation. The muscle coat of the bladder is divided, arterial anastomosis is performed to the distal aorta, the exposing the bladder mucosa. An opening is then made common iliac, or the external iliac artery. We have not in the mucosa. The donor ureter should be trimmed to used the internal iliac artery for well over a decade. After length. Care should be taken to make sure it is sufficient revascularizing the kidney, the ureteroneocystostomy is to allow a tension-free anastomosis to the bladder, but performed using an extravesicular technique. At the excessive length should be minimized because of the risk completion of the operation these larger children are of ureteral obstruction or stricture due to inadequate extubated. perfusion of the distal ureter. The end of the ureter is spatulated, and a mucosa to mucosa anastomosis is Ureteral Reconstruction in Patients performed using running 5-0 PDS suture. Running with Previous Urologic Procedures suture is adequate in this situation, but great care must The ideal urinary reservoir stores a reasonable volume at be taken to avoid cinching on the suture when the knot a low pressure, does not leak, and empties nearly comis tied because this results in a pursestring effect causing pletely with voidingn4In the majority of cases, the ideal stenosis of the anastomosis. To prevent vesicoureteral reflux, the bladder muscle wall is approximated over reservoir is the patient's bladder. If the bladder functhe ureteral anastomosis using the interrupted 4 0 PDS tioned normally before development of oliguria, it is likely suture. This allows the ureter to take a tangential course to function adequately after transplantation. Nonetheless, up to 30% of pediatric recipients will not have normal under the bladder wall so that during micturition, the bladder function, and frequently a surgical augmentatransvesical portion of the ureter is compressed by the tion or other urologic procedure has been performed overlying bladder wall. In patients with a normal bladder before referral for transplantation. and a good blood supply to the distal ureter, we do Drainage of transplanted kidneys into an augmented not routinely place a stent. If there is any concern bladder or urinary conduit is an appropriate manageregarding the ureteral anastomosis, either due to the ment strategy when the native bladder is unsuitable or donor ureter or the quality of the recipient's bladder, we absent.l0.z6 When indicated, we prefer to have the place a doubled ureteral stent. The stent can be removed several weeks after transplantation as an outpatient intended urinary reservoir created and.suitable for use before the transplant procedure. Intraoperatively, when procedure. planning the ureteroneocystostomy to an augmented After completing the ureteral anastomosis, the kidney bladder, it is important to consider the blood supply to is again inspected with attention to the renal vessels and the augmented section so as not to compromise it during the lie of the kidney once the retractor is removed. the transplant. It is preferable to perform the ureteroCareful planning and attention to detail before performneocystostomy to the native bladder, and this can be ing the anastomosis is usually well rewarded at this point.

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accomplished in most situations. We strongly believe cause significant intravascular volume depletion, which can then lead to problems with renal perfusion. In situathat an antireflux ureteroneocystostomy is mandatory for tions in which the patient is massively volume overloaded all patients, and it is most readily performed when the or has significant electrolyte abnormalities, dialysis may bladder wall is used. be indicated. Patients with kidney transplants drained into an augIf ventilated postoperatively, the smaller children are mented bladder or urinary conduit are at increased risk for urine infection, but compared with historical controls, weaned from the ventilator generally within the first 24 hours. Enteral feedings can be started at a slow rate graft survival is not adversely affected." The rate of surgical complications related to the ureteral anastomosis almost immediately after the extraperitoneal approach. is higher in these patients, approximately 20%.'5,32,43 Infants who were on tube feedings before transplantation Regardless of the etiology of the bladder dysfunction, should resume these tube feedings because they usually such patients require regular clean intermittent straight will not be fed per os in the immediate post-transplantation catheterization after transplantation. period. Hypertension can be problematic. The volume Children with obstructive uropathy from posterior ureloading associated with the procedure, as well as the thral valves will not have normal bladder function, and this use of calcineurin inhibitors for immunosuppression, can contribute to renal dysfunction after tran~plantation.~~can result in significant hypertension, which can be severe Awareness of these issues is vital, and evaluation with and require aggressive therapy to prevent seizures and follow-up urodynamic studies is frequently indicated in other sequelae. children with voiding disorders. Bladder dysfunction, In order to monitor and replace urine output on an such as hypocompliance and/or hyperreflexia, requires hourly basis we usually admit our patients to the JCU. If this can be accomplished on a surgical floor unit, medical or surgical treatment.'" larger children could be admitted to an area specializing in the care of renal transplant patients. Children who are admitted into the ICU are typically transferred to the POSTOPERATIVE CARE floor unit within 1 to 2 days. Most children can leave the Careful attention to detail in the postoperative period is hospital in 5 to 7 days after transplantation assuming essential. Special care must be directed to the fluid and they are able to eat and the family is familiar with the electrolyte status. Many children are polyuric before immunosuppression regimen. transplant, and this obligate urine loss will continue in the immediate postoperative period. Intravenous fluids are administered, taking into account urine output as EVALUATION OF EARLY ALLOGRAFT DYSFUNCTION well as insensible losses. The composition of these solutions is adjusted as needed, depending on regular measIdeally, the donor kidney should begin to make urine urement of serum electrolytes. Serum sodium, potassium, shortly after revascularization. The likelihood of this occurring depends on multiple factors, beginning with and calcium levels are followed closely and replaced as the quality of the donor organ. Living donor kidneys will necessary. Heart rate, blood pressure, and central venous pressure are carefully monitored. No single factor alone generally function immediately because of the healthy is entirely reliable in assessing intravascular volume, and state of the donor as well as the shorter cold ischemic some readings may not reflect the true status of the patient. time. For deceased donor kidneys the cold ischemic time For patients who were oliguric or who had native is generally longer. In addition and more importantly, nephrectomies before transplantation, if the graft functhere are multiple factors associated with the donor death, tions immediately, monitoring urine output is an excelincluding hypotension, the potential need for high doses lent measurement of graft function. For patients who of vasopressors, and other issues related to the overall made significant urine before transplantation, or who health of the donor. have delayed graft function, evaluation of graft function Regardless of the donor source, the assessment of the is more difficult. In situations in which the patient made graft begins in the operating room, evaluating the graft urine before transplantation, the volume of urine profor color and turgor as well as inspecting the arterial and duction is often suggestive of graft function. In addition, venous anastomoses. Particular attention should be directed to considering how the kidney is positioned once the serum creatinine concentration should fall over time. Recipients with oliguria should be carefully evaluated. the abdomen is closed and how this could impact the vasThe urinary catheter should be flushed with small volculature. The renal artery will often have a thrill suggestive umes of sterile saline. The volume status of the patient of excellent flow and low intrarenal resistance. Assuming should be carefully assessed. A fluid bolus is usually the technical aspects of the procedure appear satisfacwarranted, both as a diagnostic test and as therapeutic tory, additional volume for the kidney not making urine intervention. An ultrasound with Doppler study will be is the best option. Once the patient is adequately volume helpful at confirming adequate arterial flow to the graft loaded, loop diuretics may be used to gently encourage and adequate venous outflow. In addition, the ultrasound a diuresis. In patients who are aneuric before the procewill show if there is any evidence of fluid or blood around dure, continued failure to make urine in the postoperathe kidney, as well as assess for possible ureteral obstructive period should prompt a bedside Doppler ultrasound tion. In patients who appear to be adequately volume examination. For patients who made urine before the transplantation, determining whether the transplanted loaded and hemodynamically stable, a dose of diuretic can be given to monitor response. It is important to do kidney is making urine is more difficult, although somethis carefully because sudden massive urine output can times the amount of volume being produced will give a

CHAPTER

sign that the kidney is working. Over the next 24 hours the serum creatinine level should fall as well. If there is still concern about function, a Doppler ultrasound study should be obtained and any suggestion of problems with the arteriovenous signal should initiate a prompt return to the operating room. Generally the ultrasound will be fine, or occasionally there will be a modest reduction in flow suggestive of increased intrarenal resistance, most commonly due to acute tubular necrosis. This condition resolves without any specific intervention. Other diagnostic studies are less frequently required. Renal arteriography is rarely indicated. Radionucleotide scans are used by some centers, but we find them less helpful than ultrasonography. A radionucleotide scan may be helpful in documenting a suspected urinary leak before proceeding with percutaneous nephrostomy. Complications related to the ureteral anastomosis include leaks and obstruction. The risk of ureteral complications is approximately 9%.57A leak at the ureteral anastomosis generally becomes manifest in the first few days after the transplant. Leaks can generally be managed nonoperatively by placing a percutaneous nephrostomy tube. This tube is subsequently advanced across the anastomosis into the bladder and converted to a universal stent. The stent is usually left open to external dependent drainage for several days, at which time it can be capped until healing occurs. If a large urinoma is present, separate drainage of the perinephric fluid collection may be required. Obstruction of the urinary system can occur at any time. Obstructions that occur earlier are usually related to technical problems with the anastomosis of the donor ureter or other mechanical issues such as torsion of the ureter, if the ureter was twisted before anastomosis. Because the ureter relies on small arterial feeding vessels from the lower pole of the kidney for its vascular supply, it is prudent to avoid leaving it excessively long. Ureteral stenoses occurring late after transplant generally require operative intervention, with resection of the stenotic segment and a urologic reconstruction. Another complication after retroperitoneal kidney transplantation is lymphocele. Lymphoceles may produce discomfort or allograft dysfunction. The diagnosis is established when ultrasound-guided percutaneous aspiration reveals clear fluid with a creatinine concentration equivalent to serum. Percutaneous drainage is associated with a very high incidence of recurrence, and generally the preferred approach is creation of a peritoneal window. This can be accomplished either via a laparoscopic approach or through a small open incision with drainage of the lymphocele into the peritoneal cavity. In instances of renal vein thrombosis, the graft is usually not salvageable. The cause of renal vein thrombosis is uncertain, but it may more likely be due to immunologic factors and recipient hypercoagulable state rather than any technical issue.

IMMUNOSUPPRESSION Over the past several decades, significant advances have been made in our understanding of the immune response and several new immunosuppressive agents have been

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introduced into clinical care. There are now several regimens available, but all require a balance between prevention of rejection and unwanted side effects Some centers use associated with immun~suppression.~~ a standard protocol for all recipients, whereas other centers individualize the regimen for each patient. Immunosuppressive agents are used for induction, maintenance, and treatment of rejection episodes.

ANTIBODY PREPARATIONS Both polyclonal and monoclonal antibody preparations are utilized. Antibody preparations have a role in induction regimens and for the treatment of rejection.

Antilymphocyte Antibodies Antilymphocyte antibodies include polyclonal preparations, such as equine antithymocyte globulin (ATGAM) and rabbit antithymocyte globulin (Thymoglobulin), and the monoclonal antibody muromonab-CD3 (OKT3). These agents act by lymphodepletion, as well as by interactions with cellular receptors. The use of antilymphocyte preparations in induction regimens was routine, but their use has declined precipitously over t i m e . W e currently restrict the use of these agents to recipients at higher risk for immunologic graft loss, such as patients requiring retransplantation, highly sensitized patients, or black recipients.

An ti-In terleukin-2 Receptor Monoclonal Antibodies Two monoclonal antibodies have been developed that bind to the alpha subunit of interleukin (1L)-2 receptor (CD25) and inhibit IL-2-mediated lymphocyte proliferation. Both received approval by the U.S. Food and Drug Administration (FDA) in 1998. Basiliximab (Simulect) is a chimeric human/mouse monoclonal antibody.3g Daclizumab (Zenapax) is a humanized murine monoclonal antibody.99 Both agents are effective in reducing the incidence of acute cellular rejection, with good longterm results and no evidence of increased risk of infecThe IL-2 receptor antibodies tion or malignancy.8~63~88 are used in induction regimens but are not effective in treating rejection.

Calcineurin Inhibitors The introduction of cyclosporine after its FDA approval in 1983 is widely accepted as one of the most significant advances in transplantation. Its efficacy in pediatric renal transplantation is established." Tacrolimus received FDA approval in 1994. Both cyclosporine and tacrolimus act through inhibition of calcineurin activity. he agents first enter the cell and bind to specific cytoplasmic proteins; cyclosporine binds to cyclophilin, . and- tacrolimus binds to &crolimus binding protein (also known as FK-binding protein). Both drug-protein complexes then bind to calcineurin, a phosphatase that

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controls the transport of transcriptional regulator factors across the nuclear membrane. By inhibiting the translocation of these factors into the nucleus, both drugs inhibit transcription of several early T-cell activation genes, most significantly IL-2. Both cyclosporine and tacrolimus are effective at preventing rejecti0n.4~A recent randomized prospective open label trial performed in Europe in pediatric renal recipients compared tacrolimus to cyclosporine, along with azathioprine and steroids. There was a significantly lower incidence of acute rejection in the tacrolimus group (36.9%) compared with cyclosporine therapy (59.1%) .94 In contrast to this observation, a retrospective analysis of NAPRTCS data comparing cyclosporine to tacrolimus, along with mycophenolate mofetil and corticosteroids, showed equal rates of rejection and graft survival. Although rejection rates were similar, tacrolimus therapy was associated with improved graft function at 1 and 2 years .~~ to a recent analysis of OPTN after t r a n ~ p l a n tAccording data, most pediatric recipients were reported as being discharged on tacrolimus compared with cyclosporine (71.4% versus 22.5%) .46 The side effects of cyclosporine include hirsutism and gingival hyperplasia, whereas tacrolimus is associated with increased incidence of post-transplant diabetes and neurotoxicity. Both cyclosporine and tacrolimus share significant nephrotoxicity, and appreciation of the role of calcineurin inhibitor-induced nephrotoxicity in both renal and nonrenal transplantation is growing. It is important to balance the side effects of either agent and risk/benefit for each In children who develop a problematic side effect from one agent, conversion to the other agent is appropriate.

Mycophenolate Mofetil Mycophenolate mofetil (MMF, CellCept) inhibits purine synthesis and has essentially replaced azathioprine (Imuran) as the primary antiproliferative agent.6s4WMF is converted in vivo to mycophenolic acid, a noncompetitive inhibitor of inosine monophosphate dehydrogenase (IMPDH), which is a key enzyme in de novo purine biosynthesis. Although most cells can synthesize purines by either the de novo or the salvage pathway, B and T lymphocytes lack the salvage pathway. MMF is thus a selective inhibitor of lymphocyte proliferation. It has been demonstrated to be safe and effective in pediatric patients."."? The primary side effects are related to leukopenia and gastrointestinal intolerance. An entericcoated mycophenolate (Myfortic) has been developed with similar efficacy and side effect profile.

Prednisone Glucocorticoids have played an integral role in most immunosuppression regimens since the earliest days of transplantation. They act primarily through transcriptional regulation. They first diffuse across the plasma membrane and bind to cytoplasmic steroid receptors. This complex is translocated to the nucleus, where it binds to specific gene

promoters and other regulatory regions, inhibiting cytokine synthesis. Corticosteroids are also lymphocytotoxic and possess significant anti-inflammatory activity. They inhibit macrophage function and other nonspecific aspects of the inflammatory response. Long-term corticosteroid therapy is associated with increased risk of hypertension, hyperlipidemia, diabetes, bone loss, cosmetic disfigurement, and cataracts. Attempts at minimizing corticosteroids have not had a significant effect on these side effects, and new efforts are being directed to corticosteroid avoidance. Although it is appealing to consider withdrawal of corticosteroids over time, corticosteroid withdrawal appears associated with increased risk of acute and chronic rejection.'$ Some investigators believe that not introducing corticosteroids would prevent subsequent corticosteroid dependence. Corticosteroid-free regimens have been introduced and show promise in retrospective studies.' Sarwal and associates have shown excellent initial results in a corticosteroid-free protocol using an extended induction with daclizumab, tacrolimus, and mycophenolate m ~ f e t i l . 'With ~ a mean follow-up of 20 months, overall graft and patient survival was 98%, and the rate of acute rejection was 8% at 1year. This preliminary study has led to a prospective, multicenter randomized study that is currently underway.

Sirolimus Sirolimus, or rapamycin, is a macrolide antibiotic with immunosuppressive properties. Sirolimus inhibits a protein, target of rapamycin (TOR), a key regulatory kinase controlling cytokine-mediated cellular proliferation. A potential role for sirolimus in renal transplantation has . ~ ~ ~is~ interest ~ in using sirolimus in been e s t a b l i ~ h e dThere protocols to avoid calcineurin inhibitors or corticosteroids. Additionally, there is a role for conversion to sirolimus for complications due to other agents. Sirolimus interacts with calcineurin inhibitors, particularly cyclosporine, and careful monitoring is essential. Like many other immunosuppressive agents, there is evidence to suggest more rapid metabolism of sirolimus in children compared with adults.7gAnother agent in this class, everolimus, is under development.36 Experience with sirolimus is limited, and care is warranted given concerns for long-term risks that may be associated with the drug.

Treatment of Rejection Suspected rejection episodes should be confirmed by biopsy. The first-line therapy for acute cellular rejection is pulse corticosteroid therapy. Typically, intravenous methylprednisolone is administered for 3 days, with doses ranging from 5.0 to 25.0 mg/kg/day (maximum dose, 1.0 g) depending on local protocols. We utilize 10.0 mg/kg for children younger than age 6 and 5.0 mg/kg for children aged 6 years and older, with a maximum dose of 500 mg/day. Severe rejection, or rejection episodes refractory to pulse corticosteroid therapy, are treated with polyclonal antilymphocyte globulin or

CHAPTER

monoclonal OKT3 antibody; we prefer the former. There is no role for the use of IL-2 receptor antibodies in treating rejection. Treatment of acute rejection episodes is nearly always successful, although late episodes of rejection are more unlikely to respond appropriately. After successful treatment, many centers consider altering the maintenance immunosuppression, including changing to the other calcineurin inhibitor, or substituting sirolimus for MMF; however, there is little evidence to support this approach. An assessment of adherence to the immunosuppression regimen should also be initiated. If after treatment the patient's creatinine level does not fall to the baseline value, a follow-up biopsy should be strongly considered.

43

Renal Transplantation

1-5

6-1 0 Recipient age

11-17

1-5

6-1 0 Recipient age

11-1 7

A

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OUTCOMES

Graft and Patient Survival There are approximately 800 pediatric kidney transplants performed annually in the United States. In 2002, there were 769 transplants, with 57% living donor and 43% deceased donor k i d n e ~ s . ~ W v ethe r past decade there has been continued improvement in graft survival (Fig. 43-1). For all pediatric recipients, 1-year deceased donor kidney graft survival has increased from 83% in 1993 to 91 % for transplants performed in 2002. Similarly, graft survival after living donor transplantation increased from 90% to 97% over the same period. Current graft and patient survival after renal transplantation is excellent. At our center, for the 38 pediatric transplants performed between January 1,2001, and June 30, 2003, graft and patient survival was 100%. Nationally, graft and patient survival during the same time period was 94.5% and 98.9%, respectively. Current graft survival for pediatric recipients of living donor and deceased donor kidney transplants are shown in Figure 43-2. Recipient survival stratified by age range is summarized in Figure 43-3. While patient survival is good, it is important to realize that even with transplantation, these children face a significantly increased risk of mortality compared with the general p0pulation.5~

B

.

A, Adjusted 1- and 5-year graft survival of living donor kidney transplants by recipient age. 4 Adjusted 1- and 5-year graft survival of deceased donor kidney transplants by recipient age. (From OPTN/SRTR: 2003 OPTN/SRTR Annual Report: Transplant Data 1993-2002. HHS/HRSA/SPB/DOT; UNOS; URREA. Available online at: www.ustransplant.org.)

The past decade has seen improvement in all pediatric age ranges. This improvement is particularly noteworthy in children younger than 2 years of age who had previously had the worse outcomes; these children now have outcomes that equal the outcomes of any age g r o ~ p . 6 ~ ~ Recent reports demonstrate that the longest transplant Living donor

Deceased donor

98.5 98.0 9 m

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$

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40

95.5 96.5

-

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5 a

200 1-5

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.

4

Adjusted 1-year graft survival for pediatric kidney recipients, 1993-2002. (From SRTR analysis, August 2004.)

,

11-17

Adjusted 5-year patient survival of living and deceased donor kidney transplants by recipient age. (From OPTN/SRTR: 2003 OPTN/SRTR Annual Report: Transplant Data 1993-2002. HHS/HRSA/SPB/DOT; UNOS; URREA. Available online at: www.ustransplant.org.) ,

1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 Year

6-10 Recipient age

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half-lives of all recipients are now the youngest recipients, especially if the pediatric recipient receives an adult kidney that functions These improvements likely reflect better donor selection, improvement in surgical techniques, better immunosuppression agents, and a better understanding of immunosuppression management in children. Althou~h " the current short-term success in the ~ e d i atric population is encouraging, it is also important to realize that long-term graft survival in the adolescent group (ages 11 to 17) is poor (see Fig. 43-2). The graft survival is lower than all age groups except adults older reasons behind this significant rate than 65 yean4"he of graft loss are speculative, but noncompliance likely ~ higher incidence of recurplays a significant r 0 1 e . ~The rent FSGS in this age group may also contribute to graft loss.5 Regardless of the cause, improving the long-term outcomes in this patient population represents one of the largest challenges in pkdiatric transblantation.

injury on the subsequent immune response. DGF also limits the ability to use renal dysfunction as a sign of acute rejection, and diagnosis of rejection could be delayed. We believe that all allografts with DGF lasting longer than 5 to 7 days should be sampled, and biopsies should be performed even earlier in patients with increased risk of rejection. Because of the impact of DGF on graft survival, all efforts should be made to decrease the risk for ATN. Over the past decade, the incidence of DGF after deceased donor renal transplantation has decreased from 16% to 12.5% in 2002.46 This observation likely represents improvements in recipient management and donor selection. The rate of DGF in these pediatric recipients is half that observed in adult patients (23.4%),reflecting the differential donor selection made possible by the allocation system.

Vascular Thrombosis Post-Transplant Outcomes and Risk Factors Associated with Graft Loss Benfield and coworkers reported that the most common causes responsible for 1605 primary allograft failures reported to NAPRTCS are chronic rejection (32.4%), acute rejection (15.2%), vascular thrombosis (11.6%), death of the recipient with a functioning graft (10.1%), and recurrence of the primary disease (5.9%).%alysis of large single-center experiences and registry data has revealed risk factors associated with specific posttransplantation outcomes. For a given child, some of these risk factors are not modifiable-such as their race, age, or primary disease. Other factors are potentially modifiable, and efforts should be made to improve the risk ratio when possible. The type and timing of the transplant affect outcomes. Living donor transplantation is associated with better graft survival compared with deceased donor transplantation,28 although the difference appears to be becoming smaller in more recent cohorts of recipients6 Preemptive transplantation is associated with better graft survival compared with patients on dialysis at time of transplantation." For children on dialysis, the choice of dialysis therapy does not impact on graft survival, although graft loss from vascular thrombosis is more common in children on peritoneal dialysis compared with hemodialysis.

Delayed Graft Function Delayed graft function (DGF) is defined as the need for dialysis during the first week after transplantation and is a manifestation of significant acute tubular necrosis (ATN). DGF is more common in recipients of deceased donor kidneys compared with living donor transplants. In pediatric recipients, analysis of over 5000 transplants has demonstrated that DGF is an independent risk factor for subsequent graft loss.Yl DGF is also associated with increased risk for acute and chronic rejection. It is believed that this association reflects the impact of renal

Vascular thrombosis is the third most common reported cause of graft loss.6 Risk factors that appear associated with thrombosis include donor age younger than 6 years, cold ischemic time greater than 24 hours, prior transplant, and peritoneal dialysis below transplantation.j3 Careful consideration of donor quality, along with efforts to ensure adequate perfusion to the graft, are strategies to minimize the risk of thrombosis. Patients with ESRD have a higher incidence of hypercoagulable conditions and any history of thrombosis, including recurrent or unexplained thrombosis of hemodialysis access, should prompt further evaluation.

Acute Rejection Acute rejection typically occurs between 1 week and 3 months after transplantation, although it can happen at any time. A rise in the serum creatinine level is frequently the first sign of rejection. Other findings such as low-grade fever, graft tenderness, hypertension, or decreased urine output may or may not be present. Any evidence of renal dysfunction should be promptly investigated. A percutaneous renal biopsy should be obtained to confirm the diagnosis because many other processes can lead to allograft dysfunction, including calcineurin toxicity, ureteral obstruction, infection, renal artery stenosis, and recurrence of original disease. Acute rejection episodes are treated by either pulse corticosteroids or antilymphocyte antibodies as detailed previously. Acute rejection, and, in particular, late acute rejection episodes occurring more than 1 year after transplant, are independent risk factors for graft loss due to chronic rejection.g0 One episode of acute rejection increases the risk of graft loss from chronic rejection graft failure 3-fold, and two episodes of acute rejection increase the risk 12-fold. The incidence of acute rejection is decreasing over time and is likely the major factor for the analysis of observed improvement in graft survival."n NAPRTCS cohort from 1997-1999 yielded an acute rejection rate of 40% in the first year after transplant compared

CHAPTER

with 71% for transplants performed in 1987-1989.52 Currently, rejection rates are 20% to 30%. Acute rejection, even successfully treated, profoundly impacts graft survival and all efforts to minimize this risk are important. Unfortunately, merely intensifying the immune suppression regimen is limited by the consequences of nonspecific systemic immunosuppression. Ensuring the patient remains on therapeutic immunosuppression is vital and noncompliance can have disastrous implications. Prompt recognition and treatment of rejection is another important principle. Because serum creatinine is a relatively insensitive indicator of renal dysfunction, particularly in small children with an adult kidney, some advocate protocol renal biopsies to detect subclinical rejection that may benefit from treatment.

Chronic Allograft Nephropathy Whereas short-term results are excellent, continued graft failure becomes a progressive renal dysfunction due to chronic allograft nephropathy, the most common cause of graft failure. Chronic allograft nephropathy, often called "chronic rejection," involves both immunologic and nonimmunologic factors. Although acute rejection episodes are the major risk factor for chronic allograft nephropathy, it is clear other processes can contribute to reduce chronic allograft nephropathy as we11.4"fforts are limited by our understanding of the process. In addition to eventually causing graft loss, renal dysfunction associated with chronic allograft nephropathy also adversely impacts the recipient's general health and development.

Noncompliance Compliance with the medical regimen is essential for the success of transplantation. Noncompliance is believed to contribute to significant graft loss in all patients and be largely responsible for the poorer long-term graft survival seen in adolescent recipients. Shaw and coworkers reviewed 112 pediatric renal transplant recipients and found one third had clinically significant periods of medication nonadherence." Nonadherence was significantly more common in adolescents compared with younger recipients. Nonadherence was associated with both acute and chronic rejection, as well as graft loss. Improved parental involvement and discussion of the child-parent relationship may improve adherence.

43

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Renal Transplantation

almost immediately after transplant, and most recurrences are within the first month. Patients with FSGS should be followed closely after transplantation with urine protein measurements. Graft survival is often worse in adolescents with recurrent FSGS, with up to a 38% risk of graft loss.62 A circulating permeability factor is believed to play a critical role in the pathogenesis of FSGS. Plasmapheresis is the most frequently used therapy for recurrence, although evidence-based controlled trials supporting its efficacy are lacking." Early institution of pheresis is associated with better 0utcomes,7~and some have proposed a role for preoperative plasmapheresis to decrease the risk of recurrence." Others have suggested In addia role for intensifying the immunos~ppression.~~ tion to FSGS, other primary renal causes associated with recurrent disease and potential graft loss include membranoproliferative glomerulonephritis types 1 and 2 and IgA nephropathy.81 Again, the risk of graft loss is variable, and none constitute an absolute contraindication to transplantation. In addition to these primary glomerulopathies, there are other recurrent diseases that disproportionately affect the pediatric population. Hemolytic-uremic syndrome can recur after transplantation. The patients at greatest risk of recurrence and subsequent graft loss are those with atypical nondiarrhea-associated hemolyticuremic syndrome.45.71 Henoch-Schonlein purpura can also recur after transplantation." The 5-year risk of renal recurrence after transplantation for Henoch-Schonlein purpura is 35%, and the risk for subsequent graft loss is 11%.56 Aggressive initial progression to ESRD is associated with a higher risk of recurrence, and recurrence can occur greater than a year after disappearance of the purpura. Oxalosis (primary hyperoxaluria type 1) is a metabolic disease caused by a defect in hepatic peroxisomal alanineglyoxlate aminotransferase, which leads to increased synthesis and excretion of oxalate. The excessive oxalate load leads to urolithiasis, medullary calcinosis, and eventual ESRD. There is also significant extrarenal oxalate deposition as well. The primary metabolic defect is not corrected by kidney transplantation, and after transplantation the persistent oxalate load causes subsequent renal graft loss. The morbidity associated with the persistent extrarenal oxalate deposition is responsible for early patient death. Given this natural history, simultaneous liver-kidney transplantation has been advocated as the primary treatment in these individual^.".'^^" The risk of this approach is substantial as well, and kidney transplantation alone can be appropriate in selected patients, most notably those who are pyridoxine sensitive or those with lower oxalate burdens.74

Recurrent Disease The recurrence of the patient's primary disease is variable, and recurrence may or may not lead to graft loss. Recurrent disease is a more significant issue in the pediatric population, because of the nature of the diagnoses leading to ESRD, and their association with higher rates of graft loss after recurrence.sl FSGS is the most prevalent and clinically significant disease to recur after renal transplantation.4 In children, the recurrence rate can be as high as 40%.3 It can recur

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lnfection Infection is a constant risk of immunosuppression and is one clinical representation of the precarious balance between over and under immunosuppression. Great vigilance should be maintained during periods of heaviest immunosuppression,as occurs immediately after transplant

~

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712

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TRANSPI.ANTATION

or during treatment of rejection. Additional prophylaxis is warranted during these periods of greatest risk. Currently, post-transplant infection accounts for more hospitalizations than acute rejection, even in the first 6 months after transplantation.18Post-transplantation infections are predominantly bacterial and viral. Fungal infections, although accounting for 0.2% to 2.7% of infection-related hospitalizations, can be particularly dangerous. Several viral pathogens are worthy of discussion. Pediatric recipients are often at higher risk, because the likelihood that they will be more naive to a particular pathogen is greater than the majority of the population.

Cytomegalovirus (CMV) CMV represents the most common viral infection after transplantation. CMV infection can occur in any recipient, although the risk is highest when a seronegative recipient is transplanted with a kidney from a seropositive donor. Infection occurs in the seropositive recipient as well owing to activation of latent virus. The incidence and the severity of CMV have declined with more effective prophylaxis. The severity of CMV infection may range from asymptomatic to organ involvement and death. The typical presentation occurs 1 to 3 months after transplantation, with the patient feeling relatively well but having fevers or sometimes with flu-like symptoms. Leukopenia is a common laboratory finding. Patients with tissue-invasive CMV disease will appear toxic and there will be evidence of end-organ dysfunction. Currently, the diagnosis is confirmed using either a CMV pp65 antigenemia assay or the CMV polymerase chain reaction (PCR) assay. Both methods allow monitoring of the response to therapy. Treatment of CMV disease includes ganciclovir or valganciclovir. In more severe cases, treatment with CMV hyperimmune globulin may be helpful. Unfortunately, ganciclovir-resistant CMV strains are emerging.

Varicella-Zoster Virus (VZV) In pediatric recipients, there is high risk of a primary chickenpox infection. Treatment is with intravenous acyclovir until the lesions crust over, then conversion to oral acyclovir. Primary infections can be quite severe. We immunize our VZV seronegative candidates before transplantation. For seronegative recipients who have a defined exposure, we administer VZV immune globulin.

BK Virus BK virus is a ubiquitous polyomavirus that has recently been identified as a significant concern in renal transplantation.97 There is a high incidence of seroconversion (60% to 100%) by late childhood, and the virus is dormant in the renal epithelium until reactivated. The recent growing awareness of this pathogen may reflect the impact of more potent immunosuppression protocols. Early reports, primarily in the adult literature, suggested BK virus was an important cause of renal allograft dysfunction, and BK interstitial nephritis resulted in a loss of up to 45% to 70% of infected grafts.

BK nephropathy should be considered in the evaluation of renal allograft dysfunction. BK nephropathy can be definitively diagnosed on biopsy using immunohistochemistry, but the histology can be confused at times with acute rejection. Treatment with additional immunosuppression does not improve renal function, and it often will cause further deterioration. The initial treatment for BK nephropathy consists of lowering maintenance immunosuppression. Treatment with low doses of cidofovir or intravenous immunoglobulin has also been utilized. Measurement of BK virus by PCR is becoming more widespread, both for diagnosis and monitoring response to treatment. There has been concern that children, who may be less likely to be seropositive, will be at an increased risk of BK infection. In one study involving 18 pediatric recipients, the incidence of BK seropositivity was 56% and that of BK viruria was 33%." These figures are comparable to incidence of seropositivity and viral activation observed in adult transplant recipients. The incidence of BK virus-associated transplant nephropathy is estimated to be 4% to 7%." In the largest examination of the issue in the pediatric population, Smith and coworkers evaluated a single-center cohort of 173 renal transplant recipients and identified BK nephropathy in 6 children (3.5%).8" The diagnosis was made on biopsy at a median of 15 months after transplantation. Treatment consisted of lowering the baseline immunosuppression; and with a median of 25 months' follow-up, all grafts are functioning with stable function. In addition, Smith and coworkers demonstrated a strong association between BK nephropathy and recipient seronegativity." It is likely that improved awareness, prompt diagnosis, and treatment may reduce the risk of graft loss initially associated with this disease process.

Malignancy Transplant recipients face an increased risk of de novo malignancy related to their immunosuppression. Lymphomas, specifically post-transplant lymphoproliferative disorder (PTLD), are the most common. The incidence is approximately 1% in renal tran~plantation.I"2~ PTLD actually represents a spectrum of pathology. Epstein-Barr virus (EBV) is believed to be causative in much of the progression to PTLD, especially in the B-cell lymphomas.' The treatment and prognosis of PTLD depend on the histology.'" wide variety of factors have been proposed to be associated with an increased risk, including the use of antilymphocyte induction therapy, EBV-seronegative recipient, era of transplant, and EBV infection though these associations are not always consistently demonstrated within the pediatric population. PTLD does appear to be related to the overall intensity More ~ ~ ~recent 9 analysis suggests of i m m u n o ~ u p p r e s s i o n . ~ the incidence of PTLD is increasing, a r d young white males appear to be at greatest risk.2o The second most common cancer in pediatric recipients is skin cancer. Squamous cell carcinoma accounts for the majority of cutaneous neoplasms, followed by malignant melanoma and basal cell carcinoma. The best

CHAPTER

strategy combines sun block and sun avoidance. All transplant recipients should undergo regular skin follow-up, specifically focusing o n this risk. Longterm immunosuppression is also associated with increased risks of cervical, vulvar, and anal carcinoma.

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Renal Transplantation

713

below the healthy population, although renal transplantation offers a better outlook compared with the dialysis population. Overall quality of life for the child and the family appears to be better after transplantation compared with dialysis, although again, when compared with the normative population, there are d i ~ p a r i t i e s . ~ ~ ~ ~ ~ ~ =

Other Medical Issues In addition to the risks of infection and malignancy, transplant recipients face many other risks owing to their history of ESRD, their underlying renal disease, and the individual risks associated with all their medications. Renal transplant recipients are at higher risk for cardiovascular disease. The preexisting renal insufficiency, the time o n dialysis, and the immunosuppressive medications after transplantation all contribute to this risk. Additionally, the prevalence of hypertension in pediatric kidney recipients is 50% to 80%." Many recipients will have additional cardiovascular risk factors, including hyperlipidemia, hyperhomocysteinemia, anemia, malnutrition, and chronic inflammation.84 Matteucci and colleagues evaluated 28 pediatric renal transplant patients and demonstrated that 82% had evidence of left ventricular hypertr~phy:~'Although there are little data examining the magnitude of the risk in pediatric patients, young adult ~ a t i e n t with s ESRD have a 1000-fold higher risk of 1 " cardiovascular death compared with the general population. Although the risk of cardiovascular death decreases after successful transplantation compared with dialysis, it does not become ndrma1.m In addition to contributing. to cardiovascular risk, hypertension after transplantation is associated with a higher risk of graft dysfunction and graft lo~s.~%veryeffort should be made to modify these cardiovascular risk factors to promote health and prolong life. Transplant recipients also face significant problems with bone metabolism and growth.22 This is in part owing to the chronic renal insufficiency, malnutrition, graft dysfunction after transplantation, and immunosuppressive medications. Renal osteodystrophy is a substantial problem, but proper management withcalcium supplementation, vitamin D supplementation, and the use of other agents has improved overall bone health. The risk of osseous complications seems to be improving over time, and the risk decreases after transplantation when compared with dialysis therapy.75 The introduction of recombinant human growth hormone has proved to be safe ~h hhman growth horand effective. ~ f i h o u recombinant mone was a large stepforward in promoting linear growth in these patients, many still will not obtain optimal final adult height.' u

Cognitive and Psychosocial Development The negative impact of ESRD o n cognitive development in children has diminished over the years, owing to significant improvements in medical management and renal replacement t h e r a ~ y . ~It3is believed that children with ESRD who undergo transplants may now reach a level of cognitive function close to o r at the level of healthy children. Psychosocial development remains

REFERENCES 1. Acott PD, Pernica JM: Growth hormone therapy before and after pediatric renal transplant. Pediatr Transplant 2003;7:426-440. 2. ASTS/AST: Epstein-Barrvirus and lymphoproliferative disorders after transplantation. Am J Transplant 2004;4:59-65. 3. Baqi N, Tejani A: Recurrence of the original disease in pediatric renal transplantation.J Nephrol 1997;10:85-92. 4. Baum MA: Outcomes after renal transplantation for FSGS in children. Pediatr Transplant 2004;8:329-333. 5. Baum MA, Ho M, Stablein D, et al: Outcome of renal transplantation in adolescents with focal segrnental glomerulosclerosis. Pediatr Transplant 2002;6:488-492. 6. Benficld MR, McDonald RA, Rartosh S, et al: Changing trends in pediatric transplantation: 2001 Annual Report of the North American Pediatric Renal Transplant Coctperative Study. Pediatr Transplant 2003;7:321-335. 7. Birkeland SA: Steroid-free immunoslrppression in renal transplantation: A long-term follow-up of 100 consecutive patients. Transplantation 2001 ;71:1089-1090. 8. Bumgardner GI,, Hardie I, Johnson RW, et al: Results of 3-year phase I11 clinical trials with daclizumab prophylaxis for prevention of acute rejection after renal transplantation. Transplantation 2001;7'2:839-845. 9. Bunchman T, Navarro M, Rroyer M, et al: The use of mycophenolate mofetil suspension in pediatric renal allograft recipients. Pediatr Nephrol 2001;16:978-984. 10. Capizzi A, Zanon GF, Zarchello G, Rigamonti W: Kidney transplantation in children with reconstructed bladder. Transplantation 2004;77:1113-1116. 11. Cecka JM, Gjertson DW, Terasaki PI: Pediatric renal transplantation: A review of the UNOS data. United Network for Organ Sharing. Pediatr Transplant 1997;1:55-64. 12. ChoYW, Terasaki PI, CeckaJM,Gjertqon DW: Transplantation of kidneys from donors whose hearts have stopped beating. N Engl J Med 1998;338:221-225. 13. Cochat P, Schell M, Ranchin B, et al: Management of recurrent nephrotic syndrome after kidney transplantation in children. Clin Nephrol 1996;46:17-20, 14. Colombani PM, Dunn SP, Harmon WE, et al: Pediatric transplantation. Am J Transplant 2003;3(Suppl 4):S53-S63. 15. CooperJT, Chin LT, Krieger NR, et al: Donation after cardiac death: The University of Wisconsin experience with renal transplantation. Am J Transplant 2004;4:1490-1494. 16. Delmonico FL, Harmon WE: The use of a minor as a live kidney donor. Am J Transplant 2002;2:333-336. 17. Dharnidharka VR, Ho PI,, Stablein DM, et al: Mycophenolate, tacrolimus and post-transplant lymphopr* liferative disorder: A report of the North American Pediatric Renal Transplant Cooperative Study. Pediatr Transplant 2002;6:396-399. 18. Dharnidharka VR, Stablein DM, Harmon WE: Posttransplant infections now exceed acute rejection as cause for hospitalization: A report of the NAPRTCS. Am J Transplant 2004;4:384389. 19. DhamidharkaVR,Sullivan EK, Stablein DM, et al: Risk factors for posttransplant lymphoproliferative disorder (PTLD) in

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pediatric kidney transplantation: A report of the North American Pediatric Renal Transplant Cooperative Study (NAPRTCS). Transplantation 2001 ;71:1065-1068. 20. Dharnidharka VR, Tejani AH, Ho PI., Harmon WE: Posttransplant lymphoproliferative disorder in the United States: Young Caucasian males are at highest risk. Am J Transplant 2002;2:993-998. 21. Ellis SR, Hulton SA, McKiernan PJ, et al: Combined liverkidney transplantation for primary hyperoxaluria type 1 in young children. Nephrol Dial Transplant 2001;16:348-354. 22. Fine RN: Growth following solid-organ transplantation. Pediatr Transplant 2002;6:47-52. 23. Fine RN, Alonso EM, Fischel JE, et al: Pediatric transplantation of the kidney, liver and heart: Summary report. Pediatr Transplant 2004;8:75-86. 24. Fine RN, Tejani A, Sullivan EK: Pre-emptive renal transplantation in children: Report of the North American Pediatric Renal Transplant Cooperative Study (NAPRTCS). Clin Transplant 1994;8:474-478. 25. Fontaine E, Gagnadoux MF, Niaudet P, et al: Renal transplantatioll in children with augmentation cystoplasty: Long-term results. J Urol 1998;159:2110-2113. 26. Franc-Guimond J, Gonzalez R: Renal transplantation in children with reconstructed bladders. Transplantation 2004;77:1116-1120. 27. Gagnadoux MF, 1,acaille F, Niaudet P, et al: Long term results of liver-kidney transplantation in children with primary hyperoxaluria. Pediatr Nephrol 2001;16:946-950. 28. Gjertson DW, Cecka JM: Determinants of long-term survival of pediatric kidney grafts reported to the United Network for Organ Sharing kidney transplant registry. Pediatr Transplallt 2001;5:5-15. 29. Green M, Webber S: Posttransplantation lymphoproliferative disorders. Pediatr Clin North Am 2003;50:1471-1491. 30. Groth CG, Backman L, Morales JM, et al: Sirolimus (rapamycin)-based therapy in human renal transplantation: Similar efficacy and different toxicity compared with cyclosporine. Sirolimus European Renal Transplant Study Group. Transplantation 1999;67:1036-1042. 31. Harmon WE, Sullivan EK: Cyclosporine dosing and its relationship to outcome in pediatric renal transplantation. Kidney Int Suppl 1993;43:S50-S55. 32. Hatch DA, Koyle MA, Baskin LS, et al: Kidney transplantation in children with urinary diversion or bladder augmentation. J Urol 2001 ;I65 (Suppl):2265-2268. 33. Haysom L, Rosenberg AR, Kainer G, et al: BK viral infection in an Australian pediatric renal transplant population. Pediatr Transplant 2004;8:480-484. 34. Healey PJ, McDonald R, Waldhausen JH, et al: Transplantation of adult living donor kidneys into infants and small children. Arch Surg 2000;135:1035-1041. 35. Hoppe B, Langman CB: A United States survey on diagnosis, treatment, and outcome of primary hyperoxaluria. Pediatr Nephrol 2003;18:986-991. 36. Hoyer PF, Ettenger R, Kovarik JM, et al: Everolimus in pediatric de nova renal transplant patients. Transplantation 2003;75:2082-2085. 37. Jungraithmayr T, Staskewitz A, Kirste G, et al: Pediatric renal transplantation with mycophenolate mofetil-based immunosuppression without induction: Results after three years. Transplantation 2003;75:454461. 38. Kahan BD, Julian BA, Pescovitz MD, et al: Sirolimus reduces the incidence of acute rejection episodes despite lower cyclosporine doses in Caucasian recipients of mismatched primary renal allografts: A phase I1 trial. Rapamune Study Group. Transplantation 1999;68:1526-1532. 39. Kahan BD, Rajagopalan PR, Hall M: Reduction of the occurrence of acute cellular rejection among renal allograft

40. 41.

42. 43. 44. 45. 46. 47.

48.

49. 50.

51. 52.

53.

54. 55. 56.

57.

58.

recipients treated with basiliximab, a chimeric antiinterleukin-2-receptor monoclonal antibody. United States Simulect Renal Study Group. Transplantation 1999;67: 276-284. Kari JA, Trompeter RS: What is the calcineurin inhibitor of choice for pediatric renal transplantation? Pediatr Transplant 2004;8:437-444. Kayler LK, Merion RM, Maraschio MA, et al: Outcomes of pediatric living donor renal transplant after laparoscopic versus open donor nephrectorny. Transplant Proc 2002;34: 3097-3098. Khwaja K, Humar A, Najarian JS: Kidney transplants for children under 1 year of age-a single-center experience. Pediatr Transplant 2003;7:163-167. Koo HP, Bunchman TE, Flynn JT, et al: Renal transplantation in children with severe lower urinary tract dysfunction. J Urol 1999;161:240-245. Live Organ Donor Consensus Group. (:onsensus statement on the live organ donor. JAMA 2000;284:2919-2926. I.oirat C, Niaudet P: The risk of recurrence of hemolytic uremic syndrome after renal transplantation in children. Pediatr Nephrol 2003;18:1095-1101. Magee JC, Bucuvalas JC, Farmer DG, et al: Pediatric transplantation. Am J Transplant 2004;4(Suppl 9) :S54S71. MageeJC, Sung RS, Turcotte JG, et al: Renal transplantation at the University of Michigan 1964 to 1999. In Cecka JM, Terasaki PI, eds: Clinical Transplants 1999, Los Angeles: UCIA Tissue Typing Laboratory, 2000, pp 139-148. Manificat S, Dazord A, Cochat P, et al: Quali~yof life of children and adolescent? after kidney or liver transplantation: Child, parents and caregiver's point of view. Pediatr Transplant 2003;7:228-235. Matas AJ: Impact of acute rejection on development of chronic rejection in pediatric renal transplant recipients. Pediatr Transplant 2000;4:92-99. Matas AJ, Bartlett ST, Leichtman AB, Delmonico FL: Morbidity and mortality after living kidney donation, 19992001: Survey of United States transplant centers. Am J Transplant 2003;3:830-834. Matteucci MC, Giordano U, Calzolari A, et al: Left ventricular hypertrophy, treadmill tests, and 24hour blood pressure in pediatric transplant patient?. Kidney Int 1999;56:1566-1570. McDonald R, Ho PL, Stablein DM, et al: Rejection profile of recent pediatric renal transplant recipients compared with historical controls: A report of the North American Pediatric Renal Transplant Cooperative Study (NAPRTCS). Am J Transplant 2001;1:55-60. McDonald RA, Smith JM, Stablein D, Harmon WE: Pretransplant peritoneal dialysis and graft thrombosis following pediatric kidney transplantation: A NAPRTCS report. Pediatr Transplant 2003;7:204208. McDonald SP, Craig JC, Australian and New Zealand Paediatric Nephrology A: Long-term survival of children with end-stage renal disease. N Engl J Med 2004;350:26542662. Metzger RA, Delmonico FL, Feng S, et al: Expanded criteria donors for kidney transplantation. Am .JTransplant 2003; 3(Supp14):S114S125. Meulders Q, Pirson Y, Cosyns JP, et al: Course of' HenochSchonlein nephritis after renal transplantation: Report on ten patients and review of the literature. Transplantation 1994;58:1179-1186, Millan MT, Sarwal MM, 1,emley KV, et ai: A 100% 2-year graft survival can be attained in high-risk 15-kg or smaller infant recipients of kidney allografts. Arch Surg 2000; 135:1063-1068;discussion 1068-1069. Mitsnefes MM: Hypertension and end-organ damage in pediatric renal transplantation. Pediatr Transplant 2004; 8:394399.

CHAPTER

59. NAPRTCS: North American Pediatric Renal Transplant Cooperative Study (NAPRTCS) 2004 Annual Report. Available online at www.naprtcs.org. 60. Neu AM, Ho PL, Fine RN, et al: Tacrolimus vs. cyclosporine A as primary immunosuppression in pediatric renal transplantation: A NAPRTCS study. Pediatr Transplant 2003; 7:217-222. 61. Neu AM, Ho PL, McDonald RA, Warady BA: Chronic dialysis in children and adolescents. The 2001 NAPRTCS Annual Report. Pediatr Nephrol 2002;17:656-663. 62. Newstead CG: Recurrent disease in renal transplants. Nephrol Dial Transplant 2003;18(Suppl 6):vi68-74. 63. Offner G, Broyer M, Niaudet P, et al: A multicenter, openlabel, pharmacokinetic/pharmacodynamic safety, and tolerability study of basiliximab (Simulect) in pediatric de novo renal transplant recipients. Transplantation 2002; 74:961-966. 64. Ohl DA, KonnakJW, Campbell DA, et al: Extravesical ureteroneocystostomy in renal transplantation. J Urol 1988;139: 499-502. 65. Ohta T, Kawaguchi H, Hattori M, et al: Effect of pre- and postoperative plasmapheresis on posttransplant recurrence of focal segmental glomerulosclerosis in children. Transplantation 2001;71:628-633. 66. Ohta T, Kawaguchi H, Hattori M, et al: ABO-incompatible pediatric kidney transplantation in a single-center trial. Pediatr Nephrol 2000;14:1-5. 67. OPTN/SRTR: 2003 OPTN/SRTR Annual Report: Transplant Data 1993-2002. HHS/HRSA/SPB/DOT; UNOS; URREA. Available online at: www.ustransplant.org. 68. Parekh RS, Carroll CE, Wolfe RA, Port FK: Cardiovascular mortality in children and young adults with end-stage kidney disease. J Pediatr 2002;141:191-197. 69. Port FK, Bragg-GreshamJL, Metzger RA, et al: Donor characteristics associated with reduced graft survival: An approach to expanding the pool of kidney donors. Transplantation 2002;74: 1281-1286. 70. Pradhan M, PetroJ, PalmerJ, et al: Early use of plasmapheresis for recurrent post-transplant FSGS. Pediatr Nephrol 2003; 18:934938. 71. Quan A, Sullivan EK, Alexander SR: Recurrence of hemolytic uremic syndrome after renal transplantation in children: A report of the North American Pediatric Renal Transplant Cooperative Study. Transplantation 2001;72: 742-745. 72. Qvist E, Narhi V, Apajasalo M, et al: Psychosocial adjustment and quality of life after renal transplantation in early childhood. Pediatr Transplant 2004;8:120-125. 73. Roberti I, Reisman L, Lieberman KV, Burrows L: Risk of steroid withdrawal in pediatric renal allograft recipients (a 5-year follow-up). Clin Transplant 1994;8:405-408. 74. Saborio P, Scheinman JI: Transplantation for primary hyperoxaluria in the United States. Kidney Int 1999; 56:10941100. 75. Saland JM: Osseous complications of pediatric transplantation. Pediatr Transplant 2004;8:400-415. 76. Salomon L, Fontaine E, Guest G, et al: Role of the bladder in delayed failure of kidney transplants in boys with posterior urethral valves. J Urol 2000;163:1282-1285. 77. Sarwal MM, Cecka JM, Millan MT, Salvatierra 0 Jr: Adultsize kidneys without acute tubular necrosis provide exceedingly superior long-term graft outcomes for infants and small children: A single center and UNOS analysis. United Network for Organ Sharing. Transplantation 2000;70: 1728-1736. 78. Sarwal MM, Vidhun JR, Alexander SR, et al: Continued superior outcomes with modification and lengthened follow-up of a steroid-avoidance pilot with extended daclizumab

79. 80. 81.

82. 83. 84. 85.

86. 87. 88. 89.

90.

91.

92.

93. 94. 95.

96.

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induction in pediatric renal transplantation. Transplantation 2003;76:1331-1339. Schachter AD, Meyers KE, Spaneas LD, et al: Short sirolimus half-life in pediatric renal transplant recipients on a calcineurin inhibitor-free protocol. Pediatr Transplant 2004;8:171-177. Seikaly MG: Recurrence of primary disease in children after renal transplantation: An evidence-based update. Pediatr Transplant 2004;8:113-119. Seikaly M, Ho PL, Emmett L, Tejani A: The 12th Annual Report of the North American Pediatric Renal Transplant Cooperative Study: Renal transplantation from 1987 through 1998. Pediatr Transplant 2001;5:215-231. Shaw RJ, Palmer L, Blasey C, Sarwal M: A typology of nonadherence in pediatric renal transplant recipients. Pediatr Transplant 2003;7:489-493. Shishido S, Asanuma H, Tajima E, et al: ABO-incompatible living-donor kidney transplantation in children. Transplantation 2001;72:1037-1042. Silverstein DM: Risk factors for cardiovascular disease in pediatric renal transplant recipients. Pediatr Transplant 2004;8:386-393. Smith JM, Ho PL, McDonald RA, et al: Renal transplant outcomes in adolescents: A report of the North American Pediatric Renal Transplant Cooperative Study. Pediatr Transplant 2002;6:493-499. Smith JM, McDonald RA, Finn LS, et al: Polyomavirus nephropathy in pediatric kidney transplant recipients. Am J Transplant 2004;4:2109-2117. Smith JM, McDonald RA, Nemeth TL: Current immunosuppressive agents in pediatric renal transplantation: Efficacy, sideeffects and utilization. Pediatr Transplant 2004;8:445453. Sollinger H, Kaplan B, Pescovitz MD, et al: Basiliximab versus antithymocyte globulin for prevention of acute renal allograft rejection. Transplantation 2001;72:1915-1919. SorofJM, Sullivan EK, Tejani A, Portman RJ: Antihypertensive medication and renal allograft failure: A North American Pediatric Renal Transplant Cooperative Study report. J Am Soc Nephrol 1999;10:13241330. Tejani A, Sullivan EK: The impact of acute rejection on chronic rejection: A report of the North American Pediatric Renal Transplant Cooperative Study. Pediatr Transplant 2000;4:107-111. Tejani AH, Sullivan EK, Alexander SR, et al: Predictive factors for delayed graft function (DGF) and its impact on renal graft survival in children: A report of the North American Pediatric Renal Transplant Cooperative Study (NAPRTCS). Pediatr Transplant 1999;3:293-300. Thomas SE, Hickman RO, Tapper D, et al: Asymptomatic inferior vena cava abnormalities in three children with end-stage renal disease: Risk factors and screening guidelines for pretransplant diagnosis. Pediatr Transplant 2000; 4:28-34. Tooher RL, Rao MM, Scott DF, et al: A systematic review of laparoscopic live-donor nephrectomy. Transplantation 2004;78:404414. Trompeter R, Filler G, Webb NJ, et al: Randomized trial of tacrolimus versus cyclosporin microemulsion in renal transplantation. Pediatr Nephrol 2002; 17:141-149. Troppmann C, Pierce JL, Wiesmann KM, et al: Early and late recipient graft function and donor outcome after laparoscopic vs open adult live donor nephrectomy for pediatric renal transplantation. Aich Surg 2002;137: 908-9 15; discussion 915-9 16. U.S. Renal Data System: USRDS 2004 Annual Data Report: Atlas of End-Stage Renal Disease in the United States, National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD, 2004. Available at www.usrds.org.

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97. Vats A: BK virus-associated transplant nephropathy: Need for increased awareness in children. Pediatr Transplant 2004;8:421-425. 98. Vats AN, Donaldson L, Fine RN, Chavers BM: Pretransplant dialysis status and outcome of renal transplantation in North American children: A NAF'RTCS Study. North American Pediatric Renal Transplant Cooperative Study. Transplantation 2000;69:14141419.

99. Vincenti F, Kirkman R, Light S, et al: Interleukin-Breceptor blockade with daclizukab to prevent acute rejection in renal transplantation. Daclizumab Triple Therapy Study Group. N Engl J Med 1998;338:161-165. 100. Wolf JS Jr, Merion RM, Leichtman AB, et al: Randomized controlled trial of hand-assisted laparoscopic versus open surgical live donor nephrectomy. ~ r a n s ~ l a n t a f i o n 2001;72:284290.

Pancreas and Islet Cell lransplantation -

David E. R. Sutherland, Angelika C. Gruessner, Bernhard J. Hering, and Rainer W. G. Gruessner

Type 1 diabetes, most commonly presenting in childhood, continues to represent a therapeutic challenge. Secondary diabetes complications, observed in 30% to 50% of patients who live more than 20 years after onset of the disease, result in poor quality of life, premature death, and considerable health care costs.j4 The principal determinant of the risk of devastating diabetes complications is the total lifetime exposure to elevated blood glucose levels.' Therefore, establishing safe and effective methods of achieving and maintaining normoglycemia will have substantial implications for the health and the quality of life of individuals with diabetes. The Diabetes Control and Complications Trial (DCCT) demonstrated that, given a qualified diabetes care team and intensive insulin treatment control, near-normalization of glycemia could be achieved and sustained for several years. However, such a near-perfect level of treatment would increase a patient's burden of day-to-day diabetes management, be diff~cultto implement for many patients, require more attention and medical services than are routinely , ~ be accompanied by an available in clinical p r a ~ t i c e and increased frequency of severe hypoglycemia.' Currently, the only way to restore sustained normoglycemia without the associated risk of hypoglycemia is to replace the patient's glucose-sensing and insulin-secreting pancreatic islet beta cells, either by the transplantation of a vascularized pancreasx' or by the infusion of isolated pancreatic islets.75 The tradeoff is the need for immunosuppression to prevent rejection of allogenic tissue, and for this reason most pancreas or islet transplant recipients have been adults. However, the potential for appl
with a kidney transplant, in a uremic diabetic patient at Shortly thereafter a few the University of Minne~ota.~G institutions around the world began to perform pancreas transplants, as detailed in a comprehensive history in another bo0k.84 The success rate (long-term insulin independence) with pancreas transplantation was initially low but increased considerably in the 1980s, leading to increased application (Fig. 441). Innovations in both surgical techniques and immunosuppression were responsible for the improvements. The first pancreas transplant was a duct-ligated segthis approach was assomental (body and tail) g~-aft,~%ut ciated with multiple complications. In a series of 13 more

Pancreas Transplants Worldwide

PANCREAS TRANSPLANTATION History The first clinical pancreas transplant was performed in 1966 by Drs. William Kelly and Richard Lillehei, simultaneous

, .

.a

Annual number of U.S. and 110x1-U.S. pancreas

transplants reported to the International Pancreas Transplant Registry (IPTR), 1978-2003.

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pancreas transplants between 1966 and 1973 at the University of Minnes0ta,~8.49Lillehei devised the whole pancreas-duodenal transplant technique to the iliac vessels with enteric drainage via a duodenoenterostomy to native small bowel that is now routine at most centers. The initial results, however, were not as good as today, and several surgeons devised alternative techniques during the 1970s and early 1980s.a4 Dubernard, in Lyon, France, introduced duct injection of a synthetic polymer as a method to block secretions and cause fibrosis in the exocrine pancreas of a segmental graft with sparing of the endocrine component,lg and many pioneering centers adopted this technique, although it is little used today. Gliedman introduced urinary drainage via a ureteroductostomy for segmental grafts,Z3and Sollinger later modified this approach with direct anastomosis of a duodenal patch of a whole pancreas graft to the recipient bladder? Drs. Dai Nghiem and Robert Corry did further modification of urinary drainage,"' retaining a bubble of duodenum for duodenocystostomy as Lillehei had done for duodethe early 1980s until the midnoentero~tomy.~Vrom 1990s, the bladder-drainage technique with duodenocystostomy was the predominant technique for pancreas transplants. The bladder-drainage technique had a low acute complication rate and was helpful in monitoring for rejection by detection of a decline in urine amylase activity, but chronic complications, such as recurrent urinary tract infections or dehydration from fluid loss via the exocrine secretions, were common. Thus, in the mid-1990s, a change occurred and enteric drainage, as described by Lillehei and colleagues49and never totally out of fashi0n,~2279overtook bladder drainage as the predominant drainage procedure. In addition, portal rather than systemic venous drainage was used by some groups for enteric-drained whole pancreas duodenal transplants.6Vortal venous drainage was originally introduced by Calne in 1984 for segmental pancreas grafts as a more physiologic technique12 and was applied by several groups sporadically over the years.84 With advances in immunosuppression, including the introduction of cyclosporine by Calne and coworkers in 1979,13tacrolimus by Starzl and associates in 1989,73and mycophenolate mofetil by Sollinger and coworkers in 1995," bladder drainage had become less important for monitoring rejection. Furthermore, in recipients of simultaneous pancreas and kidney transplants from the same donor, the kidney could be monitored for rejection episodes (elevation of serum creatinine) as a surrogate marker for pancreas rejection before there was sufficient pancreas damage to cause hyperglycemia. However, in solitary pancreas transplants, serum creatinine could not be used as a marker for rejection, and in such cases bladder drainage is useful and continues to be employed.84

Details of Surgical Techniques As mentioned in the history section, a variety of techniques have been used for management of the exocrine secretions and venous drainage of pancreas transplants. The majority of pancreas grafts are procured from multiorgan deceased donors; and because the liver and pancreas

share the origins of their arterial blood supply, a wholeorgan pancreas graft usually requires r e c o n s t r ~ c t i o n . ~ ~ ~ " The blood supply to the tail of the pancreas is supplied by the splenic artery originating from the celiac axis, and the head of the pancreas is supplied by the pancreaticoduodenal arcades originating fr-om the superior mesenteric artery and the hepatic artery. Because the latter goes with the liver, along with the celiac axis, the usual approach is to attach an arterial Y-graft of the donor iliac vessels, with anastomosis of the hypogastric artery to the graft splenic artery and the external iliac artery to the graft superior mesenteric artery, leaving the common iliac artery segment of the Y-graft for anastomosis to the recipient arterial system, usually the right common iliac artery. The portal vein of the pancreas graft can be anastomosed and divided to bring it into the field or vena cava or to the recipient's superior mesenteric vein. When venous drainage is to the recipient's iliac vein, the whole pancreas graft can be oriented with the head directed into either the pelvis or the upper abdomen. When directed cephalad, enteric drainage is the only option. When directed caudad, the duodenum can be anastomosed to either the bladder (Fig. 442) or bowel (Fig. 443). Figure 442 shows the bladder-drainage technique and also depicts a kidney transplant to the left iliac vessels, but, as mentioned, with a kidney transplant, enteric drainage is more common than bladder drainage. With the bladder drainage technique, the anastomosis may be handsewn or performed with an EEA stapler brought through the distal duodenum (which is subsequently stapled closed) for connection to the post of the anvil projected through the posterior bladder via an anterior cystotomy (see Fig. 442). The inner layer is then reinforced with a running absorbable suture for hemostasis and for burying the staples under the mucosa. With enteric drainage/systemic venous drainage, the anastomosis may be handsewn in an end-to-side fashion (Fig. 443), or it can be done in a side-to-side fashion by handsewing or by using an EEA stapler.22~The barrel of the EEA stapler is inserted into the end of the graft duodenum, and the post is projected through the side wall. The anvil is inserted into the recipient bowel through an enterotomy secured around the connecting post by a pursestring suture. The two posts are connected and the stapler is fired, creating the anastomosis. The end of the duodenum is then closed with a simple stapler. The enteric anastomosis can be done directly to the most convenient proximal small bowel loop of the recipient or to a Roux-en-Ysegment of recipient bowel that is created at the time. Outcome analyses do not show any statistical advantage of a Roux-en-Y loop. For portal drainage of the pancreas graft venous effluent (Fig. 444), the head and duodenum of the graft is oriented cephalad, and the graft portal vein is anastomosed directly to the recipient superior mesenteric vein. In the illustration, the pancreas graft is- ventral to the recipient small bowel mesentery so the venous anastomosis is to the ventral side of the vein, and the arterial Ygraft must be brought through a window of mesentery for anastomosis to the recipient's aorta or common iliac artery. The graft duodenum is anastomosed to recipient small bowel by the same techniques described for systemic

CHAPTER

44

Pancreas a n d Islet Cell Transplantation

719

40 to 80 crn

, , .

..

Simultaneous pancreas and kidney (SPK) transplant

using a whole pancreas/duodenal graft from a deceased donor with systemic venous drainage to the right iliac vein and bladder drainage of the pancreas exocrine secretions via a duodenocystostomy. Both the pancreas and kidney are placed in the peritoneum through a midline incision. The donor splenic artery, supplying the pancreatic tail, and the donor superior mesenteric artery, supplying the pancreatic head, have been joined by a Y-graft constructed from the donor common external/internal iliac artery complex during a bench procedure, and the base of the Y-graft is anastomosed to the recipient common iliac artery. The mid-duodenum is anastomosed to the posterior dome of the bladder, and the duodenal stumps are oversewn. The kidney graft could be from a living donor or the same deceased donor as the pancreas graft, but in either case is preferentially placed to the left iliac vessels so the right side, with its more superficial vessels, can be used for the pancreas transplant. In this particular illustration, the donor ureter was implanted into the bladder using the Politane1,eadbetter technique via an anterior cystotomy, a technique that also allows the duodenocystostomy to be performed with an EEA stapler, with internal oversewing of the anastomotic line using an absorbable suture to cover the staples, followed by closure of the cystotomy. However, when enteric drainage is used for an SPK transplant, an external ureteroneocystostomy is usually performed. (Reproduced from Gruessner RWG, Sutherland DER [eds]: Transplantation of the Pancreas. New York, Springer-Verlag,2004.)

venous drainage, with or without (as depicted) a Rouxen-Y loop of recipient bowel. An alternative approach for portal venous drainage of the pancreas graft effluent is to place the pancreas retroperitoneally by reflecting the right colon to the left and exposing the dorsal surface of the superior mesenteric vein, as described by Boggi and associate^.^,^ The arterial Y-graft can then be anastomosed directly to the right common iliac artery, but this approach does mandate creation of a Roux-en-Y limb of recipient bowel to bring

..

Pancreas-duodenal transplant using a deceased

donor with systemic venous drainage and entcric drainage of graft exocrine secretions to a proximal loop of recipient jcjunum. In this particular case, an end-to-side two-layer duodenojejnnostomy using the distal end of the graft duodenum is illustrated and the anastomosis is located 40 to 80 cm distal to the ligament of Treitz ( i n s ~ t ) . Alternatively, a side-to-side stapled or handsewn duodenqjejunostomy, with or without a Roux-en-Y loop, can be done. (Reproduced from Gruessner RWG, Sutherland DER [eds]: Transplantation of the Pancreas. New York, Springer-Verlag, 2004.)

through the small bowel or transverse colon mesentery for a graft duodenoenterostomy. Other techniques can be used, including duct injection for a segmental graft. Segmental grafts are rarely used except in the few cases of living donor pancreas transplant~,~,",~2 and most of these have the exocrine secretions managed by either a ductoenterostomy to a Roux-en-Y limb of recipient bowel or a ductocystostomy to the recipient's bladder (Fig. 445). Segmental pancreas transplants from living donors, with or without a kidney transplant, are particularly useful in candidates who would otherwise have a long wait for a deceased donor organ, such as those with a high level of human leukocyte antigen (HLA) antibodies but with a negative crossmatch to a living volunteer. For more details concerning the variety of surgical techniques in pancreas donors (deceased and living) and recipients, the reader is referred to work by Benedetti and colleague^.^

General Information, Pancreas Transplant Categories, and Immunosuppression By the mid-1990s, more than 1500 pancreas transplants were being done annually worldwide (see Fig. 441), as reported

720

PART

IV

TR.-\IVSPI.ANTATION

.\k i'

,

...

A

M11olc pancr~as/duodenumtransplant using a

deceased donor with portal \ r e ~ ~ odrainage ~is via an end-tmide superior mesenteric vein accessed below its atiasto~nosisto the wcipic~~t confluence with the sple~iicvei~i.Drainage of exociinr secretions is viza a side-ttrsidc duodenc?iyiu~iosto~~~y, 40 to 80 cm distal to the ligatue~ltof Treitz. Note that the ccphalad position of the pancreatic head when portal venous draiti;\ge is employed, as opposed to the caudal orientation possible \yith syste~nicvellous drainage, is no diEcrent than that needed when bladder d~ainageis dolie. It1 this particular illustration, the pancryas grafi overlies the, ~.ootof the small bowel mesentery, with the dt~odei~al scp-uncntbelow thc tl.nlls\relnecolon, and the arterial Y-graft is anastomosed t o the recipient common iliac artery through a mmcnteric ttmncl. Howewi; a wtrope~itoncalappl-oacli undel- the right colon is also possible, in which case the arte~ialY-grafi can be a~~astomosed directly to the recipient iliac artel? hut the enteiic anactomosis must be cia a Roux~n-Yli111R oft-ccipic~itbowcl brought tlirougli the mesentery. If a kidney is sirnt~ltancouslytransplanted to the left iliac vessels, the into the bladder using the extravesical ureter* ureter cat1 be i~npla~ited neocystostomy (Lich) techiiiquc, as illustrated. (Reproduced from Gn~essnerRWG, Sutherland DER [eds]: Transplantation of the Pancreas. New York, Springer-Verlag, 2004.)

to the International Pancreas Transplant Registry (IPTR).2" By 2003, more than 21,000 vascularized pancreas transplants had been performed, approximately three-fourths in the United States, with very large series at some cenvast majority were done to establish insulin ters.'"he independence in patients with de novo type 1 diabetes mellitus, but enteric-drained pancreas transplants have been used to correct both endocrine and exocrine deficiency after total pancreatectomy in some patient^,^*,^^ and to treat diseases such as cystic fibrosis in others.74 Specialists in more than 120 institutions in the United States and nearly the same number elsewhere have performed pancreas transplants.29 The IPTR was founded in 1980 to analyze the cases.80In 1987, reporting of U.S. cases became obligatory through the United Network for Organ Sharing (UNOS), and annual reports have been made there~tfter.2~-~~ There are three categories of pancreas transplant recipients: (1) uremic diabetic patients who undergo a

, .

. A

I .ivii~gdot101-segmental (body artd tail) pancreas

transplant t o right ili;tc vessels (systemic vcrlous drainage) and I~laddrr drainage of exocl-inc secretions via a ductocystostomy by rrlcaris of an intraperitoneal approach. The donor splenic artery anti splenic vein are anastomosed end to side to the recipient external iliac artery and vein aftel- ligation and division of all hypogastric veins to hl-ing the main vein as supel-fitial as possible. Thc splenic arto-y atiaston~osisis lateral and proximal to the splenic vein anastotnosis. A two-layer ductocystostomy is constructed: the pai~cl-eaticduct is approximated to the arothelial layer (inner layel-) 11si11ginterrupted 7-0 ahsorhablc sutt~resover a stent (intrl). If' the kidi~cyis transpla11tc.dsi~nulta~~cot~sly, the donor ureter is in~plai~ted into the hladder using the t.xiravrsic.nl ~irctcrotieocystostotiiy (1,ich) technique. (Rcproduccd fron~ ofthe Gruessner RWG, Suthrl-land DER [cds]: Ttai~spla~itatio~~ Paxicrcas. New York, Spl-ingc~Verlag,2004.)

simultaneous pancreas and kidney (SPK) transplant from either a deceased or living donors.y; (2) nephropathic patients who already have had renal insufficiency corrected, usually by a living donor kidney transplant, and then undergo a pancreas after kidney (PAK) transplant; and (3) nonuremic diabetic patients who undergo a pancreas transplant alone (PTA). The Pancreas Transplant Registry has compared outcomes in the three categories over several eras of data c o l l e c t i o r ~ . ~ ~ - ~ ~ ) The majority of pancreas transplants have been in the SPK category, but in recent years there has been an increased emphasis in performing living donor kidney transplants to preempt the need fbr dialysis in diabetics with nephropathy. Thus, the number of PAK transplants has increased as the number of SPK transplants has declined (Fig. 44-6). Concomitantly, there has also been an increase in the number of PTA cases to treat diabetics without advanced nephropathy who have diabetic management problems justifying immunosuppression and to treat patients who would also be candidates for islet transplantation given the conditions discussed later. Immunosuppression management of' pancreas transplant recipients is similar to that of recipient? of' other solid organs, including kidneys, which the majority of pancreas recipients also receive. Thus, induction immunosuppression with anti-Txell monoclonal or polyclonal depleting

CHAPTER

'9.,

Goo

G"'.,

Gov

'".,

'9.,

o'oo

Months posttransplant

Pancreas Transplant Outcomes Current outcomes with deceased donor pancreas transplants according to recipient categories, surgical technique, and immunosuppression protocol, for U.S. cases as reported to UNOS from January 2000 to June 2004, are summarized here. During this period, more than 5,800 pancreas transplants were reported to UNOS, including more than 3,800 SPK transplants, more than 1,300 PAK transplants, and more than 400 PTAs. The primary transplant patient survival rates in the three recipient categories are shown in Figure 447. At 1 year,

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12

I 18

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24

721

Pancreas graft functional survival rates (insulin independence) for 2000-2004 U.S. deceased donor primary transplants by recipient category. PTA, pancreas transplant alone; SPK, simultaneous pancreas-kidney; PAK, pancreas after kidney transplant.

or nondepleting agents may be used or reserved for rejection episodes. Maintenance immunosuppression usually consists of a combination of a calcineurin inhibitor (cyclosporine or tacrolimus), with the dose and blood levels adjusted to minimize nephrotoxicity, and an antiproliferative agent (mycophenolate mofetil or sirolimus), with or without prednisone. Corticosteroid-free regimens are now quite common for all organ transplants, including the pancrea~.~"

0

Pancreas a n d Islet Cell Transplantation

+o+

Number of pancreas transplants performed annually in the United States from 1988 through 2003 by recipient category. PTA, pancreas transplant alone; SPK, simultaneous pancreas-kidney; PAK, pancreas after kidney transplant.

~

44

Q

30

.

36

Months posttransplant Patient survival rates for 2000-2004 U.S. deceased

donor primary transplants by recipient category. PTA, pancreas transplant alone; SPK, simultaneous pancreas-kidney; PAK, pancreas aftcr kidney t~ansplant.

95% of the SPK, 95% of the PAK, and 98% of the PTA recipients were alive; at 3 years, 90%, 8876, and 95%, respectively, were alive (P = 0.05). The highest patient survival rate was in the PTA category, presumably because this group had less advanced complications before transplantation. The primary pancreas graft survival rates in the three recipient categories are shown in Figure 448. At 1 year, 85% of the SPK, 78% of the PAK, and 76% of the PTA recipients were insulin-independent; at 3 years, 7776, 62% and 62%, respectively, were insulin-independent ( P <0.001). The highest pancreas graft survival rates are in the SPK category, presumably because the kidney graft (usually from the same donor as the pancreas) can be used to detect rejection episodes earlier than in the other categories where only the pancreas can be monitored. support for this hypothesis comes from Registry data showing no significant differences in graft technical failure rates between categories but large differences in rejection loss rates. Of the 2000-2004 primary pancreas grafts, 8% failed for technical reasons, with thrombosis being the highest risk for technical loss (5%); infection, pancreatitis, and anastomotic leak made up the rest. There were no significant differences between categories in regard to technical losses. The primary pancreas graft failure rates from rejection are shown in Figure 449. At 1 year, 2% of the SPK, 8% of the PAK, and 10% of the PTA recipients of technically successful grafts had to resume exogenous insulin (significantly lower in the SPK category; P = 0.0001) . In regard to management of pancreatic duct exocrine secretions for 2000-2004 cases, enteric drainage predominated for SPK transplants (81%); for PAK and PTA, the proportion that were enteric-drained was slightly lower (67% and 56%, respectively). Overall, the technical failure rate was slightly higher with enteric drainage than U bladder I ~ ~ (8% versus ~ ~ ~ I graft with drainage 6%). Pancreas survival rates, however, were not significantly different for enteric-drained versus bladder-drained transplants in any of the categories: at 1 year they were 85% (n = 3047) versus 87% ( n = 707) for SPK; 77% (n = 733) versus 80% (n = 364) for PAK; and 72% (n = 238) versus 79% (n = 184) for PTA cases. For PTA, the failure rate from rejection

722

PART

IV

TRANSPLANTATION Antl-T-cell Therapy & TAC & MMF

Oh

20-

o

6

,

Months posttransplant Technically successful pancreas graft immunologic

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.

12

18

24

SPK

2,500

Months posttransplant

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failure rates (return to exogenous insulin) for 2000-2004 U.S. deceased donor prima~ytransplants by recipient category. PTA, pancreas transplant alone; SPK, simultaneous pancreas-kidney;PAK, pancreas after kidney transplant.

for technically s~iccessfulgrafts was significantly lower with bladder drainage than enteric drainage: 5% (n = 161) versus 15% (n = 216) at 1 year (P=0.03). In the SPK category, bladder drainage and enteric drainage would be expected to give similar results: in most cases both grafts come from the same donor, and monitoring of serum creatinine serves as a surrogate marker for rejection in the pancreas transplant, allowing easy detection and reversal by treatment. In contrast, for solitary pancreas transplants (PAK and PTA), serum creatinine cannot be used as a marker of pancreas rejection; hyperglycemia is a late manifestation of rejection and exocrine markers must be used. Although serum amylase and lipase may elevate during a rejection episode, this does not occur in all cases; but for bladder-drained grafts, a decrease in urine amylase eventually always accompanies rejection (100% sensitive, even though it is not specific) and nearly always precedes hyperglycemia, so a rejection episode is more likely to be diagnosed in a bladderdrained graft and lead to treatment and reversal. Of note, for enteric-drained grafts in all categories, the pancreas graft survival rates were slightly lower when a Roux-en-Y loop of recipient bowel was used for the Approximately one-third of entericenteric ana~tomosis.2~ drained pancreas grafts reported to UNOS were done with a Roux-en-Y loop, but the outcomes are not improved by this procedural addition; and at least in PTA recipients the technical failure rate was higher when a Roux-en-Y loop was used.2" Another variation in surgical technique is portal drainage of the venous effluent for entericdrained grafts.G4 It establishes normal physiology and a theoretic metabolic advantage over systemic venous drainage, and some groups have reported that portal venous entericdrainage grafts are less prone to rejection than systemic venous enteric-drainage graft^.^^.^^ The latest Registry analysis shows that portal venous drainage was used for one-fifth of enteric-drainage transplants, but there were no significant differences in pancreas graft survival versus systemic venous enteric-drainage transplants in any of the categories: at 1 year, 85% (n = 610) versus 85% ( n = 2437)

81% 88%

Pancreas graft functional survival rates (insulin independence) for 2000-2004 U.S. deceased donor primary transplants by category in diabetic recipients given anti-T-cell agents for induction and tacrolimus (TAC) and mycophenolate mofetil (MMF) for maintenance immunosuppression. PTA, pancreas transplant alone; SPK, simultaneous pancreas-kidney;PAK, pancreas after kidney transplant.

for SPK; 78% (n = 168) versus 77% (n = 564) for PAR and 71% (n = 85) versus 72% (n = 153) for PTA cases. In regard to immunosuppression, according to the latest Registry analysis, anti-T-cell agents were used for induction therapy in about three-fourths of 2000-2004 U.S. panThe most frequently creas recipients in each ~ategory.~" used regimen for maintenance immunosuppression (twothirds of the recipients in each category) was tacrolimus and mycophenolate mofetil in combination, with or without prednisone. In recipients of primary deceased donor pancreas grafts given anti-T-cell agents for induction and tacrolimus and mycophenolate mofetil for maintenance immunosuppression (Fig. 44-10), the I-year graft survival rates in the SPK, PAK, and PTA categories were 88% ( n = 2500), 82% (n = 712), and 81% (n = 278), respectively. Sirolimus was used as a maintenance immunosuppressive drug in about one-sixth of recipients in each category (Fig. 441 1) , with comparable outcomes: the 1-year pancreas graft survival rates in the SPK, PAK, and PTA categories were 87% (n = 675), 82% (n = 184),

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Months posttransplant . Pancreas graft functional survival rates (insulin

independence) for 2000-2004 U.S. deceased donor primary transplants by category in diabetic recipients given sirolimus-based maintenance immunosuppression. PTA, pancreas transplant alone; SPK, simultaneous pancreas-kidney;PAK, pancreas after kidney transplant.

36

CHAPTER

and 83% (n = 67), respectively. In contrast, the remaining one-sixth of recipients given alternative immunosuppressive regimens had distinctly lower pancreas graft survival rates in each category: at 1 year, 63% in SPK (n = 666), 61% in PAK (n = 213), and 54% in PTA (n = 84) cases. A center effect may play a role in the outcomes of the Registry analysis according to immunosuppressive regimens. In regard to the logistics of pancreas transplantation, the recent Registry datSOshowed a slight increase in technical failure rates and a slight decrease in graft survival rates with increasing preservation time. For example, in the SPK category, l-year pancreas graft survival rates were 86% with 4 to 7 hours of preservation versus 81% with 28 to 31 hours of preservation. HLA matching had virtually no impact on SPK graft survival rates, but matching at least at the class I loci had a beneficial effect in the PAK and the PTA categories. " In regard to pancreas recipient age, the recent Registry analysis of 2000-2004 cases showed an effect on outcome mainly in PTA recipients, with rejection more likely in the youngest patients. In the PAK category, all recipients were older than 20 years; per an analysis of rejection rates by decade of age, at 1 year the rates varied from 4% to '7%.In the SPK category, the rejection rate at 1 year was 2% to 4% in the various age groups older than 20 years but 0% for those younger than 20 years (n = 4). In contrast, in the PTA category the rejection rate at 1 year was 50% for those younger than 20 (n = 14) and 13% for those 20 to 29 (n = 39); for PTA recipients older than 30 the 1-year reiection loss rates were 4% to 6%, similar to the other two recipient categories. Thus, the young nonuremic diabetic is highly immunocompetent and more prone to reject a pancreas graft, consistent with an earlier analysis of outcomes in U.S. pediatric pancreas transplant recipients from 1988 to 1999.27 In that analysis, out of slightly more than 8,000 pancreas transplants, only 49 were in recipients younger than 21 (
44

Pancreas and Islet Cell Transplantation

723

children with extreme lability in whom a successful pancreas transplant would be appropriate treatment, the antirejection strategies need to be optimized to improve the graft survival rates over what has been achieved in the past. with ressect to outcome measures other than insulin independence, prevention and reversal of secondary complications, improvement in quality of life, expansion of life span, and reduction of health care costs per quality-adjusted life year have all been positively demonstrated in type 1 diabetic pancreas transplant recipients.l8.'0.'"56.7".88>97 In patients with labile diabetes and hypoglycemic unawareness, a pancreas transplant can resolve an otherwise intractable and life-threatening c o u r ~ e . ~ ~ . " , ~ ~ Whether a pancreas transplant has an effect on survival probabilities for the diabetic population selected for the procedure is controversial. Two separate analyses of U.S. data from UNOS and the Organ Procurement Transplant Network (OPTN) for pancreas transplant candidates and recivients between 19^95and 2000 comvared the survival probabilities for patients who remained on the waiting ~~,~~ list versus those receiving a transplant by c a t e g ~ r y .In the first analysis,gOSPK recipients had a significantly higher probability of survival- than those remaining on the waiting list for the procedure, but for solitary (PAK or PTA) recipients just the opposite was the case. In the second analysis,32 the higher survival probability for SPK recipients was confirmed, and, in addition, the overall survival probabilities of solitary pancreas transplant recipients compared with those waiting and even after 1 vear were favbrable for transslantation. In the second analysis, patients who listed at multiple centers were identified and were counted only once, corrections were made for patients who changed categories, and longer follow-up was available. Thus, pancreas transplantation does not entail a higher risk than staying on exogenous insulin for those on the waiting list and may improve survival probabilities for solitary as well as SPK recipients.

ISLET TRANSPLANTATION The less invasive alternative to transplantation of the pancreas or an immediately vascularized graft solely for beta cell replacement is transplantation of isolated islets The first clinical islet allograft as a free graft.39,41,59,94 was in 1974 in a diabetic recipient of a previous kidney transplantjg; and more than 700 islet allotransplants have since been performed. The success rate with islet allotransplants was low until recently (beginning in 2000). However, islet autotransplants have had a relatively high success rate in preventing diabetes after total pancreatectomy for more than 2 decades, so they are briefly described before reviewing the current status of islet allografts for type 1 as well as for surgical diabetes.

Islet Autotransplants at Pancreatectomy for Benign Disease Islet autotransplants to prevent diabetes after a total pancreatectomy for benign disease, such as chronic pancreatitis,

724

PART

IV

TFUNSPLANTATION

Islet Allotransplants

,

. .,

Pylorussparing total pancreatectomy and partial

duodenectomy technique for patients with chronic pancreatitis undergoing islet autotransplants. The bile duct is transected and reimplanted into the duodenum, shown here proximal to a duodenoduodenostomy or duodenojejunostomy, but more commonly it is placed distal to the enteric anastomosis, with the site depending on the individual anatomy. When possible, only the second portion of the duodenum is resected and an end-to-end duodenoduodenostomy is created; but if viability is not maintained, the entire distal duodenum must be resected and an end-to-end or end-to-side duodenoj~junostomyperformed. The short gastric vessels are preserved, as well as the gastroepiploic artery if possible, and the spleen is not removed if its viability is maintained. (Reproduced from Gruessner RWG, Sutherland DER [eds]: Transplantation of the Pancreas. New York, Springer-Verlag, 2004.)

have been successful since the first case was performed in the 1970s, but depend on the number of islets transplanted.83-8"w Children with chronic pancreatitis and intractable pain who required pancreatectomy for resolution of narcotic dependence have had diabetes prevented by islet auto transplant^.^^,^^ The surgical technique of pylorus-sparing total pancreatectomy and duodenectomy is shown in Figure 4412. The procedure can be staged, but when the body and tail of the pancreas are removed they should always be processed for islet isolation for an intraportal autotransplant (Fig. 4413A). If a distal pancreatectomy is the primary procedure and a Whipple (completion) pancreatectomy becomes necessary, diabetes will have been prophylactically prevented by the initial islet autograft. If a Whipple procedure was the primary procedure but pain persists and a distal (body and tail) completion pancreatectomy is required, it should be done in an institution capable of isolating islets from the excised gland for an autotransplant.

Islet allografts in patients with surgical diabetes have also been associated with a very high success rate."'-89 Islet allograft transplants in patients with autoimmune type 1 diabetes have been more challenging; insulin independence in this recipient group, even on an anecdotal basis, was not achieved until the early 1990s.1 1 ,'4,"7,"33 Islet allotransplants, as with autotransplants, are usually done with embolization of the islets to the liver via the portal vein, where at least some islets will survive by nutrient diffusion until revascularization occurs (see Fig. 4413B). A drawback of islet allotransplants, as compared with pancreas transplants, is the reduced beta cell mass; much attention has been given to compensating for the attrition that occurs. Recently, increasing the mass of transplanted islet cells and choosing combinations of antirejection agents to reduce the diabetogenic side effects of immunosuppressive drugs have markedly improved the success rate of islet allografts. Shapiro and associates reported achieving insulin independence after repeated islet transplants (sequential multiple donors) in 7 of 7 type 1 diabetic patients given glucocorticoid-free immunosuppression with daclizumab, sirolimus, and relatively lowdose tacrolimus.69 Corticosteroids are highly diabetogenic and are a known risk factor for posttransplant diabetes in recipients of organ allografts of all types. Although the incidence of drug-induced diabetes is low in pancreas allograft recipients, this is because an intact normal pancreas has a high beta cell mass but with islet isolation there is a substantial reduction. Thus, in the presence of diabetogenic immunosuppression, a single islet donor may not suffice. By eliminating one agent that is diabetogenic (corticosteroids) and by reducing the dose of another diabetogenic but potent immunosuppressant, tacrolimus, and adding sirolimus (a less diabetogenic but perhaps as potent an immunosuppressant as tacrolimus), the beta cell mass transplanted was sufficient to eliminate the need for exogenous insulin in an expanding series.66 The results of the Edmonton group suggested that if a totally nondiabetogenic immunosuppressive regimen potent enough to prevent rejection could be devised, even a single islet donor could suffice." Alternatively, improving the efficiency of islet cell isolation in terms of viable beta cell mass might allow a single donor to suffice even if the immunosuppressive regimen was not completely free of diabetogenicity, as is the case for the Edmonton protocol. The diabetogenic side effects of prior conventional immunosuppressive therapy certainly is one reason for the historically poor success rate of human islet allografts. Less than 50% of the islets are usually isolated, and less than 50% of transplanted islet beta cells engraft.17That immunosuppressive drugs are diabetogenic (not only glucocorticoids but also the calcineurin inhibitors tacrolimus and cyclosporine) particularly at high doses, increasing insulin need while inhibiting insulin secre" full islet mass of an tion, is well d o ~ u m e n t e d . ~The immediately vascularized pancreas graft is able to overcome drug-induced insulin resistance whereas achieving

CHAPTER

lslet isolation

44

Pancreas a n d Islet Cell Transplantation

725

T

lslet in pancreas

, -

Islet transplantation using the portal vein for embolization to the liver where revascularization will occur, either as an autograft of islets isolated from the excised specimen after pancreatectomy for benign disease ( A ) or as an allograft of cells isolated from a donor for treatment of a patient with type 1 diabetes (B). A .

the critical beta cell mass necessary to do so with an islet graft is more difficult, at least at the moment. Fortunately, the new generation of immunosuppressive drugs has made the use of prednisone unnecessary for the majority of recipients in clinical transplantation and also has allowed calcineurin inhibitors to be used in lower, less diabetogenic doses.2',22 The ability to consistently achieve insulin independence in diabetic patients by islet allotransplants,first reported by the Ednioritori group," has been confirmed at other instit ~ i t i o n s . ~ . ~ In ~ ~ most ~ ~ ~ ~series, ~ ~ - 1however, - 1 ~ ~ the recipients

required islets from two or more donor pancrease~.2j~44."~69 For islet allotransplantation to replace pancreas transplantation, or to become a clinically significant treatment option on a large scale for the diabetic population, will require additional advances, including maximization of the islet cell yield and potency as well as minimization of immunosuppressive failures and risks. Several strategies designed to promote the potency, engraftment, and functional survival of transplanted islet cells were evaluated in two recent islet transplant trials at the University of Minnesota: (1) excluding pancreases

726

PART

IV

TRANSPI.ANTATION

from donors older than 50 years, (2) limiting ischemic injury of islets during pancreas storage, (3) avoiding islet-toxic reagents during islet processing, (4) culturing islets to allow pretransplant initiation of immunosuppression, (5) providing potent prophylactic anticoagulation and aggressive insulin therapy peritransplant, (6) increasing the immunosuppressive and anti-inflammatory potency of induction immunosuppression, and (7) avoiding glucocorticoids and minimizing calcineurin inhibitors ~ ~ pilot in maintenance i m m u n o ~ u p p r e s s i o n . ~In~ ,two islet transplant trials in type 1 diabetic patients with hypoglycemia unawareness, 12 of 14 recipients with type 1 diabetes achieved insulin independence after singledonor islet transplants, with normal HbA1, levels. The outcome suggests that some or all of the seven strategies facilitate consistent reversal of type 1 diabetes with islets prepared from one pancreas. Three of the strategies are of particular importance: First, pancreas preservation methods that are adequate for prolonged cold storage before vascularized pancreas transplants are inadequate for even a short period of cold storage before islet isolation and transplants. The cellular stress encountered during islet isolation is compounded by any preceding cold ischemic injury of the donor pancreas; moreover, such stress exceeds the cellular stress associated with reperfusion injury that islets are subjected to after a vascularized pancreas transplant.38 Experimental evidence indicates that the two-layer (perfluorodecalin/ University of Wisconsin [UW] solution) pancreas preservation method both increases the yield of the islet isolation process and preserves the ability of isolated islets to reverse diabete~.~2~~~ Second, the intravascular location of intraportally transplanted islets immediately exposes the graft to primed autoreactive, islet beta cell-directed T cells. This location may also hasten the mounting of alloimmune responses. Pretransplant islet culture permits achievement of an immunosuppressed state well before islet infusion; it may also limit the diminution of islet mass, immediately post-transplant, because of autoimmunity, alloimmunity, and innate immunity.35 The allogeneic islet mass needed to achieve insulin independence is higher in type 1 diabetic patients, as compared with surgically diabetic patients. This difference suggests that engraftment and survival of allogeneic islets is compromised in an autoimmune environment." The need for more than one donor pancreas in the Edmonton experience" may reflect the inability of anti-IL-2R monoclonal antibodies (mAbs) to abrogate early effector responses mediated by persisting autoimmunity. Consequently, we targeted autoreactive T cells in the peritransplant period with anti-CD3 antibodies or polyclonal T cell antibodies, two of the very few strategies proven effective in inhibiting activated autoreactive T cells.14~50~96 Finally, pretransplant islet culture was a critical component of our study protocols. It allows achievement of T cell-directed immunosuppression in the recipient well before islet infusion, which is likely important in reducing islet-directed immune responses mediated by autoreactive, primed T cells to which the intravascularly transplanted islets are immediately exposed.

Delaying transplantation until 2 days after the initiation of therapy with T cell-depleting antibodies prevents exposure of transplanted islets to the cytokine release associated, to varying degrees, with the first and second antibody infusions. Pretransplant culture also allows quality control studies to be performed before the infusion of tissue, thereby avoiding transplantation of tissue not meeting more thorough release criteria. Studies in animals indicate improved metabolic efficacy of cultured (as opposed to freshly isolated) i~lets.~"he results of our recent clinical trials are consistent with those of experimental studies, suggesting that pretransplant islet culture does not have deleterious, and may have beneficial, metabolic effects beyond the immunologic advantages. Thus, incorporation of several advances into revised islet transplant protocols appears to facilitate outcomes in selected islet recipients. Novel, glucocorticoid-free and calcineurin inhibitor-free, nondiabetogenic immunosup pressive regimens have proven safe and effective in the relevant preclinical nonhuman primate islet allotransplant model',gj and are expected to lead to further significant improvements in islet transplant outcomes. Nonetheless, until the lopstical and islet yield problems have been solved, pancreas transplants will remain the most efficient use of the majority of donor organs. Obviously, for correction of diabetes, a simple cell transplant is preferable to the major surgery of a pancreas transplant, but islet isolation requires a specialized facility whereas pancreas transplants can be done at virtually any hospital with a transplant program and appropriately trained surgeons. Demonstration of control and consistency of human islet processing techniques, predictability of posttransplant islet function by islet product potency assays, and documentation of clinical safety and efficacy of islet transplants are needed for licensure of isolated human islets as a biologic product. Such a license will be critical to securing third-party reimbursement, which may provide a strong incentive for maximizing donor pancreas utilization. Progress in pancreas preservation techniques and the creation of regional islet processing centers may lead to adjustments in donor pancreas allocation algorithms and overcome logistical and technical impediments, resulting in increased availability of islet transplants. At the moment, generalized immunosuppression is needed to prevent rejection of either an immediately vascularized pancreas or a neovascularized islet allograft. However, protocols designed to induce immunologic tolerance specific to the donor can be tested more readily in islet than in solid organ recipients: the magnitude of the surgical procedure and the consequences of rejection failure are less.40Thus, it is critical to continue islet allotransplants with novel immune monitoring and antirejection strategies even if at the moment pancreas transplants predominate as the clinical mode of beta cell replacement for type 1 diabetes mellitus. , Although a transition from pancreas to islet transplants as the dominant form of beta cell replacement therapy may occur over the next few years, pancreas transplants will not disappear entirely. Patients with high pretransplant insulin requirements in whom diabetes reversal

CHAPTER

with islet transplants is less likely would best be served with a vascularized pancreas transplant. Furthermore, diabetic patients with exocrine deficiency would best be served by an enteric-drained pancreas transplant. In addition, in patients who have very high insulin requirements or insulin resistance (type 2 diabetes), an intact organ may be needed to obtain a sufficient islet mass to restore insulin independence from a single donor in the presence of insulin resistance. Tissue availability will be the limiting factor in determining the magnitude of the impact of beta cell replacement therapy. Six thousand deceased donors are available each year in the United States, but it is estimated that only half have a pancreas suitable for transplantation. Thus, the maximal number of pancreas transplants that could be done in the United States is 12,000 per year, assuming that each deceased pancreas could be that living donors split for use in two recipient~,~%nd would be used for segmental pancreas transplants"" to the extent that they have been for kidney transplants (currently about 6000 per year in the United States). This scenario has not yet materialized, but the potential is there to transplant at a rate approaching half of the annual incidence of new-onset cases of type 1 diabetes (30,00O/year in the United States). The numbers could be increased further if enough islets could be isolated from one donor for transplants into more than two recipients. Although the efficacy of islet transplant protocols will continue to improve and the procedural and immunosuppressive risks now associated with islet transplants will continue to diminish, islet transplants will not be the ultimate approach to diabetes care. Just as pancreas transplants set the stage for islet transplants, the real value of islet transplants will be to create and build momentum for the development of xenogeneic and stem/precursor cellderived islet beta cell therapy10.wz71 that will then make cell replacement therapy routine and commonplace in diabetes care. Pancreas transplants, and eventually islet transplants, should be in the armamentarium of every transplant center for the treatment of diabetic patients. Likewise, every endocrinologist should consider beta cell replacement in the treatment of patients in whom type 1 diabetes is complicated by hypoglycemia-associated autonomic failurelhnd/or progressive microvascular complications. Continued clinical research on pancreas and islet transplants is needed to identify the most appropriate recipient population, the optimal timing in the course of diabetes, and the most suitable donor tissue and transplant protocol for a given patient. Both pancreas and islet transplants need to be made as economical as possible.77Studies such as those done in pancreas-kidney transplant recipients showing the efficiency in the treatment of complicated diabeteslhre needed in islet recipients as well. Currently, beta cell replacement has a well-defined clinical role for adult patients with incapacitating hypoglycemic unawareness and is also appropriate in children and adults who otherwise need immunosuppression, such as for a kidney transplant. As antirejection strategies become safer with fewer side effects, the indications for pediatric beta cell replacement therapy can be liberalized.

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ACKNOWLEDGMENT We are indebted to Heather Nelson for assistance in preparing the manuscript.

REFERENCES 1. The effect of intensive treatment of diabetes on the development and progression of' long-term complications in insulin-dependent diabetes mellitus. The Diabetes Control and Complications Trial Research Group. N Engl J Med 1993;329:977-986. 2. Adams AB, Shirasugi N, Durham MM, et al: Calcineurin inhibitor-free CD28 blockade-based protocol protects allogeneic islets in nonhuman primates. Diabetes 2002;51: 265-270. 3. Bendel-Stenzel MR, Kashtan CE, Sutherland DER, Chavers BM: Simultaneous pancreas-kidney transplant in two children with hemolytic-uremic symptoms. Pediatr Nephrol 1997;11:485-487. 4. Benedetti E, Dunn T, Massad MG, et al: Successful living related simultaneous pancreas-kidney transplant between identical twins. Transplantation 1999;67:915-918. 5. Benedetti E, Sileri P, Kandaswamy R, et al: Surgical aspects of pancreas transplantation. In Gruessner RW, Sutherland DER (eds): Transplantation of the Pancreas. New York, Springer-Verlag, 2004, pp 111-178. 6. Bloomgarden ZT: American Diabetes k3sociation Postgraduate Course, 1996: treatment and prevention of diabetes. Diabetes Care 1996;19:784-786. 7. Boggi U, Vistoli F, Del Chiaro M, et al: Portal entericdrained solitary pancreas transplantation without surveillance biopsy: Is it safe? Transplant I'roc 2004;36:1090-1092. 8. Boggi U, Vistoli F, Del Chiaro M, et al: A simplified technique for the en bloc procurement of abdominal organs that is suitable for pancreas and small-bowel transplantation. Surgery 2004;135:629-641. 9. Boggi U, Vistoli F, Signori S, et al: A new technique for retroperito~lcalpancreas transplantation with portalenteric drainage. Transplantation 2005;79:1137-1142. 10. Bonner-Weir S, Sharma A: Pancreatic stem cells. J Path01 2002;197:519-526. 11. Bretzel RG, Hering BJ, Federlin KF: Islet cell transplantation in diabetes mellitus-from bench to bedside. Exp Clin Endocrinol Diabetes 2004;103(S11ppl2) :143-159. 12. Calne RY Paratopic segmental pancreas grafting: A technique with portal venous drainage. Lancet 1984;l: 595-597. 13. Calne RY, Rolles K, White DJ, et al: (:yclosporin A initially as the only immunosuppressant in 34 recipients of cadaveric organs: 32 kidneys, 2 pancreases, and 2 livers. Lancet 1979;2:1033-1036. 14. Chatenoud L, Thervet E, Primo J, Bach JF: Anti-CD3 antibody induces long-term remission of overt autoimmunity in nonobese diabetic mice. Proc Natl Acad Sci U S A 1994;91:123-127. 15. Christiansen E, Andersen HB, Rasmussen K, et al: Pancreatic beta-cell function and glucose metabolism in human segmental pancreas and kidney transplantation. Am J Physiol 1993;264(3Pt 1):E441-E449. 16. Cryer PE: Banting lecture. ~ ~ ~ o g l ~ d e The m i a limiting : factor in the management of IDDM. Diabetes 1994;43: 1378-1389. 17. Davalli AM, Ogawa Y, Scaglia L, et al: Function, mass, and replication of porcine and rat islets transplanted into diabetic nude mice. Diabetes 1995;44:104-111.

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18. Douzdjian V, Ferrara D, Silvestri G: Treatment strategies for ins~rlin-dependent diabetics with ESRD: A costeffectiveness decision analysis model. Am J Kidney Dis 1998;31:794802. 19. Dubernard JM, Traeger J, Neyra P, et al: A new method of preparation of segmental pancreatic grafts for transplantation: Trials in dogs and in man. Surgery 1978;84:633-640. 20. Fioretto P, Steffes MW, Sutherland DER, et al: Reversal of lesions of diabetic nephropathy after pancreas transplantation. N Engl J Med 1998;339:69-75. 21. First MR: I~~~rrlutlosuppressive agents and their actions. Transplant Proc 2002;34:1369-1371. 22. First MR, Gerber DA, Hariharan S, et al: Posttransplant diabetes ~ n e l l i t ~ in~kidney s allograft recipients: Incidence, risk factors, arid management. Transplantation 2002;73: 379-386. 222. Fridell ]A, Milgrom M, Henson S, et al: Use of the end-toend anastornotic circular stapler for creation of the duodenoenterostomy for enteric drainage of the pancreas allo$raft. J Am Coil Surg 2004;198:495-497. 23. kliedman MI,, Gold M, Whittaker J, et al: Clinical segmental pancreatic transplantation with ureter-pancreatic duct anastomosis for exocrine drainage. Surgery 1973;74: 171-180. 24. Gores PF, Najarian J S , Stephanian E, et al: Insulin independence in type I diabetes after transplantation of unpurified islets from a single donor using 15-deoxyspergualin. Lancet 1993;341:19-21. 25. Goss JA, Schock AP, Br~~nicardi FC, et al: Achievement of insulin independence in three consecutive type-1 diabetic patients via pancreatic islet transplantation using islets isolated at a remote islet isolation center. Transplantation 2002;74:1761-1766. 26. Gross CR, Iimwattananon C , Matthees BJ: Quality of life after pancreas transplantation: A review. Clin Transplant 1998;12:351-361. 27. Gruessner A(:: Pediatric pancreas transplants in the USA 1988-2000. Pediatr Transplant 2000;4:100. 28. Gruessner AC, S~~therland DER: Pancreas transplant outcomes for United States and non-US cases as reported to the United Network for Organ Sharing and the International Pancreas Transplant Registry as of October 2002. In Cecka JM, Terasaki PI (eds): Clinical Transplants 2002. 1,os Angeles, UCLA Immunogenetics Center, 2003. 29. Gruessner AC, Sutherland DER: Pancreas transplant outcomes for United States (US) and non-US cases as reported to the United Network for Organ Sharing (UNOS) and the International Pancreas Transplant Registry (IPTR) as of May 2003. In Cecka JM, Terasaki PI (eds): Clinical Transplants 2003. Los Angeles, UCLA Immunogenetics Center, 2004. 30. Gruessner AC, Sutherland DER: Pancreas Transplantation Analyses of United States (US) and non-US cases as reported to the United Network for Organ Sharing (UNOS) and the International Pancreas Transplant Registry (IPTR) as of June 2004. In Cecka JM, Terasaki PI (eds): Clinical Transplants 2004. Los Angeles, UCLA Immumogenetics Center, 2005. 31. Gruessner RW, Sutherland DE, Dunn DL,, et al: Transplant options for patients undergoing total pancreatectomy for chronic pancreatitis. J Am Coll Surg 2004;198:559-567. 32. Gruessner RW, Sutherland DE, Gruessner AC: Mortality assessment for pancreas transplants. Am J Transplant 2004; 4:2018-2026. 33. Gruessner RWG, Kendall DM, Drangstveit MB, et al: Simultaneous pancreas-kidney transplantation from live donors. Ann Surg 1997;226:471-482.

34. Gruessner RWG, Manivel DC, Dunn DL, Sutherland DER: Pancreaticoduodenal transplantation with enteric drainage following native total pancreatectomy for chronic pancreatitis: A case report. Pancreas 1991;6:479-488. 35. Hering BJ, Bretzel RG, Hopt UT, et al: New protocol toward prevention of early human islet allograft failure. Transplant Proc 1994;26:570-571. 36. Hering BJ, Kandaswamy R, Ansite JD, et al: Successful single donor islet transplantation in type 1 diabetes. Am J Transplant 2003;3(S11ppI5):296. 37. Hering BJ, Kandaswamy R, Harmon JV, et al: Transplantation of cultured islets from two-layer preserved pancreases in type 1 diabetes with anti-CD3 antibody. Am J Transplant 2004;4:390-401. 38. Hering BJ, Matsumoto I, Sawada T, et al: Impact of twolayer pancreas preservation on islet isolation and transplantation. Transplantation 2002;74:1813-1816. 39. Hering BJ, Ricordi C: Islet transplantation for patients with type I diabetes. Graft 1999;Z:12-27. 40. Hering BJ, Ricordi C, Sutherland DER, Bluestone JA: Islet transplantation: At the forefront of clinical research on immune tolerance. In Nornlan DJ, Suki WN (eds): Primer on Transplantation. Thorofare, NJ, American Society of Transplant Physicians, 2000. 41. Hering BJ, Wijkstrom M, Eckman PM: Islet transplantation. In Gn~essnerRW, Sutherland DER (eds): Transplantation of the Pancreas. New York, Springer-Verlag, 2004. 42. Hiraoka K, Trexler A, Fujioka B, et al: Optimal temperature in pancreas preservation by the two-layer cold storage method before islet isolation. Transplant Proc 2001;33(1-2): 891-892. 43. Jahr H, Hussmann B, Eckhardt T, Bretzel RG: Successful single donor islet allotransplantation in the streptozotocin diabetes rat model. Cell Transplant 2002;11:513-518. 44. Kaufman DB, Baker MS, Chen X, et al: Sequential kidney/islet transplantation using prednisdne-free immunosuppression. Am J Transplant 2002;2:674677. 45. Kaufman DB, Leventhal JR, Koffron AJ, et al: A prospective study of rapid corticosteroid elimination in simultaneous pancreas-kidney transplantation: Comparison of two maintenance imn~unosuppressionprotocols: Tacrolimus/n~ycophenolate mofetil versus tacrolimus/sirolimus. Transplantation 2002;73:169-177. 46. Kelly WD, Lillehei RC, Merkel FK: Allotransplantation of the pancreas and duodenum along with the kidney in diabetic nephropathy. Surgery 1967;61:827-835. 47. Kendall DM, Rooney DP, Smets YF, et al: Pancreas transplantation restores epinephrine response and symptom recognition during hypoglycemia in patients with longstanding type I diabetes and autonomic neuropathy. Diabetes 2000;46:249-257. 48. Lillehei RC, Ruiz JO, Aquino C, Goetz FC: Transplantation of the pancreas. Acta Endocrinol 1976;83(Suppl 205): 303-320. 49. Lillehei RC, Simmons RL, Najarian JS, et al: Pancreaticoduodenal allotransplantation: Experimental and clinical experience. Ann Surg 1970;172:405-436. 50. Maki T, Ichikawa T, Blanco R, Porter J: Long-term abrogation of autoimmune diabetes in nonobese diabetic mice bv immunotherapy with anti-lymphocyte serum. Proc Natl Acad Sci U S A 1992;89:34343438. 51. Markmann JF, Deng S, Huang X, et al: Insulin independence following isolated islet transplantation and single islet infusions. Ann Surg 2003;237:741-749. 52. Marsh CL, Perkins JD, Sutherland DER, et al: Combined hepatic and pancreaticoduodenal procurement for transplantation. Surg Gynecol Obstet 1989;168:254258.

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53. Najarian JS, Sutherland DER, Matas AJ, et al: Human islet transplantation: A preliminary experience. Transplant Proc 1977;9:233-236. 54. Nathan DM: Long-term complications of diabetes mellitus. N Engl J Med 1993;328:1676-1685. 55. Navarro X, Kennedy WR, Aeppli D, Sutherland DER: Neuropathy and mortality in diabetes: Influence of pancreas transplantation. Muscle Nerve 1996;19:10091016. 56. Navarro X, Sutherland DER, Kennedy WR Long-term effects of pancreatic transplantation on diabetic neuropathy. Ann Neurol 1997;42:727-736. 57. Nghiem DD, Corry RJ: Technique of simultaneous pancreaticoduodenal transplantation with urinary drainage of pancreatic secretion. Am J Surg 1987;153:405-406. 58. Philosophe B, Farney AC, Schweitzer EJ, et al: Superiority of portal venous drainage over systemic venous drainage in pancreas transplantation: A retrospective study. Ann Surg 200 1;234:689-696. 59. Pileggi A, Ricordi C, Alessiani M, Inverardi L: Factors influencing islet of Langerhans graft function and monitoring. Clin Chim Acta 2001;310:3-16. 60. Poggioli R, Inverardi I,, Ricordi C: Islet xenotransplantation. Cell Transplant 2002;11:89-94. 61. Rayhill SC, Kirk AD, Odorico JS, et al: Simultaneous pancreas-kidney transplantation at the University of Wisconsin. In Cecka JM, Terasaki PI (eds): Clinical Transplants 1995. Los Angeles, UCLA Tissue Typing Laboratory, 1996. 62. Ricordi C, Tzakis A, Carroll PB, et al: Human islet isolation and allotransplantation in 22 consecutive cases. Transplantation 1992;53:407-414. 63. Robertson RP, Sutherland DE, Kendall DM, et al: Metabolic characterization of long-term successful pancreas transplants in type I diabetes. J Investig Med 1996;44: 549-555. 64. Rosenlof LK, Earnhardt RC, Pruett TL, et al: Pancreas transplantation: An initial experience with systemic and portal drainage of pancreatic allografts. Ann Surg 1992; 215:586-595. 65. Rosenlof LK, Earnhardt RC, Pruett TL, et al: Pancreas transplantation: An initial experience with systemic and portal drainage of pancreatic allografts. Ann Surg 1992; 215:586-595. 66. Ryan EA, Lakey JR, Paty BW, et al: Successful islet transplantation: Continued insulin reserve provides long-term glycemic control. Diabetes 2002;51:2148-2157. 67. Scharp DW, Lacy PE, Santiago JV, et al: Insulin independence after islet transplantation into type I diabetic patient. Diabetes 1990;39:515-518. 68. Secchi A, Socci C, Maffi P, et al: Islet transplantation in IDDM patients. Diabetologia 1997;40:225-231. 69. Shapiro AM, Lakey JR, Ryan EA, et al: Islet transplantation in seven patients with type 1 diabetes mellitus using a glucocorticoid-free immunosuppressive regimen [see comments]. N Engl J Med 2000;343:230-238. 70. Sollinger HW, Cook K, Kamps D: Clinical and experimental experience with pancreaticocystostomy for exocrine pancreatic drainage in pancreas transplantation. Transplant Proc 1984;16:749-751. 71. Soria B, Roche E, Berna G, et al: Insulin-secreting cells derived from embryonic stem cells normalize glycemia in streptozotocin-induced diabetic mice. Diabetes 2000;49: 157-162. 72. Starzl TE, Iwatsuki S, Shaw BW Jr, et al: Pancreaticoduodenal transplantation in humans. Surg Gynecol Obstet 1984; 159:265-272.

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73. Starzl TE, Todo S, FungJ, et al: FK 506 for liver, kidney, and pancreas transplantation. Lancet 1989;2:1000-1004. 74. Stern RC, Mayes JT, Weber FL Jr, et al: Restoration of exocrine pancreatic function following pancreas-liver-kidney transplantation in a cystic fibrosis patient. Clin Transplant 1994;8:1-4. 75. Stock PG, Bluestone JA: Beta-cell replacement for type I diabetes. Annu Rev Med 2004;55:133-156. 76. Stratta RJ: The economics of pancreas transplantation. Graft 2000;3:19. 77. Stratta RJ, Cushing KA, Frisbie K, Miller SA: Analysis of hospital charges after simultaneous pancreas-kidney transplantation in the era of managed care. Transplantation 1997;64:287-292. 78. Stratta RJ, Shokouh-Amiri MH, Egidi MF, et al: A prospective comparison of simultaneous kidney-pancreas transplantation with systemicenteric versus portal-enteric drainage. Ann Surg 2001;233:740-751. 79. Sutherland DE, Gruessner RW, Dunn DI,, et al: Lessons learned from more than 1,000 pancreas transplants at a single institution. Ann Surg 2001;233:463-501. 80. Sutherland DER: International human pancreas and islet transplant registry. Transplant Proc 1980;12(No 4, Suppl 2) :229-236. 81. Sutherland DER: Pancreas and islet transplant population. In Gruessner RWG, Sutherland DER (eds): Transplantation of the Pancreas. New York, Springer-Verlag, 2004. 82. Sutherland DER, Goetz FC, Najarian JS: Pancreas transplants from living related donors. Transplantation 1984;38: 625-633. 83. Sutherland DER, Gruessner RG, Jie T, et al: Pancreatic islet auto-transplantation for chronic pancreatitis. Clin Transplant 2004; 18(Suppl 13):17-18. 84. Sutherland DER, Gruessner RWG: History of pancreas transplantation. In Gruessner RWG, Sutherland DER (eds): Transplantation of the Pancreas. New York, Springer-Verlag, 2004. 85. Sutherland DER, Matas AJ, Najarian JS: Pancreatic islet cell transplantation. Surg Clin North Am 1978;58:365-382. 86. Sutherland DER, Morel P, Gruessner RWG: Transplantation of two diabetic patients with one divided cadaver donor pancreas. Transplant Proc 1990;22:585. 87. TaniokaY, Sutherland DER, KurodaY, et al: Excellence of the two-layer method (University of Wisconsin solution/perfluorochemical) in pancreas preservation before islet isolation. Surgery 1997;122:435-442. 88. Tyden G, Bolinder J, Solders G, et al: Improved survival in patients with insulin-dependent diabetes mellitus and end-stage diabetic nephropathy 10 years after combined pancreas and kidney transplantation. Transplantation 1999;67:645-648. 89. Tzakis A, Ricordi C, Alejandro R, et al: Pancreatic islet transplantation after upper abdominal exenteration and liver replacement. Lancet 1990;336:402-405. 90. Venstrom JM, McBride MA, Rother KI, et al: Survival after pancreas transplantation in patients with diabetes and preserved kidney function. JAMA 2003;290:2817-2823. 91. Wahoff DC, Papalois B, Najarian JS, et al: Islet autotransplantation after total pancreatectomy in a child. J Pediatr Surg 1996;31:1-6. 92. Wahoff DC, Papalois B, Najarian JS, et al: Autologous islet transplantation to prevent diabetes after pancreatic resection. Ann Surg 1995;222:562-579. 93. Warnock GL, Kneteman NM, Ryan E, et al: Normoglycaemia after transplantation of freshly isolated and cryopreserved pancreatic islet5 in type 1 (insulin-dependent) diabetes mellitus. Diabetologia 1991;34:55-58.

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94. White SA,James RF, Swift SM, et al: Human islet cell transplantation-future prospects. Diabet Med 2001;18:78-103. 95. Wijkstrom M, Kenyon NS, Kirchhof N, et al: Islet allograft survival in nonhuman primates immunosuppressed with basiliximab, RAD, and FTY720.Transplantation 2004;77: 827-835.

96. Woodle ES, Xu D, Zivin RA, et al: Phase I trial of a humanized, Fc receptor nonbinding OKT3 antibody, huOKT3gammal (Ala-Ala), in the treatment of acute renal allograft rejection. Transplantation 1999;68:608-616. 97. Zehrer CL, Gross CR: Quality of life of pancreas transplant recipients. Diabetologia 1991;34 (Suppl 1):S145-S149.

Liver Transplantation Bob H. Saggi, Douglas G. Farmer, and Ronald W. Busuttil

The treatment of liver disease in children with transplantation has its roots in the origin of liver transplantation itself, with the initial cases performed by Thomas E. Starzl on two children in 1963 and 1968.19Although the initial results were disappointing, over the ensuing 2 decades, liver transplantation developed into the standard therapy for end-stage liver disease (ESLD), certain malignancies of the liver and biliary tract, acute liver failure, and many metabolic derangements. The National Institutes of Health Development Conference designated it as such in 1983, and the National Organ Transplantation Act created a nationally regulated system of organ allocation in 1987. The United Network for Organ Sharing (UNOS) was thus created and currently regulates the field by a peer review process. In 2003, more than 5600 liver transplant procedures were performed, including 546 in pediatric patients.*' This number of transplant procedures performed has been relatively stable since the mid 1990s, but there has been a shift to utilization of an increasing number of "partial" liver grafts from cadaveric and living donors. The pediatric population offers unique challenges

.

Distribution of pediatric liver transplants by age. (Data from w . u n o s . o r g ) -

A

due to size, perhaps enhanced immune responsiveness, and a relative organ scarcity. Although nearly two thirds of the pediatric recipients of liver transplants are younger than 5 years of age, donors younger than the age of 5 comprise only 26% of the pediatric cadaveric donors (Fig. 45-I).*]As a consequence, achieving success in this patient population requires technical perfection, both from the standpoint of obtaining a suitable graft and performing a meticulous transplant operation. With reduction in transplant waiting time and improvements in immunosuppression, surgical technique, and long-term posttransplantation care, survival has been significantly improved and now approaches 90% at 1 year and 80% at 5 years, with many children surviving into adolescence and adulthood with a good quality of life."n this chapter, we review the major indications for liver transplantation in children, the basic pathophysiology and clinical presentation of liver failure, operative strategies with emphasis on the unique surgical options available to children, postoperative management with emphasis on management of surgical complications, and outcome analysis.

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INDICATIONS Liver transplantation is currently indicated for children with ESLD due to cholestatic and noncholestatic causes of cirrhosis, acute hepatic failure, some metabolic liver diseases, select tumors, and a variety of miscellaneous indications (Fig. 45-2). The general indication for liver transplantation in children is liver disease that limits long-term survival or quality of life or markedly impairs normal growth and development. Cirrhosis alone is not an indication for transplantation because many of these patients can be medically managed for a prolonged period before decompensation. In acute liver failure, the development of clear symptoms such as refractory coagulopathy, acidosis, and cerebral edema that correlate with a poor prognosis for spontaneous recovery of liver function is an indication for transplantation. Otherwise, medical support in those patients with a better prognosis is provided until liver function returns to normal.5 With long-standing cirrhosis, the development of a constellation of symptoms and signs that represent decompensation of hepatocellular function or portal hypertension heralds a need for transplantation. These include progressivejaundice, coagulopathy, protein-calorie malnutrition and growth retardation, impaired cognitive development, encephalopathy, hypersplenism, variceal hemorrhage, and advanced or refractory ascites. The majority of patients undergoing transplantation in this population are deeply jaundiced owing to secondary or primary biliary cirrhosis from long-standing intrahepatic and/or extrahepatic biliary obstruction. On physical examination, these patients often have muscle wasting, an enlarged spleen, a hard, palpable liver, abdominal distention from ascites, and peripheral edema. With decompensation, long-term survival without liver transplantation is limited, and referral for transplantation must be made before decompensation.33'2

Cholestatic Liver Disorders The most common indications for liver transplantation are the cholestatic liver disorders, with the most common

being biliary atresia. This group accounts for roughly 50% of the transplants performed on children in 2003, and biliary atresia accounts for 70% of this cholestatic group (see Fig. 45-2) .21 The management of biliary atresia rests on early diagnosis, using surgical exploration with biopsy as the central confirmatory test in most cases. The diagnostic workup is detailed elsewhere in this textbook. Portoenterostomy is the preferred treatment if diagnosis precedes the development of cirrhosis, usually before 3 months of age, although long-term results from portoenterostomy are optimal if it is done before 8 weeks.22 This procedure is essential for slowing, and in some cases arresting, the progression of liver disease to cirrhosis and portal hypertension. Unfortunately, despite effective biliary drainage, more than 70% of patients will go on to develop ESLD by the age of 5 years and require transplantation.4.2' However, in many cases, portoenterostomy allows reasonable growth and development so that transplantation is forestalled until the child is older and larger. Primary portoenterostomy performed late in the course of biliary atresia and re-exploration for failing biliary drainage are usually unsuccessful and only complicate transplantation outcomes. Instead, once a portoenterostomy has failed, patients should be evaluated for liver transplantation. Liver transplantation is indicated when the diagnosis is made in infants older than 3 months of age, when ESLD is clearly present at any age, or after a portoenterostomy failure. Patients with biliary atresia should be managed by a pediatric hepatologist experienced in the nuances of liver transplantation to ensure early transplantation is pursued when signs of liver decompensation are observed. Other uncommon causes of cholestatic liver injury and cirrhosis include familial paucity of intrahepatic bile ducts, which exists in syndromic (Alagille's syndrome) and nonsyndromic forms; familial cholestatic syndromes; primary or secondary sclerosing cholangitis; and uncorrectable choledochal cyst disease, including Caroli's disease. The cystic diseases have a component of uncorrectable extrahepatic obstruction whereas the others are the result of malformation or destruction of intrahepatic bile ducts and/or arterial systems. All of these conditions have in common a variable and unpredictable progression to

Biliary atresia

34%

7

-

/'

.

.

a

Noncholestatic cirrhosis 9% Indications for pediatric liver transplantation. (Data obtained from www.unos.org, based on 2003 transplants.)

CHAPTER

advanced fibrosis, cirrhosis, and portal hypertension. These patients typically present with progressive jaundice at an older age than patients with biliary atresia. Although their management does not entail a portoenterostomy, the indications for transplantation in these patients follow the same rationale as that for biliary atresia.

45

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733

from liver transplantation and prevents progression of extrahepatic disease. In some patients, simultaneous or sequential dual-organ transplantation may be necessary (e.g., lung, kidney, heart).

Tumors Noncholestatic Cirrhosis This is an uncommon indication for liver replacement in children, accounting for less than 10% of all procedures performed in 2003 (see Fig. 45-2)." These children usually present later in life than the cholestatic disorders. Causes of cirrhosis and ESLD in these patients include chronic autoimmune hepatitis, neonatal hepatitis, chronic viral (B or C) hepatitis, and cryptogenic cirrhosis.

Acute Liver Failure Fulminant hepatic failure is usually defined as the onset of encephalopathy within 28 days after the onset ofjaundice in a patient with acute liver failure without evidence of chronic liver disease. The hallmarks of acute liver failure include profound coagulopathy, acidosis, hypoglycemia, and progressive hyperbilirubinemia. These patients can develop acute renal failure, multiorgan failure syndrome, or cerebral edema progressing to herniation. Early referral is essential to avoid progression to a condition that contraindicates transplantation. A number of criteria to determine the need for transplantation have been devised in European centers, where these patients are managed in a highly structured and centralized manner.15 The most common known cause in children is viral hepatitis, followed by acetaminophen and other drug toxicities and Wilson's disease. However, in nearly two thirds of patients a cause cannot be identified. Liver transplantation is the only acceptable therapy in patients who meet the criteria of fulminant hepatic failure, and early referral of all patients with acute liver failure is essential."

Metabolic Liver Disease These disorders have in common an enzyme deficiency or some other defect in hepatocellular function. This impairment can result in progressive fibrosis or cirrhosis (e.g., cystic fibrosis, chronic Wilson's disease, and neonatal iron storage disease) with a typical presentation of ESLD. In other cases the liver is structurally normal but harmful byproducts of metabolism accumulate to cause neurologc injury (e.g., Crigler-Najar syndrome, ornithine transcarbamylase deficiency, and Wilson's disease), cardiovascular disease (e.g., familial hypercholesterolemia), or renal injury (familial hyperoxaluria). Some disorders are associated with the development of malignancies (e.g., tyrosinemia), and transplantation should be considered preemptively. Transplant evaluation of all patients with known metabolic disorders of the liver involves a thorough evaluation of extrahepatic organ function. This will ensure transplantation of only those patients who can benefit

The most common liver malignancy in children is hepatoblastoma.~6 Although sporadic cases have been reported, hepatocellular carcinoma is primarily seen in older children with viral hepatitis, tyrosinemia, or in association with cirrhosis from other causes. Nonmetastatic malignancies in pediatric patients are managed by surgical resection unless tumor size and/or location preclude resection. The benefit of neoadjuvant and/or adjuvant chemotherapy and rarely irradiation for hepatoblastoma has been well documented, but there is no well-established role for it in hepatocellular carcinoma.17.20 Benefit may be derived from preoperative transarterial chemoembolization and/or radiofrequency ablation.' If the lesion is unresectable, transplantation can be considered after excluding extrahepatic disease.14 The long-term survival after liver transplantation for hepatoblastoma is approximately 50%, whereas outcomes from hepatocellular carcinoma are not nearly as g ~ o d . ~The ~ , major '~ issue that remains to be resolved is whether transplantation should be attempted for large hepatoblastomas primarily or as a salvage after recurrence after resection. Data from Europe suggest a worse outcome when liver transplantation is performed as a salvage procedure. The most common benign tumor of the liver is hemangioendothelioma; and although the vast majority regress with growth and medical therapy, occasionally progression of heart failure or mass effect warrants transplantation.'"

Miscellaneous Conditions Other conditions include diagnoses such as Budd-Chiari syndrome, trauma, and biliary cirrhosis secondary to intestinal failure and long-term use of total parenteral nutrition, which is detailed in Chapter 46.

ORGAN ALLOCATION AND PRETRANSPLANT CARE Patients who have evidence of ESLD are candidates for liver transplantation. However, the small size of the pediatric patient combined with a nationwide shortage of organs relative to patients on a waiting list makes achieving transplantation in a timely fashion problematic. In 2003, there were 546 pediatric liver transplants performed. In that same year, there were 800 pediatric-aged cadaveric donors. The problem and discreparrcy is particularly evident in the younger-than-age-6-yearcategory in which there were 354 liver recipients but only 207 donors. Another problem is of course timing: at the time a pediatric donor is available, there is not necessarily a sizematched pediatric recipient available. Compounding this problem is the fact that adults older than age 18 years

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can be offered pediatric donors and therefore contribute to the pediatric donor problem (see Fig. 45-1) .21 This creates a relative shortage of organs that necessitates a system that allocates these scarce organs to those who will derive the most benefit. Since 2002, the Pediatric End-stage Liver Disease (PELD) score was implemented to allocate organs based on this "sickest first" paradigm.'? The PELD score consists of five variables: International Normalized Ratio, total serum bilirubin concentration, serum albumin level, growth retardation (= 2 standard deviations below the median height or weight for age), and young age (< 1 or 1 to 2 years). Status I is used to designate patients with fulminant hepatic failure, primary graft nonfunction after transplantation, early hepatic artery thrombosis, and miscellaneous acute conditions. Unlike adults, pediatric ESLD patients requiring care in an intensive care unit for any reason are listed as status I because their mortality is high despite minimal change in PELD score. In an effort to ameliorate the shortage of potential organs, the liver of all donors 18 years of age and younger is preferentially allocated to pediatric recipients. This combined with the widespread use of split-liver transplantation (see later) has markedly reduced waiting times and positively impacted waiting list m~rtality.~-Z~

DONOR PROCUREMENTAND HEPATOBILIARY ANATOMY Hepatobiliary Anatomy The performance of a donor hepatectomy or transplant operation requires a thorough understanding of foregut anatomy. In addition, a very detailed understanding of this anatomy is essential to the field of segmental liver transplantation and has impacted hepatobiliary surgery. The blood supply to the liver is based on a highly variable hepatic arterial and portal venous system. Venous drainage is via the right, mid, and left hepatic veins that join the inferior vena cava, which traverses the dorsal surface of the liver (the retrohepatic vena cava). The liver is composed of the major right and left lobes, which are separated by external landmarks and further subdivided into the right anterior and posterior and left medial and lateral segments. This nomenclature is still used to describe major anatomic liver resections. However, through the elegant anatomic techniques of the pioneering surgical anatomist Couinaud, hepatic anatomy was found to be much more intricate (Fig. 45-3). The "Couinaud nomenclature" describes nine hepatic segments based on portal vein branching in relationship to the transverse plane (a cross-sectional plane located at "midpoints" of the hepatic veins) and the longitudinal planes of the individual hepatic veins (see Fig. 45-3).Each of the segments is supplied by an independent portal venous and hepatic arterial branch and drained by an independent biliary radicle. The biliary tree is second only to the arterial system in its variability. The hepatic venous drainage is intersegmental. A more detailed review of the anatomy of the liver is available elsewhere and its discussion is beyond the scope of this chapter.

,

-

a

Segmental liver anatomy. The division of the liver

into independently vascularized and drained segments is based on the parallel bifurcation of the portal vein and hepatic artery.

THE DONOR OPERATION The use of organs from cadaveric donors in pediatric liver transplantation involves selecting an appropriate quality and size-matched donor, organizing an experienced transplant harvest team, and performing a precise technical operation that recognizes arterial anatomic variants and allows for multiorgan procurement. The advent of segmental liver transplantation has expanded the acceptable donor age to approximately 40 years. Preharvest donor management should focus on maintenance of hemodynamic stability with adequate but not excessive volume loading, minimizing the use of vasopressors, optimizing oxygenation without excessive use of positive end-expiratory pressure (PEEP), and correcting hypernatremia that results from diabetes insipidus. In the stable donor, once these goals are achieved, the procurement operation can be performed. In the properly selected unstable donor, unnecessary delays are to be avoided because expedient hypothermic perfusion and cold storage only help minimize the ongoing organ ischemia. The donor operation begins with midline laparotomy and median sternotomy for wide exposure. The abdominal great vessels are exposed by a medial visceral rotation of the right colon and small intestine, and the aorta and inferior mesenteric vein are cannulated. The liver quality is assessed, and the biliary tree is flushed via the gallbladder. After full systemic heparinization, the supraceliac aorta is cross-clamped and the intrapericardial inferior vena cava is incised to exsanguinate the donor. Then cold-organ perfusion is initiated through the previously placed cannulas and the abdominal cavity is immersed in ice in an attempt to achieve a liver core temperature of 4°C. University of Wisconsin (UW) solution has been

CHAPTER

used as the standard solution in the United States since 1987when it was developed by Belzer and Southhard. This solution extended the limit of preservation to as long as 12 to 18 hours, after which the incidence of primary graft failure increases substantially. However, the acceptable preservation time depends on numerous donor and recipient variables and should still be minimized when possible. This is especially important in instances of reduced size or split-liver transplantation. The UW solution is a hyperkalemic, hyperosmolar solution that prevents cellular swelling, maintains stable transmembrane electrical gradients upon reperfusion by preventing efflux of intracellular potassium during storage, and contains a variety of oxygen- free radical scavengers. Recently, some centers have employed histidine-tryptophan-ketoglutarate solution because of its low potassium content and viscosity.? However, this solution has not been thoroughly evaluated using long-term, randomized controlled trials. Until these data are available, UW solution remains the gold standard for organ preservation. Once the donor organ is procured, the harvest team typically transports the liver graft to the transplant center and prepares it for engraftment by a separate recipient team.

45

Liver Transplantation

735

, Cadaveric in-situ split liver procedure. The liver is separatedjust to the left of the umbilical fissure into a right trisegment (RTS) graft and a left-lateral segment (LLS) graft. -

A

THE LIVER TRANSPLANTATION OPERATION SEGMENTAL LIVER TRANSPLANTATION: LIVING DONOR, REDUCED SIZE AND SPLIT The shortage of pediatric organs coupled with a significant wait-list death rate has driven the development of sources. Three alternatives t o use of a alternative orcan " whole-organ graft are available: living donor, reduced size, and split liver grafts."7,*4,*5Living donor transplantation was developed as an alternative to scarce whole-organ grafts and typically utilizes a segment 2 and 3 (left-lateral segment [LLS]) graft. Because of the small but real risk of safety in a healthy donor, reduced size transplantation was simultaneously developed as an alternative and involves resecting the LLS graft before or after cold-organ perfusion and discarding the remaining liver. Obviously, this benefits the pediatric recipient but wastes an organ that could be utilized by an adult recipient. Splitting the whole organ into a right trisegment and LLS graft to utilize in an adult and pediatric recipient, respectively, was first described by Pichlmayr in Hanover, Germany, in 1988. This can be-done eithkr before cold-organ perfusion (insitu technique) (Fig. 45-4) or after cold-organ perfusion and removal of the liver from the donor (ex-vivo technique) .*4 This technique provides a suitable graft for the pediatric population without worsening the already severe organ shortage in the adult population. Although the initial results were discouraging, with increased experience and grafts are nearliequa] to the survival rates of whole-organ and living-donor transplantation, although the risk of vascular and biliary complications is somewhat higher.8.2Ut the University of California in Los Angeles ( m u ) ,we are only performing living donor transplantation when a whole or split graft is not available in a timely fashion or for special indications. There has been a marked reduction in transplant wait time since the routine use of segmental grafts following this ~trategy.~,2~

The performance of the whole-organ cadaveric liver transplantation procedure has changed little over the past 2 decades. Whereas there are tremendous individual and institutional differences in the subtleties of using certain techniques, the basic steps in the procedure remain the same. What follows is a description of how a liver transplantation procedure is generally performed at UCLA today and has been applied in over 800 pediatric cases.13 The procedure can be roughly divided into four major phases, each with its own anatomic and physiologic challenges: hepatectomy phase, anhepatic phase with engraftment, reperfusion with arterialization, and biliary reconstruction. Perhaps the most challenging step during liver transplantation is the hepatectomy. Coagulopathy, portal hypertension, and poor liver and renal function create a surgical environment in which continuous bleeding is possible. During this phase, the anesthesiologist plays a key role in maintaining volume, rapid transfusion, correcting coagulopathy and fibrinolysis, and maintaining body temperature. The goal of this phase is to devascularize the liver by ligating and dividing the hepatic artery and portal vein as well as to mobilize the suprahepatic and infrahepatic vena cava to enable removal. These goals are achieved while leaving in the recipient adequate lengths of each vessel for later implantation of the donor graft. In the majority of pediatric liver transplant operations, the retrohepatic vena cava is retained as the liver is dissected off the vena cava by dividing the tributaries from the right and caudate lobes, and often only partial occlusion of the vena cava is necessary. Meticulous but expedient surgical technique is essential during the hepatectomy in ensuring optimal patient outcome. During the anhepatic phase, the anesthesiologist must support certain aspects of hepatic function to prevent or treat acidemia, hypothermia, coagulopathy, and, occasionally, fibrinolysis. In addition, they must ensure adequate

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Whole-organ engraftment. Both the standard orthotopic and the "piggyback" techniques are depicted

circulating volume and maintain hemodynamic stability. In children, veno-venous bypass is rarely used. While the patient is anhepatic the liver graft is removed from hypothermic storage and engrafted. The insertion of the graft begins with the suprahepatic vena caval, followed by the infrahepatic vena caval and the portal anastomoses. If the retrohepatic cava was retained, the "piggyback technique is used, in which the suprahepatic vena cava of the graft is sewn to the cloacae created from the confluence of the recipient hepatic veins and the donor infrahepatic vena cava is ligated (Fig. 45-5). Before reperfusion, the liver is flushed with a cold colloid and albumin solution via the donor portal vein to reduce the risk of potential reperfusion-associated complications. Reperfusion is then undertaken in a controlled manner. Communication between the surgical and anesthesia teams is essential to allow the anesthesiologist time to institute preparative and preventive measures. Reperfusion is undertaken by first removing the suprahepatic vena cava clamp, then the infrahepatic vena cava clamp, and lastly the portal venous clamp. As blood is reintroduced into the liver allograft and allowed to drain into the right atria, many serious and potentially life-threatening complications can develop. The major challenges encountered by the anesthesiologist at this point are life-threatening hyperkalemia, acidosis, arrhythmias, and hemodynamic instability with or without surgical or coagulopathic bleeding. A factor that contributes is the return of cold, acidotic, and hyperkalemic blood directly into the right atrium. It is at this point that maintenance of physiologic stability by the surgeon and anesthesiologist in the preceding phases, the preoperative state of the recipient, and the intrinsic quality of the graft converge to determine early graft function as well as the course of the remainder of the operation. Without a doubt, this is one of the most hazardous portions of the liver transplant procedure. The hepatic arterial anastomosis is then performed. In general arterial inflow is obtained from one of the branches of the celiac trunk. However, in some instances, inflow from these vessels is not adequate, necessitating

the use of aortic conduits. A conduit can be placed either on the supraceliac or infrarenal aorta. In some cases, when the arteries are of very small caliber (<3 mm), the arterial anastomosis is performed before reperfusion. The biliary tree is then reconstructed by choledochocholedochostomy or by Roux-en-Y choledochojejunostomy, the latter being more common in small children and used exclusively in partial liver grafts because of the size of the donor duct (see Fig. 45-5). After ensuring sufficient hemostasis, drains are placed and the abdominal cavity is closed. The patient is then transferred directly to the intensive care unit. Segmental transplantation, using split, reduced-sized, or living donor grafts, involves variations in the manner in which the anastomoses are performed, but the general steps are similar (Fig. 45-6).

Left-lateral segment engraftment. NC, inferior vena cava; PHA, proper hepatic artery; SA, splenic artery; CA, celiac artery; A, aorta; PV, portal vein. (Reprinted with permission from Goss J, Yersiz H, Shackleton CR, et al: In situ splitting of the cadaveric liver for transplantation. Transplantation 1997;64:871-877.)

CHAPTER

POST-TRANSPLANTATION CARE The early and long-term postoperative care of the liver transplant recipient is almost as important as the performance of the operation in ensuring optimal outcomes. The immediate postoperative care is aimed at assessing graft function, providing supportive care for the recipient, and early detection of complications. Graft function can be assessed in many ways. Physiologic and clinical assessment can be done almost immediately, with a warm, arousable, and hemodynamically stable patient with a liver producing "golden-brown" bile (in the infrequent case in which a biliary drainage tube is placed) being the hallmark of a functional graft. Graft function is then confirmed biochemically by evidence of synthetic and metabolic function (e.g., correcting prothrombin time, reversal of acidemia). Although the degree of preservation injury, as measured by liver enzyme levels, does not linearly correlate with graft function, grafts with severe injury are more likely to exhibit delayed function or nonfunction. Failure of a graft without vascular compromise (primary nonfunction) requires retransplantation in almost all cases, with the outcome directly related to the time to retransplantation. The incidence of primary nonfunction in pediatric patients is 5% to 10%.6,10,25

TECHNICAL COMPLICATIONS Technical complications can be divided into vascular, biliary, and general surgical complications. In the early postoperative period, infectious and general surgical complications of liver transplantation today are similar to those that occur after any major abdominal operation. However, the incidence of fungal infection is higher and the incidence of bowel perforation in pediatric recipients is as high as 19% in some series.Z3

Vascular Complications Major vascular complications include hepatic artery thrombosis, portal vein thrombosis, and vena caval thrombosis or stenosis. Intravenous low-dose unfractionated heparin with or without low-molecular-weight dextran is routinely used for prophylaxis to prevent vascular thromboses. Duplex ultrasonography and computed tomography or conventional angiography are accepted means of diagnosis. Hepatic artery thrombosis is the most common vascular complication, with an incidence that varies from 5% to 18% depending on patient age and Early vascular complications are usutype of graft."l0~2~.2~ ally technical in nature, whereas immunologic and infectious (e.g., cytomegalovirus) causes have been ascribed to those occurring months after transplantation. Hepatic artery thrombosis occurring in the first week after liver transplantation is commonly associated with graft nonfunction and biliary necrosis or leak, whereas those instances occurring later do not necessarily affect graft function immediately but can produce biliary complications. These include intrahepatic biliary abscesses, biliary anastomotic stricture, and sclerosing cholangitis with

45

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737

sepsis, all of which lead to significant morbidity. If diagnosed early, some patients can be managed by thrombectomy and surgical revision. However, most patients with early hepatic artery thrombosis require urgent retransplantation. Late hepatic artery thrombosis with preserved graft function can be managed by radiologic interventional techniques, and the patient can undergo retransplantation remote from the time of the initial transplant procedure. Thrombosis of the portal vein occurs in 2% to 4% of pediatric liver transplant procedures and is usually associated with loss of the graft. Prompt retransplantation is required for patient salvage. Late portal vein thrombosis usually presents as recurrent variceal bleeding or ascites and can be managed medically, endoscopically, or surgically with either shunting or retransplantation. Vena caval or hepatic vein thrombosis or stenosis occurs in 3% to 6% of pediatric liver transplant patients and is usually best managed with balloon dilation in an interventional radiology unit.6,10,23,25

Biliary Complications Biliary complications that are not associated with hepatic artery thrombosis occur in 3% to 20% of patients depending on the type of graft and whether a choledochojejunostomy was employed. These usually result from technical errors, but occasionally warm ischemia or immunologic and infectious factors can be implicated (e.g., cytomegalovirus). Diagnosis is achieved by cholangiography, and treatment can be by endoscopic or radiologic intervention or by surgical r e v i ~ i o n . ~ , l ~ , 2 ~ , 2 ~

IMMUNOSUPPRESSIVETHERAPY AND REJECTION Immunosuppression for liver transplantation in the modern era rests on a class of drugs known as calcineurin inhibitors (CNI), the prototype of which is cyclosporine (Table 45-1). Cyclosporine, especially its microemulsion formulation that allows better bioavailability and more consistent therapeutic levels, revolutionized organ transplantation by reducing the incidence of rejection in all solid organs. The second-generation CNI tacrolimus was first used clinically in 1990. The greater potency of tacrolimus allowed for a further reduction in the early incidence of rejection after liver transplantation while also allowing the earlier weaning of corticosteroid therapy. Initial reports of a higher incidence of opportunistic infections and post-transplant lymphoproliferative disorder have been refuted by modern data. Currently, most liver transplantation centers utilize a tacrolimus-based regimen, combined with corticosteroid therapy with or without adjunctive agents. Cyclosporine and tacrolimus share certain acute and long-term side effects while having some that are unique to each agent. The most important of these is nephrotoxicity, which occurs in an acute variety from vasoconstriction of the afferent renal arterioles and is reversible, as well as a more chronic variety marked by tubular atrophy, interstitial fibrosis, and glomerulosclerosis. The chronic variety is variably reversible depending on the degree of disease. To minimize acute toxicity and to

-

Name

Mechanism of Action

Principal Use

Common Toxicities

Calcineurin inhibitors (CNI) Cyclosporine Tacrolimus

Exact and complete mechanism unknown. lnhibits 11-2 and other cytokine gene transcription, thus preventing T-helper cell expansion.

lnduction and maintenance of ~mmunosuppression long-term. Tacrolimus is the only agent approved for monotherapy, whereas cyclosporine must generally be used with another agent long term.

Glucocorticoids Methylprednisolone Prednisone Mycophenolate mofetil

Diffuse action on immune system by its anti-inflammatory properties, especially inhibition of 11-1 Purine antimetabolite, semi-selective for salvage pathway present, primarily used in lymphocytes lnhibits cell cycle progression in stimulated cells, thus preventing clonal expansion of stimulated B and T cells

lnduction of immunosuppression and maintenance. May be weaned off long-term in some patients.

Shared: nephrotoxlclty, hypertension, hyperglycemla, neurotoxlclty (se~zures,myoclonus, essential tremors) Cyclosporine: hirsutism, gingival hyperplasia, more diabetes Tacrolimus: diarrhea, anorexia, more neurotoxicity, more hypertension Hyperlipidemia, osteopenia, hypertension, diabetes, impaired wound healing, growth retardation, cushingoid features, striae, acne Myelosuppression, diarrhea, anorexia, nausea, vomiting, gastrointestinal mucosal ulceration?

Mammalian target of rapamycin inhibitors Rapamycin RAD OKT-3 monoclonal antibody

Antilymphocyte globulin (Thymoglobulin) 11-2 receptor antagonists Basiliximab Daclizumab

Clonal deletion of (CD-3+) T cells

Exact and complete mechanism unknown but produces central and peripheral deletion of lymphoid cells Competitive inhibition of 11-2 receptors

Used as an adjunctive agent to reduce the dose of CNI or corticosteroid Unclear; use in pediatric patients preliminary. May be useful in minimizing CNI dose when toxicity exists or in refractory or chronic allograft rejection Severe or refractory acute allograft rejection

Severe or refractory acute allograft rejection

lnduction of immunosuppression as an adjunct to CNI. Used to minimize other immunosuppression (CNI, corticosteroids)

Hyperlipidemia, impaired wound healing, pneumonitis, oral ulceration

Systemic inflammatory response syndrome (SIRS) and other infusional reactions, increased risk of viral infections and post-transplant lymphoproliferative disorder lncreased risk of viral infections and post-transplant lymphoproliferative disorder, lower incidence of infusional reactions than OKT-3, thrombocytopenia lncreased risk of viral infections, possible post-transplant lymphoproliferative disorder, rare infusional reactions

CHAPTER

allow lower early CNI levels, especially with pre-transplant renal insufficiency, a purine antimetabolite mycophenolate mofetil is sometimes used as an adjunctive agent (see Table 45-1). The newest class of immunosuppressive agents are the inhibitors of the mammalian target of rapamycin, the prototype of which is sirolimus. This agent has been used sparingly in pediatric liver transplantation, and only preliminary data regarding its efficacy are available. Although this drug has no nephrotoxicity, it is associated with other long-term sequelae, such as hypercholesterolemia. At present there are no perfect immunosuppressive agents available (i.e., one with minimal side effects). Acute rejection is common in pediatric liver transplantation, with the peak incidence being within the first 6 months, and 30% to 50% of patients experience at It~is, 2less j common after the first least one e p i ~ o d e . ~ . ~ post-transplantation year, occurring in less than 10% of cases. Diagnosis of acute rejection is suspected when elevated aspartate or alanine transaminase levels or elevated alkaline phosphatase levels and gamma-glutamyl transferase levels are observed. Acute rejection is an alloantigen specific, T cell-mediated inflammatory process that targets vascular endothelium and biliary epithelium but not hepatocytes. This is related to the greater expression of donor human leukocyte antigens on the former cell types. The histologic hallmark of acute rejection is a mixed inflammatory cell infiltrate (polymorphonuclear cells, lymphocytes, and eosinophils) in the portal triad with evidence of endothelitis and/or biliary epithelial injury. Rejection is graded as mild, moderate, or severe depending on the proportion of involved portal triads, the degree of infiltrate and injury, and the presence of central vein endothelitis, which is a sign of severe acute rejection. Treatment of acute rejection is centered on a high-dose methylprednisolone bolus, but unresponsive cases may require use of antibody therapy (OKT-3, ATG; see Table 45-1). Acute rejection does not influence long-term graft survival in adults or children unless it occurs in multiple Acute rejection or corticosteroid refractory epis~des.~,Y accounts for less than 3% of overall patient and graft loss. However, treatment of acute rejection is an important risk factor for the development of cytomegalovirus and Epstein-Barr virus infections in children. The latter is a risk factor for the development of post-transplant lymphoproliferative disorder. Therefore, a balance between adequate immunosuppression to prevent acute rejection and overimmunosuppression to avoid toxicity is necessary. Currently, long-term morbidity from immunosuppressive drug therapy is the major challenge facing long-term survival and quality of life in the pediatric solid organ transplantation population. Chronic rejection is a common cause of late graft loss in children, whereas disease recurrence is uncommon. Chronic rejection is not entirely alloantigen driven and may be due to a number of factors that share a final common pathway of graft injury. Its hallmark is the intrahepatic loss of bile ducts, which has been termed vanishing bile duct syndrome owing to this histologic finding noted on biopsy. Rejection is suspected by the presence of progressive jaundice and a rising serum alkaline phosphatase level. Currently, there is no prophylactic or therapeutic

45

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739

agent available to treat chronic rejection, although progression of graft fibrosis may be forestalled by sirolimus, based on animal data." The only accepted treatment when decompensated graft failure occurs is retransplantation.

INFECTIOUS COMPLICATIONS Post-transplant infections are the most common cause of morbidity and mortality after liver transplantation. The highest incidence of bacterial and fungai infections is in the first month after transplantation. Fungal infections occurring months to years after transplantation are unusual and are more commonly the atypical or endemic organisms such as ~r~ptococcui,~ u c o
OUTCOME Numerous factors are known to impact patient and graft survival in children after liver transplantation."."10~~3,2j Overall, survival has improved, with I-year and 5-year patient survival approaching 90% and 80%, respectively, in patients younger than 18 years of age.%Age, nutritional status, urgency of transplantation, the indication for transplantation, and presence of renal dysfunction are all major factors that determine outcome. Whereas early data suggested that patients with biliary atresia have worse outcomes owing to their often-malnourished state, young age, and previous surgical intervention, more recent data suggest that this difference is not ~ignificant.~ Patients with metabolic disease do exceedingly well because they often are older, do not have liver failure and its sequelae, and have not previously undergone an abdominal opera ti or^. Finally, transplantation for malignancy in children is associated with survival that is substantially below average but much better than the natural

740

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TRANSPLANTATION

Organism

Presentation

Diagnosis

Antimicrobials

Cytomegalovirus (CMV)

Infection results from: reactivation of virus; blood transfusion; infected transplanted organ. Mild viral, "flu-like" syndrome lnvasive tissue infection (retinitis, pneumonitis, myocarditis, enterocolitis, hepatitis, central nervous system) Spectrum: infectious mononucleosis to lymphoproliferative disease to lymphoma to EBV-associated soft tissue tumors Occurs with EBV and immunosuppression, 10%to 15% infant liver transplantation Gastrointestinal tract, neck, thorax, central nervous system Skin lesions, gastrointestinal tract disseminated herpes: fever, fatigue, abnormal liver functions, hepatitis, pneumonia Atypical pneumonia, can progress to life-threatening pneumonitis

Quantitative CMV-DNA PCR PP-65 Antigen Tissue cultures Blood or fluid cultures Biopsy with immunostains

Prophylaxis: intravenous ganciclovir, oral valganciclovir Therapy: intravenous ganciclovir with or without CMV immunoglobulin

Quantitative EBV-DNA PCR Blood smear Biopsy with immunostains CT scans of suspected sites

Prophylaxis: intravenous ganciclovir, oral valganciclovir Therapy: acyclovir, reduction or withdrawal of immunosuppression. Possible use of systemic chemotherapy for lymphoproliferative disorders or lymphoma

HSV-1 and HSV-2 antibodies Biopsy with viral cultures

Acyclovir

Bronchoalveolar lavage, lung biopsy

Candida

Local mucous membrane, invasive tissue infection, fungemia

Blood, fluid, and tissue cultures, fundoscopic examination

Prophylaxis: Low-dose oral trimethoprim/sulfamethoxazole, dapsone, or pentamidine Therapy: High-dose intravenous trimethoprim/sulfamethoxazole Prophylaxis: Fluconazole, in very-high-risk patients possibly lipid formulation of amphotericin B Therapy: Fluconazole (for sensitive candidal species) or lipid formulation of amphotericin B, caspofungin, or voriconazole (insensitive Candida or Aspergillus)

Aspergillus

Entry via upper or lower respiratory tract with metastatic spread (central nervous system, intra-abdominal, solid organ) Gram-negative: Enterobacteriaceae, Escherichia coli, Pseudomonas Gram-positive: Enterococcus, Staphylococcus

Blood, fluid, and tissue cultures, Bronchoalveolar lavage, CT scans Blood, fluid, and tissue cultures, Bronchoalveolar lavage, CT scans, surgical exploration

Varies

Epstein-Barr virus (EBV)

Herpes simplex virus (HSV)

Pneurnocystis

Bacteria

history of the disease. Numerous large series exist in the literature detailing the improvement in outcome with experience."1° Although outcomes have improved, many issues still remain to be resolved. The first and foremost is the organ shortage. The number of listed patients is increasing steadily, while the number of suitable donors, even with segmental liver transplantation, has plateaued. Strategies aimed at expanding the donor pool and allocating organs to those patients who have not only the greatest survival benefit compared with pretransplant survival but also the greatest chance of optimal posttransplant outcome are essential. National policies aimed at effectively identifying donors amenable for organ splitting and development of local, regional, and national sharing of split grafts still await refinement.

Finally, the development of gene therapy or optimization of hepatocyte transplantation as alternatives to wholeorgan transplantation for metabolic diseases may alleviate some of the current organ shortage. Another important challenge for the liver transplantation community is the perfection of immunosuppression. Currently, all immunosuppressive agents have long-term side effects that result in impaired growth and development, infectious morbidity, malignancies, and numerous medical complications, including renal failure. The development of drug therapy that minimizes or eliminates these complications is essential. Furthermore, a better understanding of the immunology of peripheral T-cell tolerance and chronic rejection is important. Although in the past decade we witnessed improvements in many technical and immunosuppressive aspects of

CHAPTER

liver transplantation, improvements in survival and quality of life in the next decade will rest firmly on a better understanding of our immune system on a cellular and molecular level. The quest to achieve immunotolerance has been elusive.

REFERENCES Arcement CM, Towbin RB, Meza MP, et al: Intrahepatic chemoembolization in unresectable pediatric liver malignancies. Pediatr Radio1 2000;30:779-785. Canelo R, Hakim NS, Ringe B: Experience with histidine tryptophan ketoglutaratC versus-University Wisconsin preservation solutions in transplantation. Int Surg 2003; 88:145-151. Colombani PM, Dunn SP, Harmon WE, et al: Pediatric transplantation. Am J Transplant 2003;3(Suppl 4):53-63. Diem HV, Evrard V, Vinh HT, et al: Pediatric liver transplantation for biliary atresia: Results of primary grafts in 328 recipients. Transplantation 2003;75:1692-1697. Farmer DG. Anselmo DM. Ghobrial RM. et al: Liver transplantation for fulminant hepatic failure: Experience with more than 200 patients over a 17-year period. Ann Surg 2003;237:666-675. Goss JA, Shackleton CR, McDiarmid SV, et al: Long-term results of pediatric liver transplantation: An analysis of 569 transplants. Ann Surg 1998;228:411-420. Gridelli B, Spada M, Petz W, et al: Split-liver transplantation eliminates the need for living-donor liver transplantation in children with end-stage cholestatic liver disease. Transplantation 2003;75:1197-1203. Heffron TG, Pillen T, Welch D, et al: Biliary complications after pediatric liver transplantation revisited. Transplant Proc 2003;35:1461-1462. Holmes RD, Sokol RJ: Epstein-Barr virus and post-transplant lymphoproliferative disease. Pediatr Transplant 2002;6:456464. Jain A, Mazariegos G, Kashyap R, et al: Pediatric liver transplantation in 808 consecutive children: 20-years experience from a single center. Transplant Proc 2002;34:1955-1957. Markiewicz M, Kalicinski J, Teisseyre J, et al: Rapamycin in children after liver transplantation. Transplant Proc 2003;35:22842286. McDiarmid SV, Anand R, Lindblad AS; Principal investigators and Institutions of the Studies of Pediatric

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Liver Transplantation (SPLIT) Research Group. Development of a pediatric end-stage liver disease score to predict poor outcome in children awaiting liver transplantation. Transplantation 2002;74:173-181. 13. Klintmalm GB, Busuttil RW: The recipient hepatectomy and grafting. In Busuttil RW, Klintmalm GB (eds): Transplantation of the Liver. Philadelphia, WB Saunders, 1996, pp 405-418. 14. Molmenti EP, Wilkinson K, Molmenti H, et al: Treatment of unresectable hepatoblastoma with liver transplantation in the pediatric population. Am J Transplant 2002;2:535-538. 15. O'Grady JG, Alexander GJ, Hayllar KM, et al: Early indicators of prognosis in fulminant hepatic failure. Gastroenterology 1989;97:439-445. 16. Reynolds M: Pediatric liver tumors. Semin Surg Oncol 1999;16:159-172. 17. Schnater JM, Aronson DC, Plaschkes J, et al: Surgical view of the treatment of patients with hepatoblastoma: Results from the first prospective trial of the International Society of Pediatric Oncology Liver Tumor Study Group. Cancer 2002;94:1111-1120. 18. Sieders E, Peeters PM, TenVergert EM, et al: Early vascular complications after pediatric liver transplantation. Liver Transpl 2000;6:326-332. 19. Starzl TE, Groth CG, Brettschneider L, et al: Orthotopic homotransplantation of the human liver. Ann Surg 1968;168:392-415. 20. Suita S, Tajiri T, Takamatsu H, et al: Improved survival outcome for hepatoblastoma based on an optimal chemotherapeutic regimen-a report from the study group for pediatric solid malignant tumors in the Kyushu area. J Pediatr Surg 2004;39:195-198. 21. United Network for Organ Sharing: http://www.unos.org/ data/about/viewDataReports.asp 22. Wildhaber BE, Coran AG, Drongowski RA, et al: The Kasai portoenterostomy for biliary atresia: A review of a 27-year experience with 81 patients. Transplantation 2003;75: 1692-1697. 23. Yamanaka J, Lynch SV, Ong TH, et al: Surgical complications and long-term outcome in pediatric liver transplantation. Hepatogastroenterology 2000;47:1371-1374. 24. Yersiz H, Renz JF, Hisatake GM, et al: The conventional technique in in-situ split-liver transplantation. J Hepatobiliary Pancreat Surg 2003;10:11-15. 25. Yersiz H, Renz JF, Farmer DG, et al: One hundred in situ split-liver transplantations: A single-center experience. Ann Surg 2003;238:496-505; discussion 506507.

Intestinal Transplantation Douglas G. Farmer and Sherilyn A. Gordon

The field of intestinal transplantation (ITx) has undergone significant advances over the past 10 to 15 years. From the unsuccessful attempts in the 1960s, patient survival rates approaching 80% to 90% can now be offered to selected recipients of ITx. Advances in surgical techniques have undoubtedly played a significant role. However, true leaps forward have been associated with the development of novel, more powerful immunomodulatory agents. In this chapter we review these developments and discuss the indications and techniques used in this field. Outcolnes and obstacles to more widespread success of the procedure are also reviewed.

HISTORY In the late 1950s, the experimental era of ITx was initiated by the pioneering work of two independent investio technically gators, Lillehei:'4 and S t a r ~ l , ~ % hdeveloped successful canine models of ITx. These models, coupled with the successful transplantation of human kidneys, led to nine published attempts at human ITx in the 1960s and 1970s (Table 46-I)." The outcomes of these clinical attempts performed under the standard immunosuppression of that era (steroids, azathioprine, antilymphocyte globulin, or any combination of these agents) here disheartening because of severe and uncontrollable rejection or technical failure. It was apparent that longterm survival of the lymphoid-rich intestinal allograft

Year

would require more specific immunosuppression and more technical advances before clinical application. Nearly simultaneously, the development of total parenteral nutrition (TPN) by Wilmore and Dudrick'%nd long-term intravascular central lines by Broviacfiin 1968 and 1972, respectively, enabled the short- and long-term administration of fluids, electrolytes, and nutrients to patients with insufficient intestinal function, thus dramatically changing the prognosis of this patient population. These clinical developments relegated ITx to a purely research entity for the next 15 years. The subsequent discovery and successful clinical application of cyclosporine to other solid organ transplants",l() led to renewed interest in human ITx. Importantly, several landmark clinical case reports emerged, including the first successful human multivisceral transplantation by Starzl and associates in 1987,4%solatedintestinal transin 1987, and complantation by Deltz and associate~l:~ bined liver-intestinal transplantation by Grant and colleagues in 1988 (Table 46-2)." However, success was limited to case reports and rejection remained the primary obstacle to long-term graft survival. The modern era of transplantation was ushered forth in the 1990s by the discovery and clinical application of the powerful immunosuppressant FK-506 (tacrolimus,Prograf; off-label use) With use of this agent, for the first time, reports of series of patients undergoing successful ITx were published" (personal communication, W. Burns, 2003). Today, tacrolimus remains the mainstay of most

Center

Graft

Graft Survival

Cause of Graft Loss

Boston Floating Hospital Boston Floating Hospital Univ of Minnesota Univ of S5o Paulo Univ of Paris Univ of Mississippi Univ of SBo Paulo Albert Einstein Hospital Cornell Univ Hospital

Living related isolated intestine lsolated intestine Intestine + colon lsolated intestine Intestine + colon Living related isolated intestine lsolated intestine lsolated intestine Living related isolated intestine

1 2 hours 2 days 1 2 hours 1 2 days 2 3 days 3 2 days 5 days 1 8 hours 79 days

Intestinal necrosis Intestinal necrosis Patient died of pulmonary embolism Rejection Rejection Rejection Rejection Patient died of hypovolemic shock Rejection

CHAPTER

Year Author ---

Graft

1985 1987 1987 1987 1987 1988

Isolated intestine Isolated intestine Isolated intestine Isolated intestine (living related) Multivisceral Combined liver/small bowel

Cohen Goulet Goulet Deltz Starzl Grant

-

46

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Cause of Graft Loss

1 2 days 3 hours 2 1 1 days 1 2 days 192 days 5 years

Rejection Thrombosis Rejection Rejection Patient died of multisytem organ failure Unknown

a

immunotherapeutic regimens for recipients of 1Tx and has been one of the crucial developments leading to the establishment of ITx as the standard of care for the treatment of children and adults with intestinal failure and life-threatening TPN-related morbidity.

RECIPIENT SELECTION Selection of children with intestinal failure for ITx is based on the presence of TPN-related complications, the potential for gut adaptation, and medical and surgical suitability. To better understand candidates for ITx, a brief description of short-bowel/gut syndrome, intestinal failure, and intestinal adaptation is required. In general, short-gut syndrome is a clinical entity in which patients have insufficient gastrointestinal absorptive capacity to meet their daily fluid, electrolyte, and nutritional requirements. There are a variety of congenital, surgical, and functional causes of short-gut syndrome that may potentially lead to intestinal failure and ITx (Table 46-3) . 2 j Before the availability of TPN, the diagnosis of short-gut syndrome carried an extremely poor prognosis because most patients suffered premature mortality as a result of some degree of dehydration, catabolism, or starvation (Fig. 46-1) .Z3 Not only is TPN lifesaving because it provides complete nutritional, fluid, and electrolyte support, but it

also facilitates the process of intestinal adaptation. Adaptation is a complex process in which the remnant bowel undergoes hypertrophy, dilation, and motility changes that effectively increase the net absorption of nutrients per unit of length of bowel. This process is initiated within 24 hours of the onset of intestinal resection and is probably maximal at 2 to 3 years from onset, although isolated case reports of cdmplete intestinal adaptation much later have been published.14 Several keys to adaptation as outlined in other chapters include the presence of adequate calories and nutrients provided by TPN and the presence of intestinal luminal nutrients. The prognosis for complete adaptation from TPN is dependent on a number of factors, including the length of remnant bowel, the presence or absence of an ileocecal valve, the length of remaining colon, the age of the patient, the length of time since the onset of short-gut syndrome, and the presence of residual disease in the remnant bowe1.43 Patients who carry a poor prognosis for adaptation or who fail to adapt are considered to have intestinal failure and are thus relegated to lifelong TPN support. It is estimated that in Western countries, intestinal failure will eventually be diagnosed in two infants per million live births.2 Efforts to enhance the adaptive process have included medical interventions such as the administration of intraluminal glutamine, glutathione, and short-chain fatty acids, as well as systemic growth hormone. Unfortunately, these protocols are offered only at specialized centers of bowel rehabilitation and success has been limited to procedures such as tapering select patient~.~~~"urgical

% of Pediatric

Indication Gastroschisis Volvulus Necrotizing enterocolitis Pseudo-obstruction Intestinal atresia Failed primary transplant Aganglionosis/Hirschprungs's disease Microvillus inclusion disease Short gut/other Malabsorption Dysmotility T~~mor

ITx Performed 21% 18% 12% 9% 7% 7% 7% 6% 6%

.-

o

1960 1970 1980 1990 2000 Mortality associated with short-gut syndrome before and after the clinical use of total parenteral nutrition.",","''""

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1.

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enteroplasties, artificial valves, and antiperistaltic and isoperistaltic colonic interposition have also been cited as putative methods of enhancing adaptation.12 However, like medical therapies, widespread application does not seem possible because only select patients appear to benefit from these interventions.' Recently, the serial transverse enteroplasty procedure has been advocated as a surgical method for bowel lengthening.56Unfortunately, too few patients with short follow-up limit conclusions at this time. Ultimately, approximately 50% of all children with intestinal failure will fail attempts at adaptation.29 Analysis of patients maintained on long-term home TPN therapy reveals that in general, these patients do quite well with few serious complications. Unfortunately, not all patients tolerate TPN well and instead suffer from any of a number of life-threatening complications, in addition to the lifestyle-limiting issues. The most frequent lifethreatening complications include the development of TPN-associated liver disease, loss of central vascular access sites, recurrent central line infections, difficult fluid and electrolyte management, osteopenia, vertical growth limitation, and death.29 In fact, many TPN series report 5-year survival rates of only 80%,j9 which is well below that expected for age-matched healthy cohorts.

Finally, a patient with intestinal failure and limited vascular access should also be considered for ITx. Limited access is appropriately defined as loss of approximately half the standard jugular, subclavian, or iliac vein access sites and not the extreme cases in which intrahepatic, intra-atrial, or intrathoracic access lines are the only available options. The second group in whom ITx should be considered is the subset of patients at high risk for early death or TPN failure. This group includes young infants, patients with very short lengths of remnant bowel (
Indications Simplisticallyspeaking, the indication for ITx is intestinal failure in patients in whom one or more TPN-associated life-threatening complications have developed or are at high risk for developing. Statistically, this strategy is successful because when these types of complications develop in patients with intestinal failure, their prognosis for survival on long-term TPN is worse than after ITx. Kaufman and associates from the American Society of Transplantation published the first definitive manuscript on the indications for pediatric ITx, and these indications are summarized herein.2' The first group of indications is very discretely defined and includes patients with intestinal failure and impending or existing life-threatening TPN-associated complications, including hepatic failure, recurrent central line sepsis, and loss of central access sites. Advanced liver disease secondary to TPN is perhaps the most straightforward because death from liver disease is the inevitable outcome without transplantation.29.jg However, early liver dysfunction is not as straightforward inasmuch as the rate of progression to advanced disease cannot be predicted.30 Certainly, the ability to reverse early hepatic dysfunction with isolated ITx has been reported and must be a strong consideration for such patients because the critical shortage of donor liver organs increases the mortality in patients awaiting combined liverintestinal transplantation. Recurrent line sepsis in patients with intestinal failure is also an indication for ITx. In general, this indication does not include patients with the occasional infection, but instead those with multiple, recurring infections, infections associated with metastatic foci such as endocarditis, infections associated with multiorgan failure syndromes, and infections caused by multiple-antibioticresistant microbes.

Early referral to a center offering both intestinal rehabilitation and ITx is critical for optimizing both pre-ITx care and post-ITx outcome. In particular, children who by virtue of their underlying disease are not candidates for rehabilitation therapy, such as those with gastrocolonic discontinuity and microvillus inclusion disease, warrant immediate referral so that they can be monitored closely by the transplant team for early evaluation and listing. Additionally, patients with risk factors known to be associated with decreased wait list survival, including age younger than 1 year, bridging fibrosis or cirrhosis, bilirubin levels higher than 3 mg/dL, and thrombocytopenia: require prompt evaluation. Children who are candidates for intestinal rehabilitation may undergo a cursory evaluation by the transplant team with a full workup for ITx only if criteria are met later. Otherwise, initial attempts at intestinal rehabilitation are warranted. Before listing any patient for ITx, a comprehensive evaluation of all major organ systems must be undertaken. The protocol at our center is noted in Table 464. Of note, this protocol includes many details that assist with operative planning, such as the type of transplant to be performed, the target vascular access sites, the target inflow and outflow vessels for the graft, the diseased organs to be removed, and the potential sites of gastrointestinal reconstruction. Contraindications to ITx include profound neurologic impairment, uncontrolled systemic sepsis, uncorrectable systemic illnesses not directly related to the digestive system, severe immunologic deficiencies, and the presence of unresectable malignancies. Once deemed a suitable candidate for ITx, the child is listed with the United Network for Organ Sharing (UNOS)

CHAPTER

1 Laboratory Tests

46

Intestinal Transplantation

745

Studies

Type and screen, HLA typing, cytotoxic antibody screen Serum chemistries, liver function panel, albumin, prealbumin, transferrin, cholesterol Zinc, ferritin, copper, selenium, chromium, folate, vitamin BI2, A, D, E levels Complete blood count/platelets, PT/APTT, fibrinogen Urinalysis Viral serology: Epstein-Barr virus Cytomegalovirus Human immunodeficiency virus Hepatitis B, C virus

Upper/lower gastrointestinal contrast studies Abdominal imaging via computed tomography or magnetic resonance imaging Duplex Doppler or magnetic resonance imaging of central veins Nuclear medicine glomerular filtration rate Nuclear medicine gastric emptying study Echocardiography (history of chemotherapy, known congenital defects, endocarditis)

I

1

APTT, activated partial thromboplastin time; PT, prothrombintime.

separately for each organ required and the urgency needed. For the intestine, the current categories include status 1 (urgent), status 2 (nonurgent), or status 7 (temporarily inactive, usually because of active infection). If concomitant liver transplantation is required, separate listing according to the Pediatric End Stage Liver Disease scoring system is performed.36 Finally, if concomitant pancreas transplantation is required, a third separate listing is initiated. A comment regarding listing and waiting for liverinclusive allografts is warranted. ITx recipients are allocated the liver portion of the grafts based solely on their Pediatric End Stage Liver Disease score. Unfortunately, this scoring system was developed for pediatric candidates with biliary atresia, the most common type of pediatric liver disease, to the exclusion of those with parenteral nutrition-associated liver disease. After implementation of this system, alarmingly high mortality rates were reported in the UNOS annual reviews. Fryer et al. expanded on these statistics in a 2003 reportlY and reviewed the outcome of candidates with hepatic failure who were awaiting multiorgan transplants. In retrospect, these high mortality rates were due to the fact that the natural history and progression of TPN-associated liver disease differ significantly from that of other forms of pediatric liver disease and that many of the measured variables used to calculate liver disease scores, such as the prothrombin time and international normalized ratio, do not become abnormal until late in the progression of hepatic failure. As a consequence, UNOS has now adopted measures to ensure that multiorgan recipients with liver disease are more competitive for the liver portions of their allografts. Because these measures were recently instituted, it is too early to determine their impact on ITx candidate wait-list mortality.

jejunoileum (Fig. 46-2A); (2) combined liver and intestine graft (Fig. 46-2B); (3) multivisceral graft consisting of the liver, stomach, pancreas, duodenum, or jejunoileum (Fig. 46-2C); (4) modified multivisceral graft to include option 3 without the liver; and (5) isolated liver graft.'* Isolated intestinal transplantation is indicated for patients with intestinal failure and reversible or no disease in other viscera such as the stomach, liver, and pancreas. Combined liver and intestinal grafts are offered to children who have intestinal failure with irreversible liver disease (congenital or acquired). Multivisceral grafts are reserved for children with extensive disease involving the entire gastrointestinal tract/viscera and irreversible liver disease. Pan-gastrointestinal motility disorders are common indications for this type of graft. In addition, children with low-grade malignancies such as desmoid tumors involving the root of the mesentery and requiring sacrifice of the superior mesenteric and celiac arteries may also be candidates for multivisceral grafts. A modified multivisceral graft is used in candidates who have criteria similar to those for a multivisceral graft except that the degree of liver disease is deemed reversible. Finally, the use of an isolated liver graft is an option in select candidates for ITx. Isolated liver grafts are used only when a transplant candidate has advanced liver disease but carries a good prognosis for intestinal adaptation. This situation is most common in infants with a suitable length of remnant bowel but in whom end-stage liver disease develops rapidly. It is not an appropriate option for patients with intestinal failure and evolving liver dysfunction. In appropriate cases, isolated liver transplantation cures the liver disease and allows the recipient to later adapt off TPN. Appropriate selection is absolutely critical because isolated liver transplantation in a candidate with intestinal failure in whom adaptation does not occur and the need for TPN persists carries a very poor prognosis.

GRAFC SELECTION Five general graft options are available to ITx candidates, depending on the integrity of the remnant gastrointestinal tract and the status of the other visceral organs: (1) isolated bowel consisting of all or part of the

DONOR SELECTION In addition to the standard criteria for selection of deceased donor liver grafts, including the absence of recent systemic

746

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a A, Isolated intestinal graft. B, Combined liverintestinal graft. (,; Multivisceral graft. (See cohrplnte.) (From Fishbein TM, Gondolesi GE, Kaufman SS: Intestir~altransplantation for gut failure. Gastroenterology 2003;126:1615.) -

1

.

CHAPTER

viral, bacterial, or fungal infection or malignancy, donor selection for ITx is based on size. Frequently, an ITx candidate has had multiple abdominal procedures, loss of bowel, and scarring that result in a "loss of domain" effect manifested by less intra-abdominal space for donor organs from patients of similar age and size. To circumvent this problem, targeting a donor size that is 25% to 30% smaller than the intended recipient is optimal. Furthermore, because of the sensitivity of allograft mucosa to ischemia, the donor mechanism of death, including downtime, prolonged resuscitative efforts, and the use of high-dose vasopressors that shunt blood away from the bowel, should be critically evaluated. The donor and recipient should be blood group identical/compatible. Some authors discourage the use of cytomegalovirus (CMV)-positive donor@; however, donor availability can be significantly impaired with this policy, particularly for infants who are likely to be seronegative. Human leukocyte antigen (HLA) and cytotoxic crossmatching is generally performed by most centers but is not a factor in donor selection because prolongation of cold ischemia times while awaiting results can have a great impact on graft function. In addition, the geographic location of the donor can be a factor related to cold ischemia time inasmuch as most ITx teams desire times less than 8 to 12 hours. Living donation for isolated ITx has been performed, with theoretical benefits including improved graft function because of minimal ischemia time and decreased immunologic complications because of HLA similarity in living related donors.41." Unfortunately, although singlecenter reports are quite promising, Intestinal Transplant Registry data have shown no difference in graft survival to date (Fig. 46_3).25These data, coupled with the current favorable discrepancy between ITx donors and recipients (5500 cadaveric donors versus 120 ITx recipients in the United States in 2003), limit the applicability of living donor ITx until further data regarding benefit are available.

A

I

-,.

46

Intestinal Transplantation

747

Yrs post tx Graft survival by donor type. (From International

Transplant Registry. Available at hitp://www/intestinaltransplant.org. Accessed 2004.)

OPERATIVE PROCEDURES Donor All multivisceral procurement techniques represent modifications of those originally described by Starzl et a1.4Xater modifications have been published by Grant,22 Starz1,47,j1," B u e n ~ ,and ~ Abu-Elmagd1 and their colleagues. Common to all these techniques is that procurement of thoracic and renal organs is not precluded and that minor modifications enable procurement of all of the various visceral grafts described earlier. The general principles as outlined in a previous report6l include the use of a midline incision, obtaining vascular control of the donor aorta in the supraceliac and infrarenal locations, mobilization of the target graft organ or organs, and coordinated donor perfusion (Fig. 46-44 and B) .

B

Operative approach to a multivisceral donor. A, The round and falciform ligaments have been divided and the liver completely mobilized. In addition, the left colon has been mobilized to the splenic flexure, the terminal ileum has been stapled (141 lorucr c o r n n ) , and the aortic cannula has been positioned. B, The aortic cannula is in position with the supraceliac aorta encircled with umbilical tape (lo7uer right). The donor is prepared for systemic heparin, cross-clamping, and organ perfusion. (See color plate.) (From Yersiz H, RenzJ, Histaki C;, et al: Multivisceral and isolated intestinal procurement techniques. Liver Transpl 2003;9:881.) 0

.

a

.

a

748

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After removal of the thoracic grafts, the target abdominal viscera are removed en bloc. In the case of an isolated intestinal graft, the liver, pancreas, and intestine can all be procured separately for transplantation into different recipients.' The entire jejunoileum is usually procured with vascular inflow from the celiac and superior mesenteric arteries and outflow via the suprahepatic vena cava. Of note, use of the duodenal-sparing variation for procurement of the liver-intestinal allograft (the "Omaha technique")5"epresents a modification in which the donor duodenum and the head of the pancreas are retained with the liver-intestinal graft, thus eliminating the need for recipient biliary reconstruction. Many centers now commonly use this technique. Finally, multivisceral grafts incorporate all the viscera en bloc with vascular inflow again from the celiac and superior mesenteric arteries and outflow via the suprahepatic vena cava. Ex vivo multivisceral allograft preparation, minimized through increased dissection and organ separation in situ, consists of preparation of a donor thoracic aorta conduit and oversewing of the transected pancreas and distal vena cava. Thus, total cold ischemia time is reduced and inadvertent rewarming is avoided.

Recipient The surgical approach to the recipient is challenging, and accurate preoperative assessment and operative planning are essential. Identification of an established surgical plan to include the target organs to be removed, vascular inflow and outflow targets, organ or organs to implant, and target remnant viscera for gastrointestinal continuity is crucial. In general, this operative plan is individualized for the disease and anatomy of each recipient. Multiple previous surgeries, dense adhesions, and coagulopathy/portal hypertension are the norm, especially for patients with advanced liver disease. The recipient operation can be considered in five phases, depending on the type of transplant required. Stage 1 consists of ensuring that adequate multilumen access has been obtained for intraoperative management and postoperative administration of TPN and intravenous medications. Special note should be made of preoperative vascular imaging studies to avoid complications associated with attempted access in occluded sites. Our standard is magnetic resonance venography performed during transplant evaluation to establish vascular access targets. Stage 2 is abdominal dissection and removal of diseased organs. For the recipient of an isolated intestinal graft, this can safely be performed through a midline incision with lysis of adhesions below the mesocolon and resection of the diseased remnant jejunoileum. For a liver-intestinal recipient, we prefer a bilateral subcostal incision with the initial dissection confined to the perihepatic region. Total hepatectomy is undertaken, usually with retention of the inferior vena cava and without the use of venovenous bypass. Finally, for recipients of multivisceral grafts, an en bloc foregut resection to include a partial gastrectomy, total hepatectomy, total pancreaticoduodenosplenectomy, and remnant enterectomy is performed.

After this dissection phase is complete and before implantation, vascular inflow and outflow targets are sought and vascular conduits used liberally as needed. Conduit placement allows for a much more technically facile anastomosis. It should also be noted that the preferred outflow for an isolated intestinal graft is either a branch of the recipient portal venous system or the inferior vena cava. For liver-intestinal recipients. the native foregut viscera drained by the portal venous system must also be addressed. In our experience, performing a native portacaval shunt is probably the easiest, but the use of an end-to-side donor pbrtal-to-recipient portal anastomosis is an option as well. The third phase, consisting of implantation, then ensues (Fig. 46-5). In cases of isolated ITx, intestinal revascularizatio~is achieved via anastomosis of the donor superior mesenteric artery with the recipient infrarenal aorta. In liver-containing multiorgan grafts, arterial inflow is obtained from the supraceliac aorta. We prefer to piggyback the liver, thus eliminating the need for an infrahepatic inferior vena cava anastomosis. Modified multivisceral grafts can be implanted via the same principles as for isolated intestinal grafts in some cases,-but others require more extensive resection of diseased organs such as the stomach and duodenum/pancreas. The fourth phase is devoted to restoration of gastrointestinal continuity. For an isolated intestinal graft recipient, the target proximal anastomosis is usually the remnant jejunum, but direct anastomosis to the stomach is sometimes required. A distal ileostomy is almost always created with various techniques to facilitate allograft monitoring after transplantation. In cases in which suitable remnant colon exists, anastomosis of the graft ileum to the native colon is also performed. In th; case of a multivisceral recipient, the entire foregut of the recipient has been removed, with only a small remnant of proximal stomach and colon left. heref fore, the graft stomach orjejunum is anastornosed to the recipient stomach/esophagus, and the distal anastomoses are similar to those described earlier. Pyloroplasty is required if the stomach is included.

. -,.

Operative photo, graft implantation demonstrating

complete vascular anastomoses below the graft pancreas.

CHAPTER

For the recipient of a liver-intestinal allograft, our technique necessitates dissection and removal of diseased remnant gut after reperfusion of the graft. We use this technique to avoid extensive dissection in the presence of portal hypertension and coagulopathy before removal of the native liver. Furthermore, we have been successfully able to "stage" this type of transplant in difficult cases.44 Specifically, rather than proceed with the latter stages of the transplant operation in a coagulopathic patient with significant transfusion requirements, we terminate the procedure at this stage, drain the distal end of the bowel, and pack and close the abdomen. A second-stage operation conducted after the patient has stabilized in the intensive care unit then compietes the procedure. Regardless of the method used, a liver-intestine recipient will require dissection and removal of diseased bowel with restoration of intestinal continuity as described earlier. The final phase of the operation consists of establishment of enteral access. The major centers use differing techniques. Irrespective of the technique used, having access to the trans~lantedbowel for administration of enteral nutrients and medications is essential for a successful outcome. We prefer to use a 2-in-1 gastrojejunostomy tube. With this method, one ostomy (gastrostomy) is created, and the jejunal portion of the gastrojejunostomy is manually fed down into the transplanted jejunum. Others report performing separate tube gastrostomies and jejunostomies. For closure, spatial constraints and lack of abdominal domain may require splenectomy, liver resection, or partial allograft enterectomy. Alternatives such as the use of split-liver donor grafts have been advocated. Compressive closure can lead to ischemic allograft necrosis or vascular thrombosis, or both, and is thus to be avoided. In this case, prosthetic-assisted or skin-only closures with delayed reconstruction may be indicated. The University of Miami has reported good results with transplantation of the abdominal wall after I T x . ~ ~

POSTOPERATIVE MANAGEMENT Medical Patients are monitored in the pediatric intensive care unit with invasive lines and regular assessment of volume status, gastrointestinal loss, renal function, and indicators of graft perfusion, including serial serum lactate, chemistry panels, liver function studies, and arterial blood gas analysis for the first several days postoperatively. Because of their smaller plasma volume, children are subject to greater shifts in hemoconcentration and procoagulant factor concentration than are adultsz4 This response is augmented in recipients of liver grafts as a result of initial fluctuating hepatic function. Agents such as prostaglandin, dopamine, dextran, and low-dose heparin are used at our center to promote splanchnic perfusion and prevent thrombosis. In addition, it is anticipated that the patient will require TPN until the absorptive capacity of the graft is demonstrated by tolerance of increasing volumes of dilute and then full-strength enteral feeding.

46

Intestinal Transplantation

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Immunosuppression Contemporary immunosuppression for ITx is predicated on the observation that graft and patient survival rates have improved as immunosuppression has become more potent and specific. Although various protocols vary, many centers use an induction agent for the purpose of depleting T cells or T-cell products and encouraging microchimerism or tolerance. Drugs/mechanisms used to achieve induction include antithymocyte globulin,48 alemtuzumab (off-label),58 infusion of donor bone marrowderived cells,32 and interleukin-2 receptor blockade.17~53 Tacrolimus in addition to steroids is usually the mainstay of maintenance therapies. Our protocol consists of induction of daclizumab (Zenapax, Roche Laboratories, Nutley, NJ; off-label use) preoperatively and postoperatively with initiation of enterically administered maintenance tacrolimus within 24 hours of ITx. We also administer secondary and tertiary immunosuppression consisting of intravenous steroid pulse and taper and mycophenolate mofetil (CellCept, Roche Laboratories; off-label use), with enteric conversion only after allograft absorptive capacity has been demonstrated. With this regimen we have seen a marked increase in patient and graft survival along with a decrease in rejection and infection. In cases of tacrolimus intolerance or increased risk of rejection (or both), we have demonstrated graft salvage in a subset of both adults and children who have converted to sirolimus (Rapamune, Wyeth; off-label use) rescue thera~y.2~ The primary cause of morbidity and mortality after ITx is sepsis. Based on registry data, Beath et al. report sepsis as the leading cause of death (50%) of transplant .~ intermediate and longrecipients r e v i e ~ e dTherefore, term immunosuppressive goals for most centers include steroid weaning and a reduction in trough serum levels of tacrolimus to avoid cumulative morbidity. In addition to the universal risk for infection with immunosuppression, the well-known adverse effects of prolonged steroid use, such as osteoporosis,adrenal insufficiency, peptic ulcer disease, psychosis, cataracts, growth failure, and glucose intolerance, are augmented by the toxicities associated with other immunosuppressants used in ITx. For tacrolimus, neurotoxicity, nephrotoxicity, glucose intolerance, and hypertension predominate; with mycophenolate, bone marrow depression, mucosal ulcerations, and gastrointestinal disturbances are problematic; and the use of sirolimus has been shown to result in bone marrow depression, stomatitis, and hyperlipidemia. Weaning of immunosuppression to avoid these complications must be tempered by the long-term risk for rejection, a significant problem in ITx recipients.

COMPLICATIONS Rejection After sepsis, rejection is the second most common cause of death following ITx, but the primary reason for graft loss.4 Compounding this problem is the fact that detection of rejection can be difficult when relying on nonspecific

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clinical signs and symptoms. Symptoms vary from fever to high-output gastrointestinal loss, abdominal pain, and hematochezia. Rarely, obstructive symptoms may predominate. In addition, the liver portion of the composite graft is usually late to reject, and therefore the use of liver function tests to alert the clinician to rejection often proves unreliable. Serum markers such as intestinal fatty citrulline,20 and granzyme B37have acid binding been championed as markers of rejection, but because of lack of bowel specificity, as well as changes that can occur in other inflammatory bowel conditions, none have demonstrated clinical utility. Endoscopy and biopsy are used as the gold standard for the early diagnosis of acute rejection after ITx. Endoscopic features of rejection include edema, hyperemia, mucosal granularity, loss of the fine mucosal vascular pattern, diminished peristalsis, and mucosal ulceration. Histologic features of acute rejection include mononuclear infiltration, crypt injury with nuclear enlargement and hyperchromasia, decreased cell height, mucin depletion, crypt apoptosis, and distortion of villous and crypt architecture (Fig. 466).60Recently, use of the zoom video endoscope has been advocated as a method to more accurately visualize the mucosa and diagnose rejection." Widespread application has not been achieved to date. The frequency with which surveillance endoscopy is performed depends on the center. In general, most centers initiate regular surveillance endoscopy within 1 to 2 weeks after ITx and continue these procedures at least weekly for the first 6 to 8 weeks thereafter. When clinical signs and symptoms suspicious for rejection are noted, diagnostic endoscopy and biopsy are quickly performed, regardless of timing. Treatment of rejection is based on clinical and histologic severity. Severe episodes warrant monoclonal antilymphocyte antibody therapy and are generally indicative of a high risk for graft loss. Antilymphocyte therapies require empirical antiviral therapy and carry a cumulative risk for post-transplant lymphoproliferative disorder (PTLD).

Mild to moderate episodes can be treated with an increased level of maintenance immunosuppression or a steroid bolus, or both. In patients refractory to immunotherapy, it is critical to proceed swiftly to enterectomy and cessation of immunosuppression to avoid sepsis and death.

Infection As mentioned previously, infection is the primary cause of mortality in ITx recipients. In general, the prevalence of infection/sepsis varies directly with the amount of immunosuppression used. Recipients of ITx are undoubtedly some of the most heavily immunosuppressed transplant recipients. ~urthermore,the necessiyof a long and complex abdominal procedure renders ITx recipients more susceptible to infection. Common foci of infection are intra-abdominal and pulmonary sites. Aggressive evaluation and treatment must be undertaken when clinical signs or symptoms of infection arise. Although standard intra-abdominal and pulmonary post-transplant infections occur and are serious, these types of infections are not unique to recipients of ITx. Other infections unique to this population occur and are worthy of discussion. Infectious enteritides are an increasingly recognized complication after 1Tx.a Not only do these infections mimic rejection (and many times are incorrectly treated as such), but they can also precipitate a subsequent rejection episode and graft loss. In our experience, the major infections have been viral, primarily adenovirus and rotavirus, but other agents, including Cryptospovidium, Giardia lamblia, and Clostridium difficile, have been encountered as well. CMV and Epstein-Barr virus (EBV) also present unique problems after ITx. In fact, rates of infection with these viruses can be as high as 40% after ITx62-a rate much higher than that seen after any other solid organ transplant. Both viruses can directly infect the bowel and represent a major source of morbidity and mortality. Several protocols are used to control their replication after ITx. At the University of California, Los Angeles, we have used a standard prophylaxis protocol consisting of intravenous ganciclovir for the first 100 days after ITx, followed bv conversion to oral acvclovir. In addition, we use a preemptive monitoring and therapeutic protocol consisting of frequent testing for the presence of EBV or CMV viral DNA in blood with polymerase chain reaction. Detection of CMV or EBV viral DNA prompts preemptive therapy that includes intravenous ganciclovir or CMV immune globulin (or both). With this protocol we have significantly reduced the incidence of CMV and EBV viremia and infection after ITx.62

Post-Transplant Lymphoproliferative Disorder

Histologic features of intestinal allograft acute cellular rejection, including crypt distortion with apoptosis and an extensive inflammatory infiltrate. (See tolorplate.)

PTLD is a B-cell malignancy caused in many instances by EBV infection. Intestinal Transplant Registry data reveal that PTLD is the cause of graft loss in 1.6% and patient death in 6.1% of pediatric ITx patients.4 Prompt diagnosis and treatment are necessary to improve these outcomes. A thorough evaluation of the patient should be performed,

46

CHAPTER

including physical examination and complete radiologic imagng. Suspicious adenopathy should prompt biopsy and bone marrow sampling. Treatment consists of ganciclovir, CMV immune globulin, and reduction in immunosuppression. Early data regarding graft and patient salvage with the use of humanized anti-CDPO monoclonal antibody (rituximab) as treatment of PTLD instead of chemotherapy are convincing." Severe refractory or EBV-negative patients may require chemotherapy. Prevention with a preemptive monitoring protocol such as that just outlined allows for maximal treatment success. In our experience, the incidence of PTLD has been less than 2%.

Intestinal Trallspla~ltation

751

As previously noted, outcomes after ITx have been demonstrated to be dependent on the era of immunosuppression. From the Intestinal Transplant Registry, overall patient and graft survival rates at 1 year now exceed 75% and 6,556, respectively, in select recipients (Fig. 46-7A and B) .2Wurther observations include differential prognoses based on the type of ITx, location of the recipient before ITx, and the type of induction therapy used (Fig. 46-8A to C).25 Of particular note is the fact that successful ITx is associated with a 90% rate of freedom from TPN.25 An underassessed outcome variable after transplantation of any kind has been quality of life. Sudan et al. report that pediatric ITx recipients rate their quality of

OUTCOMES To evaluate outcomes, several data sources are now available. Large, single-center series have been reported from the Universities of Pittsburgh, Miami, Nebraska, California (LosAngeles), and Mount Sinai. Additionally, pooled center data are available from two sources. The Intestinal Transplant Registry is a worldwide, voluntary registry that is believed to contain data regarding all human intestinal transplant attempts ever performed. From this standpoint, it is a unique and useful source of data analysis. Additionally, in the United States, mandatory data collection though UNOS is made available in the Scientific Registry of Transplant Recipients Annual Report. Outcome data will reflect these major sources.

Muiiiviscera~ inkstine + liver

/ I

I

I

I

I

I

I

I

-

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(

Intestine I

I

I

I

I

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0 1 2 3 4 5 6 7 8 9 10111213141516 Yrs post tx

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Patient (A) and graft ( B ) survival after intestinal

transplantation by era. (From International Transplant Registry. Available at http://www.intestinaltransplant.org. Accessed 2004.)

ALP . O l l ~ ~ ~ l ~ 0 1 2 3 4 5 6 7 8 9 10111213141516 Yrs post tx

I

A, Graft survival after i~ltestinal~transplantation by graft type (multivisceral versus intestine plus liver versus isolated intestine). B, Graft survival after intestinal transplanvation by pretransplant location. C, Graft survival by induction agent. ALP, antilymphocyte product; DAC, daclizumab; marrow, bone marrow. (From International Transplant Registry. Available at http://www.intestinaltransplant.org. Accessed 2004.)

~

l

752

PART

IV

TRANSPI.ANTATION

life as not significantly different from that of their healthy peers," thus indicating that successful ITx truly restores a patient to a better lifestyle than that preceding the transplant. However, these data must be interpreted with caution because patients undergoing long-term home TPN without complications have similar quality-oflife assessments.

CONCLUSION The field of ITx has changed dramatically since the experimental eras of the 1950s, 1960s, and 1970s. Today, ITx is a common procedure performed at a few specialized transplant centers worldwide. Recipients enjoy unprecedented success rates not seen previously after ITx. Advances in surgical techniques, immunotherapy, and experience in management have contributed significantly to these improvements. Unfortunately, the field remains limited to specialized centers and only to patients with intestinal failure and life-threatening TPNassociated complications. More widespread application will require a reduction in post-transplant surgical morbidity, infections, immunosuppression-related complications, length of hospitalization, and cost. However, as the field grows, these goals are realistically obtainable in the near future.

REFERENCES 1. Abu-Elmagd K, Fung J, Bueno J, et al: Logistics and technique for procurement of intestinal, pancreatic, and hepatic grafts from the same donor. Ann Surg 2000;232:680. 2. American Gastroenterological Association Clinical Practice Committee: AGA technical review on short bowel syndrome and intestinal transplantation. Gastroenterolog-y 2003; 125:1111. 3. Asfar S, Atkinson P, Ghent C, et al: Small bowel transplantation, a life-saving option for selected patients with intestinal failure. Dig Dis Sci 1996;441:875. 4. Beath S, deVille GoyetJ, Kelly D: Risk factors for death and graft loss after small bowel transplantation. Curr Opin Organ Transplant 2003;8:195. 5. Bore1 J, Feurer C, Magnee C, et al: Effects of the new antilyrnphocytic peptide cyclosporine A in animals. Immunology 1977;32:1017. 6. Broviac J, Cole J, Scribner B: A silicone rubber atrial catheter for prolonged parenteral nutrition. Surg Gynecol Obstet 1974;139:24. 7. Byrne T, Cox S, Karimbakas M, et al: Bowel rehabilitation: An alternative to long-term parenteral nutrition and intestinal transplantation for some patients with short bowel syndrome. Transplant Proc 2002;34:887. 8. Bueno J, Abu-Elmagd K, Mazariegos G, et al: Composite liver-small bowel allografts with preservation of donor duodenum and hepatic biliary system in children. J Pediatr Surg 2000;35:291. 9. Bueno J, Ohwada S, Kocoshis S, et al: Factors impacting the survival of children with intestinal failure referred for intestinal transplantation. J Pediatr Surg 1999;34:27. 10. Calne R, Rolles K, White D, et al: Cyclosporin-A in clinical organ grafting. Transplant Proc 1981;13:349.

11. Caniano D, Starr J, Ginn-Pease M, et al: Extensive shortbowel syndrome in neonates: Outcome in the 1980's. Surgery 1989;105:119. 12. Carlson G: Surgical management of intestinal failure. Proc Nutr Soc 2003;62:711. 13. Deltz E, Schroeder P, Gebhard H, et al: Successful clinical small bowel transplantation: A report of a case. Clin Transpl 1989;21:89. 14. DiBaise J, Young R, Vanderhoof J: Intestinal rehabilitation and the short bowel syndrome: Part 2. Am J Gastroenterol 2004;99:1823. 15. Dorney S, Ament M, Berquist W, et al: Improved survival in very short small bowel of infancy with use of long-term parenteral nutrition. J Pediatr 1985;107:521. 16. Dudrick S, Wilmore D, Rhoads J: Long-term total parenteral nutrition with growth, development and positive nitrogen balance. Surgery 1968;64:138. 17. Farmer D. McDiarmid S. Edelstein S. et al: Induction therapy with interleukin-2 receptor antagonist after intestinal transplantation is associated with reduced acute cellular rejection and improved renal function. Transplant Proc 2004;36:331. 18. Fishbein TM, Gondolesi GE, Kaufman SS: Intestinal transplantation for gut failure. Gastroenterology 2003;126:1615. 19. Fryer J, Pellar S, Osmond D, et al: Mortality in candidates waiting for combined liver-intestine transplants exceeds that for other candidates waiting for liver transplants. Liver Transpl 2003;9:748. 20. Gondolesi G, Fishbein T, Chehade M, et al: Serum citrulline is a potential marker for rejection of intestinal allografts. Transplant Proc 2002;34:918. 21. Gordon S, Yersiz H, McDiarmid S, et al: Rescue immunotherapy using sirolimus after small bowel transplantation. Presented at the IXth International Small Bowel Transplantation symposium, 2005. 22. Grant D, Wall W, Mineualt R, et al: Successful small bowel/liver transplantation. Lancet 1990;335:181. 23. Hancock B, Wiseman N: Lethal short-bowel syndrome. J Pediatr Surg 1990;25:1131. 24. Harper P, Luddington R, Carrel1 R, et al: Protein C deficiency and portal thrombosis in liver transplantation in children. Lancet 1988;2:924. 25. International Transplant Registry. Available at http: www.intestinaltranspl~nts.org. Accessed 2004. 26. Kato T, O'Brien CB, Nishida S, et al: The first case report of the use of a zoom videoendoscope for the evaluation of small bowel graft mucosa in a human after intestinal transplantation. Gastrointest Endosc 1999;50:257. 27. Kaufman S, Atkinson J, Bianchi A, et al: Indications for pediatric intestinal transplantation: A position paper of the American Society of Transplantation. Pediatr Transplant 2001;5:80. 28. Kaufman S, Lyden E, Marks W, et al: Lack of utility of intestinal fatty acid binding protein levels in predicting intestinal allograft rejection. Transplantation 2001; 71:1058. 29. Kaufman SS: Prevention of parenteral nutrition-associated liver disease in children. Pediatr Transplant 2002;6:37. 30. Kelly D: Liver complications of pediatric parenteral nutrition-epidemiology. Nutrition 1998;14:153. 31. Kino T, Hatanaka H, Miyata S, et al: FK-506, a novel immunosuppressant isolated from a Streptomyces. 11. Immunosuppressive effect of FK-506 in vitro. J Antibiot (Tokyo) 40:1256, 1987. 32. Levi D, Tzakis A, Kato T, et al: Immune responses and their regulation by donor bone marrow cells in clinical organ transplantation. Transpl Immunol2003;11:307.

CHAPTER

33. Levi D, Tzakis A, Madariaga J, et al: Transplantation of the abdominal wall. Lancet 2003;361:2173. 34. Lillehei R, Goot B, Miller F: The physiologic response of the small bowel of the dog to ischemia including prolonged in vitro preservation of the bowel with successful replacement and survival. Ann Surg 1959;150:543. 35. Mdlister V, Grant DR: Clinical small bowel transplantation. In Grant DR, Rim (eds): Small Bowel Transplantation. London, Edward Arnold, 1994, pp 121-132. 36. McDiarmid SV, Anand R, Lindblad AS: Principal Investigators and Institutions of the Studies of Pediatric Liver Transplantation (SPLIT) Research Group. Development of a pediatric end-stage liver disease score to predict poor outcome in children awaiting liver transplantation. Transplantation 2002;74:173. 37. McDiarmid S, Farmer D, Kuniyoshi J, et al: Perforin and granzyme B. Cytolytic proteins up-regulated during rejection of rat small intestine allografts. Transplantation 1995; 69:762. 38. McGhee W, Mazariegos G, Sindhi R, et al: Rituximab in the treatment of pediatric small bowel transplant patients with post transplant lymphoproliferative disorder unresponsive to standard treatment. Transplant Proc 2002; 34:955. 39. Manez R, Kusne S, Green M, et al: Incidence and risk factors associated with the development of cytomegalovirus disease after intestinal transplantation. Transplantation 1995;59:1010. 40. The Organ Procurement and Transplantation Network: Available at http://www.optn.org. Accessed 2004. 41. Pollard S: Intestinal transplantation: Living related. Br Med Bull 1997;53:868. 42. Potts W: Pediatric surgery. JAMA 1955;157:627. 43. Quiros-Tejeira R, Arnent M, Reyen L: Long-term parenteral nutritional support and intestinal adaptation in children with short bowel syndrome: A 25-year experience.J Pediatr 2004;145:157. 44. RenzJ, McDiarmid S, Edelstein S, et al: Application of combined liver-intestinal transplantation as a staged procedure. Transpant Proc 2004;36:314. 45. Starzl T, Hakala T, Shaw B, et al: A flexible procedure for multiple cadaveric organ procurement. Surg Gynecol Obstet 1984;158:228. 46. Starzl T, Kaupp H: Mass homotransplantations of abdominal organs in dogs. Surg Forum 1960;11:28.

46

Intestinal Transplantation

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Starzl T, Miller C, Bronznick B, et al: An improved technique for multiple organ harvesting. Surg Gynecol Obstet 1987;165:343. Starzl T, Murase N, Abu-Elmagd K, et al: Tolerogenic immune suppression for organ transplantation. Lancet 2003; 361:1502. Starzl T, Rowe M, Todo S, et al: Transplantation of multiple abdominal viscera. JAMA 1989;261:1449. Starzl T, Todo S, Fung J, et al: FK 506 for liver, kidney, and pancreas transplantation. Lancet 1989;2:1000. Starzl T, Todo S, Tzakis A, et al: Abdominal organ cluster transplantation for the treatment of upper abdominal malignancies. Ann Surg 1989;210:374. Starzl T, Todo S, Tzakis A, et al: The many faces of multivisceral transplantation. Surg Gynecol Obstet 1991;172:335. Sudan D, Chinnakotla S, Horslen S, et al: Basiliximab decreases the incidence of acute rejection after intestinal transplantation. Transplant Proc 2002;34:940. Sudan D, Horslen S, Botha J, et al: Quality of life after pediatric intestinal transplantation: The perception of pediatric recipients and their parents. Am J Transplant 2004;4:407. Sudan D, Iyer K, Deroover A, et al: A new technique for combined liver-intestinal transplantation. Transplantation 2001;72:1846. Tannuri U: Serial transverse tapering enteroplasty (STEP): A novel bowel lengthening procedure, and serial transverse enteroplasty for short bowel syndrome. J Pediatr Surg 2003;38:1845. Tesi R, Beck R, Lambiase L, et al: Living-related small bowel transplantation: Donor evaluation and outcome. Transplant Proc 1997;29:686. Tzakis A, Dato T, Nishida S, et al: Alemtuzumab (Campath 1-H) combined with tacrolimus in intestinal and multivisceral transplantation. Transplantation 2001;75:1512. Vantini I, Benini L, Bonfante F, et al: Survival rate and prognostic factors in patients with intestinal failure. Dig Liver Dis 2004;36:46. Wu T, Abu-Elmagd K, Bond G, et al: A schema for histologic grading ofsmall intestine allograft acute rejection. Transplantation 2002;75:1241. 61. Yersiz H, Renz J, Hisatake G, et al: Multivisceral and isolated intestinal procurement techniques. Liver Transpl2003;9:881. 62. Ziring D, Tran R, Edelstein S, et al: Infectious enteritis after intestinal transplantation: Incidence, timing, and outcome. Transplantation 2005;79:702.

Heart Transplantation Thomas L. Spray and Stephanie M. I? Fuller

Thoracic organ transplantation has been successfully performed in pediatric patients since the mid-1980s and now serves as an important option in the treatment of both congenital and end-stage heart and lung disease in children. Approximately 350 pediatric heart transplants are performed annually in the Unites States, or roughly the clini10% of all thoracic organ tran~plants.~.lWespite cal success of heart and lung transplantation in children, limited donor availability has prevented more widespread application of this therapy. Complications such as acute and chronic rejection, graft coronary artery disease (CAD), and bronchiolitis obliterans, as well as the infectious and neoplastic complications of current methods of immunosuppression, threaten cardiac transplant longevity. This chapter focuses on the clinical aspects of heart transplantation in infants and children, including indications, preoperative evaluation, operative techniques, postoperative management, complications, and outcome.

HISTORICAL NOTES Kantrowitz et al. performed the first pediatric heart transplant in 1967hhen they transplanted the heart of an infant with anencephaly into a 3-week-old infant with tricuspid atresia. The next year, Cooley transplanted the heart and lungs of a newborn with anencephaly into a 3-month-old with an atrioventricular septa1 defect and pulmonary hypertension. Although neither of the infants survived for more than a few hours because of allograft rejection, these pioneering procedures emphasized the technical feasibility of thoracic organ transplantation in children. It was only in 1980 with the introduction of cyclosporine as an immunosuppressive agent that meaningful clinical success became possible. In November 1985, Bailey performed the first successful cardiac transplantation on a 4dayald neonate with hypoplastic left heart syndrome (HLHS) at Loma Linda.' Throughout the last 2 decades, outcomes have been improved- by technical advances, better immunosuppression, including reduced steroid use and the advent of induction therapy, a decreased incidence of rejection, increased attention tb viral prophylaxis, and aggressive treatment of post-transplant lymphoma and other post-transplant complications.

INDICATIONS As published by the Registry for the International Society for Heart and Lung Transplantation in the Seventh Official Pediatric Report in May 2004, the number of pediatric heart transplants has remained relatively constant over the last 10 years (Fig. 47-1).4 The most common indications for cardiac transplantation in the pediatric population remain congenital cardiac disease and cardiomyopathy, as demonstrated in Figures 47-2 to 47-4. According to age distribution, congenital heart disease is seen more commonly in infants, most of whom are younger than 2 months, whereas cardiomyopathy is more prevalent in older children. As expected, the incidence of retransplantation increases with increasing patient age. The primary indication for heart transplantation in infancy remains complex congenital heart disease without a reasonable corrective or palliative surgical option. Of such conditions, the most common anomaly treated by transplantation is HLHS, a group of defects characterized by aortic or mitral atresia/stenosis with a diminutive

, Age distribution o f pediatric heart recipients by year of transplantation performed frornJanuary 1996 t o J u n e 2005. (Reprinted f r o m Journal of Heart and L u n g Transplantation, August 2004, with permission f r o m International Society of Heart and 1,ung Transplantation.) -

1

CHAPTER

- - ---

47

H e a r t Transplantation

755

--

I -1 Myopathy 67%

81%

2%

1%

'Other

66%

W ReTX

100

--

.Myopathy

-Congenital . - l - . - I L - - . _ _

J

1988 1989 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 MOZ

,

Diagnoses for pediatric heart transplant recipients (age <1 year). ReTX, retransplantation. (Reprinted fromJournal of Heart and Lung Transplantation, August 2004, with permission from International Society of Heart and Lung Transplantation.) -

1

left ventricle. Initial poor results with a staged palliative approach to HLHS led some centers to consider orthotopic heart transplantation as the primary treatment of this anomaly. Long transplant waiting lists have led other institutions to advocate performing a stage I palliation (Norwood or Sano procedure) to help stabilize the patient and then list the patient for transplantati~n.~ However, with improvement in early survival from the Norwood procedure followed by a Fontan repair, the majority of cardiac centers have abandoned primary transplantation as initial therapy for HLHS. Instead, transplantation is an option now reserved for patients with unusually high risk, including aortic atresia with a diminutive ascending aorta and severe tricuspid regurgitation." Other forms of congenital heart disease that have been treated by cardiac transplantation during infancy include an unbalanced atrioventricular canal, single ventricle, complex truncus arteriosus, double-outlet right ventricle, Ebstein's anomaly, L-transposition of the great arteries, and pulmonary atresia with an intact ventricular septum.%ven the most complex forms of congenital heart disease, such as heterotaxy syndromes with anomalies of systemic and venous drainage, are amenable to cardiac

4

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:

~

I

l

1 ia Congenital

m Other IJ ReTX

50

Diagnoses for pediatric heart transplant recipients (age - 11 to 17 years). ReTX, retransplantation. (Reprinted from Journal of Heart and Lung Transplantation, August 2004, with permission from International Society of Heart and Lung Transplantation.)

transplantation with suitable reconstruction. 14 Other pediatric candidates include infants with congenital heart disease who have undergone previous corrective or palliative procedures yet who exhibit residual or progressive cardiac dysfunction manifested by left ventricular failure that ultimately requires transplantation. In these cases, postoperative cardiac dysfunction is often related to atrioventricular or semilunar valvar insufficiency that eventually results in dilated cardiomyopathy. Of note, multiple previous palliative procedures do not preclude successful transplantation.*Z Cardiomyopathy is the other most common indication for heart transplantation in infancy and childhood. Most pediatric heart transplantations outside infancy are performed for idiopathic cardiomyopathy. Other causes of cardiomyopathy include viral, familial, and hypertrophic. Despite the diverse causes of cardiomyopathy, several variables have been associated with poor outcome, including very high left ventricular end-diastolic pressure, a left ventricular ejection fraction less than 20%, ventricular arrhythmia, and a family history of cardiomy0pathy.18.~~ Cardiomyopathy attributable to inflammation or arrhythmia tends to have a more favorable outcome, and these patients should be supported as long as possible before transplantation to allow for the possibility of spontaneous recovery. Other less common indications for cardiac transplantation are doxorubicin-induced cardiotoxicity from chemotherapy for malignancy and obstructive cardiac tumors such as fibromas and rhabdomyomas that are not amenable to surgical resection.

37%

PREOPERATIVE WALUATION 100

f

75-

The pretransplant evaluation is a -Congenital - - - - Myopathy --.......-..------ _ . . - - - -screening process that serves as the I _ . _ .

a 1 Diagnoses for pediatric heart transplant recipients (age 1 to 10 years). ReTX, retransplantation. (Reprinted from Journal of Heart and Lung Transplantation, August 2004, with permission from International Society of Heart and Lung Transplantation.)

multidisciplinary key to successful organ transplantation (Table 47-1). Potential recipients undergo a thorough physical and psychosocial evaluation with careful examination of the cardiac, pulmonary, neurologic, renal, infectious, and socioeconomic systems. The presence of an adequate family support system is of paramount importance to survival postoperatively. Parents must demonstrate the ability and resources to

756

PART

IV

TRANSPLANTATION

History and physical examination Blood type Panel-reactive antibody Complete blood count with differential Chemistry panel with electrolytes Liver function tests Lipid profile Serologic examination for antibodies to varicella, CMV, EBV, herpes simplex, measles, hepatitis A to D, HIV, toxoplasmosis Chest radiograph Chest computed tomography Pulmonary function tests Cardiology evaluation with electrocardiogram, echocardiogram, MUGA scan-ventricular ejection fraction, cardiac catheterization, exercise stress test Consultation with pediatric cardiologist, transplant coordinator, infectious disease specialist, pulmonologist, nutritionist, psychiatrist, social worker, dentist

CMV, cytomegalovirus;EBV, Epstein-Barrvirus; HIV, human immunodeficiencyvirus; MUGA, multiple uptake gated acquisition.

comply with the complex medical regimens required and to cope with the potential for long or frequent hospitalizations even years after transplantation. As part of this multidisciplinary evaluation, patients undergo screening laboratory tests, including a viral serology panel (e.g., human immunodeficiency virus [HIV] , cytomegalovirus [CMV], human Epstein-Barr virus [EBV], hepatitis). Cardiac evaluation is performed mainly by kchocardiography and cardiac catheterization in which the anatomy of the systemic and pulmonary venous connections of the heart and lungs are precisely identified. Important hemodynamic data, including systemic cardiac output and pulmonary vascular resistance (PVR), both indexed to the patient's body area, are obtained at cardiac catheterization and used to screen candidates. These numbers become significant because the major contraindication to transplantation is fixed pulmonary hypertension unresponsive to pulmonary vasodilators. Patients with elevated PVR ( > 4to 6 wood units) are tested with pulmonary vasodilators, including sodium nitroprusside, oxygen (FIo? loo%), and inhaled nitric oxide, to establish whether the pulmonary vascular bed is reactive. In general, the presence of a fixed PVR in excess of 6 to 8 Wood units is a contraindication to orthotopic heart transplantation because the donor heart is unable to tolerate right-sided dilation caused by high pulmonary resistance. Patients who demonstrate improvement with vasodilators may undergo transplantation with a survival rate comparable to that in patients with normal resistance.lZ Although patients with fixed pulmonary hypertension have successfully undergone transplantation, they have a much higher mortality rate, usually because of postoperative right ventricular failure. Other contraindications to cardiac transplantation include multiple noncardiac congenital anomalies, active malignancy, infection, severe metabolic disease (i.e., diabetes mellitus), multiple organ failure, multiple congenital anomalies, and the lack of an adequate family support

system, in addition to socioeconomic factors that lead to noncompliance with drug regimens and follow-up care. Children suffering from cardiomyopathy and manifesting symptoms of chronic congestive heart failure that limit activity or uncontrollable arrhythmias are often referred for transplantation, particularly if these patients are unresponsive to medications. The timing for transplantation in these children, especially those with hypertrophic cardiomyopathy, is less clear because some patients may improve with medication and conservative therapy. As previously stated, the mortality for idiopathic dilated cardiomyopathy in children is highest in the first year after diagnosis and is mainly determined by the degree of left ventricular failure. Children listed for heart transplantation should be closely monitored until their transplantation, either as outpatients if their condition permits or while hospitalized. Good nutritional status should be maintained and supplementation such as tube feedings or total parenteral nutrition used as needed. A close watch for infectious complications is important, and any subtle indications of infection should be thoroughly investigated. Major infections require patients to have their transplantation status put on hold until they are treated adequately. Anticongestive therapy should be optimized with digoxin, diuretics, and afterload reduction with captopril or other angiotensin-converting enzyme inhibitors. If heart failure worsens, hospitalization may be required for inotropic support with dobutamine or phosphodiesterase inhibitors such as milrinone. Long-term therapy may require the placement of an intravenous access device such as a Broviac catheter. The use of extracorporeal membrane oxygenation (ECMO) as a bridge to cardiac transplantation in critically ill children has been limited mostly to those with postcardiotomy ventricular failure. In general, the results have been poor, although several studies show survival rates ranging from 45% to 73% when ECMO is used as a bridge to cardiac transplantation.*3J6Older children and adolescents have excellent survival with the use of long-term ventricular assist devices as a bridge to transplantation, although size restrictions limit their application in the infant population. A neonate referred for cardiac transplantation requires several other unique considerations. Infants with complex congenital heart disease such as HLHS are commonly confined to a neonatal intensive care unit and are usually maintained on a continuous infusion of prostaglandin E, to prevent closure of the ductus arteriosus if there is ductdependent physiology. Implantation of expansile stents in the ductus may allow discontinuation of prostaglandin during waiting. Balloon atrial septostomy with or without stenting to improve mixing of saturated and desaturated blood and to decompress the left atrium may be helpful if there is a restrictive patent foramen ovale. Other important issues are the maintenance of adequate nutritional support, avoidance of renal and metabolic complications, and prompt and thorough treatment of any infectious complications, especially line sepsis, in these fragile infants. Common neonatal problems such as seizures, necrotizing enterocolitis, and intraventricular hemorrhage are also seen in these patients. At the minimum, 10% to 20% of infants die while awaiting a donor heart.

CHAPTER

As mentioned earlier, initial palliative procedures such as the Norwood procedure for HLHS or a Blalock-Taussig shunt for lesions with ductal-dependent pulmonary blood flow can be performed in the face of a prolonged wait for a donor. The United Network for Organ Sharing determines organ allocation and in 2002 revised their classification for pediatric patients awaiting heart transplantation. Status 1A applies to patients requiring ventilatory or mechanical circulatory support (i.e., left ventricular assist device, ECMO, or a balloon pump) or multiple- or highdose inotropes, infants younger than 6 months with pulmonary pressure greater than 50% of systemic levels, or any patient with a life expectancy of less than 14 days without a heart transplant. Status 1B applies to patients requiring singledose inotropic support or infants younger than 6 months who have significant failure to thrive (less than the 5th percentile for weight or height or loss of 1.5 SD of expected growth). All other patients with less acuity are classified as status 2. A patient's status may change depending on changes in clinical condition, or the patient may be placed on hold (status 7) because of an infectious, malignant, or other complication and then later be reactivated.

DONOR EVALUATION AND ORGAN PROCUREMENT The criteria for an ideal organ donor are as follows: meets requirements for brain death, consent from next of kin, ABO compatibility in older children, weight compatibility (one to three times that of the recipient), normal echocardiogram, age younger than 35 years, and normal heart by visual inspection at the time of harvest. A history of cardiopulmonary resuscitation is not an absolute contraindication to cardiac donation for pediatric recipients. All potential donors are evaluated carefully for the cause of death, including the presence of chest trauma, need for cardiopulmonary resuscitation, and cardiac function before death. For neonates, most donors have suffered sudden infant death syndrome or birth asphyxia, whereas older donors are victims of violence and car accidents. The shortage of suitable organ donors, especially for neonatal recipients, has led to many attempts at expanding the donor pool. Hearts from donors with moderately impaired ventricular function by echocardiography (left ventricular shortening fraction greater than 25% without major wall motion abnormalities) have been successfully transplanted into infant recipients.14 Donor-to-recipient weight ratios of up to 4:l have been used in infants. Tamisier and colleagues demonstrated that the higher the PVR, the larger the donor heart needed for successful transplantation and that hearts with PVR values thought to be in excess of normal can also be used.Z8 Although ideal donor ischemia time is from 2 to 4 hours, ischemic times have been successfully extended beyond 9 hours. Deviations from the "ideal" donor criteria should be individualized, and even though the use of a marginal donor for a dying infant maintained on ECMO may be justified, use of the same heart for a child who is stable as an outpatient might not. ABO-incompatible transplantation has been introduced as a method to decrease recipient waiting times and

47

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757

associated waiting list mortality.29 Because neonates do not have the ability to produce antibodies to T-cell antigens, including major blood group antigens, ABO incompatibility becomes a negligible complication. ABO-incompatible transplantation has been infrequently used in the United States, and the age at which it is no longer feasible is still not clearly defined. Good donor management is a vital part of successful organ transplantation. The main goals are maintenance of normothermia, euvolemia, and adequate tissue perfusion and prevention of infection. Often, donors with poor cardiac function on initial evaluation will respond to volume loading and lowdose inotropic support with a significant improvement in function after heart retrieval, usually as part of a multiorgan retrieval procedure. All donors are screened for agents that might cause serious infection in an immunocompromised host, such as CMV, EBV, H w hepatitis, and Toxoplasma. The presence of antibodies to CMV, EBV, and 7bxoplasma is not a contraindication to transplantation but helps guide post-transplant therapy. The four major goals in procurement of a donor heart are to (1) work effectively with the other teams to ensure optimal condition of each recovered organ, (2) evaluate the hemodynamic status of the patient and the gross function of the heart by inspection, (3) use an effective cardioplegia and venting procedure that maximizes preservation of the heart, and (4) expertly remove the heart and adjoining vascular connections to ensure optimal anatomy for implantation. Procurement is performed via a median sternotomy. Donor blood is obtained for viral titers and retrospective HLA typing. The initial dissection involves separating the aorta from the main pulmonary artery to allow cross-clamping. Careful inspection of the heart is performed, and the patient is systemically heparinized. Procurement commences when the aorta is cross-clamped. Cardioplega solution is infused through the aortic root, and the heart is vented via the right atrial appendage or superior vena cava for the right side and the superior pulmonary vein or left atrial appendage for the left side. The superior vena cava is dissected free of its pericardial attachments up to the innominate vein, and the azygos vein is ligated and divided. The pericardial reflections around the right superior pulmonary vein and the inferior vena cava are sharply divided. The cardiectomy begins with inferior vena cava transection, followed by right and left pulmonary vein transection at the pericardial reflection. The main pulmonary artery is divided and then the posterior pericardial attachments and the superior vena cava. Last of all, the aorta is transected at the level of the innominate artery or more distally if the aorta is needed for the recipient. The donor heart is immersed in cold (4" C) ,sterile saline and then triple-bagged in a sterile manner for transport. In general, the cold ischemia time should be limited to a maximum of 4 to 5 hours.

RECIPIENT PREPARATION AND TECHNIQUES OF IMPLANTATION The standard technique for orthotopic heart transplantation was first described by Lower and Shumway in 1960 and consists of biatrial anastomoses, thus avoiding

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Standard heart transplantation using biatrial anastomosis. A, A recipient ventricular mass has been removed, and the left atrial anastomosis has been started. B, Final appearance after all anastomoses are complete. .

A

individual caval and pulmonary vein connections (Fig. 47-5) .lWurrently, however, the majority of cardiac transplant centers now use the bicaval technique because it preserves atrial morphology and kinesis and is simpler when reconstruction after previous congenital heart repair is necessary. Once adequate hemodynamic monitoring is in place and the recipient is properly anesthetized, a median sternotomy is performed and the heart is suspended in a pericardial cradle. If previous sternotomies have been performed, appropriate precautions should be taken, including exposing the groins in the sterile field for access for femoral bypass. Once in the chest, the main pulmonary artery is dissected off the aorta past the bifurcation, and the pericardial reflection is mobilized off the aortic arch. Normally, aortic and bicaval cannulation is used. In the case of a recipient with HLHS, the aortic arch vessels are mobilized proximally and controlled with snares, and the descending thoracic aorta is dissected to a level 2 to 3 cm below the insertion of the ductus arteriosus. The right and left pulmonary arteries are mobilized and controlled with snares in preparation for cardiopulmonary bypass. After heparinization, the main pulmonary artery is cannulated for arterial inflow, and a single venous cannula is placed in the right atrium because circulatory arrest will be used. Immediately on instituting cardiopulmonary bypass, the pulmonary arteries are snared tight and the body perfused through a patent ductus arteriosus. The recipient is cooled to l 8 O C for circulatory arrest. Once the donor organ is available in the operating room and the patient has been adequately cooled, circulatory arrest is established, the arch vessels are snared

tightly, and the patient is exsanguinated into the venous reservoir. The aorta is divided just above the valve and incised longitudinally along the lesser curve of the aortic arch to a level 1 to 2 cm below the ductal insertion site on the descending aorta. The ductus is ligated next to the pulmonary artery and divided, and then the main pulmonary artery is transected just below the bifurcation. The right atrial incision is started superiorly at the base of the appendage. This incision is then carried down into the coronary sinus and across the atrial septum into the left atrium. The superior aspect of the right atrial incision is next carried across the septum to open the roof of the left atrium. The lateral wall of the left atrium is incised above the left pulmonary veins, with the left atrial appendage included with the specimen. The donor organ is prepared on the back table in cold saline solution. The right atrium is incised from the inferior vena cava laterally to the base of the appendage; the area of the sinoatrial node is avoided if atrial anastomoses rather than caval anastomoses are to be performed. The pulmonary vein confluence is excised off the back of the left atrium, leaving an opening comparable in size to the recipient left atrial cuff. The pulmonary artery is transected just below the bifurcation to provide a wide anastomosis. The aorta is trimmed, depending on the level required in the recipient. Care must be taken to check for and adequately close a patent foramen ovale, which is frequently present, especially in infant hearts. Failure to do so may result in significant postoperative right-to-leftshunting in the face of pulmonary hypertension. The implantation is begun by anastomosing the lateral wall of the left atrium from the level of the left atrial

CHAPTER

appendage inferiorly. A left ventricular vent is placed through the right superior pulmonary vein, and the left atrial anastomosis is completed by reconstructing the intra-atrial septum. The arch of the aorta is then reconstructed. The right atrial anastomosis is begun at the inferior vena cava orifice and then taken superiorly along the intra-atrial septum. Once the right atrial anastomosis is completed, the ligature is removed from the donor superior vena cava and the venous cannula is placed through the vena caval stump. The ascending aorta

, Technique for transplantation in hypoplastic left heart syndrome (with the use of bicaval anastomosis). A, Recipient anatomy before cardiectomy. B, Appearance of the recipient after cardiectomy. Note that the aortic incision must be extended into the descending aorta beyond the level of the arterial duct. C, Final appearance aftel- all anastomoses are complete. -

A

47

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is then cannulated by a new purse-string suture, air is evacuated, and cardiopulmonary bypass is resumed. The snares are released from the head vessels and warming is commenced. The pulmonary anastomosis is then performed in an end-to-end fashion. If time permits, this step may be done during circulatory arrest in a drier field. After adequate warming, the patient is weaned from cardiopulmonary bypass and the cannulas removed (Fig. 47-6).I%ght atrial, left atrial, and occasionally pulmonary artery pressure catheters are placed before

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discontinuing bypass and brought out through the skin below the incision. In older children with cardiomyopathy or infants without aortic arch abnormalities, the recipient procedure is similar to that performed in adults. The ascending aorta is mobilized to the pericardial reflection and used for arterial cannulation. The child is cooled to 28' C to 34' C because the implantation is performed under aortic cross-clamp rather than circulatory arrest. After the left atrial anastomosis has been completed, the right atrial connection can be sewn either directly or by using a bicaval technique if a previous cavopulmonary connection has been performed. This may decrease the incidence of tricuspid regurgitation in certain patients. The aortic anastomosis is then completed in an end-to-end fashion in the mid-ascending aorta. The pulmonary artery anastomosis may or may not be performed during aortic cross-clamp, depending on how long the implant procedure takes. Numerous other variations of the implantation procedure can be used, depending on the recipient anatomy present. Modifications accounting for a persistent left superior vena cava, previous cavopulmonary shunt or Fontan procedure, corrected transposition of the great arteries, and situs inversus totalis have all been described.

POSTOPERATIVE MANAGEMENT The recipient is returned from the operating room to an isolation room in the intensive care unit. Mechanical ventilation is required initially but is weaned as rapidly as possible. Antibiotics are continued until all monitoring lines and chest tubes have been removed. Some level of inotropic support is required in virtually all heart transplant recipients. Isoproterenol is often an ideal choice owing to its pulmonary vasodilatory effects, as well as its inotropic and chronotropic effects because many patients have a slower than optimal heart

rate initially. This transient sinus node dysfunction is rarely permanent. Dobutamine and dopamine, especially at "renal doses," are also frequently used to augment ventricular contractility. Epinephrine and norepinephrine are usually reserved for poor graft function. Sodium nitroprusside infusion or phosphodiesterase inhibitors are used for afterload reduction in the early postoperative period. Right ventricular dysfunction secondary to pulmonary hypertension may respond to phosphodiesterase inhibitors such as milrinone. Inhaled nitric oxide has been shown to be an effective selective pulmonary vasodilator with few systemic side effects and is useful in cardiac transplant recipients with pulmonary hypertension.

TRANSPLANT IMMUNOSUPPRESSION A combination of immunosuppressive agents are used for the prevention and treatment of rejection. Standard triple-drug immunosuppression therapy consisting of prednisone, cyclosporine, and azathioprine has been successfully used in pediatric cardiac transplant recipients and remains the most common regimen." The induction and maintenance doses of medications used for immunosuppression at the Children's Hospital of Philadelphia are listed in Table 47-2. Because of the adverse effects of corticosteroids, withdrawal from prednisone is usually attempted 6 months after transplantation. Up to 80% of recipients may be successfully weaned from steroids; only a quarter of these patients have an episode of rejection in the first 6 months.*OTacrolimus (formerly called FK-506) has been shown" to be an effective immunosu~~ressive agent in children, and its use has increased over the last 5 years, with approximately 40% of all pediatric cardiac transplant patients receiving it for maintenance immunosuppression 1 year after transplantation in the place of cyclosporine.4 Overall, patients taking tacrolimus appear to have a lower incidence of rejection. Side effects of 1 1

Drug

Dosage

Azathioprine/ mycophenolate mofetil (MMF)

2 mg/kg IV given in the operating room, before transplantation Then 2 mg/kg IV given once daily for 5 days (neonates), 7 days (infants), or 9 days (adolescents) Change to MMF, 120 mg/kg/day IV given twice daily (target level, 2.5-3.0), after the azathioprine course is completed Change to MMF orally as intestinal function returns 0.02 mg/kg/hr IV infusion beginning in the operating room, before transplantation Then 0.02 mg/kg/hr IV infusion for 2 4 hr (target level, 100) Change to ATG on postoperative day 3 and give 1.5 mg/kg IV once daily for 3 days (neonates), 5 days (infants), or 7 days (adolescents) Change back to cyclosporine orally after ATG course is completed to maintain target levels of approximately 125 in neonates and 150-175 in older children by discharge Dosing should be carefully adjusted over the next 2 months to achieve levels of 125-150 in neonates, 175-200 in infants, 250 in 6- to 12-year-olds, and 250-300 in adolescents 10-15 mg/kg IV given in the operating room, before transplantation Then 3 mg/kg IV twice daily for 3 doses

Cyclosporine

Solu-Medrol

ATG, rabbit antithymocyte globulin; IV, Intravenous.

CHAPTER

47

H e a r t Transplantation

761

suppression is a problem. Routine CMV prophylaxis is not used in cardiac transplant recipients at our institution. Y e a r 5 (N = 384)

EARLY COMPLICATIONS

Cyclosporine

. -.

Tacmlimus

Rapamycin

MMF

Azalhioprino

Prednisone

Pediatric heart recipients: maintenance immuno-

suppression at the time of follow-up between January 2000 and June 2003. Different patients were analyzed at years 1 and 5. MMF, mycophenolate mofetil. (Reprinted from Journal of Heart and Lung Transplantation, August 2004, with permission from International Society of Heart and Lung Transplantation.)

azathioprine therapy, such as bone marrow depression, have precipitated the use of mycophenolate mofetil in its place. It is well tolerated with few side effects and has been shown in large clinical trials to have benefits in survival and treated rejection episodes17 (Fig. 47-7). An increasing number of centers recommend the use of induction immunosuppression in pediatric cardiac recipients, with close to 40% of patients now receiving either a polyclonal anti-T-cell preparation, OKT3 (a murine monoclonal CD3 antibody), or an interleukin-2 receptor antibody immediately after transplantation (Fig. 47-8). However, there have been no significant differences in the average number of rejection episodes in patients treated for rejection regardless of the type of induction agent used.4 Infectious prophylaxis includes oral nystatin for fungal prophylaxis and oral trimethoprim-sulfamethoxazole three times per week. Pentamidine inhalation treatment is an effective alternative to trimethoprim-sulfamethoxazole for Pneumocystis carinii prophylaxis if bone marrow

Acute rejection and infection are the most common early complications after cardiac transplantation. Nearly 60% to 75% of patients have at least one episode of rejection, and it should be expected that about a third will have an episode in the first 3 months and 50% within the first year Some studies suggest that infants after tran~plantation.~ may be less prone to rejection than older children. Rejection surveillance is based on clinical evaluation, echocardiography, and endomyocardial biopsy. Clinical assessment includes observation of changes in a patient's activity or appetite. Atrial or ventricular ectopy, including tachycardia, is suspicious for rejection and mandates evaluation. Echocardiography is particularly useful in neonates, in whom biopsy is technically difficult and carries significant risk because of patient size. Echocardiographic evaluation is typically performed weekly for the first month and then monthly for the first year after transplantation. Echocardiography-guided transjugular endomyocardial biopsy has been shown to be an effective means of monitoring pediatric transplant recipients for rejection and remains the gold standard for detection of rejection.9 An aggressive approach consisting of routine endomyocardial biopsy weekly for the first month after transplantation, every second week for the second month, and then once monthly for the remainder of the first year has been adopted at the Children's Hospital of Philadelphia for rejection surveillance. Subsequent biopsies are obtained twice annually or whenever rejection is clinically suspected. Most biopsies are performed on an outpatient basis. The international grading system for cardiac transplant rejection is shown in Table 47-3. Episodes of acute rejection are usually treated with a 3-day course of intravenous methylprednisolone (10 mg/kg). OKT3 and antithymocyte globulin are reserved for an incomplete response or rejection refractory to steroids. Response is confirmed by follow-up biopsy 1 to 2 weeks after treatment.

Grade 0 Grade 1 A Grade 1B

Any Induction

Polyclonal ALGIATG

OK13

ILZR-antagonist

Pediatric heart recipients: induction immunosuppression (follow-up from January 2001 to June 2003). ALG, antilyrnphocyte globulin; ATG, antithymocyte globulin; IL-2R, interleukin9 receptor. (Reprinted from Journal of Heart and Lung Transplantation, August 2004, with permission from International Society of Heart and Lung Transplantation.)

Grade 2 Grade 3 A Grade 38 Grade 4

No evidence of cellular rejection Focal perivascular or interstitial infiltrate without myocyte injury Multifocal or diffuse sparse infiltrate without myocyte injury Single focus of dense infiltrate with myocyte injury Multifocal dense infiltrate with myocyte injury Diffuse, dense infiltrate with myodyte injury Diffuse and extensive polymorphous infiltrate with myocyte injury-may have hemorrhage, edema, and microvascular invasion

From Rodriguez ER: The pathology of heart transplant biopsy specimens: Revisiting the 1990 ISHLTworkingformulation. J Heart LungTransplant2003;22:3.

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Although infectious complications are common in cardiac transplant recipients, infection-related deaths do not appear to be. Bacterial infections are most frequent in the early post-transplant period but can occur late after transplantation and usually respond to proper antibiotic therapy. Of viral infections, CMV appears to be the most common and is treated with intravenous ganciclovir. Viral respiratory infections usually occur at a frequency similar to that in normal children and appear to be well tolerated by the recipient. Aside from rejection and infection, the immediate postoperative complications after heart transplantation are hypertension, seizures, renal dysfunction, and diabetes. Nearly 10% of infant heart transplant recipients require perioperative peritoneal dialysis. Among neonates, 10% to 15% require phenobarbital therapy for postoperative seizures, which may result from the use of circulatory arrest in these patients.'

LATE COMPLICATIONS The primary late complications in pediatric cardiac transplant recipients are chronic rejection, PTLD, and transplant CAD. Rejection may account for up to 40% of deaths Lymphoproliferative disease after cardiac tran~plantation.~ . . is currently treated by a reduction in immunosuppressants, acyclovir, and chemotherapy. The onset of transplant CAD has a prevalence of 10% to 15% and may be sGggested by sym$oms of congestive heart failure in recipients. Echocardiograms are performed routinely during follow-up visits of heart transplant recipients, and worsening ventricular function is a sign of graft CAD. A new onset of arrhythmias after transplantation, especially ventricular arrhythmias, may also be an indication of underlying CAD.23 Additionally, CAD may be found on routine follow-up catheterization or intracoronary ultrasound, without any previous suggestion of disease. A number of causes have been implicated in the development of graft CAD, including chronic cellular rejection, hyperlipidemia, vascular rejection, and CMV infection. Unlike adult cardiac transplant recipients, CAD appears to develop in pediatric patients relatively early after transplantation, with one series demonstrating an after transdantation.8 A incidence of 35% bv, 2 vears , review of 815 pediatric transplant patients found nearly 8% to have significant CAD by angiogram or autopsy findings.22 The mean time after transplantation to diagnosis was 2.2 years, with one patient having significant CAD 2 months after transplantation. Only 20% of patients in whom graft CAD was diagnosed were still alive, and most of the deaths were sudden o r unex~ected.Retransulantation appears to be the only viable option for these patients, although the results in general are not encouraging, with 1- and 3-year survival rates of 71% and 47%, respectively, and CAI) developing in the second grafts in 20% of retransplantation patients.20 However, the Loma Linda group has reported a significantly better retransplantation experience in infants who were first transplanted when than 6 months.14 In this group, a 10-~earactuarial survival rate of 91% was observed after retransplantation, potentially related to this center's early adoption of

a steroid-free immunosuppressive regimen. In addition, medical treatment targeted at cholesterol and lipidlowering therapies are currently under investigation.2"

RESULTS The largest group of infant cardiac transplant recipients reported in the literature is from Loma Linda, where 233 heart transplantations in infants younger than 6 months have been performed.14 Nearly 65% were for HLHS, and the rest were for other complex congenital anomalies (29%) or cardiomyopathy or tumor (8%).The operative (30-day) survival rate was 89%, with the primary causes of mortality being primary graft failure, technical problems, pneumonia, or acute rejection. The overall 1-year survival rate was 84%, with a 5- and 10-year actuarial survival rate of 73% and 68%, respectively. In addition, patients undergoing transplantation when younger than 30 days had a significantly better outcome than did older infants, with an actuarial survival rate of 80% and 77% at 5 and 10 years, potentially related to improved immune tolerance in the younger subgroup. Stanford University24 reported its series of 72 patients younger than 18 years who have undergone heart transplantation since 1977. Only 25% were younger than 1 year (mean of 9 years), and nearly two thirds had cardiomyopathy unrelated to congenital heart disease. The operative survival rate was 87.5%, with deaths mainly caused by pulmonary hypertension/right ventricular failure and acute rejection. There were 20 late deaths; 24% were due to rejection and 17% were due to graft CAD. Actuarial survival rates at 1, 5, and 10 years were 75%, 60%, and 50%, respectively. At St. Louis Children's Hospital, 45 heart transplantations were performed from 1983 to 1993, more than half in infants with HLHS.26 The infant group had a survival rate (92%) similar to that of the Loma Linda series, whereas the pediatric group (older than 1 year) had an 80% early survival rate. Results from the Registry of the International Society for Heart and Lung Transplantation reveal a perioperative mortality rate higher for infants than for older children (Fig. 47-9).4 Despite the much greater early mortality,

r ---4

9

.

1

0

.

-

,

1

2

3

Year (N=1,286) 11-17Years (N=2.048)

4

5

6

7

8

-

1-10Years (N=1,962) (N15296)

-Overall

9 1 0 1 1 1 2 1 3 1 4 1 5

Years Pediatric heart transplantation: Kaplan-Meier survival

(January 1982 to June 2002). (Reprinted from Journal of Heart and Lung Transplantation, August 2004, with permission from International Society of Heart and Lung Transplantation.)

CHAPTER

however, the half-life of 13.3 years is longer than that of the childhood or adolescent survivors. For the childhood age group of 1 to 10 years, the half-life was 17.5 years versus 13.7 years for the adolescent age group, thus conferring the younger patients a significant survival advantage. Averaged over 15 years, an infant recipient would have an approximate 2% per year risk of mortality, whereas for older children it remains approximately 4%, again indicating a long-term survival advantage for younger cardiac transplant recipients. The most predictive risk factors for 1-year mortality in the pediatric population remain congenital heart disease, retransplantation, donor age, pulmonary artery systolic pressure greater than 35 mm Hg, and need for mechanical ventilation and hospitalization while awaiting transplantation. Among the most significant risk factors for 5-year mortality are dialysis, congenital heart Causes df death Gclude CAD. disease, and female gender. " acute rejection, lymphoma, graft failure, and infection. Prevalent post-transplant morbidities for survivors include hypertension (45%), renal dysfunction (5.4%), hyperlipidemia (9.9%). , . and diabetes (3.2%).4 ~ s i d kfrom survival, it has been demonstrated that transplanted hearts in children appear to grow normally and the left ventricle increases muscle mass to maintain the normal left ventricular mass-volume ratio over time.31 Exercise testing in older children has shown peak heart rate and oxygen consumption to be consistently two thirds of that predicted in heart transplant recipients.Z1Somatic growth appears to be normal in infants after heart transplantation, and neurologic development is generally preserved, although some neurologic abnormalities may be seen in up to 20% of neonatal-recipients on long-term follow-up.4

CONCLUSION Despite further improvements in surgical technique, im~unosuppressioi, perioperative management, and rejection surveillance, long-term results of pediatric heart transplantation have shown little change, with a 15-year survival rate of approximately 50% (see Fig. 47-9). Chronic rejection, graft CAD, and the long-term effects of steroids on growth continue to cloud the development of cardiac transplantation as the primary treatment of for many complex congenital heart disease. children with-end-stage cardiomyopathy and structural heart disease not amenable to corrective surgery, transplantation is the only option. Future areas of research interest include the use df xenografts, ABO incompatibility, permanent mechanical support, and widening the bridge to transplantation with smaller and more adaptable assist devices.

ow ever,

REFERENCES 1. Bailey LL: Role of cardiac replacement in the neonate. J Heart Lung Transplant 1985;4:506. 2. Bailey LL, Gundry SR, Razzouk AJ, et al: Bless the babies: One hundred fifteen late survivors of heart transplantation during the first year of life. J Thorac Cardiovasc Surg 1993;105:805.

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3. Boucek MM, Bernstein D: Heart transplantation in infancy. Prog Pediatr Cardiol 1993;2(4):20. 4. Boucek MM, Edwards LB, Keck BM, et al: The Registry of the International Society for Heart and Lung Transplantation: Seventh Official Pediatric Report--2004. J Heart Lung Transplant 2004;23:933. 5. Bove EL: Transplantation after first-stage reconstruction for hypoplastic left heart syndrome. Ann Yhorac Surg 1991; 52:701. 6. Bove EL: Surgical treatment for hypoplastic left heart syndrome. Jpn J Thorac Cardiovasc Surg 1999;47(2):47. 7. Braunlin EA, Canter CE, Olivari MT, et al: Rejection and infection after pediatric cardiac transplantation. Ann Thorac Surg 1990;49:385. 8. Braunlin EA, Hunter DW, Canter CE, et al: Coronary artery disease in pediatric cardiac transplant recipients receiving triple-drug immunosuppression. Circulation 1991;84(Suppl):III303. 9. Canter CE, Appleton RS, Soffitz JE, et al: Surveillance for rejection by echocardiographically guided endomyocardial biopsy in the infant heart transplant recipient. Circulation 1991;84(Suppl 111)111-310. 10. Canter CE, Moorehead S, Soffitz JE, et al: Steroid withdrawal in the pediatric heart transplant recipient initially treated with triple immunosuppression. J Heart Lung Transplant 1994;13:74. 11. Canter CE, SoffitzJE, Moorehead S, et al: Early results after pediatric cardiac transplantation with triple immunosuppression therapy. Am J Cardiol 1993;71:971. 12. Cooper MM, Fuzesi L, Addonizio LI, et al: Pediatric heart transplantation after operatictns involving the pulmonary arteries. J Thorac Cardiovascular Surg 1991;102:386. 13. del Nido PJ, Armitage JM, Fricker FJ, et al: Extracorporeal membrane oxygenation support as a bridge to pediatric heart transplantation. Circulation 1994;90(5 Pt 2, Suppl):II66. 14. Fortuna KS, Chinnock RE, Bailey LL, et al: Heart transplantation among 233 infants during the first six months of life: The Loma Linda experience. Loma Linda Pediatric Heart Transplant Group. Clin Transpl 1999;263. 15. Hosenpud JD, Bennen LE, Keck BM, et al: The Registry of the International Society for Heart and Lung Transplantation: Eighteenth Official Report-2001. J Heart Lung Transplant 2001;20:805. 16. Kirshborn PM, Bridges ND, Myung RJ, eta]: Use of extracorporeal membrane oxygenation in pediatric thoracic organ transplantation. J Thorac Cardiovasc Surg 2002;123:130. 17. Kobashigawa JA: Mycophenolate mofetil in cardiac transplantation. Curr Opin Cardiol 1998;13:117. 18. Lewis AB: Prognostic value of echocardiography in children with idiopathic dilated cardiomyopathy. Am Heart J 1994;128:133. 19. ' ~ o w e RR, r Shumway NE: Studies on orthotopic homotransplantations of the canine heart. Surg Forum 1960;11:18. 20. Michler RE, Edward NM, Hsu D, et al: Pediatric retransplantation. J Heart Lung Transplant 1993;12:5319. 21. Nixon PA, Fricker FJ, Noyes BE, et al: Exercise testing in pediatric heart, heart-lung and lung recipients. Chest 1995; 107:1328. 22. Pahl E, Zalos VR, Ficker FI, et al: Posttransplant coronary artery disease in children: A multicenter national survey. Circulation 1994;9(5Pt 2, Suppl):II56. , 23. Park JK, Hus DT, Hordof AI, et al: Arrhythmias in pediatric heart transplant recipients: Prevalence and association with death, coronary artery disease, and rejection. J Heart Lung Transplant 1993;12:596. 24. Sarris CE, Smith JA, Bernstin D, et al: Pediatric cardiac transplantation: The Stanford experience. Circulation 1994;90(5 Pt 2, Suppl) 3151.

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25. Seipelt IM, Crawford SE, Rodgers S, et al: Hypercholesterolemia is common after pediatric heart transplantation: Initial experience with pravastatin. J Heart Lung Transplant 2004;23:31'7. 26. Spray TL: Transplantation of the heart and lungs in children. Annu Rev Med 1994;45:139. 27. SwensonJM, Fricker FJ, Armitage JM: Immunosuppression switch in pediatric heart transplant recipients: Cyclosporine to FK506. J Am Coil Cardiol 1995;25:1183. 28. Tamisier D, Vouhe P, Le Bidois J, et al: Donor-recipient size matching in pediatric heart transplantation; a word of

caution about small grafts. J Heart Lung Transplant 1996; 15:190. 29. West LJ, Pollock-Barziv SM, Dipchand AI, et al: ABOincompatible heart transplantation in infants. N Engl J Med 2001;344:'793. 30. Wiles HB: Prognostic features of children with idiopathic dilated cardiomyopathy. Am J Cardiol 1991;68:1372. 31. Zales VR, Wright KL, Pahl E, et al: Normal left ventricular muscle mass and mass/volurne ratio after pediatric cardiac transplantation. Circulation 1994;90(5 Pt 2, Suppl):II61.

Lung Transplantation Charles B. Huddleston and Joel Cooper

The first reported attempt at lung transplantation occurred in 1963 and was performed by Dr. James Hardy at the University of Mississippi Medical Center.27 The patient did not survive the hospitalization, dying 18 days after the transplant. There were a number of additional attempts at this over the next few years, with most failures related to poor healing in the airway anastomosis. Approximately 20 years after Dr. Hardy's ill-fated effort, the first truly successful lung transplant was performed in Toronto, Canada, by a team led by Dr. Joel Cooper. This patient had a single-lung transplant for pulmonary fibrosis and survived for more than 6 years, ultimately dying of renal failure.8 Over the years since, and particularly in the late 1990s, pediatric lung transplantation has emerged as a viable treatment option for children with end-stage pulmonary parenchymal and vascular diseases. However, the number of children undergoing transplants throughout the world since 1989 remains relatively small, representing only 4% of all lung transplants performed.67 In this chapter, pediatric lung transplantation is described as an isolated procedure and heart-lung transplantation is not included.

INDICATIONS Isolated lung transplantation is applicable to any child with life-threatening and progressive disability due to pulmonary parenchymal or vascular disease. In general, this treatment modality is indicated for increasing the duration of life, not solely for improvement of the quality of life. The current long-term survival after lung transplantation is approximately 50% at 5 years. Thus, the selection of patients for transplantation and the timing of the procedure are critically important. One would like to be able to predict when a child would be within 2 years of dying without any form of medical treatment. Obviously this may be very difficult. The major diagnostic groups for pediatric lung transplantation are cystic fibrosis, interstitial lung disease with pulmonary fibrosis, primary pulmonary hypertension, pulmonary hypertension associated with congenital heart disease, retransplantation, and a "miscellaneous" category (Table 48-1).

Chronic obstructive lung disease, the most common indication for transplantation in adults, is remarkably absent from this list.67

Cystic Fibrosis This disease, the most common lethal hereditary disease in North America, comprises the largest diagnostic group of children younger than age 18 years undergoing lung transplantation. Although the median survival now exceeds 29 years, one third of the deaths from cystic fibrosis occurs in the pediatric age group. without' question, the most common cause of death is respiratory. About 100 transplants are performed annually in the United States for cystic fibrosis,l3 and although this number is growing slokly each year, donor availability still remains a major limiting factor. As with other diagnostic groups, timing of transplantation in the course of a chronic disease is a crucial issue. Kerem, in the early 1990s, demonstrated that an FEV, less than 30% of predicted, Pao2 less than 55 mm Hg, and/or a Pco2 greater than 50 mm Hg was associated with a survival beyond 2 years of less than 5076." The impact of these factors is magnified in the pediatric age group, particularly in girls. However, more recent studies on the natural history of cystic fibrosis patients once they have severely compromised lung function show that an isolated measure of the FEV, alone may not be sufficiently predictive.

Cystic fibrosis Pulmonary fibrosis Pulmonary vascular disease Primary pulmonary hypertension Eisenmenger's syndrome Bronchiolitis obliterans Retransplant Other

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The rate of decline in the FEVl may be a more accurate determinant of surviva1.47,58 Other factors that may serve as relative indicators in deciding to proceed toward transplantation include the need for continuous supplemental oxygen, increased frequency for hospitalizations, and diminished weight for height (below the 80th percentile) .39 The presence of antibiotic-resistant organisms in the sputum is a relative contraindication to lung transplant. The synergistic effectiveness of antibiotic combinations is certainly an important evaluation of any resistant organism, whether consideration for transplantation is underway or not. It is reasonable to proceed with transplantation in the presence of most organisms with a highly resistant antibiotic profile as long as there are synergistic combinations available. However, Burkholdm'a cepacia colonization is associated with a particularly poor prognosis and ~ , ~ ~hypertension therefore is of particular c o n ~ e r n . *Portal with hepatic cirrhosis occurs in 5% to 10% of patients with cystic fibrosis. These children are at risk for variceal bleeding as well as derangements of synthetic function. In general, if the synthetic function is preserved, decompression of the portal venous system with percutaneous procedures will lower the risk to a level satisfactory for lung tran~plantation.~~ However, when there is also synthetic dysfunction of the liver, combined liver-lung transplantation may be the only appropriate option.11 Diabetes mellitus is generally not considered a contraindication to transplantation unless there is evidence of vasculopathy, bearing in mind that control of serum glucose will be more difficult after transplantation.Ig As many as 10% to 15% of CF lung transplant candidates will have had prior thoracotomies for either pneumothorax or pulmonary resection. Most centers do not consider this a contraindication to transplantation, although the resultant adhesions from these prior operations do increase the difficulty and the risk of bleeding.18 Mechanical ventilation or presence of a tracheostomy are not in and of themselves contraindications to transplantation, but the overall medical condition of patients requiring this level of support must be carefully considered.

Pulmonary Vascular Disease This rather broad classification of patients includes those with primary pulmonary hypertension (PPH) and those with pulmonary hypertension associated with congenital heart disease (PH/CHD). The latter category includes patients with Eisenmenger's syndrome but is not limited to this. These patients die of either progressive rightsided heart failure, arrhythmias, or a lethal episode of hemoptysis. It is difficult to predict when a patient might have a fatal arrhythmia or hemoptysis episode. However, most patients with pulmonary vascular disease will die of progressive right-sided heart failure over a protracted period of time.l"n the past several years a number of somewhat selective pulmonary vasodilators have become available for use in these patients. These include intravenous prostacyclin,' prostacyclin analogues iloprost (inhaled)ZYand betaprost (oral),50and b o ~ e n t a n ,an ~ endothelin receptor antagonist. These drugs have enabled patients to put off the need for transplantation

for years. In fact, the number of patients undergoing transplantation for pulmonary vascular disease has significantly dropped in recent years. The timing of transplantation for patients with pulmonary vascular disease is influenced significantly by the response to medical therapy and the underlying cause of the pulmonary vascular disease. While primary pulmonary hypertension and Eisenmenger's syndrome result in identical histologic changes in the pulmonary vascular bed. the latter of these two is associated with a much more favorable long-term prognosis. A retrospective analysis by Hopkins of 100 adults with severe pulmonary hypertension due to either Eisenmenger's syndrome or PPH revealed that, in the former group, actuarial survival without transplantation was 97% at 1 year, 89% at 2 years, and 7'7% at 3 years. In contrast, survival was 77%, 69%, and 35% over the same respective time intervals in the PPH cohort." It is presumed that the intracardiac defect allows the right ventricle to "decompress" via the defect when the afterload in the pulmonary vascular bed becomes prohibitively high. 0;the basis of this and other observations, atrial septostomy performed in the cardiac catheterization suite has been demonstrated to provide clinical benefit in patients with PPH.41Results from a multicenter study of patients with PPH performed before the advent of long-term intravenous prostacyclin therapy demonstrated a median survival from time of diagnosis of 2.8 years. In that study, a formula was developed incorporating hemodynamic variables to assist in hredicting the 2-year mortality" and it was recommended that patients should be listed when this figure is less than or equal to 50%. Studies regarding natural history in adults have been applied to children, but it is unclear whether this disease behaves the same in a younger population. Clabby and coworkers reviewed 50 patients from many centers to provide a means of estimating survival in chiidren with PPH.6 There was a direct correlation of mortality with the product of the mean right atrial pressure and the pulmonary vascular resistance.With progress in the medical therapy of PPH to identify selective pulmonary vasodilators as well as the underlying mechanisms of this disease, these formulas predicting survival may be obsolete. The durability of medical therapy is unclear. How this therapy might be applied to secondary pulmonary hypertension, such as Eisenmenger's syndrome, is speculative. The two main issues in considering patients with Eisenmenger's syndrome or PH/CHD for lung transplantation are the timing of listing and the complexity of the cardiac lesion to be repaired. As noted earlier, it is clear that, once the diagnosis is made, these patients can live much longer than those with PPH.SOThe mode of " death in these patients is by progressive heart failure, pulmonary hemorrhage, stroke, or sudden death presumablv due to arrhvthmias.6 Patients should be listed when symptoms develop, when there has been a single pulmonary hemorrhage, or perhaps ai'bitrarily when they reach their late 30s. Most patients with PH/CHD have an atrial septal defect, ventricular septal defect, or patent ductus arteriosus. All of these require relatively simple cardiac repairs. However, there are patients with unrepaired atrioventricular canal defects, transposition of the great arteries, and truncus arteriosus who would

CHAPTER

require more complex procedures. An alternative for these patients would be a heart-lung transplant. The likelihood of obtaining a donor heart-lung block for anyone over 40 kg is low because of the distribution policy for thoracic donor organs. In addition, the long-term survival after heart-lung transplantation is particularly poor (approximately 40% at 5 years post transplant) .67 These two issues must be factored into the decision as to whether one should perform the higher-risk procedure of lung transplantation in combination with repair of a complex cardiac lesion or a heart-lung transplantation. Some patients with congenital heart disease who have undergone repair may not experience the expected decline in pulmonary vascular resistance after appropriate correction. Occasionally the repair has been performed relatively late in life, but there are children who have undergone timely repair and still present later on with sekere pulmonary hypertension. It is not clear how to cjassify these patients. In general, this is a less uniform group than either the patients with PPH or those with Eisenmenger's syndrome. They seem to follow a clinical course similar to that seen in patients with PPH and should be treated in a similar fashion.gO Another diagnostic group with pulmonary vascular disease are patients with an inadequate pulmonary vascular bed. Examples of this include pulmonary atresia, ventricular septal defect and multiple aortopulmonary collaterals, and congenital diaphragmatic hernia, where there is primarily a general deficiency of pulmonary parenchyma. In the former group, complete correction (repair of the ventricular septal defect combined with reconstruction of the right ventricular outflow tract with a conduit to the unifocalized aortopulmonary collaterals) represents a high-risk but viable option for the majority of these patients. However, when the anatomy of the aortopulmonary collaterals is not amenable to unifocalization or when unifocalization has not produced satisfactory growth of the pulmonary vascular tree, the result is progressive cyanosis or progressive pulmonary hypertension or both. Lung transplantation with repair of the residual cardiac defect may be the only feasible option for survival. Children with congenital diaphragmatic hernias, despite having undergone a successful hernia repair, may still be left with inadequate pulmonary parenchyma and vascular bed to handle the full cardiac output. The resultant severe pulmonary hypertension is the usual cause of death in these infants and is an indication for transplantation. The problem here is that these infants often will require extracorporeal membrane oxygenator support during the perioperative period. This reduces the time that patients such as this can wait for a donor offer once listed for lung transplantation. It is possible that a single-lung transplant on the affected side would be sufficient in this circumstance. In this scenario, once the patient has grown it may be possible to remove the transplanted lung altogether, leaving the patient with a presumably normal contralateral lung to maintain normal respiratory function. In reality, those patients with insufficient pulmonary reserve will have to be identified very early in the course for lung transplantation to be a realistic option. The mortality is quite high even when donor organs are identified.

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In all the previous situations, isolated lung transplantation is appropriate only when left ventricular function is normal. Poor left ventricular function will result in elevated left ventricular enddiastolic pressure post transplant, which will add significantly to problems with pulmonary edema and early graft failure. Right ventricular function is frequently poor, particularly in the patient group with PPH. That should not be a deterrent to isolated lung transplantation because the right ventricular function always returns to normal within a relatively short period of time.53 Although a prior thoracotomy is generally not a contraindication to lung transplantation in patients with pulmonary parenchymal disease, this is not true for those with pulmonary vascular disease, especially when secondary to congenital heart disease and associated with cyanosis. The adhesions that develop after a thoracotomy for palliation of cyanotic congenital heart disease are extremelv vascular. Intercostal and internal mammarv arteries will form direct connections through the pleura into the parenchyma of the lung in a compensatory attempt to enhance pulmonary blood flow. The bleeding that results during the recipient pneumonectomy portion of the transplant procedure is often horrendous and life threatening.

Pulmonary Fibrosis These patients account for 5% to 10% of pediatric patients undergoing lung transplantation." Placed in this category are those patients with "usual" interstitial fibrosis, radiation-induced fibrosis, bronchopulmonary dysplasia, and pulmonary fibrosis secondary to chronic aspiration. The progression of these disease processes is quite variable. Generally, patients should be listed when normal activities are markedly limited and minor viral illnesses lead to significant deterioration. Most patients will be oxygen dependent and may well have evidence of coexistent pulmonary hypertension. For those in whom aspiration is the underlying problem, the source of the aspiration must be eliminated. The prognosis of children with idiopathic pulmonary fibrosis is not altogether clear. This may be because there is not a "usual interstitial pulmonary fibrosis" disease in children-the underlying causes are frequently unique and unusual. Decisions regarding listing for transplantation are somewhat difficult because of this. Pulmonary fibrosis presenting during infancy was once believed to have a poor prognosis; however, recent studies have demonstrated much improved survival with high doses of corticosteroid therapy.51 The prognosis for adults with total lung capacity less than 60% predicted is still poor; nearly all are dead within 2 years.37It is difficult to translate this information into the pediatric experience. Pulmonary hypertension frequently accompanies this disease as it progresses. These patients-should be evaluated and listed for transplantation when they become symptomatic. If there is a favorable response to corticosteroids they can be followed with standard (age > 5 years) or infant (age < 5 years) pulmonary function tests. One problem with this disease is that patients with progression of their disease tend to remain on relatively high

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doses of corticosteroids and come to transplantation in a rather cushingoid state. This should not exclude them from transplantation.

issue is unresolved. One can only advise use of proper judgment in selecting only the best candidates when the issue of retransplantation arises.

Bronchiolitis Obliterans and Retransplantation

Miscellaneous

Bronchiolitis obliterans is not a specific disease but rather a histologic description characterized by the obstruction and destruction of the distal airways. It may occur as a consequence of any severe lung injury, including viral pneumonia, graft-versus-host disease after bone marrow transplant, autoimmune diseases, chemical injury, Stevens-Johnson syndrome, and others. Of course, it is a relatively common late complication of lung transplantation (see later). The underlying etiology is unknown. "Primary" bronchiolitis obliterans (not related to a prior lung transplant) is a perfectly legitimate indication for lung transplantation: it is a slowly progressive disease in virtually all cases with no known effective treatment. When this disorder occurs as a consequence of an isolated lung injury, transplantation is a fairly straightforward decision process. However, those patients with prior bone marrow transplants (usually for leukemia) offer special considerations." Although the standard definition of "cure" is remission of the malignancy for more than 5 years, most of these patients present within 2 or 3 years. Another problem is the deranged immune competency seen after bone marrow transplant and how the immunosuppressant agents used after lung transplantation might further affect this. We have found that these patients have less acute rejection than most other lung transplant recipients but may be more prone to opportunistic infecti0ns.5~However, the number of patients transplanted in this setting is low. For patients who acquire bronchiolitis obliterans through other immunologic injuries, such as autoimmune disorders, there are concerns about the likelihood of recurrence in transplanted lungs. One would have to ascertain that the primary process has completely abated before transplantation. Retransplantation for acute graft failure after transplantation has an extremely poor prognosis4gand is not an option from a practical standpoint because of the long waiting times. Rarely, consideration may be given to this option in infants who generally have significantly shorter waiting times. Retransplantation for bronchiolitis obliterans is a controversial issue. Bronchiolitis obliterans accounts for the majority of deaths occurring more than 90 days post transplant." This figure is borne out in our pediatric ~ e r i e s . ~ W t h o u gearly h mortality after retransplantation is higher than for "first-time" lung transplants, those who do survive this early phase have long-term survival similar to the non-redo transplant^.^^ Risk factors for poor early outcome include nonambulatory status, short period of time since the first transplant, transplantation at a center with limited experience, and dependence on mechanical ventilation. We have further noted that a low glomerular filtration rate is an independent risk factor. Because patients continue to die on the waiting list, one could argue that no patient should ever be retransplanted because this might deprive an otherwise lower-risk patient from receiving organs in a timely fashion. At present this

A variety of diagnoses fall into this group. Congenitally based pulmonary parenchymal diseases constitute one of the more interesting broad categories. Typically, these fullterm newborns present with severe respiratory distress and no obvious cause such as meconium aspiration, sepsis, or persistent fetal circulation. The diagnoses falling into this category include surfactant protein B deficiency, other forms of pulmonary alveolar proteinosis, alveolar-capillary dysplasia, pulmonary dysmaturity, congenital interstitial pneumonitis, and others. These infants usually have severe respiratory failure and require a high level of ventilatory support. Often extracorporeal membrane oxygenation (ECMO) has been or is currently being used. An open-lung biopsy is often necessary to either make the diagnosis or to exclude other diagnoses. Surfactant protein B deficiency can now be diagnosed by looking for the specific genetic mutation in peripheral blood and assaying tracheal effluent for the presence of this surfactant protein.Z5All children with this diagnosis survive less than 3 months even with aggressive therapy. Additionally, because the surfactant proteins are expressed only in the lungs, extrapulmonary organ dysfunction is rare. Until other therapies become available, lung transplantation is the only viable therapeutic option. Abnormalities in the gene coding surfactant protein C have also been identified as a cause for interstitial lung disease in infants, which may progress to the point of requiring lung transplantation.26 In general, the waiting time for an organ offer is relatively short in infants. Therefore, one might realistically believe that an infant with a 3-month life expectancy could undergo a transplant and survive. When an infant is on ECMO every effort should be made to wean from it using whatever means possible, including high-frequency oscillating ventilator and/or nitric oxide. Although ECMO is not an absolute contraindication to transplantation, one should be very cautious in this setting because of the relatively high incidence of other organ dysfunction.

CONTRAINDICATIONS Contraindications to transplantation in children are also based on experience obtained in adults (Table 48-2). Absolute contraindications include systemic disease with major extrapulmonary manifestations or severe dysfunction of other organ systems. Thus, widespread malignancy, collagen vascular disease, human immunodeficiency virus infection, and severe neuromuscular disease are absolute contraindications. The acceptable degree of renal insufficiency is open to some interpretation. Given the nephrotoxicity of cyclosporine and tacrolimus, the drugs that form the basis of nearly all immunosuppressant regimens, a serum creatinine value greater than 2.0 mg/dL and a probable need for post-transplant dialysis are clinical parameters that would mitigate strongly against proceeding with transplantation. A glomerular filtration rate

CHAPTER

Absolute Malignancy Human immunodeficiency virus infection Multisystem organ failure Left ventricular dysfunction Active collagen vascular disease Severe neuromuscular disease Relative Renal insufficiency Liver function impairment Malnutrition Resistant organisms in the sputum Poorly controlled diabetes mellitus Osteopenia Prior thoracotomies in the presence of pulmonary vascular disease Prior pneumonectomy with mediastinal shift Extreme prematurity Poor compliance Inadequate psychosocial support system

less than 50 mL/min has been associated with a poor outcome in some patients. Significantly deranged hepatic synthetic function precludes transplantation unless concomitant liver transplantation is also being undertaken. More complex issues include severe malnutrition, poorly controlled diabetes mellitus, osteopenia, vertebral compression fractures, and the need for mechanical ventilation. None of these factors in and of themselves serves as an absolute contraindication. Nonetheless, all such concerning aspects of the clinical presentation must be evaluated and carefully considered in the scope of the patient's overall state of health to assess the likelihood for successful recovery after the transplant. Chronic administration of corticosteroids before the transplant is considered to be undesirable; and, when possible, one should reduce the total daily dose or change to an every-other-daydosage schedule. Previously, corticosteroidswere believed to have a significant negative impact on airway healing, particularly in the case of double-lung transplant with a tracheal anastomosis. Bilateral sequential lung transplantation with bronchial anastomoses has obviated this problem to a large degree. Severe psychiatric disorder in either the patient or, in the case of a young child, the care provider is a strong relative contraindication. Finally, a history of poor compliance with either a medical regimen or in keeping follow-up appointments is considered by most to be a strong relative contraindication to transplantation. Graft failure due to lack of proper care not only results in death to the recipient involved but also results in either a delayed or denied transplant for a more appropriate candidate.2"

Special Circumstances Some infants born extremely prematurely survive the early days of their lives only to develop severe bronchopulmonary dysplasia with respiratory failure within

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the first year of life. The incidence of significant cerebral injury in this group is high; approximately 50% of those surviving have some disability.45 We can only assume that the incidence is higher in those with severe residual lung disease requiring transplantation. It is often difficult to assess the neurologic status in these infants because of their small size and often the need for sedation and neuromuscular paralysis for maintenance of satisfactory ventilation. It is probably unwise to submit an infant born at 25 to 28 weeks' estimated gestational age to lung transplantation unless there has been an opportunity for an accurate neurologic examination. Imaging studies may offer some reassurance but are inconclusive. Another unusual situation that arises where lung transplantation may be considered appropriate is the child with severe acute respiratory distress syndrome. Those children still in the acute phase of this illness often have other organ dysfunction and their condition is too unstable for them to wait the obligatory time once listed for transplantation given the current organ allocation system. Those who survive the early phase of acute respiratory distress syndrome and are left with fibrotic lungs and stable ventilatory requirements should be evaluated. Finally, occasionally a patient with a history of prior pneumonectomy will be referred for lung transplantation. After pneumonectomy in children, the mediastinum shifts to the affected side. This distorts the hilar structures to the point that bilateral or single lung transplant is virtually impossible. When possible, a patient undergoing pneumonectomy who might require lung transplant in the future should have a prosthetic spacer placed in that side of the chest to maintain normal mediastinal geometry.

DONOR EVALUATION AND ORGAN PROCUREMENT Donor availability remains a major limitation to the applicability of transplantation for end-stage lung disease. Donors must be matched by ABO blood type compatibility and within a reasonable size range of the recipient. Height is used as the most accurate correlate to lung size. Height that falls within 25% of the recipient height is probably suitable. Extending this range upward is certainly feasible, because it is not difficult to reduce the size of the lungs by trimming off the edge or even using only the lower lobes. However, extending the lower limit should be done with great caution-the transplanted lungs may not fill the chest and may be more prone to pulmonary edema. Donors are excluded in the presence of positive HIV serology, active hepatitis, history of asthma, tuberculosis, or other significant pulmonary disease. A history of limited cigarette smoking is probably acceptable if other parameters of the evaluation fall within the guidelines. 1n general, the upper limit of donor age is approximately 55 years. The chest radiograph should be free of infiltrates and the arterial oxygen tension should be more than 300 mm Hg on an inspired oxygen fraction of 1.0 with an appropriate tidal volume and 5 cm H 2 0 positive end-expiratory pressure. Mild pulmonary contusions and subsegmental atelectasis would not necessarily exclude a dono; as long as these criteria are met. when the procurement team arrives at the donor institution,

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flexible bronchoscopy should be performed to examine the airways for erythema suggestive of aspiration of gastric contents. In addition, this provides an opportunity to assess the nature and quantity of pulmonary secretions. The presence of purulent secretions that do not clear well with suctioning should exclude the donor even if the chest radiograph is clear and the oxygenation is adequate. he surgical part of the procurement process is performed via a median sternotomy. Both pleural spaces are opened widely to allow visual inspection of the lungs and also the topical application of cold saline and slush. The trachea is dissected out between the superior vena cava and aorta. It may be helpful to develop the interatrial groove also to allow a more accurate division of the left atrial tissue that must be shared with the cardiac donor team in most situations. The principles of the procurement process beyond this are (1) anticoagulation with high dose (300 units/kg) heparin; (2) bolus injection of prostaglandin El (50 to 70 pg/kg) directly into the main pulmonary artery; (3) decompressing the right side of the heart by incising the inferior vena cava; (4) decompressing the left side of the heart by amputating the left atrial appendage; (5) high volume (50 mL/kg), low pressure flush of cold (4°C) pulmonary preservation solution of choice; (6) topical application of cold saline and slush to the lungs; and (7) continued ventilation of the lungs with low volumes and low pressures using an Fi02 of 0.4. When all the preservation solution has been administered, the lungs are excised en bloc with the posterior mediastinal tissue, including the esophagus and descending aorta. The esophagus is isolated with a stapling device to avoid contamination. The trachea is divided while the lungs are held in gentle inflation (pressure of 20 cm H 2 0 ) with the FiO, at 0.4. The lungs are then extracted, placed in a bag containing the preservation solution used for the flush, and then placed in cold storage for transport. Much research has been devoted to finding the "ideal" preservation solution to extend potential ischemic times and avoid reperfusion injury.35 A full discussion of this complex topic goes beyond the scope of this chapter. The most commonly employed preservation solutions at this time are modified Euro-Collins solution, University of Wisconsin solution, Perfadex, and Celsior. None of these is clearly superior to the others, and all work reasonably well. However, none reliably allows for preservation times greater than 8 hours and none completely avoids reperfusion injury.

-

TECHNIQUE OF TRANSPLANTATION The surgical technique used for children is like that for adults with the exception that virtually all children will require cardiopulmonary bypass, whereas that is not always necessary in adults. Transplantation without cardiopulmonary bypass would require single-lung ventilation during the procedure. Maintaining single-lung ventilation in these small children is extremely difficult because the airways are too small to accommodate double-lumen endobronchial tubes. Bilateral lung transplant is performed for

nearly all children because of concerns over the growth potential of the transplanted lungs. Trans-sternal bilateral anterior thoracotomy incision (the so-called "clamshell incision") via the fourth intercostal space provides excellent exposure of the heart and hilar regions. Absorbable suture is used for all anastomoses to provide the greatest potential for growth.20 We recommend a simple end-toend rather than a telescoping anastomosis for the airway because of the high incidence of stenosis in the latter.l7,32 If the patient requires concomitant repair of an intracardiac lesion (e.g., with Eisenmenger's syndrome), that is best performed after the recipient pneumonectomies and before implanting the donor lungs. Many of these patients have significant aortopulmonary collaterals resulting in significant pulmonary venous return to the heart while on cardiopulmonary bypass. After the recipient lungs have been removed, the absence of pulmonary venous return to the heart from bronchial arteries and other collateral vessels will allow for a bloodless operative field for the intracardiac repair. The subsequent period during which allograft implantation is performed provides sufficient time for cardiac reperfusion before weaning from cardiopulmonary bypass. Living donor lobar transplantation, and the use of cadaveric lobes, has become more commonplace as an alternative to standard cadaveric "whole lung" transplantation.62 This has been driven primarily by donor shortage. Although the upper lobes have been used, lower lobes seem better suited anatomically, with each lobe serving as an entire lung. When lobes come from a living donor there is less bronchial and vascular tissue with which to work and thus longer cuffs of the bronchus, pulmonary artery, and pulmonary vein of the recipient will facilitate the procedure. A technique has been devised whereby a single left lung can be partitioned such that the upper lobe is used on the right and the lower lobe on the left.I2 The circumstances under which one might employ this technique would be quite unusual-a single left lung from a large donor being made available to a desperately ill child. Nonetheless, it is another attempt at solving the ongoing problem of inadequate donor organ supply.

IMMUNOSUPPRESSION Although the precise protocols differ from one center to another, most employ the so-called triple-drug immunosuppression approach (Table 48-3). Combinations of these immunosuppressant drugs allow for a better overall effect with a relatively less toxic dose of any one agent. Drug regimens generally include cyclosporine or tacrolimus in combination with azathioprine and prednisone. There is no clear advantage of cyclosporine over tacrolimus or vice versa in terms of efficacy or side effect profile. The use of induction cytolytic therapy using antithymocyte globulin or OKT3 is somewhat controversial but is generally not recommended because of infectious complications associated with their use. Daclizumab and basiliximab, specific monoclonal antibodies to interleukin 2, have been introduced as an alternative to cytolytic

CHAPTER

48

Lung Transplantation

771

transplantation because there has been evidence of impaired wound and airway healing resulting in serious Class of Drug

complication^.^^

Side Effects

Interleukin-2 Synthesis inhibitors Cyclosporine Hypertension, seizures, nephrotoxicity, hirsutism, gingival hyperplasia Tacrolimus Hyperglycemia, seizures, nephrotoxic Lymphocyte Proliferation Inhibitors Azathioprine Leukopenia, nausea Mycophenolate mofetil Leukopenia, nausea, diarrhea, elevated liver enzymes Sirolimus Hypertriglyceridemia,delayed wound healing Corticosteroids Hypertension, hyperglycemia, cushingoid appearance Induction Agents Antithymocyte globulin

OKT3

Daclizumab, basiliximab

Fever, chills, leukopenia, cytomegalovirus infections, post-transplant lymphoproliferative disorder Fever, chills, cytomegalovirus infections, post-transplant lymphoproliferative disorder Nausea, diarrhea

agents to "induce" t ~ l e r a n c eRather .~ than cytolytic, these drugs work by blocking a critical pathway in the activation of lymphocytes involved in cellular rejection. The low infection rate using. " these monoclonal antibodies has stimulated the reemergence of induction therapy early after lung transplant.3 The initial target trough cyclosporine blood level is 300 to 400 ng/mL by whole blood monoclonal assay. When tacrolimus is used, that target trough level is 10 to 15 ng/mL. The initial corticosteroid dose is 0.5 mg/kg daily of prednisone or methylprednisolone. Azathioprine is given in a dose of 2.5 to 3.0 mg/kg daily. Acute rejection is treated with 3 consecutive days of intravenous methylprednisolone at a dose of 10 mg/kg. Rejection refractory to methylprednisolone is treated with antithymocyte globulin for 7 to 10 days. Recurrent (>2) bouts: of acute rejection prompt a change of the baseline immunosuppression from cyclosporine and azathioprine to tacrolimus and mycophenolate mofetil. Although the corticosteroid dose is gradually tapered over time, we do not believe it is appropriate to stop this drug altogether. The side effects of immunosuppressive drugs in children are similar to those seen in adults, although-the hirsutism associated with cyclosporine is clearly a more significant problem in young, female children. This adverse effect may be of sufficient magnitude to occasionally warrant a switch to tacrolimus. Sirolimus (rapamycin) is chemically similar to tacrolimus but inhibits the proliferative response of lymphocytes to interleukin-2." It does not share the nephrotoxic potential of tacrolimus. It is currently reserved for situations of failure of other immunosuppressant drugs. Some caution should be exercised in using sirolimus as initial immunosuppression early after L,

All patients receive prophylaxis against Pneumocystis carinii pneumonia with either sulfamethoxazole-trimethoprim orally three times per week or monthly treatment with aerosolized pentamidine when sulfa allergy or intolerance is present. Prophylaxis against mucocutaneous Candida infections is also employed.

POST-TRANSPLANT SURVEILLANCE Surveillance after transplantation is based on periodic spirometry and bronchoscopy with biopsies and bronchoalveolar lavage. Before discharge from the hospital, patients are provided with a home spirometer and are asked to perform spirometry at least once daily. A decrease in FEVl of greater than 10% from baseline is considered an indication for evaluation. All patients, regardless of size, undergo regularly scheduled surveillance bronchoscopy to diagnose lower respiratory infections, subclinical graft rejection, and airway anastornotic complications. Virtually all episodes of suspected rejection should be confirmed with transbronchial biopsies. The main challenge occurs in small infants in whom a flexible fiberoptic bronchoscope large enough to provide a lumen for biopsy forceps may obstruct the airway. A technique of nonbronchoscopic "blind transbronchial biopsy using a suction catheter for guiding the biopsy forceps into the proper position has been devised.48More recently, a mini-forceps has been developed for use in the 3.5-mm pediatric flexible fiberoptic bronchoscope. Bronchoscopy with biopsy is performed at 10 to 14 days, 6 weeks, and then 3 , 6 , 9 , 12, 18, and 24 months after transplant as a surveillance procedure. Worsening pulmonary function, infiltrates on a chest radiograph, or deterioration in clinical status, such as fever or an oxygen requirement, also prompt bronchoscopy and biopsy. Bronchoalveolar lavage is performed at these procedures for quantitative bacterial, routine viral, and fungal cultures.

POST-TRANSPLANT COMPLICATIONS Surgical Complications Anastomotic Complications Anastomotic complications can involve either the airway or the vascular anastomoses. Airway dehiscence was the major source of early morbidity and mortality in the early days of lung transplantation when tracheal anastomoses were performed. Not until this problem was solved by using an omental wrap for the airway anastomosis could dehisclinical lung transplantation progre~s.~,Currently, cence is rare in spite of the fact that most do not use the omental wrap any longer but rather approximate donor and recipient peribronchial tissue over the anastomosis. Dehiscence of the airway may be either partial or total. Partial dehiscence can usually be treated expectantly

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but puts the airway at increased risk of late ~tenosis.~" Complete dehiscence requires emergent therapy and is generally a lethal complication. Although reanastomosis should be attempted when possible, it is associated with a high failure rate and transplant pneumonectomy is required. Smaller airway size in children prompted concerns about whether the incidence of bronchial anastomotic stenosis would be higher and also whether the anastomoses would grow. Current evidence suggests that the airways at the anastomoses grow and that the incidence of bronchial stenosis is not affected by age or size Bronchial stenosis is usually at the time of tran~plant.3~2" treated with dilatation initially with either progressively larger rigid bronchoscopes or with an angioplasty balloon. Balloon dilatation of a stricture may be preferable because it is less likely than a rigid bronchoscope to traumatize the distal airway. Repeat bronchoscopy 10 to 14 days after initial dilatation of a bronchial stenosis is necessary to judge the overall effectiveness and to assess the likelihood of recurrence. Depending on the severity of the initial stricture or the rapidity with which it recurs, one might consider placing a stent. There are two basic types of stents applicable to this situation: Silastic and wire mesh. In general, wire mesh stents are easier to insert but much more difficult to remove and Silastic stents are harder to place and easier to remove. Alternatives to stent placement include sleeve resection (of the bronchus or upper lobe) or retransplantation. Resection has been performed with good results in adults but would be a very difficult procedure in children.5g Retransplantation should be reserved for situations in which the stricture extends beyond the bronchial bifurcation on either side and cannot be managed with either endobronchial techniques or local resection.

Vascular Anas tom0tic Complications Problems with either the arterial or venous anastomoses are rare. In most instances, a stenosis in either of these is secondary to excessive length on the donor pulmonary artery or left atrial cuff or torsion of either of these structures when undertaking the anastomosis. Stenosis in one of the pulmonary artery anastomoses may or may not be manifest by right ventricular hypertension. Because pulmonary artery catheters are not often placed in children, one should check the right ventricular pressure by direct puncture once off cardiopulmonary bypass. If elevated, the pressure distal to each anastomosis should be checked also by direct puncture. Unilateral mild to moderate pulmonary arterial anastomotic stenosis may not result in significant elevation of right ventricular pressure. A perfusion lung scan is routinely performed within 24 hours of the transplant to screen for technical problems with the vascular anastomoses. Any significant discrepancy between right- and left-sided perfusion should be immediately evaluated with either direct visualization in the operating room or angiography. Stenosis in either or both pulmonary venous anastomoses is manifest by pulmonary hypertension, profuse pink frothy sputum, and diffuse infiltrates on a chest radiograph. These findings may also be present with a severe reperfusion injury or diffuse alveolar damage. However, the pulmonary

capillary wedge pressure is generally normal in the latter two instances and elevated with a stenosis in the pulmonary venous anastomosis. Transesophageal echocardiography is particularly helpful in the diagnosis of pulmonary venous anastomotic problems. Confirmation of the diagnosis usually requires direct measurement of the pulmonary venous and left atrial pressures, particularly in small children. Early correction is mandatory.

Bleeding A number of factors place these patients at increased risk for bleeding after transplantation. Nearly all transplants in children require prolonged cardiopulmonary bypass for recipient pneumonectomies and implantation of donor organs. Additionally, many of these patients have undergone prior thoracotomies or sternotomies. Aprotinin is an important adjunct in the prevention of bleeding complications in these patients.38 Patients with cyanotic heart disease and a prior thoracotomy have the greatest risk of serious bleeding, as mentioned earlier.

Phrenic Nerve Injury This complication occurs in about 20% of lung transplants and is secondary to trauma due to stretch while retracting to expose the hilar regions; it is more common on the right side.60 Recovery of diaphragmatic function within 6 months of transplantation is the general rule. The reason for the right side being injured more commonly probably relates to the proximity of the nerve to the pulmonary artery and the superior vena cava on that side. The superior vena cava (and thus the phrenic nerve) must be retracted to expose the proximal right pulmonary artery. Prior thoracotomy puts the nerve at greater risk for injury because it may be obscured by adhesions.

Hoarseness Vocal cord paralysis caused by recurrent laryngeal nerve injury has an incidence of approximately 10%.This diagnosis is made at the time of flexible fiberoptic bronchoscopy with direct examination of the cords. In most cases, anatomic asymmetry improves without directed therapy within 6 months of transplantation. The left vocal cord is nearly always the one involved, and the injury presumably occurs as a result of dissection of the left pulmonary artery in the region of the ligamentum arteriosum.

Gastrointestinal Complications Gastroesophageal reflux has occurred almost exclusively in the very young infants undergoing lung transplantation. Fifty percent of infants surviving moGe than 30 days in our series suffered this complication, as documented by upper gastrointestinal series, 24hour esophageal pH probe, or evidence of aspiration by the presence of lipidladen macrophages on bronchoalveolar lavage.34The etiology of this high incidence of gastroesophageal reflux is not clear but may be due to injury to the vagus nerves

CHAPTER

bilaterally in the process of performing the recipient pneumonectomies. Decreased intestinal motility is also a common problem in all age groups. A relatively high incidence of gastroesophageal reflux has been noted in adults undergoing lung transplantation. A link to bronchiolitis obliterans has been proposed by some.16 Patients with cystic fibrosis are at risk for distal intestinal obstruction syndrome. This can be avoided by aggressively treating with osmotic cathartics after transplant. Gastrografin enemas may be necessary if there is no response to oral cathartics.

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is also of utmost importance. The treatment of reperfusion injury is mostly supportive, although nitric oxide14 and prostaglandin may be of some primary benefit. Rejection is a common occurrence after lung transplantation, perhaps more so than in other solid organ transplants (Fig. 48-1). The lung has a much larger endothelial surface than other organs. Because the major histocompatibility antigen expression on endothelial surfaces is the primary signal for local immune recognition, the lung would seem to be the least easily camouflaged organ in the body. In addition, the lung graft comes with its own parenchymal bronchial lymphocytes and macrophages. Gradually, these are replaced by Atrial Flutter the recipient lymphocytes and macrophages. This rather Atrial arrhythmias are relatively common with significant intense immunologic activity adds to the risk of rejecepisodes of atrial flutter occurring in 10% of transplant tion. Acute graft rejection early after transplant presents recipients. Many require long-term treatment.z1 Recent in such a nonspecific fashion that each suspected investigation into this entity using a model of lung transepisode should be documented with histologic evidence plantation has shown that the suture lines for the left obtained via either transbronchial biopsy or open-lung atrial anastomoses provide sufficient substrate for the biopsy. The great majority of episodes of acute rejection maintenance of atrial flutter when initiated by prooccur in the first 6 months after the transplant. Although the incidence of acute rejection in all children is about grammed extrastimulus.22 the same as that seen in adults, it appears that infants have a much lower in~idence.~"he precise reason for this is unclear but may have to do with the relative immaGraft Complications turity of the immunologic system in infants. Reperfusion injury manifesting as graft failure with difBronchiolitis obliterans is viewed by most clinicians to fuse infiltrates on chest radiography, frothy sputum, and be a manifestation of chronic rejection and occurs in poor oxygenation is the most common graft complicanearly 50%of all long-term survivor^.^ The precise cause is unknown, although donor ischemic time and episodes of tion early after lung transplantation, occurring in 20% to 30% of transplant recipients.42 It is the most common early acute rejection have been identified as risk factors.33 cause of death within the first 30 days after t r a n ~ p l a n t . ~ ~Bronchiolitis obliterans presents as a significant fall in The underlying cause is probably multifactorial, with FEVl without other obvious cause. The chest radiograph is both donor and recipient conditions contributing to this generally clear, and the computed tomographic examinaproblem. The best preventive measures include careful tion of the chest is usually without infiltrates. Ventilation/ evaluation and procurement of the donor organs as well perfusion lung scanning demonstrates a mosaic pattern as having a recipient free of active infection or other of perfusion with air trapping. Bronchoscopy with transbronchial biopsy and bronchoalveolar lavage should be acute problems. A well-conducted transplant procedure

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Present are multiple lymphocytes in a perivascular position involving many blood vessels, which can be seen better on higher power. This was interpreted as grade A2 acute rejection.

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TRANSPLANTATION I . A : Histologic slide taken from the lung of a patient undergoing retransplantation for bronchiolitis obliterans. Small airways are obliterated by fibrous tissue.

done as part of the evaluation to rule out other potential causes such as acute rejection or infection and to assess the degree of active lymphocytic infiltration of the airways. The histologic picture of bronchiolitis obliterans is one of dense scarring of the membranous and respiratory bronchioles (Fig. 48-2). It may be inferred by the absence of identifiable bronchioles on biopsy material. Diagnosis of bronchiolitis obliterans by histologic examination of transbronchial biopsy material may be very difficult, however, and many do not consider it necessary to establish the diagnosis. A staging system has been established based on the degree of decline of FEV, from the peak value: post-transplant stage 1 = 20% to 35%, stage 2 = 35% to 50% decline, and stage 3 = more than 50% decline.1° The current recommended treatment for bronchiolitis obliterans is to augment immunosuppression beginning usually with antithymocyte globulin daily for 7 to 10 days; the clinical response has been variable. A change in the maintenance immunosuppression is also appropriate. Antiproliferative agents may provide a more effective approach but that has yet to be proved. Total lymphoid irradiation and photopheresis are other modalities that have been proposed. Patients not responding to these measures may be suitable candidates for retransplantation. As mentioned earlier, this is a somewhat controversial topic because there is a shortage of donor organs and the results with retransplantation overall are not quite as good as first-time transplants. However, if the candidates are ambulatory, not ventilator dependent, and at an experienced lung transplant center, the survival results are not significantly different from first-time transplant^.^^ Post-transplant lymphoproliferative disease (PTLD) occurs in 5% to 10% of patients undergoing lung transplantation. PTLD occurs more frequently in association with a primary Epstein-Barr virus (EBV) infection.@ Children may be somewhat more prone to this complication because they are frequently seronegative for EBV infection at the time of transplant and therefore likely to

acquire a primary EBV infection during their post-transplant life. Reduction in immunosuppression is the mainstay of early therapy, although this may be insufficient and not uncommonly leads to the subsequent development of bronchiolitis obliterans. Rituximab, an anti-CD20 monoclonal antibody, has been used effectively in the treatment of PTLD.64Other treatment modalities include conventional chemotherapy," irradiation,20 and infusion of human leukocyte antigen-matched T lyrnphocytes.52

Infection Although infection is generally common after any solid organ transplant, lung transplant recipients are at greater risk. Donors are all on mechanical ventilation, resulting in colonization of the airway with bacteria from an intensive care unit. With the exception of the small bowel, the lung is the only solid organ constantly in contact with the nonsterile outside world. An endotracheal tube necessary early after the transplant bypasses some of the natural defenses available to the respiratory tract. Obligate denervation of the lung that occurs with transplantation results in the cough reflex being markedly diminished or absent altogether. These and numerous other factors demand that the caregivers maintain constant vigilance in the diagnosis and treatment of respiratory infections and also emphasize to the recipient the importance of pulmonary toilet. All potential candidates are screened for the presence of organisms in the airway and evidence of previous infections. Evidence of prior viral infections is evaluated by serologic testing for antibodies to cytomegalovirus, herpes simplex virus, varicella, EBV, hepatitis A, B, and C, and human immunodeficiency virus. Viral serologic screening is less informative in young infants whose immunoglobulin pool reflects passively transferred maternal antibodies. The initial antimicrobial therapy given in the early post-transplant period is directed in

CHAPTER

part by the results of pretransplant studies. Ganciclovir is given at a dose of 5 mg/kg/day for 6 weeks for any positive donor or recipient serology for cytomegalovirus. If patients have evidence of present or past Aspergillus infection, intravenous amphotericin B (3.0 mg/kg/day) is given for 5 to 10 days, followed by aerosolized amphotericin B (10 mg three times a day) depending on the clinical situation. A number of viral respiratory infections are quite common in pediatric patients. Adenovirus and parainfluenza viruses are particularly bothersome in these children. As for cytomegalovirus,primary disease is generally more likely to be severe than reactivation disease.*OAs mentioned earlier, primary infection with EBV is an important risk factor for the development of PTLD. Fungal infections are uncommon but potentially devastating. Nystatin oral suspension is employed to reduce the risk of infection from Candida species. Virtually all infections caused by Candida species can be successfully treated with oral or intravenous triazole antifiingal agents. Invasive Aspergillus infections, however, are much more difficult to treat and may result in widespread dissemination if appropriate antifungal therapy is delayed. Bacterial infections are the most common serious infection after lung transplantation. Bacterial lower respiratory tract infections, which include both purulent bronchitis and pneumonia, occur in most patients at some point after transplantation. Patients with cystic fibrosis are more likely to experience this complication, with the organism usually the same as that colonizing the airway before the transplant. Prophylaxis against lower respiratory tract infections in cystic fibrosis lung transplant recipients may be accomplished by administering aerosolized antibiotics (tobramycin or colistin) just as one might for end-stage cystic fibrosis.

Other Complications Hypertension is a common problem after transplantation and is presumably due to treatment with the calcineurin inhibitors cyclosporine and tacrolimus as well as

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prednisone. Renal insufficiency occurs with increasing time after transplantation and is also related to treatment with cyclosporine and tacrolimus. Diabetes mellitus occurs in approximately 15% of patients after transplant, primarily in patients with cystic fibrosis.8 Tacrolimus predictably increases the likelihood for the development of hyperglycemia.

SURVIVAL The 3- and 5-year actuarial survival for children undergoing lung transplantation is approximately 54% and 45%, respectively, according to the International Society for Heart and Lung Transplantation registry (Fig. 48-3).67 Acute graft failure accounts for the majority of deaths in the first 30 days. Infection is the cause of death in approximately 50% of those dying in the first year beyond the transplant hospitalization. Bronchiolitis obliterans is the cause of death in 50% of patients beyond 1 year after transplant and is clearly the major impediment to longterm ~urvival.~"

PULMONARY FUNCTION AND GROWTH It is unclear whether transplanted lungs grow in terms of number and size of alveoli, and experimental data are inconclu~ive.'~.~0 Measurement of lung growth is fraught with a number of complicating factors. One cannot use pulmonary function tests and lung volume size as measured by either chest radiograph or computed tomography because there are a number of elements that affect these studies that would not accurately reflect the number or size of alveoli. The impact of lung growth is particularly critical in small infants because their transplanted lungs will have to grow substantially over the rest of their lives to handle the physiologic load presented to them. Those children in our series too young to undergo standard pulmonary function testing underwent infant pulmonary function tests that provide a measurement of functional residual capacity, a reasonable surrogate for

Kaplan-Meier survival

curve for pediatric lung transplantation. (From Boucek MM, Faro A, Novick RJ, et al: The Registry of the International Society for Heart and Lung Transplantation: Fourth official pediatric report-2000. J Heart Lung Transplant 2001;20:39-52.)

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lung volume. The average functional residual capacity per centimeter in height at 3 months after transplant was 2.3 mL/cm and remained between 2.1 and 2.8 mL/cm through 15 months after transplant. During this time substantial somatic growth occurred in these infant^.^ Thus, in the absence of central or peripheral airway obstruction, these data suggest that lung growth appropriate for size is occurring. We do not know whether this represents an increase in the number of alveoli and/or an increase in the size of existing alveoli, however.

LIVING DONOR LUNG TRANSPLANTATION The use of living donors for lung transplantation (LDLTx) follows the same path proposed for kidney and liver transplantation in which successes (especially with the kidney) had already been experienced. The principle with this is that a normal, healthy adult should be able to donate a lower lobe from either the right or left lung to a child (or small adult) and have it serve as a "whole lung."" The donor presumably would have sufficient reserve so that the 20% to 25% loss of lung volume would not result in any loss of functional capacity for day-to-day living. The differences between LDLTx and living donor tranGlants for the kidnev or liver is that two donors are required for LDLTx and the procurement is performed via a thoracotomy, which is generally perceived to be a higher risk procedure than laparotomy. Thus, two normal individuals Are risking " their lives for one. There are obviously significant ethical issues involved in this, particularly given the survival statistics for lung transplantation. However, there are clearly some advantages over cadaveric lung transplantation: short ischemic times for the donor lungs, extensive evaluation to ensure that the donors have normal lungs, a scheduled transplant at a time optimal l better human for all concerned, and the ~ o t e n t i a for leukocyte antigen matching. It is a more challenging procedure technically, however. LDLTx is reserved for situations in which the recipient will not survive long enough to receive donor lungs-from a cadaveric s o u r c e - ~ h esurvival in these patients after LDLTx has been similar to that seen in patients transplanted with lungs from a cadaveric source. o n e fascinating finding in this group has been the . ~ ~ may very low incidence of bronchiolitis ~ b l i t e r a n sThis be related to the very short ischemic times in the LDLTx donor organs, which are harvested in an adjoining hospital. Another possible explanation is an immunologic advantage in the case of the donors being close relatives.

FUTURE CONSIDERATIONS Factors that limit the success of lung transplantation in children are similar to those in adults: donor shortage, balance of immunosuppression and prevention of infection, and development of bronchiolitis obliterans. As part of the solution to the donor shortage issue, it is likely that living donor lung transplantation will be used more commonly over the next several years but will likely not have a major impact overall on the donor pool and waiting

times. Xenotransplantation may eventually offer another solution, but realistically this is many years from application. Newer immunosuppressive agents aimed at more specific areas of the immune response involved with organ recognition are necessary. Bronchiolitis obliterans remains the "Achilles heel" of long-term survival after lung transplantation. Although still not completely characterized as to its precise cause, most investigators ascribe this development to chronic rejection. To that end, clinical and basic research aimed at understanding the vectors of injury and disease progression in bronchiolitis obliterans are of paramount importance to the field of lung transplantation. Because the airway as the site of injury is accessible for assessment and therapy, bronchiolitis obliterans may provide a model system whereby chronic rejection, which also affects long-term success in heart, kidney, and liver transplantation, can be understood and overcome.

REFERENCES 1. Barst RJ, Rubin LJ, Long WA, et al: A comparison of continuous intravenous epoprostenol (prostacyclin) with conventional therapy for primary pulmonary hypertension. N Engl J Med 1996;334:296-302. 2. Boucek MM, Faro A, Novick RJ, et al: The Registry of the International Society for Heart and Lung Transplantation: Fourth official pediatric report-2000. J Heart Lung Transplant 2001;20:39-52. 3. Brock MV, Borja MC, Ferber L, et al: Induction therapy in lung transplantation: A prospective, controlled clinical trial comparing OKT3, anti-thymocyte globulin, and daclizumab. J Heart Lung Transplant 2001;20:1282-1290. 4. Bumgardner GL, Hardie I, Johnson RW, et al: Phase 111 Daclizumab Study Group: Results of 3-year phase 111 clinical trials with daclizumab prophylaxis for prevention of acute rejection after renal transplantation. Transplantation 2001;72:839-845. 5. Channick RN, Simonneau G, Sitbon 0 , et al: Effects of the dual endothelin-receptor antagonist bosentan in patients with pulmonary hypertension: A randomised placebo-controlled study. Lancet 2001;358:1119-1123. 6. Clabby ML, Canter CE, Moller JH, Bridges ND: Hemodynamic data and survival in children with pulmonary hypertension. J Am Coll Cardiol 1997;30:554560. 7. Cohen AH, Mallory GB, Ross K, et al: Growth of lungs after transplantation in infants and in children younger than 3 years of age. AmJ Respir Crit Care Med 1999;159:1747-1751. 8. Cooper JD, Ginsberg RJ, Goldberg M, the Toronto Lung Transplant Group: Unilateral transplantation for pulmonary fibrosis. N Engl J Med 1986;314:1140-1145. 9. Cooper JD, Pearson FG, Patterson GA, et al: Technique of successful lung transplantation in humans. J Thorac Cardiovasc Surg 1987;93:173-181. 10. Cooper JD, Billlingham M, Egan T, et al: A working formulation for the standardization of nomenclature and for clinical staging of chronic dysfunction in lung allografts. J Heart Lung Transplant 1993;12:713-716. 11. Couetil JP, Houssin DP, Soubrane 0 , et al:. .Combined lung and liver transplantation in patients with cystic fibrosis: A 4 $$-year experience. J Thorac Cardiovasc Surg 1995; 110:1415-1422. 12. Couetil J-P, Achkar A, Chevalier P, et al: Split lung with bilateral lobar transplantation: A two-year experience. J Heart Lung Transplant 1995;14(Suppl):S60.

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13. Cystic Fibrosis Foundation: Patient Registry 1999 Annual Report. Bethesda, MD, September 2000. 14. Date H, Triantafillou AN, Trulock EP, et al: Inhaled nitric oxide reduces human lung allograft dysfunction. J Thorac Cardiovasc Surg 1996;111:913-919. 15. D' Alonzo GE, Barst RJ, Ayres SM, et al: Survival in patients with primary pulmonary hypertension: Results from a national prospective registry. Ann Intern Med 1991;115: 343-349. 16. Davis RD, Lau CL, Eubanks S, et al: Improved lung allograft function after fundoplication in patients with gastroesophageal reflux disease undergoing lung transplantation. J Thorac Cardiovasc Surg 2003;125:533-542. 17. Egan TM, Westerman JH, Lambert CJ, et al: Isolated lung transplantation for end-stage lung disease: A viable therapy. Ann Thorac Surg 1992;53:590-596. 18. Egan TM, Detterbeck FC, Mill MR, et al: Improved results of lung transplantation for patients with cystic fibrosis. J Thorac Cardiovasc Surg 1995;109:224235. 19. Finkelstein SM, Wielinski CL, Elliott GR, et al: Diabetes mellitus associated with cystic fibrosis. J Pediatr 1988;112: 373-377. 20. Friedman E, Perez-Atayde AR, Silvera M, Jonas RA: Growth of tracheal anastomoses in lambs. J Thorac Cardiovasc Surg 1990;100:188-193. 21. Gandhi SK, Bromberg BI, Mallory GB, Huddleston CB: Atrial flutter-a newly recognized complication of pediatric lung transplan tation. J Thorac Cardiovasc Surg 1996;112: 984991. 22. Gandhi SK, Bromberg BI, Schuessler RB,et al: Left sided atrial flutter-characterization of a novel complication of pediatric lung transplantation in an acute canine model. J Thorac Cardiovasc Surg 1996;112:992-1001. 23. Ganne V, Siddiqi N, Kamaplath B, et al: Humanized antiCD20 monoclonal antibody (Rituximab) treatment for posttransplant lymphoproliferative disorder. Clin Transplant 2003;17:417-422. 24. Gilligan PH, Neuringer IP, Gott KK, et al: The effects of panresistant bacteria in cystic fibrosis patients on lung transplant outcome. Am J Respir Crit Care Med 1997; 155:1699-1704. 25. Hamvas A, Mallory GB, Spray TL, et al: Lung transplantation for treatment of infants with surfactant protein B deficiency. J Pediatr 1997;130:231-239. 26. Hamvas A, Nogee LM, White FV, et al: Progressive lung disease and surfactant dysfunction with a deletion in surfactant protein C gene. Am J Respir Cell Mol Biol 2004; 30:771-776. 27. Hardy JD, Webb WR, Dalton ML, et al: Lung homotransplantation in man. JAMA 1963;186:1065-1074. 28. Hislop AA, Odom NJ, McGregor CGA, Haworth SG: Growth potential of the immature transplanted lung: An experimental study. J Thorac Cardiovasc Surg 1990;100: 360-370. 29. Hoeper MM, Schwarze M, Ehlerding S, et al: Long-term treatment of primary pulmonary hypertension with aerosolized iloprost, a prostacyclin analogue. N Engl J Med 2000;342:18661870. 30. Hopkins WE, Ochoe LL, Richardson GW, Trulock EP: Comparison of the hemodynamics and survival of adults with severe primary pulmonary hypertension or Eisenmenger syndrome. J Heart Lung Transplant 1996;15:100-105. 31. Huddleston CB, Spray TL, Mallory GB: Airway complications following pediatric lung transplant. J Heart Lung Transplant 1995;14 (Suppl):S60. 32. Huddleston CB: Airway complications in children following lung transplantation. In Cooper DKC, Miller L,

33. 34. 35. 36.

37. 38. 39. 40. 41. 42. 43. 44. 45. 46. 47. 48. 49. 50. 51. 52.

53. 54.

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Patterson GA (eds): The Transplantation and Replacement of Thoracic Organs. Lancaster, UK, Kluwer, 1996, pp 581-588. Huddleston CB, Sweet SC, Cohen AH, et al: Bronchiolitis obliterans after pediatric lung transplantation. J Heart Lung Transplant 1998;17:65. Huddleston CB, Sweet SC, Mallory GB, et al: Lung transplantation in very young infants. J Thorac Cardiovasc Surg 1999;118:796-804. Huddleston CB, Mendeloff EN: Heart and lung preservation for transplantation. J Cardiac Surg 2000;15:108-121. Ibrahim JE, Sweet SC, Flippin MC, et al: Rejection is reduced in thoracic organ recipients when transplanted in the first year of life. J Heart Lung Transplant 2002;21: 311-318. Jackson LK: Idiopathic pulmonary fibrosis. Clin Chest Med 1982;3:579. Jaquiss RDB, Huddleston CB, Spray TL: Use of aprotinin in pediatric lung transplantation. J Heart Lung Transplant 1995;14:302-307. Kerem E, Reisman J, Corey M, et al: Prediction of mortality in patients with cystic fibrosis. N Engl J Med 1992;326: 1187-1191. Kern JA, Tribble CG, Flanagan TL, et al: Growth potential of porcine reduced-size mature pulmonary lobar transplants. J Thorac Cardiovasc Surg 1992;104:1329-1332. Kerstein D, Levy PS, Hsu DT, et al: Blade balloon atrial septostomy in patients with severe primary pulmonary hypertension. Circulation 1995;91:2028-2035. King RC, Binns OAR, Rodriguz F, et al: Reperfusion injury significantly impacts clinical outcome after pulmonary transplantation. Ann Thorac Surg 2000;69:1681-1685. King-Biggs MB, Dunitz JM, Park SJ, et al: Airway anastomotic dehiscence associated with use of sirolimus immediately after lung transplantation. Transplantation 2003;75:1437-1443. Klima LD, Kowdley KV, Lewis SL, et al: Successful lung transplantation in spite of cystic fibrosis-associated liver disease: A case series. J Heart Lung Transplant 1997;16:934938. Kurland G: Pediatric lung transplantation: Indications and contraindications. Semin Thorac Cardiovasc Surg 1996;8: 277-285. Matsuzaki Y, Waddell TK, Puskas JD, et al: Amelioration of post-ischemic lung reperfusion injury by prostaglandin El. Am Rev Respir Dis 1993;148:882-889. Milla CE, Warwick WJ: Risk of death in cystic fibrosis patients with severely compromised lung function. Chest 1998;113:1230-1234. Mullins D, Livne M, Mallory GB, Kemp JS: A new technique for transbronchial biopsy in infants and small children. Pediatr Pulmonol 1995;20:253-257. Novick RJ, Stitt LW, Al-Kattan K, et al: Pulmonary retransplantation: Predictors of graft function and survival in 230 patients. Ann Thorac Surg 1998;65:227-234. Okano Y, Yoshioka T, Shimouchi A, et al: Orally active prostacyclin analogue in primary pulmonary hypertension. Lancet 1997;349:1365. Osika E, Muller MH, Boccon-Gibod L, et al: Idiopathic pulmonary fibrosis in infants. Pediatr Pulmonol 1997;23:49-54. Papadopoulos EB, Ladanyi M, Emanuel D, et al: Infusions of donor leukocytes to treat Epstein-Barr virus-associated lyrnphoproliferative disorders after allogeneic bone marrow transplantation. N Engl J Med 1994;330:1185-1191. Pasque MK, Trulock EP, CooperJD, et al: Single lung transplantation of pulmonary hypertension: Single institution experience in 34 patients. Circulation 1995;92:2252-2258. Pechet TV, de la Morena MT, Mendeloff EN, et al: Lung transplantation in children following treatment for malignancy. J Heart Lung Transplant 2003;22:154160.

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Ramirez J, Patterson GA: Airway complications after lung transplantation. Semin Thorac Cardiovasc Surg 1992;4: 147-153. Rand KH, Pollard RB,Merigan TC: Increased pulmonary superinfections-cardiac transplant recipients undergoing primary cytomegalovirus infection. N Engl J Med 1987; 298:951-953. Ro PS, Bush DM, Kramer SS, et al: Airway growth after pediatric lung transplantation. J Heart L U I I ~ Transplant 2001;20:619-624. Robinson W, Waltz DA: FEV, as a guide to lung transplant referral in young patients with cystic fibrosis. Pediatr Pulmonol 2000;30:198-202. Schafers HJ, Schafer CM, Zink C, et al: Surgical treatment of airway complications after lung transplantation. J Thorac Cardiovasc Surg 1994;107:1476-1480. Sheridan PH, Cheriyan A, Doud J, et al: Incidence of phrenic neuropathy after isolated lung transplantation. J Heart Lung Transplant 1995;14:684691. Snell GI, de Hoyos A, Krajden M, et al: Pseudomonas cepacia in lung transplant recipients with cystic fibrosis. Chest 1993;103:466-471. Starnes VA, Barr ML, Cohen RG: Lobar transplantation: Indicati~ns,technique, and outcome. J Thorac Cardiovasc Surg 1994;108:403-411. Stepkowski SM, Chen H, Daloze P, Kahan BD: Rapamycin, a potent immunosuppressive drug for vascularized heart, kidney and small bowel transplantation in the rat. Transplantation 1991;51:22-26.

Sundaresan S, Trulock EP, Mohanakumar T, et al: Prevalence and outcome of bronchiolitis syndrome after lung transplantation. Ann Thorac Surg 1995;60: 1341-1346. Sweet SC, Spray TL, Huddleston CB, et al: Pediatric lung transplantation at St. Louis Children's Hospital 1990-1995. Am J Respir Crit Care Med 1997;155:1027-1035. Swinnen LJ, Mullen GM, Carr TJ, et al: Aggressive treatment for postcardiac transplant lymphoproliferation. Blood 1995;86:3333-3340. Trulock EP, Edwards LB, Taylor DO, et al: The Registry of the International Society for Heart and Lung Transplantation: Twentieth official adult lung and heart-lung transplant report-2003. J Heart ~ u n gTransplant fi03;22: 625-635. Walker RC, Paya CV, Marshall WF, et al: Pretransplantation sero-negative Epstein-Barr virus status is the primary risk factor for post-transplantation lymphoproliferative disease in adult heart, lung and other solid organ transplantation. J Heart Lung Transplant 1995;14:214221. Woo MS, MacLaughlin EF, Horn MV, et al: Bronchiolitis obliterans is not the primary cause of death in pediatric living donor lobar lung transplant recipients. J Heart Lung Transplant 2001;20:491-496. Wood NS, Marlow N, Costeloe K, et al: Neurologic and developmeiltal disability after extremely preterm birth. N Engl J Med 2000;343:378-384. Wood P: The Eisenmenger syndrome or pulmonary hypertension with reversed central shunt. BMJ 1958;2:701-762.

Surgical Implications Associated with Bone Marrow Transplantation Paul M . Colombani and Mark L. Kayton

Bone marrow transplantation (BMT) is now being used to treat children with a variety of disorders, including hematologic malignancies, solid tumors, and immunologic disorders. Pediatric surgeons are called on regularly to provide vascular access and to address complications that occur in BMT patients. Understanding the process, indications, and problems associated with BMT can position pediatric surgeons to become important contributors to the patient care effort in this growing patient population. The term bone marrow transplantation is often used as a catch phrase to subsume all prevalent methods of reconstituting hematopoietic stem cells, but in practice the stem cells may be provided from umbilical cord blood, peripheral blood stem cells, or bone marrow itself.Z5The cells may be autologous (collected when the patient is in remission) or allogeneic (from, for instance, a relative who is a close human leukocyte antigen [HLA] match). The recipient of the transplant receives a preparative regimen of chemotherapy with or without total-body irradiation, and this regimen is geared toward ablation of the underlying hematologic malignancy as well as ablation of the hematopoietic progenitor cells, thus paving the way for reconstitution of the blood with donor cells. An immunosuppressive regimen, as well as a prophylactic regimen designed to eliminate graft-versus-host disease (GVHD), is administered. As expected, complications at any phase of this process, whether involving cell harvest, immune system ablation, immunosuppression, or GVHD, routinely require involvement by a pediatric surgeon.

STEM CELL HARVEST AND VASCULAR ACCESS ISSUES At our institutions we use a variety of temporary catheters in the groin or neck when one-time venous access is desired for blood cell harvest, but, increasingly, we have been placing tunneled, cuffed, dual-lumen

subclavian vein lines (8 French Medcomp catheter for small children or 13.5 French Hickman catheter for older adolescents) that can function for pheresis and then remain in place to serve the long-term central venous access needs of the child. BMT patients may require temporary access for dialysis or hemofiltration. For example, at the University of Minnesota, 5% of pediatric BMT patients needed dialysis period.l3 Some have for acute renal failure over a 12-year , implicated the use of cyclosporine and amphotericin B, and the use of total-body irradiation, in the development of renal insufficiency in pediatric recipients of BMT.33 Acute access needs may arise in the intensive care unit (ICU) setting. To try to improve outcome among children with acute respiratory distress syndrome (ARDS), a group at Stanford University instituted early continuous venovenous hemofiltration (CVVH) at the time of intubation in a cohort of 10 pediatric oncology patients with respiratory failure and ARDS.4 Six of the 10 children had undergone BMT. Eight (80%) survived; although there was no control group, this survival rate contrasts notably to that reported in the literature. For instance, a retrospective study of BMT patients from the Great Ormond Street Hospital found only a 40% rate of survival to ICU discharge among BMT patients with respiratory failure.1° If this practice of early CVVH becomes more widespread, the need for surgeons to address vascular access will only escalate. Even more dramatic needs for vascular access can arise. Leahey and colleagues at the Children's Hospital of Philadelphia have provided a case report on the use of extracorporeal membrane oxygenation (ECMO) 3 days after BMT.IThe patient, an 8-month-old girl with severe combined immunodeficiency syndrome {SCID) and bronchiolitis from respiratory syncytial virus and influenza A virus, survived 15 days of ECMO and suffered a stroke but succeeded in engraftment of her transplant from an HLAidentical sibling, recovering adequate lymphocyte counts to resist infection. She survived and was discharged from the hospital. x

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COMPLICATIONS OF IMMUNE SYSTEM ABLATION AND IMMUNOSUPPRESSION Intestinal Complications The differential diagnosis of abdominal pain with diarrhea in the pediatric BMT recipient should include GVHD, mucositis secondary to medications, bacterial gastroenteritis, viral gastroenteritis (including adenovirus, rotavirus, and cytomegalovirus), Clostridium dfficik infection, and amebiasis. Some of these causes are elaborated on because they are not common considerations in pediatric surgery. In particular, considerations of intestinal GVHD will often prompt consultation with a pediatric surgeon to obtain, or else to manage the complications that may follow, upper or lower gastrointestinal biopsies. Upper gastrointestinal biopsies may be taken during endoscopy of the esophagus, stomach, or duodenum. A report by Ramakrishna and Treem recommends caution in biopsy of the duodenum in thrombocytopenic patients, with duodenal hematomas arising in &oepediatric bone marrow transplant patients with platelet counts of 55,000/mm3 and 65,00O/mm3, respectively.23 Whereas the stomach and duodenum remain important sites to consider a biopsy, we have had success in diagnosing GVHD in specimens taken from the rectum using a rectal suction biopsy gun, which can be performed with little or no t the ward unit and obviates the sedation of the ~ a t i e non need for general anesthesia in the operating room. In an intestinal tract already compromised by GVHD, unexpected pathologic processes may be noted. For instance, trophozoites of Entamoeba histolytica were recovered from the stool of two patients in Chile who had incomplete improvement after corticosteroid administration for concurrent GVHD.21 Adenovirus enterocolitis has been described in a similar setting of intestinal GVHD.27 Clostridium difficik colitis can develop with striking manifestations in this population. One case report described C. difficile colitis in a 13-year-old BMT recipient who progressed to an obstructing post-colitis stricture of the descending colon requiring a transverse colo~tomy.~2 Although rare, typhlitis (neutropenic enteropathy) does occur in BMT recipients (Fig. 49-1). Clinically, typhlitis presents as fever, abdominal pain or tenderness, and neutropenia. Hobson and colleagues noted that diarrhea In a retrowas often observed in patients with typhliti~.~ spective from Alberta, Canada, 5 of 142 pediatric BMT patients developed typhlitis. All were treated with bowel rest, total parenteral nutrition, and broad-spectrum antimicrobial medications, including systemic antifungal agents, and all survived and were discharged. This is in striking contrast to classic surgical teaching concerning typhlitis in adults in whom a 50% mortality is observed. Improvements in outcome after typhlitis may be a reflection of earlier diagnosis, aggressive use of granulocyte colony-stimulating factor, better antimicrobial agents, or all of these factors. Surprisingly, not all patients required computed tomography (CT) to make the diagnosis of typhlitis. One patient had the diagnosis made by plain abdominal radiography, and two of the five had an ultrasound study without CT.1 On CT in children with typhlitis,

,

-

..

Typhlitis in a teenager with acute myelocytic leukemia who had undergone BMT. Note the thickened, onionskin appearance of the cecal wall and the pinpoint lumen. This patient underwent right hemicolectomy with ileostomy and mucous fistula; 1 year later, still in clinical remission from her leukemia, her condition was successfully reversed. Most cases of typhlitis are handled nonoperatively.

abnormal thickening of the cecal wall associated with surrounding inflammatory changes is observed.

Hepatobiliary Problems Abnormal results of liver function tests are common among BMT patients, and surgeons will frequently be called on to differentiate obstructive biliary conditions from hepatocellular processes. Safford and colleagues have provided retrospective data regarding the incidence and natural history of gallstones among pediatric Of 235 patients undergoing post-transBMT ~atients.2~ plant ultrasound, 20 (8.5%) had gallstones. After stratifjing these children based on the underlying diagnosis prompting transplant, Safford and colleagues found that among patients who received their transplant for neoplasia, inherited metabolic disorders, or immunologic disorders, about 7% had gallstones, whereas among patients receiving transplantation for various anemias and primary bone marrow disorders, 27% had gallstones, which suggests that factors such as hemolysis were more prevalent in the latter group. Nonetheless, of the 20 BMT recipients with gallstones, only 3 required surgical intervention (at a mean interval of 1.9 years after diagnosis of cholelithiasis),whereas 5 showed sonographic resolution of their gallstones (at an average of 150 days after diagnosis of cholelithiasis). Although this was not a prospective study, this observation should give surgeons some pause before being tempted to incidentally remove a stone-laden but asymptomatic gallbladder. Another vexing problem affecting the liver in BMT patients is veno-occlusive disease. This refers to a syndrome usually seen within the first month after BMT, which may be a toxic response to the ablative and conditioning regimens used at the time of transplant.

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This condition is characterized by congestion and fibrotic obliteration of the liver sinusoids and hepatic venules. Injury to zone 3 hepatocytes and endothelial cells is postulated as the inciting event. Hypercoagulable states and release of cytokines such as tumor necrosis factor-a may also play a role.2g The clinical diagnosis, summarized by the McDonald criteria,l8 is made when any two of the following three signs are present shortly after BMT: (1) ascites with a weight gain over 2% of baseline; (2) hepatomegaly or right upper quadrant tenderness; and (3) a total serum bilirubin level above 2 mg/dL. Prophylactic treatment with heparin has not been convincingly shown to improve outcome in this disease. Other strategies that have been described, although not validated in controlled studies, include the use of tissue plasminogen activator administered with heparin14 and, in one pediatric case report, performance of a liver tran~plantation.~ Veno-occlusive disease has also been described in the lungs, may present as pulmonary hypertension, and has Echocardiography been fatal in nearly all instance~.~2 can contribute to the diagnosis, but unfortunately most cases have been diagnosed at autopsy and some by openlung biopsy.

Pulmonary Complications A number of conditions, most far more common than veno-occlusive disease, can be diagnosed by lung biopsy. Infectious conditions include those caused by bacteria, viruses, fungi, Legionella, mycobacteria, and Pneumocystis. Among viral infections, cytomegalovirus, respiratory syncytial virus, adenovirus, and herpesviruses figure prominently. Noninfectious causes include hemorrhage, malignancy, drug toxicity, and interstitial pneumonitis, the last referring to an observed inflammatory response in the presence of negative cultures.30Finally, bronchiolitis obliterans organizing pneumonia (BOOP), a corticosteroid-responsive restrictive disease in which granulation tissue is deposited in terminal airways, also may be observed.I6 Requests for lung biopsies are common in BMT centers. There is active debate about their impact on outcome. Shorter and coworkers, recounting the experience from 1976 to 1986 at Children's Hospital of Philadelphia, observed that 13 of 21 patients continued to deteriorate and died within 11 weeks despite the procedure, and only two patients required a significant change in therapy leading to survival.28 Dunn and associates" described 15 stem cell transplant recipients. Eight of nine patients who required mechanical ventilation at the time of biopsy died. Therapy was changed by the results of biopsy in only 1 of the 15 patients. A more recent retrospective series by Hayes-Jordan and colleagues recapitulates these findings: a large proportion (7 of 19 [37%]) died within 30 days after lung biopsy, and only 3 of the 19 patients had a change in treatment leading to longterm surviva1.R One subgroup that may benefit more from open-lung biopsy, if the entire involved area can be excised, are the patients with aspergillosis. The St. Jude group reported

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that 27 of 43 patients with aspergillosis had BMT.'j Those patients who had all involved lung parenchyma resected had a significant survival benefit compared with those who did not have their lung that was involved with Aspergillus resected. This was not a randomized or prospective study, and all four survivors (with follow-up ranging from 1.7 to 43 months) had disease amenable to wedge resection, with one lobectomy. However, pulmonary aspergillosis is a disease process associated with a nearly 100% mortality in immunocompromised children. This implies it is reasonable to consider surgical resection in these cases.

Soft Tissue Complications Skin and deep soft tissue infections including necrotizing fasciitis, necrotizing myositis, and cutaneous infection with Mucor may occur in BMT patients, especially during periods of neutropenia. Several case series exist describing soft tissue infections among neutropenic pediatric oncology patients, with some transplant recipients included in these groups.11J9Notably, enteric organismsincluding Escherichia coli, Pseudomonas, and Enterococcusare recovered from the cultures of BMT recipients. It is postulated that bacterial translocation from the gastrointestinal tract is a factor, resulting in hematogenous dissemination. This contrasts to standard assumptions that soft tissue infections originate when gram-positive bacteria or anaerobes colonize soft tissues after breaks in the skin. In the BMT population, broad-spectrum antibiotic coverage is required, including agents that target gram-negative organisms. Surgical dkbridement is every bit as much of an emergency as it is in other patient populations and can be even more challenging if bone marrow ablation has depleted the platelet count. Granulocyte colony-stimulating factor and granulocyte infusions should be considered in neutropenic patients. Johnston and associatesll described fever, tachycardia, and localized pain out of proportion to findings on examination as helpful diagnostic signs and symptoms. If uncertainty exists, magnetic resonance imaging (MRI) may be useful, provided that time and the patient's clinical condition permit. Cutaneous infection with Mucor (mucormycosis) should be considered in the differential diagnosis of any skin and soft tissue infection. This fungal infection, like bacterial soft tissue infections, usually mandates early dkbridement. In young BMT recipients, cutaneous infection with Mucor may present as tender induration that can progress to necrosis. Hyphae are demonstrable on microscopic examination of the involved tissue and blood ve~sels.20~3~

Hemorrhagic Cystitis Bleeding from the bladder epithelium can become a clinically devastating problem in BMT recipients. Hemorrhagic cystitis may be associated with toxicity from conditioning chemother-apies such as cyclophosphamide or busulfan,*6 or it may result from viral infections. Presentation may range from microscopic hematuria to

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gross hematuria with clots causing bladder outlet obstruction. Ultrasound shows thickening of the bladder wall; addition of color Doppler imaging may identify the focal areas of hypervascularity or active bleeding, which often leads to diagnostic cystoscopy.17 Depending on the clinical severity of hemorrhagic cystitis, patients may be treated by intravenous hydration with forced diuresis, by Foley catheter drainage using continuous bladder irrigation, or by cystoscopy with removal of clot and fulguration of the bladder epithelium. The urethra in small children may not permit passage of a large enough Foley catheter to prevent recurrent obstruction by clot. In these patients, operative placement of large suprapubic catheters may be n e c e ~ s a r y . ~ ~

Thrombocytopenia Refractory thrombocytopenia can be seen after BMT and often prompts the consideration of splenectomy. Thrombocytopenia may be related to medications, decreased marrow production of megakaryocytes, or platelet sequestration. However, platelets may be sequestered at other sites, and splenectomy does not prove curative in all patients with platelet sequestration. Hammersmith and associates have described a nuclear medicine technique for documenting splenic sequestration of platelets that can contribute to the decision Platelets are labeled whether to perform splene~tomy.~ with indium-111 and infused; platelet sequestration in the spleen is confirmed by observing the ratio of labeling density in the spleen to labeling density in the liver at various time points after infusion. A spleen-to-liver ratio of greater than 1.9 is consistent with abnormal splenic sequestration. However, this technique is not widely available and there are no data as to whether a positive scan predicts a good outcome after splenectomy. Thus, clinicians caring for patients with refractory thrombocytopenia must still make an empirical decision as to whether to perform splenectomy.

can contaminate preparations of red cells, plasma, or platelets, mediate an immune response against the immunocompromised recipient. Manifestations of transfusion-associated GVHD include rash, abnormal liver function test results, pancytopenia, and, in 84% of affected patients, death.2 Two techniques-leukocyte filtration and irradiation-are used respectively to reduce the load of, and to inactivate, leukocytes in banked blood products. Thus, blood products for BMT patients should be both leukocyte filtered and irradiated.

Chronic GVHD Chronic GVHD is characterized by generalized sclerosis of skin and soft tissue structures and sometimes cholestatic jaundice. Even acquired phimosis has been observed in an advanced case, requiring circumcision in a 13-year-oldboy.

CONCLUSION Whereas the development of BMT has traditionally been in the realm of medical, pediatric, and oncologic specialists, this discussion highlights the multitude of organ systems that can manifest surgical pathologic processes after BMT. The lungs, intestinal tract, liver, spleen, bladder, soft tissue, and hematologic system are all subject to various surgical complications. Moreover, virtually every patient subjected to BMT will require vascular access for medications, alimentation, dialysis, or cell harvest. These expected implications of BMT mandate that every hospital with a pediatric BMT program have access to a general pediatric surgeon. In return, pediatric surgeons should educate and position themselves to advise their medical colleagues, manage these problems with expertise, and contribute to the development of this expanding aspect of transplantation.

REFERENCES

Unusual Problems Acute suppurative thyroiditis has been described in a case report, in a 3-year-old undergoing a second BMT for chronic myelomonocytic leukemia.22 Although the patient received total-body irradiation, which has been implicated as causing thyroid dysfunction, he developed swelling of the thyroid gland and hypothyroidism shortly after transplantation. In this instance, the authors considered the problem unrelated to radiation. Ultrasound showed "translucent" zones in the thyroid gland, and surgical drainage of purulent material was required.

COMPLICATIONS OF TRANSFUSIONS Because surgeons and surgical house staff are often involved in ordering blood products for perioperative usage, it is important to remember that transfused blood itself can cause GVHD. Passenger T lymphocytes, which

1. A1 Otaibi A, Barker C, Anderson R, et al: Neutropenic enterocolitis (typhlitis) after pediatric bone marrow transplant. J Pediatr Surg 2002;37:770-772. 2. Anderson KC, Weinstein HJ: Transfusion-associated graftversus-host disease. N Engl J Med 1990;323:315-321. 3. Bunin N, Leahey A, Dunn S: Related donor liver transplant for veno-occlusive disease following T-depleted unrelated donor bone marrow transplantation. Transplantation 1996; 61:664666. 4. DiCarlo JV, Alexander SR, Agarwal R, et al: Continuous veno-venous hemofiltration may improve survival from acute respiratory distress syndrome after bone marrow transplantation or chemotherapy. J Pediatr Hematol Oncol 2003;25:801-805. 5. Dunn JC, West KW, Resurla FJ, et al: The utility of lung biopsy in recipients of stem-cell transplantation. J Pediatr Surg 2001;36:1302-1303. 6. Gow KW, Hayes-Jordan AA, Billups CA, et al: Benefit of surgical resection of invasive pulmonary aspergillosis in pediatric patients undergoing treatment for malignancies and

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immunodeficiency syndromes. J Pediatr Surg 2003;38: 13541360. Hammersmith SM,Jacobson AF, Mankoff DA: Scintigraphy with indium-111 labeled homologous (donor) platelets in the platelet transfusion refractory bone marrow transplant patient. J Nucl Med 1997;38:1135-1138. Hayes-Jordan A, Benaim E, Richardson S, et al: Open lung biopsy in pediatric bone marrow transplant patients.J Pediatr Surg 2002;37:446452. Hobson MJ, Carney DE, Molik KA, et al: Appendicitis in childhood hematological malignancies: Analysis and comparison with typhlitis. J Pediatr Surg 2005;40:214219; discussion 219-220. Jacobe SJ, Hassan A, Veys P, et al: Outcome of children requiring admission to an intensive care unit after bone marrow transplantation. Crit Care Med 2003;31:1299-1305. Johnston DL, Waldhausen JHT, Park JR: Deep soft tissue infections in the neutropenic pediatric oncology patient. J Pediatr Hematol Oncol 2001;23:443-447. Kavan P, Sochor M, Nyc 0 , et al: Pseudomembranous Clostridium after autologous bone marrow transplantation. Bone Marrow Transplant 1998;21:521-523. Lane PH, Mauer SM, Blazar BR, et al: Outcome of dialysis for acute renal failure in pediatric bone marrow transplant patients. Bone Marrow Transplant 1994;13:613-617. Leahey AM, Bunin NJ: Recombinant human tissue plasminogen activator for the treatment of severe hepatic veno-occlusive disease in pediatric bone marrow transplant patients. Bone Marrow Transplant 1996;17:1101-1104. Leahey AM, Bunin NJ, Schears GJ, et al: Successful use of extracorporeal membrane oxygenation (ECMO) during BMT for SCID. Bone Marrow Transplant 1998;21:839-840. Mathew P, Bozeman P, Krance RA, et al: Bronchiolitis obliterans organizing pneumonia (BOOP) in children after allogeneic bone marrow transplantation. Bone Marrow Transplant 1994;13:221-223. McCarville MB, Hoffer FA, Gingrich JR, et al: Imaging findings of hemorrhagic cystitis in pediatric oncology patients. Pediatr Radio1 2000;30:131-138. McDonald GB, Sharma P, Matthews DE, et al: Veno-occlusive disease of the liver after bone marrow transplantation: Diagnosis, incidence, and predisposing factors. Hepatology 1984;4:116-122. Murphyg, Granger R, Blair GK, et al: Necrotizing fasciitis in childhood. J Pediatr Surg 1995;30:1131-1134. Nomura J, Ruskin J, Sahebi F, et al: Mucormycosis of the vulva following bone marrow transplantation. Bone Marrow Transplant 1997;19:859-860.

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Perret C, Harris PR, Rivera M, et al: Refractory enteric amebiasis in pediatric patients with acute graft-versus-host disease after allogeneic bone marrow transplantation. J Pediatr Gastroenterol Nutr 2000;31:86-90. Poelman M, Benoit Y, Laureys G, et al: Acute suppurative thyroiditis complicating second allogeneic transplant for juvenile CMML. Bone Marrow Transplant 1992;lO: 547-548. Ramakrishna J, Treem WR: Duodenal hematoma as a complication of endoscopic biopsy in pediatric bone marrow transplant recipients. J Pediatr Gastroenterol Nutr 1997; 25:426429. Safford SD, Safford KM, Martin P, et al: Management of cholelithiasis in pediatric patients who undergo bone marrow transplantation. J Pediatr Surg 2001;36:86-90. Sanders JE: Bone marrow transplantation for pediatric malignancies. Pediatr Clin North Am 1997;44:1005-1020. Seber A, Shu XO, Defor T, et al: Risk factors for hemorrhagic cystitis following BMT. Bone Marrow Transplant 1999;23:35-40. Shayan K, Saunders F, Roberts E, et al: Adenovirus enterocolitis in pediatric patients following bone marrow transplantation. Arch Pathol Lab Med 2003;127: 1615-1618. Shorter NA, Ross AJ 111, August C, et al: The usefulness of open-lung biopsy in the pediatric bone marrow transplant population. J Pediatr Surg 1988;23:533-537. Shulman HM, Hinterberger W: Hepatic veno-occlusive disease-liver toxicity syndrome after bone marrow transplantation. Bone Marrow Transplant 1992;lO:197-214. Stokes DC: Pulmonary complications of tissue transplantation in children. Curr Opin Pediatr 1994;6:272-279. Trigg ME, Comito MA, Rumelhart SL: Cutaneous Mucor infection treated with wide excision in two children who underwent marrow transplantation. J Pediatr Surg 1996; 31:976977. Trobaugh-Lotrario AD, Greffe B, Deterding R, et al: Pulmonary veno-occlusive disease after autologous bone marrow transplant in a child with stage IV neuroblastoma: Case report and literature review.J Pediatr Hematol Oncol 2003;25:405-409. Van Why SK, Friedman AL, Wei LJ, et al: Renal insufficiency after bone marrow transplantation in children. Bone Marrow Transplant 1991;7:383-388. Vogeli TA, Peinemann F, Burdach S, et al: Urological treatment and clinical course of BK polyomavirus-associated hemorrhagic cystitis in children after bone marrow transplantation. Eur Urol 1999;36:252-257.

HEADA N D NECK

Craniofacial Anomalies Henry K. Kawamoto, Jr.

Craniofacial anomalies are devastating when they occur. A lasting impression is made on initial encounter, and confusion may reign as to care. Some of these malformations are relatively common, such as a cleft of the lip or palate. Others are rare to the point that they may never be witnessed during a clinician's professional life. Yet, gathered together, the total number of children disfigured by craniofacial malformations is vast. The term craniofacial surgery is automatically associated with the name of its founder Paul L. Tessier. Until the late 1960s, when word of his seminal work spread, only what now seems like a Band-Aid approach was available to correct these malformation^.^^ Tessier and his coworkers showed that anatomic correction could be achieved by widely exposing the twisted craniofacial skeleton, restoring anatomic alignment with osteotomies, replacing missing parts with autogenous tissues, providing stable fixation, and adding an intracranial approach when indicated. The classic teaching of avoiding purposeful contamination (i.e., exposing the sterile intracranial environment to the filth of the nasal and oral cavities) was challenged directly under the cover of antibiotics. The concern about infection and other morbid events was shown to be unfounded as a new subspecialty was born. Over the next 25 years, visiting Paris to observe Dr. Tessier's work became obligatory for surgeons who wished to gain proficiency in the field. Knowledge disseminated and expanded quickly. Now, throughout the world, most major medical centers have craniofacial anomalies teams composed of an anesthesiologist, audiologist, geneticist, neurosurgeon, ophthalmologist, oral surgeon, orthodontist, otolaryngologist, pediatrician, plastic surgeon, radiologist, social worker, and speech pathologist to care for patients with these complex anomalies. Although the variety of craniofacial anomalies is enormous, they can be conveniently divided into two large groups: (1) craniofacial clefts and (2) craniosynostosis. The latter can be further subdivided into nonsyndromic and syndromic malformations. Entire texts are devoted to describing these entities. Additional books detail their surgical treatment, but centers differ in terms of timing

and techniques. What follows is an overview that highlights the more common anomalies and their correction. Acquired disfigurement owing to neoplasm and trauma is also part of the field, but its discussion lies beyond the scope of this chapter.

BASIC CRANIOFACIAL SURGICAL PRINCIPLES Immediately beneath the thin veneer and variety of expression of a child's face lies the complex end organs that produce sight, olfaction, hearing, speech, and mastication. Children with a craniofacial malformation are seriously handicapped in their social interactions. They deserve the coordinated long-term care of a dedicated team of specialists to look after their complicated needs. Surgeons who undertake such repairs must have special training and experience. A moment of carelessness can destroy the chance for normalcy forever. The primary concern in the timing of surgical intervention is the preservation and restoration of function. Once these demands are satisfied, attention is focused on coordinating the operation with facial growth and development and the psychosocial needs of the child. Normal individual anatomic differences as well as inherent disparate growth of a malformed part must be considered. Surgical treatment generally is directed toward the end of the growth curve of each regional component. Access to the deformed area is gained through concealed incisions. Wide exposure of the pathologic process is required to relocate the affected craniofacial skeleton through socially invisible coronal, palpebral, and intraoral incisions (Fig. 50-1). If a visible scar is unavoidable, the incisions should so be designed as to mimic normal anatomic features or fall within aesthetic facialjunctions or units. The distorted facial skeleton must be restored as close to normal as possible. Similar to any project, establishing a sound foundation should precede the details. Thus, reconstructing the integrity of the facial skeleton receives priority. Anatomic relocation of maligned sections is basic. Missing parts should be replaced with autogenous material whenever possible. For osseous reconstruction,

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Degloving Inciwon and exposure of craniofacial skeleton. Shaded areas represent areas of exposure provlded by each mcision.

split calvarial bone is the popular choice because of its proximity to the main surgical field, a low percent of resorption, minimal associated morbidity, and an embryonic origin that is similar to the bone that it replaces. Alloplastic building blocks are poor substitutes for the real thing, and their use should especially be avoided on the growing skeleton.

CRANIOFACIAL CLEFTS The kaleidoscopic world of craniofacial clefts is bewildering on first glance. Similar to a kaleidoscope, a slight turn can convert a forme fruste expression into a complete representation of the malformation. A further twist can produce more bizarre alterations or an entirely new entity. Various classification systems have been proposed in an attempt to bring some order to the seeming chaos. enjoys the widest acceptance The Tessier cla~sification26,5~ (Fig. 50-2). The categorization is founded on Tessier's personal observations and is clinically oriented. The topographic meridians prompt a search for any underlying faults in the facial skeleton. On the map of clefts, cleft 8 occupies the equator, clefts 0 to 7 depict the facial clefts, and clefts 9 to 14 delineate their cranial prolongations. Although a cleft may appear to be confined to either the facial or cranial hemisphere, careful inspection made along the entire meridian often will reveal subtle yet important findings. Some craniofacial clefts are extremely rare and are noted only by surgeons who see a large number of these

Tessier classification. Meridian represents the pathology of craniofacial clefts and their relationship to anatomic facial features. When both are present, facial clefts (0 to 7 ) usually follow their cranial (9 to 14) counterparts along the same meridian.

patients. Therefore, this discussion is focused on those more commonly observed examples.

Cleft Lip and Palate These clefts are described in detail in Chapter 51.

Craniofacial Microsomia Other common names for craniofacial microsomia are the f i s t and second branchial arch syndrome, hemifacial microsomia, and otomandibular dysostosis. In the Tessier classification, it is represented as cleft 7 (see Fig. 50-2). Earliest recording of this malformation is said to be about 2000 BC in the teratologic tables scribed by Chaldeans of Me~opotamia.~ The first contemporary language report was by Reissman in 1869.46The incidence of craniofacial microsomia is estimated to be between 1 in 30004' and 1 in 5642l9 live births. Unilateral expression is the rule. Nevertheless, approximately 10% show bilateral involvement and features that are asymmetrical.lO.48 The affected structures are all

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789

Craniofacial microsomia (Tessier cleft 7). Note rnacrostomia, ear tags, and also the groove running toward a microtic ear.

derived from the embryonic first and second branchial arches. Beginning at an enlarged oral commissure (macrostomia), a groove is commonly seen that is directed toward the ear with ear tags scattered along the route (Fig. 50-3). Partial absence of the external ear (microtia) is frequent and accompanied by a conductive hearing loss. Portions of the mandible, zygoma, and maxilla are deficient (Fig. 50-4). The ascending mandible shows the greatest range of hypoplasia by being entirely absent to displaying minor discrepancies of the condyle and ramus. Being derivatives of the first and second branchial arches, the muscles of facial expression (Mobius syndrome) and mastication also can be involved in varying degrees. Hypoplasia or absence of the parotid gland is also seen. Treatment varies with the degree of severity. Usually, greater disruptions demand earlier intervention. The correction of the macrostomia with local flaps and the removal of ear tags are performed generally within the first year of life. When the entire ramus is absent, it can

\

\

Line drawing of skeletal malformation of craniofacial microsomia. The rarnus is partially absent, as is the zygomatic arch. The maxilla is also hypoplastic.

be replaced with a costochondral bone graft.32 At the University of California at Los Angeles, we prefer to perform this surgery when the patient is about 6 years old. This is the same age that the construction of the external ear with a costochondral graft is initiated. When more of the ramus is present, distraction osteogenesis, using the Ilizarov principle, is used to lengthen the existing mandible or a previously inserted costal bone graft.33When most of the ramus is present, correction of the maxillofacial skeletal deformities can be deferred until late adolescence and the cessation of facial growth. As a necessary preliminary step, the teeth are orthodontically aligned within each jaw. The maxilla and the mandible are repositioned using a LeFort I osteotomy and intraoral bilateral ramal sagittal splitting procedure, respectively. An osseous genioplasty centers and elongates the deviated and retruded chin (Fig. 50-5). All the bony segments are rigidly held with biocompatible miniature plates and screw, thus eliminating the need to wire the jaws together and greatly simplifying the postoperative course.

Treacher Collins Syndrome A confluence of clefts 6, 7, and 8 in the Tessier classification represents the Treacher Collins malformation (see Fig. 50-2). The earliest report of this entity was by Thompson in 1847.43However, Berry6 is credited with the first description of the eyelid malformation, followed by Treacher Collins recording two cases with hypoplastic malar bones.56 The syndrome is also known as mandibulofacial dysostosis. A comprehensive narrative of a series of 200 patients is recounted by Rogem4g The incidence of the malformation is estimated at 1 in 10,000 live births. Inheritance is in afi autosomal dominant manner with high but variable penetrance and expressivity.17 Mutations in the TCOFl gene have been identified in family members with the malforrnation.l2J3 Clinically, symmetrical bilateral involvement is seen of the eyelids, ears, zygomas, maxilla, and mandible (Fig. 50-6). The palpebral fissures are oriented with an

E Patient with craniofacial micro! LeFort I (maxillary), sagittal splitting ramal oste E and Postoperative views.

D nia. A, Preoperative frontal appearance. B, PIrofile view showing retrogenia. C, Line drawing of ~mies,and osseous genioplasty. D,Appearanc:e after relocations of segments and fixation.

Patient with Treacher Collins syndrome. Note bilateral involvement of antimongoloid slant of palpebral fissures, absence of malar prominence, microtia, and retruded mandible and chin.

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antimongoloid slant, and a coloboma occupies the lower eyelid, which lacks eyelashes in its medial two thirds. The zygomatic bones are hypoplastic and absent in the full expression of the malformation. Microtia of varying degrees is associated with conductive hearing loss. The preauricular hair is swept forward onto the cheek. The shortened posterior maxillary height restricts the size of the posterior choana and the passage of air. The mandible is also deficient in ramal height and body length. The intervening antegonial notch is acutely accentuated, and the chin is severely retruded. The severity of the malformation dictates the timing of surgical intervention. Mandibular retrusion can be so profound as to compromise the airway and create a need for a tracheostomy. Early distraction osteogenesis can be used to increase the size of the airway and avoid a tracheostomy or allow its early removal. Construction of the external ears with costal chondral grafts usually begins around the age of 6 years when the

Patient with Treacher Collins syndrome. A and B, Preoperative appearance. C arid D,Appearance after construction of zygomas, lateral orbital rim, lateral canthopexies, and upper to lower laterally based skin flaps.

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auricle is approximately 95% of adult size. Less popular means of fabricating an auricle are the use of alloplastic implants or external prosthesis. In the same period, the zygomas and orbits are built using calvarial bone grafts and simultaneously the lower eyelid colobomas and antimongoloid slant of the palpebral fissures are corrected with local flaps. At the end of the adolescent period, definitive management is directed to the maxillary and mandibular deformities using techniques that are similar to those applied to craniofacial microsomia (Fig. 50-7).

Cranial Clefts The laterally placed types of the cranial clefts 9 to 14 are rare. As the midline is approached, their numbers increase in frequency. Nevertheless, the true incidence of each of these clefts is unknown because of their small numbers.

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Those clefts located medially to the orbit (clefts 11 to 14) disturb the position of the orbit by increasing the interorbital distance. Hypertelorbitism is thus produced. It is a sign and not a syndrome per se. Birth defects and orbital encroaching neoplasms can cause similar deformation. The medial orbital wall (interdacryon interval) is used to measure the interorbital distance. The normal measurement for a woman is 25 mm and is achieved by 13 years of age. Men reach their maximum of 28 mm by age 21 years.21 Tessier classified the hypertelorbitism into three grades: (1) 30 to 34 mm, (2) greater than 34 mm with normal shape and orientation of the orbits, and (3) greater than 40 mm." Depending on the magnitude of separation, an extracranial approach alone or combined with an intracranial one is used, with the former being reserved for the lesser displacements. Surgical correction is elective. No evidence exists that shows early intervention prevents amblyopia or alternating vision. Thus, surgical management is mainly directed at restoring normal facial features. In most centers the 5- to 7-year period is used as an appropriate age for correction. These children are starting to attend

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school, and this is a time when the upper face has attained most of its growth. In other centers operation is done as early as the second year of life. In any case, treatment of these complex malformations is best reserved for teams that routinely care for these children. These procedures are not for the occasional surgeon. " By and large, a combined intracranial and extracranial approach is required. The neurosurgeon provides the exposure of the orbital roof via a frontal craniotomy. The classic periorbital box osteotomies originally described by Tessie~-528%largely have been replaced by a midline bipartition of the face (Fig. 50-8).50 he basic steps include &masking the craniofacial skeleton through coronal and maxillary vestibular incisions (see Fig. 50-I), performing a frontal craniotomy, freeing the bony orbits using the classic box or facial bipartition technique, removing the excess bone from the nasal midline, closing the space by bringing the orbits together, securing rigid fixation of the segments, and closing of the wounds. If all goes well, the child spends a few days in the intensive care unit and is usually discharged after approximately a week's stay.

D

Patient with asymmetrical hypertelorbitism due to frontonasal dysplasia and left unilateral coronal synostosis. A and B, Preoperative view showing increased interorbital distance, orbital dystopia, greater left facial height, and flattened left forehead. C, Line drawing of skeletal deformity and osteotomies. D, Skeletal reconstruction and fixation of segments. E and Postoperative view.

CHAPTER

During the first year the brain more than doubles its size and attains 60% of its adult eight.^ Except for the uniqueness of the cranial vault sutures, the brain would be intolerably imprisoned and irreversibly damaged by mounting intracranial pressure. In the past the sutures were believed to be sites of active growth that push the plates apart, but further investigation has shown their role to be passive. In response to the rapidly enlarging brain, bone is deposited along their edges and the epicranium while resorption occurs along the dural Normally, the cranial sutures are patent at birth and progress in early infancy to a yielding fibrous union that allows continuation of appositional bony growth. By 6 years of age the cranium has attained 90% of its adult size,%ut complete solid bony union of the sutures must await at least the 50s.31,3'Should a suture close prematurely, however, growth is arrested in a direction perpendicular to the fused suture, whereas compensatory expansion occurs in a parallel plane to the affected suture (Virchow's law). The resulting distortion of the skull depends on the suture or sutures that are closed. The two subdivisions of craniosynostosishave important genetic and long-term growth implications. In general, the malformations of the nonsyndromic subset occur sporadically, whereas the syndromic ones have a hereditary component. Furthermore, after surgical correction, normal craniofacial development is the rule for the

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nonsyndromic patients, whereas those with syndromic attributes fare poorly.

Nonsyndromic Craniosynostosis The overall incidence of nonsyndromic premature stenosis of cranial sutures has been stated to be 1 in 1000 live births.' This includes all forms of single suture fusion, with the sagittal suture being most commonly affected and unilateral coronal, metopic, and lambdoidal areas following in frequency. Bilateral fusion of the coronal as well as multiple suture involvement also occurs. There would be less confusion if the specific name of the closed suture were used to describe the deformation of the calvarial cap. The following descriptive terms are widely acknowledged: scaphocephaly (boat shaped)-sagittal; plagiocephaly (oblique)-unilateral coronal; brachycephaly (short)-bilateral coronal; trigonocephaly (triangular)metopic; and acrocephaly (topmost) or turn'cephaly (tower) or oxycephaly (sharp)-multiple sutures (Fig. 50-9). Diagnosis can be established in most cases on clinical examination alone because of the characteristic deformation of the skull cap and on palpation of a ridge formed by the fused suture. Plain radiographic skull views can be taken to help confirm the clinical impression. A radiographic linear opacity replaces the wormian lucency of a patent suture. For unilateral coronal synostosis, a

Representation of nonsyndromic craniosynostosis. Shaded areas indicate premature fused suture. A, Sagittal synostosis with resulting scaphocephaly. B, Unilateral coronal synostosis producing plagiocephaly. C, Bilateral coronal synostosis creating brachycephaly. D, Metopic synostosis with trigonocephaly deformation. E, Multiple suture involvement and turricephaly (acrocephaly).

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classic harlequin eyesign formed by the elevated ipsilateral lesser wing of the sphenoid can be seen on a posteroanterior skull radiograph. Computed tomography (CT) usually is not needed nor is it diagnostically very helpfully unless reformatted in a three-dimensional manner. The importance of establishing a clear diagnosis cannot be overstressed. The deformation of the craniofacial skeleton can be secondary. Muscular torticollis, cervical spinal abnormalities, and favored sleeping positions can produce positional distortions. The sutures are patent in these conditions. Treatment should be focused primarily on the cause of positional deformations rather than on the physical warping of the skull. When the sutures are open, early infant institution of molding helmets can restore normal contours but they are ill advised as primary therapy for true craniosynostosis contortions. To lessen the possibility of sudden infant death syndrome, the American Academy of Pediatrics promoted a "Back to Sleep" program in June of 1992.1 A substantial rise in the number of infants with unilateral or bilateral

E

occipital deformations was experienced by all craniofacial anomalies centers.3~57These positional deformations were sometimes misdiagnosed, and blame fell on a "sticky" lamb doid suture when radiographs failed to verify opacification of the suture. Unnecessary posterior calvarial vault reconstructions were performed, which should have been avoided if differentiating clinical signs had been observed. Positional posterior plagiocephaly, when viewed from the vertex, has an oblique orientation of the skull cap, and the ear on the affected side is pushed anteriorly and away from the flattened posterior side. In contrast, true unilateral lambdoidal synostosis produces a trapezoid deformation with the ipsilateral ear being drawn toward the defective suture.20 Fortunately, heightened awareness of deformation has dramatically reduced the number of operations for positional deformations to practically zero. Nonsyndromic craniostenosis should be corrected because of the severe distortions that can be reflected onto the face. Other reasons address possible functional problems that the condition might cause, all of which are

F

Patient with premature closure of sagittal suture (scaphocephaly). A and B, Preoperative appearance showing anteroposterior elongation of skull cap, decreased biparietal width, and anterior location of ears with greater posterior length. C, Illustration of n (pi) osteotomy with s h a d ~ darea representing areas of resection. D,After decreasing anteroposterior dimension and lateral displacement of temporoparietal bone segments. E and Postoperative views.

CHAPTER

related to increased intracranial pressure. Renier and associates found 13% of infants with single suture synostosis have elevated pressures and that this occurred in 42% of those with multi~lesuture involve men^.^^ Visual impairment can occur but is rare when only one suture prematurely fused.35 Whether higher intracranial pressure is associated with developmental retardation is debated. One study showed an assdciation,47 and another did n0t.29 ~efore'the era of craniofacial surgery, the classically accepted method of treatment was a linear strip craniectom; of the pathologic suture. The incidence of refusion and continued deformation, however, was disappointingly high. In a review of 519 cases, Shillito and Matson50found that satisfactory . appearance was achieved in only 52%, with the best results seen in infants with isolated sagittal synostosis. An unusual technique of total removal of the calvarial vault and orbital roofs was published by Powiertowsky and Matlosz in 1965.44Because of unpredictable reossification

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resulting in full-thickness defects and irregular contours, the method has fallen into disuse. To take advantage of the rapidly expanding infant brain, early operative intervention is advised. Most centers favor the period of 3 to 6 months of age; others wait longer. All would agree that an operation should be performed before passage of the first year. Early correction produced better resdts in a long-term study of patients treated for metopic synostosis.15 Because of disappointment with the strip craniectomy techniques, the principles of treatment rhanged. Regardless of the type of craniosynostosis, emphasis was directed toward releasing the affected suture and immediately restoring normal architecture by repositioning and recontouring the deformed bones'(~igs.50-10 r ~ ~ these measures and 50-11).Hoffman and M ~ h applied in their treatment of unilateral coronal synostosis. Marchac and Renier"," refined the approach, and

F

Example of unilateral coronal synostosis. A and B, Preoperative view. Note asymmetry of facial height of left and right side with ipsilateral side being taller, curvature of facial midline with contralateral deviation of chin and ipsilateral flattening, and contralateral bossing of forehead. (:, Line drawing of deformity and osteotomies. D,Restoration of contour and fixation of mobilized segments. Eand E Postoperative appearance.

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numerous geometric designs and fixation methods followed. Surgeons were attracted to the benefits offered by rigid fixation provided by using biocompatible metallic plates and screws. Subsequently, their use on a growing skull cap found the devices being translocated from the epicranium onto the dura.l6 Although initial reaction was one of alarm, detrimental consequences have not been observed.Z7 Nevertheless, the metallic fixation hardware has been replaced by biodegradable plates and screws. The strip craniectomy has been revived with the addition of endoscopic surgical techniques plus the use of a cranial molding helmet.j,z5The involved suture is removed with the aid of the endoscope, and additional osteotomies of the cranial vault are made depending on the involved suture(s). A molding helmet is then used to obtain the desired contour. The benefits of this approach are a less invasive procedure, less blood loss, and a shorter hospital stay. The disadvantages are the additional cost of the molding helmet and increased postoperative visits for

adjustment. Furthermore, to obtain satisfactory results, use of this method is limited to the first 5 rnonths of life.

Syndromic Craniosynostosis In contrast to nonsyndromic fusion, syndromic craniosynostosis behaves differently and has genetic implications. Early release of fused sutures does not lead to subsequent normal growth of the craniofacial skeleton. Therefore, additional operations will be required as the child matures. In contrast to the sporadic occurring nonsyndromic group, patterns of inheritance have been established for these malformations.

Crouzon Syndrome It is somewhat ironic that a French surgeon, Paul Tessier, launched a subspecialty on a craniofacial malformation

Patient with Crouzon syndrome. A and B, Preoperative view of child with exorbitism, midfacial retmsion, and pseudomandibular prognathisrn. C and D, Appearance after monobloc frontofacial advancement with advancement of forehead, normal globe position, and overcorrection of midfacial retrusion.

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originally described over a half century before by a French neurologist.^^ Crouzon syndrome is the most commonly seen syndromic craniosynostosis anomaly, and its incidence has been estimated as being as high as 1 in 100,000 births.17 The inheritance Dattern is autosoma1 dominant with almost complete penetrance. Mutations in the FGFRZ gene have been established in patients with the syndrorne.l8,24,28,38,45 Although any or all of the cranial sutures can be involved, bilateral coronal synostosis is most commonly observed. Cardinal features of the face include exorbitism (normal ocular contents housed in a hypoplastic orbit), midfacial retrusion with a collapsed maxilla, pseudomandibular prognathism, and a parrot beak appearance of the nose (Fig. 50-12).Mild hypertelorbitism can also be seen. Intelligence falls within the normal

Child with Apert syndrome. A and B, Appearance before correction with flattened facies, retruded forehead and midface, and moderate exorbitism and hypertelorbitism. C and D, Appearance after monobloc frontofacial advancement to correct facial retrusion and facial bending to restore curvature to face and reduction of interorbital distance.

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range. Features of the rest of body are normal, in contrast to the digital anomalies found in individuals with other malformations of this series.

Apert Syndrome Originally described by Wheaton in 1894,"g this malformation is known by the name of another French neurologist who described four cases 12 years later and applied the term acrocephalosyndactyly.2 Its incidence has been estimated to be 1:160,000 live births.17The inheritance mode is that of autosomal dominant, although occurrence tends to be sporadic. As with Crouzon syndrome, a defect in the FGFR2 gene has been identified.m~~l.60 The exorbitism, midfacial retrusion with maxillary constriction, and pseudomandibular prognathism,

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as in Crouzon syndrome, are present (Fig. 50-13). The exorbitism is more moderate and asymmetrical. The distance between the orbits is greater. The face also is flattened transversely. A major distinguishing feature is the symmetrical syndactyly of the hands and feet, with fusion of the interphalangeal joints that can be severe enough to produce a mitten deformity. In addition, an acne-like rash distributed over the face, trunks, and extremities appears in adolescence. Also unique is the presence of mild mental retardation.

Other Syndromes Over 50 syndromes associated with craniosynostosis have been described in addition to the most common ones of Crouzon and Apert syndrome^.^ Because they are few in number, their frequency is not well established. Pfeiffer, Carpenter, and Saethre-Chotzen syndromes belong to this group and are distinguished respectively by broad toes and thumbs (Pfeiffer), preaxial polysyndactyly with soft tissue syndactyly of shortened fingers (Carpenter), and soft tissue webs between the second and third digits (Saethre-Chotzen). Pfeiffer and SaethreChotzen syndromes are transmitted in an autosomal dominant manner, and Carpenter syndrome is autosoma1 recessive. Once seen, the rare kleeblattschadel (cloverleaf skull) anomaly is not easily forgotten. The skull cap assumes a trilobular configuration with a protruding vertex and bulging temporal regions (Fig. 50-14).

Treatment The surgical management of all the syndromic craniosynostosis malformations generally falls into three chronologic stages. In contrast to the nonsyndromic variety, in this group normalization of facial growth is not realized after surgical intervention. Treatment is directed at the immediate problem; thus, a staged approach is used. Elements that must be addressed are release of elevated intracranial pressure caused by the premature suture closure, compromise of the airway by severe midfacial retrusion, and protection of the corneas because of the exorbitism. During the first year of life, the synostotic suture is released and a fronto-orbital advancement is performed (Fig. 50-15). This frees the rapidly expanding brain, more normal calvarial contours are achieved, and the corneas are offered more protection. Treatment schemes and timing will then vary according to experience and preference of the surgeon. The management protocol at the University of California at Los Angeles is one that is popular. A second operation is performed around the sixth year of life when the orbits and skull cap have attained 90% of their adult size.8 If the forehead is of normal shape, the classic LeFort I11 midfacial advancement is used to bring the entire midface forward. The maxilla is placed deliberately in an overcorrected anterior position, knowing that future midfacial growth will be limited (Fig. 50-16). This will open the crowded nasopharynx and correct the exorbitism.

Example o f kleeblattschadel (cloverleaf)malformation produced by premature closure of multiple sutures. A, Note trilobular configuration o f skull cap and retrusion o f forehead and midface. B, Appearance 8 years after fronto-orbital advancement in infancy and after monobloc advancement at 6 years o f age.

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D

Fronto-orbital advancement used to correct bicoronal synostosis of infant with Apert syndrome. A and B, Preoperative views showing recession of superior orbital rims and forehead and exorbitism. Cand D,Appearance after operation with normalization of forehead contours and orbital relationships.

If the forehead is found to be recessed, as is often the case, two alternative paths can be followed. As a preliminary operation, a second fronto-orbital advancement is performed. Approximately 6 months later, a LeFort I11 procedure is added. This approach is safer because sterility is maintained by separating a clean intracranial procedure from the contamination introduced by the subsequent

extracranial midfacial advancement. The dura expands slowly in a child of this age as compared with during infancy. Thus, a longer period must pass as the brain enlarges to obliterate the epidural dead space created by the fronto-orbital advancement. The other approach is the monobloc frontofacial a d ~ a n c e m e n tThe . ~ ~ advantage of this technique is that

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HEADAND NECK Illustration of LeFort 111 midface advancement. A, Line drawing depicting midfacial retrusion, pseudomandibular prognathism, and design of osteotomies. B, After mobilization to overcorrected anterior position and fixation.

only o n e operation is required to reposition the forehead a n d midfacial mass. T h e best cosmetic results a r e often achieved." T h e risk of infection is increased, however, a n d t h e procedure is best avoided when a s h u n t is present that will inhibit the expansion of t h e brain a n d prolong the existence of the d e a d space.28 Many of t h e hazards of the monobloc acute advancem e n t s have b e e n r e d u c e d by applying distraction osteogenesis with its gradual frontofacial advancement rate of 1 m m / ~ l a y . ~ l When hypertelorbitism is present, a facial bipartition (see Fig. 50-8) procedure can b e a d d e d to either t h e LeFort I11 o r frontofacial monobloc advancement. This procedure is particularly indicated i n correcting the flattened forehead a n d midface that is typically seen i n patients with Apert syndrome.54 T h e final stage must await t h e completion of facial growth. After presurgical orthodontic alignment of t h e dentition, the pseudomandibular prognathism is corrected with a LeFort I (maxillary) advancement. A simultaneous advancement osseous genioplasty is frequently required t o correct t h e retruded chin.

REFERENCES 1. American Academy of Pediatrics Task Force on Infant Positioning and SIDS: Positioning and SIDS. Pediatrics 1992;89:1120-1126. 2. Apert E: De I'acrocephalosyndactylie. Bull Soc Med H6p Paris 1906;23:1310. 3. Argenta LC, David LR, Wilson JA, et al: An increase in infant cranial deformity with supine sleeping position. J Craniofac Surg 1996;7:5-11.

4. Ballatyne JW: The teratological records of Chaldea. Teratologia 1894;1:127. 5. Barone CM,Jimenez EF: Endoscopic craniectomy for early correction of craniosynostosis. Plast Reconstr Surg 1999; 104:1965-1973. 6. Berry GA: Note on a congenital defect (? coloboma) of the lower lid. Roy Lond Ophth Hosp Rep 1889;12:255. 7. Bertelson TL: The premature synostosis of the cranial sutures. Acta Ophthalmol Suppl 1958;51:47. 8. Blinkov SM, Glezer 11: The Human Brain in Figures and Tables: A Quantitative Handbook. New York, Plenum Press, 1968. 9. Cohen MM Jr: Craniosynostosis and syndromes with craniosynostosis: Incidence, genetics, penetrance, variability, and new syndrome updating. Birth Defects 1979; 15:13-63. 10. Converse JM, Coccaro PJ, Becker M, Wood-Smith D: On hemifacial microsomia: The first and second branchial arch syndrome. Plast Reconstr Surg 1973;51: 268-279. 11. Crouzon 0: Dysotose, cranio-faciale hCrCditaire. Bull Soc Med H6p Paris 1912;33:545. 12. Dixon MJ, Hann E, Baker E, et al: Association of Treacher Collins syndrome and translocation 6p21.31/16p13.11: Exclusion of the locus from these candidate regions. J Hum Genet 1991;48:274280. 13. Dixon MJ: Treacher Collins syndrome. Hum Mol Genet 1996;5(Spec):1391-1396. 14. Enlow DH, Azuma M: Functional growth boundaries in the human and mammalian face. Birth Defects 1975;ll: 217-230. 15. Fearon JA, KolarJC, Munro IR: Trigonocephaly-associated hypotelorbitism: Is treatment necessary? Plat Reconstr Surg 1996;97:503-509. 16. Fearon JA, Munro IA, Bruce DA: Observations on the use of rigid fixation for craniofacial deformities in infants and young children. Plast Reconstr Surg 1995;95: 634637.

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17. Gorlin RJ, Pindborg JH, Cohen MM Jr: Syndromes of the Head and Neck, 2nd ed. New York, McGraw-Hill, 1976, pp 220-224. 18. Gorry MC, Preston RA, White GJ, et al: Crouzon syndrome: Mutations in two spliceoforms of FGFR2 and a common point mutation shared with Jackson-Weiss syndrome. Hum Mol Genet 1995;4:1387-1390. 19. Grabb WC: The first and second branchial arch syndrome. Plast Reconstr Surg 1965;36:485-508. 20. Gruss JS: The diagnosis of plagiocephaly due to lambdoid suture synostosis: Clinical, radiological and operative findings. Craniofacial Surgery: State of the Art Symposium. New York, March 20, 1996. 21. Hangman CB: Growth of interorbital distance and skull thickness as observed in roentgenographic measurements. Radiology 1966;86:87. 22. Hoffman HJ, Mohr G: Lateral canthal advancement of the supraorbital margin. J Neurosurg 1976;45: 376-381. 23. Hollway GE, Phillip HA, Ades LC, et al: Localization of craniosynostosis Adelaide type to 4p16. Hum Mol Genet 1995;4:681-683. 24. Jabs EW, Li X, Scott AF, et al: Jackson-Weiss and Crouzon syndromes are allelic with mutations in fibroblast growth factor receptor. Nat Genet 1994;8:275-279. 25. Jimenez DF, Barone CM, McGee ME, et al: Endoscopy-assisted wide-vertex craniectomy, barrel stave osteotomies, and postoperative helmet molding therapy in the management of sagittal suture craniosynostosis. J Neurosurg Spine 2004;100:407-417. 26. Kawamoto HK: The kaleidoscopic world of rare craniofacia1 clefts: Order out of chaos (Tessier classification). Clin Plast Surg 1976;3:529-572. 27. Kawamoto HK, McCarthy JG: Discussion of Fearon JR, et al: Observation on the use of rigid fixation for craniofacial deformities in infants and young children. Plast Reconstr Surg 1995;95:638. 28. Kawamoto HK Jr, Stuzin JM: Complication associated with the monobloc-frontofacial advancement. Presented before the American Association of Plastic Surgeons meeting, Palm Beach, May 3, 1988. 29. Kapp-Simon KA, Figueroa A, Jocher A, Schafer M: Longitudinal assessment of mental development in infants with nonsyndromic craniosynostosis with and without cranial release and reconstruction. Plast Reconstr Surg 1993;92: 831-839. 30. Lewanda AF, Cohen MM Jr, Hood J, et al: Cytogenetic survey of Apert syndrome: Reevaluation of translocation (2;9)(p11.2;q34.2) in patient suggests the breakpoints are not related to the disorder. Am J Dis Child 1993;147: 1306-1308. 31. Marchac D: Radical forehead remodeling for craniostenosis. Plast Reconstr Surg 1978;61:823-835. 32. Marchac D, Renier D: Craniofacial Surgery for Craniosynostosis. Boston, Little Brown, 1982. 33. McCarthy JG: The role of distraction osteogenesis in the reconstruction of the mandible in unilateral craniofacial microsomia. Clin Plast Surg 1994;21:625-631. 34. Molina F, Ortiz-Monasterio F: Mandibular elongation and remodeling by distraction: A farewell to major osteotomies. Plast Reconstr Surg 1995;96:825-840. 35. Montaut J, Stricker M: Dysmorphies Craniofaciales: Les Synostoses Prematuries (Craniostenosis et Faciostenosis). Paris, Masson, 1977. 36. Moss ML: New studies of cranial growth. Birth Defects 1975;11:283-295.

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37. Murray DJ, Kaban LP, Mulliken JB: Analysis and treatment of hemifacial microsomia. Plast Reconstr Surg 1984;74: 186-199. 38. Neilson KM, Friesel RE: Constitutive activation of fibroblast growth factor receptor-2 by a point mutation associated with Crouzon syndrome. J Biol Chem 1995;270: 26037-26040. 39. Oldridge M, Wilkie AO, Slaney SF, et al: Mutations in the third immunoglobulin domain of the fibroblast growth factor receptor-2 gene in Crouzon syndrome. Hum Mol Genet 1995;4:1077-1082. 40. Ortiz-Monasterio F, Fuente del Campo A, Carrillo A: Advancement of the orbits and the midface in one piece, combined with frontal repositioning for the correction of Crouzon's deformities. Plast Reconstr Surg 1978;61: 507-516. 41. Park W-J, Theda C, Maestri NE, et al: Analysis of phenotypic features and FGFR2 mutations in Apert syndrome. Am J Hum Genet 1995;57:321-328. 42. Poswillo D: Orofacial malformations. Proc R Soc Med 1974;67:343-349. 43. Poswillo D: The pathogenesis of the Treacher Collins syndrome (mandibulofacial dysostosis). Br J Oral Surg 1975;13:1-26. 44. Powiertowsky H, Matlosz Z: The treatment of craniostenosis by a method of extensive resection of the vault of the skull. In: Proceedings of the Third International Congress on Neurosurgery. Excerpta Med Int Cong Ser 1965;110:834. 45. Readon W, Winter RM, Rutland P, et al: Mutations in the fibroblast growth factor receptor 2 gene cause Crouzon syndrome. Nat Genet 1994;8:98-103. 46. Reissmann H: Ein Fall von Makrostoma. Arch Minerva Chir 1869;6:858. 47. Renier D, Sainte-Rose C, Marchac D, Hirsh JF: Intracranial pressure in craniosynostosis. J Neurosurg 1982;57:370-377. 48. Renier D, Marchac D.: Craniofacial surgery for craniosynostosis: Functional and morphologic results. Ann Acad Med Singapore 1988;17:415. 49. Rogers BO: Berry-Treacher Collins syndrome: A review of 200 cases. Br J Plast Surg 1964;17:109-137. 50. Shillito J, Matson DD: Craniosynostosis: A review of 519 surgical patients. Pediatrics 1968;41:829-853. 51. Taub PJ, Bradley JP, Stuzin JM, Kawamoto HK: Decreased morbidity in monobloc advancement with distraction osteogenesis. Presented before the 71st annual meeting of the American Society of Plastic Surgery, San Antonio, TX, November 4,2002. 52. Tessier P: Orbital hypertelorism: I. Successive surgical attempts, materials and methods, causes and mechanisms. Scand J Plast Reconstr Surg 1972;6:133-155. 53. Tessier P: Anatomical classification of facial, craniofacial and laterofacial clefts. J Maxillofac Surg 1976;4:69-92. 54. Tessier PL: Apert's syndrome: Acrocephalosyndactyly type I. In Caronni E (ed): Craniofacial Surgery. Boston, Little Brown, 1985, p 280. 55. Tessier P, Guiot B, Rougerie J, et al: Ostkotomies cranionaso-orbito-faciales hypertklorisme. Ann Chir Plast 1967; 12:103-118. 56. Treacher Collins E: Case with symmetrical congenital notches in the outer part of each lower lid and defective development of the malar bones. Tran's Ophthalmol Soc UK 1900;20:190. 57. Turk AE, McCarthy JG, Thorne CHM, et al: The "Back to Sleep" campaign and deformational plagiocephaly: Is there cause for concern? J Craniofac Surg 1996;7:12-18.

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58. van der Meulen JC: Medial faciotomy. Br J Plast Surg 1979;32:339. 59. Wheaton SW: Two specimens of congenital cranial defonnities in infants in association with fusion of the fingers and toes. In Smith DW (ed): Major Problems in Clinical Pediatrics, Vol 7, Recognizable Patterns of Human Malformation. Philadelphia, WB Saunders, 1982, p 308.

60. Wilkie AOM, Slaney SF, Oldridge M, et al: Apert syndrome results from localized mutations of FGFR2 and is allelic with Crouzon syndrome. Nat Genet 1995;9: 165-172. 61. Wolfe SA, Morrison G, Page LK, et al: The monobloc frontofacial advancement: Do the pluses outweigh the minuses? Plast Reconstr Surg 1993;91:977-987.

Cleft Lip and Palate A. Michael Sadove and Barry L. Eppley

Clefting anomalies of the lip and palate are the most frequently encountered congenital facial defects. They constitute most of major congenital facial malformations and the majority of all orofacial cleft types. Clefts of the lip may be associated with dentoalveolar defects anterior to the incisive foramen and are classified as clefts of the primary palate. Clefts that disrupt the hard and soft portions of the palate posterior to the incisive foramen are called clefts of the secondary palate. Clefts can occur in many different forms and combinations from the most minor. incomplete isolated lip clefts to the most severe, complete bilateral cleft lip and palate. The differences in racial occurrence are well known and are the result of ethnic variations in the timing and coordination of the facial merging process in utero. This may be due to the differences in facial tissue thickness between differing races. As a result of these differences, the frequency of occurrence of cleft lip may range from an incidence of 1 in 500 live births in Asians and Native Americans to 1 in 1500 to 2000 live births in African-American populations. Susceptibility of whites is intermediate at 1 in 750 to 900 live births.18 The left side of the lip, for reasons as yet unclear, is more often cleft than the right. In contrast, the frequency of isolated cleft palate is much more similar among the races (approximately0.50 in 1000 live births).

DEVELOPMENT OF CLEFT LIP Facial processes arise as a result of migration and later p r e liferation of neural crest mesenchyme. Coalescence of these facial processes, around day 30 in the human embryo, results in the formation of the primary lip or palate, which creates the initial separation between the oral and nasal cavities. This eventually gives rise to portions of the upper lip and maxilla. Virtually all cases of cleft lip are due to the failure of the median nasal (globular) process either to contact or to maintain contact with the lateral nasal and maxillary processes. A failure to merge or to adhere after contact (failure of contact maintenance) in any one component of this midfacial convergence of processes can result in the presentation of a facial cleft (Fig. 51-1).

DEVELOPMENT OF CLEFT PALATE The development of the hard and soft palate requires a consideration of both the primary palate (prepalaie) and the secondary palate (palate proper). The primary palate is related to the development of structures anterior to the incisive foramen (i.e., the face, lips, premaxilla, and upper four incisor teeth). It is closely related to the facial merging process that has been described for cleft lip, and it commences during the fourth week of gestation and is completed by the seventh week. For thisreason, cleft lip and palate implies a complete deformity extending from the lip through the alveolus back through the soft palate (Fig. 5 1-2A). The secondary palate relates to structures posterior to the incisive foramen (i.e., hard palate, soft palate, and maxillary teeth). This region develops bilaterally from the processes or of the maxillary bones, which become prominent during the sixth to seventh weeks. They extend from the primary palate to the tonsillar pillars and hang vertically beside the tongue. Between the eighth and ninth weeks, the palatal processes commence a positional change from the vertical to a horizontal plane. For a time, the palatal shelves are kept apart by the tongue, but as the tongue lowers in the floor of the mouth and moves forward, the two palatal plates fuse. Failure of the tongue to lower produces palatal clefts (see Fig. 51-2B). The best clinical example of this intersequence, in relatedprocess is found in the Pierre ~ o b i n which a soft palatal cleft, glossoptosis, and mandibular hypoplasia are present, which predisposes to a potential airway obstruction.

UNUSUAL FACIAL CLEFTS Whereas cleft lip and palate as described earlier is the traditional type of facial cleft, other more unusual patterns may occur radiating out from the orofacial r e g i ~ n . ~ They may be midline through the upper lip (Tessier 0), obliquely skirting around the nose toward the eye (Tessier 4, 5, and 6), or out from the corner of the mouth (Tessier 7). These types of facial clefts occur more

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Variations in cleft lip. A, Minor cleft (forme fruste). B, Incomplete unilateral cleft lip. C, Bilateral complete cleft lip.

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Variations in cleft palate. A, Complete palatal cleft associated with cleft lip. B, Cleft of the soft palate only.

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Atypical facial clefts. A, Oblique Tessier 4 cleft. B, Lateral Tessier 7 cleft.

rarely, involve different anatomic structures, and require innovative repair techniques. They usually are associated with more global facial defects and/or deficiencies. When present, they merit close evaluation of the face and brain because median lip clefts should be evaluated for frontonasal and brain dGformities, whereas oblique and lateral oral clefts may involve eye, ear, and jaw deformities (Fig. 51-3).

ETIOLOGY OF CLEFTS The cause of cleft lip and palate is multifactorial, involving both genetic and environmental factors. Although facial clefts occur in a variety of genetic syndromes (about 15% of cleft cases are syndromic; more than 170 syndromes have it as a feature), identification of a single gene controlling lip and palatal clefts has not yet been found.'8,24 Clefting loci have been identified on chromosomes 1, 2, 4, 6, 11, 14, 17, and 19. Certain specific chromosomal aberrations are consistently seen (e.g., trisomy D syndrome with medial cleft lip) or cleft lip associated with lower lip pits (van der Woude's syndrome). Because of their frequent syndromic association, it is important to search for other congenital defects, which occur most commonly on other parts of the head and neck, heart, and extremities. Only a few environmental factors are known, including certain drugs taken during gestation (phenytoin, retinoic acid, folic acid antagonists). Maternal smoking is now well known to increase the

incidence of clefting.WMtivitamin supplementation, particularly the folates, during the first 4 months of pregnancy, is currently thought to have a protective effect."

SURGICAL CLER CORRECTION Team Management The anatomic complexity of the cleft deformity and its effects on multiple orofacial functions (facial growth, dental eruption and hygiene, jaw development, hearing, speech) as well as its effect on orofacial growth and development make a team approach to the cleft patient mandatory. Cleft teams consisting of specialists in plastic surgery, dentistry (pedodontics, orthodontics, and oral surgery), audiology, speech pathology, otolaryngology, and genetics can best provide the many needs of the cleft patient over time. Such a team approach offers the combined expertise to blend treatment intervention with growth and development, providing more efficient and cost-effective services.'

Neonatal Management Parents The presence of a facial cleft at birth may be historically unexpected, but the contemporary use of prenatal

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Cleft Lip With or Without Cleft Palate (%I

Cleft Palate (%I

Frequency in general population Risk of second affected child (a) If both parents are normal ( b )If one parent has cleft similar to patient's Risk of third affected child (a and b) Risk of first affected child if parent has a cleft

ultrasound allows for early detection of facial deformities.13 This allows parents today an opportunity to seek prenatal counseling and consult with the cleft team before the birth of the child to lay the foundations of subsequent surgical reconstruction. Parents often feel guilty with the unfounded assumption that the cleft deformity could have been prevented. Reassurance to the parents can be done by arranging for genetic counseling to discuss the risk to future offspring (Table 51-1).

Child Besides the obvious facial deformity from an external cleft lip, immediate functional concerns are for airway patency and the ability to feed. Certain cleft deformities isolated to the palate (e.g., Pierre Robin sequence) involve airway obstruction and may require differing forms of management. The disruption of the lip and hard palate makes suckling difficult because of the inability to create negative pressure by compression of the tongue against an open palate. Therefore, nasal regurgitation of liquids is common, and altered feeding regimens, including the use of a cross-cut nipple and a palatal obturator, may be needed to create effective feeding.

Neonatal Maxillary Orthopedics In complete cleft lip and palate deformities in which the maxilla and hard palate are disrupted, repositioning of the displaced dentoalveolar segments before lip repair with various forms of intraoral and extraoral orthodontic appliances has been advocated. These methods may include simple methods such as adhesive taping across the cleft lip and circumferential elastic traction. Nasoalveolar molding orthopedic devices, however, are becoming popular because they are the most effective method of molding the nose, lip, and alveolus into the best possible presurgical position.Vhis makes the lip repair easier by decreasing the distance between the lip segments. This is of particular value in bilateral cases, in which the prolabial segment containing the premaxilla and central lip is anteriorly positioned. More involved mechanical methods such as fixed intraoral appliances have been used in some patients but increase the risk of injury to developing teeth by pinning into the bone, which is full of developing teeth.

Surgical Timing The cleft lip is always repaired first at 3 to 4 months of age. Although it can technically be repaired within the

first few weeks of life, a more traditional repair is obtained when the infant is older. The historic rule of 10s is a good guideline: 10 weeks of age, 10 grams of hemoglobin, and 10 pounds of weight. These conditions favor adequate wound healing and safe anesthesia. Associated anomalies, such as congenital heart disease, may alter the timing of repair until a later age. The cleft palate is traditionally repaired after the lip and may be done between 9 and 15 months of age depending on the surgeon's philosophy. Early surgical efforts are purported to result in better speech function. Although this is controversial, delaying the repair until after 18 months of age is clearly associated with poorer speech outcomes. An exception to this would be the child with a history of early respiratory difficulties (e.g., Pierre Robin sequence). Delaying repair up until the age of 18 months may be necessary in such a child to decrease the risk of postoperative airway obstruction from decreasing the size of the nasopharyngeal airway. The cleft alveolus (tooth-bearing portion of upperjaw) is usually repaired with an autogenous bone graft between 5 and 8 years of age. This not only establishes maxillary arch continuity but also permits subsequent tooth eruption and provides improved support for the cleft nasal base. A few centers favor early bone grafting before palate repair, around 9 to 12 months of age provided there is end-to-end maxillary segment alignment, in an effort to provide an earlier stabilization of the maxilla and closure of the oronasal fistula.

Cleft Lip Repair The many types of cleft lip repairs attest to the fact that not all clefts are the same. They differ in both amount and extent of contiguous anatomic disruption. Therefore, it is difficult to find one operation that is the ideal solution for all cleft cases. The Millard rotation-advancement cleft lip repair, however, has become the most commonly performed procedure for repair of the unilateral cleft lip.21 It effectively returns displaced lip and nasal structures into their normal position, allows the resultant scars to be less discernible because they lie along anatomic boundaries, and minimizes the amount of tissue discarded. The concept involves an inferior rotation of the medial lip segment with an advancement of the lateral lip segment into the subcolumellar space to join with the medial lip segment (Fig. 51-4). This procedure achieves a lengthening of the lip along the philtral line, reconstruction of the orbicularis muscle across the cleft, rotation of the

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Cleft L.ip a n d Palate

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Rotation-advancement unilateral cleft lip repair. A, Original deformity with widened nasal base, lip cleft, and shortened medial and lateral lip elements. B, Cuts and separation of the lip elements around the nasal base and lateral lip, across the base of the columella to the opposite philtral ridge as well as the raising of bilateral vermilion flaps. The arrows indicate the downward rotation of the medial lip element and the advancement of the lateral lip element toward the columella. C, Completed skin closure afterjoining the orbicularis muscle across the defect.

displaced nasal base medially, a slight lengthening of the columella, and establishment of a labial sulcus. The conceptual simplicity and the ability to tailor and make adjustment as the repair proceeds is one of the major strengths of this type of lip repair. In addition, the minimal sacrifice of tissue and the location of the scar lines favor secondary revisions of the repair, which are almost always needed. Additions to the technique revolve around concurrent manipulation of the nose, mobilizing and translocating the ipsilateral lower alar cartilage and nasal base.'" The bilateral cleft lip represents more than just a doubling of the problem of the unilateral cleft lip. The lack of a columella, splaying of the alar cartilages and nasal bases, and protrusion of the underlying premaxilla not

only make the initial lip repair different from a unilateral cleft but also ensure that subsequent operations will be needed. Decisions regarding repair of the bilateral cleft include whether to repair both lip clefts simultaneously or in stages, whether to adhese the lip elements before a definitive lip repair, and how to manage the protrusive premaxilla. All of these issues are controversial, and approaches may vary widely among deft teams. Our approach is to do synchronous lip repair if the width of the clefts and the premaxilla permit closure without excessive tension on the orbicularis muscle coaptation and skin suture lines.22 The technique of Millard's rotationadvancement is effective in creating a Cupid's bow and bilateral straight philtral lines (Fig. 51-5). When the premaxilla is too protrusive and concern exists regarding

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Bilateral cleft lip repair. A, Original deformity

with protruding premaxilla and prolabium. Note the absence of a columella. B, The raising of a central prolabial skin flap, lateral lip flaps, and bilateral vermilion tissue converge to form the bilateral repair after the orbicularis muscle is joined over the protruding premaxilla. C, Completed lip repair.

the potential integrity of the lip repair, a more simplified lip adhesion may be performed first at 8 to 10 weeks of age. The definitive lip repair is then performed 2 to 3 months later after the premaxilla is retropositioned.

Cleft Palate Repair Despite a long history, the surgical treatment of the cleft palate is controversial owing to conflicting opinions about how the type of surgical repair influences subsequent speech and facial skeletal development.25 As such, cleft palate operations differ in regard to timing of intervention, staged versus complete hard and soft palatal repairs, and the arrangement of the tissue flaps to create palatal closure. The fundamental goals of the procedure are a soft palatal muscular reconstruction, a two-layer

(nasal and oral) lining closure of both hard and soft palatal defects, and adequate palatal length. Although there remains no uniform palatal repair technique or approach, the operation may be conceived as three basic types: straight-line closure, V-Y lengthening, or Z-plasty rearrangement. Opening the mucosa along the cleft edges, mobilizing tissue at the subperiosteal level, and mobilizing of the palatal flaps medially enables a straight-line repair to be completed in two layers. This technique, known as the von Langenbeck repair, is straightforward but may not provide adequate soft palatal length. To achieve this goal, the straight-line repair has been modified by the creation of oblique incisions anteriorly to connect with the incision along the posterior alveolar ridge. Once the palatal flaps are mobilized, they are moved posteriorly and medially, which results in a V-Y rearrangement (Fig. 51-6).

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V-Y pushback cleft palate repair. A, Outline of incision placement. B, Raising of full-thickness mucoperiosteal flaps based on the greater palatine vessels, mucosal nasal lining closure, and soft palatal muscle apposition. C, Oral closure obtained by lengthening of the palate by a posterior repositioning of the palatal mucosal tissues, leaving an open area of anterior palatal bone. I

As such, this technique has become known as a push-back palatal procedure or a Veau-Wardill-Kilner repair. With either approach, the aberrant attachments of the levator and tensor palatini muscles are detached from the posterior and medial edges of the palatal shelves and sutured together in the midline of the soft palatal closure (intravelar veloplasty). A more recent addition to palatal repair techniques has been the clever application of the Z-plasty principle with double-reversing musculomucosal flaps of oral and nasal tissue, often referred to as the Furlow palate This not only effectively reorients the soft palatal muscular fibers but also increases palatal length (Fig. 51-7). Mounting clinical evidence indicates that longterm speech outcomes may be improved with this type of muscular repair.l"n addition, the risk of postoperative fistula formation is decreased because the suture lines between the oral and nasal linings do not lie directly over each other.

support subsequent tooth eruption. The use of autogenous bone is generally accepted as the graft material of choice, and most centers undertake graft placement when the child is between 5 and 8 years of age.kJJAt this time, the canine teeth have sufficient root development so that the graft may provide support for the path of subsequent tooth eruption into the proper position in the dental arch. A few centers favor earlier alveolar bone graft placement within the first year of life in an effort to prevent maxillary collapse and decrease the need for extended orthodontic care later in life.2' Long-term assessment of this technique shows favorable facial growth, improved maxillary arch forms, and decreased need for maxillary osteotomies and bone grafting at a later age.28 Boneless alveolar bone grafts, in which a periosteal closure is obtained across the cleft defect by tibia1 periosteal grafts (periosteoplasty), have also been tried, but significant regenerated bone has not been consistently shown.

Alveolar Bone Grafting

Secondary Clef&Management

Bone grafting of the tooth-bearing portion of the maxilla (alveolus) completes the primary repair sequence of the original cleft deformities. his not only unifies the maxilla into a single unit and eliminates any residual oronasal fistulas but also provides the proper tissue to

Lip and Nasal Revision Despite optimal execution of primary facial repair, most clefts require secondary revision of the lip, nose, or both. These revisions may entail a variety of procedures,

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Z-plasty cleft palate repair. A, Outline of incision

placement. B, The basis of the repair is the creation and closure of double-apposing mucosal and musculomucosal soft palatal flaps. C;, This not only properly reorients the soft palatal musculature but also adds length to the soft palate.

including scar revision, vermilion realignment, philtral lengthening, nasal base rotation, or the correction of nasal tip cartilage^.^' In particular, the secondary creation of a columella in the bilateral cleft patient is necessary because this nasal element is congenitally absent in this cleft def~rmity.~%anyof these lip and nasal revisions are done in the 2- to 4year age range to allow scar maturation to occur before the child enters the public scrutiny of the school environment. Further cleft lip revisions in adolescence are also likely as the psychosocial demands of the teenage years escalate.14Most patients will eventually require a complete septorhinoplasty reconstruction to treat the entire nose once the pubertal growth phase has been passed."

Palatal Revisions The incidence of postoperative fistula formation after primary repair of the cleft palate is relatively high, averaging

10% to 20% even in experienced hands. These usually occur at the junction of the hard and soft palate posteriorly or at the premaxillary-maxillaryjunction anteriorly. Palatal fistula closure using local tissue may be necessary depending on the magnitude of its associated symptoms, such as nasal liquid regurgitation and nasal air escape affecting speech. In large fistulas or those occurring anteriorly behind the upper incisor teeth, the need for regional tissue coverage from the tongue through pedicled reconstructive techniques may be needed. If the soft palate fails to contact the posterior pharyngeal wall properly during speech, excessive air escape through the nose occurs, resulting in hypernasal speech. This occurs in about 15% of all patients who have had clefts involving the secondary palate. This velopharyngeal dysfunction may require surgical management based on a nasoendoscopic assessment of palate and pharyngeal Competent velopharyngeal function wall rno~ement.'~ may be attained by either rearranging tissues of the lateral

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811

Pharyngeal flap for velopharyngeal dysfunction.

A, Outline of incisions, including a split of the soft palate for access and flap inset and a superiorly based musculomucosal flap of the posterior pharyngeal wall. B, Raising of the pharyngeal flap and inset into the soft palate using small catheters to size the lateral port? and closure of the pharyngeal wall donor site. C,Closure of the soft palate. The flap effectively separates the velopharyngeal orifice into two small lateral orifices, thus decreasing nasal air loss during spccch.

and posterior pharyngeal walls to create a tightening of the velopharyngeal sphincter16 or attaching a musculomucosal flap from the posterior pharyngeal wall to the soft palate pharyngeal flap,' which decreases the cross-sectional dimensions of the velopharyngeal airway (Fig. 51-8). The success of these operations is dependent on matching the type of operation to the decision made at the pre-operative assessment of velopharyngeal dysfunction as determined by nasoendoscopy.

Orthognathic Surgery The negative growth affect of clefting on the maxilla is typically manifest by restrictive anterior and transverse bone development. This creates a midfacial deficiency by appearance and a cross-bite/underbite type of occlusion. As a result, orthodontic alignment of the teeth and bony

osteotomies may be needed to properly place the maxilla into a correct skeletal and occlusal relationship with the mandible. The need for LeFort I advancements is estimated to be 20% to 30% in all cleft patients.10 In cases of severe midfacial retrusion, as may occur in the bilateral cleft patient, the midfacial skeleton may need to be moved by osteotomies combined with postoperative distraction devices to obtain a significant movement that is postoperatively stable.Z0

ASSOCIATED CONGENITAL ANOMALIES Lip Fistulas (pits) This condition, often inherited, may or may not be associated with cleft lip and palate. Symmetrical blind-ended

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fistulas or pits occur on the central segment of the lower lip vermilion. Known as van der Woude's syndrome, treatment consists of excision with removal of the mucosal tract and adjacent glandular tissue between 1 and 3 years of age.26

Submucous Cleft Palate This seemingly least serious form of cleft palate often escapes detection until speech development occurs. Careful intraoral examination must demonstrate three physical findings: median depression or notch in the hard palate, a bifid uvula, and failure of the soft palatal muscles to join in the midline even though the overlying mucous membrane is intact. It may cause velopharyngeal dysfunction and require surgical therapy.30

Pierre Robin Sequence The classic triad of cleft of the soft palate, posterior positioning of the tongue (glossoptosis), and mandibular hypoplasia is well known as the Pierre Robin sequence. It is not rare and should be excluded when clefts of the soft palate only are discovered. The significant mandibular retropositioning frequently causes airway issues immediately after birth that may require differing forms of management, including surgery, depending on its severity.19Palate repair is frequently delayed beyond 1year of age in these patients to decrease the risk of secondary airway problems. By this time, growth of the mandible helps to bring the tongue forward.

REFERENCES 1. American Cleft Palate/Craniofacial Association: Parameters for the evaluation and treatment of patients with cleft lip/palate or other craniofacial anomalies. Cleft Palate Craniofac J 1993;30(suppl 1) :4. 2. Cable BB, Canady JW, Karnell MP, et al: Pharyngeal flap surgery: Long-term outcomes at the University of Iowa. Plast Reconstr Surg 2004;113:475. 3. Chung KC, Kowalski CP, Kim HM, Buchman SR: Maternal cigarette smoking during pregnancy and the risk of having a child with cleft lip/palate. Plast Reconstr Surg 2000; 105:485. 4. Cohen M: Cleft lip and palate. Clin Plast Surg 2004;31:57. 5. Cutting C: Secondary cleft lip nasal reconstruction: State of the art. Cleft Palate Craniofac J 2000;37:538. 6. Dempf R, Telzrow T, Kramer FJ, Hausamen JE: Alveolar bone grafting in patients with complete clefts: A comparative study between secondary and tertiary bone grafting. Cleft Palate Craniofac J 2002;39:18. 7. Eppley BL: Pediatric plastic surgery revisited. Clin Plast Surg 2001;28:731. 8. Eppley BL, van Aalst J, Robey A: The spectrum of orofacial clefting. Plast Reconstr Surg 2005;115:101e-114e. 9. Grayson BH, Cutting CB: Presurgical nasoalveolar orthopedic molding in primary correction of the nose, lip, and alveolus of infants born with unilateral and bilateral clefts. Cleft Palate Craniofac J 2001;38:193.

10. Heliovaara A, Ranta R, Hukki J, Rintala A: Skeletal stability of LeFort I osteotomy in patients with isolated cleft palate and bilateral cleft lip and palate. Int J Oral Maxillofac Surg 2002;31:358. 11. Horswell BB, Henderson JM: Secondary osteoplasty of the alveolar cleft defect. J Oral Maxillofac Surg 2003;61:1082. 12. Johns DF, Rohrich RJ, Awada M: Velopharyngeal incompetence: A guide for clinical evaluation. Plast Reconstr Surg 2003;112:1890. 13. Johnson N, Sandy J: Prenatal diagnosis of cleft lip and palate. Cleft Palate Craniofac J 2003;40:186. 14. Kane AA, Pilgram TK, Moshiri M, Marsh JL: Long-term outcome of cleft lip nasal reconstruction in childhood. Plast Reconstr Surg 2000;105:1600. 15. LaRossa D, Jackson OH, Kirschner RE, et al: The Children's Hospital of Philadelphia modification of the Furlow double-opposing Z-palatoplasty: Long-term speech and growth results. Clin Plast Surg 2004;31:243. 16. Losken A, WilliamsJK, Burstein FD, et al: An outcome evaluation of sphincter pharyngoplasty for the management of velopharyngeal insufficiency. Plast Reconstr Surg 2003; 112:1755. 17. Loffredo LC, Souza JM, Freitas JA, Mossey PA: Oral clefts and vitamin supplementation. Cleft Palate CraniofacJ 2001; 38:76. 18. Marazita ML, Mooney MP: Current concepts in the embrvology and genetics of cleft lip and palati. Clin Plast S U ~ 2004:31:125. 19. Matsas R, Thomson A, Goodacre T: Management of infants with Pierre Robin sequence. Cleft Palate Craniofac J 2004; 41:219. 20. Molina F: Distraction osteogenesis for the cleft lip and palate patient. Clin Plast Surg 2004;31:291. 21. Mulliken JB, Martinez-Perez D: The principle of rotation advancement for repair of unilateral complete cleft lip and nasal deformity: Technical variations and analysis of results. Plast Reconstr Surg 1999;104:1247. 22. Mulliken JB: Primary repair of bilateral cleft lip and nasal deformity. Plast Reconstr Surg 2001;108:181. 23. Mulliken JB, Wu JK, Padwa BL: Repair of bilateral cleft lip: Review, revisions, and reflections. J Craniofac Surg 2003; 14:609. 24. Murray JC: Gene/environment causes of cleft lip and/or palate. Clin Genet 2002;61:248. 25. Pigott RW, Albery EH, Hathorn IS, et al: A comparison of three methods of repairing the hard palate. Cleft Palate Craniofac J 2002;39:383. 26. Rizos M, Spyropoulos MN: Van der Woude syndrome: A review. Cardinal signs, epidemiology, associated features, differential diagnosis, expressivity, genetic counseling and treatment. Eur J Orthod 2004;26: 17. 27. Rosenstein SW: Early bone grafting of alveolar cleft deformities. J Oral Maxillofac Surg 2003;61:1078. 28. Rosenstein SW, Grasseschi M, Dado DV: A long-term retrospective outcome assessment of facial growth, secondary surgical need, and maxillary lateral incisor status is a surgicalorthodontic protocol for complete clefts. Plast Reconstr Surg 2003;lll:l. 29. Salyer KE, Genecov ER, Genecov DG: Unilateral cleft lipnose repair: A 33-year experience. J Craniofac Surg 2003; 14:549. 30. Sommerlad BC, Fenn C, Harland K, et al: Submucous cleft palate: A grading system and review of 40 consecutive submucous cleft palate repairs. Cleft Palate Craniofac J 2004; 41:114. 31. Stal S, Hollier L: Correction of secondary cleft lip deformities. Plast Reconstr Surg 2002;109:1672.

Otolaryngologic Disorders William I? Potsic and Ralph F. Wetmore

EAR

Anatomy The ear is divided into three anatomic and functional areas: the external ear, the middle ear, and the inner ear. The external ear consists of the auricle, external auditory canal, and the lateral surface of the tympanic membrane. The auricle is a complex fibroelastic skeleton that is covered by skin and subcutaneous tissue that directs sound into the external ear canal. The external auditory canal is oval with the long axis in the superior to inferior direction. In neonates, the external canal is almost entirely supported by soft, collapsible cartilage. As the temporal bone grows over several years, the bony portion of the canal enlarges to comprise the inner one third, leaving the outer two thirds supported by firm cartilage. Hair and cerumen glands are present in the outer two thirds of the external canal. The ear canal is lined by skin that is continuous with the lateral surface of the tympanic membrane, and it is innervated by cranial nerves V, VII, and X and cervical nerve 111. The tympanic membrane separates the external ear canal from the middle ear. It has three layers: an outer layer of skin; a middle layer of fibrous tissue that is attached to the malleus, the most lateral middle ear ossicle; and an inner layer of mucosa that is continuous with the mucosa lining the middle ear. The fibrous layer is also attached to a thick fibrous annulus that anchors it to the temporal bone. The middle ear is an air-filled space within the temporal bone of the skull that is lined by ciliated, columnar respiratory epithelium. The middle ear communicates with the mastoid air cell system posteriorly and is lined by the same mucosa. It also communicates with the nasopharynx anteriorly through the eustachian tube. The mucociliary transport system of the middle ear moves mucus and debris into the nasopharynx, where it is swallowed. Secretory cells are not evenly distributed throughout the middle ear and mastoid complex and are more numerous anteriorly near the eustachian tube. Three ossicles are present in the middle ear-the malleus, incus, and stapes-that transmit sound from the

vibrating tympanic membrane to the stapes footplate. Stapes movement creates a fluid wave in the inner ear that travels to the round window membrane and is dissipated by reciprocal motion to the stapes. There are two striated muscles in the middle ear. The tensor tympani muscle lies along the side of the eustachian tube, and its tendon attaches to the medial surface of the malleus. The stapedius muscle lies along the vertical portion of the facial nerve in the posterosuperior part of the middle ear. Its tendon attaches to the head of the stapes. These muscles stiffen the ossicular chain in the presence of sustained loud noise. The facial nerve traverses the middle ear with its horizontal portion lying superior to the stapes. Posterior to the stapes, the facial nerve turns inferiorly in a vertical fashion to exit the stylomastoid foramen deep to the tip of the mastoid. The chorda tympani nerve is a branch of the facial nerve that innervates taste to the anterior two thirds of the tongue. It exits the facial nerve in the vertical segment and passes under the posterosuperior surface of the tympanic membrane, crossing the middle ear lateral to the long process of the incus and medial to the malleus. The facial nerve lies within a protective bony canal throughout its course in the middle ear. However, the bony canal may be absent (in the horizontal portion) in as many as 30% of patients. Cranial nerve IX supplies sensation to the floor of the middle ear. The inner ear consists of the cochlea, semicircular canals, and vestibule. The cochlea is a coiled fluid-filled tube consisting of 23/4 turns surrounded by dense bone. It contains the membranes that support the organ of Corti and has hair cells that detect the fluid wave from vibration of the stapes footplate. The hair cells create the neural impulses that are transmitted from the auditory nerve (cranial nerve VIII) to the brain, providing the sensation of hearing. The three paired semicircular canals (horizontal, superior, and inferior) are also fluid-filled tubes surrounded by dense bone. The semicircular canals each have a hair cell-containing structure (the ampulla) that detects motion. The utricle and saccule of the vestibule also have hair cell structures that detect a~celeration.~"

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should be taken to secure the child to prevent sudden movement, and the ear curet should be used gently to The external ear develops during the sixth week of avoid causing pain and a laceration of the ear canal. gestation and is completely developed by the 20th week. Examination of a child with an apparent or suspected Six hillocks fuse to form the basic units of the pinna. ear condition often requires objective assessment of hearDefects in the fusion of the hillocks lead to preauricular ing by audiometry. Current technology and expertise makes tags and sinuses. The external auditory canal develops it possible to test a child at any age. from the first pharyngeal cleft. A solid epithelial plug forms during the beginning of the third month of gestation and Behavioral audiometry can usually be accurately percanalizes in the seventh month to form the external audiformed for a child who is older than 6 months of age by tory canal. sound-field testing. Older children are presented with a The middle ear canal develops from the first pharyngeal tone through insert earphones and a range of frequenpouch. The ossicles develop from the first and second phacies between 250 and 8000 Hz for ear-specific testing. ryngeal arches. The inner ear arises from neuroectodermal The hearing thresholds are recorded at each presented tissue within the otic placode that forms the otic pit.26 frequency; and this represents the air conduction threshAny combination of anomalies may occur. Abnormalities old. The sound has to traverse the ear canal, tympanic of the development of the ear may create anomalies of membrane, and middle ear. The inner ear must respond the pinna, external auditory canal, middle ear structures, by creating electrical impulses that are transmitted to the and inner ear. One of the anomalies that involves the brain. Normal thresholds are less than 20 dB for children. external and middle ear is aural atresia (absence of the Bone conduction thresholds test the sensorineural external auditory canal). Absence of the external canal component of hearing. A bone oscillator is used to test a may occur with a deformed or normal external ear. The range of frequencies by vibrating the skull, which stimuossicles may be deformed and are usually fused to each lates the inner ear, directly bypassing the external and other as well as the bony plate representing the undevelmiddle ear. Normally, air conduction thresholds require oped tympanic membrane. The facial nerve may also less energy than bone conduction thresholds. If bone be altered in its course through the temporal bone. conduction thresholds require less sound intensity than Reconstruction of the atretic canal, removal of the bony air conduction to be heard, the child has a conductive tympanic plate, release of the fused ossicles, and reconstruchearing loss. If air conduction and bone conduction tion of a new eardrum is a complex surgical procedure that thresholds are elevated but the same, the child has a senmay improve hearing. Rarely there is incomplete develsorineural hearing loss. Most sensorineural hearing loss in children is a result of hair cell dysfunction in the organ opment of the inner ear structures. The most common of Corti. Hearing loss may be conductive, sensorineural, or of these is dysplasia of the cochlea, and it may vary in severity. Dysplasia causes sensorineural hearing l o ~ s . ~ , l ~ mixed. Electrophysical tests such as brainstem auditory evoked response and sound emission tests that measure the intrinsic sounds from the inner ear (otoacoustic emissions) may be employed in young infants and children who Examination cannot participate in behavioral audiometry.A mechanical The examination of the ear should always start with test of tympanic membrane compliance (tympanometry) inspection of the outer ear and surrounding structures. may also be used for audiometric assessment. All of these Deformities of the outer ear structure may suggest the tools are employed by pediatric audiologists.23 presence of other anomalies, such as a first branchial cleft For purposes of describing hearing loss, a threshold sinus. A first branchial cleft sinus usually presents below between 20 and 40 dB is considered mild, 40 to 65 dB is the ear lobe near the angle of the jaw. The sinus tract may moderate, 55 to 70 dB is moderately severe, 70 to 90 dB connect to the ear canal or, rarely, the middle ear. is severe, and greater than 90 dB is profound. Four of The external auditory canal and tympanic membrane 1000 children are born with a hearing loss, and 1 of are best examined with a hand-held otoscope with a those children is born with a severe to profound hearing loss. bright fiberoptic light source. The largest speculum that comfortably fits in the external canal should be used to Conductive hearing loss may be corrected with otologic maximize visualization and minimize pain. A very small surgery. Hearing aids and FM systems may be helpful to speculum may be inserted deeply, but it might lacerate children with both conductive and sensorineural hearing the ear canal as well as limit visibility of the tympanic loss. Assistance may be needed through auditory training, membrane. The otoscope permits visualization of the ear speech language therapy, and education to maximally develop communication skills. When a child has a sencanal and tympanic membrane. A translucent tympanic sorineural hearing loss that is too severe to be helped membrane will also permit visualization of the contents of the middle ear. with hearing aids, a cochlear implant may be considered. Cerumen may be encountered in the ear canal that A cochlear implant is an electrical device that is implanted under the scalp behind the ear: Its processor obstructs the view of the tympanic membrane. Removal of cerumen may be performed by using an operating converts sound to electrical impulses. A cable travels otoscope head and an ear curet. However, the use of through the mastoid and facial recess to reach the middle a headlight such as the Lumiview (Welch Allyn, ear, and the electrode array is inserted into the scala tymSkaneateles, NY) or operating microscope permits the pani of the cochlea through an opening that is made in use of both hands and superior visualization. Care the cochlea.

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Cochlear implants stimulate the neural elements of the cochlea directly and bypass the hair cells. Because the vast majority of sensorineural hearing loss in children is due to hair cell dysfunction, nearly all children get sound perception from a cochlear implant. Rare conditions such as an absent auditory nerve or an absent cochlea preclude the use of a cochlear implant. A multidisciplinary evaluation by a cochlear implant team is required to evaluate a child and determine family expectations before performing a cochlear implant. A temporal bone computed tomographic (CT) scan and/or magnetic resonance imaging (MRI) is performed to assess the cochlea and auditory nerves. Children who are born deaf and are younger than the age of 3 years, as well as children who have already developed communication skills, language, and speech before losing their hearing, derive the greatest benefit from cochlear implants. Cochlear implantation is approved for children 12 months of age or older by the U.S. Food and Drug Administration.After a cochlear implant is performed, considerable auditory oral training is required to maximize a child's benefit to develop skills of audition, speech, and language. A child who has been deaf and without sound perception for several years is expected to benefit to a lesser degree.33

Otitis Media with Effusion and Inflammatory Disorders Otitis media with effusion is the most common chronic condition of the ear during childhood. All children are born with small eustachian tubes that may at times be unable to clear mucus that is secreted in the mastoid and middle ear. Fluid may develop in the middle ear during an upper respiratory infection. It usually clears within a few weeks as the upper respiratory tract infection resolves. Children with craniofacial anomalies such as cleft palate and Down syndrome are also prone to middle ear effusions; there is no medication that is consistently effective in resolving such effusions. Persistent effusion may cause a conductive hearing loss in the range of 20 to 40 dB. A middle ear effusion may also function as a culture medium and predispose children to recurrent acute suppurative otitis media (ASOM). When fluid persists in the middle ear for 3 to 4 months, causing a hearing loss or is associated with ASOM, myringotomy and tympanostomy tube placement is helpful to resolve the hearing loss and reduce the frequency and severity of infection. Myringotomy and placement of a tube is performed under general anesthesia using an operating microscope. A small incision is made in any quadrant of the tympanic membrane except the posterosuperior quadrant, where there would be risk of injuring the ossicles. The mucus is suctioned from the ear, and a Silastic tube is placed in the myringotomy to provide prolonged ventilation of the middle ear. The tube will usually be extruded and the tympanostomy will heal in 6 months to 1 year. When the

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ear is no longer ventilated by a tube, the eustachian tube must ventilate the middle ear. If fluid recurs and persists, a repeat procedure may be needed. Most children outgrow this problem as their eustachian tube grows. Occasionally, adenoid tissue in the nasopharynx may contribute to the persistence of middle ear effusion and may also be removed at the time that a tube is placed. Children who have had multiple sets of tubes are candidates for adenoidectomy.

Acute Suppurative Otitis Media Acute suppurative otitis media is the most common infection of childhood except for acute upper respiratory tract infections. It is the most common condition for which children seek medical care from their primary care physician. Usual pathogens causing ASOM include Streptococcuspneumoniae, Haemophilus influenzae, and Moraxella ~atarrhalis.~~ Acute suppurative otitis media usually causes severe deep ear pain, fever, and a conductive hearing loss in the affected ear. The purulence in the middle ear is also present in the mastoid air cells because they are connected. ASOM is treated with broad-spectrum oral antibiotics; however, there is growing concern that indiscriminant use of antibiotics may result in antibiotic resistance. For this reason, accurate diagnosis by otoscopy should be made before initiating a course of antibiotics. Occasionally, ASOM does not respond as expected to standard antibiotic therapy. When this occurs, culture and sensitivity testing can be obtained by tympanocentesis. After sterilizing the ear canal with alcohol, a 22-gauge spinal needle can be placed through the posterior or anterior inferior quadrant of the tympanic membrane and fluid can be aspirated with a small syringe. Complications of ASOM are uncommon if appropriate antibiotic therapy is used. The conductive hearing loss resolves as the middle ear effusion clears. However, infection may necrose the tympanic membrane, causing a spontaneous perforation. Small perforations usually heal in less than 7 days, but larger perforations may persist, cause a conductive hearing loss, and require a tympanoplasty for closure. The ossicular chain may also be disrupted by necrosis of the long process of the incus requiring ossicular reconstruction to restore hearing. Acute coalescent mastoiditis occurs when infection erodes the bony mastoid cortex and destroys bony septa within the mastoid. A subperiosteal abscess may also be present. There is usually postauricular erythema and edema over the mastoid area. The auricle is displaced laterally and forward (Fig. 52-1). Otoscopy reveals forward displacement of the posterior superior skin of the ear canal. In addition to antibiotics, treatment should include a wide field myringotomy from the anterior inferior quadrant to the posterior inferior quadrant; a tympanostomy tube placement for middle ear drainage, and a postauricular mastoidectomy to drain the subperiosteal abscess and the mastoid. Facial nerve paralysis may occur from inflammation of that portion of the facial nerve that is exposed in the

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Acquired cholesteatoma develops from skin entering the middle ear after a tympanic membrane perforation or a retraction pocket from eustachian tube dysfunction. Cholesteatomas are usually painless, cause a conductive hearing loss, and, in acquired cases, often present as otorrhea. The otorrhea should be treated with ototopical antibiotic eardrops, but the only treatment of cholesteatomas is complete surgical excision by tympanomastoid surgery and ossicular reconstruction.27[~~ '8-591 The potential complications of cholesteatomas are the same as those for ASOM.

Trauma

•

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Acute mastoiditis. Extension of the acute inflammatory

process from the middle ear and mastoid air cell systems to the overlying soft tissues displaces the auricle in an inferior and lateral direction from the side of the head. Fluctuance may be palpated over the mastoid cortex, and a defect in the cortical bone can frequently be appreciated. Surgical drainage with mastoidectomy is required.

middle ear during ASOM. Treatment with parenteral antibiotics, ototopical antibiotic drops applied in the ear canal, and a wide field myringotomy and tympanostomy tube placement almost always result in complete recovery of facial function. Facial nerve recovery may take a few weeks to several months. Intracranial complications of ASOM may include meningitis, epidural abscess, brain abscess, otitic hydrocephalus, and lateral sinus thrombosis. Meningitis is the most common intracranial complication of ASOM and may be associated with profound sensorineural hearing loss and loss of vestibular function. Treatment of the intracranial complications of ASOM is focused on appropriate treatment of the intracranial process, in addition to a wide field myringotomy and tympanostomy tube placement in the affected ear.2

Chronic Otitis Media Chronic otitis media is a descriptive term that refers to a persistent perforation of the tympanic membrane or the presence of a cholesteatoma of the middle ear. A cholesteatoma is a squamous epithelial-lined cyst that may be congenital or acquired. Congenital cholesteatomas are caused by epithelial rests that persist in the middle ear during temporal bone development. They present behind an intact tympanic membrane and appear as a white, smooth mass in the middle ear. They expand over time and are filled with squamous debris and may erode the ossicular chain and extend into the mastoid.

Objects stuck deeply into the ear canal such as a cottontipped applicator may perforate the tympanic membrane. This usually causes acute pain, bleeding, and a conductive hearing loss. If the ossicular chain is not disrupted, the vast majority of these perforations will heal spontaneously in about 2 weeks. If the tympanic membrane is perforated and the middle ear is contaminated with water, oral antibiotics should be given. Lacerations of the auricle should be cleaned to prevent tattooing and repaired by careful approximation of the skin and soft tissue to restore the contours of the ear. The cartilage itself does not usually need to be sutured. Partially or totally avulsed tissue should be replaced. If necrosis of tissue occurs, it can be dkbrided as needed. In severe injuries of the auricle, oral antibiotic treatment is helpful to prevent chondritis and loss of the cartilage framework. Blunt trauma to the ear is commonly seen in wrestlers, in children with poor neuromuscular tone, or in children with self-injurious behaviors. Blood or serum collects between the periosteum and the auricular cartilage. If the cartilage is fractured, the collection may occur on both sides of the ear. Evacuation of the collection is required to restore the contours of the ear, prevent infection, and prevent scarring with formation of a "cauliflower ear." Aspiration of the fluid and placement of a mastoid dressing for compression may be tried but is most often unsuccessful. Incision and drainage provides for complete evacuation of the blood or serum. Cotton dental rolls placed in each side of the auricle and held in place with bolster mattress sutures is the most effective management. The dental rolls should be left in place for 7 to 10 days while the patient also continues with a course of oral antibiotics. No outer dressing is required."[pp lf)61091 Blunt head trauma may disrupt the inner ear membranes causing sensorineural hearing loss and vertigo. No treatment is required, and the injury and symptoms may resolve spontaneously, but the sensorineural hearing loss may persist. Severe head trauma may cause fracture of the temporal bone of the skull. Temporal bone fractures can be classified as longitudinal, transverse, or mixed (Fig. 52-2) but are often complex and do not neatly fit into one category or another. A high-resolution, thin section CT scan of the temporal bone will define the extent of the fracture. The middle ear and mastoid are filled with blood when a fracture is present. The blood causes a conductive hearing loss that resolves when the ear clears.

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A , -

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6

A, Longitudinal temporal bone fracture. These fractures run parallel to the petrous pyramid. The otic capsule is generally not affected by the fracture lines. Balance, hearing, and facial function are generally preserved. B, Transverse temporal bone fracture. These fractures generally extend through the cochlea and facial canal and result in deafness, vertigo, and facial nerve paralysis of immediate onset. Facial nerve exploration with repair should always be considered in these cases.

Otoscopic evaluation of a child with a temporal bone fracture may reveal a laceration of the ear canal and tympanic membrane. Blood is usually present in the ear canal, and the tympanic membrane appears to be dark blue because the middle ear is filled with blood. There is often ecchymosis of the mastoid area (Battle's sign). It is important during evaluation of a skull and temporal bone fracture to note and record the function of the facial nerve if the patient is not unconscious. Facial nerve paralysis may be immediate or delayed in onset. Delayed facial nerve paralysis has a good prognosis for spontaneous recovery. Immediate facial paralysis may indicate disruption of the nerve or compression by bone fragments. Immediate facial nerve paralysis requires exploration and repair once the patient is stable and sufficiently recovered from any associated trauma. The facial nerve should be decompressed in the mastoid, middle ear, and middle cranial fossa. Bone chips impinging on the nerve should be removed, and the nerve should be sutured or grafted if needed. All patients with temporal bone fractures should have an audiogram once their condition has stabilized. If the fracture disarticulates the ossicles, a conductive hearing loss will persist after the blood has cleared from the middle ear and mastoid. Fractures of the temporal bone may transverse the cochlea and vestibular apparatus. These fractures usually cause a severe sensorineural hearing loss and loss of vestibular function on the affected side. A concussive injury of the cochlea may also simultaneously be present in the opposite ear in severe head trauma. Temporal bone fractures may permit leakage of cerebrospinal fluid (CSF) into the middle ear and mastoid. CSF may also drain through the lacerated tympanic

membrane, causing CSF otorrhea. These leaks usually stop spontaneously, but persistent CSF otorrhea may require a lumbar drain to reduce the pressure and permit healing. Rarely, tympanomastoid exploration is required to close the leak. Persistent CSF leaks in the ear are associated with meningitis.

Tumors Benign and malignant tumors of the ear are rare. Glomus tympanicum tumors and neuromas of the facial nerve may present in the middle ear. Also, eosinophilic granuloma and rhabdomyosarcoma may involve the structures of the temporal

Anatomy The nose can be divided into three anatomic sections. The bony vault is the immobile portion of the nose. It consists of the paired nasal bones, the frontal process of the maxillary bone, and the nasal process of the frontal bone. The cartilaginous vault is supported by the upper lateral cartilages and the cartilaginous,nasal septum. The nasal lobule is supported by the lower lateral cartilages and the cartilaginous septum. The nasal septum is formed by the quadrilateral cartilage anteriorly. The posterior septum is composed of bone from the vomer, perpendicular plate of the ethmoid, nasal crest of the maxillary bone, and palatine bone.

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Both the internal and external carotid artery systems supply blood to the nose. The roof and lateral i a l i o f the internal nasal cavity are supplied by the anterior and posterior ethmoidal arteries, sphenopalatine artery, and greater palatine artery. The septum is supplied by the anterior and posterior ethmoidal arteries, palatine artery, and the superior labial artery. The convergence of these vessels in the anterior segment of the nose is referred to as Kiesselbach's plexus or Little's area. Venous drainage is accomplished mainly by the ophthalmic, anterior facial, and sphenopalatine veins. The olfactory bulb is positioned high in the roof of the nasal cavity and is responsible for the sense of smell. Sensory information is transported by nerves that penetrate the cribriform plate and traverse cranial nerve I (the olfactory nerve) to the brain. Smell is also an important component of what is perceived as taste. Bony projections, turbinates, form the lateral nasal wall and significantly increase the surface area of the nose, allowing for more efficient humidification and warming of the air to 36°C. Three turbinates are usually present (i.e., inferior, middle, and superior). A supreme turbinate, which is essentially a flap of mucosa, is occasionally present. The turbinates contribute to the turbulent airflow that creates approximately 50% of the total airflow resistance to the lungs. Cleaning o f a i r is accomplished through the nasal hairs (vibrissae) and the mucosal surface. Anteriorly, the nose is lined with stratified squamous epithelium, which changes to respiratory epithelium immediately anterior to the turbinates. Trapped debris is transported in a posterior direction into the nasopharynx by a mucociliary transport mechanism. speech is affected by nasal anatomy and pathologic conditions. Hyponasality from nasal obstruction or hypernasality from an excessive air leak can affect voice quality and intelligibility of speech.

Embryology The nose serves as a drainage port for the paranasal sinuses. The meati are spaces between the lateral aspect of the nasal turbinates and the medial aspects of the lateral nasal wall. Each meatus is named for the turbinate that surrounds it. The maxillary, frontal, and anterior ethmoidal sinuses drain into the middle meatus. The posterior ethmoidal sinuses drain into the superior meatus. The sphenoidal sinus drains into an area known as the sphenoethmoidal recess that is located posterior and superior to the superior turbinate. The nasolacrimal duct drains into the inferior meatus. The nasal cavities develop from the nasal pits in the 4week embryo. These pits deepen and move medially to form the nasal cavity. The oronasal membrane that separates the nose from the mouth resolves in the seventh week to permit communication between the nose and nasopharynx. The paranasal sinuses develop from an outpouching of the lateral nasal walls during the third and fourth months of development. The maxillary and ethmoidal sinuses are present at birth. The frontal and sphenoidal sinuses begin to develop several years after birth. The frontal

sinus begins to develop at 7 years of age but is not fully aerated until adulthood.'

Inflammatory Conditions Viral rhinosinusitis (the common cold) accounts for the majority of nose and sinus infections. It is caused by many strains of viruses and is a self-limited infection. Symptoms of fever, nasal congestion, headache, and clear rhinorrhea usually resolve over 5 to 7 days. Treatment is symptomatic.

Bacterial Rhinosinusitis Acute bacterial rhinosinusitis may often follow an acute viral upper respiratory tract infection. The most common bacteria causing rhinosinusitis are Streptococcus pneumoniae, Haemophilus injuenzae, and Moraxella catawhalis. Acute rhinosinusitis causes malaise, headache, and nasal congestion. There may also be pain localized to the sinus region or pain on palpation over the maxillary or frontal sinuses. Chronic sinus infection may persist after the acute phase and symptoms often last longer than 30 days. The "gold standard" for diagnosing sinusitis is a CT of the sinuses, but a thorough history and nasal examination is usually sufficient to diagnose acute rhinosinusitis. The nasal cavity can be visualized by using a large speculum on an otoscopic head. The posterior nasal cavity can be visualized with either a straight rod endoscope or a flexible fiberoptic nasopharyngoscope. The treatment of rhinosinusitis includes oral antibiotics, short-term use of topical nasal decongestants (e.g., oxymethazoline), and saline nasal sprays. Topical nasal corticosteroid sprays may be helpful for the treatment of chronic sinusitis. Chronic sinusitis in a child mav be exacerbated bv gastroesophageal reflux disease, immunodeficiencies, mucociliary dysfunction, and, more commonly, upper respiratory allergy. These predisposing conditions should be managed while treating the sinus infection. If the signs and symptoms of chronic sinus infection persist, a sinus CT is required to evaluate the condition of the sinus mucosa and the drainage pathways. Endoscopic sinus surgery may be necessary to open the involved sinuses to provide drainage. Chronic inflammation of the nasal and sinus mucosa may lead to nasal and sinus polyp formation that chronically obstructs the nose and sinuses. Antrochoanal polyps are large polyps that originate from the walls of the maxillary sinus and extend through the nasal cavity into the nasopharynx. Nasal polyps maybe removed endoscopically, but a large antrochoanal polyp may require removal through an open maxillary sinus procedure. Nasal polyps in a child should always prompt an evaluation for cystic fibrosis.

Complications of Sinusitis The sinuses surround the orbit so a common complication of acute rhinosinusitis in children is orbital cellulitis

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with erythema and edema of the eyelids. Chemosis (edema The obstruction may be visualized with a narrow flexible nasopharyngoscope after the nasal cavity has been sucof the ocular conjunctiva) is usually absent. However, if a tioned of mucus and the nasal mucosa has been constricted periorbital subperiosteal abscess forms adjacent to an with a nasal decongestant (e.g., oxymetazoline). The infected sinus, there may be proptosis, chemosis, ophthalmoplegia, and loss of vision. Infection in the ethmoidal diagnosis is best made with CT of the nasal cavity. CT will demonstrate the atresia, define the tissue (bony or memsinuses most commonly results in this complication. branous), and show the configuration of the entire nasal Subperiosteal periorbital abscess is demonstrated best by cavity. sinus CT. Initial treatment should include intravenous antibiotics. Endoscopic or external drainage may be Choanal atresia may be successfully treated by removing required in some cases. the obstructing tissue transnasally. Curets, bone punches, and drills may all be effective to remove the atresia plate. Intracranial complications of sinusitis include cerebritis, cavernous sinus thrombosis, as well as epidural, subdural, However, when the bony plate is very thick and there is and brain abscess. Treatment of intracranial complicaan extremely narrow posterior nasal cavity, a transpalatal tions or impending intracranial complications requires repair is more direct. A transpalatal repair provides better access for more effective removal of the bony plate surgical drainage of the involved sinus and concurrent treatment of the intracranial lesion by a n e u r o s ~ r g e o n . ~ ~and posterior septum (Fig. 52-3). Stents fashioned from endotracheal tubes are placed and secured with sutures to the septum. They are removed in several weeks. The stents must be moistened with saline and suctioned sevFungal Sinusitis eral times daily to prevent mucus plugging and acute respiratory distress. Transpalatal repair of choanal atresia Fungal sinusitis may occur in immunocompromised 1962053 has a lower incidence of restenosis.27[~~ children, specifically severe diabetics, children undergoing chemotherapy, and bone marrow transplant recipients. The treatment of fungal sinusitis involves surgical drainage Nasal Dermoid and intravenous antifungal agents. Nasal dermoid cysts or sinuses present in the midline of However, a chronic form of fungal sinusitis is allergic the nasal dorsum (Fig. 52-4). They usually appear as a fungal sinusitis. These patients usually have other signs round bump or a pit with hair present in the pit (Fig. 52-5). of allergy, such as asthma. The treatment of this condiThey also may become infected. Nasal dermoid sinuses tion is corticosteroids and dibridement of the involved sinuses. The diagnosis is made by sinus CT findings and may extend through the nasal bones into the nasofrontal area and have an intracranial component. Both CT and the presence of eosinophils as well as fungi in the sinus MRI may be necessary to demonstrate the extent of the secretions that are removed at the time of surgery.ll dermoid. Surgical removal is required to prevent infection and recurrence. This may be done between ages 3 and 5 years if prior infection has not occurred. Dermoids Congenital Malformations confined to the nose are resected completely using a midline incision with an ellipse around the sinus tract.

Pyriform Aperture Stenosis

Congenital stenosis of the anterior bony aperture causes partial nasal obstruction that may be severe enough to cause difficulty feeding, respiratory distress, and failure to thrive. Anterior rhinoscopy demonstrates a very constricted nasal opening bilaterally. CT of the nose shows marked narrowing of the pyriform aperture. Neonates are obligate nasal breathers, and severe stenosis must be surgically corrected. Because the stenotic segment is very anterior and the remainder of the nasal cavity is normal, removal of the constricting bone with drills is done through a sublabial approach. The nasal openings are stented with 3.0-mm endotracheal tube stents that are sutured in place and removed after a few days.

Choanal Atresia Choanal atresia may be unilateral or bilateral. The obstructing tissue is usually a bony plate, but a few cases will have only membranous atresia. Unilateral choanal atresia presents as chronic unilateral rhinorrhea. There is no significant respiratory distress. Because neonates are obligate nose breathers, bilateral choanal atresia is associated with severe respiratory distress, difficulty feeding, and failure to thrive. The diagnosis is suspected if catheters cannot be passed through the nose and into the pharynx.

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Choanal atresia. This disorder frequently presents at

birth with respiratory distress.

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The tract is followed to its termination, and the nasal bones may need to be separated to reach the end of the tract.Z7[pp188-1911 If an intracranial component is present, a combined craniotomy and nasal approach with a neurosurgeon is recommended.

Nasal Glioma and Encephalocele A nasal glioma presents as an intranasal mass and may be confused with a nasal polyp. The mass contains dysplastic brain tissue and may have an intracranial connection. CT and MRI are important to define the extent of the glioma and intracranial component as well as to plan the surgical approach. An encephalocele presents as a soft compressible mass and may also be confused with a nasal polyp. Intranasal encephaloceles extend through a defect in the skull at the cribriform plate. CT and MRI define the extent of the encephalocele and are necessary to design the surgical approach. Surgical removal often includes a frontal craniotomy. Nasal encephaloceles may be associated with CSF rhinorrhea and meningitis.

Trauma Nasal Fracture

, -

Nasal dermoid presenting in the midline

An infant may be born with the soft nasal bones and the septum deviated to one side either as a result of a difficult delivery or from persistent intrauterine compression of the nose. The nasal structures can most often be returned to the midline with digital manipulation. If the nasal deformity is partially reduced, the nose usually straightens with growth during the first year to 18 months of age. Nasal bone and nasal septal fractures in older children usually occur from a blow to the face during sports. There is usually a brief period of epistaxis and deviation of the nasal dorsum to one side. Swelling occurs rapidly, and the degree of the cosmetic deformity or the need for fracture reduction may not be easily determined. At the fourth to sixth day after injury, the edema subsides and the need for reduction can be determined. Nasal bone radiographs are of little help in making this judgment, so the need for nasal fracture reduction is usually based solely on clinical examination. Effective nasal fracture reduction may be done up to 2 weeks after the injury. Closed reduction under general anesthesia is the method of choice. Oral antibiotics prevent infection and are essential if nasal packing is used to support the nasal bone. Although nasal fracture reduction is not urgent, a septal hematoma from a fractured septum should be excluded by the initial physician seeing the child. A septal hematoma that remains untreated may cause cartilage necrosis and loss of nasal support, with a resulting saddle-nose deformity. Treatment of a septal hematoma is with incision and evacuation of the clot. The mucoperichondral flap should then be sutured in place by bolster sutures through the septum. A small rubber band drain should remain i n place for 12 to 24 hours, and antibiotics should be given. Epistaxis in children usually occurs in Little's area of the anterior septum and frequently results from digital L,

.

Nasal dermoid. These lesions typically present on the nasal dorsum as a single midline pit, often with a hair extruding from the depths of the pit. The pits may also be found on the columella. The dermoid will then tract through the septum toward the cranial base.

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trauma (nose picking). The bleeding usually stops with pressure by squeezing the nasal ala. Infrequently, cauterization of the vessels under general anesthesia is needed.

Nasal Foreign Bodies Children may be observed inserting a foreign body into their nose, or they may inform their parents of the event. Most children, however, present with a foul-smelling unilateral purulent nasal discharge and deny putting anything into their nose. Most nasal foreign bodies are painless and do no harm to the nose except cause a foul nasal discharge. Disc batteries, on the other hand, cause very rapid alkali burns of the nasal cavity and pain. Batteries must be removed from the nose quickly because the chemical burn occurs in minutes to hours. If extensive tissue necrosis occurs, it may cause a nasal stenosis. Removal of a nasal foreign body is aided by decongesting the nasal mucosa and using a headlamp to visualize the foreign body. A variety of forceps or hooks may be used. If the object is deep in the nose, the removal is best performed under general anesthesia. The endotracheal tube prevents aspiration of the object into the tracheobronchial tree if it is pushed back into the nasopharynx. One must remember that multiple foreign bodies may be present.

Nasal Lacerations Nasal lacerations should be closed with care to match edges and restore the contours of the nose. Standard wound closure technique is employed. The nasal mucosa does not need to be sutured unless a large flap is displaced.

Nasal Tumors Rhabdomyosarcoma, lymphoma, squamous cell carcinoma, and esthesioneuroblastoma may occur in the nose and sinuses of children. Fortunately, these malignant tumors are very rare in children. The treatment of children with malignant tumors of the nose and sinuses usually involves a multidisciplinary, multimodal approach. Juvenile nasopharyngeal angiofibroma is a benign tumor of adolescent males that originates from the lateral wall of the nose and nasopharynx~The tumor may completely obstruct the nose and fill the nasopharynx. This type of angiofibroma may also extend intracranially through the base of the skull. Patients with these tumors present with nasal obstruction; recurrent epistaxis, and rhinorrhea. The tumor may be seen with a flexible fiberoptic nasopharyngoscopk or a rod lens telescope after decongesting the nasal mucosa. It appears as a smooth reddish mass. Biopsy of the mass should be avoided because of the potential for severe bleeding. CT and MRI define the extent and location of the tumor. MR angiography helps to delineate the blood supply, which may originate from both the internal and external carotid arteries. Contrast angiography may be reserved for presurgical planning and embolization of the copious blood supply that is often present.

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The treatment ofjuvenile nasopharyngeal angiofibroma is complete surgical resection after preoperative embolization. Depending on the material used, the embolization may be effective for days to weeks. A variety of surgical approaches may be used, including endoscopic resection of small tumors. Extensive tumors may require a combined midfacial and craniotomy approach.29 Some authors have proposed radiation therapy as the primary treatment of juvenile nasopharyngeal angiofibroma, but many surgeons are concerned about the long-term effects of radiation in children, including the induction of malignant tumors.

ORAL CAVITY/ PHARYNX Anatomy The boundaries of the oral cavity include the lips anteriorly, the cheeks laterally, and the palate superiorly. The posterior boundary is a plane that extends from the soft palate to the junction of the anterior two thirds and posterior one third of the tongue. The oral cavity is composed of the vestibule, the space between the lips and cheeks and alveolar ridges, and the oral cavity proper. The vestibule and oral cavity proper are separated by the alveolar ridge and teeth. The vestibule is divided in the midline by the labial frenula of the upper and lower lips. The alveolar ridge is contiguous superiorly with the hard palate. The parotid ducts (Stensen's ducts) enter the vestibule opposite the second maxillary molars. The submandibular ducts (Wharton's ducts) enter the floor of mouth near the lingual frenulum. The palate is formed by a fusion of the primary palate anteriorly and medial growth of the palatal processes that form the secondary palate. The hard palate divides the nasal and oral cavities and is formed by the premaxilla and the horizontal plates of the palatine bones. The soft palate is formed by a muscular aponeurosis of the tensor veli palatini tendon. Five muscles insert into this aponeurosis and include the tensor veli palatini, levator veli palatini, palatoglossus, palatopharyngeus, and the musculus uvulae. Defects in formation of the hard and/or soft palate result in clefting. The sensory and motor innervation of the palate is through the trigeminal nerve and pharyngeal plexus. The circumvallate papillae divide the tongue into the anterior two thirds that lies in the oral cavity and the posterior one third lying in the oropharynx. The innervation and vascular supply to the two major divisions of the tongue reflect their differences in origin-the anterior two thirds of the tongue being a first branchial arch derivative (trigeminal) whereas the posterior one third being a combination of third and fourth arch derivatives (pharyngeal plexus). The hypoglossal nerve supplies motor innervation to the intrinsic musculature. In addition to the intrinsic tongue musculature, the action of four extrinsic muscles combine to provide mobility. The genioglossus protrudes and depresses, the hyoglossus retracts and depresses, the styloglossus retracts, and the palatoglossus elevates. In addition to the circumvallate papilla, other taste buds on the tongue surface include conical, filiform, fungiform, and foliate papillae.

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The pharynx is a fibromuscular tube that extends from the skull base to the level of the cricoid cartilage of the larynx and can be divided into three levels. The nasopharynx extends from the skull base to the level of the soft palate, the oropharynx extends from the soft palate to the tongue base, and the hypopharynx extends from the tongue base to the cricoid cartilage. Three muscular constrictors combine to form the muscular portion of the pharynx: superior, middle, and inferior constrictors. Passavant's ridge is a muscular segment of the superior constrictor that is involved in velopharyngeal closure. Lower fibers of the inferior constrictor help to form the upper esophageal sphincter. The motor and sensory innervation of the pharynx is from the glossopharyngeal and vagus nerves via the pharyngeal plexus. A collection of lymphoid tissue within the pharynx forms Waldeyer's ring that includes the palatine tonsils, the adenoid (pharyngeal tonsil), and lymphoid follicles lining the lateral and posterior pharyngeal walls.

Acute Pharyngotonsillitis In addition to the acute onset of sore throat, viral pharyngitis typically presents with fever and malaise. Signs include erythema of the pharynx and cervical lymphadenopathy. Depending on the viral agent, associated symptoms of nasal obstruction and rhinorrhea mav also be present. Rhinovirus, coronavirus, parainfluenza virus, respiratory syncytial virus, adenovirus, and influenza virus are agents responsible for viral pharyngitis. Primary herpetic gingivostomatitis, caused by herpes simplex types 1 or 2, presents as fever, adenopathy, and vesicles and ulcers on the lips, tongue, buccal mucosa, soft palate, and pharyngeal- mucoia. Herpangina and hand-foot-and-mouth disease are viral infections that involve the oropharynx. Epstein-Barr virus (EBV) infection (infectious mononucleosis) presents as acute pharyngotonsillitis, fever, generalized adenopathy, malaise, and splenomegaly. Although EBV infection is suspected by the appearance of 10% or more atypical lymphocytes on a complete blood cell count and the presence of a positive Monospot test, the definitive diagnosis is confirmed by elevated titers of EBV. Group A P-hemolytic Streptococcus (GABHS, i.e., S. fiogenLs) commonly infects the pharynx. In addition to sore throat, associated symptoms include fever, headache, and abdominal pain. Associated signs include pharyngeal erythema, halitosis, tonsillar exudates, and tender adenopathy. Diagnosis may be confirmed initially with a rapid streptococcal antigen test. Because rapid antigen testing is more sensitive than formal plating on blood agar, a negative test does not need confirmation, but positive rapid streptococcal tests should be confirmed with formal plating. Other bacterial pathogens that cause acute pharyngitis include Haernophilus influenzae and groups C and G P-hemolytic streptococci. Occasionally, concurrent infection with penicillin-resistant Staphylococcus aureus may interfere with treatment of a GABHS infection.Z8 Although many cases of GABHS infections respond to treatment with penicillin V or amoxicillin, emerging resistance to oropharyngeal pathogens mandates treatment of

recalcitrant cases with an antibiotic having known effectiveness against klactamase-producing organisms. In cases in which a lack of compliance is suspected, intramuscular benzathine penicillin or ceftriaxone may be used. Acute pharyngitis may also be associated with acute bacterial infections of the nose, nasopharynx, and sinuses. These infections may be caused by a variety of viral and bacterial pathogens; and in addition to sore throat, symp toms include fever, mucopurulent nasal drainage, nasal obstruction, and facial pain.

Recurrent Pharyngotonsillitis Recurrent infection of the pharynx may be either viral or bacterial. GABHS are the most worrisome bacterial organisms because recurrent infection may lead to complications such as scarlet fever, acute rheumatic fever, septic arthritis, and acute glomerulonephritis. In addition to a history of multiple positive cultures for S. pyogenes, elevated antistreptolysin-O (ASO) titers may identify patients with chronic infection who are at risk for developing complications. Some asymptomatic children may be chronic carriers of GABHS, and elevated AS0 titers may not be a reliable indicator for distinguishing between an active infection and the carrier state. Treatment of recurrent streptococcal infection or the child who is a carrier should include a trial course of an antibiotic shown to reduce carriage (e.g., clindamycin, vancomycin, or rifampin). Children with recurrent pharyngotonsillitis unresponsive to medical therapy or those who suffer a complication should be considered for surgical management. Whereas treatment of each child should be individualized, suggested guidelines for surgical candidates include seven infections in 1 year, five or more infections per year for 2 years, or three or more infections per year for 3 years.Z4Other factors to be considered in employing a surgical option include severity of infection, response to antibiotic therapy, loss of time from school, and need for hospitalization.

Chronic Pharyngotonsillitis The pharynx and specifically the tonsils may be the target of chronic infection. Mected children complain of chronic throat pain, halitosis, and production of white particles or tonsilliths. Signs include erythema of the tonsils, cryptic debris, and chronically enlarged cervical adenopathy. A variety of viral and bacterial agents can be blamed for chronic infection of the pharynx. Cultures may or may not be positive in these patients, because surface cultures may be negative while core tissue is positive. Antibiotic therapy directed at anaerobes or S. aureus may be helpful in resistant cases. Children with infections unresponsive to medical management are candidates for tonsillecto~iy.

Peritonsillar Cellulitis/Abscess Localized extension of tonsillar infection may result in peritonsillar cellulitis. The same pathogens that cause

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acute pharyngotonsillitis are responsible for peritonsillar cellulitis. In addition to severe sore throat, symptoms and signs include drooling, trismus, muffled voice, ipsilateral referred otalgia, and tender lymphadenopathy. The affected tonsil is usually displaced in a medial and inferior position. Peritonsillar cellulitis may progress to frank abscess formation (quinsy). Early cases of peritonsillar cellulitis may respond to oral antibiotics, such as the penicillins, cephalosporins, erythromycins, or clindamycin. Unresponsive cases of cellulitis or abscess should be treated with intravenous antibiotics. In children with suspected abscess formation, a variety of surgical drainage procedures can be performed. Needle aspiration or incision and drainage have been shown to be equally effective." In persistent cases or in those children who will require general anesthesia for drainage, consideration should be given to performing a tonsillectomy (quinsy tonsillectomy).

Retropharyngeal/Parapharyngeal Space Infections Signs and symptoms of deep neck space (retropharyngeal,' parapharyngeal) infections that involve the pharynx typically present as fever, drooling, irritability, decreased oral intake, torticollis, and/or trismus. Often there is a history of a preceding viral illness. Stridor or symptoms of upper airway obstruction may be seen in half of patients3' A neck mass or enlarged cervical nodes may be present depending on the location of the infection. Usual pathogens include coagulase-positive staphylococci and GABHS. Anaerobic bacteria have been found in as many as 50% of cases.32 Complications of deep neck space infections include airway obstruction, bacteremia, rupture of the abscess into the pharynx with aspiration, mediastinal extension of infection, jugular thrombosis, and carotid artery rupture. In suspected cases, the diagnosis of a retropharyngeal/parapharyngeal space infection is confirmed with either contrast medium-enhanced CT or MRI. Widening of the retropharynx on a lateral neck radiograph suggests a retropharyngeal infection. While ultrasound can detect the presence of an abscess cavity, CT or MRI are most helpful in demonstrating the extent of infection and the location of surrounding structures of importance, specifically the great vessels. Contrast medium-enhanced CT is particularly useful in distinguishing a phlegmon (cellulitis) from cases of frank suppuration. Demonstration of a hypodense region with surrounding rim enhancement has been shown to correlate with an abscess in 92% of cases (Fig. 52-6). The initial management of a deep neck infection should begin with intravenous antibiotics, including oxacillin, clindamycin, cefazolin, P-lactamase penicillins, or a combination thereof. Surgical drainage should be reserved for those children who fail to show clinical improvement or progress to frank abscess formation on CT. The usual approach to surgical drainage is intraoral if the abscess points medial to the great vessels or extraoral if the infection points lateral to the great vessels.

a Retropharyngeal abscess. Computed tomography of the cervical area demonstrates fluid loculated in the retropharyngeal space. The abscess is qpically unilateral and frequently extends into the medial aspect of the peripharyngeal space. In the absence of associated complications, drainage can be done intraorally.

Complications of deep neck infections should be treated aggressively. Mediastinal spread requires prompt surgical drainage in most cases. An infectedjugular thrombosis (Lemierre's syndrome) can be a source of metastatic spread of infection as septic emboli. Signs and symptoms include spiking chills and fever (picket-fence fevers) and a neck mass in spite of appropriate antibiotic therapy. Ligature or excision of the infected thrombus may be required to eradicate the infection.

Sleep-Disordered Breathing In the past decade, the impact of sleep-disordered breathing (SDB) on the health of children has been well described, beginning with the report of normative sleep Children appear to data by Marcus and ~olleagues.2~ have briefer but more frequent episodes of partial (hypopnea) and complete (apnea) obstruction. Because an apnea of less than 10 seconds may represent several missed breaths in a child, an apnea of any duration is abnormal. In most cases the site of obstruction during sleep is in the pharynx. In contrast to adults with this di; order in whom the pharyngeal impingement is due to adipose tissue surrounding the pharyngeal musculature, the major cause of airway obstruction in children results , from adenotonsillar hypertrophy. The apnea index represents the number of apneas in an hour, with a normal value being less than 1 in children. Because most children have an increased freauencv of partial obstructions compared with adults, a measure of hypopneas may be more significant. A hypopnea is variably described as a reduction in airflow or respiratory

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.

. Tonsillar hypertrophy. Tonsillar hypertrophy is rated on a scale of 1 to 4. Grade 1+ tonsils are hypertrophic, grade 2+ tonsils extend slightly beyond the tonsillar pillars, grade 3+ tonsils extend in a medial direction beyond the anterior tonsillar pillars, and grade 4+ tonsils touch in the midline.

effort or oxygen desaturation or combination thereof. Respiratory disturbance index is a measure of both apneas and hypopneas in an hour and may be a better reflection of SDB in children. A respiratory disturbance index greater than 5 is abnormal. Upper airway resistance syndrome represents obstructed breathing with normal respiratory indices but with sleep fragmentation and electroencephalographic arousals that indicate disordered sleep. The major group at risk for SDB includes children with adenotonsillar hypertrophy secondary to lymphoid hyperplasia (Figs. 52-7 and 52-8). Whereas the age of affected children ranges from 2 years through adolescence, the prevalence mirrors the age of greatest lymphoid hyperplasia, 2 to 6 years, the age the tonsils and adenoids are largest in size. Other at-risk groups include syndromic children with Down syndrome, children with craniofacial disorders, and patients with cleft palate or storage diseases (Hunter's, Hurler's syndromes). Adverse effects of obstructive sleep apnea on children include poor school performance, failure to thrive, facial and dental maldevelopment, and, rarely, severe cardiac impairment, including systemic hypertension, cardiac arrhythmias, and cor pulmonale. Daytime symptoms include noisy mouth-breathing, nasal obstruction and congestion, hyponasal speech, and dyspnea on exertion. In contrast to adults, hypersomnolence is uncommon in children because of the lower incidence of gas exchange abnormalities, specifically hypercarbia. Children may complain of headaches, seem irritable, and perform poorly in school. Nighttime symptoms are more obvious and include snoring, gasping and choking respirations, apnea, coughing, and a variety of

• Adenoid hypertrophy. Hypertrophy of the adenoids may cause the nasopharynx to be obstructed with tissue. Smaller am,unt, of tissue are also able to obstruct nasal respiration by growing into the posterior choana as shown in this photograph.

other behaviors including sleepwalking, sleeptalking, rocking, head banging, and bruxism. Enuresis may appear in children with airway obstruction and then resolve after surgical treatment. In addition to enlarged tonsils, signs include the presence of a posterior pharyngeal flap in cleft palate patients, a craniofacial disorder, adenoid facies, and, rarely, evidence of right-sided heart failure. The diagnosis of SDB is suggested by history and physical examination. Confirmation of obstruction and apnea may be made with overnight pulse oximetry and video or audio monitoring of sleep. The "gold standard" in the diagnosis of obstructive sleep apnea remains formal polysomnography, including measures of nasal and oral airflow, chest wall movements, electrocardiography, extraocular muscle movements, and gastric pH monitoring in selected cases. Depending on the suspected site of obstruction, adjuvant studies such as a lateral neck radiograph, MRI of the head and neck, and flexible upper airway endoscopy might be helpful. The nonsurgical management of SDB consists of weight loss in obese patients and treatment of underlying allergies and gastroesophageal reflux. Nasal and dental appliances to maintain airway patency that may be useful in adults are usually poorly tolerated in children. Nasal continuous positive airway pressure, the mainstay of treatment in adults, is tolerated in many children and should be considered as a treatment option, especi'ally in patients in whom other therapies have been exhausted or proven ineffective. The initial surgical treatment for most children with SDB remains a tonsillectomy and adenoidectomy, a therapy that is usually curative. In patients with documented sleep apnea or a sleep disorder, both procedures should

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be utilized even if the tonsils appear small. Tonsillectomy and adenoidectomy techniques that have been standard for decades have been supplanted in some institutions by new technology including use of Coblation, Harmonic Scalpel, and the microdebrider. Efficacy of these newer techniques over established methods remains unproven. Complications after tonsillectomy and adenoidectomy usually consist of respiratory compromise and acute or delayed bleeding. Since the advent of modern pediatric anesthesia, respiratory complications such as aspiration with resultant pneumonia and lung abscess are rare. Humidification, corticosteroids, and antibiotics have all been shown to improve the postoperative course after tonsil and adenoid surgery. Young children are most vulnerable to complications, and in most institutions children younger than 4 years of age are observed overnight for signs of dehydration and respiratory compromise. Adjuvant surgery in the management of SDB includes craniofacial repair or posterior flap revision surgery in appropriate patients. Midface, mandibular, and hyoid advancement have proved useful in selected patients, along with nasal surgery such as septoplasty, partial inferior turbinectomy, or nasal polypectomy. Tracheostomy remains the treatment of last resort in patients who fail to respond to other forms of therapy.

Ankyloglossia Ankyloglossia or tongue-tie is a common congenital disorder involving the lingual frenulum (Fig. 52-9). Neonates with diminished tongue mobility due to a foreshortened frenulum may have problems in sucking and feeding. Because the frenulum is thin and relatively avascular in neonates and young infants, it can often be incised as an office procedure. In older children the greatest effect of ankyloglossia is on speech. Because the tip of the tongue curls under on extrusion and has limited

, -

Ankyloglossia. Abnormal development of the

lingual frenulum that limits extension of the tongue tip beyond the mandibular incisors frequently causes articulation disorders and should be corrected.

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lateral and superior movement, speech articulation may be affected. Surgical treatment in these patients may require a short general anesthetic as the frenulum is thicker and more vascular, requiring surgical correction that includes either simple division with or without a Z-plasty repair.

Macroglossia Macroglossia is uncommon. Generalized macroglossia, as seen in association with omphalocele, visceromegaly, and adrenal and renal disorders (Beckwith-Wiedemann syndrome), with glycogen storage diseases (Hunter's and Hurler's syndromes) or hypothyroidism, is rare. Relative macroglossia can be seen normally on occasion but is most common in Down syndrome. The most serious complication of this condition is airway obstruction. In infants, macroglossia should be distinguished from focal enlargement of the tongue seen in patients with a lymphatic malformation or hemangioma. Glossoptosis, posterior displacement of a normal-sized tongue, is seen in association with cleft palate and micrognathia in infants afflicted with the Pierre Robin sequence. Infants with airway obstruction secondary to an enlarged or displaced tongue may require a tracheostomy. Macroglossia in older children that affects cosmesis, interferes with speech, or causes drooling may be treated with a variety of tongue reduction techniques.

Benign Lesions Epulis is a congenital granular cell tumor that typically presents as a soft, pink submucosal mass on the anterior alveolar ridge of the maxilla (Fig. 52-10). Females are

.

-

Congenital epulis. The congenital cpulis is an

unusual benign lesion that frequently arises from the anterior maxillary alveolar ridge. Airway and feeding difficulties may develop secondary to large lesions. Surgical excision is required.

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• A ranula is a pseudocyst caused by obstruction of a sublingual gland. It generally presents as a unilateral, painless swelling in the floor of the mouth.

more commonly affected, and symptoms are usually confined to feeding problems. Surgical excision is curative. Ranula is a pseudocyst located in the floor of the mouth that may occur congenitally or result from intraoral trauma (Fig. 52-11). Large ranulas may extend through the mylohyoid musculature and present in the neck as a "plunging ranula." Treatment of ranulas is by excision or marsupialization of the pseudocyst, often in conjunction with excision of the sublingual gland. Mucoceles are also pseudocysts of minor salivary gland origin and frequently rupture spontaneously. Recurrent or symptomatic mucoceles respond to surgical excision. Hemangioma is a proliferative endothelial lesion found commonly in the head and neck. Their growth characteristics include enlargement during the first year of life, followed by spontaneous resolution. Surgical excision or treatment with corticosteroids may be necessary in lesions that cause ulceration and bleeding, airway obstruction, cardiovascular compromise, or platelettrapping coagulopathy (Kasabach-Merritt syndrome). Vascular malformations, including venous, arterial, or arteriovenous malformations, rarely occur in the oral cavity and pharynx and necessitate intervention only if they cause pain, bleeding, ulceration, or heart failure. Management of complicated cases is by surgical excision or sclerotherapy for low-flow lesions (venous) and angiographic embolization for high-flow lesions. Lymphatic maljomzation, formerly known as lymphangioma or cystic hygroma, is congenital and usually presents before 2 years of age. Histologically, lymphatic malformations consist of multiple dilated lymphatic channels or may contain either capillary or venous elements (venolymphatic malformations). Lymphatic malformations can occur anywhere in the neck and may cause extensive cosmetic deformity and functional problems in

cases with involvement of the tongue, floor of mouth, mandible, or larynx. Surgical resection of lymphatic malformations may be fraught with difficulty because they lack a capsule and are infiltrative. During surgical excision, care should be taken to avoid damaging nearby vital structures, and debulking is an acceptable option to total radical excision in many cases. Postoperative suction drains can be helpful in preventing the recurrence of lymphatic drainage under skin flaps. Carbon dioxide laser therapy has been employed in superficial lymphatic malformations of the tongue, and sclerotherapy of large cystic lesions may be an option. Fmegut cysts are true cysts, lined with respiratory epithelium, that present in the floor of mouth and should be distinguished from dermoid cysts, lined with stratified squamous epithelium and skin appendages, which may also be found in this location. A thyroglossal duct cyst may rarely present in the base of the tongue. Likewise, aberrant thyroid tissue, lingual thyroid, presents as a purple mass in the tongue base. Thyroid tissue in this location is usually hypofunctioning, and affected children require thyroid supplementation. Other aberrant rests of tissue, choristomas, consist of gastric, enteric, or neural tissue of normal histology in an abnormal location. Second branchial cleft derivatives will rarely present as a cystic mass near the superior pole of the tonsil. Their extent and associated tracts can be demonstrated on MRI. Tornwaldt's cyst is a blind pouch in the nasopharynx that represents a persistence of an embryonic connection between the primitive notochord and the pharynx. Other benign nasopharyngeal masses include nasopharyngeal teratomas, dermoid lesions (hairy polyp), and nasopharyngealencephaloceles. Most of these lesions are best evaluated by CT and/or MRI to determine their extent and the presence of an intracranial connection. Surgical excision is curative in most cases. Squamous papillomas are benign slow-growing lesions typically found on the soft palate, uvula, and tonsillar pillars and are the result of infection with serotypes 6, 14, or 22 of the human papillomavirus (HPV). Because of concern that these lesions could spread to the larynx or trachea, complete surgical excision is usually recommended. Pleomorphic adenoma (mixed tumor) is a benign neoplasm of minor salivary glands with a predilection for the palate, although it may also be found in the lip and buccal mucosa. Treatment is with surgical excision.

Malignant Lesions Rhabdomyosarcoma, the most frequent soft tissue malignancy of childhood, typically occurs in the 2- to 6-year age group and is derived from embryonic skeletal muscle.4J~ In the oral cavity and oropharynx it presents as a rapidly growing mass in the tongue, palate, and uvula or cheek. These tumors metastasize early to local nodes, lung, and bone. Surgical therapy is limited to biopsy, excision of small lesions, or surgical salvage of treatment failures. The usual therapy includes a combination of chemotherapy and radiation therapy. Lymphoma of the oral cavity and oropharynx typically involves the lymphoid tissue of Waldeyer's ring and presents

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as a mass of the tonsil or in the na~opharynx.~ The diagnosis may be suspected by evidence of involved adenopathy in the neck but is confirmed by surgical biopsy. Treatment is with a combination of chemotherapy and radiation therapy. Other rare malignant neoplasms of the oral cavity and pharynx include malignant salivary gland tumors (mucoepidermoid carcinoma) and epidermoid or squamous cell carcinoma. This latter tumor has been reported in organ transplant patients and adolescents who use snuff or chewing tobacco.lVreatment is usually surgical depending on the site and extent of involvement.

With the exception of the hyoid bone, the major structural framework of the larynx consists of cartilage and soft tissue. The hyoid bone lies superior to the larynx and is attached to it by the thyrohyoid membrane and strap muscles. The hyoid bone is derived from the second and third branchial arches. The cartilaginous structures of the larynx are composed of hyaline cartilage, with the exception of the epiglottis, which is composed of elastic cartilage. The cartilaginous structures of the larynx develop from the fourth, fifth, and sixth branchial arches. There are nine laryngeal cartilages, three that are single (thyroid, cricoid, and epiglottis) and six that are paired (arytenoid, cuneiform, and corniculate). The thyroid cartilage consists of two quadrilateral cartilages that form the anterior framework of the larynx. The cricoid cartilage is the only complete cartilaginous structure in the airway and provides posterior stability and a base of support for the cricoarytenoid and cricothyroid joints. The cricothyroid muscles are paired extrinsic laryngeal muscles that serve to tilt the larynx down and forward, tensing the vocal folds. Paired intrinsic muscles-the thyroarytenoid, thyroepiglottic, and aryepiglottic muscles-act as a sphincter to close the larynx. The vocalis muscle comprises the internal fibers of the thyroarytenoid muscle and attaches to the vocal ligament. Action of this muscle serves to regulate the pitch of the vocal ligament. The other set of paired muscles includes the posterior cricoarytenoid, lateral cricoarytenoid, and interarytenoid muscles. The posterior cricoarytenoid muscles serve to abduct the vocal folds, whereas the cricoarytenoid and interarytenoid muscles adduct the vocal folds. The quadrangular membrane is a connective tissue covering of the superior larynx that ends in a free margin along the vestibular ligament of the false cord. The conus elasticus is a membrane of elastic tissue that extends superiorly from the cricoid cartilage to form the paired vocal ligaments, the supporting structures of the vocal folds. The blood supply of the larynx arises from the superior and inferior laryngeal arteries. The former is a branch of the superior thyroid artery, whereas the latter is a branch from the thyrocervical trunk. The intrinsic muscles of the larynx are innervated by the recurrent laryngeal nerve, which also supplies sensory branches to

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the inferior larynx. The superior laryngeal nerve has two branches: the external branch innervates the cricothyroid muscle, while the internal branch supplies sensation r to the s u ~ e r i o larvnx. The larynx has multiple functions within the upper airway. During respiration, it regulates airflow by opening during inspiration. The posterior cricoarytenoid muscle contracts with each inmiration to abduct the cords just before activation of the diaphragm. The protective function of the larynx produces two reflexes: cough and closure. Cough is important to expel mucus and foreign objects. The closure reflex serves to prevent aspiration of foreign matter. In addition to closure, the larynx elevates during swallowing. Both closure and elevation occur simultaneo~slyalongcyith relaxation of the cricopharyngeus muscle during the swallow of a bolus. Finally, the larynx plays an important role in speech production by generating sound. Vibration of the mucosa covering. t h e vocalis structures produces sound whose pitch and register is altered by changes in tension, length, and mass of the underlying vocalis muscle and ligament. The larynx of an infant sits much higher than that of an adult. The cricoid is located at the level of C4, whereas the tip of the epiglottis is at C1. The close approximation bf the epigloitis to the soft palate makes the infant an obligate nose breather. By 2 years of age, the larynx has descended to the level of C5 and reaches the adult level of C6 to C7 by puberty. The glottis of the newborn is 7 mm in the anterdposterior dimension and 4 mm in the lateral dimension. The narrowest area of the infant airway, the subglottis, is approximately 4 mm in diameter. L,

Upper Airway Assessment Symptoms of acute airway obstruction include dyspnea, cough, vocal changes, dysphagia, and sore throat. Dyspnea and rapid or labored breathing are indications of inadequate ventilation and may be triggered by changes in Pco, and Pop. A stimulus anywhere in the airway may produce cough. It is difficult to localize the site of the stimulus from the quality of the cough. Changes in the child's vocal character such as hoarseness or a muffled or weak cry may help in localizing the area of obstruction. Dysphagia for solids and/or liquids is often associated with airway obstruction. Depending on the cause of airway obstruction, affected patients may complain of sore throat. The child's overall appearance is the first sign to be assessed in airway obstruction, because airway status often dictates how quickly further evaluation and intervention need to be performed. The level of consciousness should be determined because the unconscious or obtunded patient may need immediate airway management. Along with cyanosis in a patient without cyanotic heart disease, the presence of anxieiy, restlessness, and diaphoresis are all ominous signs of impending airway compromise. Other symptoms of airway obstruction include tachypnea and substernal retractions. The child with airway obstruction is often tachycardic. The presence of bradycardia is a

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late indicator of severe hypoxia. The presence of a muffled cry often suggests obstruction at the level of the pharynx, whereas a barking cough is associated with laryngeal inflammation and edema. Stertor is a snorting sound whose origin is often in the pharynx. Stridor is noise produced by turbulent airflow in the laryngeal or tracheal airway. Inspiratory stridor suggests turbulence at or above the glottis. Expiratory stridor results from turbulent airflow in the distal trachea or bronchi. Biphasic stridor suggests a tracheal source. The degree and loudness of the sound is not always indicative of the severity of obstruction, because stridor can become softer just before complete obstruction. Other important signs of airway obstruction include drooling and use of accessory respiratory muscles. In addition to determination of the child's physical status, assessment of the degree of airway obstruction should include an evaluation of the ventilatory status. Pulse oximetry provides an immediate record of arterial oxygenation while transcutaneous monitoring of COP is a good indicator of ventilation. The lateral neck radiograph remains the best study for the initial evaluation of a child with airway obstruction because it demonstrates the anatomy from the tip of the nose to the thoracic inlet. The anteroposterior view of the neck is also helpful, specifically in defining areas of narrowing, such as a steeple sign associated with subglottic edema. A chest radiograph is also important in the initial assessment to identify foreign bodies or other conditions such as unilateral emphysema, atelectasis, or pneumonia that may account fbr the child's respiratory compromise. If time permits, a barium swallow or airway fluoroscopy may provide additional information. Additional airway evaluation may include a brief flexible endoscopic examination. The nose is first sprayed with a combination of 2% lidocaine and oxymetazoline, and the child is gently restrained. The airway can be examined from the nares to the glottis. Attempts to pass a flexible scope through the glottis in a child with airway obstruction should be avoided. Likewise, flexible endoscopy should be avoided in a child with supraglottitis because of the possibility of precipitating complete obstruction. Children with suspected airway pathology distal to the glottis or those in whom the possibility that flexible endoscopy could compromise the airway should undergo any airway examination in the operating room where rigid endoscopes and other airway equipment is immediately available to secure the airway if necessary. Nonsurgical intervention in the child with acute airway obstruction may begin with just observation alone in a high surveillance unit. Humidified oxygen administered by face mask will improve PO?and clearance of secretions. Racemic epinephrine administered by nebulizer acts to reduce mucosal edema and is useful in conditions such as laryngotracheobronchitis (infectious croup). Because its length of action lasts 30 to 60 minutes, treated patients should be observed for signs of rebound for 4 to 6 hours after administration. Corticosteroids have been shown to have value in the management of postintubation croup, adenotonsillar hypertrophy that results from EBV infection, allergic edema, and spasmodic croup. Use of corticosteroids in infectious croup and in infants with a subglottic hemangioma remains controversial.10~16

Other adjuvant therapies include antibiotics and inhalation of helium/oxygen mixture (heliox). Although viral agents are often responsible for inflammation in the larynx and trachea, bacterial superinfection is also common. Because of the prevalence of penicillin-resistant organisms, broad-spectrum antibiotics, including a higher-generation cephalosporin, penicillinase-resistant penicillin, or p-lactamase penicillin, are useful in preventing or eradicating infection. Heliox is a mixture of gas in which helium is used to replace nitrogen. The advantage of the helium-oxygen mixture is that its low density reduces air turbulence and gas resistance, allowing improved delivery of oxygen in patients with airway obstruction. Nonsurgical airway management may include use of nasal or oral airways, endotracheal intubation, and, rarely, transtracheal ventilation. Nasal airways of rubber or other synthetic material can be easily inserted into the nose of most children after adequate lubrication with a water-soluble lubricant. Their best use is in cases where the pharynx is the site of obstruction. Oral airways are not as readily tolerated by children and only serve as a brief solution to an airway problem. During the 1970s, endotracheal intubation with polyvinyl chloride tubes revolutionized the management of supraglottitis,and even today intubation remains the mainstay of initial airway therapy in most children with severe airway obstruction. The size of the endotracheal tube used correlates with the age of the child. The subglottis, the narrowest part of the infant airway, typically admits a 3.5- or 4.0-mm inner diameter tube. The tube used in children older than a year can be roughly estimated by using the following formula: tube size = (16 + age in years) t 4. Once the airway has been established, the tube should be carefully secured and the child appropriately sedated and/or restrained if necessary to avoid accidental self-extubation. Another method of airway management should be considered in children with an unstable cervical spine or in whom oral or neck trauma makes visualization difficult. Transtracheal ventilation, insertion of a 16-gauge needle through the cricothyroid membrane for the delivery of oxygen, should be reserved for emergencies and used only until a more stable airway can be obtained. The surgical management of the child with acute airway obstruction should begin with endoscopy. The larynx can be visualized with one of a variety of pediatric laryngoscopes and the airway secured with a rigid pediatric ventilating bronchoscope of appropriate size. Once the airway is secured, a more stable form of airway management can be utilized. Rarely, in a child with acute airway obstruction, an airway cannot be established, and a cricothyrotomy may need to be performed. As in adults, this procedure avoids some of the risks of bleeding and pneumothorax inherent in a formal emergency tracheostomy. A small endotracheal or tracheostomy tube can be inserted through the incision it1 the cricothyroid membrane, but conversion should be made to a more stable airway as soon as possible. Tracheostomy remains the preferred airway in cases of acute obstruction in which a translaryngeal approach is unsuccessful or must be avoided. The emergent tracheostomy should be avoided if at all possible to lessen complications of bleeding, pneumothorax, pneumomediastinum, subcutaneous

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Laryngomalacia. This disorder classically presents as an omega-shaped epiglottis. The arytenoid mucosa is redundant, and the aryepiglottic folds are foreshortened. The result is a hooding of tissue over the glottic inlet that leads to airway obstruction on inspiration. I

emphysema, or damage to surrounding structures. The incidence of these complications can be reduced by careful attention to surgical technique, good lighting, and adequate assistance.

Congenital Laryngeal Anomalies Lavyngomalacia is the most common cause of newborn stridor and is caused by prolapse of the supraglottic structures (arytenoid cartilages, aryepiglottic folds) during inspiration (Fig. 52-12). Symptoms typically appear at birth or soon thereafter and include inspiratory stridor, feeding difficulties, and, rarely, apnea or signs of severe airway obstruction. Gastroesophageal reflux disease tends to worsen symptoms of laryngomalacia. The diagnosis is confirmed by flexible endoscopy of the larynx, and other airway pathology can be excluded with lateral neck, chest, and barium swallow radiography. In most cases, laryngomalacia is self-limited and resolves by 18 months of age. Changes in positioning and feeding, treatment of reflux, and, in some neonates, use of monitoring may be necessary. In severe cases, surgical intervention with either a supraglottoplasy (surgical division of the aryepiglottic folds) or a tracheostomy may be necessary. Tracheobronchomalacia is defined as collapse of the tracheobronchial airway. It may be congenital or acquired (from long-standing intubation and infection) and may be segmental or involve the entire tracheobronchial tree. Depending on the extent and location, symptoms include low-pitched biphasic stridor and signs of respiratory compromise. The diagnosis is usually made with endoscopy, although fluoroscopy of the airway may often demonstrate it. Treatment ranges from observation in most cases to airway management with a tracheostomy tube and positive-pressure ventilation in severe cases.

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Vocalfold paralysis is the second most common congenital laryngeal anomaly (after laryngomalacia) and may be unilateral or bilateral. Congenital vocal fold paralysis may be caused by neurologic abnormalities (hydrocephalus, Arnold-Chiari malformation), birth trauma, or rarely in association with neoplasms of the larynx or neck. Neonates with bilateral involvement typically present with highpitched inspiratory or biphasic stridor but a good cry. Respiratory compromise and feeding difficulties may accompany the stridor. In infants with unilateral involvement, the airway may be adequate although a few infants will show evidence of compromise, especially during feeding. The cry is often hoarse or breathy. Acquired vocal fold paralysis may result from trauma or from neoplasms of the chest or neck or may be iatrogenic, typically after surgery of the neck or arch of the aorta. The diagne sis of unilateral or bilateral vocal fold paralysis is confirmed with endoscopy. Additional studies in the evaluation of patients with vocal fold paralysis include lateral neck and chest radiography, barium swallow, and CT or MRI of the head and neck. Most cases of unilateral involvement can be observed, but infants with bilateral vocal fold paralysis often require a tracheostomy. In addition, infants with associated feeding difficulties may necessitate a gastrostomy. In older children (> 4 or 5 years of age) a more permanent solution such as a cordotomy or arytenoidectomy can be considered to improve the glottic airway. Congenital subglottic stenosis is the third most common congenital laryngeal anomaly and is defined as a neonatal larynx that fails to admit a 3.5-mm endotracheal tube without a history of prior instrumentation or intubation (Fig. 52-13). The underlying abnormality is a cricoid cartilage that is either small or deformed. Infants with congenital subglottic stenosis present with inspiratory or biphasic stridor, barking cough, and other symptoms of airway obstruction. The diagnosis is often suggested by narrowing of the subglottis on a lateral neck radiograph and confirmed by endoscopy. Treatment depends on the severity of symptoms and ranges from observation to laryngeal reconstruction to tracheostomy.

Subglottic stenosis. Congenital and acquired stenosis create airway obstruction, depending on the severity and type of stenosis. Various forms of reconstruction are available (see Chapter 63). I

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, Subglottic hemangiomas typically arise from the posterior lateral aspect of the larynx. Small lesions may be managed conservatively,whereas lesions with aggressive growth patterns require tracheotomy to bypass the laryngeal obstruction.

A child with a subglottic hemangoma presents with the onset of progressive stridor during the first few months of life (Fig 52-14). Hemangiomas are proliferative endothelial lesions that can form in the submucosa of the posterior subglottis. Occasionally, they may involve the subglottis in a circumferential pattern. Associated cutaneous hemangiomas may be found in approximately 50% of patients. Symptoms are dependent on the amount of airway compromise and include biphasic stridor, barking cough, difficulty feeding, and other symptoms and signs of airway obstruction. The diagnosis may be suggested on a lateral neck radiograph but is confirmed with endoscopy. Nonsurgical management of infants with a subglottic hemangioma includes observation or treatment with systemic corticosteroids. Surgical therapy includes laser excision, open excision through a laryngofissure, or a tracheostomy. A laryngoceleis an air-filled dilatation of the saccule of the larynx that communicates with the laryngeal airway. It may present internally into the posterior superior false cord region or externally through the thyrohyoid membrane. A saccular cyst is fluid filled and protrudes between the true and false vocal folds. The diagnosis of this lesion is confirmed endoscopically, and CT of the larynx is helpful in assessing its extent and if it is fluid or air filled. Treatment is with endoscopic marsupialization or excision through a laryngofissure.

Inflammatory Disease of the Upper Airway Lavyngotracheobronchitis (viral croup) is an inflammation of the subglottic airway caused by a variety of parainfluenza and influenza viral agents. The infection may involve the

entire glottis and extend into the trachea and bronchi. Affected children fall typically into the 1- to 3-year age group; males are more commonly affected than females. Symptoms and signs of viral croup include biphasic stridor, barking cough, and hoarseness, often in association with a prodromal viral upper respiratory tract infection. The diagnosis of croup is made clinically, but endoscopic examination may help to exclude other pathologic processes. Care should be taken not to instrument the subglottis, causing more swelling and inflammation and precipitating acute obstruction. Lateral neck radiography demonstrates subglottic narrowing, whereas anteropostenor neck films show a "steeple sign," the result of subglottic edema. Treatment of viral croup is typically supportive with humidification. Use of corticosteroids remains controversial. Treatment with nebulized racemic epinephrine in the emergency department or hospital setting often relieves symptoms; however, rebound of signs may occur several hours later and children should be monitored accordingly. Severely affected children may require intubation for respiratory failure. A smaller than normal tube should be employed. In rare cases, a tracheostomy may be required if the inflammation fails to resolve. A child younger than 1 year of age with recurrent bouts of "croup" should be suspected of having either congenital subglottic stenosis or a hemangioma. Spasmodic croup is the recurrence of croup-like symptoms in a child who is otherwise well. Fever is rarely present, and the attacks frequently occur at night. Gastroesophageal reflux disease has been suggested as a possible inciting process. Treatment of spasmodic croup is usually observant, although corticosteroids or reflux medications may prove beneficial. Supraglottitis (epiglottitis) is an infectious disease that involves the supraglottic larynx. In children the typical pathogen is type B Haemophilus inJuenzae (HIB). Other pathogens have been implicated in adolescent and adult cases. The incidence of supraglottitis in children has diminished markedly since the introduction of the conjugated HIB vaccine in the early 1990s.17Affected children are somewhat older than those seen with croup-in the 3 to 6-year age group. Symptoms and signs have a rapid onset, progress quickly to frank airway obstruction, and include stridor, dysphagia, fever, muffled voice, and signs of systemic toxicity. Affected children frequently sit and assume the "sniffing" position in an attempt to maximize their airway. Intraoral or endoscopic examination should be avoided in suspected patients because of concern for precipitating complete obstruction. Lateral neck radiography demonstrates a classic "thumbprinting" of the epiglottis but should only be obtained if facilities are present in close proximity to secure the airway. Prompt airway management is essential in children with supraglottitis. The child's airway should be secured in either the emergency department or operating room with team members who include a pediatrician, anesthesiologist, critical care physician, otolaryngologist, or pediatric surgeon or others familiar with the pediatric airway. After inducing the child with general anesthesia, the airway should be intubated. Examination of the supraglottis may be made, and cultures of the larynx and blood are obtained. Equipment to perform a tracheostomy should

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be readily available. The child should remain intubated for 24 to 72 hours and should be supported with intravenous fluids and antibiotics that treat antibioticresistant Haemophilus (third-generation cephalosporins, chloramphenicol) . Bacterial tracheitis (membranous croup) often occurs as a complication of another infection, such as measles, varicella, or other viral agents. The most common organisms include S. aureus, GABHS, M. catarrhalis, or H. injluenzae. It can occur in any age child and present with stridor, barking cough, and low-grade fever. Symptoms and signs then progress to include high fever and increasing obstruction and toxicity. The diagnosis may be suspected by diffuse narrowing of the tracheal air shadow on chest radiograph but is confirmed by endoscopic examination in the operating room. Purulent debris and crusts can be removed at this time. Cultures of secretions and crusts may be helpful in guiding intravenous antibiotic therapy that should be aimed initially at the usual pathogens. The airway should be secured with an endotracheal tube or, rarely, a tracheostomy. Repeat endoscopic examination of the airway may be warranted to continue dkbridement and to determine the feasibility of extubation.

Chronic Airway Obstruction The chronic management of subglottic stenosis and other prolonged airway disorders is discussed in Chapter 63.

Benign Laryngeal Neoplasms Recurrent respiratory papillomatosis is the most common benign neoplasm of the larynx in children. Squamous papillomas involve the larynx and occasionally the trachea and lower respiratory tract as exophytic lesions. Because of its recurrent nature, recurrent respiratory papillomatosis causes morbidity and, rarely, mortality due to malignant degeneration. Patients may be almost any age, but the disease is more aggressive in children. Human papillomavirus subtypes 6,11,16, and 18 have all been identified within papilloma tissue. The first two subtypes have been associated with genital warts, whereas the latter two have been associated with cervical and laryngeal cancers. The exact mechanism of human papillomavirus infection in the larynx remains unknown. Transmission of virus to the child from a mother with genital warts is suspected in many cases, but there is no concrete evidence to support this route of infection. Children afflicted with recurrent respiratory papillomatosis present initially with hoarseness but may also have symptoms and signs of airway obstruction, including stridor. Lateral neck radiography may suggest laryngeal involvement, but the diagnosis is confirmed by direct laryngoscopy and biopsy (Fig. 52-15). In addition to the trachea and bronchi, squamous papillomas may also be found in the oral cavity. Surgical excision is the mainstay of therapy in patients with recurrent respiratory papillomatosis. In the past, papillomas were excised using the carbon dioxide laser. More recently, the laryngeal microdebrider has become

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Recurrent respiratory papillomatosis. Severe

papillomatosis may completely obstruct the larynx. Papillomas are characterized by malignant degeneration and aggressive growth patterns.

the preferred method of excision in many centers. In aggressive cases with swift recurrence and accompanying airway obstruction, tracheostomy may be necessary for airway management, although tracheostomy has been implicated in the spread of disease to the trachea and lower respiratory tract. Medical adjuvant therapy that has been employed with mixed results includes interferon, photodynamic therapy with dihematoporphyrin ether, indole-3-carbinol, or antiviral agents such as cidofovir. Other benign laryngeal neoplasms are rare and include connective tissue tumors such as chondromas or fibromas, neurogenic tumors such as neurofibromas, or granular cell tumors and other cell types such as hamartomas or fibrous histiocytomas. Malignant tumors of the larynx are also rare and include squamous cell carcinoma and a variety of epithelial and connective tissue malignancies such as spindle cell carcinoma, rhabdomyosarcoma, mucoepidermoid carcinoma, and chondrosarcoma. Metastatic tumors and lymphoma may also rarely involve the larynx in children. Diagnosis is suspected by the sudden appearance of stridor, hoarseness, and airway obstruction and confirmed by biopsy. Treatment is dependent on cell type and may include surgical excision, radiation therapy, and/or chemotherapy.

NECK Anatomy The surgical anatomy and embryology of the neck is discussed in Chapter 56.

Clinical Evaluation The initial examination of a disease or disorder of the neck begins with a thorough history. A detailed history can often serve to focus the differential diagnosis of a neck disorder. The age of the child is an important

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first consideration. The appearance of a neck mass in an infant often suggests a congenital disorder, whereas the sudden appearance of a mass in an adolescent might suggest a malignant process. Inflammatory diseases of the neck may occur in any age group but typically mirror the incidence of upper respiratory tract infections in children. Growth and temporal relationships are often important clues to a diagnosis. Neck masses that grow rapidly suggest either an inflammatory or malignant process, whereas slow-growing masses are typically benign. A history of systemic infection elsewhere in the body or recent travel or exposure to farm animals often points to an infectious origin. A history of trauma to the neck may explain the sudden appearance of a neck mass. Likewise, changes in the size of a neck mass with eating may suggest a salivary gland origin. Vascular lesions enlarge with straining or crying. Finally, systemic symptoms of fever, weight loss, night sweats, or fatigue in association with the sudden develop ment of a neck mass may indicate a malignant process. The physical examination of a child with a neck mass should begin with a comprehensive examination of the entire head and neck. Because the vascular, neural, and lymphatic patterns of the head drain into the neck, the source of neck disorders may be found in the head. Depending on the differential diagnosis, a physical examination of the entire body, including an assessment of lymph nodes in the groin and axillae and the presence of an enlarged spleen or liver, is essential. Palpable lymph nodes in the neck of children are a common finding, but lymph nodes larger than 2 cm fall outside the range of normal hyperplastic nodes and should be either monitored or investigated. The sudden appearance of large nodes in either the posterior cervical or supraclavicular regions may suggest a malignan~y.~~ The consistency of a neck mass is also important in narrowing the differential diagnosis. Hard masses tend to be associated with either infection or malignancy. Fixation of a neck mass to skin or nearby structures is also suggestive of a malignancy. Cysts or abscesses tend to have a characteristic feel on palpation. Depending on the differential diagnosis after a history and physical examination, radiologic studies may be useful. A lateral neck radiograph may demonstrate an abnormality of the nasopharynx, retropharynx, or cervical spine. Likewise, a chest radiograph may identify a malignancy, sarcoidosis, or tuberculosis. Infection or a neoplastic process in the sinuses may appear on a sinus series. CT and MRI are useful in the evaluation of a neck mass. Demonstration of hypodensity on CT suggests an inflammatory or necrotic process. Ring enhancement of a hypodense region on a contrast CT scan is indicative of an abscess. MRI is excellent for distinguishing fine detail within soft tissue and in the evaluation of vascular lesions of the neck. Finally, ultrasound is helpful in distinguishing solid and cystic masses. Use of ultrasound preoperatively in patients with a thyroglossal duct cyst is also a simple and economic way to assess the presence of normal thyroid tissue when it is not easily felt. Ultrasound and thyroid scanning should be employed in the assessment of any thyroid mass. Selected laboratory studies may be helpful in the evaluation of a child with a neck disorder. A complete blood

cell count with differential may identify patients with either a malignancy or systemic infection. Serologic testing for EBV or cytomegalovirus infection, toxoplasmosis, or cat-scratch disease may be diagnostic. Thyroid function testing is essential in any child with a suspected thyroid disorder. Finally, collection of urine for catecholamine metabolites (vanillylmandelic acid) may assist in the diagnosis of neuroblastoma. If the diagnosis remains in doubt at this point, incisional or excisional biopsy may be indicated. Biopsy provides material for pathologic examination, culture, and other more sophisticated testing if necessary. Fine-needle aspiration of a neck mass in children for suspected malignancy is not as reliable as in adults.

Congenital Tracts and Cysts Congenital sinuses and cysts are discussed in Chapter 56.

Inflammatory and Infectious Masses Viral adenitis is the most common infectious disorder to involve the neck in children. Enlarged or hyperplastic lymph nodes are frequently the result of viral upper respiratory tract illnesses. Common pathogens include rhinovirus, adenovirus, and enterovirus, but measles, mumps, rubella, varicella, EBV, and cytomegalovirus may also cause lymphadenopathy. The diagnosis is often suspected by other findings in the history or physical examination and can be confirmed by serologic testing. Acute human immunodeficiency virus infection may present, as do other viral syndromes, with fever, headache, malaise, gastrointestinal symptoms, and a neck mass. The usual source of bacterial cervical adenitis is the pharynx. Causative organisms are often streptococcal or staphylococcal species. Patients present with systemic symptoms of fever and malaise in addition to a neck mass that is diffusely swollen, erythematous, and tender. In contrast to viral adenitis, which is frequently bilateral, bacterial infections of the neck are usually unilateral. CT with contrast medium enhancement may be helpful in the evaluation of large infectious neck masses that may contain an abscess cavity. Needle aspiration of suspected infectious masses may provide material for culture and decompress the mass. Broad-spectrum antibiotic therapy, administered either orally or intravenously, may be curative, although surgical drainage is usually necessary in extensive cases. Cat-scratchdisease is caused by Bartonella henselaeinfection. The clinical picture includes the sudden appearance of unilateral lymphadenopathy after a scratch from a cat. Fever and malaise may be accompanying symptoms in many cases. Serologic testing for antibodies to Bartonella is diagnostic. Cat-scratch disease is usually self-limited, although some benefit has been described with the use of erythromycins and other antibiotics.Z1 In the past most mycobacterial infections have been caused by atypical organisms such as Mycobacterium auium-intracellulare, M. scrofulaceurn, M. bouis, or M. kansasii. In the past decade or so, mycobacterial tuberculosis has

CHAPTER

made a resurgence as the pathogen responsible for a neck infection. Atypical mycobacterial infections present as nontender nodes in the preauricular, intraparotid, or posterior triangle regions. The skin overlying the node typically assumes a violet color, and systemic symptoms are rare. A chest radiograph should be obtained if M. tuberculosis is suspected. The diagnosis is made by obtaining material for acid-fast stain and culture with needle aspiration, surgical drainage, or excision of involved nodes. Surgical curettage or total excision is curative for atypical lesions. Tuberculosis should be treated with appropriate antituberculin chemotherapy. Rarely, the neck may be involved with infections such as tularemia, brucellosis, actinomycosis, plague, histoplasmosis, or toxoplasmosis. Inflammatory disorders that may affect the neck include Kawasaki syndrome, sarcoidosis, sinus histiocytosis (Rosai-Dorfman disease), Kikuchi-Fujimoto disease, and PFAPA syndrome (periodic recurrent fever).

Malignant Neoplasms Thyroid malignancies are not uncommon in the adolescent age group, with 10% of thyroid carcinomas occurring in patients younger than 21 years of age.3Welldifferentiated tumors, usually papillary carcinoma, make up the majority of tumors. Follicula?;mixed, and medullary tumors occur less commonly. Most patients present with a painless midline neck mass. On presentation, cervical adenopathy can be palpated in a majority of patients, a finding that reflects the high incidence of papillary disease that metastasizes via the lymphatic^.^ Other important symptoms and signs include a rapid rate of growth, pain, hoarseness, and dysphagia. Children who have received prior radiation are at greater risk of thyroid malignancy. The occurrence of thyroid malignancy may be associated with iodine deficiency, Hashimoto's thyroiditis, and Graves' disease.9~22Preoperative assessment should include thyroid nucleotide scanning to distinguish between cold (hypofunctioning) and hot (hyperfunctioning) nodules. Up to a third of cold nodules can be malignant, whereas hot nodules are rarely malignant.'? Ultrasonography can distinguish between solid and cystic lesions, and fine-needle aspiration is an alternative to surgical biopsy for diagnosis. Surgical management includes near-total or total thyroidectomy, neck dissection if indicated, and postoperative 1311 ablation. Lymphoma is a common pediatric malignancy and can present in the neck as painless lymphadenopathy. Hodgkin 's disease occurs most often in late adolescence and has four histologic subtypes: lymphocyte predominance, nodular sclerosing, mixed cellularity, and lymphocyte depletion. Lymphocyte predominance and nodular sclerosing types make up most cases. Staging of Hodgkin's disease depends on the amount and location of nodal involvement and the presence or absence of systemic or B symptoms (fever, night sweats, weight loss). Treatment is with multiple-agent chemotherapy and localized radiation therapy. Non-Hodgkin's lymphoma can be divided into low-, intermediate-, or high-grade subtypes.

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High-grade tumors may be further divided into large cell, lyrnphoblastic, and small cell types. Staging of nonHodgkin's lymphoma is by location and extent. Treatment is with multiple-agent chemotherapy. Langerhans' cell histiocytosis (previously histiocytosis X ) includes the disease entities known as eosinophilic granuloma, Hand-Schiiller-Christian syndrome, and Letterer-Siwe disease. The exact nature of this entity remains an enigma: it may represent a neoplasm or a hyperimmune response.' Symptoms and signs include lymphadenopathy, rashes, otorrhea, oral lesions, and hepatosplenomegaly. Diagnosis is dependent on the identification of Langerhan's cells on pathologic specimens. Treatment ranges from curettage or excision to intralesional or systemic corticosteroids to chemotherapy and radiation therapy. Two major categories of neural tumors may be found in the neck. Neurofibromatosis is a benign disorder that in some forms (plexiform) may infiltrate surrounding tissues. For this reason, CT and/or MRI are vital in the preoperative evaluation of these lesions. Surgical resection is the mainstay of treatment. Neuroblastoma is a malignancy that develops from neural crest cells and may present as a solitary tumor or as lymphadenopathy. Clinical staging determines the mode of therapy that includes surgery, chemotherapy, and radiation therapy. Rhabdomyosarcoma rarely presents as a primary tumor in the neck, more often being found as a primary tumor in the orbit, temporal bone, or nasopharynx. The diagnosis is made by biopsy, and patients are staged according to involvement. Treatment includes surgery, chemotherapy, and radiation therapy. Malignancies of almost any type and location in the body can metastasize to the neck. The most common are thyroid malignancies. In adolescents, carcinomas, especially those arising in the nasopharynx, may spread to the neck lymphatics.

REFERENCES 1. Anon JB, Rontal M, Zinreich SJ: Anatomy and Embryology of the Paranasal Sinuses. New York, Thieme, 1996. 2. Bluestone CD, Klein JO: Otitis media and eustachian tube dysfunction. In Bluestone CD, Stool SE, Alper CM, et a1 (eds): Pediatric Otolaryngology, 4th ed. Philadelphia, WB Saunders, 2003, pp 474686. 3. Buckwalter JA, Guril NJ, Thomas CG Jr: Cancer of the thyroid in youth. World J Surg 1981;5:15-25. 4. Cole RR,Cotton RT: Pediatric malignancies. In Bailey BJ, Johnson JT, Kohut RI, et a1 (eds): Head and Neck SurgeryOtolaryngology. Philadelphia, JB Lippincott, 1993, p 1388. 5. Cunningham MJ: Neoplasms of the ear and temporal bone. In Wetmore RF, Muntz HR, McGill TJ, et a1 (eds): Pediatric Otolaryngology: Principles and Practice Pathways. New York, Thieme, 2000, pp 385-408. 6. De la Cruz A, Chandrasekhar SS: congenital malformations of the temporal bone. In Brackman DE, Shelton C, Arriaga MA (eds): Otologic Surgery. Philadelphia, WB Saunders, 1994, pp 69-84. 7. Devaney KO, Putzi MJ, Ferlito A, et al: Head and neck Langerhans' cell histiocytosis. Ann Otol Rhino1 1,aryngol 1997;106:526-532.

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8. Fierstein J, Thawley S: Lymphomas of the head and neck. Laryngoscope 1978;88:582-593. 9. Geiger JD, Thompson NW: Thyroid tumors in children. Otolaryngol Clin North Am 1996;4:711-719. 10. Hawkins DB, Crockett DM, Shum TK: Corticosteroids in airway management. Otolaryngol Head Neck Surg 1983; 91:593-596. 11. Houser SM, Corey JP: Allergic fungal sinusitis: Pathophysiology, epidemiology and diagnosis. Otolaryngol Clin North Am 2000;33:399. 12. Hung W, Anderson KD, Chandra R: Solitary thyroid nodules in 71 children and adolescents. J Pediatr Surg 1992;27: 1407-1409. 13. Jacobs IN, Potsic WP: Glomus tympanicum in infancy. Arch Otolaryngol Head Neck Surg 1994;120:203-205. 14. Jahrsdoerfer RA, Yeakley JW, Aguilar EA, et al: Grading system for the selection of patients with congenital aural atresia. Am J Otol 1992;13:612. 15. Johnson RF, Stewart MG, Wright CC: An evidence-based review of the treatment of peritonsillar abscess. Otolaryngol Head Neck Surg 2003;128:332-343. 16. Kairys SW, Olmstead EM, O'Connor GT: Steroid treatment of laryngotracheitis: A meta-analysis of the evidence from randomized trials. Pediatrics 1989;83:683-693. 17. Kessler A, Wetrnore RF, Marsh R R Childhood epiglottitis in recent years. IntJ Pediatr Otorhinolaqngol 1993;25:155-162. 18. Kodet R, Fajstavr J, Kabelka Z, et al: Is fetal cellular rhabdomyoma an entity or a differentiated rhabdomyosarcoma? A study of patients with rhabdomyoma of the tongue and sarcoma of the tongue enrolled in the intergroup rhab domyosarcoma studies I, I1 and 111. Cancer 1991;67: 2907-2913. 19. LeeYW, Gisser SD: Squamous cell carcinoma of the tongue in a nine-year renal transplant survivor: A case report with a discussion of the risk of development of epithelial carcinoma in renal transplant survivors. Cancer 1978;41:1-6. 20. Marcus CL, Omlin KJ, Basinki DJ, et al: Normal polysomnographic values for children and adolescents. Am Rev Respir Dis 1992;146:1235-1239. 21. Maurin M, Birtles R, Raoult D: Current knowledge of Bartonrlla species. Eur J Clin Microbiol Infect Dis 1997; 16:487-506. 22. Millman B, Pellitteri PK: Thyroid carcinoma in children and adolescents. Arch Otolaryngol Head Neck Surg 1995; 121:1261-1264.

23. Neault MW: Pediatric audiology. In Wetmore RF, Muntz HR, McGill TJ, et a1 (eds): Pediatric Otolaryngology: Principles and Practice Pathways. New York, Thieme, 2000, pp 183-202. 24. Paradise JL, Bluestone CD, Bachman RZ, et al: Efficacy of tonsillectomy for recurrent throat infection in severely affected children: Results of parallel randomized and nonrandomized clinical trials. N Engl J Med 1984;310: 674683. 25. Pichichero ME: First-line treatment of otitis media. In Alper CM, Bluestone CD, Casselbrant ML, et al (eds): Advanced Therapy of Otitis Media. Hamilton, ON, BC Decker, 2004, p 32. 26. Poje CP, RechtwegJS: Structure and function of the temporal bone. In Wetmore RF,Muntz HR, McGill TJ, et a1 (eds): Pediatric Otolaryngology: Principles and Practice Pathways. New York, Thieme, 2000, pp 127-146. 27. Potsic WP, Cotton RT, Handler SD (eds): Surgical Pediatric Otolaryngology.NewYork, Thieme, 1997, pp 18-59, 106109, 188-191, 196-205. 28. Quie PG, Pierce HC, Wannamaker LW: Influence of penicillin-producing staphylococci and the eradication of group A streptococci from the upper respiratory tract by penicillin treatments. Pediatrics 1966;37:467-476. 29. Radkowski D, McGill TJ, Healhy GB, et al: Angiofibroma: Changes in staging and treatment. Arch Otolaryngol Head Neck Surg 1996;122:122-129. 30. Richardson MA: Regional and intracranial complications of sinuses. In Wetmore RF, Muntz HR, McGill TJ, et a1 (eds): Pediatric Otolaryngology: Principles and Practice Pathways. New York, Thieme, 2000, pp 487-496. 31. Torsiglieri AJ, Tom LWC, Ross A, et al: Pediatric neck masses: Guidelines for evaluation. Int J Pediatr Otorhinolaryngol 1988;16:199-210. 32. Wetmore RF, Mahboubi S, Soyupak SIC Computed tomography in the evaluation of pediatric neck infections. Otolaryngol Head Neck Surg 1998;119:624627. 33. Woolley AL, Lusk RP: Pediatric cochlear implantation. In Wetmore RF, Muntz HR, McGill TJ, et a1 (eds): Pediatric Otolaryngology: Principles and Practice Pathways. New York, Thieme, 2000, pp 359-370.

Salivary Glands Nina L. Shapiro, MD

Salivary gland disorders are rare in children. They often present as a painful or, less commonly, a painless swelling in the affected gland. Disease processes may be of infectious, inflammatory, systemic, autoimmune, congenital, neoplastic, or traumatic origin.Treatrnent is guided by the medical or surgical nature of the specific disease process.

CLASSIFICATION Salivary glands may be divided into major and minor categories. The former category includes the parotid, submandibular, and sublingual glands, all of which are paired structures with their own well-defined anatomy, including blood supply and ductal drainage. Their function is augmented and facilitated by the minor salivary glands, which include the mucus-secreting tissues in the buccal mucosa, palate, mucosal surfaces of the lips, and floor of the mouth.

in the buccal mucosa at the level of the second maxillary molar. The deep lobe of the parotid gland lies medial to the facial nerve branches and the mandible. Deep lobe parotid gland masses may extend to the parapharyngeal space and present as intraoral growths. The submandibular gland is located in the submandibular triangle of the neck. The main submandibular duct (Wharton's duct) exits the gland at a right angle and enters the mouth just lateral to the midline lingual frenulum. The sublingual gland is located at the lateral aspect of the floor of the mouth.6 Physiologc function of the salivary glands may be initiated by various stimuli, including cerebral, visual, olfactory, or gustatory. These stimuli promote the flow of saliva, which acts to lubricate the mouth for hygiene, speech, and deglutition; to moisten food for taste and mastication; and to initiate early starch digestion with a-amyla~e.~

PATHOLOGY EMBRYOLOGY In the sixth week of gestation, solid epithelial buds of ectoderm from the developing mouth invaginate into the surrounding mesenchyme. A groove from this invagination develops into a tunnel, which subsequently forms branches of salivary ductal tissue. The mesenchymal tissue forms the capsule and connective tissue of the salivary glands. The ends of the solid ducts form secretory acini, which become hollow. This process is similar for all of the major salivary gland embryogenesis.9 During early gestation, the parotid ductules begin to grow around the facial nerve and its branches. This is of great clinical and surgical significance, because the facial nerve may be compressed or invaded by parotid gland lesions or its branches may be injured during parotid gland surgery.Z8

The response of a salivary gland to any pathologic process is swelling, which may be accompanied by symptoms such as pain, tenderness, erythema, or abnormal ductal discharge. Lesions may be congenital or a ~ q u i r e d . ~ ' Congenital lesions include hemangiomas and lymphatic malformations. The majority of salivary masses in children are congenital vascular lesions, with hemangiomas seen in 50% to 60% of salivary gland masses and lymphatic malformations in approximately 25%.Ucquired lesions are of inflammatory, infectious, autoimmune, traumatic, or neoplastic origin. Major salivary gland disease initially presents as swelling of the gland and its surrounding structures. Advanced stages of disease may lead to cranial nerve involvement with resultant paresis or paralysis.

DIAGNOSIS ANATOMY AND PHYSIOLOGY

History

The parotid gland is located in the space between the external auditory canal and the mandible. Its main duct (Stensen's duct) crosses the masseter muscle and opens

A careful history should be taken, with specific focus on duration of the lesion, its bilateral or unilateral presentation, and whether there is any symptom fluctuation

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associated with eating. A complete medical history is essential because the salivary glands may be involved in several systemic conditions.

Physical Examination The physical examination should include careful inspection of the overlying skin, both local and distant, to evaluate for any cutaneous hemangiomas, as well as of the intraoral mucosa to evaluate for intraoral extension of the mass. Bimanual examination of the parotid glands and submandibular glands is crucial to fully evaluate the nature of the lesion. Longitudinal duct massage will assess for duct obstruction or purulent material in the saliva. Benign salivary lesions tend to be mobile, soft, and spongy, whereas malignant lesions are more often fixed and firm on palpation.

Radiographic Imaging Plain radiographs of the salivary glands are helpful in glandular calcifidetecting " salivarv duct calculi or diffuse " cation.6 Sialography is performed by injecting radiographic contrast medium through a small polyethylene tube into the salivary duct (Stensen's duct or Wharton's duct) in question. This technique is useful in identifying strictures, sialectasis, calculi, or saccular dilatation (Fig. 53-I)." The major limitation of this study is that it may cause pain; and in younger children, sedation or general anesthesia may be necessary.

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Doppler ultrasound study shows vascular pooling in a

parotid hemangioma.

High-resolution ultrasonography is a useful, noninvasive technique in the diagnosis of sialectasis and salivary gland calculi.1g The addition of color-flow Doppler imaging can provide accurate information regarding the consistency of the lesion and its vascular pattern and blood flow (Fig. 53-2).66

Computed Tomography Computed tomography (CT) is an excellent diagnostic modality to assess both pathology and anatomy of the salivary glands. It can aid in distinguishing intrinsic or extrinsic lesions and can identify abscess formation by ring enhancement surrounding inflamed tissue. Instillation of an intravenous contrast agent is necessary to evaluate the presence of an abscess or to delineate vascularity of congenital and acquired vascular lesion^.^ These features aid in both medical and surgery planning.loJ6

Magnetic Resonance Imaging

a

gland.

-

Magnetic resonance imaging (MRI) provides the best soft tissue detail of the salivary glands, and it is the only imaging technique that can delineate the facial nerve anatomy within the parotid glands. Signa! intensity variations (TI- and T2-weighted images) provide additional valuable information regarding the nature of the ma~s.2~258 For instance, hemangiomas, which are the most commonly seen narotid masses. have a characteristic annearance of I high flow with intermediate intensity on TI-weighted images and high intensity on T2-weighted images.6 I

sialogram shows saccular sialolithiasis of the parotid

CHAPTER

Biopsy Fine-needle aspiration biopsy is an excellent tool in the It can diagnostic evaluation of salivary gland ma~ses.8.2~ often be performed using local anesthesia in an outpatient setting with a cooperative child. The overall diagnostic accuracy is 84%.1.40Obtaining an adequate needle biopsy specimen may preclude the necessity for surgical therapy or, more often, aid in surgical planning. For deeper salivary gland tumors, fine-needle aspiration may be performed under ultrasound, CT, or MRI guidance. Open excisional biopsy is the definitive tool for investigation and may be curative. If the lesion is amenable to excision, an intraoral or extraoral approach may be used. When a biopsy specimen is obtained, it should be sent to the pathologist with a complete clinical description and proper markers to provide a precise orientation of the lesion. In many instances, a definitive diagnosis cannot be obtained on the frozen section and it is therefore desirable to wait until the permanent histologic report is received before further extensive and potentially disfiguring surgery is done. If the size and location of the lesion are favorable, the entire tumor may be resected intact with a clear surrounding cuff of normal tissue. The diagnosis of Sjogren's syndrome may be obtained by incisional biopsy of the minor salivary glands of the labial mucosa, or, alternatively, of the parotid gland.3Y

INFLAMMATORY DISEASE Viral Sialadenitis Acute inflammation of the salivary glands may be viral in up to 85% of cases, and the majority of viral sialadenitis involves the parotid glands. Viral infections are characterized by a benign self-limiting course over a 2- to 3-week period. Antipyretics, analgesics, and anti-inflammatory agents may be given for relief of symptoms. Causative organisms include coxsackievirus A and echovirus. Before the development of the mumps vaccine, mumps virus (paramyxovirus) was the most common cause of acute parotid inflammation in children.13 As a result of nearly universal mumps immunization in the United States, which began in 1967, mumps parotitis is exceedingly rare.".4"50 Other potential causes of viral sialadenitis include cytomegalovirus, which is most commonly seen as a component of disseminated cytomegaloviral infecg Epstein-Barr tion in infants and young ~ h i l d r e n , ~and virus (EBV), which in healthy children is associated with infectious mononucleosis and in chronically ill children may be associated with human immunodeficiency virus (HIV) infection. I4z6O

53

Salivary Glands

837

are usually Staphylococcus aureus and Streptococcus v i r i d a n ~ . ~ ~ Acute sialadenitis often occurs in dehydrated patients because of decrease in salivary flow and dry oral mucosa. Most cases will respond to antistaphylococcal antibiotics, with careful attention to hydration, oral hygiene with mouthwashes, warm local compresses, and sialogogues such as sour lemon drop candies to stimulate salivary flow. Rarely, acute sialadenitis will not respond to medical therapy and the infected tissue will coalesce to form an abscess. Treatment of a salivary gland abscess includes intravenous antibiotics and surgical drainage." If an abscess develops in the parotid gland, surgical drainage is carried out via a parotidectomy incision, with skin flap elevation. Multiple fascia1 incisions parallel to the course of the facial nerve are made to drain the abscess. If the facial nerve is paretic preoperatively, abscess drainage will usually facilitate resolution of nerve f ~ n c t i o n . ~

Chronic Sialadenitis Chronic sialadenitis is the most common cause of inflammatory salivary gland disease in children (Fig. 53-3). Repeated episodes of infection may lead to a progressive sequence of structural changes in the gland, including sialectasis with stasis and resultant acinar destruction. It is important to distinguish between obstructive and nonobstructive causes of this condition. Obstruction is caused by ductal stenosis, which may be congenital or caused by a stone. Endogenous injury may result from chewing or biting the ductal opening. In such cases, the duct should be probed with a small-diameter lacrimal probe and laid open for continuous drainage. Nonobstructive chronic sialadenitis may occur in conjunction with metabolic disorders such as Sjogren's syndrome or chronic granulomatous disease such as sarcoidosis, tuberculosis, or atypical mycobacterial disease. The treatment of obstructive sialadenitis is initially conservative, with warm compresses and anti-inflammatory medications. Ductal dilatation or marsupialization may be necessary for recalcitrant disease. Gland excision is rarely required. Sialolithiasis (salivary gland or duct calculi) is rare in children. When present, it occurs in the submandibular gland in 80% of cases. When the stone is at the distal salivary duct and is visible or palpable intraorally, it may be excised by a simple incision at the orifice of Wharton's or Stensen's duct. Temporary stent placement through the duct may be necessary to avoid duct scarring and stricture. Rarely, a large calculus will be located in the proximal salivary duct or salivary gland parenchyma. If this results in chronic inflammation, complete gland excision with the stone-containing duct may be required.

Bacterial Suppurative Sialadenitis Acute suppurative sialadenitis most often presents as r a p idly developing pain and swelling, with associated fever and poor oral intake. There may be associated purulent drainage from the duct of the affected gland. It is primarily seen in the parotid glands and less commonly in the s u b mandibular or sublingual glands. The causative organisms

CYSTIC DISEASE Cystic disease may be acquired, congenital, or traumatic. It occurs most often in the minor salivary glands or in the parotid glands.64Congenital cystic disease may occur in the salivary glands, but it is not of salivary gland origin. Work type I and type I1 first branchial cleft cysts may present as

838

PART

V

HEADAND NECK

A

B

, -

A, Sialogram of patient with history of recurrent parotid swelling. Note normal ductal system with early diffuse punctate sialectasis B, Parotid gland swelling between acute attacks of inflammation.

parotid gland masses.65 Congenital lymphatic malformations may also present in the parotid, submandibular, or sublingual glands. Large, bilateral intraparotid lyrnphoepithelial cysts are characteristic of HIV infection." Small mucous retention cysts may present in the minor salivary glands of the labial or buccal mucosa; these cysts usually result from single or repeated local trauma to the minor salivary glands and may lead to recurrent local mucosal swellings. If they do not resolve spontaneously, they will require complete excision. Local drainage or marsupialization will result in recurrence.

Surgical management of ranulas is an area of much debate. Although some groups recommend marsupialization as definitive the rap^,^^,^^ others have described high incidence of cyst recurrence and subsequent extension to the neck via the mylohyoid (plunging ranula) and advocate complete sublingual gland excision as the definitive therDuring sublingual gland excision, care must be taken to avoid Wharton's duct injury. This can be avoided by placing a lacrimal probe in the duct intraoperatively to avoid duct entry. The lingual nerve must also be meticulously dissectedjust deep to the sublingual gland.

Ranula

NEOPLASMS

A ranula is a mucus extravasation cyst of the sublingual gland. Initial presentation is that of a bluish, cystic mass at the floor of mouth, which may lead to lingual elevation and difficulty with deglutition (Fig. 53-4).

Salivary gland neoplasms are extremely rare in children.3~51 Less than 5% of salivary gland neoplasms occur in patients younger than 16 years of However, when present, a pediatric salivary tumor must be assessed to rule out malignan~y.~,~~,54

Benign Neoplasms and Malformations

k

4

II I

X

.

-

elevation.

F

lo or of mouth ranula with posterosuperior lingual

Benign neoplasms account for 60% of salivary tumors in chil&en and are most commonly vascular'in origin.3 Vascular lesions include hemaneiomas and lvm~hatic mal" , x formations, which are both congenital lesions (Fig. 53-5).

Hemangiomas Hemangiomas are one of the most common salivary (primarily intraparotid) neoplasms in children. They usually present in infancy as a soft, nontender parotid swelling, with or without associated pigmented cutaneous lesions.45 Diagnosis is usually confirmed by ultrasound with colorflow Doppler studies or MRI.38 Biopsy of a suspected is rarely> .~erformed.15 salivary , cland hemangioma " Parotid hemangiomas often resolve spontaneously and do not require medical or surgical therapy. If they are

-

CHAPTER

.

53

Salivary Glands

839

.

Vascular malformation of the parotid gland, showing large, irregular vascular spaces. (Hematoxylin-eosin stain, ~ 5 0 . )

Pleomorphic adenoma (mixed tumor) of the parotid gland. Epithelial areas are mixed with myxomatoid and chondroid stroma. (Hematoxylin-eosin stain, ~ 5 0 . )

rapidly growing or are causing functional impairments such as facial nerve weakness, external auditory canal obstruction, or cutaneous breakdown, systemic therapy such as corticosteroids or interferon alfa-2a or -2b are viable options to inhibit vascular growth and promote involution of the tumor.5~3~ A less common vascular tumor is the kaposiform hemangioendothelioma. This is a benign, although locally aggressive, tumor that is firm to palpation with a nodular growth pattern and violaceous pigmentation. Therapy is controversial and may include systemic corticosteroids, interferon alfa, or surgical re~ection.~?

masses, most often in the parotid gland, with an average age at presentation of 9.5 years within the pediatric population.2"." The tumor presents as a painless, slowly growing mass and is rarely infiltrative.'? Treatment of superficial lobe tumors includes superficial parotidectomy with facial nerve dissection and preservation. Recurrence rates have been reported to be up to 4O%, so long-term follow-up is recommended.36," Rarely, recurrent pleomorphic adenomas may undergo malignant degeneration. The submandibular glands, minor salivary glands, tongue, and soft palate may also develop pleomorphic adenomas, although these are rare.g

Lymphatic Malformations Lymphatic malformations are less common than hemangiomas, and the biology of these congenital vascular malformations results in a clinical course that differs They do not undergo sponfrom that of hernangioma~.~j taneous involution, are usually present at or soon after birth, and grow with the growth of the child. They are not actual salivary lesions, but they are most commonly seen in the submandibular and parotid region in infants and young ~hildren.~"ecause they are lesions of the lymphatic system, they are susceptible to infection, with potential for cellulitis, intralesional bleeding, abscess formation, or lymphatic fluid extension to the floor of mouth or trachea with airway compromise. Treatment modalities have been an area of much investigation. Surgical resection must be complete to obviate recurrence. This is often difficult, owing to the fragility of the tumor lining and its proximity to major vessels and branches of the facial nerve.'3,'9 In an effort to avoid surgical morbidity, success with intralesional sclerotherapy has been demonstrated, resulting in reduction in tumor size and minimal scarring or r e c ~ r r e n c e . ~ '

Pleomorphic Adenomas Pleomorphic adenomas (benign mixed tumors) are the most common nonvascular benign salivary tumors in children (Fig. 53-6).j'z" They present as firm, rubbery

Monomorphic Adenomas Monomorphic adenomas are rare in children. Histologically, they may resemble adenoid cystic carcinoma, a highly aggressive malignant salivary tumor." Treatment includes complete surgical resection and close long-term follow-up.

Papillary Cystadenoma Lymphomatosum (Warthin's Tumor) These tumors are most commonly seen in men and are often bilateral parotid lesions. They may rarely present as is similar benign parotid tumors in children."reatment to that for pleomorphic adenomas.

Malignant Neoplasms Malignant salivary neoplasms are rare in children. When present, they are often low-grade lesions, located most commonly in the parotid gland, and have a female prep ~ n d e r a n c e Diagnostic .~~ evaluation should include CT or MRI and fine-needle aspiration biopsy. Treatment is surgical, with complete tumor excision with clear margins. Invasive malignancies may require sacrifice of the facial nerve branches, with subsequent nerve grafting to

840

PART

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HEADAND NECK

restore facial muscle function. Postoperative radiation therapy is recommended for high-grade lesions.27,4*

Mucoepidermoid Carcinoma Mucoepidermoid carcinoma is the most common pediatric salivary malignancy and is most commonly low grade and located in the parotid gland. Surgery with superficial or total parotidectomy, depending on tumor extent, is usually curative.",s4 For high-grade mucoepidermoid carcinomas, or those involving the submandibular or minor salivary glands, concomitant neck dissection and adjuvant radiation therapy is recommended by many institutions.l725,53

Acinic CeN Carcinoma

.

-

Rhabdomyosarcoma of the parotid gland showing

Acinic cell carcinornas present in a similar fashion as mucoepidermoid carcinomas. They tend to be low grade, and treatment is similar to that of mucoepidermoid carcinoma (Fig. 53-7).

spindle cell sarcoma with myogenous differentiation. (Hematoxylineosin stain, x100.)

Adenoid Cystic Carcinoma

SURGICAL CONSIDERATIONS

Adenoid cystic carcinoma is a rare, high-grade salivary gland tumor. Perineural invasion may result in facial paralysis or, for submandibular gland tumors, in lingual nerve, hypoglossal nerve, and marginal mandibular branch deficits. There is a high incidence of regional nodal metastases, as well as distant metastases to the lungs, liver, and bone. Treatment includes wide surgical resection, neck dissection, and adjuvant radiation therapy.Z7

The anatomic studies by Davis and colleag~es2~ and the contribution by Beahrs and Chong2have laid the foundations for parotid surgery. Careful facial nerve dissection and preservation intraoperatively is enhanced by routine use of the facial nerve monitor." Collaboration with anesthesia colleagues regarding reversal of muscle paralysis at the onset of surgery is crucial.

Parotid Gland Rhabdomyosarcoma Rhabdomyosarcoma may present as a parotid mass. Histologic variants include undifferentiated and embryonal types (Fig. 53-8). Treatment and outcomes depend on tumor stage and may include wide local surgical resection, with radiation and chemotherapy.

•

-

Acinic cell carcinoma of the parotid gland showing

invasive proliferation. (Hematoxylin-eosin stain, x100.)

An S-shaped incision is made, beginning in the preauricular crease and extending in a curvilinear fashion to the postauricular region, followed by an inferior extension to 2 fingerbreadths below the angle of the mandible (Fig. 53-9). Skin flaps are elevated in a plane deep to the subcutaneous tissue and superficial to the investing fascia of the parotid gland. Posteriorly, skin flaps are elevated in the subplatysmal plane until the anterior border of the sternocleidomastoid is visualized. The greater auricular nerve and posterior facial vein will be identified and may need to be sacrificed to expose the posterior border of the parotid gland. To identify the main trunk of the facial nerve, which will divide the superficial and deep lobes of the gland, the earlobe must be retracted superiorly and the parotid gland is retracted anteriorly. Blunt dissection along the tragal pointer and mastoid process will allow visualization of the main trunk of the facial nerve as it emerges from the stylomastoid foramen. Meticulous dissection along the facial nerve branches in an anterior direction will elevate the superficial lobe of the parotid gland. If deep lobe dissection is required, the nerve branches must be gently retracted to gain access to the deep extent of the tumor. Careful blunt dissection, with utilization of the bipolar cautery and facial nerve monitor, will maximize excellent surgical results with minimal morbidity.l*

CHAPTER

53

Salivary Glands

841

Sup. temporal v. and a

FACIAL NERVE

FACIAL NERVE Mastiod process

-

''4Techn~quefor parotidectorny.

Submandibular Gland For submandibular gland resection, a horizontal skin incision is made in a natural skin crease approximately 2 fingerbreadths inferior to the body of the mandible. The dissection plane is carried out below the subcutaneous

tissue and platysma, to the investing fascia of the submandibular gland. Exposure should reveal the mylohyoid muscle anteriorly, the sternocleidomastoid muscle posteriorly, and the digastric muscle inferiorly. The submandibular gland fascia is entered sharply. Identification and division

842

PART

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HEADAND NECK

of the anterior facial vein, just d e e p to this fascia, will facilitate protection a n d elevation of t h e marginal mandibular branch of t h e facial nerve. T h e hypoglossal nerve will b e visualized d e e p to the digastric muscle. Anterior retraction of the mylohyoid muscle a n d downward retraction o n the submandibular gland will enable identification of the lingual nerve a n d Wharton's duct. Division of the d u c t will free the lingual nerve from the gland a n d allow for complete blunt dissection of the gland.18

COMPLICATIONS AND RESULTS Although salivary gland disorders are rare in childhood, the surgeon's knowledge of the anatomy of the major salivary glands a n d understanding of both systemic a n d neoplastic physiology is critical in performing appropriate evaluation a n d therapy. Neoplasms of the salivary glands are very rare i n children a n d are commonly benign.5"valuation a n d management should b e tailored to the specific entity, whether it b e of systemic o r neoplastic origin. A multitude of diagnostic tools are available a n d may include radiologic o r pathologic studies. Inflammatory a n d infectious disorders are often treated medically, whereas neoplastic disorders require surgical intervention. T h e surgeon must have experience with facial nerve dissection a n d must have a n understanding of the variations of facial nerve anatomy i n infants, young children, a n d adolescents. Patients a n d families must b e counseled regarding potential short- a n d long-term complications of facial nerve injury, whether temporary from nerve traction o r permanent from nerve transection o r sacrifice. Despite the rigorous demands of parotid a n d submandibular gland surgery, in experienced hands, with adequate monitoring a n d meticulous dissection a n d hemostasis, surgical results a r e e ~ c e l l e n t . ~ ~

REFERENCES 1. Al-Khafaiji BM, Nestok BR, Katz RL: Fine needle aspiration of 154 parotid masses with histologic correlation: Ten year experience at the University of Texas MD Anderson Cancer Center. Cancer 1998;84:153. 2. Beahrs OH, Chong GC: Management of the facial nerve in parotidectomy. Am J Surg 1972;124:473. 3. Bentz BG, Hughes A, Ludemann JP, MaddalozzoJ: Masses of the salivary gland region in children. Arch Otolaryngol Head Neck Surg 2000;126:1435-1439. 4. Bianchi A, Cudmore RE: Salivary gland tumors in childhood. J Pediatr Surg 1978;13:512. 5. Blei F, Isakoff M, Deb G: The response of parotid hemangiomas to the use of systemic interferon alfa-2a or corticosteroids. Arch Otolaryngol Head Neck Surg 1997; 123:841-844. 6. Bower CM, Dyleski RA. Diseases of the salivary glands. In Bluestone CD, Stool SE, Kenna M (eds): Textbook of Pediatric Otolaryngology. Philadelphia, WB Saunders, 2004, pp 1251-1267. 7. Camacho AE, Goodman ML, Eavey RD: Pathologic correlation of the unknown solid parotid mass in children. Otolaryngol Head Neck Surg 1989;101:566571.

8. Candel A, Gattuso P, Reddy V, et al: Is fine needle aspiration biopsy of salivary gland masses really necessary? Ear Nose Throat J 1993;72:485. 9. Carlson GW: The salivary glands: Embryology, anatomy, and surgical applications. Surg Clin North Am 2000;80:261-273. 10. Casselman JW, Mancuso AA: Major salivary gland masses: comparison of MR imaging and CT. Radiology 1987; 165:183. 11. Castro EB, Huvos AG, Atrong EW, Foote FW Jr: Tumors of the major salivary glands in children. Cancer 1972;29:312. 12. Centers for Disease Control: Mumps prevention. MMWR Morb Mortal Wkly Rep 1989;38:338-392, 397-400. 13. CherryJD: Mumps virus. In Feigen RD, CherryJD, Demmler GJ, Kaplan SL (eds): Textbook of Pediatric Infectious Diseases, 5th ed. Philadelphia, WB Saunders, 2004, pp 2305-2314. 14. Chetty R, Vaithilingum M, Thejpal R: Epstein-Barr virus status and the histopathological changes of parotid gland lymphoid infiltrates in HIV-positive children. Pathology 1999;31:413-417. 15. Childers EL, Furlong MA, Fanburg-SmithJC: Hemangioma of the salivary gland: A study of ten cases of a rarely biopsied/excised lesion. Ann Diagn Pathol 2002;6:339-344. 16. Corr P, Cheng P, Metrweli C: The role of ultrasound and computed tomography in the evaluation of parotid masses. Aust Radiol 1993;37:195. 17. Conley J, Tinsley PP Jr: Treatment and prognosis of mucoepidermoid carcinoma in the pediatric age group. Arch Otolaryngol 1985;111:322-324. 18. Cunningham MJ: Tumors of the head and neck. In Bluestone CD, Stool SE (eds): Atlas of Pediatric Otolaryngology. Philadelphia, WB Saunders, 1995, pp 530-570. 19. Cvetinovic M, Jovic N, Mijatovic D: Evaluation of ultrasound in the diagnosis of pathologic processes in the parotid gland. J Oral Maxillofac Surg 1991;49;147. 20. Davis RA, Anson BJ, Budinger JM, Kurth LR: Surgical anatomy of the facial nerve and parotid gland based on 350 cervicofacial halves. Surg Gynecol Obstet 1956;102:358. 21. Dean GT, Briggs K, Spence RAG: An audit of surgery of the parotid gland. Ann R Coll Surg Engl 1995;77:188. 22. Ethunandan M, Ethunandan A, Macpherson D, et al: Parotid neoplasms in children: Experience of diagnosis and management in a district general hospital. IntJ Oral Maxillofac Surg 2003;32:373-377. 23. Fageeh N, Manoukian J, Tewfik T, et al: Management of head and neck lymphatic malformations in children. J Otolaryngol 1997;26:253-258. 24. Freling NJ, Molenaar WM, Verney A. Malignant parotid tumors: Clinical use of MR imaging and histological correlation. Radiology 1992;185:691. 25. Friedman M, Levin B, Grybauskas V, et al: Malignant tumors of the major salivary glands. Otolarpgol Clin North Am 1986;19:625-636. 26. Galick R: Salivary gland neoplasms in children. Arch Otolaryngol 1969;89:878. 27. Garden AS, el-Naggar AK, Morrison WH, et al: Postoperative radiotherapy for malignant tumors of the parotid gland. Int J Radiat Oncol Biol Phys 1997;37:79. 28. Gasser RF: The early development of the parotid gland around the facial nerve branches. Anat Rec 1992;15:244. 29. Giguere CM, Bauman NM, Smith RJ: New tfeatment options for lyrnphangioma in infants and children. Ann Otol Rhino1 Laryngol2002;111:10661075. 30. Greene AK, Rogers GF, Mulliken JB: Management of parotid hemangioma in 100 children. Plast Reconstr Surg 2004;113:53-60. 31. Haberal I, Gocmen H, Samim E: Surgical management of pediatric ranula. Int J Pediatr Otorhinolaryngol 2004;68: 161-163.

CHAPTER

32. Hicks J, Flaitz C: Mucoepidermoid carcinoma of the salivary glands in children and adolescents: Assessment and proliferation of markers. Oral Oncol 2000;36:454460. 33. Ilgit ET, et al: Digital subtraction sialography techniques: Advantages and results in 107 cases. Eur J Radiol 1992;15:44. 34. Jaques DA, Krolls SO, Chambers RG: Parotid tumors in children. Am J Surg 1976;132:469-471. 35. Kobayashi T, Ochi K, Komatsuzaki Y, et al: Blanket removal of the sublingual gland for treatment of plunging ranula. Laryngoscope 2003;113:386388. 36. Koral K, Sayre J, Bhuta S, et al: Recurrent pleomorphic adenoma of the parotid gland in pediatric and adult patients: Value of multiple lesions as a diagnostic indicator. AJR Am J Roentgen01 2003;180:1171-1174. 37. Krolls SO, Trodahl JN, Boyers R: Salivary gland lesions in children. Cancer 1972;30:459. 38. Lowe LH, Stokes LS,Johnson JE, et al: Swelling at the angle of the mandible: Imaging of the pediatric parotid gland and periparotid region. Radiographics 2001;21:1211-1227. 39. McGuirt WF, Whang C, Moreland W: The role of parotid biopsy in the diagnosis of pediatric Sjogren syndrome. Arch Otolaryngol Head Neck Surg 2002;128:1279-1281. 40. Megerian CA, Maniglia AJ: Parotidectomy: A ten-year experience with fine needle aspiration and frozen section biopsy correlation. Ear Nose Throat J 1994;73:377. 41. Mendenhall WM, Morris CG, Amdur RJ, et al: Radiotherapy alone or combined with carbogen breathing for squamous cell carcinoma of the head and neck: A prospective, randomized trial. Cancer 2005;104:332-337. 42. Metry DW, Hebert AA: Benign cutaneous vascular tumors of infancy: When to worry, what to do. Arch Dermatol 2000;136:905-914. 43. Modlin JF: Current status of mumps in the United States. Infection 1975;132:106. 44. Morita Y, Sato K, Kawana M, et al: Treatment of ranulaexcision of the sublingual gland versus marsupialization. Auris Nasus Larynx 2003;30:311-314. 45. Mulliken JB, Glowacki J: Hemangiomas and vascular malformations in infants and children: A classification based on endothelial characteristics. Plast Reconstr Surg 1982;69: 412420. 46. Orvidas LJ, Kasperbauer JI,: Pediatric lymphangiomas of the head and neck. Ann Otol Rhino1 Laryngol2000;109:411-421. 47. Orvidas LJ, KasperbauerJL, Lewis JE, et al: Pediatric parotid masses. Arch Otolaryngol Head Neck Surg 2000;126:177-184. 48. Pandit RT, Park AH: Management of pediatric ranula. Otolaryngol Head Neck Surg 2002;127:115-118.

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49. Pershall KE, Koopman CF, Coultard SW: Sialadenitis in children. J Pediatr Otolaryngol 1986;11:199. 50. Peter G (ed): 1997 Red Book: Report of the Committee on Infectious Diseases, 24th ed. Elk Grove Village, IL, American Academy of Pediatrics, 1997, pp 366-369. 51. Ribeiro Kde C, Kowalski LP, Saba LM, de Camargo B: Epithelial salivary gland neoplasms in children and adolescents: A forty-four year experience. Med Pediatr Oncol 2002;39:504600. 52. Rice DH: Non-neoplastic diseases of the salivary glands. In Paparella MM, et a1 (eds): Otolaryngology. Philadelphia, WB Saunders, 1991. 53. Rogers DA, Rao BN, Bowman L, et al: Primary malignancy of the salivary gland in children. J Pediatr Surg 1994;29: 4447. 54. Schuller DE, McCabe BF: Salivary gland neoplasms in childhood. Otolaryngol Clin North Am 1977;10:39. 55. Shikani AH, Johns ME: Tumors of the major salivary glands in children. Head Neck Surg 1998;10:257. 56. Siefert G, Sobin LH: The World Health Organization's Histological classification of salivary gland tumours: A commentary on the second edition. Cancer 1992;70:379. 57. Sung MW, Lee DW, Kim DY, et al: Sclerotherapy with picibinal (OK-432) for congenital lymphatic malformation in the head and neck. Laryngoscope 2001;111:1430-1433. 58. Tabor EK, Curtin HD: MR of the salivary glands. Radiol Clin North Am 1989;379:27. 59. Variend S, O'Neill D, Arnold P: The possible significance of cytomegaloviral parotitis in infant and early childhood deaths. Arch Path01 Lab Med 1997;121:1272. 60. Venkateswaran L, Gan YJ, SixbeyJW, Santana VM: EpsteinBarr virus infection in salivary gland tumors in children and young adults. Cancer 2000;89:463-466. 61. Watanabe Y, et al: Facial nerve palsy as a complication of parotid surgery and its prevention. Acta Otolaryngol Suppl (Stockh) 1993;504:137. 62. White AK: Salivary gland diseases in infancy and childhood. J Otorhinolaryngol 1992;21:422. 63. Woods JE: Parotidectomy: Points of technique for a brief and safe operation. Am J Surg 1983;145:678. 64. Work WP: Cysts and congenital lesions of the parotid gland. Otorhinolaryngol Clin North Am 1977;10:339. 65. Work WP: Newer concepts of first branchial cleft defects. Laryngoscope 1972;82:1581. 66. Yang WT, Ahuja A, Metreweli C: Sonographic features of head and neck hemangiomas and vascular malformations: Review of 23 patients. J Ultrasound Med 1997;16:39.

Lymph Node Disorders Kurt D. Newman and Andrea A. Hayes-Jordan

GENERAL APPROACH TO ADENOPATHY An enlarging or persistent neck mass in a child is a common source of concern for parents and pediatricians and is a frequent reason for referral to a surgeon. Most cervical masses in children are either congenital lesions (i.e., thyroglossal duct or branchial cleft origin) or enlarged lymph nodes. Clinically palpable cervical lymphadenopathy is extremely common during childhood, with a reported prevalence of 28% to 55% in otherwise normal infants and children.*3,3'Although reactive hyperplasia caused by presumptive or proven infection accounts for most cases of cervical lymphadenopathy, the possibility of a malignant condition must be considered in all clinically suspicious lesions that become chronic or persist despite antibiotic therapy.19 Surgical intervention is indicated in specific infectious conditions, such as atypical mycobacterial adenitis, and may be required in inflammatory lymphadenitis that is complicated by suppuration or fistula formation or is recalcitrant to appropriate medical management. Persistent lymphadenopathy despite 2 weeks of antibiotic therapy, unilateral adenopathy involving the supraclavicular or posterior triangle of the neck, and adenopathy in the presence of an unclear diagnosis are best treated by expedient excisional biopsy to exclude the possibility of malignancy. Diagnostic imaging may be helpful in distinguishing a solid versus cystic or mixed lesion.'"

This scheme describes nodal groups as follows: level Isubmental triangle nodes; levels 11, 111, and IV-upper, middle, and lower thirds of the internal jugular chain, respectively; level V-posterior cervical triangle nodes; level VI-tracheoesophageal groove nodes; and level VIIsuperior mediastinal nodes.

ACUTE LYMPHADENITIS The most common cause of self-limiting, acute, inflammatory lymph node enlargement is a viral infection.5 Acute bilateral cervical adenopathy is most often caused by a viral respiratory tract infection or streptococcal pharyngitis, whereas unilateral cervical lymphadenitis is usually caused by a streptococcal or staphylococcal infection in 40% to 80% of cases.ZgBilateral lymphadenopathy secondary to viral infections usually resolves spontaneously. Acute suppurative lymphadenitis is typically caused by

n ,

Submandibular Superficial parotid

Retro-auricular

ANATOMY The regional lymph node groups of the head and neck are shown in Figure 541. Drainage to lymphatic basins follows predictable, anatomic routes, with the nomenclature reflecting the site of the lymph nodes. The face and oropharynx drain predominantly to the preauricular, submandibular, and submental nodes: the uosterior scalp drains to the occipital nodal group; and the mouth, tongue, tonsils, oropharynx, and nasopharynx drain to suoerficial and deeo chains of the anterior cervical nodes. Significant lymphatic collateralization exists. A classification system for grouping cervical lymph nodes has been described by Shah and associates (Fig. 542).49

chain Regional lymph node groups of the head and neck. (From Bodenstein L, Altman RP: Cervical lymphadenitis in infants and children. Semin Pediatr Surg 1994;5:134. Used with permission.) -

1

CHAPTER

*"

54

Lymph Node Disorders

845

""a,,

, . A Lymphatic node levels of the neck. Level VI (tracheoesophageal) and level VII (superior mediastinum) groups are not shown. (From Shah JP, Medina JE, Shaha AR, et al: Cervical lymph node metastasis. Curr Prob Surg 1993;30:273.Used with permission.)

bacterial infection from penicillin-resistantstaphylococci, group A streptococci, or both.3 Staphylococcus infection leading to lymphadenitis seems to occur more commonly bacteria, group B streptococci, in infants.2"aerobic and Haemophilus influenzae type B are less frequent causal organisms.8.20~47Recently, a new pattern of resistance has been identified. Community-acquired methicillin-resistant, clindamycin-sensitive Staphylococcus aureus (MRSA) has been isolated from superficial abscesses and suppurative Regardless of the causative lymphadenitis in ~hildren.29,~~ bacterial agent, the local inflammatory signs of suppurative lymphadenitis strongly suggest the diagnosis. Children typically present with unilateral, tender adenopathy that involves the submandibular or deep cervical nodes (or both) draining the oropharynx. Erythema of the overlying skin may be present. Fever, malaise, and signs of systemic illness occur to varying extents. A careful search for a primary infection in the head and neck region, including the oropharynx and middle ear, should be conducted and treated appropriately. Initial therapy for uncomplicated cervical lymphadenitis should begin with an empirical 5- to 10-day course of an oral, p-lactamase-resistant antibiotic. Most patients can be treated safely and effectively on an outpatient basis. If systemic signs of infection, including associated cellulitis, are present or if infection occurs in very young infants, intravenous antibiotics may be more clinically appropriate. Response of the infectious process should be observable within the first 72 hours of therapy. Failure to note clinical signs of improvement indicates the need for further diagnostic testing, including ultrasonography or fine-needle aspiration (FNA) of the involved m a s s . T h e determination of the causative organism or organisms by aspirate culture allows for appropriate,

Although not necessary in the vast majority of cases, this CT scan demonstrates a deep cervical abscess from suppurative lymphadenitis. This 2-year-old child presented with diffuse unilateral cervical edema secondary to abscess, located posterior to the left carotid sheath. -

4

organism-specific antimicrobial therapy; however, FNA may require sedation or anesthesia to be performed safely in children. The aspirate should be sent for aerobic, anaerobic, and acid-fast bacterial stain and culture. Treatment should be based on aspirate results. If the aspirate reveals MRSA, clindamycin treatment should be ~ s e d . 2 ~ 8 ~ ~ Ultrasonography may help to differentiate between solid and cystic masses in the neck. In addition, identification of fluid associated with enlarged, inflammatory nodes may assist in determining the necessity for operative drainage. Other diagnostic methods such as computed tomography (CT) and magnetic resonance imagng (MRI) for suspected adenitis are unnecessary in most cases (Fig. 543). The enlarged lymph node will generally respond to appropriate antimicrobial therapy with prompt resolution of the lymphadenitis. The development of fluctuance caused by suppuration of the involved nodes can be effectively treated with repeated aspiration and antibiotics7 or more definitively with open incision and drainage. In a retrospective study of 110 children, 95 had 107 cervical infectious sites drained surgically. The remaining 15 improved with medical therapy. CT accurately predicted operative findings in only 81 ('76%)of cases. Of the 26 cases with a discrepancy between CT and operative findings, 18 showed false-positive findings in which the CT scan showed an abscess but only cellulitis was found at operation.l6

ATYPICAL MYCOBACTERIALADENITIS The genus Mycobacterium is characterized on light microscopy to be bacilli distinguished by their dense

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lipid capsules. The lipid capsules resist decolorization by acid alcohol after staining and thus are termed acid-fast bacilli.1 Atypical mycobacteria are now the most common causative agents in mycobacterial lymphadenitis. The more common atypical mycobacteria include M. auiumintracellulare, M. scrojulaceum, M.fortuitum, and M. che1onei.l In contrast to tuberculous adenitis, atypical (or nontuberculous) mycobacterial adenitis is generally considered a local infectious process, without systemic involvement in immunocompetent hosts.35Disseminated disease is more commonly observed in patients with underlying acquired or congenital immunodeficiency states. Atypical mycobacterial adenitis is not contagious, and the portal of entry in otherwise healthy children is presumed to be the oropharynx.2 Atypical mycobacterial adenitis usually occurs in young children between 1 and 5 years of age. The common clinical presentation is focal, unilateral involvement of the jugulodigastric, preauricular, or submandibular nodal group. In contrast to acute suppurative lymphadenitis, the involved nodal group with atypical mycobacterial disease is minimally tender, firm, and rubbery to palpation, is well circumscribed, and may adhere to underlying structures. Although remarkably nontender, these lesions occasionally present as a draining sinus tract.36 Signs of systemic illness or inflammation are usually minimal or nonexistent. Chest radiographs are typically normal. Skin testing with tuberculin purified protein derivative (PPD) or old tuberculin (tine) in patients with atypical mycobacterial adenitis may yield an intermediate reaction resulting from cross-reactivity.58 Specific, atypical mycobacterial antigens for skin testing have been developedj.26 but are not widely available for clinical use. An in-vitro whole-blood assay measuring increased lymphocyte production of interferon-y in patients with atypical mycobacterial adenitis has also been described.l5 FNA may yield acid-fast bacteria and provide a definitive diagnosis by aspirate culture. However, the preoperative clinical distinction between tuberculous and nontuberculous adenitis often remains difficult. Cervical lymphadenitis arising from infection with tuberculous and atypical mycobacteria has been reported but is extremely infrequent.35 Unlike tuberculous adenitis, atypical mycobacterial adenitis generally does not respond to chemotherapy. The treatment of choice is complete surgical excision with primary wound closure. In a literature review of the surgical treatment of atypical mycobacterial cervicofacial adenitis in children, excision, incision and drainage, curettage, and needle aspiration were compared among 16 studies. The cure rates were 92%, lo%, 86%, and 41%, respectively. Also, of 510 patients who underwent surgical excision, 11 transient and 1 permanent seventh nerve palsies were observed. Thirteen patients had persistent drainage after excision, and there were seven recurrences beneath the incision site.18At least 15 of 70 patients who underwent incision and drainage suffered draining sinuses. Of the 35 patients from four different studies who underwent curettage as treatment of atypical mycobacterial adenitis, 2 experienced delayed healing, in 1 a second curettage was necessary, and there was 1 recurrence.18 Incision and drainage alone should be avoided. Elliptical excision of the overlying skin, subcutaneous

tissue, and the involved node is required; formal lymph node dissection is not necessary. Curettage is recommended only if surgical excision is not possible. A nerve stimulator may be helpful for lesions at the angle of the mandible to avoid injury to branches of the facial nerve. Antituberculous chemotherapy or patient isolation is not required for confirmed cases of atypical mycobacterial adenitis treated with adequate local excision.

Tuberculous lymphadenitis, or scrofula, is almost exclusively caused by M. tuberculosis in developed countries (Fig. 54-4). Before control of bovine tuberculosis, the predominant cause of tuberculous adenitis was M. bouis. Occasional cases of M. bouis are observed in patients from underdeveloped regions in which consumption of contaminated raw milk occurs. Patients proven to have human tuberculous adenitis often report previous exposure to a known carrier of tuberculosis,48 but most patients have no evidence of active disease on a chest r a d i ~ g r a p hTuberculous .~~ adenopathy is generally associated with other clinical symptoms and signs, including a strongly positive tuberculin PPD skin test and hilar adenopathy or apical calcification on a chest radiograph.56 One study found a 92% sensitivity when two of three of the following criteria were fulfilled: positive PPD skin test, abnormal chest radiograph, or contact with someone Tuberculous with known infectious t~berculosis.4~ adenitis is therefore currently considered to be a local manifestation of a systemic disease and not an initial, primary focus of tuberculous infection.5J0 Clinically, patients

Cervical tuberculous adenitis (ear at right of photograph). Posterior cervical lymph nodes in a 7-year-old boy with a family history of contact and a positive PPD skin test. Medical management of tuberculosis with two-drug therapy for 7 months led to complete resolution. (From Jones PG: Glands of the neck. In Welch KJ, et a1 (eds): Pediatric Surgery, 4th ed. St. Louis, Mosby-Year Book, 1986. Used with permission.)

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with tuberculous adenitis are usually older children and adolescents who present with nonsuppurative lymphadenitis,31 which may be bilateral. A retrospective review of 24 immunocompetent children with tuberculous lymphadenitis showed that no patient had bilateral disease and the submandibular (29%) and the anterior cervical (71%) sites were the only areas of lymph node involvement.44 However, posterior triangle nodal involvement does occur.34 The diagnosis of tuberculous adenitis can be made in the setting of an appropriate history, suspicious adenopathy associated with a strongly positive tuberculin PPD skin test, and positive acid-fast bacteria on stain or culture of nodal tissue. Diagnostic confirmation may be aided by FNA with aspirate culture and cytologic e ~ a m i n a t i o n . ' ~ , ~ ~ Rapid diagnosis of tuberculous adenitis by DNA amplification of nodal material using polymerase chain reaction (PCR) has been reported.42 In contrast, a negative tuberculin PPD test essentially excludes the diagnosis of tuberculous adenitis. If a diagnostic dilemma persists, Cervical lymph node involvement in a patient with excisional biopsy in the operating room with the patient cat-scratch disease. The organism responsible for this infection is the under general anesthesia is warranted. Incisional biopsy pleomorphic, gram-negative bacillus Bartonella henselae (formerly or incision and drainage should be avoided to prevent Rochalimaea). (From Jones PG: Glands of the neck. In Welch KJ, et al development of chronic, draining sinus t r a ~ t s . ~ , ~ ~ , ~ ~ [eds]: Pediatric Surgery, 4th ed. St. Louis, Mosby-Year Book, 1986. Fistula and cheloid formation can be seen in up to 100% Used with permission.) of patients who underwent incision and drainage of tuberculous infected lymph nodes.44 Tuberculous adenitis generally responds to medical Initial infection occurs at a portal of entry in the skin, management that consists of multiple-agent chemotherapy. such as a scratch or bite. Papule formation may be If tuberculous infection is directly observed, the World observed at the site of inoculation in 3 to 5 days, with Health Organization recommends directly observed development of subacute lymphadenopathy at regional short-course therapy, which includes isoniazid, rifampin, nodal drainage basins within 1 to 2 weeks. Early systemic and pyrazinamide for the first 2 months, followed by symptoms of fever, malaise, myalgia, and anorexia are isoniazid and rifampin for an additional 4 months60 commonly reported. Although most cases involve the Although antituberculous chemotherapy remains essenlymph node of the limbs, approximately 25% of cases tial, the role of complete surgical excision of involved involve the cervical lymph nodes." Diagnosis based on a nodes is more controversial.6J2 Complete excision of history of exposure to cats, presence of a site of inoculainvolved nodes is prudent when biopsy is required for tion (which may be healed by the time lymphadenopathy diagnosis; when a chronic, draining sinus tract evolves develops), and regional lymphadenopathy. Identification during medical treatment; or when optimal medical of Bartonella organisms from involved lymph nodes by management fails. Warthin-Starry silver impregnation stain has traditionally been used, but recently this stain has been found to be PCR for unreliable and found to lack species ~pecificity.~~ CAT-SCRATCH DISEASE B. henselae using paraffin sections from lymph nodes or other tissue is more reliable and accurate.40 Because of Cat-scratch disease is a common cause of lymphadenitis its usual benign, self-limiting course, lymphadenopathy in children, with an estimated incidence in the United States resolves in most cases within 6 to 8 weeks without specific of 9.3 per 100,000 ambulatory pediatric and adult treatment.39 Suppuration is unusual. Excisional biopsy is patientsAperyear.2' The highest ~g~-specific incidence is generally unnecessary but may be warranted if a draining among children younger than 10 years of age.32 Current sinus tract develops or if the diagnosis is uncertain and microbiologic and PCR-directed DNA analysis demonthe potential for malignancy cannot be excluded. strates that the pleomorphic, gram-negative bacillus Bartonella henselae (formerly Rochalimaea) is the causative ~ b s cases t can be organism of cat-sciatch dikea~e.~J~222 directly related to contact with a cat, and the usual site MISCELLANEOUS LESIONS of inoculation is a limb. Subseauent adenitis occurs at Various other infectious and inflammatory conditions regional lymphatic drainage basins (inguinal, axillary, can produce lymphadenopathy in infants and children. epitrochlear nodes) .I1 Similarly, cervical lymphadenopaMost patients with these disorders do not require surgithy is observed with scratches in the head and neck cal management or, in particular, excisional biopsy of the region (Fig. 545). Although the primary manifestation lesions. A systematic approach to evaluation of these of B. henselae infection is lymphadenopathy, some series patients, including a thorough history, physical examinareport up to 25% of cases result in severe systemic tion, and directed diagnostic tests, generally leads to the illnesses.30 ,

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correct diagnosis. Surgical management of these lesions should be directed to patients who present diagnostic dilemmas, have nodal disease in suspicious areas (supraclavicular or posterior cervical triangle), or have persistent adenopathy despite adequate medical therapy. Lymphadenopathies caused by infectious agents include toxoplasmosis (caused by Toxo@lasmosisgondii), tularemia (caused by Francisella tularensis) , and infectious mononucleosis (caused by Epstein-Barr virus) .28,53,57 Infection with Actinomyces israelii in the head and neck may lead to cervicofacial actinomycosis that is characterized by a woody, indurated cervical mass and development of chronic, draining fistulas. Direct involvement of the lymph nodes is uncommon, but the induration can make clinical differentiation d i f f i c u l t . ~ n f e c t i o nwith human immunodeficiency virus can produce generalized lymphadenopathy in infants and children.17 Other less frequent disorders that present as lymphadenopathies include Kawasaki disease or mucocutaneous lymph node syndrome. Kawasaki disease is a febrile disorder of childhood that is characterized in part by the abrupt onset of erythematous changes in the oropharyngeal mucosa; acute vasculitis; and extensive, nonsuppurative, nontender cervical adenopathy.Z4 Histiocytic necrotizing lymphadenitis, or Kikuchi's disease, may present as cervical lymphadenopathy that resolves spontaneously. This disease can be clinically confused with malignant lymphadenopathy, and the patients often appropriately undergo diagnostic excisional lymph .~~ disease, node biopsy for definitive d i a g n o s i ~Castleman's or giant lymph node hyperplasia, may also occasionally present as a solitary, enlarged cervical node.45 These disorders do not require lymph node biopsy or excision. Lymphomas are one of the more common malignant conditions in children. They may present as primary neck adenopathy that does not resolve with antibiotics or is enlarging. Patients with congenital or acquired immunodeficiency states, including human immunodeficiency virus infection, are at greater risk for developing malignant lymphoproliferative conditions.17 The surgical management of Hodgkin's disease and non-Hodgkin's lymphoma is discussed in detail in Chapter 35. It is important to reiterate that although most neck masses in children are benign, a high index of suspicion regarding any neck mass that persists despite otherwise appropriate therapy must be maintained. Such masses must be assumed to be malignant until proven otherwise by excisional biopsy. Although lymphoma is the most common malignant disorder manifested by cervical adenopathy, neuroblastoma and thyroid carcinoma are other childhood cancers that can also present as enlarged cervical lymph nodes. In neuroblastoma, cervical adenopathy is often bilateral. These patients have stage 4 disease, and the abdominal adrenal primary may not be palpable. After imaging of the chest, abdomen, and pelvis, if an abdominal primary tumor is detected, excisional biopsy of cervical lymph nodes may be done for initial diagnosis of stage 4 neuroblastoma (see Chapter 28). A child with metastatic thyroid carcinoma may present with unilateral cervical lymph node enlargement that should not be mistaken for ectopic thyroid gland. If thorough neck

examination does not reveal a thyroid nodule, and a history of neck irradiation or other high-risk factors is obtained, thyroid ultrasound should be included in the evaluation of neck adenopathy.

REFERENCES 1. Albright JT, Pransky SM: Nontuberculous mycobacterial infections of the head and neck. Pediatr Clin North Am 2003;50:503-514. 2. Altman RP, Margileth AM: Cervical lymphadenopathy from atypical mycobacteria: Diagnosis and surgical treatment. J Pediatr Surg 1975;10:419. 3. Barton LL, Feigin RD: Childhood cervical lymphadenitis: A reappraisal. J Pediatr 1974;84:846. 4. Bergmans AM, Groothedde JW, Schellekens JF, et al: Etiology of cat-scratch disease: Comparison of polymerase chain reaction detection of Bartonella (formerly Rochalimaea) and Ajpia felis DNA with serology and skin tests. J Infect Dis 1995;171:916. 5. Bodenstein L, Altman RP: Cervical lymphadenitis in infants and children. Semin Pediatr Surg 1994;3:134. 6. British Thoracic Society Research Committee: Short course chemotherapy for tuberculosis of lymph nodes: A controlled trial. BMJ 1985;290:1106. 7. Brodsky L, Belles W, Broday A, et al: Needle aspiration of neck masses in infants and children. Clin Pediatr 1992; 31:71. 8. Brook I: Aerobic and anaerobic bacteriology of cervical adenitis in children. Clin Pediatr 1980;19:693. 9. Burden P: Actinomycosis.J Infect 1989;19:95. 10. Cantrell RW, Jensen JH, Reid D: Diagnosis and management of tuberculous cervical adenitis. Arch Otolaryngol 1975;101:53. 11. Carithers HA: Cat-scratch disease: An overview based on the study of 1,200 patients. Am J Dis Child 1985;139:1124. 12. Castro DJ, Hoover L, Zuckerbraun L: Cervical mycobacterial lymphadenitis: Medical vs. surgical management. Arch Otolaryngol 1985;111:816. 13. Dalton MJ, Robinson LE, Cooper J, et al: Use of Bnrtonclla antigens for serologic diagnosis of cat-scratch disease at a national referral center. Arch Intern Med 1995;155:1670. 14. Dasgupta A, Ghosh RN, Poddar AK, et al: Fine needle aspiration of cervical lymphadenopathy with special reference to tuberculosis. J Indian Med Assoc 1994;92:44. 15. Davidson PM, Creati K, Wood PR, et al: Lymphocyte production of gamma-interferon as a test for non-tuberculous mycobacterial lymphadenitis in childhood. Eur J Pediatr 1993;152:31. 16. Elden LM, Grundfast KM, Vezina G: Accuracy and usefulness of radiographic assessment of cervical neck infections in children. J Otolaryngol 2001;30:82. 17. Falloon J, Eddy J, Weinter K, Pizzo PA: Human immunodeficiency virus infection in children. J Pediatr 1989; 114:l. 18. Fergusson JAE, Simpson E: Surgical treatment of atypical mycobacterial cervicofacial adenitis in children. Aust NZ J Surg 1999;69:426. 19. Filston HC: Common lumps and bumps of the head and neck in infants and children. Pediatr Ann 1989;18:180. 20. Fishaut JM, Mokrohisky ST: Cervical lymphadenitis caused by Haemophilus influenzae type B. Am J Dis Child 1977; 131:925. 21. Fulcher AS: Cervical lymphadenopathy due to Kikuchi disease: US and CT appearance. J Comput Assist Tomogr 1993:17:131.

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22. Goral S, Anderson B, Hager C, et al: Detection of Rochalirnaea henselae DNA by polymerase chain reaction from suppurative nodes of children with cat-scratch disease. Pediatr Infect Dis J 1994;13:994. 23. Hartzog LW: Prevalence of lymphadenopathy of the head and neck in infants and children. Clin Pediatr 1983;22:485. 24. Hicks RV, Melish ME: Kawasaki syndrome. Pediatr Clin North Am 1986;33:1151. 25. Hieber JP, Davis AT: Staphylococcal cervical adenitis in young infants. Pediatrics 1976;57:424. 26. Huebner RE, Schein MF, Cauthern GM, et al: Usefulness of skin testing with mycobacterial antigens in children with cervical lymphadenopathy. Pediatr Infect DisJ 1992;11:450. 27. Jackson LA, Perkins BA, Wenger JD: Cat-scratch disease in the United States: An analysis of three national databases. Am J Public Health 1993;83:1707. 28. Jacobs RF, Condrey YM, Yamauchi T Tularemia in adults and children: A changing presentation. Pediatrics 1985;76:818. 29. Johnigan RH, Periera KD, Poole MD: Community-acquired methicillin-resistant Staphylococcus aureus in children and adolescents: Changing trends. Arch Otolaryngol Head Neck Surg 2003;129: 1049. 30. Kaplan S, Rawlings J, Paddock C, et al: Cat-scratch disease in children. MMWR 2002;51:212. 31. Lai KK, Stottmeier KD, Sherman IH, McCabe WR: Mycobacterial cervical lymphadenopathy: Relation of etiologic agents to age. JAMA 1984;251:1286. 32. Larsson LO, Bentzon MW, BergKelly K, Mellander L: Palpable lymph nodes of the neck in Swedish school children. Acta Paediatr 1994;83:1091. 53. Lau SK, Wei WI, Kwan S, Yew WW: Combined use of fineneedle aspiration cytologic examination and tuberculin skin test in the diagnosis of cervical tuberculous lymphadenitis. Arch Otolaryngol Head Neck Surg 1991;117:87. 34. Leung AK, Robson WL: Childhood cervical lymphadenopathy. J Pediatr Health Care 2004;18:3. 35. Lincoln EM, Gilbert LA: Disease in children due to mycobacteria other than Mycobacten'um tubmculosis. Am Rev Respir Dis 1972;105:683. 36. Mair IWS, Elverland HH: Cervical mycobacterial infection. J Laryngol 1975;89:933. 37. Margileth AW: Management of nontuberculous (atypical) mycobacterial infections in children and adolescents. Pediatr Infect Dis 1985;4:119. 38. Margileth AM: Cat-scratch disease: No longer a diagnostic dilemma. Semin Vet Med Surg 1991;6:199. 39. Margileth AM: Antibiotic therapy for cat-scratch disease: Clinical study of therapeutic outcome in 268 patients and a review of the literature. Pediatr Infect Dis J 1992;11:474. 40. Margolis B, Kuzu I, Herrmann M, et al: Rapid polymerase chain reaction-based confirmation of cat-scratch disease and Bartonella henselae infection. Arch Path01 Lab Med 2003;127:706-710. 41. Martinez-Aguilar G, Hammerman WA, Mason EO Jr, Kaplan SL: Clindamycin treatment of invasive infections

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caused by community-acquired methicillin-resistant and methicillin-susceptible Staphylococcus aureus in children. Pediatr Infect Dis J 2003;22:593. 42. Narita M, Shibata M, Togashi T, Kobayashi H: Polymerase chain reaction for detection of Mycobacterium tuberculosis. Acta Pediatr 1992;81:141. 43. Ord RJ, Matz GJ: Tuberculosis cervical lymphadenitis. Arch Otolaryngol 1974;99:327. 44. Panagiotis S, Maltezou HC, Hantzakos A, et al: Mycobacterial cervical lymphadenitis in children: Clinical and laboratory factors of importance for differential diagnosis. Scand J Infect Dis 2001;33:362. 45. Penfold CN, Cottrell BJ, Talbot R: Neonatal giant lymph node hyperplasia (Castleman's disease) presenting in the head and neck. Br J Oral Maxillofac Surg 1991;29:110. 46. Piersimoni C, Felici L, Giorgi P, et al: Mixed mycobacterial infection of the cervical lymph nodes. Pediatr Infect Dis 1991;10:544. 47. Rathmore MH: Group B streptococcal cellulitis and adenitis concurrent with meningitis. Clin Pediatr 1989;28:411. 48. Schuit KE, Powell DA: Mycobacterial lymphadenitis in childhood. Am J Dis Child 1978;132:675. 49. Shah JP, Mdina JE, Shaha AR, et al: Cervical lymph node metastasis. Curr Prob Surg 1993;30:273. 50. Sigalet D, Lees G, Fanning A: Atypical tuberculosis in the pediatric patient: Implications for the pediatric surgeon. J Pediatr Surg 1992;27:1381. 51. Siu KF, Ng A, Wong J: Tuberculous lymphadenopathy: A review of results of surgical treatment. Aust NZ J Surg 1983;53:253. 52. Speck WT: Tuberculosis. In Behrman RE, et a1 (eds): Nelson Textbook of Pediatrics, 14th ed. Philadelphia, WB Saunders, 1992. 53. Sumaya CV, EnchY Epstein-Ban-virus infectious mononucleosis in children: I. Clinical and laboratory findings. Pediatrics 1985;75:1003. 54. Taha AM, Davidson PT, Bailey WC: Surgical treatment of atypical mycobacterial lymphadenitis in children. Pediatr Infect Dis 1985;4:664. 55. Talmi YP, Cohen AH, Finkelstein Y, et al: Mycobacterium tuberculosis cervical adenitis: Diagnosis and management. Clin Pediatr 1989;28:408. 56. Telander RL, Filston HC: Review of head and neck lesions in infancy and childhood. Surg Clin North Am 1992; 72:1429. 57. Thomaidis T, Anastassea-Vlachou K, MandalenakiLambrou C, et al: Chronic lymphoglandular enlargement and toxoplasmosis in children. Arch Dis Child 1977;52:403. 58. Tomblin JL, Roberts FJ: Tuberculous cervical lymphadenitis. Can Med Assoc J 1979;121:324. 59. Wear DJ, Margileth AM, Hadfield TL, et al: Cat-scratch disease: A bacterial infection. Science 1983;221:1403. 60. World Health Organization: Global Tuberculosis Program: Global Tuberculosis Control. WHO report 1997, publication WHO/TB/225. Geneva, World Health Organization, 1997.

Surgical Diseases of the Thyroid andpParathyroidGlands Michael A. Skinner

Diseases of the thyroid or parathyroid gland are uncommon in the pediatric age group. In one population-based study of school-aged children in the United States, thyroid disease prevalence was 36.7 per 1000 individuals.36 Diffuse gland hypertrophy (goiter) was the most common diagnosis, occurring in about half of cases, and thyroiditis was the second most common abnormality. Thyroid nodules and thyroid hormone level disorders were less common, and malignant neoplasms were exceedingly rare; only two cases of papillary thyroid carcinoma were found in this population of nearly 5000 children observed clinically for 3 years. Surgical evaluation or treatment of thyroid disease may be necessary in patients with benign or malignant neoplasia or in children exhibiting a physiologic abnormality, such as increased hormone secretion.

EMBRYOLOGY The thyroid gland is the first endocrine organ to mature in embryologic development, arising at about 24 days' gestation as an outpouching of the embryonic alimentary tract at the primitive pharyngeal floor. As the embryo enlarges, the developing thyroid gland descends into the neck from the base of the tongue, passing ventrally to the hyoid bone and the laryngeal cartilages, and maintaining a tubular connection to the tongue known as the thyroglossal duct. The opening of this duct into the base of the tongue is called the foramen cecum. Typically, the thyroglossal duct changes from a hollow structure to a solid diverticulum; the original opening into the oropharynx usually remains as a blind pit at the base of the tongue. The thyroid gland has usually reached its final location in the neck by 7 weeks' gestation. Accessory thyroid tissue originating from remnants of the thyroglossal duct may appear in the tongue or anywhere along the course of caudal migration during development. Of occasional surgical importance, the gland fails to descend altogether, resulting in a lingual thyroid. Incomplete descent results in the gland appearing high in the neck or near the hyoid bone.

Histologically, in about the tenth week of gestation, the primordial thyroid cells begin to form discrete cords that further differentiate to form small cellular groups. Colloid begins to form, and thyroxine can be demonstrated in the embryo in about the 11th week. Early in the development of the thyroid gland, the ventral portions of the fourth pharyngeal pouches develop into the ultimobranchial bodies. These structures contain neural crest cells that fuse with the embryonic thyroid gland to form the parafollicular cells or C cells. The parathyroid glands derive from the third and fourth pharyngeal pouches beginning in about the fifth week of gestation. During the sixth week of development, the parathyroid glands associated with the third pair of pharyngeal pouches migrate caudally with the thymic primordium, finally coming to rest on the dorsal surface of the thyroid gland low in the neck. The parathyroid glands arising from the fourth pharyngeal pouches also descend in the neck, ultimately coming to rest at a position superior to the glands derived from the third pouches. Functioning chief cells are active during fetal development to assist in regulating calcium metabolism.

PHYSIOLOGY Production of thyroid hormone occurs in the thyroid gland at the interface between the follicular cell and the thyroglobulin or colloid. The initial step in thyroid synthesis is the iodination of tyrosine molecules to form either monoiodotyrosine, if there is one iodine molecule attached, or diiodotyrosine, if two iodine molecules are bound. These iodinated tyrosine molecules are then coupled to form the definitive thyroid hormones triiodothyronine (T3) and thyroxine (T4).If monoiodotyrosine is attached to diiodotyrosine, then T3 results; two diiodotyrosines bound together constitute a Tq molecule. The thyroid gland secretes primarily T4;approximately 80% of the Tg in the circulation represents metabolized T4,which has been partially deiodinated in the liver, kidney, or other peripheral tissues. In the circulation, most

CHAPTER

55

of the thyroid hormones are protein bound to increase their solubility. The most abundant hormone carrier is thyroid-binding globulin (TBG); other carriers include prealbumin and albumin. Because the protein-bound thyroid hormone is physiologically inactive, the plasma levels of these proteins must be considered when evaluating patients-for abnormalities of thyroid function. Whereas T4 is nearly 50-fold more concentrated in the plasma than T,, the latter moiety binds much more avidly to the thyroid receptor and therefore accounts for most effect of thvroid hormone. of the ~hvsio1og.i~ The produczon and secretion of T, and T4by the thyroid gland is chiefly controlled by thyroid-stimulating hormone (TSH). his protein is secreted by the anterior pituitary gland, principally in response to thyrotropinreleasing hormone (TRH), which is secreted by the hv~othalamus. Under the influence of TSH. thvroid foli l licular cells extend pseudopods into the colloid'to encircle the thyroglobulin and form vesicles that then fuse with protease-containing lysosomes. The thyroglobulin is then subjected to hydrolysis and proteolysis to release free thyroxine into the circulation. L

Surgical Diseases of the Thyroid and Parathyroid Glands

851

in the serial evaluation of nodules managed nonoperatively. Radionuclide scintigraphy is another commonly used test. The three nuclides usually available for diagnoitic imaging include iodine-123 (lt31), iodine-131 (1311), and technetium-99m (9hTc). The radioiodines are most effective in detecting ectopic thyroid tissue or metastatic thyroid carcinoma, whereas g9mTc-pertechnetateis thought by some radiologists to enable superior imaging of thyroid gland nodules or tumors.

,

NON-NEOPLASTIC THYROID CONDITIONS The evaluation of a child with thyroid disease should begin with a physical examination of the neck to assess the size and consistency of the gland. Diffuse enlargement makes the diagnosis of simple colloid goiter more likely; or if the child is hyperthyroid, Graves' disease should be suspected. Chronic iymphocytic (Hashimoto's) thyroiditis is classically associated with a gland that feels granular or pebbly. Firmness in the gland suggests an infiltrative process, whereas a very hard gland is more suggestive of neoplasia. Tenderness in the thyroid gland is most commonly associated with an acute inflammatory process. Finally, the presence of enlarged neck lymph nodes should be noted; thyroid carcinoma may be associated with local metastases before the primary tumor can be palpated. Laboratory tests are essential to assess for altered thyroid function. The TSH is elevated in hypothyroid states. .. The plasma free T4 level is an accurate measure of the biologcally active hormone, because it is generally unaffected by the amount of protein binding in the circulation. Conversely, when plasma total T3 and T4 are measured, an evaluation of TBG may be necessary to gauge the level of biologically active (unbound) hormone. Plasma levels of TBG are altered in a number of conditions, affecting the level of total thyroxine. In particular, TBG is increased in the neonatal period and decreased in the presence of exogenous glucocorticoids, androgens, and anabolic corticosteroids. Other medications that affect thyroxine metabolism include phenytoin and phenobarbital, which induce hepatic degradation of T4 and decrease hormone binding to TBG. Finally, there exist rare conditions in which the TBG level is congenitally altered. Several radiologic modalities are available to assist in imaging the thyroid gland. Ultrasonography is increasingly used to assess for thyroid cysts and in the evaluation of multinodular glands. This modality is especially useful

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d

~

Disorders of hypothyroidism are rarely treated surgically and may result from a defect anywhere in the hypothalamicpituitary-thyroid axis. In rare cases, a hypothyroid state mav be seen in conditions of thvroid hormone unreswonsiviness, such as when there is a defect in the thiroid receptor gene; in such cases, the plasma thyroxine level is often elevated. The most common cause of hypothyroidism diagnosed in neonatal screening programs is thyroid gland dysgenesis, accounting for approximately 90% of these patients. In about a third of these infants, no thyroid tissue is seen on radionuclide scanning; in the rest of the patients, a rudimentary gland may be found in an ectopic location, such as at theubase of the tongue. Children dth complete thyroid agenesis are often asymptomatic at birth, owing to the transplacental passage of maternal thyroid hormone through development. In some cases, ectopically located thyroid tissue may supply a sufficient amount of thyroxine .for years or the ditinutive gland may fail in childhood. Such conditions may come to clinical attention with the discovery of a sublingual or midline neck mass, and surgeons should be mindful of this possibility when evaluating children with neck masses. Consideration should be given to performing radionuclide thyroid scanning before removing any unusual neck mass to ensure that the functioning thyroid tissue is not accidentally resected.

Goiter and Thyroiditis A goiter is found in about 3% of the population when children are specifically surveyed for abnormalities of the thyroid gland." Goiters may be classified as either diffusely enlarged or nodular, and they may be associated with normal hormone secretion or thyrotoxicosis. The differential diagnosis of diffuse thyroid enlargement is listed in Table 55-1. Physiologically, diffuse goiters may be related to autoimmune diseases or as a response to a nonautoimmune inflammatory condition, or the enlargement may be a compensation for some defect in hormone production. Most children with goiters are euthyroid, and surgical resection is rarely indicated. . In a population-based study of over 5000 Croatian schoolchildren, thyromegaly was found in 2.78% of the subjects.19The causes of thyroid enlargement in this population are presented in Table 55-2. As in other populations with adequate dietary iodine intake, most of these patients had simple colloid goiter, also frequently called

~

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Autoimmune Mediated Chronic lymphocytic (Hashimoto's) thyroiditis Graves' disease Simple colloid goiter

Compensatory Iodine deficiency Medications Goitrogens Hormone or receptor defect

Inflammatory Conditions Acute suppurative thyroiditis Subacute thyroiditis

adolescent goiter or nontoxic goiter. The diagnosis is established after normal levels of TSH and thyroid hormone are documented and when the diffuse nature of the goiter is documented scintigraphically or by ultrasound. The natural history of colloid goiter is not well known, but in one study in which adolescents with the condition were reevaluated some 20 years later, nearly 60% of the glands were found to be normal in size." The spontaneous rate of colloid goiter resolution was not significantly different than the response rate in children treated with exogenous thyroid hormone. Thus, simple colloid goiters should generally not undergo any specific treatment. In rare cases, surgical resection of the gland may be indicated if there are symptoms related to the size of the goiter, if there is a suspicion of neoplasia, or for cosmetic reasons. Chronic lymphocytic thyroiditis, also known as Hashimoto's thyroiditis, is another common cause of diffusely enlarged thyroid glands in children. This condition occurs most commonly in adolescent females and is part of the spectrum of autoimmune thyroid disorders. Indeed, the condition is associated with the presence of other autoimmune disorders such as juvenile rheumatoid arthritis, Addison's disease, and type 1 diabetes mellitus. Patients are usually euthyroid and slowly progress to become hypothyroid. Approximately 10% of these patients are

Diagnosis Simple goiter Chronic lymphocytic thyroiditis Graves' disease Benign adenoma Cyst Total

Frequency (%) 2.3 0.35 0.07 0.04 0.02 2.78

Adapted from Jaksic J, Dumic M, Filipovic B, et al: Thyroid disease in a school population with thyromegaly. Arch Dis Child 1994;70:103-103.

hyperthyroid; this condition has been termed hashitoxicosis. Patients with chronic lymphocytic thyroiditis are characterized by high titers of the circulating antithyroglobulin and antimicrosomal autoantibodies, which are presumably responsible for the B-lymphocytic infiltrate found in the thyroid gland on histologic evaluation. Children with chronic lymphocytic thyroiditis generally come to clinical evaluation because of thyroid gland enlargement. The gland is generally pebbly or granular and may be mildly tender, and the diagnosis may be established by the discovery of high-titer antithyroid antibodies in association with the proper clinical and laboratory circumstances. Plasma thyroid hormone levels are generally not very useful, but the TSH level may be elevated in 70% of patients. Thyroid ultrasound demonstrates diffuse hypoechogenicity, and scintigraphy shows a patchy uptake of the tracer. In rare cases, fine-needle aspiration (FNA) of the gland may be needed to confirm the diagnosis if autoantibodies cannot be detected. The management of chronic lymphocytic thyroiditis is usually expectant; as many as a third of adolescent patients with the condition will resolve spontaneously, with normalization of gland size and disappearance of the antithyroid antibodies. Administration of thyroid hormone to euthyroid patients has not been shown to be useful in reducing the size of the goiter and is thus probably not indicated.39 Thyroid function studies should be obtained every 6 ~nurlths,and exogenous hormone should be administered if hypothyroidism develops. Subacute (de Quervain's) thyroiditis is caused by a viral infection and is very rarely seen in children. Physical findings include tender, painful swelling of the thyroid gland. Usually, there is mild thyrotoxicosis owing to injury to the thyroid follicles with leakage of thyroid hormone into the circulation. Radioactive iodine uptake is decreased, as a result of thyroid follicular cell dysfunction; this finding distinguishes subacute thyroiditis from Graves' disease. Histologically, granulomas and epithelioid cells may be seen. Treatment is symptomatic and generally consists of nonsteroidal anti-inflammatory agents or corticosteroids. The disease usually lasts 2 to 9 months, and complete recovery may be expected. Acute suppurative thyroiditis is caused by a bacterial infection of the gland, and the patient may have evidence of sepsis, with an acutely inflamed thyroid gland. Patients are usually euthyroid. The offending organisms are usually staphylococci or mixed aerobic and anaerobic flora. There may be a congenital pharyngeal sinus tract predisposing to infection. Treatment consists of antibiotics; if an abscess develops, incision and drainage may be necessary. The thyroid gland may be expected to recover completely.

Hyperthyroidism With rare exceptions, hyperthyroidism of childhood is caused by Graves' disease, which is also termed dqfuse toxic goiter Other possible causes of this condition are listed in Table 55-3. In these patients, the onset of the condition may be delayed until 2 to 3 weeks after birth.

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Graves' disease (toxic diffuse goiter) Toxic nodular goiter Subacute thyroiditis Chronic lymphocytic thyroiditis Neonatal thyroiditis Thyroid-secretinghormone-secreting pituitary tumor McCune-Albright syndrome Thyrotropin receptor mutation

Graves' disease occurs in girls about five times more often than in boys, and the incidence steadily increases throughout childhood, peaking in the adolescent years. The condition usually develops insidiously over several months, and initial symptoms include nervousness, emotional lability, and declining school performance. Later in the course of the disease there will be weight loss and increased sweating, palpitations, heat intolerance, and malaise. True exophthalmos is an unusual finding in children, but a conspicuous stare is common. The thyroid gland is smooth, firm, and nontender, and a goiter is evident on physical examination in over 95% of cases. A bruit may be heard on auscultation. Laboratory evaluation usually demonstrates elevated free Tqand a decreased TSH. In 10% to 20% of patients there is only elevation of T3, a condition known as Tg toxicosis. The diagnosis of Graves' disease is further supported by the presence of TSH-stimulating immunoglobulins. Graves' disease is an autoimmune disease caused by TSH receptor antibodies, which stimulate the thyroid follicles to increase iodide uptake and induce increased production and secretion of thyroid hormone. It has been suggested that the TSH-binding proteins are present in a number of gram-positive and gram-negative bacteria, and it is possible that infection with such organisms may elicit production of antibodies that cross-react with the TSH receptor.47An infectious cause of Graves' disease is further supported by some epidemiologic reports of disease c l ~ s t e r i n g . ~ ~ Graves' disease is currently managed by antithyroid medications, or the thyroid gland is ablated using either radioactive '"1 or surgical resection.ll Most pediatric endocrinologists initiate therapy with antithyroid medications, although there is increasing use of radioablation as the first line of treatment.Z6 The most commonly used antithyroid medications are methimazole or propylthiouracil (PTU), which reduce thyroid hormone production by inhibiting follicle cell organification of iodide and coupling of iodotyrosines. Methimazole is usually the preferred antithyroid medication because of its longer half-life and increased potency. The initial dose is 30 mg once daily, which should be reduced if the patient is younger than the usual adolescent. The TSH should be monitored carefully; rising levels signal overtreatment and may cause further increase in the goiter size. When the patient is euthyroid, as determined by normal Tg and Tq levels, the dose of methimazole should be reduced to 10 mg and maintained at a level to ensure normal thyroid hormone levels.

Surgical Diseases of the Thyroid and Parathyroid Glands

853

course of the drug. The onset of a sore throat with fevers should raise concern, and a neutrophil count should be obtained. Typically, the granulocyte count will rise 2 to 3 weeks after stopping the drug, but in rare cases, fatal opportunistic infections have been reported. Treatment with parenteral antibiotics during the recovery period has been recommended. Other adverse reactions to methimazole include nausea, minor skin reactions, urticaria, arthralgias, arthritis, and fevers. The length of medical treatment is controversial. Usually, treatment is continued for 3 to 4 years. Remission of Graves' disease is approximately 25% if medication is discontinued after 2 years of treatment, and the continuing remission rate is about 25% every 2 years. In most children, the remission of Graves' disease will occur within 6 months of discontinuing antithyroid therapy. The resolution rate is decreased in children who have persistent detection of TSH receptor antibodies during and after treatment. In patients with Graves' disease who do not respond to treatment with antithyroid medications, or if there is a severe reaction to the medication, then the thyroid gland must undergo definitive ablation. Current methods of definitively treating Graves' disease include either surgical resection or ablation with radioactive '3'1. Neither of these modalities is without complications. Whereas lSIItherapy is effective, and the disease remission rate is low, patients have a 50% to 80% incidence of long-term hypothyroidism after treatment.3 In some cases, larger doses of radioiodine have been administered to intentionally destroy the entire gland and to induce an easily managed state of permanent hypothyroidism.26 Recent studies demonstrate there is no scientific merit to concerns over the possibility of teratogenic or carcinogenic effects of 1311 therapy in these younger patient~.~,22 Surgical treatment may be occasionally recommended for pediatric patients with Graves' disease refractory to medical treatment. Subtotal thyroidectomy is the surgical procedure of choice for the treatment of Graves' disease and is appropriate treatment for patients who refuse radioiodine treatment or who fail medical management or if the thyroid is so large that there are symptoms related to compression. Patients should be rendered euthyroid with methimazole before undergoing surgery. Moreover, P-adrenergic blocking agents such as proprano101 may be used to ameliorate the adrenergic symptoms of hyperthyroidism. Finally, iodine in the form of Lugol's solution, 5 to 10 drops/day, should be administered for 4 to 7 days before surgery to reduce the vascularity of the gland. In large studies of adults treated with a subtotal thyroidectomy for Graves' disease, the rate of recurrent hyperthyroidism is 6% to 10% at 10 years' follow-up.3 Patients continue to relapse even later, and 30% of patients will exhibit recurrent hyperthyroidism 25 years after their subtotal thyroidectomy. * There is also a significant risk of permanent hypothyroidism in these patients, affecting approximately 5% of patients 1 year after surgery, increasing to as high as 50% of patients

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who are observed for 25 years. These findings demonstrate the importance of carefully observing such patients postoperatively to monitor thyroid status.

NEOPLASTIC THYROID CONDITIONS Thyroid Nodules Thyroid nodules are uncommon in children but can be the presenting finding in cases of thyroid cancer. In recent pediatric studies, the incidence of malignancy in This is a thyroid nodules has been 20% or less.2,8,16,53 much lower incidence of cancer than was reported in previous decades and probably reflects the decreased number of children whd have bken e x ~ o s e dto neck irradiation for trivial reasons. It is important to properly evaluate and manage these lesions, because the cancer may be at an easily curable stage. A summary of pathologic results from recent studies of children who underwent surgery for thyroid nodules is presented in Table 55-4. The differential diagnosis of solitary thyroid nodules is listed in Table 55-5. In most large pediatric series, females having nodules outnumber males approximately 2 to 1 ." The majority of patients will come to clinical attention because of the mass in their neck. A careful neck examination should be performed, with special attention directed to determine if there are enlarged cervical lymph nodes suspicious for locally advanced carcinoma. The serum TSH level should be measured to identify patients with unsuspected thyrotoxicosis resulting from an autonomously functioning nodule. Imaging studies are

No. of patients No. malignant (%) Histologic subtype Papillary Follicular Mixed Anaplastic Medullary No. benign (%) Diagnosis Thyroiditis Thyroglossal cyst Follicular adenoma Colloid nodule Branchial cyst Other

Yip et al., 1 9 9 4

Lafferty and Batch, 1 9 9 7

122 1 6 * (13)

52 1 7 (33)

12 3 0 0 0 1 0 6 (87)

7 7 0 0 3 35 (67)

17 0 26 57 0 6

1 2 16 2 0 14

L *One patient in this series had lymphoma of the thyroid gland. Data from Yip MIK, ReeveTS, Poole AG, Delbridge L: Thyroid nodules in childhood and adolescence. Aust NZJ Surg 1994;64:676-678;and Lafferty AR, Batch JA: Thyroid nodules in childhood and adolescence-thirty years of experience. J Pediatr Endocrinol Metab 1997:10:479-486.

Adenoma Carcinoma Thyroid cyst Ectopic thyroid gland Cystic hygroma Thyroglossal duct remnant Germ cell tumor

unreliable at distinguishing benign from malignant nodules. For example, malignant nodules may be either functioning or nonfunctioning on thyroid scintiscan. Ultrasonography is also nondiagnostic because malignant nodules may be either solid or cystic. Thus, such imaging studies should be interpreted carefully in the evaluation of thyroid nodules in pediatric patients. A therapeutic trial of exogenous thyroid hormone to induce nodule regression is not recommended. The use of FNA cytology to evaluate thyroid nodules is well established in adults, but the effectiveness of this technique is still being defined in children. Children are usually more difficult to evaluate than adults, owing to the smaller size of the nodules and the frequent need to sedate the child to allow safe and accurate aspiration. Moreover, the effectiveness of any diagnostic test is in part dependent on the pretest probability of a positive result. Because in young children there is a higher incidence of cancer in any thyroid nodule (when compared with adults), there is a slightly increased probability of a negative cytologic result that in fact may be associated with cancer. Such a false-negative cytologic result would delay the diagnosis and treatment of thyroid cancer. However, in light of the overall good clinical outcome in children with differentiated thyroid neoplasia, it must be acknowledged that such a delay will probably not result in any negative impact on survival. In adolescent patients, thyroid nodules may be safely evaluated with FNA. The pattern of thyroid disease in the adolescent age group is similar to that of adults, in whom the safety of FNA has been established. In one large series, the incidence of malignancy in thyroid nodules in patients from 13 to 18 years old was only 11%." In another study of 57 children with thyroid nodules evaluated by FNA, the incidence of malignancy was 18%.34There was one papillary carcinoma initially misdiagnosed as a benign lesion, which was eventually recognized as a malignancy with clinical follow-up. In another study of 57 children subjected to FNA for the evaluation of thyroid nodules, there was a similar incidence of cancer and 1 child initially had a false-negative FNA. In this case, the nodule was noted to increase in size over the ensuing 6 months, and excisional biopsy demonstrated the presence of Hiirthle cell carcinoma.20 Thus, these studies in mostly adolescent patients support the safety and effectiveness of FNA in this population. The results of FNA cytology either will indicate unequivocal cancer or a benign lesion or the diagnosis will be indeterminant for carcinoma. If the nodule is

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judged to be benign, then it can be followed with serial physical examinations and with ultrasound studies. Surgical resection should be performed if the nodule is malignant or indeterminant or if a benign nodule is shown to increase in size. Some endocrinologists suppress benign thyroid nodules with exogenous thyroid hormone, but this has not been shown to alter the natural history of such nodules. If a cystic lesion disappears after aspiration, then surgery may be deferred. The lesion should be removed if it recurs. Whereas cyst fluid may be sent for cytologic analysis, the sensitivity of this test is probably low for detecting the presence of cancer.25 In prepubertal children, there is increased difficulty in obtaining aspiration cytology and the pattern of benign disease is different than adults; thus, the natural history of these lesions is unknown and the safety of nonoperative treatment has not been demonstrated. Therefore, it is recommended that all thyroid nodules be removed in children younger than 13 years. Some surgeons obtain preoperative ultrasound examination and thyroid scintigraphy as an aid in determining the anatomy.16327 It cannot be overstated that if there is any question about the reliability of the cytologic evaluation, then excisional biopsy of all thyroid nodules irrespective of patient age should be performed.

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Recent research has elucidated some of the genetic events responsible for the neoplastic process in thyroid tumors. The RET proto-oncogene, a receptor tyrosine kinase molecule located on the 10th chromosome. is frequently rearranged in papillary cancers so that the intracellular portion of the gene is juxtaposed to one of several ubiquitously expressed genes. The fusion genes are termed RET/PTC and exhibit increased expression of the tyrosine kinase activity of the molecule. These genetic rearrangements involving RET are especially frequent in radiation-induced thyroid tumors. After the Chernobyl accident, children from Belarus with thyroid cancer were found to exhibit RET fusion genes in over 62% of cases." In some studies, the particular RETfusion gene combination has been correlated with particular histologic subtypes.41 The RET proto-oncogene is also important in the development of medullary thyroid carcinoma (MTC), and various mutations in RET are associated with the multiple endocrine neoplasia type 2 syndromes (MEN 2A, MEN 2B) and familial medullary thyroid carcinoma (FMTC). MTC is usually the first tumor to develop in these patients. Moreover, as many as 40% of patients with sporadic nonfamilial MTCs possess RE7'mutations.lO The RET mutations in the susceptible tissues perturb the intracellular signaling pathways to alter the proliferation or differentiation of the neural crest-derived tissues involved in the MEN 2 syndromes. Thyroid Carcinoma Carcinoma of the thyroid gland typically presents Carcinoma of the thyroid gland is relatively unusual in clinically as a thyroid mass, as enlarged cervical lymph children, and population-based studies in Wales and Los nodes, or with both of these findings. In one large clinical study of thyroid carcinoma in-children, the more Angeles demonstrate that the yearly incidence of thyroid recently diagnosed patients were somewhat less likely to carcinoma is between 1 and 2 cases per million individuals have enlarged regional lymph nodes at their initial presyounger than 20 years of age.l42" This represents only entation.'" compilation of the clinical aspects of several about 3% of all pediatric malignancies. The peak incirecent, large clinical series of pediatric patients with difdence of thyroid cancer in children occurs between 10 and ferentiated thyroid carcinoma is presented in Table 55-6. 18 years of age, and girls usually outnumber boys 2 to 1. Approximately 10% of all malignant thyroid tumors The pathologic diagnosis can be established either using FNA cytology or by frozen-section analysis of a biopsy occur in children. The incidence of thyroid tumors in specimen at the time of surgery. Recent studies have children has decreased over the past 2 decades owing to the reduced use of radiation to treat benign diseases. suggested that frozen-section analysis is less accurate in The importance of radiation as a cause of thyroid cancer evaluating follicular lesions. As shown in Table 55-6, was recently reemphasized by the marked increase of most of these patients will have papillary thyroid carcinoma. Before surgery, most children should have a such tumors noted in the Republic of Belarus following the 1986 Chernobyl nuclear power plant ~atastrophe.2"~~ thyroid scan, to determine if the thyroid mass contains The latency period for the development of thyroid functioning thyroid tissue. Some investigators also reccancer after radiation exposure is 4 to 6 years, and in ommend an ultrasound study to determine if the lesion the Belarus population there was a 62-fold increase in is cystic and to serve as a guide during the surgical procedure.z7 Because of the relatively high incidence thyroid tumor incidence after the Chernobyl accident. of pulmonary metastasis in children having thyroid Thyroid carcinoma also occurs at an increased incidence carcinoma, preoperative chest radiography or computed after treatment for a previous childhood malignancy. In tomography should be performed. one study, thyroid cancers constituted about 9% of second The surgical management of thyroid cancer in children malignancies occurring after treatment for childhood t~mors.~Wodgkin's lymphoma is the most common first is controversial, because there have been no prospective malignancy associated with the subsequent development clinical trials comparing more aggressive to less extensive of thyroid cancer, and most thyroid neoplasms follow the surgical management options. As show11in Table 55-6, the long-term outcome is usually excellent, irrespective of the previous use of radiation to the neck, but alkylating agents particular surgcal procedure employed. surgeons argualone also predispose to thyroid cancer. The median interval ing in favor of aggressive thyroid resections hold that total from radiation therapy to the recognition of thyroid disthyroidectomy, with lymph node dissection if the regional ease is about 12 years,l underscoring the importance of careful surveillance for second tumors in children who nodes are involved with cancer, is the most successful have been successfully treated for cancer. method of obtaining local control of the tumor.jJ3328.4'

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metastases, use of 1311radiotherapy in the initial management, or the antecedent exposure to radiation.Y8 On balance, it appears that tumor factors may be more important than treatment factors in determining the clinical outcome in children having differentiated thyroid Total number of patients cancer. Mean age Therefore, in the absence of controlled prospective Percent female trials, it is difficult to make firm recommendations regardHistology ing the surgical management of differentiated thyroid Papillary Follicular cancer in children. However, a consensus is emerging Medullary that more aggressive resections are preferred.I7 Surgeons Other and pediatric endocrinologists increasingly recommend % With metastasis either total or near-total thyroidectomy, followed by '"1 Surgical procedure remnant ablation in conjunction with long-term suppres178 Total thyroidectomy sive thyroxine therapy. A modified neck dissection Subtotal thyroidectomy 55 should be performed to remove as much gross disease as Lobectomy or other 96 possible if there are large lymph nodes suggestive of the Lymph node procedure 255 presence of regional metastasis. In patients with locally % Receiving radiotherapy 43 advanced disease, it is especially important to remove as Median follow-up (yr) 11.3 much of the thyroid gland as possible to allow subsequent 0.7 Cancer mortality (%) scanning and re-treatment with radioiodine as necessitated by tumor recurrence. Tumors involving the recurData from Newman KD, BlackT, Heller G, et al: Differentiatedthyroid cancer: rent laryngeal nerve should not be aggressively resected Determinantsof disease progression in patients <21 years of age at diagnosis: to sacrifice the nerve, because residual tumor on the nerve A report of the Surgical DisciplineCommittee of the Children's Cancer Group. can be adequately treated with radioiodine. Ann Surg 1998;227:533-541, The risk of major surgical complications increases with the extent of the surgical procedure,Z4and compliMoreover, removing the entire thyroid gland makes adjucations occur significantly more frequently in younger vant radioiodine ablative therapy more effective, because children than older patients. The most common severe complications of thyroid resection include recurrent there is less functioning normal thyroid tissue to compete with remaining tumor for the uptake of radionuclide. laryngeal nerve injury and permanent hypoparathyFinally, if all of the thyroid gland has been removed or roidism. To reduce the likelihood of hypoparathyroidism, ablated, then the serum thyroglobulin levels can be used the inferior thyroid artery should be ligated near the to assess for tumor recurrence. thyroid capsule.46One method of preserving parathyroid gland function is to identify and autotransplant one or Surgeons favoring lesser thyroid gland resection argue that differentiated thyroid carcinoma in children two of the glands into the sternocleidomastoid muscle or If parathyroid gland into the nondominant f0rearm.~~l,?2 is a relatively indolent disease and that survival is apparently not related to the extent of gland remo~a1.2~9s~perfusion is compromised during the dissection, then Moreover, there is an increased incidence of major surgibne should immediately autotra<splant the gland into cal complications associated with total thyroidectomy in the nearby sternocleidomastoid muscle. To aid in the children. For example, the reported incidence of recuridentification and protection of the recurrent laryngeal rent laryngeal nerve injury is 0% to 2 4 % l G n d the nerve, intraoperative nerve stimulation has been employed; the usefulness of this technique in children has been reported frequency of permanent hypocalcemia is 6% to 27%.7J"Z4 Such complications are reported to occur less demonstrated in one r e p ~ r t . ~ commonly in the more recent clinical series.'" The incidence of pulmonary metastases at diagnosis of In one retrospective study of 329 children treated thvroid cancer in childhood is about 6%."35~4 In such cases for differentiated thyroid cancer there was multivariate there is nearly always significant cervical lymph node metasanalysis of the factors predicting early disease recurrence.28 tasis. Postoperative radioiodine treatment is required. Plain The only disease or treatment features significantly prechest radiographs may demonstrate the pulmonary disdictive of early recurrence were a lower age at diagnosis ease in only about 60% of cases.50 Thus, scanning with radioiodine is necessary to detect these metastatic deposits. and the presence of residual neck disease after surgery. It should be recalled that radionuclide scans may be falsely Children older than 15 years of age at diagnosis were less likely to experience tumor recurrence than younger chilnegative if there is significant residual thyroid gland dren. After a median follow-up of l l .3 years, the tumor remaining in the neck, supporting the current recommenrecurrence rate after treatment was 32% and there were dations for aggressive thyroid resection in children with only two cancer-related deaths. The overall progressiondifferentiated thyroid cancer." free survival of patients with differentiated thyroid canThe recurrence rate of thyroid cancer in patients folcer in this series was 67% at 10 years and 60% at 20 years lowed for 20 years is about 30%,24,28!42emphasizing the importance of aggressive, early treatment and relatively after diagnosis. Factors not affecting progression-free frequent, long-term followup. An '"1 whole-body scan and survival included extent of thyroid surgery or node dissection, primary tumor size, extrathyroidal extension chest CT scan performed approximately 6 weeks after the thyroid resection will detect residual tumor remaining in of tumor, regional lymph node involvement, distant

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the neck and in the lungs.17 In most cases, therapeutic doses of the radionuclide should then be administered to ablate residual thvroid tissue. This treatment should be repeated as necessary to manage residual metastatic disease.13To assay for recurrence of the neoplasm, diagnostic radioiodine scans should be repeated yearly. Recently, thyroglobulin has been shown to be a useful marker of residual or metastatic thyroid cancer; the plasma level of this protein should be measured yearly, and an elevated value should raise the sus~icionfor recurrent disease." The diagnostic accuracy of this test is significantly decreased in children having residual thyroid tissue and in those who are taking thyroid hormone supplementation. To increase the sensitivity of thyroglobulin measurements for residual or recurrent thyroid cancer, the TSH can be raised by inducing a short period of iatrogenic hypothyroidism or by the administration of recombinant human TSH.17 Approximately 5% of thyroid neoplasms in children are medullary carcinomas that arise from the parafollicular C cells. MTC may occur sporadically, and familial tumors develop in patients having MEN type 2A or MEN 2B or the FMTC syndrome. MTC is usually the first tumor to develop in MEN patients. The neoplasm is particularly virulent in patients with MEN 2B and has been reported As with other thyroid neoplasms, to occur in infan~y.~O.~O the clinical diagnosis of MTC is usually made after there is significant spread of the tumor to the adjacent cervical lymph nodes or to distant sites." Surgical resection is the only effective treatment for MTC, underscoring the importance of early diagnosis and therapy before metastasis occurs. Therefore, current management of MTC in children from families having the MEN 2 syndrome relies on the presymptomatic detection of the RETproto-oncogene mutation responsible for the disease, followed by prophylactic total thyroidectomy by about the age of 5 years, before the cancer spreads beyond the thyroid gland.51Approximately 80% of children who have thyroidectomy based solely on the presence of the RET mutation will already have foci of MTC within the thyroid gland.43 Owing to the increased virulence of the MTC in children having MEN 2B, it may be preferable for them to have their thyroid glands removed in infancy.

THE PARATHYROID GLANDS The parathyroid glands regulate calcium and phosphate homeostasis. Parathyroid hormone (PTH) is secreted as an 84amino acid protein that is cleaved in the liver and kidney into the carboxy-terminal, amino-terminal, and midregion fragments. In the kidney, PTH interacts with its receptor to stimulate the production of the active vitamin D metabolite 1,25-dihydroxycholecalciferol, which then acts on the intestinal mucosa to increase calcium absorption. In the bones, PTH directly stimulates the mobilization of calcium through a process that also requires vitamin D. The biologic activity of PTH resides in the aminoterminal segment, but the plasma level of this moiety is quite low, owing to its very short half-life in the circulation.

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Most clinical assays of plasma PTH measure carboxyterminal levels of the hormone, whose concentration is 50- to 500-fold those amino-terminal fragment. These assays are usually quite effective for the evaluation of hyperparathyroidism, but it should be noted that the carboxy-terminal fragment is cleared in the kidney and that plasma levels of the protein may therefore be elevated if there is impaired renal function. The laboratory hallmark of hyperparathyroidism is the finding of an elevated plasma PTH level with hypercalcemia. Radiographic evaluation is useful in patients who have had chronically elevated PTH levels, but the characteristic bone findings are not seen acutely. The first step in the evaluation of hypercalcemia is to obtain a 24hour measurement of urinary calcium to rule out familial hypocalciuric hypercalcemia. This condition, also known as familial benign hypercalcemia, usually comes to clinical attention in an asymptomatic child with an elevated serum calcium level. Serum levels of magnesium may also be elevated, and other family members may be affected. The condition is caused by an inherited mutation in the gene coding for the calcium sensing receptor, resulting in an insensitivity to calcium ion at the cellular level. There is an autosomal dominant inheritance pattern. The PTH level and parathyroid glands are normal, and there is usually no benefit to parathyroidectomy. In rare cases, a newborn born to affected parents may present with severe and life-threatening hypercalcemia owing to mutations in both alleles of the gene. These infants often have hyperplasia of the parathyroid glands and benefit from parathyroidectomy. The differential diagnosis of hypercalcemia in childhood is presented in Table 55-7. Children, unlike adults, very rarely develop abnormal serum calcium levels related to neoplasms. However, some pediatric neoplasms may secrete a parathyroid-related polypeptide that will elevate the calcium level; this has been reported in malignant rhabdoid tumor, mesoblastic nephroma, rhabdomyosarcoma, neuroblastoma, and lymphoma. In these cases, the PTH level is generally normal or decreased.

Elevated parathyroid hormone level Primary hyperparathyroidism Secondary hyperparathyroidism Tertiary hyperparathyroidism Ectopic parathyroid hormone production Hypervitaminosis D Sarcoidosis Subcutaneous fat necrosis Familial hypocalciuric hypercalcemia Idiopathic hypercalcemia of infancy Thyrotoxicosis Hypervitaminosis A Hypophosphatasia Prolonged immobilization Thiazide diuretics

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A

B

-

A, Parathyroid adenoma responsible for hypercalcemia. The large arrow identifies the enlarged upper gland, and the small arrow identifies the normal-sized lower gland. B, Resected parathyroid adenoma. a

Primary hyperparathyroidism in childhood most commonly results from a solitary hyperfunctioning adenoma, as demonstrated in Figure 55-1. More rarely there is diffuse hyperplasia of all four glands." Hyperparathyroidism resulting from hyperplasia in all four glands is a feature of MEN syndrome. Moreover, parathyroid hyperplasia is a feature in approximately 30% of patients having MEN 2A, but hypercalcemia in this syndrome rarely occurs in childhood.lVrimary hyperparathyroidism of infancy is a rare disorder that is often fata1Z3," and demonstrates a familial component in about half of cases. The condition usually develops within the first 3 months of life, and presenting signs include hypotonicity, respiratory distress, failure to thrive, lethargy, and polyuria. Early recognition and treatment of primary hyperparathyroidism of infancy is essential to allow normal growth and development of the baby. Pathologically, there is usually diffuse parathyroid gland hyperplasia. There is no place for medical management of primary hyperparathyroidism in children; and once the diagnosis of hyperparathyroidism is established, the offending parathyroid tissue should be resected. Recent advances in imaging and real-time PTH measurements have allowed the use of minimally invasive technique^.^^^^^ Currently, it is recommended that patients with primary hyperparathyroidism undergo preoperative localization with 9"nTc-sestamibi scan."f the scan demonstrates a single parathyroid lesion, a less invasive procedure can be considered. A small incision can be made over the offending gland, which can often be localized using a hand-held gamma probe. To confirm that the offending gland has been removed, a rapid parathyroid hormone analysis can be performed while the child remains asleep.48 These modalities have not been widely used in children, but their use in adults has demonstrated a reduction in morbidity, hospital stay, and costs.49 The preferred surgical management of parathyroid gland hyperplasia involving all of the glands remains controversial. Some surgeons recommend removing

three and one-half glands, whereas others prefer to remove all of the glands and heterotopically transplant some tissue into the nondominant forearm." The latter approach has the advantage of avoiding repeated neck explora~ionif hyperparathyroidism should recur and has been shown to be safe in infants and children.43 Moreover, there is evidence that total parathyroidectomy with heterotopic autotransplantation results in improved survival in infants with severe hypercalcemia.38 Secondary hyperparathyroidism occurs when the parathyroid glands are stimulated to increase PTH secretion in response to a decreased serum calcium level. This is most commonly associated with renal insufficiency but may also be associated with malabsorption syndromes. Patients with secondary hyperparathyroidism usually respond to medications that decrease intestinal phosphorus absorption. In rare cases, children will develop severe renal osteodystrophy manifested by skeletal fractures and metastatic calcifications; these children are candidates for either three and one-half gland parathyroidectomy or total parathyroidectomy with a~totransplantation.3~ In some patients with chronic renal failure and secondary hyperparathyroidism who undergo renal transplantation, there is persistent hyperfunction of the glands even after the inciting stimulus (hypocalcemia from renal failure) is removed. This is termed tertiary hyperparathyroidism and results from four-gland hyperplasia; children with this condition are also candidates for total parathyroidectomy with autotransplantation.

REFERENCES 1. Acharya S, Sarafoglou K, LaQuaglia MP, et al: Thyroid neoplasms after therapeutic radiation for malignancies during childhood or adolescence. Cancer 2003;97:2397-2403. 2. Al-Shaikh A, Ngan B, Daneman A, et al: Fine-needle aspiration biopsy in the management of thyroid nodules in children and adolescents. J Pediatr 2001;138:140-142.

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3. Berglund J, Christensen SB, Dymling JF, et al: The incidence of recurrence and hypothyroidism following treatment with antithyroid drugs, surgery, or radioiodine in all patients with thyrotoxicosis in Malmo during the period 1970-1974.J Intern Med 1991;229:435-442. 4. Brauckhoff M, Gimm 0 , Thanh PN, et al: First experience in intraoperative neurostimulation of the recurrent laryngeal nerve during thyroid surgery in children and adolescents. J Pediatr Surg 2002;37:14141418. 5. Ceccarelli C, Pacini F, Lippi F, et al: Thyroid cancer in children and adolescents. Surgery 1988;104:1143-1148. 6. Chen H: Surgery for primary hyperparathyroidism: What is the best approach? Ann Surg 2002;236:552-553. 7. de Roy van Zuidewijn DBW, Songun I, Kievit J, et al: Complications of thyroid surgery. Ann Surg Oncol 1995;2: 56-60. 8. Desjardins JG, Khan AH, Montupet P, et al: Management of thyroid nodules in children: A 20-year experience. J Pediatr Surg 1987;22:736-739. 9. Dickman PW, Holm L-E, Lundell G, et al: Thyroid cancer risk after thyroid examination with '"1: A population-based cohort study in Sweden. Int J Cancer 2003;106:580-587. 10. Eng C, Smith DP, Mulligan LM, et al: Point mutation within the tyrosine kinase domain of the RET proto-oncogene in multiple endocrine neoplasia type 2B and related sporadic tumours. Hum Mol Genet 1994;3:237-241. 11. Franklyn JA: The management of hyperthyroidism. N Engl J Med 1994;330:1731-1738. 12. Gorlin JB, Sallan SE: Thyroid cancer in childhood. Endocrinol Metab Clin North Am 1990;19:649-662. 13. HarnessJA, Thompson NW, McLeod MK, et al: Differentiated thyroid carcinoma in children and adolescents. World J Surg 1992;16:547-554. 14. Haselkorn T, Bernstein L, Preston-Martin S, et al: Descriptive epidemiology of thyroid cancer in Los Angeles County, 1972-1995. Cancer Causes Control 2000;11:163-170. 15. Howe JR, Norton JA, Wells SA Jr: Prevalence of pheochromocytoma and hyperparathyroidism in multiple endocrine neoplasia type 2A: Results of long-term follow-up. Surgery 1993;114:1070-1077. 16. Hung W, Anderson KD, Chandra RS, et al: Solitary thyroid nodules in 71 children and adolescents. J Pediatr Surg 1992;27:1407-1409. 17. Hung W, Sarlis NJ: Current controversies in the management of pediatric patients with welldifferentiated nonmedullary thyroid cancer: A review. Thyroid 2002;12:683-702. 18. Irkin GL 111, Molinari AS, Figueroa C, et al: Improved success rate in reoperative parathyroidectomy with intraoperative PTH assay. Ann Surg 1999;229:874879. 19. Jaksic J, Dumic M, Filipovic B, et al: Thyroid disease in a school population with thyromegaly. Arch Dis Child 1994;70: 103-106. 20. Khurana KK, Labrador E, Izquierdo R, et al: The role of fine-needle aspiration biopsy in the management of thyroid nodules in children, adolescents, and young adults: A multi-institutional study. Thyroid 1999;9:383-386. 21. Kirk JM, Mort C, Grant DB, et al: The usefulness of serum thyroglobulin in the follow-up of differentiated thyroid carcinoma in children. Med Pediatr Oncol 1992;20: 201-208. 22. Klein I, Becker DV, Levey GS: Treatment of hyperthyroid disease. Ann Intern Med 1994;121:281-288. 23. Kulczycka H, Kaminski W, Wozniewicz B, et al: Primary hyperparathyroidism in infancy: Diagnostic and therapeutic difficulties. Klin Padiatr 1991;203:116118. 24. La Quaglia MP, Corbally MT, Heller G, et al: Recurrence and morbidity in differentiated thyroid carcinoma in children. Surgery 1988;104:1149-1156.

Surgical Diseases of the Thyroid and Parathyroid Glands

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25. Mazzaferri EL: Management of a solitary thyroid nodule. N Engl J Med 1993;328:553-559. 26. Nebesio TD, Siddiqui AR, Pescovitz OH, et al: Time course to hypothyroidism after fixed-dose radioablation therapy of Graves' disease in children. J Pediatr 2002;141: 99-103. 27. Newman KD: The current management of thyroid tumors in childhood. Semin Pediatr Surg 1993;2:69-74. 28. Newman KD, Black T, Heller G, et al: Differentiated thyroid cancer: Determinants of disease progression in patients < 21 years of age at diagnosis. Ann Surg 1998;227:533-541. 29. Nikiforov Y, Gnepp DR: Pediatric thyroid cancer after the Chernobyl disaster: Pathomorphologic study of 84 cases (1991-1992) from the Republic of Belarus. Cancer 1994;74: 748-765. 30. Norton JA, Froome LC, Farrell RE, et al: Multiple endocrine neoplasia type IIb: The most aggressive form of medullary thyroid carcinoma. Surg Clin North Am 1979;59:109-118. 31. Pacini F, Vorontsova T, Molinaro E, et al: Thyroid consequences of the Chernobyl nuclear accident. Acta Paediatr Suppl 1999;433:23-27. 32. Paterson ICM, Greenlee R, Adams Jones D: Thyroid cancer in Wales 1985-1996: A cancer registry-based study. Clin Oncol 1999;11:245-251. 33. Phillips DI, Barker DJ, Rees Smith B, et al: The geographical distribution of thyrotoxicosis in England according to the presence or absence of TSH-receptor antibodies. Clin Endocrinol 1985;23:283-287. 34. Raab SS, Silverman JF, Elsheikh TM, et al: Pediatric thyroid nodules: Disease demographics and clinical management by fine needle aspiration biopsy. Pediatrics 1995;95:4649. 35. Rabes HM, Demidchik EP, Siderow JD, et al: Pattern of radiation-induced RET and NTRKl rearrangement in 191 post-Chernobyl papillary thyroid carcinomas: Biological, phenotypic, and clinical implications. Clin Cancer Res 2000; 6:1093-1103. 36. Rallison ML, Dobyns BM, Meikle AW, et al: Natural history of thyroid abnormalities: Prevalence, incidence, and regression of thyroid diseases in adolescents and young adults. Am J Med 1991;91:363-370. 37. Ross AJ 111: Parathyroid surgery in children. Prog Pediatr Surg 1991;26:48-59. 38. Ross AJ 111, Cooper A, Attie MF, et al: Primary hyperparathyroidism in infancy.J Pediatr Surg 1986;21:493-499. 39. Rother KI, Zimmerman D, Schwenk WF: Effect of thyroid hormone treatment on thyromegaly in children and adolescents with Hashimoto disease. J Pediatr 1994;124: 599-601. 40. Samaan NA, Draznin MB, Halpin RE, et al: Multiple endocrine syndrome type IIb in early childhood. Cancer 1991;68:1832-1834. 41. Santoro M, Thomas GA, Vecchio G, et al: Gene rearrangement and Chernobyl related thyroid cancers. Br J Cancer 2000;82:315-322. 42. Schlumberger M, De Vathaire F, Travagli JP, et al: Differentiated thyroid carcinoma in childhood: Long term follow-up in 72 patients. J Clin Endocrinol Metab 1987;65:1088-1094. 43. Skinner MA, DeBenedetti MK, Moley JF, et al: Medullary thyroid carcinoma in children with multiple endocrine neoplasia types 2A and 2B. J Pediatr Surg 1996;31:177-182. 44. Skinner MA, Norton JA, Moley JF, et al: Heterotopic autotransplantation of parathyroid tissue in children undergoing total thyroidectomy.J Pediatr Surg 1997;32:510-513. 45. Smith MB, Xue H, Strong L, et al: Forty-year experience with second malignancies after treatment of childhood cancer: Analysis of outcome following the development of the second malignancy. J Pediatr Surg 1993;28:1342-1349.

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46. Thomusch 0, Machens A, Sekulla C, et al: The impact of surgical technique on postoperative hypoparathyroidism in bilateral thyroid surgery: A multivariate analysis of 5846 consecutive patients. Surgery 2003;133:180-185. 47. Tomer Y, Davies TF: Infection, thyroid disease, and autoimmunity. Endocrine Rev 1993;14:107-120. 48. Udelsman R, ArunyJE, Donovan PI, et al: Rapid parathyroid hormone analysis during venous localization. Ann Surg 2003;237:714721. 49. Udelsman R, Donovan PI, Sokoll LJ: One hundred consecutive minimally invasive parathyroid explorations. Ann Surg 2000;232:331-339. 50. Vassilopoulou-Sellin R, Klein MJ, Smith TH, et al: Pulmonary metastases in children and young adults with differentiated thyroid cancer. Cancer 1993;71:1348-1352.

51. Wells SAJr, Chi DD, Toshima K, et al: Predictive DNA testing and prophylactic thyroidectomy in patients at risk for multiple endocrine neoplasia type 2A. Ann Surg 1994;220: 237-250. 52. Wells SA Jr, Farndon JR, Dale JK, et al: Long term evaluation of patients with primary parathyroid hyperplasia managed by total parathyroidectomy and heterotopic autotransplantation. Ann Surg 1980;192:451-458. 53. Yip FWK, Reeve TS, Poole AG, et al: Thyroid nodules in childhood and adolescence. Aust NZ J Surg 1994;64: 67fj-678. 54. Zimmerman D, Hay ID, Gough IR, et al: Papillary thyroid carcinoma in children and adults: Long-term follow-up of 1039 patients conservatively treated at one institution during three decades. Surgery 1988;104:1157-1163.

Cysts and Sinuses of the Neck C. D. Smith

Cysts and sinuses of the neck constitute one of the most intriguing areas of pediatric pathology. Although congenital in origin, they may not be recognized or cause clinical problems until well into adulthood. In adulthood, In childhood, even they. may. masquerade as car~inoma."~ though normally benign, they may, in rare cases, harbor malignan~y.~.'~ The most common lesions, thyroglossal duct cysts and second branchial anomalies, are usually easily diagnosed on physical examination, do not necessarily require additional.workup, and can often be excised safely in a day surgery unit. There are many pitfalls, however, for the surgeon, who through ignorance of anatomic variants or of well-established surgical techniques, may predispose the patient to the &orbidity of -multiple, painful recurrences or nerve deficits. A working knowledge of the embryologic origin of these cysts and sinuses and their relationshin to normal neck structures is a nre1 requisite for successful management, as is the knowledge that total excision is required for a successful outcome. In addition, a familiarity with a number of unusual presentations, such as acute suppurative thyroiditis (piriform sinus arising from third or fourth branchial anomaly), otorrhea (first branchial anomaly), severe respiratory distress or sudden death in an infant (thyroglossal duct cyst, branchial anomaly), or an ectopic thyroid mimicking a thyroglossal duct cyst prevents delay in proper treatment. This chapter focuses on pertinent features of the embryology of-the neck. usual and unusual presentations of each entity are described, and surgical strategies for primary and recurrent lesions are discussed. New approaches that challenge conventional management principles and initial forays into the application of minimally invasive approaches to these congenital neck lesions are highlighted.

EMBRYOLOGY There are potentially six branchial arches supplied by six aortic arches connecting the paired dorsal and ventral aortas in the primitive embryo (Fig. 56-1). The fifth arch is present transiently, if at all, and disappears without

a trace. Each branchial arch is covered externally with ectoderm, lined internally with endoderm, and filled with mesoderm, containing an artery, a nerve, a cartilage rod, and muscle. The depressions between the arches are called clefts externally and pouches internally. The clefts are lined with ectoderm and the pouches endoderm (Fig. 56-2). The point at which they oppose each other is called the closing membrane. In the human, obliteration of these membranes does not normally occur to form a true gill as it does in the fish. The contribution that each arch, cleft, and pouch makes to the formation of the neck and jaw is summarized in Table 56-1. Theories about the origin of cysts and sinuses of the neck are based on the relationship of these anomalies to adjacent arteries, muscles, and nerves; on known pathways taken by the thyroid, parathyroid, and thymus glands in their embryonic migrations; and, to a lesser extent, on the type of epithelial lining of the various anomalies. Figure 56-1 shows the transformation of the aortic arches and aortas into the definitive vascular pattern. Three examples illustrate how knowledge of this process has been used to deduce the origin of branchial anomalies. First, one can predict that a piriform sinus tract (third or fourth branchial arch lesion) will course posterior to the internal carotid artery, a third arch structure, rather than between the internal and external carotid arteries, as is the case with second branchial cleft anomalies (Fig. 56-3). Second, an external sinus opening anterior to the sternocleidomastoid muscle in the lower neck does not distinguish between second, third, and fourth branchial cleft remnants. In the embryo, these clefts have a common exit site in the neck, the cervical sinus of His, which forms when the second branchial arch overgrows the openings of these clefts (Fig. 56-44). The relationship of a cyst, sinus, or fistula to internal neck structures, such as the carotid, bifurcation, the hypoglossal nerve, or the stylohyoid and digastric muscles, therefore, determines the site of origin of one of these particular anomalies, not the location of an external opening.76 Third, although a complete fourth branchial cleft fistula has yet to be identified clinically, its

862

V

PART

,, .

HEADAND NECK External carotid

Dorsal aorta,

Internal carotid

-

arte?'

Rinht vat

vagus nerve

*-

-

7th Intersegmental

A, Diagram of the aortic arches and dorsal aortas before transformation into the definitive vascular pattern. B, Diagram of the aortic arches and dorsal aortas after the transformation. Obliterated components are indicated by broken lines. Note the patent ductus arteriosus and position of the seventh intersegmental artery on the left. C,The great arteries in the adult. Compare the distance between the place of origin of the left common carotid artery and the left subclavian in Band C. After the disappearance of the distal part of the sixth aortic arch (the fifth arches never form completely), the right recurrent laryngeal nerve hooks around the right subclavian artery. O n the left, the nerve remains in place and hooks around the ligamentum arteriosum. (From Sadler TW: Head and neck. In

B

Langman's Medical Embryology, 7th ed. Baltimore,

Left ~nternalcarot~dartery

Williams & Wilkins, 1995.) h

Right subclav~an Brach~ocephal~c

Left common carotid artery Left subclav~anartery

,

- Llgamentum arterlosum

Ascending aorta

Descending aorta

Pulmonary artery

C

course has been predicted to differ on the two sides of the neck. On the left side, this fistula would dive into the superior mediastinum beneath the arch of the aorta, the successor of the left fourth embryonic aortic arch. Because the right fourth embryonic aortic arch becomes the subclavian artery, the fistula would pass beneath that structure on the right side (see Figs. 56-1 and 56-5). The nerves of the arches are important landmarks not only for deducing the origin of the various branchial anomalies but also for being at risk during excision of each one of them. In first branchial anomalies the tract may pass below, between, or above the branches of the 6 is the reason identification of the facial n e r ~ e . ~This branches of this nerve is a cardinal principle in the excision

Tuberculum impar

,

of one of these lesions. The danger of injuring an adjacent nerve is much less of a clinical problem with uncomplicated lesions of the lower clefts but can become more of an issue when previous inflammation or operative procedures result in distortion of the normal anatomy. Figures 56-3 and 56-5 illustrate the paths of second, third, and fourth branchial fistulas vis-5-vis the glossopharyngeal (IX), the superior laryngeal and recurrent branches of the vagus (X), and the hypoglossal (XII) nerves. Knowledge of the location of the internal openings of branchial cleft tracts can be helpful in both diagnosis and operative management. A first branchial anomaly often enters the external auditory canal (or rarely the middle ear). A second branchial anomaly enters the

ARCH Mandibular n. Fascial n. Glossopharyngeal n.

Branchial pouch Foramen cecum Branchial n

e

Branchial artery Branchial cartilage

w

e

4

k

Superior laryngeal branch of vagus 5 disappears

Recurrent laryngeal branch of vagus

Early development of branchial apparatus. (From Donegan JO: Congenital neck masses. In Cummings CW, et a1 [eds]: Otolaryngology-Head and Neck Surgery, 2nd ed. St Louis, Mosby-Year Book, 1993.)

CHAPTER

I Arch External maxillary artery Nerve V Cleft Pouch

II Arch Stapedial artery Nerves VII and Vlll Pouch 111 Arch Internal carotid artery Nerve IX Pouch IV Arch Arch of aorta (L) Part of subclavian artery (R) Nerve X Pouch

56

Cysts a n d Sinuses of the Neck

863

Dorsal

Ventral

Midline Floor of Pharynx

Incus body Malleus head Pinna External auditory canal Eustachian tube Middle ear cavity Mastoid air cells

Meckel's cartilage Malleus

Body of tongue

Stapes

Styloid process Hyoid (lesser horn and part of body)

Root of tongue Foramen cecum Thyroid gland's median anlage

Palatine tonsil Supratonsillar fossa

Hyoid (greater horn and part of body) Part of epiglottis Thymus Inferior parathyroid Piriform fossa

Thyroid cartilage Cuneiform cartilage Part of epiglottis Superior parathyroid (lateral anlage of thyroid gland)

Thymus (inconstant)

v Arch Pouch

Ultimobranchial body (lateral anlage of thyroid gland)

VI Arch Pulmonary artery Ductus arteriosus (L) Nerve X (recurrent laryngeal)

Cricoid Arytenoid Corniculate cartilage

I

From Skandalakis JE, Gray SW, Todd NW: The pharynx and its derivatives. In SkandalakisJE, Gray SW (eds): Embryology for Surgeons, 2nd ed. Baltimore, Williams & Wilkins, 1994.

supratonsillar fossa. Third and fourth pouch sinuses and fistulas enter the pharynx through the piriform sinus but in different extremes of the sinus. Franciosi and associates have emphasized that third branchial cleft anomalies enter the base (superior portion) of the piriform sinus and ascend over the superior laryngeal nerve, whereas fourth anomalies enter the apex (inferior portion) and descend below that nerve.Z4 The only pouch, closing membrane/cleft complex to persist is the first one, which becomes the eustachian tube/middle ear, tympanic membrane, and external auditory canal (see Fig. 5 6 - 4 ) . The remainder of the branchial pouches normally give rise to the tonsils, the thymus, the parathyroids, and the C cells of the thyroid gland. The outer cleft components regress (see Figs. 564B and 566). Of these glands, only the tonsils remain at their pouch of orign. The third branchial pouch becomes elongated and

eventually loses its communication with the pharynx. It differentiates dorsally into the future inferior parathyroid (111),coming to rest close to the inferior pole of the thyroid and ventrally into the ipsilateral lobe of the thymus in the superior mediastinum. Embryologists agree that the future superior parathyroid gland arises from the fourth branchial pouch. They disagree as to whether the ultimobranchial body (lateral anlage of the thyroid gland and source of the calcitonin-producing C cells) arises from the fourth branchial or a vestigial fifth pouch (see Fig. 56-4). Based on immunohistochemical studies of resected specimens of the thyroid glands and fitulas from 15 patients, Miyauchi and colleagues have argued convincingly that these fistulas are in fact remnants related to the ultimobranchial body.5* Himi and Kataura's work on the distribution of C cells in the thyroid gland with pirifonn sinus fistula supports this i n t e r p r e t a t i ~ n . ~ ~

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The migration of fourth pouch structures is much less extensive than that of the third pouch derivatives: the parathyroid tissue normally is found on the dorsal surface of the superior thyroid, and the C cells find their way into the thyroid gland itself. Lateral cysts and sinuses of the neck can result from persistence of the second, third, or fourth pouches themselves or from rests of thymic or parathyroid tissue, which may be left anywhere along the route of their migrations. Demonstration of thymic tissue within a cyst wall does not reliably indicate origin because both third and fourth pouches may normally contain thymic tissue. The thyroid gland develops from a bilobate diverticulum in between the muscular forerunners of the anterior and posterior portions of the tongue at a site that persists as the foramen cecum (Fig. 56-6). The gland descends in the midline of the neck anterior to the hyoid bone and comes to rest in the lower neck. Its transient connection to its point of origin is a cord of cells known as the thyroglossal duct. The lower end 'of this duct often persists as the pyramidal lobe. When the thyroglossal duct itself persists, the most important features to remember from a surgical point of view are the relation of this duct to the hyoid bone and the structure of the ductal remnants between the hyoid bone and the foramen cecum. The demonstration by three-dimensional reconstructions of thyroglossal duct surgical specimens by Horisawa elegantly shows why the central portion of the hyoid bone as well as a core of tissue from the hyoid to the foramen cecum must be removed with the cyst to prevent recurrence (Fig. 56-7).35 Rarely the thyroid gland may not complete its descent. It most commonly remains in the base of the tongue but

Second branchial cleft cyst and sinus tract (right); third branchial cleft cyst and sinus tract (left). (From Donegan JO: Congenital neck masses. In Cummings CW, et a1 [eds]: Otolaryngology-Head and Neck Surgery, 2nd ed. St Louis, Mosby-Year Book, 1993.)

Maxillary process

+ :/

prOces)cl\ I : "m ys;P

Pharyngeal

External auditory meatus

Auditory tube Palatine

Parathyroid gland

Epicardial ridge

\

1 1

Ultirnobranchial body

A, Schematic representation of the development of the pharyngeal clefts and pouches. Note that the second arch grows over the third and fourth arches, thereby burying the second, third, and fourth pharyngeal clefts. B, Remnants of the second, third, and fourth pharyngeal clefts form the cervical sinus, which is normally obliterated. Note the structures formed by the various pharyngeal pouches. (From Sadler 7Ui: Head and neck. In Langman's Medical Embryology, 7th ed. Baltimore, Williams & Wilkins, 1995.)

CHAPTER

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Cysts a n d Sinuses of the Neck

865

Hyoid bone

Diagram of the common running pattern of the thyroglossal duct based on anatomic reconstruction. a, Horizontal distance from midline to the most distant thyroglossal duct; b, length of the single duct above the hyoid bone; c, point where the diameter of the duct is measured. (From Horisawa M, Niinomi N, Ito T: What is the optimal depth for core-out toward the foramen cecum in a thyroglossal duct cyst operation? J Pediatr Surg 1992;27:710.) Anatomic relationships of probable course of fourth branchial fistula.(From Liston SL: Fourth branchial fistula. Otolaryngol Head Neck Surg 1981;89:520.)

at times can come to rest at a more distal site along the route to the base of the neck. This anomaly now has not only surgical, but also medicolegal implications related to informed consent, preoperative workup, and intraoperative management.@ Auditory tube

INCIDENCE ,Ventral

I

side of

cecum

Palat~netonsil

Superior parathyroid gland

Ultimobranchialbody

In a review of 481 procedures in 445 pediatric patients 18 years and younger whose neck masses were excised at Children's Hospital of Philadelphia during a 5-year period, congenital neck masses were diagnosed in 244 paticnts (55%). Of these, 78 (32%) were branchial cleft anomalies, 73 (30%) were thyroglossal duct cysts, and 43 (18%) were dermoids.78 Thyroglossal duct cysts were somewhat more common than branchial anomalies in the Mayo Clinic series of 612 adults and children: 55% versus 45%.72In a 15-year French series of 191 children, defects of midline closure outnumbered those of branchial migration: 53% had thyroglossal duct cysts, 11%had dermoid cysts, 19% had second cleft anomalies, 10% had first cleft anomalies, 4% had fourth pouch anomalies, and 2% had thymic

SECOND BRANCHIAL ANOMALIES Schematic representation of migration of the thymus, parathyroid glands, and ultimobranchial body. The thyroid gland originates in the midline at the level of the foramen cecum and descends to the level of the first tracheal ring. (From Sadler TW: Head and neck. In Langman's Medical Embryology, 7th ed. Baltimore, Williams & Wilkins, 1995.)

More than 90% of branchial cleft anomalies are estimated to arise from the second branchial system. Approximately 8% are attributed to first branchial malformations, whereas those of the third and fourth systems rarely occur.ll The ma1e:female ratio is generally reported to be equal. When a sinus is present, most branchial anomalies

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are diagnosed in the first decade of life; when there is no external sinus, the diagnosis may not be made until well into adulthood. Seventy-four percent of the branchial anomalies in the Mayo Clinic series were cysts, 25% were fistulas, and 1% were skin tags or cartilage^.^' Surprisingly, in the review from the Hospital for Sick Children, London, 92 of 98 second branchial cleft/pouch anomalies over a 32-year period had sinus openings in the neck, which may be partially explained by the fact that all but two of the patients were diagnosed by the age of 10 and 78% by the age of 5 years.Y3 Six patients had cartilaginous remnants in the neck without a sinus opening (Fig. 56-8). Six (6%) anomalies were bilateral. Other reports of bilaterality range from 2% to 10%.Y6 Typically, drainage from a tiny pit in the skin anterior to the lower third of the sternocleidomastoid muscle draws attention to the presence of a second branchial cleft sinus or fistula (Fig. 569). A cord may be palpable running upward in the neck from the ostium. Milking or stripping the tract provides a mucoid discharge. A cyst presents as a soft mass deep to the upper third of the same muscle. The sudden appearance of a painful mass in this location may be the first sign of one of these lesions. Unusual presentations include stridor, pharyngeal cyst causing sore throat, feeling of fullness in the throat, hyponasal speech, dysphagia or odynophagia, a cold nodule on thyroid scan,70a hot nodule on thyroid scan,70 an isolated hypoglossal nerve palsy? or multiple cranial nerve palsies.I8 Branchial anomalies may occur as part of the branchio-oculofacialsyndrome.44Branchiogenic carcinoma has been diagnosed in adults but not in children.27 Because of the likelihood of infection developing in any of the branchial cleft anomalies, excision is generally recommended at the time of diagnosis in a noninfected lesion. Surgery in infants is delayed until 3 to 6 months. Excision is delayed in any patient in the presence of infection. Antibiotics and possibly needle aspiration are advised to eradicate the infection. Incision and drainage are avoided when possible because this results in distortion

Site of branchial cleft sinuses. (From Ford GR, et al: Branchial cleft and pouch anomalies. J Laryngol Otol 1992;106:137.)

Unilateral discharging second cleft sinus. (From Ford GR, et al: Branchial cleft and pouch anomalies. J 1,aryngol Otol 1992;106:137.)

of normal tissue planes, which may contribute to the higher recurrence rate after excision in this group of patients. Two thirds of the patients in the Mayo Clinic series who had recurrences after surgery for branchial cleft anomalies had had previous surgery or infection (or both) .72 In a child, a second branchial anomaly with an external opening can usually be excised through a single incision incorporating the sinus opening, whereas in adolescents and adults two stepladder incisions may be required. In contrast to thyroglossal duct cysts, these tracts are single and relatively well defined, which allows one to stay close to the tract wall in the dissection. Placement of a catheter, Prolene suture, or metal probe in the tract may be helpful. Injection of methylene blue into the tract can complicate the dissection if there is any spillage. Preoperative fistulography can be helpful but is not generally employed.lO The primary objective in the excision of all of these lesions is to do a complete excision without injuring important adjacent structures, which, in a second branchial anomaly, includes the external and internal carotid arteries and the hypoglossal and glossopharyngeal nerves (see Fig. 563). The excision of a second branchial cyst varies only in that the incision is made over the cyst and adjacent to the carotid artery bifurcation. Techniques for minimally invasive surgery on the neck are in the process of development using porcine and cadaver model^.^^,^^ A telescope and two dissecting ports placed in three incisions located at the base of the neck are employed. Use of a hernia balloon designed for laparoscopic herniorrhaphy to create a surgical pocket that can be maintained with compressed carbon dioxide pressures as low as 4 mm Hg has been demonstrated in

CHAPTER

these models to be free of complications noted in earlier techniques, namely, subcutaneous emphysema, pneumothorax, pneumomediastinum, and air embolism. "Compelling" advantages in further porcine experiments by these same researchers using endorobotic technology (the DaVinci system) were noted: increased surgical precision and dexterity and decreased impact of tremor with the three-dimensional imaging, Endowrist articulation, and motion scaling." The technique has been used successfully only once in this country as of this writing to remove a lymph node, but broader application, including use in excision of congenital neck lesions, may be on the horizon as the technique is refined and instrumentation is improved.'

FIRST BRANCHIAL CLEFT ANOMALIES First branchial cleft anomalies can be hard to diagnose. They are rare, yet when inflamed they may present in the same areas where infected submandibular or sebaceous glands typically manifest themselves (Fig. 56-10). Several hints may serve to alert the clinician that a first branchial anomaly is the underlying cause: a history of drainage below the angle of the mandible before infection, lack of deep induration, relatively nonpurulent drainage from the ear, or a cystic lesion of the tympanic membrane or middle ear coexisting with a sinus or abscess above the hyoid bone.16.77 Obviously a careful otologic examination is an important part of the evaluation of such patients. As with second cleft anomalies, cysts outnumber sinuses and fistulas in all age groups and tend to present later. Of 460 patients with branchial cleft anomalies treated at the Mayo Clinic from 1950 to 1978,38 (8%)were defects of the first branchial cleft. Twenty-six of the 38 (68%) were cysts, and 17 (65%) occurred in females. The mean age of patients with cysts was 15 years with a range of 13 to 18 years. In contrast, patients with sinuses and fistulas are diagnosed or first treated at a younger age when sex distribution tends to be Infection, which commonly occurs before the correct diagnosis is made, leads to scar formation and distortion of normal landmarks.

56

Cysts a n d Sinuses of t h e Neck

867

Two types of anomalies have been distinguished by h o t 6 and Work.83 The rarer of the two, type I, is considered a duplication of the membranous external auditory canal. It presents at a later age, is located lateral to the facial nerve, has an ectodermal (squamous epithelial) lining, and tends to parallel the external canal presenting just in front orjust behind the ear. Twe I1 lesions are duplication anomalies of the membranous external auditory canal and pinna and consist of both ectodermal and mesodermal (cartilage) elements (Fig. 5611). Olsen and coworkers maintain that a classification dividing the lesions into isolated cysts, sinuses, or fistulas more accurately depicts the anatomic findings and achieves a better understanding of the appropriate diagnosis and management." When a first branchial anomaly is suspected, it may be helpful to obtain a sonogram or computed tomographic (CT) scan to demonstrate the course of the tract and its relationship to the facial nerve and middle ear. First branchial anomalies are hazardous to repair, particularly in younger age groups. The most important point in this operation is to expose the main trunk of the facial nerve at the beginning of the operation and to expose all branches of the nerve to the periphery40 It is important to emphasize the fact that injury to the facial nerve during parotid surgery is one of the most common causes of facial paralysis in children.2~42On the basis of dissections in infant cadavers, Farrior and Santini point out why: in children, the facial nerve is smaller, more superficial, and more difficult to identify because of the underdevelopment of surrounding structures.2 They and others55

External canal

i

Postauricular

17

Angle mandible

\

General location of first branchial cleft anomalies. (From Olsen KD, Maragos NE, Weiland LH: First branchial cleft anomalies. Laryngoscope 1980;90:423.)

Type I branchial cleft abnormality (right); type I1 branchial cleft abnormality (lqt). (From Donegan JO: Congenital neck masses. In Cummings CW, et a1 [eds]: Otolaryngology-Head and Neck Surgery, 2nd ed. St Louis, Mosby-Year Book, 1993.)

868

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PlRlFORM SINUS FISTULAS

Facial nerve trunk exits stylomastoid foramen through triangle formed by cartilaginous ear canal, sternocleidomastoid muscle, and digastric muscle (dotted lines). In infants, pes anserinus is located posterior to ramus of the mandible. (From Farrior JB, Santini H: Facial nerve identification in children. Otolaryngol Head Neck Surg 1985;93:173.)

recommend initial exposure of the nerve as it exits the stylomastoid foramen by making a retroauricular, rather than preauricular, incision and identifying it in the triangle formed by the sternocleidomastoid muscle, posterior belly of the digastric muscle, and cartilaginous ear canal (Fig. 5612). In cases in which previous infection makes identification of the facial nerve outside the temporal bone difficult, Todd alternatively recommends finding the nerve within the mastoid, then following it to the stylomastoid foramen.76 After the main trunk of the nerve is exposed, its branches are dissected peripherally and the superficial lobe of the parotid gland is removed. When the tract is located deep to the nerve, a total parotidectomy is carried out. The tract is then separated from the branches of the nerve and followed to its junction with the ear canal. Even when the tract does not enter the canal, a portion of the adjacent cartilage and skin lining of the ear canal should be excised to prevent recurrence. The resulting defect in the canal is allowed to close by secondary intention and rarely results in stenosis. It is uncommon for the tract to involve the tympanic membrane or middle ear, but when it does, partial tympanic membrane excision, tympanoplasty, and curettage of the small portion of the tract that traverses the temporal bone is required.77 Ikarashi and colleagues state that in excising one of these lesions the surgeon should recognize the possibility that the tract may extend parallel to .~~ the eustachian tube as far as the n a ~ o p h a r y n x When the tract is closely adherent to the submandibular gland, this gland should be removed with the tract? Electrophysiologic facial nerve localization has been used in type I branchial cleft cyst excision to allow safe total excision through a smaller surgical approach than generally advocated, obviating facial nerve trunk localization. In a report on 11 children operated on over a 9-year period, Isaacson and Martin emphasize that this technique is appropriate when the lesion is superior to the stylomastoid foramen and not previously infected or surgicallyviolated.38

The rarest anomalies of the branchial apparatus, those attributed to remnants of the third and fourth pouch/ cleft complexes, have the potential for causing two difficult clinical scenarios: life-threatening respiratory compromise in the neonatal period12,24,45,"," and acute t h y r ~ i d i t i s .Because ~ ~ , ~ ~ both presentations are rare, delay in diagnosis often occurs, with the result that landmarkdistorting incision and drainage procedures are done, which complicate definitive management. More rommonly, children with a piriform sinus give a history of repeated upper respiratory tract infections and sore throats and often pain and tenderness of the thyroid with or without suppuration. Adults with the condition often recall their initial episodes from childhood. Hoarseness is frequent. Swallowing is often painful, and the head may be held preferentially in extension.51 The keys to correct diagnosis are a high index of suspicion and the demonstration of the mouth of a fistula in the piriform sinus. As noted previously it is now believed that third branchial anomalies enter the base of the piriform sinus (superior portion) and fourth branchial anomalies enter the apex (inferior portion) .24 Most of these anomalies-and all of them in neonates reported to date--occur on the left side of the neck. In utero diagnosis has now been made.'j5 In this report the possibility of the development of congenital high airway obstruction syndrome (CHAOS) was entertained and a multidisciplinary team was assembled at delivery for management of possible life-threatening airway obstruction, which fortunately did not occur.'j5A prenatally diagnosed cyst may be absent at birth only to become evident with feedings.12 Beyond the newborn period, delay in diagnosis occurs when patients present with evidence of infection associated with a swelling usually in the left neck adjacent to the upper pole of the thyroid gland. This may be diagnosed as unilateral thyroiditis or as suppurative lymphadenitis. Because incision and drainage can complicate definitive management, it is important to recognize the possibility of an underlying piriform sinus fistula as the source of the infection. Upper endoscopy or imaging can be used to make the diagnosis. In one retrospective study comparing the effectiveness of barium esophagography, CT, magnetic resonance imaging (MRI), and sonography, CT was the most reliable study for visualizing the sinus or fistulous tract and for evaluating the extent of the lesion.60 In the presence of acute infection a barium esophagogram may fail to show the fistula, which is then able to be demonstrated when the infection resolves. At the time of definitive surgery, cannulation with a Fogarty catheter, guidewire, or lacrimal duct probe, most easily performed by direct, rather than flexible, endoscopy, has been reported to be an aid in the dissection during surgery, as has placing an esophageal bougie Nonomura to aid in the palpation of the ~atheter.2~,+3-58JY and associates advocate a horizontal incision of the thyroid cartilage ala followed by medial retraction of the strap muscles, vertical incision of the inferior pharyngeal constrictor muscle, disarticulation of the cricothyroid joint, and anterior retraction of the thyroid ala." Others favor exposing the thyroid gland near its upper pole and then

CHAPTER

laryngeal nerve

Recurrent

Approach B

Piriform sinus f

Approach A

'

Common carotid

Schema of surgical approaches to a piriform sinus fistula. Approach C is approach recommended by Nonomura and colleagues. (From Nonomura N, et al: Surgical approach to piriform sinus fistula. Am J Otolaryngol 1993;14:111.)

dissecting superiorly51 or identifying the fistula at the inferior border of the thyroid cartilage after incising the skin over the cricoid cartilage, retracting the thyroid gland laterally, and then exposing the cricothyroid and cricopharyngeal muscles (Fig. 56-13).53 Enepekides stresses that the recurrent laryngeal nerve, which runs deep and medial to these lesions, must be identified and protected and notes that partial resection of the thyroid cartilage may be required for adequate exposure.2Vhe external branch of the superior laryngeal nerve is also at risk in these dissections (Fig. 56-14). Resection of the

:

yifor& sinus 1

d

'~ecurrentlaryngeal n.

Thyroid abscess with piriform sinus tract. The tract passed up to the superior laryngeal nerve and superficial to the recurrent laryngeal nerve. Note: this would correspond to the course of a fourth branchial cleft sinus opening at the apex of the piriform sinus and descending deep to the superficial laryngeal nerve.

56

Cysts a n d Sinuses of t h e Neck

869

tract, adjacent scar tissue, and a portion of the thyroid gland or even hemithyroidectomy, when adherent to the tract, as well as ligation of the fistula opening in the piriform sinus, are regarded as essential steps in totally eradicating these lesions and reducing the chance of recurrence to a minimum. There are possible exceptions to the rule of complete excision to prevent recurrence in the piriform sinus fistulas. The course of fourth branchial anomalies remains theoretical, a complete tract as illustrated in Figure 56-5 looping around the subclavian artery on the right and around the aorta on the left never having been demonstrated. Shugar and Healy advise against an overly aggressive attempt to remove a mediastinal tract.67 To date, dissections of suspected fourth cleft tracts descending deep to the clavicle have been performed from the neck with no attempt to expose the aorta without reported r e ~ u r r e n c e . 2 8 ,Furthermore, ~~,~~ there are now reports of obliteration of the piriform sinus tracts endoscopically with either electrocautery39 or trichloroacetic acid.60 Follow-up in the limited number of patients so treated has been short with the longest follow-up only 6 years. Additional experience with these techniques may support their use in patients in whom repeated infection and previous surgery make further attempts at complete excision hazardous.

THYROGLOSSAL DUCT CYSTS Surgeons may rarely be in doubt preoperatively about the diagnosis of a midline neck mass, but they are often wrong. Knight and coworkers found specific preoperative diagnosis made by 28 surgeons over a 10-year period The l surgeon's to be correct in only 61% of 146 c a s e ~ . ~ postoperative diagnosis was the same as the final diagnosis in only 83% of the cases. Slightly more than 50% of their cases were thyroglossal duct cysts, 25% were epidermoid cysts, 15%were enlarged lymph nodes, 1.4% were median ectopic thyroid, and the remaining 5% were inflammation of unknown cause. Similarly, Torsiglieri and colleagues found only 70% of 97 children with thyroglossal duct cysts were diagnosed correctly before surgery.72 In the Mayo Clinic series, the presentation was that of a cyst in 78% of 263 cases and a draining sinusalways the result of spontaneous or surgical drainage-in the remainder; 40% were located slightly lateral to the midline.72 In a collected series of 381 patients, 60% were adjacent to the hyoid, 24% above the hyoid, 13% below A third had history of the hyoid, and 8% intraling~al.~ prior infection, and a fourth had prior surgical intervention. A variety of aerobic and anaerobic organisms have been isolated. Haemophilus injluenzae and Staphylococcus aureus were the most commonly identified bacteria in one large series.GgMales and females are equally affected in most series. Most cases have a relatively benign presentation as a painless swelling, a draining sinus, or a tender mass. Occasionally, a patient complains of a bad taste in the mouth associated with spontaneous decompression of a cyst. Movement of the cyst with swallowing is often cited as a reliable diagnostic sign but can be difficult to evaluate

870

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in young children and is often present with other lesions when located near the hyoid bone. Unusual pediatric pres entations include severe respiratory distress or even sudden infant death when these lesions are located at the a solitary j cold thyroid nod~le,~8270 base of the t ~ n g u e , ~ @ lingual thyroid presenting after previous thyroglossal cyst excision,3 a lateral neck mass,70anterior tongue fistula,56 actinomycosis in a persistent thyroglossal duct73 sublingual contiguous thyroglossal and dermoid cysts,17 Hodgkin's disease,29 and coexistence of thyroglossal and branchial cleft cvsts.72 It is ideal to be as accurate as possible preoperatively about the diagnosis of a suspected thyroglossal duct cyst; however, more important is determining when not to operate and when to alter a planned procedure intraoperatively. The question of what preoperative tests are needed for suspected thyroglossal duct cysts is a complex and controversial one. Many authorities state categorically that a thyroid scan should be done in all such cases to rule out an ectopic thyroid gland. Hypothyroidism as a result of removing a patient's only functioning thyroid tissue could thereby be avoided, although as Enepekides points out, most patients with cervical ectopic thyroid are hypothyroid.20 Treatment with exogenous thyroid in such patients might result in reduction in the size of an ectopic gland that has hypertrophied in response to increased metabolic needs. In such cases, surgery could be avoided altogether. Furthermore, it has been reported anecdotally that physicians have been successfully sued for excising an ectopic The financial implications of scanning all patients with midline masses in the neck, however, are significant, and alternate strategies for dealing with this issue have been proposed. The incidence of ectopic thyroid misdiagnosed as a thyroglossal duct cyst is reported to be between 1% and 2%.4The incidence is lower if one considers that the denominator should include dermoid cysts and anterior cervical lymph nodes, which are also frequently misdiagnosed as thyroglossal duct cysts. It would therefore theoretically require performing more than 100 negative scans to identify one ectopic thyroid, a substantial expense, not to mention the unnecessary radiation exposure to hundreds of patients. Basing their recommendations on a retrospective study of children undergoing thyroid scans at Boston Children's Hospital, Cleveland's Rainbow Babies, and Children's H o s ~ i t a lbetween 1978 and 1987. Radkowski and colleagues advise obtaining scans only when a careful history and physical examination or abnormal thyroid function studies suggest hypothyroidism (i.e., chronic constipation, developmental and growth delay, excessive somnolence, weight gain despite poor feeding habits, and elevated thyroid-stimulating hormone) ." Others recommend obtaining a scan when preoperative ultrasound indicates the neck mass to be solid or thyroid tissue cannot be demonstrated in the normal locaWhen a solid lesion is discovered unexpectedly at surgery, it is reasonable to obtain a frozen section to confirm the diagnosis. A decision then has to be made whether to preserve the gland by autotransplantation or

to excise the possibly dysgenetic gland. In both cases, lifetime treatment with exogenous thyroid is generally recommended, although in some cases with residual thyroid tissue supplementation has not been necessary.30 Ideally, parents should be informed preoperatively about these possibilities. CT,21 MRI,S1 fi~tulography,~~ and fine-needle aspiration63 in addition to thyroid hormone levels, ultrasound, and thyroid scans have all been described or advocated for preoperative workup of midline cervical masses. Their use in children in the absence of associated pathologic adenopathy, suspicion of impingement on laryngeal structures, or multiple recurrences is rarely needed; however, with appropriate indications, they can be helpful (Figs. 56-15 and 56-16). An infected thvro~lossal duct cvst should be treated , " initially with antibiotics and, if necessary, needle aspiration. Incision and drainage, which may result in seeding of ductal epithelium, is to be avoided when possible to reduce the-chance of recurrence after subseauent excision. Perioperative antibiotics are recommended at the time of a Sistrunk procedure for a previously infected cyst. Overnight admission after excision is not required in the absence of difficulty with breathing or swallowing or an unreliable family situation.33 Management of recurrent thyroglossal duct cysts has been addressed in a number of re~orts.I"~"~"61.75 Although most recurrences are identified early, intervals of up to 39 years have been reported." Young patient age, skin involvement, previous or concurrent infection, lobulation of the cyst, rupture of the cyst at operation, and failure to remove the central portion of the hyoid and a core of tissue above it are all factors that predispose to recurrence. Principles in reoperations include a wider dissection extending inferiorly to remove a pyramidal lobe if present, removal of the central 3 to 4 cm of strap muscles down to the level of the pretracheal fascia, and a wider re-excision of the mid-hvoid bone and core of tissue to the foramen cecum.50Adherence to these guidelines should reduce the 25% to 35% recurrence rates reported after re-excision.~0~69 It is estimated that less than 1% of thyroglossal duct ~ of the 158 cases cited cysts develop c a r ~ i n o m a .Most through 1994 have occurred in adults, but a child as , ~ ~are ; papyoung as 6 years old has been r e p ~ r t e d ~80% illary carcinoma, but all types of thyroid malignancy are ~~ represented except for medullary c a r ~ i n o m a .A Sistrunk procedure is considered adequate treatment when invasion of the capsule and regional or distant metastases are not present. Cure rate of 95% is expected for papillary carcinoma with this procedure. More radical surgery and postoperative radiation are indicated for other types of carcin~rna.~O

DERMOID CYSTS The diagnosis of a cervical dermoid cyst is based on the histologic findings of epidermis with epidermal appendages, such as hair follicles, hair, and sebaceous glands, within the cyst wa11.I4 These cysts form along the

CHAPTER

56

Cysts a n d Sinuses of the Neck

871

Lateral (A) and anteroposterior (B) views of the two anterior neck masses in a clinically euthyroid l4year-old girl. The superior one had been present for a year. The lower one had been present for 2 to 3 months and was increasing in size.

lines of embryonic fusion in the anterior neck. They are frequently confused preoperatively with thyroglossal duct cysts because they have the same distribution and may become inflamed. Similarly, there may also be confusion intraoperatively when these lesions are closely approximated to the hyoid bone. It is now recommended that a Sistrunk procedure be performed when "~~ or opening these cysts may there is d o ~ b t . l Aspirating result in spillage of cyst contents, which, in turn, may lead to infection or recurrence.

PREAURICULAR CYSTS

Anterior view of a 99mTc sodium pertechnetate thyroid scan performed after ultrasound showed the masses to be solid. The thyroid-stimulating hormone level was found to be at the upper limits of normal. Activity in the two clinically obvious masses, a previously unrecognized lingual mass at the base of the tongue, and no activity in the lower neck are evident. These findings were consistent with ectopic thyroid tissue at the three sites. The patient received '"1 for ablation of this tissue at the recommendation of a pediatric endocrinologist. The masses resolved. Now 9 years later as a pharmacy student she continues to d o well on thyroid replacement therapy.

Preauricular cysts are included in this discussion not because they truly represent cysts or sinuses of the neck but because they need to be distinguished from first branchial cleft cysts. The former are common; are often bilateral; tend to be inherited; and only in rare cases are complicated by infection, involve the facial nerve, or enter into the external auditory canal.4YThey are believed to arise as a result of anomalies in the formation of the external ear from the two sets of three hillocks located on the dorsal end of the first two branchial arches. Singer stressed the fact that typically a series of cysts are found in continuity with the cutaneous sinus.@ Successful excision through an inverted L-shaped incision requires removal of all ductal epithelium, which can be quite difficult when there is scarring from prior infection. It is generally agreed that surgery is indicated for symptomatic lesions, but it is not clear when or if asymptomatic ones should be removed. Many never cause a problem.

CHAPTER

44. Lin AE, Losken HW, Jaffe R, Biglan AW: The branchiooculo-facial syndrome. Cleft Palate Craniofac J 1991;28:96. 45. Lin JN, Wang KL: Persistent third branchial apparatus. J Pediatr Surg 1991;26:663. 46. Liston SL: The relationship of the facial nerve and first branchial cleft anomalies-embryologic considerations. Laryngoscope 1982;92:1308. 47. Massoud TF, Schnetler JF: Case report: Taste of success in thyroglossal fistulography. Clin Radio1 1992;45:281. 48. McHenry CR, Danish R, Murphy T, MartyJ: Atypical thyroglossal duct cyst: A rare cause for a solitary cold thyroid nodule in childhood. Am Surg 1993;59:223. 49. Melnick M, Myrianthopoulos NC, Paul NW: External ear malformations: Epidemiology, genetics, and natural history. Birth Defects Orig Artic Ser 1979;15:i. 50. Mickel RA, Calcaterra TC: Management of recurrent thyroglossal duct cysts. Arch Otolaryngol 1983;109:34. 51. Miller D, Hill JL, Sun CC, et al: The diagnosis and management of pyriform sinus fistulae in infants and young children. J Pediatr Surg 1983;18:377. 52. Miyauchi A, Matsuzuka F, Kuma K, Katayama S: Piriform sinus fistula and the ultimobranchial body. Histopathology 1992;20:221. 53. Miyauchi A, Matsuzuka F, Kuma K, Takai S: Piriform sinus fistula: An underlying abnormality common in patients with acute suppurative thyroiditis. World J Surg 1990;14:400. 54. Mouri N, Muraji T, Nishijima E, Tsugawa C: Reappraisal of lateral cervical cysts in neonates: Pyriform sinus cysts as an anatomy-based nomenclature. J Pediatr Surg 1998; 33:1141. 55. Murthy P, Shenoy P, Khan NA: First cleft branchial fistula in a child-a modified surgical technique. J Laryngol Otol 1994;108:1078. 56. Ngo HH, Frenkiel S, Satin R: Thyroglossal duct cyst presenting as an anterior tongue fistula, J Otolaryngol 1988; 17:227. 57. Nicollas R, Guelfucci B, Roman S, Triglia JM: Congenital cysts and fistulas of the neck. Int J Pediatr Otorhinolaryngol 2000;55:117. 58. Nonomura N, Ikarashi I?, Fujisaki T, Nakano Y: Surgical approach to pyriform sinus fistula. Am J Otolaryngol 1993;14:111. 59. Olsen KD, Maragos NE, Weiland LH: First branchial cleft anomalies. Laryngoscope 1980;90:423. 60. Park SW, Han MH, Sung MH et al: Neck infection associated with pyriform sinus fistula: Imaging findings. AJNR Am J Neuroradiol 2000;21:817. 61. Pelausa ME, Forte V: Sistrunk revisited: A 10-year review of revision thyroglossal duct surgery at Toronto's Hospital for Sick Children. J Otolaryngol 1989;18:325. 62. Pinczower E, Crockett DM, Atkinson JB, Kun S: Preoperative thyroid scanning in presumed thyroglossal duct cysts. Arch Otolaryngol Head Neck Surg 1992;118:985.

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63. Pitts WC, Tani EM, Skoog L: Papillary carcinoma in fine needle aspiration smears of a thyroglossal duct lesion. Acta Cytol 1988;32:599. 64. Radkowski D, Arnold J, Healy GB, et al: Thyroglossal duct remnants: Preoperative evaluation and management. Arch Otolaryngol Head Neck Surg 1991;117:1378. 65. Robichaud J, Papsin BC, Forte V: Third branchial cleft anomaly detected in utero. J Otolaryngol 2000;29:185. 66. Samuel M, Freeman NV, Sajwany MJ: Lingual thyroglossal duct cyst presenting in infancy. J Pediatr Surg 1993;28:891. 67. Shugar MA, Healy GB: The fourth branchial cleft anomaly. Head Neck Surg 1980;3:72. 68. Singer R: A new technic for extirpation of preauricular cysts. Am J Surg 1966;111:291. 69. Solomon JR, Rangecroft L: Thyroglossal-duct lesions in childhood. J Pediatr Surg 1984;19:555. 70. Sonnino RE, Spigland N, Laberge JM, et al: Unusual patterns of congenital neck masses in children. J Pediatr Surg 1989;24:966. 71. Takimoto T, Yoshizaki T, Ohoka H, Sakashita H: Fourth branchial pouch anomaly.J Laryngol Otol 1990;104:905. 72. Telander RL, Deane SA: Thyroglossal and branchial cleft cysts and sinuses. Surg Clin North Am 1977;57:779. 73. Terris DJ, Haus BM, Gourin CG: Endoscopic neck surgery: Resection of the submandibular gland in a cadaver model. Laryngoscope 2004;114:407. 74. Terris DJ, Monfared A, Thomas A, et al: Endoscopic selective neck dissection in a porcine model. Arch Otolaryngol Head Neck Surg 2003;129:613. 75. Tetteroo GW, Snellen JP, Knegt P, Jeekel J: Operative treatment of median cervical cysts. Br J Surg 1988;75:382. 76. Todd NW: Common congenital anomalies of the neck: Embryology and surgical anatomy, Surg Clin North Am 1993;73:599. 77. Tom LW, Kenealy JF, Torsiglieri AJ Jr: First branchial cleft anomalies involving the tympanic membrane and middle ear. Otolaryngol Head Neck Surg 1991;105:473. 78. Torsiglieri AJ Jr, Tom LW, Ross AJ 3rd, et al: Pediatric neck masses: Guidelines for evaluation. Int J Pediatr Otorhinolaryngol 1988;16:199. 79. Tyler D, Effmann E, Shorter N: Pyriform sinus cyst and fistula in the newborn: The value of endoscopic cannulation. J Pediatr Surg 1992;27:1500. 80. Van Vuuren PA, Balm AJ, Gregor RT, et al: Carcinoma arising in thyroglossal remnants. Clin Otolaryngol 1994;19:509. 81. Wadsworth DT, Siege1 MJ: Thyroglossal duct cysts: Variability of sonographic findings. AJR Am J Roentgen01 1994;163:1475. 82. Wagner CW, Vinocur CD, Weintraub WH, Golladay ES: Respiratory complications in cervical thymic cysts.J Pediatr Surg 1988;23:657. 83. Work WP: Newer concepts of first branchial cleft defects. Laryngoscope 1972;82:1581.

Torticollis Spencer Beasley

There are many causes of torticollis in childhood (Table 57-l), but most of these causes are rare. The most common cause of torticollis is tightness and shortening of one sternomastoid muscle, a condition that occurs in about 0.4% of all births. Typically, at about 3 weeks of age, a visible or palpable swelling develops in part or all of the muscle; this swelling is called a sternomastoid tumor. It affects the right side in about 60%,31is bilateral in 2% to 8%,4"4bndoften persists for up to 1 year. Older children may have a fibrotic, shortened sternomastoid muscle, which is presumed in many to be the legacy of a previously unrecognized sternomastoid tumor.

HISTORY Alexander the Great may have had torticollis, according to Plutarch." Antyllus is said to have performed tenotomies in 350 AD, but the first authenticated division of the sternocleidomastoid was by Minnus in Amsterdam in 1641.44

A sternocleidomastoid tumor was described by Heusinger in 1826.Z3 Torticollis was also a subject of interest to Dupuytren.l8

ETIOLOGY Little is known about the etiology of sternomastoid fibrosis, although several theories have been put forward to explain the condition. It may be due to an idiopathic intrauterine embryopathy29 or could be the manifestation of an intrauterine positional disorder with development of the sternocleidomastoid compartment syndrome.Z5The high incidence of obstetric difficulties, such as breech presentation and the need for assisted delivery,l0Jl may be the result rather than the cause of the shortened sternomastoid muscle. There is no report of a sternomastoid .~~ tumor detected by antenatal u l t r a s o ~ n dConcomitant hip dysplasia is common.1°

PATHOLOGY

/ cause Sternomastoid tumor Abnormal position in utero Cervical hemivertebrae Cervical lymphadenitis/ abscess Retropharyngeal abscess21 Posterior fossa tumors46 Acute atlantoaxial subluxation Atlantoaxial rotatory subluxation Spasmodic with gastroesophageal reflux Postural

Comment Common; appears at 3 weeks of age Tends to improve with age Structural; confirmed on plain radiograph Acute; usually occurs in first 2 years of life Acute; signs of toxicity A rare cause; other neurologic signs present May occur after tonsillectomy2 Significance disputed25; diagnosed on dynamic CT Sandifer's syndrome Familial

1

The basic abnormality on histology is fibrous replacement of muscle bundles." Joneszy has described endomysial fibrosis involving the deposition of collagen and fibroblasts around individual muscle fibers that undergo atrophy. The sarcoplasmic nuclei are compacted to form giant cells that appear to be multinucleated. The maturity of the fibrous tissue in neonates suggests that the disease may begin before birth17,29," and may therefore contribute to the frequency of obstetric difficulties during delivery. The reported incidence of breech deliveries is about 20% to 30%'-much higher than the normal incidence. About 60% of affected infants are involved in a complicated birth,14 which suggests that the fibrosis may affect the position of the fetus in utero and perhaps prevent normal engagement of the head in the maternal pelvis. The natural history of untreated sternomastoid fibrosis is complete resolution in 50% to 70% of patients at 6 months of age. In about 1076, the tumor and sternomasThe toid shortening persist beyond 12 months of severity and distribution of the fibrosis vary and have led

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to a variety of classifications based either on a palpable localized sternomastoid tumor or thickening and shortening of the whole muscle or on ultrasonographic findin~gs.2~~~2 The systems of classification have some prognostic significance in that localized lesions within the sternomastoid (clinically or ultrasonographically) are more likely to resolve spontaneously than those involving the whole muscle. In older children with torticollis, the appearance of degenerating fibers is more consistent with disuse atrophy produced by limitation of movement caused by the fibrosis.

CLINICAL FEATURES

.

Sternomastoid Torticollis The tumor is a hard, spindle-shaped, painless discrete swelling usually about 1 to 3 cm in diameter within the substance of the sternomastoid muscle. Over 90% develop before the age of 3 months.1° However, it usually first becomes evident at about 3 weeks after birth. Obvious head tilt or torticollis tends to develop later.49In infants, the head is rotated to the side opposite the tumor, with only slight flexion of the head to the affected side (Fig. 57-1). In other patients, the sternomastoid tumor is less discrete, and the sternomastoid appears to be thickened and tightened along its whole length. These changes restrict rotation and lateral flexion of the head (Fig. 57-2). The rotational component of the action of the sternomastoid is easy to measure. It is assessed by standing behind the child's head and passively rotating the head while it is held between both hands. The sternomastoid muscle is stretched to its maximum length by rotation to the side of the affected muscle. Where the muscle is fibrotic, it cannot be stretched to its full length, and rotation to the ipsilateral side is restricted. Older children with torticollis comDensate for the more pronounced tilt by elevating one shoulder to enable the eyes to keep as level as possible (Fig. 57-3). Such compensation is not seen in infants because there is no need &r them to maintain their eyes in a horizontal plane until Moreover, ~ older children do not turn they stand ~ p . 2 their heads to the contralateral side as much because

-

Appearance o f a right sternomastoid tumor in

infancy;the head is turned to the contralateral side.

they tend to compensate by twisting the neck and back to keep their eyes pointing forward.

Differential Diagnosis Initial clinical assessment must establish whether the wry neck is caused bv shortness of one sternomastoid musclk or by some other condition. In sternomastoid fibrosis, the anterior border of the muscle stands out as a tight band, although " in some small infants in whom the neck is relatively short, the muscle may be difficult to see readily. For this reason, the full length of the muscle must be palpated to determine whether there is an area of thick&ing or fibrosis along part or all of its length. In about two thirds, there is a definite localized swelling (tumor) in the muscle; in the remainder, the whole muscle appears to be affected. Though not required for diagnosis, it has a ~ r ~may ~h~ characteristic appearance o n ~ u l t r a ~ o n o that help predict (to a degree) the likelihood of spontaneous r e ~ o l u t i o n . l ~It~can ~ ~ ,also ~ 2 be diagnosed on magnetic rese nance imaging (MIU)l9 and computed tomography (CT).33 In cases in which the muscle is neither prominent nor shortened, the torticollis is not caused by an abnormality

D Normal range

Neutral position

Limited range

, -

Restriction o f

rotation o f the head secondary to shortening o f the sternomastoid muscle as viewed from above the head. The black bars represent the right sternomastoid muscle and show that its inability to lengthen limits rotation to that side.

CHAPTER

, Appearance of torticollis as a result of sternomastoid fibrosis in an older child. The eyes are kept horizontal, but the shortened sternomastoid muscle causes compensatory elevation of the shoulder. (From Beasley SW: Pediatric Diagnosis. London, Chapman & Hall, 1994.)

of the sternomastoid muscle, and alternative diagnoses must be sought (see Table 57-1 and Fig. 57-4).3,28 A squint may cause head tilt from imbalance in rotation of the eyes. The squint may not be obvious at first because the tilt compensates for the abnormal position of the eyes. When the head is straightened passively, the squint becomes apparent. Occasionally, sternomastoid fibrosis may occur coincidentally with ocular torticollis. Posterior fossa tumors may compress the brainstem at the foramen magnum and produce acute stiffness of the neck that causes it to be held to one side. The neck is frozen in this position and is difficult to move actively or passively. The presence of a central nervous system tumor may be known already, but occasionally, acute torticollis is the first manifestation. Careful neurologic examination may show abnormalities of the lower cranial nerves and cerebellar function, and the causative lesion is demonstrated on CT or MRI. Hemivertebrae involving the cervical spine may produce a tilt of the head that is evident from birth and does not progress. Vertebral lesions can be identified clinically by inspection and palpation of the dorsal cervical spines and confirmed on plain radiographs of the neck.

57

Torticollis

877

, Torticollis caused by atlanto-occipital subluxation after tonsillectomy. Notice that there is no tightness of the sternomastoid muscle on either side. (From Beasley SW: Pediatric Diagnosis. London, Chapman & Hall, 1994.)

Acute torticollis has been attributed to atlantoaxial rotatory subluxation as determined on dynamic CT,36837 but others doubt the existence or significance of these findings and suggest that CT scans are not necessary at the initial examination.24 Atlantoaxial subluxation has been reported after tonsillectomy.2 Acute torticollis can also result from inflammatory conditions of the neck, including retropharyngeal abscess,2I and can be a symptom of acute lymphoblastic leukemia.39

SECONDARY EFFECTS OF TORTICOLLIS Table 57-2 lists the secondary effects of torticollis.

Infant Older children

Plagiocephaly Facial hemihypoplasia Compensatory scoliosis

878

PART

V

HEADAND NECK

.

Gravity

Tight muscle

-

Plagiocephaly.

- - Head held rotated

Half occiput and face flattened

Plagiocephaly

Plagiocephaly In small infants with torticollis and fixed rotation of the head, gravity deforms the relatively soft head as it lies in the same position for a prolonged period. Flattening of one occiput leads to secondary flattening of the contralateral forehead (Fig. 57-5). This asymmetric skull deformity is called plagzocephaly and develops in the first few months of life.26 It is best observed from above the head. Once the child begins to sit up or the torticollis resolves, the plagocephaly tends to resolve as we11.35 It may take several years to disappear, and a few children have a slight permanent deformity.

Facial Hypoplasia

of the mandible and maxilla embodies an important principle of pediatrics: normal growth of bones depends on normal muscular movement. The degree of hemihypoplasia of the face can be determined by the angle between the plane of the eyes and the plane of the mouth. Normally these lines are parallel, but they form an angle to each other when the face is asymmetric. The development of hemihypoplasia is one indication for surgery; division of the tight sternomastoid muscle allows resolution of the skeletal abnormality and subsequent normal growth.25 Significant facial hemihypoplasia takes about 8 months is more often recognized at about 3 to to develop2"ut 4 years of age.15 It becomes less obvious with ongoing growth once the torticollis has resolved.

-

Progressive facial deformity is seen when one stemomastoid muscle immobilizes the face for a long time. The malar eminence on the side of the face limited by the fibrotic muscle grows more slowly than the normal side does2bnd causes progressive asymmetry (Fig. 57-6).This inhibition of growth

pOStura~ ~olnpensation When children are old enough to walk, the eyes are kept horizontal to facilitate balance and horizontal eye movement. The child compensates for the short fibrous sternomastoid by elevating the ipsilateral shoulder (see Fig. 57-3). In addition, there maybe compensatory cervical and thoracic scoliosis. Adjacent muscles, such as the trapezius, may be wasted because of inacti~ity.2~

CONSERVATIVE MANAGEMENT

.

Facial hemihypoplasia on the right side.

Sternomastoid fibrosis resolves spontaneously in the vast majority of infants. Therefore, surgery is required only rarely. The value of manipulation of the head and neck has not been proved,49 although it is widely used and may have some benefit in the first year of life.I2 Physiotherapy and regular neck exercises appear to be safe12 and may make the parents feel that "something is being done" for their infant. Unintentional snapping during manipulation has been reported with no apparent deleterious effect on outcome.8 Some clinicians advocate early institution of intensive passive neck range-of-motion stretching exercises but ~ ~no '~~~~ and have reported high rates of r e ~ o l u t i o n , 5 ~ convincing evidence has shown that these measures alter the natural history of the condition.

CHAPTER

Others consider it important to encourage parents to place toys and other desirable objects on the ipsilateral side to encourage the infant to turn toward the affected side.zWgain, this strategy probably helps the parent more than the infant but is unlikely to do any harm. Attempts to put the infant to sleep with the head facing toward the affected side tend to fail, particularly if the muscle is tight. In most cases, reassurance is all that is required.

57

Torticollis

879

Sternomastoid

\ nerve

OPERATIVE TREATMENT Indications for Surgery Indications for surgery include 1. Persistent sternomastoid tightness limiting head rotation beyond 12 to 15 months of age4' " 2. Persistent sternomastoid tightness with progressive facial hemihypoplasia 3. Diagnosis in children older than 1 year16

Operative Technique The procedure is performed under general anesthesia with laryngeal or endotracheal intubation, according to the expertise and preference of the pediatric anesthetist. The child is placed supine with the shoulders elevated and the neck rotated to the contralateral side. The muscle is best divided at its lower end,25," although division at its upper end,30 at both ends,l.7.22 or in its midportion20,2" have all been described. Endoscopic tenotomy of the muscle is also f e a ~ i b l e . ~ ~ l " ~ ~ A 3- to 4cm transverse incision is made in a skin crease about 1 cm above the sternal and clavicular heads of the affected sternomastoid (Fig. 57-7). The platysma is divided in the line of the incision. The external jugular vein can be retracted if it is within the field of view.

.

Brachial plexus (immediately deep to fascia)

Division of the sternomastoid and investing cervical fascia to the anterior border of the trapezius.

The two heads of the sternomastoid muscle are dissected free, and the muscle is divided via diathermy so that no bleeding occurs. The investing cervical fascia anterior and posterior to the muscle must also be divided and the division continued posteriorly across the lower part of the posterior triangle of the neck (Fig. 57-8). Tightness of the cervical fascia between the sternomastoid and trapezius is usually palpable, and the fascia should be divided under direct vision to avoid damage to other structures, particularly the accessory nerve and branchial plexus. The wound is infiltrated with bupivacaine or other local anesthetic agent. The platysma is closed with continuous 4 0 absorbable suture and the skin with subcuticular 5-0 Monocryl absorbable suture. No drains are required. The procedure can be performed as a day case, and no postoperative restriction of movement is necessary. Full range of the neck is normally achieved within 1 week of surgery. Physiotherapy is usually unnecessary, although some advocate an extended period of physiotherapy postoperatively.' In older children, however, it may take longer, and the final cosmetic appearance is less certain."

Complications

@

-

muscle.

Clavicle Skin incision for low division of the sternomastoid

A hematoma may develop if hemostasis was inadequate at the time of surgery. Diathermy dissection keeps blood loss to a minimum. Larger superficial veins may require ligation and division if they cannot be retracted. Incomplete division of both heads of the sternocleidomastoid muscle or failure to divide the cervical fascia over the posterior triangle of the neck may produce persistent torticollis. Careful inspection and palpation of the neck for residual tightness and bands at the time of surgery should prevent this complication from occurring. Recurrent torticollis is rare after surgical treatment and is seen in less than 3% of patients.48

880

PART

V

HEADAND NECK

Follow-up Patients should be monitored until (1) the torticollis has resolved completely, (2) there is full range of movement of the head and neck, and (3) the sternomastoid muscle feels normal. In an older child with secondary scoliosis, follow-up, including radiologic studies if required, should continue until the scoliosis has resolved.

REFERENCES 1. Arslan H, Gunduz S, Subasy M, et al: Frontal cephalometric analvsis in the evaluation of facial asvmmetrv in torticollis. and outcomes of bipolar release in patients over six years of age. Arch Orthop Trauma Surg 2002;122:489. 2. Bedi HS, Angliss RD, Williams SA, Connelly DP: Torticollis following adenotonsillectomy. Aust N Z J Surg 1999; 69:63. 3. Bredenkamp JK, Hoover LA, Berke GS, Shaw A: Congenital muscular torticollis. A spectrum of disease. Arch Otolaryngol Head Neck Surg 1990;116:212. 4. Burstein FD, Cohen SR: Endoscopic surgical treatment for congenital muscular torticollis. Plast Reconstr Surg 1998;101:20. 5. Cameron BH, Langer JC, Cameron GS: Success of non-operative treatment for congenital muscular torticollis is dependent on early therapy. Pediatr Surg Int 1994; 9:391. 6. Celayir AC: Congenital muscular torticollis: Early and intensive treatment is critical. A prospective study. ' ~ e d i a t rInt 2000;42:504. 7. Chen CE, KoJY: Surgical treatment of muscular torticollis for patients above six years of age. Arch Orthop Trauma Surg 2000;120:149. 8. Cheng JC, Chen TM, Tang SP, et al: Snapping during manual stretching in congenital muscular torticollis. Clin Orthop 2001;384:237. 9. Cheng JC, Tang SP: Outcome of surgical treatment of congenital muscular torticollis. Clin Orthop 1999;362:190. 10. Cheng JC, Tang SP, Chen TM: Sternocleidomastoid pseudotumor and congenital muscular torticollis in infants: A prospective study of 510 cases. J Pediatr 1999;134:712. 11. Cheng JC, Tang SP, Chen TM, et al: The clinical presentation and outcome of treatment of congenital muscular torticollis in infants-a study of 1,086 cases. J Pediatr Surg 2000;35: 1091. 12. Cheng JC, Wong MW, Tang SP, et al: Clinical determinants of the outcome of manual stretching in the treatment of congenital muscular torticollis in infants. A prospective study of 821 cases. J Bone Joint Surg Am 2001;83:679. 13. Cole R: Endoscopic surgical treatment for congenital muscular torticollis. Plast Reconstr Surg 1998;102:579. 14. Davids JR, Wenger DR, Mubarak SJ: Congenital muscular torticollis: Sequela of intrauterine or perinatal compartment syndrome. J Pediatr Orthop 1993;13:141. 15. de Chalain TM, Katz A: Idiopathic muscular torticollis in children: The Cape Town experience. Br J Plast Surg 1992;45:297. 16. Demirbilek S, Atayurt HF: Congenital muscular torticollis and sternomastoid tumour: Results of non-operative treatment. J Pediatr Surg 1999;34:549. 17. Dunn PM: Congenital sternomastoid torticollis: An intrauterine postural deformity.J Bone Joint Surg Br 1973;55:877. 18. Dupuytren G: Lecons Orales de Clinique Chirurgicale. Paris, JB Bailliere et Fils, 1839.

19. Entel RJ, Carolan FJ: Congenital muscular torticollis: Magnetic resonance imaging and ultrasound diagnosis. J Neuroimaging 1997;7:128. 20. Gurpinar A, Kiristioglu I, Balkan E, Dogruyol H: Surgical correction of muscular torticollis in older children with Peter G. Jones technique. J Pediatr Orthop 1998;18:98. 21. Harries PG: Retropharyngeal abscess and acute torticollis. J Laryngol Otol 1997;111:1183. 22. Hellstadius A: Torticollis congenita. Acta Chir Scand 1972;62:586. 23. Heusinger KP: Berichte von konighlichen, anthropanatomis chen Anstalt zur Wurtzburg, Ber F D Schuljahr 1824/25, Etlinger, Wurtzburg 1826;4:43. 24. Hicazi A, Acaroglu E, Alanay A, et al: Atlantoaxial rotatory fixation-subluxation revisited: A computed tomographic analysis of acute torticollis in pediatric patients. Spine 2002;27:2771. 25. Hirschl RB: Sternocleidomastoid torticollis. In Spitz L, Coran A (eds): Rob & Smith's Operative Surgery: Pediatric Surgery, 5th ed. London, Chapman & Hall, 1995. 26. Hollier L, Kim J, Grayson BH, McCarthy JG: Congenital muscular torticollis and the associated craniofacial changes. Plast Reconstr Surg 2000;105:827. 27. Hsu TC, Wang CL, Wong MK, et al: Correlation of clinical and ultrasonographic features in congenital muscular torticollis. Arch Phys Med Rehabil 1999;80:637. 28. Hutson JM, Beasley SW: The Surgical Examination of Children. London, Heinemann, 1988. 29. Jones PG: Torticollis in Infancy and Childhood. SpringfieldIL, Charles C Thomas, 1967. 30. Lange C: Zur Behandlung des Schiefhalses. Wochenschr Orthop Chir 1910;27:440. 31. Lin JN, Chou ML: Ultrasonographic study of the sternocleidomastoid muscle in the management of congenital muscular torticollis. J Pediatr Surg 1997;32:1648. 32. MacDonald D: Sternomastoid tumour and muscular torticollis.J Bone Joint Surg Br 1969;41:432. 33. McGuire KJ, SilberJ, Flynn JM, et al: Torticollis in children: Can dynamic computed tomography help determine severity and treatment? J Pediatr Orthop 2002;22:766. 34. Middleton DS: The pathology of congenital torticollis, Br J Surg 1930;18:188. 35. Morrison DL, Macewan GD: Congenital muscular torticollis: Observations regarding clinical findings, associated conditions and results of treatment. J Pediatr Orthop 1982;2:500. 36. Muniz AE, Belfer RA: Atlantoaxial rotary subluxation in children. Pediatr Emerg Care 1999;15:25. 37. Nicholson P, Higgins T, Fogarty E, et al: Three-dimensional spiral CT scanning in children with acute torticollis. Int Orthop 1999;23:47. 38. Peterson F: Zur Frage des Kopfnickerhamatoms bei Neugeborenen. Zentralbl Gynzkol 1886;10:777. 39. Rauch R, Jungert J, Rupprecht T, Greil J: Torticollis revealing as a symptom of acute lymphoblastic leukaemia in a 14 month old girl. Acta Paediatr 2002;90:587. 40. Sasaki S, Yamamoto Y, Sugihara T, et al: Endoscopic tenotomy of the sternocleidomastoid muscle: New method for surgical correction of muscular torticollis. Plast Reconstr Surg 2000;105: 1764. 41. Stassen LF, Kerawala CJ: New surgical technique for the correction of congenital muscular torticollis (wry neck). Br J Oral Maxillofac Surg 2000;38:142. 42. Tang SF, Hsu KH, Wong AM, et al: Longitudinal followup study of ultrasonography in congenital muscular torticollis. Clin Orthop 2002;403:179. 43. Thomsen JR, Koltai PJ: Sternomastoid tumour of infancy. Ann Otol Rhino1 Laryngol 1989;98:955. 44. Tubby AH: Deformities, 2nd ed. London, Macmillan, 1912.

CHAPTER

45. Tufano RP, Tom LW, Austin MB: Bilateral sternocleidomastoid tumors of infancy. Int J Pediatr Otorhinolaryngol 1999;51:41. 46. Turgut M: Torticollis secondary to posterior fossa tumors. J Pediatr Orthop 1998;18:415. 47. Wei JL, Schwartz KM, Weaver AL, Orvidas LJ: Pseudotumor of infancy and congenital muscular torticollis: 170 cases. Laryngoscope 2001;111:688.

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Torticollis

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48. Wirth CJ, Hagena FW, Wuelker N, Siebert WE: Biterminal tenotomy for the treatment of congenital muscular torticollis. Long-term results. J Bone Joint Surg Am 1992;74:427. 49. Wright JE: Sternomastoid tumour and torticollis in infancy and childhood. Paediatr Surg Int 1994;9:172.

Disorders of the Breast Mary L. Brandt

Development of the breast begins at around 35 days' gestation, when the ectoderm on the anterior body wall thickens into a ridge known as the milk line, milk ridge, or Hughes line.20 This ridge of tissue extends from the area of the developing axilla to the area of the developing inguinal canal. In term infants, the milk line extends into the axilla and inferior to the inguinal area onto the medial thigh. The ridge above and below the area of the pectoralis muscle recedes around the 10th week of gestation, leaving the mammary primordium, which is the origin The initial ducts form between of the lactiferous du~ts.l2,~l weeks 10 and 20 and become interspersed through the developing mesenchyma, which becomes the fibrous and fatty portions of the breast.12 The breast bud becomes palpable at 34 weeks' gestation.12 The nipple appears much later, at 8 months' gestation. It is initially a depression and later becomes elevated.41 Thelarche, or the onset of pubertal breast development, occurs between the ages of 8 and 13 years, at an average 11 to 11.5years." Lack of development by age 13 is considered delayed and warrants endocrinologic evaluation.48 Normal breast development is hormonally mediated.19 Adipose tissue and the lactiferous ducts grow in response to estrogen. Progesterone stimulation results in lobular growth and alveolar budding.19,50 The normal development of the breast, which occurs over a period of 2 to 4 years after thelarche, is classified by the Tanner system into five stages (Table 58-1). Menarche usually occurs approximately 2 years after Tanner stage 2.

18% of girls with premature thelarche who are followed over time.44 Serial examinations, with particular emphasis on growth velocity and secondary sexual characteristics such as pubic hair and pigmentation of the labia or areola, are usually sufficient to identify precocious puberty in grls with premature thelarche.12~47Radiographs to estimate bone age may be indicated in some patients if precocious puberty is suspected.44 Unless a patient with thelarche has associated signs of precocious puberty, the parents should be reassured and the child followed.50Ninety percent of patients with isolated premature thelarche have resolution of the breast enlargement 6 months to 6 years after diagnosis.46 In asymmetrical premature thelarche, the resolution may also be asymmetrical.47 Long-term follow-up has shown that patients with isolated premature thelarche develop normal breasts at puberty and are at no increased risk for disorders or tumors of the breast.46

Tanner Stage

Description

1 (preadolescent)

Elevation of breast papilla only Elevation of breast bud and papilla as small mound Enlargement of areola diameter Areola becomes more pink Further enlargement of breast and areola, with no separation of their contours Montgomery's tubercles appear Further enlargement, with projection of areola and papilla to form a secondary mound above the level of the breast Projection of papilla only, resulting from recession of areola to general contour of breast Erectile areolar tissue

2

3

PREMATURE THELARCHE Although normal thelarche occurs between 8 and 13 years of age, breast buds can appear in those as young as 1 to 3 years and have been reported to be present at birth.47 Although the vast majority of patients with premature thelarche have no associated medical problems, hypothyroidism is a rare cause of premature thelarche that should be considered.lg Premature thelarche is often an isolated condition but may be the first symptom of precocious puberty, particularly in girls older than 2 years.47 Precocious puberty has been reported to occur in up to

4

5 (mature stage)

.

From Duflos D, et al: Breast diseases in adolescents. In Sultan C (ed): Pediatric and Adolescent Gynecology. Basel, Karger, 2004; and Templeman C, Hertweck SP: Breast disorders in the pediatric and adolescent patient. Obstet Gynecol Clin North Am 2000;27:19-34.

886

PART

VI

THORAX

CONGENITAL ANOMALIES OF THE BREAST Amastia and Hypomastia Complete absence of the breast, or amastia, is rare and is thought to occur from lack of formation or obliteration of the milk line.41Amastia can be associated with syndromes of more diffuse ectodermal anomalies such as congenital ectodennal dy~plasia.2~2~~ It can also be associated with anomalies of the underlying mesoderm, such as the abnormal pectoralis muscle seen in Poland's syndrome.l4,41 Bilateral amastia is associated with other congenital anomalies in 40% of patients.ZYAthelia is defined as presence of breast tissue with absence of the nipple. This is not infrequent in accessory breasts but is very rare in the normal location.41Amastia or hypomastia can also result from injuries sustained during thoracotomy, chest tube placement, inappropriate biopsy of the breast bud, radiotherapy, or severe bums.12 Because the nipple complex does not normally develop until the eighth month of gestation, it can be difficult to identify in premature infants. As a result, placement of chest tubes or central lines can inadvertently injure the developing breast (Fig. 58-1). Polymastia. This complete breast, with nipple complex, is located in the most common position, just below the normal breast. .

Polymastia and Polythelia Supernumerary breast tissue, most commonly accessory nipples, occurs in approximately 1% to 2% of the popuThe abnormally placed tissue is almost lation.1g~20,41 universally located in the axilla orjust inferior to the normally positioned breast along the embryonic milk line.41 The normal axillary extension of breast tissue (the tail of Spence) should not be confused with supernumerary breast tissue. Sixty-five percent of children with supernumerary breast tissue have a single accessory nipple or breast, and 30% to 35% have two.41The largest number of reported supernumerary structures is 10.41A complete accessory breast is termed polymastia (Fig. 58-2). Supernumerary nipples are referred to as polythelia. Some studies have suggested an association between polythelia and abnormalities of the urinary tract and

-

a

congenital heart disease, although this is debated by others.l2,20,29,45True ectopic breast tissue, or breast tissue found outside the normal milk line, is exceedingly rare but has been reported on the face, back, and perineum Polymastia and in the midline of the anterior tors0.2~,2"~~ warrants surgical excision in girls to prevent painful swelling during pregnancy. Resection of accessory nipples is usually warranted for cosmetic reasons.

Congenital Anomalies of the Nipple Inverted nipples may predispose patients to infection, which can usually be prevented by careful attention to hygiene of the recessed area.l"urgica1 correction is possible, but elevation of the nipple inevitably divides the lactiferous ducts and makes L u r e breast-fkeding probr of the lematic if not i r n p o s ~ i b l e . ~ W t h eanomalies nipple that have been described include bifid nipples and intra-areolar polythelia, which is also called dysplastic divided nipples (Fig. 58-3)

Breast Asymmetry and Hypomastia

Breast deformity from placement of a neonatal chest tube.

Some degree of asymmetry is normal in women and may be more pronounced during puberty, while the breasts are de~eloping.lg,~~ Significant hypomastia may be associated with connective tissue disorders or mitral valve prolapse.lY Hypomastia is frequently familial.IZ Unilateral hypoplasia has been reported in association with a Becker's nevus of the breast, which on examination appears as a clear brown stain.12 This nevus has been reworted to have increased androgenic receptors, which may explain the hypomastia.12Hypomastia can also occur after radiation therapy to

CHAPTER

58

Disorders of the Breast

887

~-Penicillamineand marijuana have also been reported as exogenous causes of macromastia."'

Juvenile or Virginal Hypertrophy

-

.

Intra-areolar polythelia, which is also called a dysplastic

divided nipple.

the chest wall. Girls with bilateral breast hypoplasia should be evaluated for ovarian dysfunction, hypothyroidism, or androgen-producing tumors.1Wypoplastic breast tissue is also associated with a tuberous breast anomaly. In this condition, the base of the breast is limited, and the hypoplastic breast tissue "herniates" into the areolar comp l e ~ . ' "Plastic ~ ~ surgery to correct the areolar complex and augment the hypoplastic breast may be indicated.

Spontaneous massive growth of the breast in an adolescent, which may be unilateral or bilateral, is thought to be the result of excessive end-organ sensitivity to gonadal hormones."' The number of hormonal receptors in the hypertrophic breast tissue is normal, as are serum estradiol level~.~2."An autoimmune cause has been suggested by some authors because of the occasional association with autoimmune disorders such as Hashimoto's thyroiditis, rheumatoid arthritis, and myasthenia.l2 The breast growth in patients with juvenile hypertrophy is rapid, begins shortly after thelarche, and can be dramatic, resulting in breasts that weigh up to 50 pounds Spontaneous resolution is very rare.32 Skin changes, such as peau d'orange and even necrosis, may occur during phases of rapid g r o ~ t h . ~ 2 Treatment depends on whether breast growth has been completed. If the patient is still growing, progesterone or antiestrogen medications can be used to control breast growth.44 If this is U ~ S U C C ~ or S Sif~ breast U ~ , growth is complete, breast reduction surgery is n e c e s ~ a r y . ~ ~ Patients should be counseled that lactation may be affected byjuvenile hypertrophy, particularly after breast reduction surgery, but there is no increased risk of breast cancer.32

BREAST ENLARGEMENT Macromastia

INFECTIONS OF THE BREAST

Excessively large breasts are referred to as macromastia. The differential diagnosis of macromastia in adolescents includes juvenile hypertrophy, pregnancy, tumors of the breast, and excessive endogenous or exogenous levels of estrogen or progesterone or both (Table 58-2).32

Neonatal mastitis is an uncommon infection that usually occurs in term or near-term infants.l"t affects female infants twice as often as male infants.'" Approximately 50% of infants with neonatal mastitis develop a breast abs~ess.~Udolescents may develop nonpuerperal mastitis or a breast abscess as a result of irritation of the skin, a foreign body, or infection of an epidermal The initial therapy of all breast infections is antibiotics and analgesics.13 Adolescent girls with mastitis may have symptomatic relief with breast support.44 Although Staphylococcus aureus is the offending organism in almost all cases, in infants, infections with Shigella, Escherichia coli, and Klebsiella have been reported.13 In most communities, the incidence of methicillin-resistant S. aureus has become significant enough to warrant using clindamycin or vancomycin for up to 10 days. Gram-negative coverage may be indicated until culture results are obtained. Whether in an infant or an older child, small abscesses should be aspirated with a needle, using ultrasound guidance if necessary, and followed as antibiotic therapy is continued.44 Larger abscesses may need incision and drainage, although some authors recommend needle aspiration initially, with surgery reserved for aspiration failure.44 If incision and drainage are performed, a small, periareolar incision is indicated. Probing and disrupting of the tissue should be kept to a minimum to avoid injury to the underlying breast bud in a prepubertal child.

Juvenile hypertrophy Tumors of the breast Giant fibroadenoma Hamartoma49 Cystosarcoma phyllodes Carcinoma Hormonally active tumors Ovarian granulosa cell tumor Ovarian follicular cyst Adrenal cortical tumor Exogenous hormones Estrogen Testosterone Gonadotropins Corticosterone Medications D-Penicillamine Marijuana

888

PART

VI

THORAX

NIPPLE DISCHARGE Bloody Discharge The differential diagnosis of bloody discharge in children and adolescents includes mammary duct ectasia, chronic cystic mastitis, intraductal cysts, and intraductal papillomas. Mammary duct ectasia is a condition of benign dilatations of the subareolar ducts that results in inflammation and fibrosis. This is thought to be an anomaly of duct development that results from "pleats" of obstructing epithelium in the lumen of the duct.12-4' This obstruction can lead to bacterial overgrowth and abscess, most commonly with S. aureus." o t h e r ~ r o o o s e dcauses include chronic inflammation of the periductal stroma with duct obliteraInfants with tion, trauma, and autoimmune rea~tion.~2 mammary duct ectasia typically present with a bloody distypically present with a retroareolar ~ h a r g e . ~Adolescents 2 mass, often bluish in color. There may be a bloody or brownish discharge. All children with bloody discharge should have the- discharge cultured and appropriate antibiotics started." Ductal ectasia often resolves spontaneously.l2,30,50There may be recurrences, but these usually respond to conservative therapy. Surgical excision may be indicated for persistent or recurren<syrnptoms or fo; an ~ the excision should be associated persistent c y ~ tIn. ~girls, limited to any identified cyst, with great care taken not to injure the underlying breast bud. fn boys with this condition, a simple mastectomy is curative.50 Intraductal papillomas are rare subareolar lesions that are often difficult to palpate.lThey are bilateral in 25% of patients.lg Cytology of the bloodydischarge shows ductal cells.19 Local excision, through a circumareolar incision, is curative.l%denoma of the nipple, which is very rare, may also present with erosion of or discharge from the nipple.43 In adolescent athletes, bloody discharge may be due to chronic nipple irritation (jogger's nipple) or cold trauma (cyclist's nipple) .Z7 2

1

Galactorrhea Milky discharge from the neonatal breast is a normal response to fetal prolactin levels, which peak at birth (Fig. 58-4)." In an adolescent, nonpuerperal lactation can be classified as neurogenic, hypothalamic, pituitary, endocrine, drug-induced, or idiopathic in origin.3" Neurogenic lactation occurs as a result of disorders of the chest wall, thorax, or breast. Neurogenic lactation has been reported after thoracotomy, burns or injuries of the chest wall, herpes zoster, or chronic stimulation of the nipple." Pituitary tumors, especially prolactinomas, are the most common hypothalamic or pituitary cause of galactorrhea." The most common cause of galactorrhea A wide variety of in adolescents is hyp~thyroidism.~~ drugs has been implicated in causing galactorrhea, including dopamine receptor blockers and catecholaminedepleting Patients with galactorrhea require a careful history and physical examination directed at the possible causes of galactorrhea. If there is a question whether the discharge is true galactorrhea, it should be sent for fat staining. Laboratory studies should

Normal breast bud and milky discharge in a neonate.

include serum prolactin, follicle-stimulating hormone, luteinizing hormone, and thyroid function studies.38 Discharge from the areolar glands of Montgomery in an adolescent may be normal and should not be confused with galactorrhea.19

BREAST MASSES Prepubertal Breast Masses Neonatal breast hypertrophy is a normal response to maternal estrogen and occurs in both boys and girls in the first weeks of life.lg Stimulation, such as attempting to squeeze the breast to promote discharge, may result in persistence of the hypertrophied tissue. Neonatal breast hypertrophy resolves spontaneously, and no treatment is necessary. Breast development at the onset of thelarche starts with a firm, disklike area of tissue under the areolar complex that can be mistaken for a mass. It is often unilateral initially.50 This is almost universally a normal physiologic process, but unilateral thelarche has been reported as a side effect of cimetidine administration and is reversible is contraindicated, as with stoppage of the drug."iopsy this can result in injury to the developing breast.48 Hemangiomas and lymphangiomas can involve the developing breast (Fig. 58-5). Although hemangiomas may involute after an initial growth spurt, compression of the breast bud during rapid growth can lead to injury and subsequent breast deformity. The diagnosis is usually made on physical examination but can be confirmed with ultrasonograpy or magnetic resonance imaging (MRI). If there is doubt about the diagnosis, a fine-needle biopsy may be indicated. Rapid growth of herrlangiomas may require resection (if technically possible) or treatment with steroid^.^,^^ In girls, the risk of injuring the breast bud by resection must be weighed against injury to the breast bud from the enlarging hemangioma or lymphangioma. MRI may aid in determining the resectability of the lesion and hence the risk-benefit ratio of surgical

CHAPTER

* * -.-*a

.

Hemangioma of the breast in a newborn infant.

resection. Surgical resection of the lesion, with protection of the normal breast tissue, is indicated for complications such as ulceration or h e m ~ r r h a g e . ~ ~ Other soft tissue or metastatic tumors of the breast are rare but can present in prepubertal children (Table 58-3). The majority of lesions are benign, but if the diagnosis is uncertain, fine-needle or open biopsy may be indicated."

Fibroadenomas The most common mass seen in adolescent girls is fibroadenoma. These masses usually occur in late adolescence but can occur as early as 1 to 2 years before menarche.19 Fibroadenomas are most often located in the upper outer quadrant of the breast and are more common in African American patients." The average size is 2 to 3 cm, but they can become massive (Fig. 58-6).44 Ten percent of patients have bilateral lesions.44 Up to 25% of patients have multiple fibroadenomas, a condiThe lesions may tion called fibroadenomato~is.~2,~~ enlarge slightly during the menstrual cycle.50The physical examination is usually diagnostic; these lesions are well circumscribed, "rubbery," mobile, and nontender. In equivocal cases, ultrasonography may be helpful in

Unilateral breast bud development (premature thelarche) Hemorrhagic cyst50 Abscess50 LymphangiomasO Hemangiomaso Lipomas0 Metastatic tumor Galactocele4

Disorders o f the Breast

889

Giant fibroadenoma, mimickingjuvenile hypertrophy, in an adolescent girl.

making the diagnosis.15 Mammography is not indicated in adolescent patients because the large amount of fibroglandular tissue makes interpretation diffi~ult.5~ Fibroadenomas are thought to develop because of a to estrogen tim mu la ti on.^^ local exaggerated The natural history of these lesions is usually an initial period of growth, during which the mass doubles in size over 6 to 12 months. and then stabilization. Onlv 5% of Fibroadenomas fibroadenomas grow more rapidly." , have been reported to resolve ~ p o n t a n e o u s l yThis . ~ ~ ~is~ supported by findings of sclerotic vestiges of these lesions inwomen over the age of 40.10 In 99 women aged 14 to 55 years (median age, 20) followed over 7 to 9 years, 38% of 107 clinically diagnosed fibroadenomas resolved spontaneously.7 One group reported that up to 40% of presumed fibroadenomas in adults decreased in size over a 2-year period.33 Even if some of these lesions were not true fibroadenomas, these findings support observation of presumed fibroadenomas as an alternative to early resection. All presumed fibroadenomas less than 5 cm can be safely observed for at least one or two menstrual cycles. If there is growth of the lesion, excisional biopsy is warranted.33 If the lesion remains stable, there are two options that should be discussed with the patient and family:

response

-

Masses in Adolescent Girls

58

.

1. Observation with or without fine-needle aspiration. Approximately 200 cases of carcinoma of the breast have been reported in adults with f i b r o a d e n o m a ~ . ~ ~ There are no reports of malignant fibroadenomas in adolescents. f he risk of malignancy in an adolescent girl with a typical fibroadenoma on examination is exceedingly low. In the setting of a classic examination and no tumor growth, there is essentially no risk in observing these lesions. Excisional biopsy. Many authors recommend excision of all lesions that persist to adulthood, so a case could be made to excise all fibroadenomas that persist during adolescence.50 Patients should be counseled that the biopsy may result in cosmetic changes to the breast. Persistent local pain following removal of a fibroadenoma has also been reported.40

890

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THORAX

Giant Fibroadenomas Fibroadenomas greater than 5 cm are termed giant fibroadenomas. On examination, these may be softer than typical fibroadenomas and may even resemble the normal surrounding breast tissue.44There may also be dilated veins over the surface, and the skin overlying the mass may be warm to the touch (see Fig. 58-6).44Giant fibroadenomas should be excised because they cannot be distinguished from cystosarcoma phyllodes by physical In addiexaminination, mammography, or ~onography.~ tion, these tumors have been reported to double in size in as little as 3 months in rare patients.lg Fine-needle aspiration and core needle biopsy can be helpful for planning the operative approach if the histology leads to a definitive diagnosis of cystosarcoma phyllodes. However, it is very difficult to distinguish between fibroadenoma and cystosarcoma phyllodes by aspiration or needle biopsy, so a negative result should not affect the decision to operate.8 Incisions for giant fibroadenoma removal can be problematic. Whenever possible, a periareolar incision should be used. Large lesions can be removed through a periareolar incision by placing them in a bag and morcellating them before removal." If the mass is close to the inframammary crease, this offers a second, cosmetically appropriate approach. Excision of large fibroadenomas can result in significant deformity of the breast. Placing a drain is not recommended because this results in adherence of skin to the chest wall. However, leaving the space to fill with serum or blood is also suboptimal; this too may result in contraction of the space and skin adherence. I distend the space with a mixture of saline and local anesthetic by inserting an intravenous catheter using a "Z" puncture. In most patients, this prevents the rapid influx of serum and decreases the risk of skin adherence.

Phyllodes Tumors Phyllodes tumors were first described by Muller in 1838, who coined the term cystosarcoma phyllodes. This term is misleading, however, because these tumors are rarely cystic and do not have the malignant potential of most sarcomas.33For that reason, they are better termed phyllodes tumors. Phyllodes tumors are stromal tumors that are histologically classified as benign, intermediate, or malignant.30 The distinction is largely semantic, because benign phyllodes lesions can metastasize and may recur locally. The median age of presentation of phyllodes tumors is 45 years; however, they have been reported to occur in girls as young as 10 years.23" These tumors may occur more frequently in African American adolescents.lY The diagnosis is difficult to make without a biopsy. On examination, the tumor may resemble a giant fibroadenoma. Large tumors may cause skin stretching and ulceration and venous distention.lg If the nipple complex is involved, there may be a bloody discharge.Ig Ultrasound findings that are suggestive, but not diagnostic, of phyllodes tumors include lobulations, a heterogeneous echo pattern, and the absence of microcalcifications.8

The treatment of benign phyllodes tumors is total surgical excision with a l-cm margin of normal tissue.34 Patients with histologically malignant phyllodes tumors ~ authors have should undergo m a ~ t e c t o m y .Some reported that adolescents with malignant phyllodes tumors have a more "benign" course than adults and suggest that the breast can be preserved in these patients.33 Only clinically palpable nodes, which are present in approximately 20% of patients, should be resected.28 The role of sentinel node biopsy has not been clarified for this tumor. The majority of nodes are enlarged in response to tumor necrosis and inflammation; metastases occur by hematogenous, not lymphatic, dissemination.lYRe-excision is indicated if adequate margins were not obtained at the first surgery.zR If an adequate margin cannot be achieved on the chest wall, local radiation therapy should be considered.28 Local recurrence occurs in up to 20% of patients with phyllodes tumors and is treated with re-excision or mastectomy.33 Systemic recurrence has been reported in 14% to 15% of patients.z8Metastases can occur in the lung, pleura, soft tissue, bone, pancreas, and central nervous system and usually occur without lymph node involvement.28.33 There have been isolated reports of palliation from single or multiple chemotherapeutic agents, but in general, adjuvant therapy plays a limited role in the successful treatment of phyllodes tum0rs.~3 The 5-year survival rate in adults with benign, borderline, and malignant phyllodes tumors is 96%, 74%, and 66%, re~pectively.~~ Overall, the 5-year survival rate for malignant phyllodes tumors in adults is approximately 80%.33Because adolescents with phyllodes tumors may have a biologically less aggressive tumor than adults, their prognosis may be better.33

Retroareolar Cysts Montgomery's tubercles are the small papular projections on the edge of the areola and are related to the glands of Montgomery, which may play a role during lactation.44 In adolescents, these glands can obstruct and present as either acute inflammation (62%) or an asymptomatic mass (38%).22The diagnosis of retroareolar cysts, also referred to as cysts of Montgomery, is primarily clinical but can be confirmed with ultrasonography, which most commonly demonstrates a single cystic lesion, usually unilocular, located in the expected retroareolar location. The most common presentation of patients with retroareolar cysts is acute inflammation with localized tenderness, erythema, and swelling under the areola and extending into the breast tissue.22 Treatment with oral antibiotics directed at Staphyloccocus and nonsteroidal anti-inflammatory agents usually results in resolution of the acute inflammation within 7 days.22 Only rarely is drainage of a persistent abscess necessary. Following this nonoperative treatment, an asymptomatic mass is usually present. Patients with retroareolar cysts may describe a brownish discharge from one of Montgomery's tubercles, particularly with compression of the mass. In the absence of persistent infection or other complications, retroareolar cysts should be observed with serial physical examinations and, if needed, repeat ultrasonography.

CHAPTER

More than 80% of these cysts resolve spontaneously, although this can take up to 2 years.22 Patients should be instructed not to compress the area, as this may prevent resolution of the mass. Resection may be indicated if the mass persists or if the diagnosis is in question.44

Fibrocystic Changes Fibrocystic changes in the breast can result in both localized masses and pain in the breast, or mastalgia. Patients should be reassured that this is a normal variant of female physiology, with these changes reported in 50% of women of reproductive age and 90% of women on aut0psy.4~Physical examination alone usually suffices to make this diagnosis because there is usually significant change with serial examinations done at different points in the menstrual cycle. Ultrasonography may be helpful if the diagnosis is equivocal, but mammography is not indicated. The treatment of mastalgia is a firm brassiere and nonsteroidal anti-inflammatory drugs.lg Oral contraceptives have been reported to improve symptoms in 70% to 90% of women.44Treatment with vitamin E or evening primrose oil and the avoidance of caffeine are unproved but popular method^.^^,^^

Other Benign Breast Masses A variety of benign tumors of the breast have been described in adolescents and young adults (Table 58-4). Hamartomas of the breast are rare tumors composed of normal breast components that can present as unilateral rnacr~mastia.~Y They have also been called lipofibromas, Only eight cases adenolipomas, and fibroadenolip~mas.~~ have been reported in women younger than 20 years4g The treatment of hamartomas is total excision. Adenomas of the nipple are very rare but have been reported to occur in children and adolescents. They are ar cannot be treated by local e x ~ i s i o n . ~ T u b u ladenomas distinguished from fibroadenomas by history or examination, and the diagnosis is usually made by pathologic evaluation.10 No further treatment is necessary after local excision.

Fibroadenoma Cyst of Montgomery Duct ectasia Fat necrosis Vascular lipomasO Subareolar neuromasO Hamart~ma~~ Abscess50 Lymphangiomas0 HemangiomasO Lipomaso Juvenile secretory carcinoma Ductal carcinoma Metastatic disease

58

Disorders of the Breast

891

Erosive adenomatosis is a rare benign tumor that presents with erythema, erosion, and crusting of the nipple.3 Serosanguineous discharge may occur, and a nodule may or may not be palpable.3 Treatment is local excision of the lesion, which may be delayed until breast growth is complete; successful treatment with cryosurgery has also been r e p ~ r t e d . ~ Juvenile papillomatosis is a benign, localized, proliferative lesion usually seen in girls older than 10 years, although it has been reported in prepubertal boys as we11.35 Juvenile papillomatosis usually presents with a mass, similar on examination to a fibroadenoma, in one breast. When resected, this is a well-demarcated mass with multiple cysts separated by fibrous stroma, giving it a "swiss cheese" appearance.10 Juvenile papillomatosis is considered a marker for increased breast cancer risk in family members but not necessarily in the patient, ~~ in situ and invasive unless it is r e ~ u r r e n t .However, carcinoma (usually juvenile secretory carcinoma) have been reported in up to 15% of patients with juvenile p a p i l l ~ m a t o s i s .The ~ ~ treatment of juvenile papillomatosis is total resection, with preservation of the normal breast.35 Trauma can result in lesions that resemble either an infection or a mass in adolescents. In particular, fat necrosis that occurs after trauma can resemble a solid mass in the breast.19 This has been reported following seat-belt injury and other direct blows to the breast.51

Malignant Tumors of the Breast Primary carcinoma of the breast has been reported in 39 children 3 to 19 years of age.31.50 More than 80% of these patients were diagnosed with juvenile secretory carcinoma, with the remainder having intraductal carcinoma. Juvenile secretory carcinoma has been reported in association with juvenile papillomatosis.50 Juvenile secretory carcinoma often has a thick-walled capsule, which may cause the lesion to appear cystic on ultra~onography.~~ The treatment of primary breast cancer in children is complete surgical excision, usually by mastectomy." The role of sentinel node mapping has not been determined in children. Estrogen and progesterone receptors should be determined. Local recurrence is treated by re-excision or completion mastectomy. Adjuvant therapy for juvenile secretory carcinoma is rarely used, and the prognosis for these patients is excellent following local excision. Adjuvant therapy for intraductal carcinoma is based on the node status and hormone receptors, with most oncologists using modified adult protocols for the treatment of children with this tumor. Chest wall radiation, usually given to treat Hodgkin's lymphoma, increases the lifetime risk for breast cancer. This is particularly true for girls who ate 10 to 16 years old when they receive radiation therapy, because this is a period of rapid breast growth.18 Girls with Hodgkin's disease who require radiotherapy of the chest have an 82 times increased risk of breast cancer, with almost 40% of patients ultimately developing breast cancer.lR The median time from radiation therapy to diagnosis of

892

PART

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THORAX

breast cancer is 20 years. The risk of breast cancer is also increased if there is a significant family history. Mutations in the BRCAl and BRCA2 genes have been identified in 7% to 9% of all breast cancers.44Girls who have mutations in one of these genes have a 3.2% risk of breast cancer at age 30 and an 85% risk by age 70.44 Sarcoma of the breast is rare in all age groups and exceedingly rare in children. Rhabdomyosarcoma can occur as a primary tumor of the breast, usually in adolescent girls.5 These tumors are typically rapidly growing mobile masses with no skin involvement; histologically, they Angiosarcoma of are usually alveolar rhabdomyo~arcomas.~ the breast has been reported in adult women following external beam radiation for breast conservation.2 This rare tumor has also been reoorted in adolescent^.^^ The treatment is mastectomy without routine axillary dissection.34 Liposarcoma has been reported within a phyllodes tumor These tumors may of the breast in an adolescent ~atient.2~ appear encapsulated but shodd be treated by wide locd excision.2 Fibrosarcoma and malignant fibrous histiocytoma may be the most common soft tissue sarcomas of the breast; other rare primary sarcomas of the breast include leiomyosarcoma and osteogenic sarcoma.? Primary nonHodgkin's lymphoma of the breast has been reported in children.37 Treatment of these rare primary malignancies of the breast is based on established orotocols for more common tumors of childhood. Cancer metastatic to the breast has been reported in children with primary hepatocellular carcinoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, neuroblastoma, and rhabdomyosarcoma, particularly the alveolar variant.9zfl,50 Other less common tumors that have been reported to metastasize to the breast in children include histiocytosis, medulloblastoma, renal Bilateral breast disease carcinoma, and neurobla~toma.~ occurs in 30% of children with rhabdomyosarcoma .~ is the diagnosmetastatic to the b r e a ~ tUltrasonography tic tool of choice because it can often differentiate these lesions from more common benign lesions.9

GYNECOMASTIA Gynecomastia occurs in up to 70% of boys at the time of p~berty.l~.'~ The majority of boys have bilateral gynecomastia, with only 10% having unilateral breast enlargement." A history of drug ingestion should be obtained, because gynecomastia has been reported to occur secondary to anabolic steroids, digitalis, isoniazid, tricyclic antidepressants, spironolactone, and marijuana." Gynecomastia can be classified using a scale defined by Nydick, which is similar to the Tanner stages of breast development in girls. Stage 1 is limited to the subareolar area but does not reach the edge of the areola; stage 2 extends to the edge of the areola (B2) or beyond the edge (B3). In stage 4 and 5 gynecomastia, the breast assumes the characteristics of a female breast." Examination of the testes is important as well. The combination of gynecomastia with hypogonadism suggests the diagnosis of Klinefelter's syndrome. In the vast majority of boys, physiologic gynecomastia resolves spontaneously as puberty progresses, although it may take several years. Some boys, however, suffer from

-

-

Stage 5 gynecomastia in an adolescent boy

low self-esteem because of their large breasts (Fig. 58-7). These boys require surgery to allow normal psychological growth and development. Although plastic surgeons have promoted liposuction as an alternative to resection, an open approach is favored by most pediatric surgeons.l6J7 A simple mastectomy is performed through a periareolar incision. Drains are often necessary in cases of a significant breast tissue to prevent postoperative seromas. A "pad" of breast tissue should be left underneath the nipple to avoid adherence of the nipple to the chest walI.50

REFERENCES 1. Akyuz C, et al: Management of cutaneous hemangiomas: A retrospective analysis of 1109 cases and comparison of conventional dose prednisolone with high-dose methylprednisolone therapy. Pediatr Hematol Oncol 2001;18:47-55. 2. Alabassi A, Fentiman IS: Sarcomas of the breast. Int J Clin Pract 2003;57:886889. 3. Albers SE, et al: Erosive adenomatosis of the nipple in an eight-year-old girl. J Am Acad Dermatol 1999;40:834837. 4. Al Salem AH, Al Nazer M: An unusual cause of breast enlargement in a 5-year-old boy. Pediatr Pathol Mol Med 2002:21:485-489. 5. Binokay F, et al: Primary and metastatic rhabdomyosarcoma in the breast: Report of two pediatric cases. Eur J Radiol 2003;48:282-284. 6. Bosman JM, Bax NM, Wit JM: Premature thelarche: A possible adverse effect of cimetidine treatment. Eur J Pediatr 1990;149:534535. 7. Cant PJ, et al: Non-operative management of breast masses diagnosed as fibroadenoma. Br J Surg 19.95;82:792-794. 8. Chao TC, et al: Sonographic features of phyllodes tumors of the breast. Ultrasound Obstet Gynecol 2002;20:6471. 9. Chateil JF, et al: Breast metastases in adolescent girls: US findings. Pediatr Radiol 1998;28:832-835. 10. Dehner LP, Hill DA, Deschryver K: Pathology of the breast in children, adolescents, and young adults. Semin Diagn Pathol 1999;16:235-247.

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11. De Sanctis V, et al: Pubertal gynecomastia. Minerva Pediatr 2002;54:357-361. 12. Duflos D, et al: Breast diseases in adolescents. In Sultan C (ed): Pediatric and Adolescent Gynecology. Basel, Karger, 2004. 13. Efrat M, et al: Neonatal mastitis-diagnosis and treatment. Isr J Med Sci 1995;31:558-560. 14. Fokin AA, Robicsek F: Poland's syndrome revisited. Ann Thorac Surg 2002;74:2218-2225. 15. Fornage BD, Lorigan JG, Andry E: Fibroadenoma of the breast: Sonographic appearance. Radiology 1989;172: 671-675. 16. Fruhstorfer BH, Malata CM: A systematic approach to the surgical treatment of gynaecomastia. Br J Plast Surg 2003; 56:237-246. 17. Gabra HO, et al: Gynaecomastia in the adolescent: A surgically relevant condition. Eur J Pediatr Surg 2004;14:3-6. 18. Gold DG, Neglia JP, Dusenbery KE: Second neoplasms after megavoltage radiation for pediatric tumors. Cancer 2003;97:2588-2596. 19. Greydanus DE, Parks DS, Farrell EG: Breast disorders in children and adolescents. Pediatr Clin North Am 1989; 36:601-638. 20. Gross1 NA: Supernumerary breast tissue: Historical perspectives and clinical features. South Med J 2000;93: 29-32. 21. Hanna RM, Ashebu SD: Giant fibroadenoma of the breast in an Arab population. Australas Radio1 2002;46:252-256. 22. Huneeus A, et al: Retroareolar cysts in the adolescent. J Pediatr Adolesc Gynecol 2003;16:45-49. 23. Jimenez JF, et al: Liposarcoma arising within a cystosarcoma phyllodes. J Surg Oncol 1986;31:294298. 24. Koltuksuz U, Aydin E: Supernumerary breast tissue: A case of pseudomamma on the face. J Pediatr Surg 1997;32: 1377-1378. 25. Lazala C, Saenger P: Pubertal gynecomastia. J Pediatr Endocrinol Metab 2002;15:553-560. 26. Leung W, Heaton JP, Morales A. An uncommon urologic presentation of a supernumerary breast. Urology 1997; 50:122-124. 27. Loud KJ, Micheli LJ: Common athletic injuries in adolescent girls. Curr Opin Pediatr 2001;13:317-322. 28. Mangi AA, et al: Surgical management of phyllodes tumors. Arch Surg 1999;134:487-492. 29. Merlob P: Congenital malformations and developmental changes of the breast: A neonatological view. J Pediatr Endocrinol Metab 2003;16:471-485. 30. Miller JD, Brownell MD, Shaw A: Bilateral breast masses and bloody nipple discharge in a 4year-old boy. J Pediatr 1990;116:744747. 31. Murphy JJ, et al: Breast cancer in a 6-year-old child. J Pediatr Surg 2000;35:765-767.

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32. O'Hare PM, Frieden IJ: Virginal breast hypertrophy. Pediatr Dermatol 2000;17:277-281. 33. Parker SJ, Harries SA: Phyllodes tumours. Postgrad Med J 2001;77:428-435. 34. Rainwater LM, et al: Angiosarcoma of the breast. Arch Surg 1986;121:669-672. 35. Rice HE, et al: Juvenile papillomatosis of the breast in male infants: Two case reports. Pediatr Surg Int 2000;16: 104106. 36. Rivera-Hueto F, et al: Long-term prognosis of teenagers with breast cancer. Int J Surg Path01 2002;10:273-279. 37. Rogers DA, et al: Breast malignancy in children. J Pediatr Surg 1994;29:48-51. 38. Rohn RD: Galactorrhea in the adolescent.J Adolesc Health Care 1984;5:37-49. 39. Rojananin S, Ratanawichitrasin A: Limited incision with plastic bag removal for a large fibroadenoma. Br J Surg 2002;89:787-788. 40. Siegal A, Kaufman Z, Siegal G: Breast masses in adolescent females. J Surg Oncol 1992;51:169-173. 41. SkandalakisJ, et al: The anterior body wall. In Gray S (ed): Embryology for Surgeons: The Embryologic Basis for the Treatment of Congenital Anomalies. Baltimore, Williams & Wilkins, 1994, pp 539-593. 42. Stringel G, Perelman A, Jimenez C: Infantile mammary duct ectasia: A cause of bloody nipple discharge. J Pediatr Surg 1986;21:671-674. 43. Sugai M, et al: Adenoma of the nipple in an adolescent. Breast Cancer 2002;9:254256. 44. Templeman C, Hertweck SP: Breast disorders in the pediatric and adolescent patient. Obstet Gynecol Clin North Am 2000;27:19-34. 45. Urbani CE, Betti R: Accessory mammary tissue associated with congenital and hereditary nephrourinary malformations. IntJ Dermatol 1996;35:349-352. 46. Van Winter JT, et al: Natural history of premature thelarche in Olmsted County, Minnesota, 1940 to 1984.J Pediatr 1990; 116:278-280. 47. Verrotti A, et al: Premature thelarche: A long-term follow-up. Gynecol Endocrinol 1996;10:241-247. 48. Weinstein SP, et al: Spectrum of US findings in pediatric and adolescent patients with palpable breast masses. Radiographics 2000;20:1613-1621. 49. Weinzweig N, Botts J, Marcus E: Giant hamartoma of the breast. Plast Reconstr Surg 2001;107:1216-1220. 50. West KW, et al: Diagnosis and treatment of symptomatic breast masses in the pediatric population. J Pediatr Surg 1995;30:182-186. 51. Williams HJ, et al: Imaging features of breast trauma: A pictorial review. Breast 2002;11:107-115.

Congenital Chest Wall Deformities Robert C. Shamberger

Congenital chest wall deformities are usually divided into five categories: pectus excavatum, pectus carinatum, Poland's syndrome, sternal defects, and the miscellaneous dysplasias or the thoracic deformities seen in diffuse skeletal disorders. Most are not life-threatening lesions and produce limited functional abnormalities. Rare lesions such as thoracic ectopia cordis and Jeune's asphyxiating thoracic dystrophy are, however, almost uniformly fatal.

flexibility of costal cartilages in individuals with pectus excavatum, but abnormalities in the proteoglycan or collagen distribution between affected individuals and . ~ family ~ history of controls were not d e m ~ n s t r a t e d A chest wall deformity, identified in 37% of cases, supports a genetic predisposition.lZ5

Clinical Presentation DEPRESSION DEFORMITIES: PECTUS MCAVATUM Pectus excavatum (funnel chest, trichterbrust, or thorax en entonnoir) is the most common anterior chest wall deformity, involving posterior depression of the sternum and the lower costal cartilages. It occurs more frequently in boys than in girls by a greater than 3:l ratio. In 90% of cases, it is noted within the first year of life.lZ5Although cases of spontaneous resolution occur, they are infrequent, and the advice that a child will "grow out" of the pectus depression should be offered cautiously. Children with pectus excavatum, in addition to the central chest depression, are often noted to be tall and lanky, with poor posture, and to have an overall decrease in anteroposterior (AP) chest depth.100.118

Children present with a wide spectrum of depression deformities (Fig. 59-l), from a mildly depressed sternum to a severe case in which the sternum almost abuts the vertebral bodies. The depression is created by two components: (1) posterior angulation of the body of the sternum, generally beginning just below the insertion of the second costal cartilage, and (2) posterior angulation of the costal cartilages to meet the sternum. In older teenagers and adults, posterior angulation of the most anterior portion of the osseous ribs occurs. The depression may be deeper on the right than on the left, and the

Cause The cause of pectus excavatum has not been established. Purported theories include intrauterine pressure, rickets, and abnormalities of the diaphragm resulting in posterior traction on the sternurn.l5J".2' Some support for this last theory has been provided by reports of pectus excavatum occurring after repair of agenesis of the diaphragm or congenital diaphragmatic hernia.136 The association between pectus excavatum and other musculoskeletal abnormalities, particularly scoliosis (15% incidence) and Marfan's syndrome (Table 59-l ) , suggests that abnormal connective tissue plays a role. Studies have demonstrated abnormalities in the costal cartilage, including decreased levels of zinc and increased levels of magnesium and calcium.~iomechanicalanalysis has suggested increased

Abnormality Scoliosis Kyphosis Myopathy Poland's syndrome Marfan's syndrome Pierre Robin syndrome Prune-belly syndrome Neurofibromatosis Cerebral palsy Tuberous sclerosis Congenital diaphragmatic hernia

No. of Patients 107 4 3 3

From Shamberger RC, Welch KI: Surgical repair of pectus excavatum. J Pediatr Surg 1988:23:615-622.

CHAPTER

,

A -

59

Congenital Chest Wall Deformities

895

B

.

A, Preoperative clinical photograph of a 14%-year-old boy with a symmetrical pectus excavatum deformity. B, Postoperative clinical photograph a year after repair using retrosternal struts shows full correction of the deformity.

sternum may be rotated as well. The AP depth of the ribs may be different between the two sides, and in many children, the AP depth of the chest is narrower than norma1.100 Children may have a broad, shallow defect or a narrow central pocket. An asthenic build and slumped posture are frequently associated findings. Congenital heart disease was identified in 1.5%of children undergoing chest wall correction in one series, and the frequency of chest wall deformities among children with congenital heart disease was 0.17%.'2" Many methods of assessing the severity of the depression have been developed. Most include the distance between the sternum and the spine as a primary factor. Willitall48 and Klinke et al. '2 used a ratio between the depth of the depression and the AP diameter of the chest. Welchl4~mployeda ratio of the sternovertebral distance divided by the AP depth of the chest at the angle of Louis and added additional increments of severity if the cardiothoracic ratio was greater than 50% or the rib angles were greater than 25 degrees from horizontal. Backer et al.5 used a ratio between the vertebral body diameter and the distance between the xiphosternal junction and the posterior border of the vertebral body to express the severity of the depression. Haller et al. proposed a method of grading that uses transverse and AP measurements obtained from computed tomography (CT) of the chest, but similar measurements can be obtained from standard chest radiographs.50 Pectus excavatum is well tolerated in infancy and childhood. Chronic upper airway obstruction because of tonsillar and adenoidal hypertrophy may accentuate

the depression in an infant with a flexible chest but is not causative. Older children may complain of pain in the area of the deformed cartilages or of precordial pain after sustained exercise. Occasionally, palpitations occur, which presumably are the result of transient atrial arrhythmias and may be associated with mitral valve prolapse. A systolic ejection murmur is frequently identified in individuals with pectus excavatum. It is attributed to the close proximity between the posterior aspect of the sternum and the pulmonary artery, which results in transmission of a flow murmur.45 The physiologic impact of pectus excavatum has been the topic of many reports and much debate. Some authors contend that no cardiovascular or pulmonary impairment results from pectus excavatum. This position contrasts with the clinical impression that many patients have increased stamina and exercise tolerance after surgical repair. The cardiopulmonary impact of pectus excavatum has been extensively studied, with variable results. Despite 6 decades of work in the field, no consensus has been achieved on what degree of cardiopulmonary impairment, if any, this common chest wall deformity produces. Early pathologic studies of patients with pectus excavatum demonstrated compression of the heart between the vertebral column and the depressed sternum. The left lung was also compressed more than the right because of the frequent asymmetry of the deformity. Translation of these anatomic findings into their physiologic components has been the goal of many subsequent studies. A 1988 review tabulated this long series of studies.lz3

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Pulmonary Function Evaluation Deformity of the chest wall led many early authors to attribute the symptomatic improvement after pectus surgery to an improvement in pulmonary function. In an early work, Brown17 performed respiratory studies on patients before and after surgical repair. Vital capacity was normal in these patients, but maximal breathing capacity was markedly diminished (50% or more) in 9 of 11 cases. Maximal breathing capacity increased an average of 31% after surgical repair. Orzalesi and Cook102 performed studies in 12 children with severe pectus excavatum deformities. The data for individual patients were within two standard deviations of normal values based on height except for three patients with low vital capacity and one with low maximal breathing capacity. In the aggregate, however, the group showed a significant ( P < 0.001) decrease in vital capacity, total lung capacity, and maximal breathing capacity compared with height-matched normal children. Weg et al.141 evaluated 25 Air Force recruits referred for respiratory symptoms and pectus excavatum and compared them with 50 unselected basic trainees. Although the lung compartments of both groups were equal, as were mean vital capacity and maximal voluntary ventilation, which best reflects chest wall function, muscular ability and patient effort showed a significant deviation from predicted normal values ( P = 0.005). Liese and Biihlmannsl determined preoperative and postoperative lung volume and physical work capacity in an upright position on a bicycle ergometer in 12 adults with severe funnel chest. Postoperative studies were performed 3 to 11 years (mean, 8 years) after surgical correction. Absolute lung volume increased only in patients who had grown in height after surgery. Work capacity increased in 9 of 10 patients but was difficult to assess, given the interval between testing. GodfreV4 reported on a select group of five patients with pectus excavatum and segmental bronchomalacia involving the left mainstem bronchus. Radionuclide pulmonary scans demonstrated severe gas trapping in the left lung in two patients and underventilation and underperfusion of the left lung in a third patient. This appeared to be a clinically distinct group of patients with bronchomalacia demonstrated at bronchoscopy in all cases. It is not clear that the bronchomalacia was caused by the pectus deformity. Castile et a1.21 extensively evaluated eight patients, seven with pectus excavatum and one with pectus carinatum deformity. Five patients were symptomatic with exercise but were asymptomatic at rest. Complete pulmonary mechanics studies were performed, including standard lung volume, forced vital capacity (FVC), static pressurevolume curve, and progressive steady-state exercise testing on a bicycle ergometer. Flow and volume for the one patient with pectus carinatum were normal. The mean total lung capacity as a percentage of predicted in the pectus excavatum patients was 79%, a mild restrictive deficit. Flow volume configurations were normal and did not suggest airway obstruction. Workload tests revealed a normal dead-space response to exercise; tidal volume ratio and alveolar-arterial oxygen difference did not

suggest a significant ventilation-perfusion abnormality in the symptomatic patients. However, the measured oxygen uptake increasingly exceeded predicted values as the workload approached maximum; this was a strikingly different pattern when compared with normal subjects, who exhibit a linear response. The mean oxygen uptake at maximal effort exceeded the predicted values by 25.4% in the symptomatic patients. The three asymptomatic patients demonstrated normal linear oxygen uptake during exercise. Increased oxygen uptake suggests increased work of breathing in these symptomatic individuals, despite normal or mildly reduced vital capacity. Increases in tidal volume with exercise were uniformly depressed in those with pectus excavatum. No postoperative studies were werformed in these subiects. ., Cahill et al.19 performed pre- and postoperative studies (3 to 9 months postoperatively) in 19 children and adolescents with pectus carinatum (5) and excavatum (14) ranging fro& 6 to 1'7 years of age. No preoperative abnormalities or postoperative changes were demonstrated in the pectus carinatum patients. The pectus excavatum patients demonstrated low-normal vital capacity that wasunchanged by operation. Surgical correciion did, however, result in a small improvement in their total lung capacity (3.21 1.12 to 3.49 f 1.07; P < 0.02) and a significant improvement in maximal voluntary ventilation (65.1 f 31.5 to 78.9 f 31.5 L/minute; P < 0.001). Exercise tolerance was also improved after surgery, as determined by both total exercise time and maximal oxygen consumption (1.26 0.44 to 1.46 f 0.42 mL/kg per minute; P <0.01), although both these factors are clearly effort related. The heart rates at three identical work rates were assessed for each patient in the preoperative and postoperative workload study. There was a consistent decrease in heart rate at a given power output in the postoperative study ( P <0.02 by paired t-test) of the excavatum patients, but no decrease was observed in the carinatum patients. No difference in oxygen consumption at each work rate after surgery could be defined to support an improved efficiency of work. The observed decrease in heart rate at each workload level suoworted x the hypothesis that some of the improvement in exercise capacity was a result of increased cardiac stroke volume. Mead et al.gOstudied rib cage mobility by assessing intraabdominal pressure. The 6nding of -normal abdominal pressure tracings in subjects with pectus excavatum suggested normal rib cage mobility. Derveaux et aL30 used wulmonarv function tests to evaluate 88 subjects with pectus excavatum and carinatum before and 1 to 20 years (mean, 8 years) after repair involving a fairly extensive chest wall dissection. Preoperative studies were within the normal range (i.e., >80% predicted values) except in those subjects with both scoliosis and pectus excavatum. The postoperative values for forced expiratory volume in 1 second (FEV1)and vital capacity were decreased in all groups when expressed as a percentage of predicted values, although the absolute values at follow-up may have been greater than at the preoperative evaluation. Radiologic evaluation of these individuals confirmed improved chest wall configuration, so the deterioration in pulmonary function was not the result of recurrence of the pectus deformity. An inverse

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CHAPTER

relationship was found between preoperative and postoperative function. Those with less than 75% of predicted function preoperatively had improved function after surgery, whereas postoperative results were worse if the preoperative values were greater than 75%. Almost identical results were found in a study by Morshuis et who evaluated 152 subjects before and a mean of 8 years after surgery for pectus excavatum. These physiologic results were in contrast to the subjective improvement in symptoms reported by the subjects and their improved chest wall configurations. The decline in pulmonary function in the postoperative studies was attributed to the surgery, because the preoperative defect appeared to be stable on sequential studies regardless of the age at initial repair. Both these studies were marred by the obvious lack of an age-matched and severity-matched control group without surgery. Derveaux et al.31 evaluated transpulmonary and transdiaphragmatic pressures at total lung capacity in 17 individuals with pectus excavatum. Preoperative and long-term follow-up evaluations were performed a mean of 12 years apart. Reduced transpulmonary and transdiaphragmatic pressures showed that the increased restrictive defect was produced by extrapulmonary rather than pulmonary factors, suggesting that surgery produced increased rigidity of the chest wall. Wynn et al.150 assessed 12 children with pectus excavatum by pulmonary function tests and exercise testing. Eight had repair and were evaluated preoperatively and postoperatively. Four had two sets of evaluations but no surgery. A decline in total lung capacity was identified in the repaired children, whereas values were stable in the control group. Cardiac output and stroke volume increased appropriately with exercise before and after operation in both groups, and operation was thought to have no physiologically significant effect on the response to exercise. Kaguraoka et a1.7l evaluated pulmonary function in 138 individuals before and after repair of pectus excavatum. A decrease in vital capacity occurred during the initial 2 months after surgery, with recovery to preoperative levels by 1 year after surgery. At 42 months, the values were maintained at baseline, despite a significant improvement in chest wall configuration. Tanaka et al.l32 had similar results and demonstrated that individuals with a more extensive sternal turnover procedure had more significant and long-term decreases in vital capacity. Morshuis et a1.X evaluated 35 subjects with pectus excavatum repaired as teenagers or young adults (age 17.9 f 5.6 years). Preoperative evaluations were performed and repeated 1 year after surgery. Preoperative total lung capacity (86.0 f 14.4% of predicted) and vital capacity (79.7 f 16.2%) were significantly lower than predicted values and decreased further after surgery (-9.2 f 9.2'7% and -6.6 10.7%, respectively). The efficiency of breathing at maximal exercise improved significantly after operation. Ventilatory limitation of exercise occurred in 43% of the subjects after surgery, and there was a tendency toward improvement after operation. The group with no ventilatory limitation, however, initially demonstrated a limitation after operation, with a significant increase in oxygen consumption.

+

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Congenital Chest Wall Deformities

897

Haller et al." evaluated 36 patients with pectus excavatum and 10 normal controls. Six months after surgery, the studies were repeated on 15 patients and 6 controls. Before surgical correction, a decrease in FVC was seen in the excavatum cohort, and no change occurred after repair. Although 58% of patients had subjective complaints of exercise limitation that improved after surgery in 66%, they exercised at similar workloads as controls. The respiratory parameters during exercise were similar between the two groups, suggesting that exercise was not limited by restrictive disease. After surgery, the subjects could exercise longer and had higher pulse oxygen levels than before surgery, with no change in the controls. The enhanced exercise tolerance was attributed to improved cardiac function, as demonstrated by increased pulse oxygen levels and no change in pulmonary function parameters. Borowitz et aL12 performed an early evaluation of patients undergoing the minimally invasive repair of pectus excavatum (MIRPE) technique. In that study of 10 patients, normal pulmonary function was demonstrated both before and after surgical repair. Sigalet et aI.129 also reported on the early effects of MIRPE in 11 patients, based on an evaluation of pulmonary function, exercise tolerance, and cardiac function as assessed by echocardiography. Although patients reported a subjective improvement in their exercise tolerance, pulmonary function (FVC and vital capacity) was significantly reduced at 3 months; similarly, maximal oxygen uptake was reduced. In contrast, cardiac function was enhanced, with an increase in stroke volume. Malek et al.84 evaluated 21 physically active patients with pectus excavatum. The observed values for FVC, FEV,, maximal voluntary ventilation, and diffusing capacity of the lung for carbon monoxide were significantly lower than normal values, but those for total lung capacity and residual volume were not. Exercise testing revealed that the maximal oxygen uptake and oxygen tension were significantly lower than in normal controls. It was thought that the subjects' limitation in maximal exercise had a cardiovascular rather than a pulmonary cause, as demonstrated by an abnormally low metabolic threshold for lactate accumulation. This impairment was greatest in those with the most severe pectus deformities. In composite, these studies of pulmonary function over the last 4 decades have failed to document consistent improvement in pulmonary function resulting from surgical repair. In fact, many studies demonstrated deterioration in pulmonary function at long-term evaluation, attributable to increased chest wall rigidity after surgery. Despite this finding, several workload studies have shown improvement in exercise tolerance after repair.

Cardiovascular Function Posterior displacement of the sternum can produce deformity of the heart, particularly anterior indentation of the right ventricle. Garusi,42 using angiography, showed displacement of the heart to the left side, with a sternal imprint on the anterior wall of the right ventricle. Bevegirdg in 1962 studied 16 patients with pectus excavatum using right heart catheterization and

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workload studies. The physical work capacity at a given heart rate was significantly lower in the sitting than in the supine position. Those with a 20% or greater decrease in physical work capacity from the supine to the sitting position had a shorter sternovertebral distance than did those with a less than 20% decrease. Measured stroke volume at rest decreased from the supine to the sitting position a mean of 40.3%,similar to normal subjects. In the supine position, stroke volume increased 13.2%with exercise. In the sitting position, the increase in stroke volume from rest to exercise was l8.5%, significantly lower (P < 0.001) than the 51% increase measured in normal subjects. Thus, increased cardiac output can be achieved primarily by increased heart rate, despite a limited stroke volume. This explains the lower work capacity achieved at any given heart rate in the sitting position. Intracardiac pressures were normal in all subjects measured at rest and with exercise, despite the apparent limitation of ventricular volume. Beiser et a1.8 provided further evidence that cardiac function is impaired during upright exercise yet is relatively normal in the supine position. Cardiac catheterization was performed in six subjects with moderate pectus excavatum. Normal right atrial, right ventricular, pulmonary artery, and pulmonary capillary wedge pressures were obtained at rest in the supine position. The cardiac index during moderate exercise was normal, although the response to upright exercise was below that predicted in two subjects and at the lower limit of normal in three. The difference in cardiac performance in an upright position was produced primarily by a smaller stroke volume in s u b jects with pectus excavatum. Stroke volume was 31% lower and cardiac output was 28% lower during upright exercise compared with supine exercise. Postoperative studies were performed in three subjects; two achieved a higher level of exercise after repair. The cardiac index increased an average of 38%. An enhanced stroke volume response produced this increase, because heart rate at maximal exercise was not higher after repair. Radionuclide angiography was used by Peterson et al.104 to assess cardiac volume and output in 13 subjects with pectus excavatum. Eleven subjects were symptomatic before surgical repair, but the degree of symptoms could not be correlated with the severity of the anatomic deformity. Upright exercise was performed with a bicycle ergometer at progressive workloads until 85% of the agepredicted maximal heart rate was achieved or the patient could not continue because of fatigue or shortness of breath. Ten of the 13 subjects were able to reach the target heart rate before surgical repair, yet only 4 did so without symptoms. After operation, all but one subject reached the target heart rate during the exercise protocol, and 9 of 13 subjects did so without becoming symptomatic. This documentation of a marked decrease in symptoms after surgical correction of pectus excavatum in a regulated exercise protocol substantiated many anecdotal reports in the early literature regarding symptomatic improvement. The role of conditioning and subjective response to surgery is difficult to assess. Radionuclide injections were performed on subjects at rest and then at the target heart rate or exercise end point. This study

failed to demonstrate any significant change after pectus repair in the left ventricular ejection fraction either at rest or during exercise. The left ventricular end-diastolic volume was consistently increased after repair at rest, and the mean stroke volume increased 19% after repair but did not consistently increase with exercise. The cardiac index did not increase significantly after operation at rest or during exercise. Kowalewski et a1.73 performed a similar study with echocardiographic evaluation of cardiac function in 42 patients both before and 6 months after repair of pectus excavatum. Statistically significant changes were seen in the right ventricular volume indices (systolic, diastolic, and stroke volume) after surgery. No correlation could be defined between the changes in the pectus index and the cardiac changes. These results support those cited earlier by Haller et al.,51Sigalet et al.,'" and Malek et al.?4 which all suggest that limitations in the stroke volume result from right ventricular compression. Additional studies are needed to further define the relationship between pectus excavatum and cardiopulmonary function. Dynamic or exercise studies have been most promising in this area. Methods to better evaluate preoperative cardiopulmonary function are needed to identify which children may achieve symptomatic and physiologic improvement after surgical repair.

Echocardiographic Studies Prospective echocardiographic studies in adults with pectus excavatum demonstrated mitral valve prolapse in 6 of 33 subjects (18%) studied by Udoshi et a1.134 and in 11 of 17 subjects (65%) studied by Saint-Mezard et al.H3Anterior compression of the heart by the depressed sternum may deform the mitral valve annulus or the ventricular chamber and produce mitral valve prolapse in these subjects. Resolution of mitral valve prolapse was seen in 10 of 23 children and adolescents after repair.127

Meyergo in 191 1 and Sauerbruchll5 in 1913 first achieved surgical repair of pectus excavatum. Significant changes in the method of repair have evolved as experience has increased and the primary components of the deformity have been identified. In 1939 Ochsner and DeBakeyg8 summarized the early, sometimes fatal experience with a variety of repairs. Ravitchlo8in 1949 reported a technique that involved excision of all deformed costal cartilages with the perichondrium, division of the xiphoid from the sternum, division of the intercostal bundles from the sternum, and transverse sternal osteotomy displacing the sternum anteriorly with Kirschner wires in the first two patients and silk sutures in later patients. His technique was later modified to preserve the perichondrial sheaths, but he continued to separate the intercostal bundles and the sheaths from the sternum.lo9 In 1957 and 1958 Baronofsky7 and Welch,142 respectively, reported similar techniques that emphasized total preservation of the

CHAPTER

perichondrial sheaths of the costal cartilage, preservation of the upper intercostal bundles, sternal osteotomy, and anterior fixation of the sternum with silk sutures. Haller et al.52 subsequently developed a technique called tripodfixation in which subperichondrial resection of the abnormal cartilages is followed by a posterior sternal osteotomy. The most cephalad normal cartilages are then divided obliquely in a posterolateral direction. When the sternum is elevated, the sternal ends of the cartilage rest on the costal ends, providing further anterior support of the sternum. Several authors used rib or cartilage placed posterior to the sternum for support, but this technique was never widely accepted.27JOg A variation on this technique uses a vascularized rib." Support of the sternum by an external brace secured to the mobilized sternum with sutures or wire has also been employed by numerous authors, but the duration of its use must be limited to avoid infection ~ , ~ 4 gof , l the 5 l sternum of the surgical ~ o ~ n d . ~ " ~ ~ , ~Support by metal struts has also been promoted by multiple authors."-53 Rehbein1Io developed struts that could be placed into the marrow cavity of the ribs at the costochondral iunction. The struts were secured anterior to the sternum to create an arch, and the sternum was attached to this arch. Paltiai03 placed a transverse strut through the caudal end of the sternum with the two ends of the strut supported laterally by the ribs, firmly fixing its location. Adkins and Blades' and later Jensen et al.66 used retrosternal elevation by a metal strut. Willita114s employed a similar retrosternal strut after creating multiple chondrotomies in the costal cartilages to provide flexibility to the sternum and the chest wall. Innovations in these methods include the use of bioabsorbable struts, Marlex mesh or a Dacron vascular graft as a strut, or miniature metallic plates. There is no evidence, however, that any of these are preferable to traditional methods. 29,43,76,78,85,90,97 , ~ ~ proand J ~ n grespectively, In 1954 and 1956 posed the sternal turnover in the French literature. This method has been used primarily in Japan, where a large series was reported by Wada et al.1" This technique uses a free graft of sternum, which is rotated 180 degrees and then secured back to the costal cartilages from which it was divided. This method has a significant incidence of severe complications, including wound infection, dehiscence, and necrosis of the sternum. Taguchii" modified this method by preserving the internal mammary artery in an effort to Drevent osteonecrosis and wound infection. Others have described microvascular anastomosis of one set of internal mammary vessels to preserve perfusion of the sternum.133Sternal turnover is a radical approach for children with pectus excavatum deformity, given the acceptable alternatives for repair. A final method of repair is implantation of a Silastic mold into the subcutaneous space to fill the deformity.2,34J40 Although this approach may improve the contour of the chest, it achieves no increase in intrathoracic volume and is often complicated by early seroma or hematoma formation. The MIRPE technique described by Nuss is presented in the addendum to this chapter. J

59

Congenital Chest Wall Deformities

899

Surgical Technique The surgical technique is depicted in Figure 59-2. In females, particular care is taken to place the incision within the projected inframammary crease to avoid injury to the breast bud or the creation of a scar extending onto the breast." I currently use a retrosternal strut to secure the sternum firmly in an anterior position. I avoid skeletonizing the sternum; however, this may be required to achieve adequate mobility of the sternum for suture fixation. Preservation of the connections between the intercostal bundles, the perichondrium, and the rectus muscles provides a more normal chest contour. Perioperative antibiotics are used, giving one dose immediately before surgery and three doses postoperatively. All patients are warned not to take aspirin or ibuprofen-containing compounds for 2 weeks before surgery to avoid abnormalities of platelet function. The Hemovac drain is removed when the drainage is less than 15 mL for an 8-hour shift. Rehbein or retrosternal struts are removed 6 months after repair to allow solid fixation of the sternum. The retrosternal struts are removed through a small incision over one end of the strut.

Complications Complications of surgical repair should be limited, including wound infection and pneumothorax. Use of electrocautery can avoid the need for blood transfusion in most cases. Most pneumothoraces can be simply observed, unless they are large enough to produce pulmonary impairment. Recurrence is the bane of this procedure and can occur regardless of the technique used. I have shifted to strut fixation of the sternum to optimize early results, and I delay repair until the child is well into his or her pubertal growth spurt. Growth of the chest may produce the opportunity for remodeling of the chest wall and subsequent recurrence. No randomized study of strut fixation versus no strut fixation has been performed, and it is doubtful that such a study could ever be completed. In large series with adequate follow-up, recurrence is reported to occur in 5% to 15% Progressive deterioration of the of cases.~~~o7,128~~37~~4~ repair over time is well described, particularly during the Rigid fixation is interval of rapid growth at p~berty.l~.~2.74 fairly uniformly applied to patients with Marfan's syndrome because of their well-recognized high risk of recurrence.Ii7 One serious complication has been noted in children who undergo repair at an early age, generally younger than 4 years: impaired growth of the ribs after resection of the costal cartilages,which produces a bandlike narrowing of the midchest (Fig. 59-3). In some cases, the first and second ribs have relative overgrowth, producing anterior protrusion of the upper sternum. In 1990 Martinez8Wrst described this deficiency in thoracic growth after repair of pectus excavatum during the preschool years. In 1995 Haller48 reported this occurrence in three boys who presented in their teens after resection of the costal cartilages at an early age, labeling this complication

900

PART

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THORAX

,,-..___.'-\, .___.--

.-• Surgical technique for pectus excavatum repair. A, A transverse incision is placed below and well within the nipple lines at the site of the future inframammary crease. Skin flaps are mobilized using electrocautery, primarily in the midline to the angle of Louis superiorly and to the xiphoid inferiorly. The pectoralis major muscle is elevated from the sternum, along with portions of the pectoralis minor and serratus anterior muscles. B, The correct plane of dissection of the pectoral muscle flap is defined by passing an empty knife handle directly anterior to a costal cartilage after the medial aspect of the muscle is elevated with electrocautery. The knife handle is then replaced with a right-angle retractor, which is pulled anteriorly. The process is then repeated anterior to an adjoining costal cartilage. The lateral extent of muscle dissection and elevation is to the costochondral junctions of the third to fifth ribs. Anterior distraction of the muscles during the dissection facilitates identification of the avascular areolar plane and avoids entry into the intercostal muscle bundles. Continued

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CHAPTER

59

Congenital Chest Wall Deformities

901

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I . Cont'd C, Subper~chondrialresection of the costal cartrlages IS achieved by Incising the perichondnum anteriorly It 1s then dissected away from the costal cartilages in the bloodless plane between the penchondrium and the costal cartilage. Cutt~ngback the penchondnum 90 degrees in each d~rectionat ltsjunctlon ulth the sternum (znset) fac~htateswsualization of the back wall of the costal cart~lageL), The cartilages are d~vrdedat the lunctron of the sternum w t h a knife A Welch perrchondr~alelevator is held posterlor to the cartilage to protect the rnediastinum (znset) The diwded cartilage can then be held with an Allrs clamp and elevated, and the costal cartilage is excised, presemng a 5- to 10-mm margln on the r ~ to b protect the costochondral junctron and the long~tudinalgrowth plate Segments of the sixth and seventh costal cart~lagesare resected to the point where they flatten tojoln the costal ulth the cross-sectional shape of the arch Fam~liar~ty med~alends of the costal carillages fac~litatestheir removal The second and third cartilages are broad and flat, the fourth and fifth are circular, and the slxth and seventh are narrow and deep Contznned

Incision at junction with sternum

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attributed this acquired Jeune's disease. Haller et complication to injury during surgical repair of the costochondral junctions, the longitudinal growth centers for the ribs. Martinez8Wemonstrated experimentally in &week-old normal rabbits that resection of the costal cartilage produced a marked impairment in chest growth, particularly the AP diameter, during a 5.5-month period of observation. Less severe impairment occurred if only the medial three fourths of the costal cartilage was resected, preserving the growth centers at the costochondral junction. This impairment was attributed to fibrosis and

scarring within the perichondrial sheaths. Perichondrial sheaths, bone, or other prosthetic tissues that cannot grow should not be joined posterior to the sternum, because they will form a bandlike stricture across the chest. This complication can be avoided by delaying surgery until the children are older. Preservation of the costochondral junction by leaving a segment of the cartilage on the osseous portion of the rib may partially minimize growth impaira method of improving the ment. Weberls"escribed severe pulmonary impairment encountered in one patient with acquired Jeune's syndrome. A sternotomy was performed and wedged open permanently with rib struts.

902

PART

VI

THORAX ,,,- '

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Rectus sheath

Osteotomy closure with thumb pressure

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, Complete closure of rectus sheath to pect. m.

I . Cont'd E, The sternal osteotomy is created above the last deformed cartilage at the point of posterior angulation of the sternum. This is generally above the insertion of the third cartilage, or occasionally the second. Two transverse sternal osteotomies are created through the anterior cortex with a Hall air drill (Zimmer USA, Inc., Warsaw, Ind.) 2 to 4 mm apart. The short intervening segment of anterior cortex is then removed, along with the underlying cancellous bone. The base of the sternum and the rectus muscle flap are elevated with two towel clips, and the posterior plate of the sternum is fractured. The xiphoid can be divided from the sternum with electrocautery, allowing entry into the retrosternal space. This step is not necessary with the use of a retrosternal strut. Preservation of the attachment of the sheaths and xiphoid avoids an unsightly depression, which can occur below the sternum. G, When a strut is not used, the osteotomy is closed with several heavy silk sutures as the sternum is elevated to an overcorrected position with the assistant's thumb. H, A single-limb medium Hemovac drain (Snyder Laboratories, Inc., New Philadelphia, Ohio) is brought through the inferior skin flap to the left of the sternum and placed in a right parasternal position to the level of the highest costal cartilage resection. The pectoral muscle flaps are secured to the midline of the sternum, advancing the flaps to achieve coverage of the entire sternum. The rectus muscle flap, if divided, is joined to the pectoral muscle flaps.

Contznued

CHAPTER

59

Congenital Chest Wall Deformities

903

Retrosternal /strut Costal cartilage

A+

. Cont'd I, Use of both retrosternal struts and Rehbein struts is demonstrated. The Rehbein struts are inserted into the marrow cavity (inset)of the third or fourth ribs and are then joined to each other medially to create a metal arch anterior to the sternum. The sternum is sewn to the arch to secure it in a forward position. The retrosternal strut is placed behind the sternum and is secured to the rib ends laterally to prevent migrati0n.J Anterior depiction of the retrosternal strut. The perichondrial sheath to either the third or fourth rib is divided at its junction with the sternum, and the retrosternal space is bluntly dissected to allow passage of the strut behind the sternum. An adequate space must be created to avoid injury to the pericardium. The strut is secured with two pericostal sutures laterally to prevent migration. ( A to H, From Shamberger RC, Welch KJ: Surgical repair of pectus excavatum. J Pediatr Surg 1988;23:615-622.I a n d J From Shamberger RC: Chest wall deformities. In Shields TW [ed]: General Thoracic Surgery, 5th ed. Philadelphia, 1,ippincott Williams & Wilkins, 2000.)

904

PART

VI

THORAX .-•

A, Eighteen-year-old

man 15 years after pectus excavatum repair with a central broad recurrence and relative overgrowth of the upper unresected costal cartilages and ribs. B, Lateral radiograph demonstrates the sternum (arrow) lying parallel to the spine and the relative protrusion of the upper ribs.

The pleura was opened bilaterally, along with subperichondrial resection of six ribs. Pulmonary function was improved after the procedure. Fracture of struts left in place for extended periods has been reported, with erosion of the strut into the myocardium.101For this reason, most struts should be removed after an adequate interval to allow complete healing of the chest wall.

pectus carinatum or pectus exca~aturn."~ Two associations provide some clues to its origin: (1) a family history of chest wall deformity has been identified in 26% of patients, suggesting some genetic predisposition,l22 and (2) scoliosis in 15% of patients implies a diffuse abnormality in connective tissue development.

Clinical Presentation PROTRUSION DEFORMITIES: PECTUS CARINATUM Pectus carinatum consists of a spectrum of deformities that are less frequent than pectus excavatum by a ratio of 1:5.122 It occurs more frequently in boys than in girls (4:l),as does pectus excavatum. In almost half the children, the deformity is not appreciated until after the 1lth birthday. A mild deformity noted at birth or in early childhood often worsens as the child grows, particularly at puberty. As a result, most children present for repair as teenagers.

Cause The origin of pectus carinatum is no better established than that of pectus excavatum. Early investigators implicated abnormal development of the diaphragm, but this has Others proposed that excessive never been ~onfirrned.'~," growth of the ribs or costal cartilages produces either

The most frequent form of pectus carinatum is symmetrical protrusion of the body of the sternum (gladiolus) and costal cartilages, termed chondrogladiolar protrusion (Fig. 594). An associated lateral depression of the ribs (runnels or Harrison's grooves) is often present. It has been likened to a pant hand crushing the chest from each side.61 Protrusion can also be asymmetrical, limited to one side of the sternum, with the costal cartilages producing a keel-like protrusion (Fig. 59-5). A mixed deformity also occurs with components of both protrusion and depression. The sternum is often rotated posteriorly toward the depressed side. This variant is most frequently seen in conjunction with Poland's syndrome. The rarest form of pectus carinatum, chondromanubrial protrusion, is produced by protrusion of the manubrium and the superior costal cartilages, with a relative depression of the body of the sternum (Fig. 59-6). It is frequently associated with premature fusion of the sternal sutures and a broad comma-shaped or Z-shaped sternum. An increased incidence of congenital heart

CHAPTER

A

59

Congenital Chest Wall Deformities

905

B

A, Nineteen-year-old man with symmetrical chondrogladiolar pectus carinatum. B, Postoperative photograph shows correction of the protruding sternum and costal cartilages.

disease has been identified in these children.2" Lees and Caldicott7"dentified anomalies of sternal fusion in 135 of 1915 children. Twenty percent of those with sternal fusion had congenital heart disease.

Treatment Surgical repair of pectus carinatum has a colorful past In 19'13 Welch and that has been reviewed e1~ewhere.l~~ Vosl44 reported their approach to these deformities in

, . .

Twelve-year-old boy with asymmetrical pectus carinatum has protrusion of the costal cartilages on only the right side, producing a keel-like deformity.

26 children. They stressed the need to preserve the perichondrial sheaths and to tailor the osteotomies to achieve the appropriate position of the sternum. A similar method was used by Pickard et al.105 Attempts to treat pectus carinatum by orthotic bracing have been reported, and success in younger children has been a~hieved.~"~~,g" In older children, poor compliance with bracing programs is common, presumably due to the discomfort.

Surgical Technique Initial exDosure for repair of pectus carinatum is through a transverse incision, identical to that for pectus excavatum repair, followed by mobilization of skin and pectoral muscle flaps. Many authors stress the need to remove all deformed or partially deformed ~artilages,~~~J22 because with continued growth, mild deformities worsen and become apparent. In the chondrogladiolar deformity, a single or occasionally a double osteotomy allows the posterior plate of the sternum to be fractured, returning the sternum to a normal position (Fig. 59-7A). The wound is drained and closed in a fashion identical to that for pectus excavatum repair. In the mixed deformity, the oblique position of the sternum must be corrected, as well as the position of the depressed and protruding costal cartilages. After subperichondrial resection of the abnormal costal cartilages is completed, a wedge-shaped osteotomy is created in the anterior sternal plate, with the broad portion of the wedge on the depressed side of the sternum (Fig. 59-7B). Closure of the osteotomy both elevates and rotates the sternum into a corrected position. It is secured with sutures to close the osteotomy or with a strut. With chondromanubrial and mixed deformities, management of the sternum requires special consideration.

B

A

A, Fifteen-year-old boy with chondromanubrial deformity. Note the posterior depression of the lower sternum accentuated by the anterior bowing of the second and third costal cartilages. B, After repair, the sternal contour is improved, and costal cartilages reform in a more appropriate position.

Wedge osteotomy (4 x 1 mm) 1

-

Wedge

1.5 cm

.

,

':/35' 20'

.

A, Single or double osteotomy after resection of the costal cartilages allows posterior displacement of the sternum to an orthotopic position. B, Mixed pectus deformity is corrected by full and symmetrical resection of the third to seventh costal cartilages, followed by transverse offset wedge-shaped sternal osteotomy. Closure of this defect permits both anterior displacement and rotation of the sternum. C, Chondromanubrial deformity is corrected with a broad, wedge-shaped sternal osteotomy placed through the anterior cortex at the obliterated sternomanubrial junction. Closure of the osteotomy after fracture of the posterior cortex achieves posterior displacement of the superior portion of the sternum, which is secured only by its attachment to the first rib. The lower portion of the sternum is overcorrected 20 to 35 degrees. (B, From Shamberger RC, Welch KJ: Surgical correction of pectus carinatum. J Pediatr Surg 1987;22:48-53.C, From Shamberger RC, Welch KJ: Surgical correction of chondromanubrial deformity (CurrarinoSilverman syndrome).J Pediatr Surg 1988;34:319-322.)

CHAPTER

In the chondromanubrial form, the upper position of the sternum protrudes, and the lower body is angled toward the spine. In Ravitch'slo8 first description of the repair of this deformity, he removed a wedge of the anterior plate of the sternum at its point of maximal protrusion and created a second osteotomy at the site of the second angle of the Z-shaped sternum. In my experience, the sternum has been comma shaped and truncated, so a second osteotomy was not required (Fig. 59-7C).124When the osteotomy is closed, both the posterior depression of the lower portion of the sternum and the anterior angulation of the manubrium are corrected as the manubrium rotates posteriorly on its attachment to the first costal cartilage.

Complications Complications of repair should be infrequent, including infection, pneumothorax, pneumonia, or wound separation. Blood transfusions are rarely required with the use of electrocautery. Results from correction are overwhelmingly successful, and recurrence is rare. Incomplete correction of the deformity and repair at an early age before complete development of the deformity are the primary reasons for reoperation. 14912*

POLAND'S SYNDROME The initial description of Poland's syndrome appeared in the English literature in 1841,'" although German and French cases had been described ea1-lier.~l.128Poland reported a case in which he performed an anatomic dissection while still a medical student. He described a constellation of anomalies, including absence of the pectoralis major and minor muscles and syndactyly. Subsequent reports added other components of the syndrome, including absence of ribs, chest wall depression, athelia or amastia, absence of axillary hair, and limited subcutaneous fat. Thompson first summarized the full spectrum of anomalies in 1895.128Although described previously by others, this syndrome has been labeled Poland's syndrome since 1962, when ClarksonZ3 first applied this eponym to a group of patients.

Embryology Poland's syndrome has a sporadic occurrence estimated at 1 in 30,000 to 32,000 live births; it is rarely fa1nilia1.~~,88 Various causes have been suggested, including abnormal migration of the embryonic tissues forming the pectoral muscles, hypoplasia of the subclavian artery, and in utero injuries from attempted abortion, but none of these theories has been uniformly accepted.13,Z8Although some forms of syndactyly have been described as autosomal dominant traits, a similar pattern has not been demonstrated in patients with Poland's syndrome, which is generally sporadic. Poland's syndrome is associated with a second rare syndrome, Mobius' syndrome, involving bilateral or unilateral facial palsy and abducens oculi palsy. Fontaine and Ovlaque39 identified 19 such cases, but a unifylng cause was

59

Congenital Chest Wall Deformities

907

lacking. Boaz et al.1° reported an unusual association between Poland's syndrome and childhood leukemia.

Clinical Presentation Children demonstrate remarkable diversity in this syndrome (Fig. 59-8). The predominant defect varies, depending on the extent of involvement of the different components. By definition, all children with Poland's syndrome have aplasia or hypoplasia of the sternocostal portion of the pectoralis major muscle and at least one other associated lesion. The degree of abnormality of the hand, breast, or chest wall can be quite variable. Thomps0n,*2~in his early summary of this syndrome, found the pectoralis major muscle entirely absent in 20 cases and partially defective in 63; generally, the sternocostal component is the missing portion. The pectoralis minor was described as absent in 53 cases and defective in many others. In no case was it described as normal. Children do not present with functional deficiency of the ipsilateral arm, however, because they compensate well for the missing pectoral muscles. Hand anomalies vary widely. In the report by Ireland et al.," all their patients had syndactyly and a variable degree of brachydactyly, an obvious result of the authors' patient selection and referral patterns. In another series of 75 children with Poland's syndrome, 50 had anomalies of the hand, and 37 had absence or hypoplasia of the breast or nipple.120 In many, the nipple was lightly pigmented and higher on the chest than the normal contralateral nipple. There was no correlation between the severity of chest wall and hand anomalies. A broad range of thoracic deformities was seen in these children, ranging from a normal configuration of the ribs to aplasia of two to three ribs (Table 59-2; Fig. 59-9). Few children have a chest wall deformity so severe that it requires surgery. CT scans have proved helpful in assessing the configuration of the chest wall and its need for reconstruction (Fig. 59-10).WT scans can also evaluate the extent of muscular involvement. In one case, failure of a latissimus dorsi myocutaneous flap was attributed to unrecognized hypoplasia of the latissimus dorsi muscle.Z4 All patients with absent ribs should be considered candidates for repair. The aplastic ribs are generally some combination of the second to the fifth, with the second two cases have being least frequently in~olved.~2Wnly

Deformity None Hypoplasia of ribs without depression Depression deformity of ribs Major Minor Aplasia of ribs

No. of Patients 41 10

11 5 8

From Shamberger RC, Welch KJ, UptonJ Ill: Surgicaltreatment of thoracic deformity in Poland's syndrome. J Pediatr Surg 1989;24:760.

908

PART

VI

THORAX

_

..

Poland's syndrome. A, Muscular 15-year-old

boy with a mildly hypoplastic left chest and absent pectoralis minor muscle and costomanubrial component to the pectoralis major muscle, causing loss o f the anterior axillary fold. B, Eight-year-old boy with aplasia o f the third to fifth ribs o n the left, rotation o f the sternum to the left, and concave deformity of the remaining ribs o n the left. Note also the hypoplastic left nipple and ectromelia o f the hand. C,Fourteen-year-old girl with moderate depression o f the chest wall o n the right side in conjunction with a hypoplastic high-riding nipple and amastia. T h e second to fourth ribs were aplastic anteriorly. (From Shamberger RC, Welch KJ, U p t o n J 111: Surgical treatment o f thoracic deformity in Poland's syndrome. J Pediatr Surg 1989;24:760.)

been published in which there was involvement of all the ribs inserting into the sternum below the first. Patients with a severe ipsilateral concave deformity of the chest wall should also be considered for repair.

Treatment Ravitch109 and others have described reconstruction of aplastic ribs with autologous rib grafts. Use of the latissimus

dorsi muscle to provide coverage for the ribs produces an improved appearance but involves the possibility of functional loss when the pectoralis major muscle is also hypoplastic.37'8,gg Use of the latissimus d o ~ s flap i may be justified in females to optimize breast reconstruction, but its use in males-in whom arm strength is more importantis subject to debate, although it has been combined with implants in males to correct hypoplasia of the chest wall.85 Haller et al.49and Urschel et al.,l35 in separate reports p u b lished in 1984, combined simultaneous latissimus dorsi

CHAPTER

Sternum

Costal ca

59

Congenital Chest Wall Deformities

909

UtPHtSb

..

, _ Spectrum of rib cage abnormalities seen in Poland's syndrome. A, Most frequently, the rib cage is normal, with only absent pectoral muscles. B, Depression of the involved side of the chest wall, with rotation and often depression of the sternum. A carinate protrusion of the contralateral side is frequently present. C, Hypoplasia of ribs on the involved side but without significant depression. This usually does not require surgical correction. I>, Aplasia of one or more ribs is usually associated with depression of adjacent ribs on the involved side and rotation of the sternum. (From Shamberger RC, Welch KJ, Upton J 111: Surgical treatment of thoracic deformity in Poland's syndrome. J Pediatr Surg 1989;24:760.)

-

.

Computed tomography scan of the patient shown in Figure 59-8C. Marked depression of the ribs is apparent (curved arrow),as well as aplasia of the ribs in the lower two frames. Hypoplasia of the latissimus dorsi muscle is also noted on the lower right frame (straightarrow). (From Shamberger RC,Welch KJ, Upton J 111: Surgical treatment of thoracic deformity in Poland's syndrome. J Pediatr Surg 1989;24:760.)

910

PART

VI

THORAX

muscle flaps with placement of rib grafts or Marlex mesh. The vital components of chest wall repair include correction of the abnormal position and rotation of the sternum, as well as replacement of the aplastic ribs. Haller et a1.47described the frequent carinate deformity of the contralateral ribs, which require resection to optimize results. Resection also allows correction of the depression and rotation ofthe sternum. Hypoplasia of the ribs without localized depres sion is not surgically correctable (see Fig. 599C).

.'.- -

I\\\\ 8

' '.\ '. .

'L.

\

2

'\

,8

fl-

..-* 8-*\

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I I I

.----(

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I I

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1

\

,/------

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C

Initial exposure of the chest wall is obtained through a transverse incision, as for pectus excavatum repair (Fig. 59-1lA ). In patients requiring surgical correction, there is invariably severe depression of the involved side (occasionally with absent ribs) and rotation of the sternum, often producing a carinate protrusion on the contralateral side (Fig. 59-llB). Caution must be used

*-

\',**# 2..

-----,-a0

\

----'---.

*-

Surgical Technique

.-•

A, A transverse incision is placed below the nipple

-maels, in the inframammary crease. B, Schematic depiction of the deformity, with rotation of the sternum, depression of the cartilages on the involved side, and carinate protrusion on the contralateral side. C, In cases with aplasia of the ribs, the endothoracic fascia is encountered directly below the attenuated subcutaneous tissue and pectoral fascia. The pectoral muscle flap is elevated on the contralateral side and the pectoral fascia, if present, is elevated on the involved side. Subperichondrial resection of the costal cartilages is then carried out, as shown by the dashed lines. Rarely, this must be carried to the level of the second costal cartilage. Continued

CHAPTER

-

59

Congenital Chest Wall Deformities

911

.

Cont'd D,A transverse of£set wedge-shaped sternal osteotomy is created below the second costal cartilage. Closure of this defect with heavy silk sutures or by strut support corrects both the posterior displacement and the rotation of the sternum. E, In cases with rib aplasia, split rib grafts are harvested and secured medially with wire sutures into previously created sternal notches and with wire to the hypoplastic ribs laterally. Ribs are split as shown along their short axis to maintain maximal mechanical strength. (From Shamberger RC, Welch KJ, Upton J 111: Surgical treatment of thoracic deformity in Poland's syndron~e. J Pediatr Surg 1989;24:760.)

during this dissection when ribs are absent, because there is only a thin layer of attenuated pectoral fascia between the skin flaps and the endothoracic fascia (Fig. 59-llC). Violation of this layer should be avoided to prevent entry into the thoracic cavity. Subperichondrial resection of the costal cartilages is performed on both sides, removing the entire third, fourth, and fifth cartilages up to the costochondral junctions, which are preserved. Segments of the

Harvest rib from contralateral side and split for grafts

sixth and seventh costal cartilages are resected to the point where they flatten to join the costal arch. To correct the rotational deformity of the sternum and the depression of the involved ribs, a transverse wedge-shaped osteotomy is placed, as for the mixed pectus carinatum deformity (Fig. 59-1l D ) . Closure of this osteotomy corrects both components of the abnormal sternal position. In patients with absence of the second, third, and fourth ribs, a rib

912

PART

VI

THORAX

craft "

is harvested from the contralateral fifth or sixth rib through the anterior incision used for the repair; the periosteum is left in situ to allow regeneration of the rib. A split rib graft is generally used to facilitate revascularization of the graft through the marrow cavity. This often achieves correction of the defect with only one harvested rib (Fig. 59-11E). The graft is secured to notches created in thesternum befor; bringing the sternum anteriorly and to the involved ribs laterally with wire sutures placed through drill holes in the native rib and the graft. The rib grafts can be covered with a prosthetic mesh if further-support is needed. Breast reconstruction is required in most girls but is best delayed until late puberty to optimize the match between 'the contralateral and reconstructed breasts. Implants are generally required, often in conjunction with a latissimus dorsi flap. Customized implants have been used that correct both the hypoplasia of the chest wall and the absent breast tissue, but they have not been uniformly s u c ~ e s s f u l . ~ ~ ~ 9

Complications and Outcome The patient, his or her parents, and the surgeon must enter into correction of this deformity with appropriate expectations. The components of the chest wall deformity must be well defined to identi9 the correctable factors. Diffuse hypoplasia of the ribs without depression is not correctable. Ipsilateral depression and contralateral protrusion with rotation of the sternum can generally be improved, as can aplasia of the ribs. The concavity below the clavicle created by the hypoplastic pectoralis major muscle is frequently bothersome in girls, because this area is apparent when wearing a bathing suit or gown. It can be partially corrected with rotation of the latissimus dorsi muscle flap at the time of breast reconstruction, but these flaps have been noted to atrophy with time.8"

STERNAL DEFECTS Sternal defects are rare compared with pectus excavatum and pectus carinatum, yet they have received a great deal of attention in the medical literature. Indeed, documentation of their occurrence dates to the ancient cuneiform tablets that made up the Royal Library of Nineveh.lZ5 Translations of those tablets reveal that the ancients believed that births with "the heart open, and that has no skin" predicted calamity. Dramatic presentations of such defects since that time, particularly involving the naked heart, have led to many isolated case reports in the modern medical literature, as well as several excellent reviews. Weese128 provided the first anatomic classification of sternal defects in 1818, dividing them into ectopia cordis cum sterni fissura, ectopia suprathoracica, and ectopia subthoracica. Breschet1Z8in 1826 provided three comparable divisions: 1'ectopie thoracique d u coeur, l'ectopie abdominale, and l'ectopie ciphalique. Roth128 in 1939 divided these lesions into ectopia cordis thoracalis extrathoracica, ectopia cordis ventralis, and ectopia cordis suprathoracica (cervicalis);

the first division was further subdivided into defects in the manubrium, defects in the body of the sternum, and ectopia cordis pectoralis sterrzoepigastrica. Similarly, Shao-tsul2" divided sternal defects into ectopia cordis ceruicalis, with the heart in the neck; ectopia cordis thoracalis, with the heart outside the thorax and a sternal fissure; ectopia cordis thoracoabdominalis; and ectopia cordis abdominalis. Despite these classifications, subsequent case reports often blurred the divisions and confused the field that had been so well defined by early authors. One sternal defect that was not accounted for in these classifications was the bifid or cleft sternum. In this deformity, the heart is in an orthotopic position in the thoracic cavity, but the sternum is cleft or only partially fused overlying the heart. Skin coverage is normal or with only a small superficial ulceration. More than a century after these descriptions and classifications, Cantrell and RavitchZOsummarized a group of patients with ectopia subthoracica or ectopia abdominale deformity, along with its associated defects of the diaphragm, pericardium, abdominal wall, and heart. Subsequently, these patients were often referred to as having Cantrell's pentalogy, adding to the confusion. A more recent report summarized the world literature and tabulated the associated anomalies that occur in these infants and children.I21 Review of this topic provides four basic types of sternal defects based on tissue coverage of the heart, with limited overlap between categories. Further divisions seem artificial and do not clarify the anatomy or have prognostic significance.

Thoracic Ectopia Cordis Thoracic ectopia cordis consists of the ectopia cordis cum sternifissura of Weese and the ectopie thoracique d u coeur of Breschet. These lesions constitute the classic naked heart with no overlying somatic structures. The orientation of the apex of the heart is anterior antd often superior (Fig. 59-12). Intrinsic cardiac anomalies are frequent, and associated lesions have been summarized.121 Many case reports do not provide information on the intrinsic cardiac anatomy owing to the striking external appearance of the heart. The sternum may be intact superiorly at the manubrium or entirely split; in rare cases, the heart may protrude through a defect in the central portion of the sternum. There is a severe lack of midline somatic tissues, and many attempts at primary closure have failed. Evaluation by CT has confirmed that the intrathoracic cavity is small in these infants." Most successful repairs have not been achieved in true thoracic ectopia cordis but rather in thoracoabdominal ectopia cordis. Cutler and Wilens2'jfirst attempted repair in 1925 by skin flap coverage, but this failed because of cessation of cardiac function, presumably from pressure on the heart. In more than 29 attempts, only four survivors have been re~orded.32,7~.~~.ll~ The first successful repair of ectopia cordis was achieved by Koop in 1975, as reported by Saxena."Wn infant with a normal heart had skin flap coverage at 5 hours of age, with inferior mobilization of the anterior attachments of the diaphragm. The sternal bands were

CHAPTER

59

Congenital Chest Wall Deformities

913

location (see Fig. 59-12B). Of note, in the successful cases, intrinsic cardiac lesions and associated abdominal defects were absent, except for a muscular ventricular septa1 defect and a ventricular diverticulum in the case of Morales94; these characteristics distinguish the successful cases from the failures rather than any differences in surgical technique. In cases repaired with autologous tissue grafts (bone or cartilage) or synthetic materials, infection and extrusion of the graft invariably occur. Ultimate success can be achieved only with tissue coverage over the displaced heart that avoids posterior compression of the heart into an already limited thoracic space. This type of coverage may require the use of tissues from sites distant from the anterior chest wall or extensive mobilization of local tissues. The severe intracardiac defects associated with thoracic ectowia cordis also make ultimate survival difficult. Regrettably, the only advancement in management of this lesion has been prenatal ultrasonographic identification, including definition of the intracardiac lesions and termination of the pregnancy if desired by the parents.14" Upper abdominal wall defects are also frequent in these patients, including upper abdominal omphalocele, diastasis recti, and rarely, eventration of the abdominal viscera. The presence of abdominal wall defects in conjunction with thoracic ectopia cordis should not, however, lead to the classification of these lesions as thoracoabdominal ectopia cordis; this term should be reserved for cases in which the heart is covered at birth.

B

Cervical Ectopia Cordis

, - .

A, Infant with thoracic ectopia cordis with no significant abdominal wall defect. B, Repair via skin flap coverage was achieved by extensive mobilization of the skin flaps laterally on the day of birth. Repair of the intracardiac defect-tetralogy of Fallot with long-gap pulmonary atresia-was achieved later through the skin flaps. (Courtesy of Craig W. Lillehei, MD.)

2 inches apart and could not be approximated primarily without cardiac compression and compromise. At 7 months of age, an acrylic resin of Dacron and Marlex mesh was inserted to widen the sternal cleft, with primary skin closure. Necrosis of the skin flaps complicated the postoperative course, and infection of the prosthetic material necessitated its removal. This child has survived to age 18 years and is reported to be entirely well. The case of Dobell et a1.32 is notable because surgical correction was performed in two stages: skin flap coverage was provided as a newborn, and at 19 months of age, rib strut grafts were placed over the sternal defect and covered with pectoral muscle flaps. The pericardium was divided from its anterior attachments to the chest wall, allowing the heart to fall back partially into the thoracic cavity. Only Arnato et and Morales et a1.g4achieved complete soft tissue coverage in one stage. The unifylng theme of successful management is the construction of a partial anterior chest cavity surrounding the heart and the avoidance of attempts to return the heart to an orthotopic

Cervical ectopia cordis (ectopia suprathoracica of Weese and ectopie ciphalique of Breschet) has historically been defined as a separate entity from thoracic ectopia cordis, based on the extent of superior displacement of the heart. Fusion between the apex of the heart and the mouth is often present, as are severe craniofacial anomalies. This lesion is relatively rare compared with thoracic ectopia cordis, but patients share the same dismal prognosis. In the summary of Shao-tsu,lZ8only five infants were classified with cervical ectopia cordis, whereas 121 infants had the thoracic variety. No survivors or attempts at closure in this group of severely deformed infants have been reported.

Thoracoabdominal Ectopia Cordis Thoracoabdominal ectopia cordis includes those lesions classified as ectopia subthoracica by Weese and ectopie abdominale by Breschet. It combines the rather artificial divisions of ectopia cordis thoracalis extrathoracica sternoepigastm'ca and ectopia cordis ventralis of Roth and the ectopia cordis thoracoabdominalis and ectopia cordis abdominalis of Shao-tsu. In this group, the heart is covered by a membrane of thin, often pigmented skin with an overlying, inferiorly cleft sternum (Fig. 59-13). The heart lacks the severe anterior rotation present in thoracic ectopia cordis. A 1798 report of this lesion by Wilson77 clearly defined the associated somatic defects of the abdominal

914

PART

VI

THORAX

defect or prosthetic mesh closure. Primary closure is often difficult to achieve because of the wide distance between the two rectus muscles, which are attached superiorly to the splayed costal arches, limiting midline mobility. The costal cartilages are divided laterally in one modification of closure, allowing them to rotate medially.68 Complete repair of the intracardiac defect is best performed before placement of any prosthetic material over the heart. Once skin coverage is achieved, closure of this defect is important, primarily for mechanical protection of the heart. Fatal pulmonary hypoplasia has occurred in some infants with this an0maly.~21

Cleft or Bifid Sternum Infant with thoracoabdominal ectopia cordis demonstrating a small abdominal wall defect covered by an omphalocele below the costal arch. The infant's head is to the right, and the heart (arrozu) is visiblejust below the superior margin of the defect, covered by a thin membrane. Primary skin closure was achieved during the initial operation, with subsequent repair of the cardiac defect. e

-

.

wall, diaphragm, and pericardium, as well as the intrinsic cardiac anomalies, more than 150 years before the reviews by Major"3and Cantrell and Ravitch.20 These patients almost invariably have associated abdominal wall defects (omphalocele, diastasis recti, or ventral hernia), along with anterior semilunar defects in the diaphragm and pericardium. Intrinsic cardiac lesions are frequently present in these patients and have been summarized.l2*The position of the heart varies; it may lie within the thoracic cavity, with only the diaphragmatic and pericardial defect below it, or it may reside entirely within the abdominal cavity, with the major vessels extending through the defect in the diaphragm. Diverticula of the left ventricle occur with surprising frequency in this anomaly. In many cases, the diverticulum protrudes through the diaphragmatic and pericardial defect into the abdominal cavity. Successful repair and long-term survival are more frequent in thoracoabdominal ectopia cordis than in thoracic ectopia cordis. Arndt3 attempted the first repair in 1896, but return of the heart to the thoracic cavity '~~ the first successresulted in death. W i e t i r ~ gperformed ful surgical repair with primary closure of the diaphragm and abdominal wall fascia in 1912. Initial surgical intervention must address the skin defects overlying the heart and abdominal cavity. Primary excision of the omphalocele with skin closure is preferred to avoid infection and mediastinitis, although several cases have been managed successfully by local application of topical astringents, allowing secondary epithelialization to occur. Several early cases document the viability of individuals with thoracoabdominal ectopia cordis when there is intact skin coverage over an intra-abdominal heart. Advances in pediatric cardiac surgery now allow correction of the intrinsic cardiac lesions that were often fatal in the past. An aggressive approach in these infants is appropriate. Closure of the abdominal wall defect or diastasis can be managed by either primary closure of the

Cleft or bifid sternum is the fourth and least severe anomaly of the sternum. Infants in this group have an orthotopic heart, normal skin coverage, an intact pericardium, and a partially or completely cleft sternum (Fig. 59-14). Omphalocele is not associated with cleft sternum. The sternal defect, if partial, involves the upper sternum and manubrium, in contrast with the sternal defect in thoracic or thoracoabdominal ectopia cordis, in which partial defects involve primarily the lower sternum. Most cases are partially split (Table 59-3), with an intact xiphoid or lower third of the body of the sternum. The bifid or cleft sternum is distinct from the other three categories of sternal defects, in that intrinsic cardiac defects are rare. Several distinct somatic associations are seen, including bandlike scars extending from the umbilicus to the inferior aspect of the sternal defect. Other children have superior scarlike extensions to the neck or mandible; rarely, a split mandible occurs (gnathoschisis). Fischer3'jreported an unexplained association with cervicofacial hemangiomas in 1879, and Ingelrans and Debeugny63 later reported the occurrence of fatal postoperative hemorrhage from presumed hemangioma of the trachea after repair of a sternal defect. In most cases, these infants' sternal defects are asymptomatic. Repair is performed to provide protective coverage for the heart. It may also improve respiratory mechanics, which are compromised by the paradoxical ~ was allegedly motion of the defect. L a n n e l o n g ~ ein~1888 the first to repair a cleft sternum, but his intervention was limited to excision of a small circular ulcer overlying

Defect Upper cleft Upper cleft to xiphoid Complete cleft Lower defect with manubrium or midsegment intact Central defect with manubrium and xiphoid intact Skin ulceration noted in only

No. of Patients 46 33 23 , 5

2 3 cases

From Shamberger R, Welch KI: Sternal defects. Pediatr Surg Int 1990;5:156-164.

CHAPTER

A

. - .

59

Congenital Chest Wall Deformities

915

B

Six-week-old infant with bifid sternum. Note the marked protrusion from the defect when crying (A) and depression of the defect with inhalation (B). Capillary hemangiomas are also visible on the lips.

the sternal defect. He created two relaxing incisions laterally, allowing primary closure of the skin, but ignored the underlying sternal separation. The first complete repair of a cleft sternum was accomplished by placing a cartilage graft from the costal arch over the defect.ls Maier and Bortone82 achieved the first primary closure in 1949 in a &week-old infant. Subsequent methods have included bilateral oblique incisions through the costal cartilages to produce greater length and allow midline approximation of the sternal halves (sliding chondrotomies of Sabiston112);division of the cartilages laterally, swinging them medially to cover the defect (door-wing plasty of Meissnergl); coverage with various autologous grafts (costal cartilage, rib, parietal skull); and coverage with prosthetic materials. Maier and Bortone8' first stressed the importance of early repair in infancy, when the chest is most flexible, to achieve primary closure (Fig. 59-15). In most reported cases of primary repair, correction took place within the first 3 months of life (18 of 22 cases) and rarely after 1 year of age (2 cases).121In contrast, some form of chondrotomy was required in 22 patients, 8 of whom were older than 1 year. Often a wedge of cartilage must be excised from the point where the two sternal halves unite to allow approximation without tension.

THORACIC DEFORMITIES IN DIFFUSE SKELDAL DISORDERS Asphyxiating Thoracic Dystrophy: Jeune's Syndrome In 1954Jeune et al.@described a newborn with a narrow, rigid chest and multiple cartilage anomalies. The patient died early in the perinatal period because of respiratory insufficiency. Subsequent authors further characterized this form of osteochondrodystrophy, which has variable skeletal involvement. It is inherited in an autosomal recessive pattern and is not associated with chromosomal abnormalities. Its most prominent feature is a narrow, bell-shaped thorax and protuberant abdomen. The thorax is narrow in both the transverse and the sagittal axes and has little respiratory motion because of the horizontal direction of the ribs (Fig. 59-16). The ribs are short and wide, and the splayed costochondral junctions barely reach the anterior axillary line. The costal cartilage is abundant and irregular, similar to a rachitic rosary. Microscopic examination of the costochondral junction reveals disordered, poorly progressing endochondral ossification resulting in decreased rib length.

I 916

PART

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THORAX Pericardium and

/ endothoracic fascia Midline incision

Tevdek or PDS sutures

Undermine

I

k wedge

. - .

A, Repair of bifid sternum is best performed through a longitudinal incision extending the length of the defect. B, Directly beneath the subcutaneous tissues, the sternal bars are encountered, with pectoral muscles present lateral to the bars. The endothoracic fascia and pericardium are just below these structures. C,The endothoracic fascia is mobilized off the sternal bars posteriorly with blunt dissection, to allow safe placement of the sutures. Approximation of the sternal bars may be facilitated by excising a wedge of cartilage inferiorly. Repair is best accomplished in the neonatal period, when there is greatest flexibility of the chest wall. D,Closure of the defect is achieved with nonabsorbable sutures. (From Shamberger RC, Welch KJ: Sternal defects. Pediatr Surg Int 1990;5:156164.)

Associated skeletal abnormalities that occur with this syndrome include short, stubby extremities with relatively short and wide bones. The clavicles are in a fixed and elevated position, and the pelvis is small and hypoplastic, with square iliac bones. This syndrome has variable expression and extent of pulmonary impairment. Although the initial cases

reported resulted in neonatal deaths, subsequent reports document a wide range of survival in patients with this syndrome.75 The pathologic findings at autopsy are variable, showing a spectrum of abnormal pulmonary development. In most cases, however, bronchial develop ment is normal, with fewer alveolar divisions, as described by Williams et a1.147 Surgical attempts to enlarge the

CHAPTER

A

59

Congenital Chest Wall Deformities

917

B

A, Anteroposterior radiograph shows the short horizontal ribs and narrow chest of an infant with Jeune's syndrome (asphyxiating thoracic dystrophy). B, Lateral radiograph demonstrates the short rib ends ending at the midaxillary line (arrow) and abnormal flaring at the costochondral junction. The infant died of progressive respiratory insufficiency at 1 month of age, and postmortem examination revealed alveolar hypoplasia. I

-

-

thoracic cavity are generally unsuccessful and result in prolonged hospitalization and ultimate respiratory failure and death.

Spondylothoracic Dysplasia: Jarcho-Levin Syndrome Spondylothoracic dysplasia is an autosomal recessive dkforkity described by ~ a r c h oand L e v i r ~in~ 1938 ~ that is associated with multiple vertebral and rib malformations. Death often occurs in early infancy from respiratory failure and pneumonia. Patients have multiple alternating hemivertebrae that affect most if not all of the thoracic and lumbar spine. The vertebral ossification centers rarely cross the midline. Multiple posterior fusions of the ribs and remarkable shortening of the thoracic spine result in a crablike radiographic appearance of the chest (Fig. 59-17). One third of patients with this syndrome have associated malformations, including congenital heart disease and renal anomalies. Heilbronner and Renshawj7

reported its occurrence primarily in Puerto Rican families. Bone formation is normal in these patients. The thoracic deformity is secondary to the spinal anomaly, which results in close posterior approximation of the origin of the ribs. Most infants with this entity succumb before 15 months of age, and no surgical efforts have been proposed or attempted.

Cerebrocostomandibular Syndrome The association of severe rib defects, micrognathia, and other anomalies was first described by Smith et aI.lm in 1966 and later by McNicholl et al.89Infants with this constellation of anomalies have ossified ribs with an aplastic segment a short distance beyond the posterior rib angles. They also have micrognathia, abnormal tracheal cartilage, and defects of the soft and hard palates. Mild to moderate mental retardation occurs in 50% of infants surviving beyond the first year of life.130The extent of rib defects is variable, both in the number of involved ribs

918

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. - -

Chest radiograph of an infant with spondylothoracic dysplasia. Severe abnormality of the spine is apparent, with multiple alternating hemivertebrae and the crablike ribs.

a n d in t h e extent of t h e defect, ranging from a narrow g a p to a rudimentary rib. The third to seventh ribs a r e most frequently involved. T h e rib g a p may contain fibrous tissue, skeletal muscle, o r cartilage with variable calcification. The rib gaps produce a flail chest, a n d t h e prognosis f o r these infants is poor. Forty percent d i e from respiratory failure d u r i n g t h e first year of life.130 T h e underlying cause a n d t h e inheritance pattern a r e n o t known. a n d chromosomal studies a r e normal.

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34. Erbella J Jr, Behmand R, Cederna PS: Endoscopically assisted pectus excavatum repair. Surg Laparosc Endosc Percutan Tech 2001;11:213-216. 35. Feng J, Hu T, Liu W, et al: The biomechanical, morphologic, and histochemical properties of the costal cartilages in children with pectus excavatum. J Pediatr Surg 2001; 36: 1770-1776. 36. Fischer H: Fissura sterno congenita mit partieller Bauchspalte. Dtsch Z Chir 1879;12:367-369. 37. Fodor PB, Khoury F: Latissimus dorsi muscle flap in reconstruction of congenitally absent breast and pectoralis muscle. Ann Plast Surg 1980;4:422-425. 38. Fonkalsrud EW, Salman T, Guo W, et al: Repair of pectus deformities with sternal support. J Thorac Cardiovasc Surg 1994;107:37-42. 39. Fontaine G, Ovlaque S: Le syndrome de Poland-Mobius. Arch Fr Pediatr 1984;41:351-352. 40. Freire-Maia N. et al: The Poland svndrome: Clinical and geneaological data, dermatoglyphic analysis, and incidence. Hum Hered 1973;23:97-104. 41. Froriep R: Beobachtung eines Falles Von Mange1 der Brustdruse. Notizen aus dem Gebiete der Naturund Heilkunde 1839:10:9-14. 42. Garusi G: Angiocardiographic patterns in funnel chest. Cardiologia 1964;45:312-330. 43. Genc A, Mutaf 0 : Polytetrafluoroethylene bars in stabilizing the reconstructed sternum for pectus excavatum operations in children. Plast Reconstr Surg 2002;110:5457. 44. Godfrey S: Association between pectus excavatum and segmental bronchomalacia. J Pediatr 1980;96:649-652. 45. Guller B, Hable K: Cardiac findings in pectus excavatum in children: Review and differential diagnosis. Chest 1974;66:165-171. 46. Haje SA, Bowen JR: Preliminary results of orthotic treatm&t of pectus deformities in children and adolescents. J Pediatr Orthop 1992;12:795-800. 47. Haller JA J r : Severe chest wall construction from growth retardation after too extensive and too earlv, (<4 - vears) , pectus excavatum repair: An alert. Ann Thorac Surg 1995; 60:1857-1858. 48. HallerJA Jr, Colombani PM, Humphries CT, et al: Chest wall constriction after too extensive and too early operations for pectus excavatum. Ann Thorac Surg 1996;61:1618-1624. 49. Haller JA Jr, Colombani PM, Miller D, et al: Early reconstruction of Poland's syndrome using autologous rib grafts combined with a latissimus muscle flap. J Pediatr Surg 1984;19:423-429. 50. Hallen JAJ Jr, Kramen SS, Lietman SA: Use of CT scans in selection of patients for pectus excavatum surgery: a preliminary report. J Pediatr Surg 1987;22:904906. 51. Haller JA Jr, Loughlin GM: Cardiorespiratory function is significantly improved following corrective surgery for severe pectus excavatum: Proposed treatment guidelines. J Cardiovasc Surg (Torino) 2000;41:125-130. 52. Haller JA Jr, Peters GN, Mazur D, et al: Pectus excavatum: A 20 year surgical experience. J Thorac Cardiovasc Surg 1970;60:375-383. 53. Haller.]A.]r, Scherer LR, Turner CS, et al: Evolving management Gf pectus excavatum based on a single institutional experience of 664 patients. Ann Surg 1989;209:578-582. 54. Hayashi A, Maruyama Y Vascularized rib strut technique for repair of pectus excavatum. Ann Thorac Surg 1992; 53:34&348. 55. Haynor DR, Shuman WP, Brewers DK, et al: Imaging of fetal ectopia cordis: Roles of sonography and computed tomography. J Ultrasolind Med 1984;3:25-27. 56. Hecker WC, Procher G, Dietz HG: [Results of operative correction of pigeon and funnel chest following a modified

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r

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80. Lester C: The surgical treatment of funnel chest. Ann Surg 1946;123:1003-1022. 81. Liese W, Biihlmann A: Arbeitskapazitat und lungenvolumina vor und nach chirurgischer korrektur einer trichterbruszt. Schweiz Med Wochenschr 1974;104:83-86. 82. Maier HC, Bortone F: Complete failure of sternal fusion with herniation of pericardium. J Thorac Surg 1949; 18:851-859. 83. Major JW: Thoracoabdominal ectopia cordis. J Thorac Surg 1953;26:309-317. 84. Malek MH, Fonkalsrud EW, Cooper CB: Ventilatory and cardiovascular responses to exercise in patients with pectus excavatum. Chest 2003;124:870-882. 85. Marks MW, Argenta LC, Izenberg PH, et al: Management of the chest-wall deformity in male patients with Poland's syndrome. Plast Reconstr Surg 1991;87:674678. 86. Martinez D: The effect of costal cartilage resection on chest wall development. Pediatr Surg Int 1990;5:170-173. 87. Matsui T, Kitano M, Nakamura T, et al: Bioabsorbable struts made from poly-L-lactide and their application for treatment of chest deformity. J Thorac Cardiovasc Surg 1994;108:162-168. 88. McGillivray BC, Lowry RB: Poland syndrome in British Columbia: Incidence and reproductive experience of affected persons. Am J Med Genet 1977;1:65-74. 89. McNicholl B, Egan-Mitchell B, Murray JP, et al: Cerebrocosto-mandibular syndrome: A new familial developmental disorder. Arch Dis Child 1970;45:421-424. 90. Mead J, Sly P, Le Souef P, et al: Rib cage mobility in pectus excavatum. Am Rev Respir Dis 1985;132:1223-1228. 91. Meissner F: Fissura sterni congenita. Zentralbl Chir 1964;89:1832-1839. 92. Meyer L: Zur chirurgischen behandlung der angeborenen trichterbrust. Verh Berliner Med Gesellschaft 1911; 42:364373. 93. Mielke CH, Winter RB: Pectus carinatum successfully treated with bracing: A case report. Int Orthop 1993; 17:350-352. 94. Morales JM, Patel SG, Duff JA, et al: Ectopia cordis and other midline defects. Ann Thorac Surg 2000;70:111-114. 95. Morshuis W, Folgering H, Barentsz J, et al: Pulmonary function before surgery for pectus excavatum and at longterm follow-up. Chest 1994;105:1646-1652. 96. Morshuis WJ, Folgering HT, Barentsz JO, et al: Exercise cardiorespiratory function before and one year after operation for pectus excavatum. J Thorac Cardiovasc Surg 1994;107:1403-1409. 97. Nakajima H, Chang H: A new method of reconstruction for pectus excavatum that preserves blood supply and costal cartilage. Plast Reconstr Surg 1999;103:1661-1666. 98. Ochsner A, Debakey M: Chone-chondrosternon: Report of a case and review of the literature. J Thorac Surg 1939; 8:469-511. 99. Ohmori K, Takada H: Correction of Poland's pectoralis major muscle anomaly with latissimus dorsi musculocutaneous flaps. Plast Reconstr Surg 1980;65:400-404. 100. Ohno K, Nakahira M, Takeuchi S, et al: Indications for surgical treatment of funnel chest by chest radiograph. Pediatr Surg Int 2001;17:591-595. 101. Onursal E, Toker A, Vostanci K, et al: A complication of pectus excavatum operation: Endomyocardial steel strut. Ann Thorac Surg 1999;68:1082-1083. 102. Orzalesi MM, Cook CD: Pulmonary function in children with pectus excavatum. J Pediatr 1965;66:898-900. 103. Paltia V: Operative technique in funnel chest: Experience in 81 cases. Acta Chir Scand 1958;116:90-98. 104. Peterson RJ, Young WG Jr, Godwin JD, et al: Noninvasive assessment of exercise cardiac function before and after

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130. Smith KG, Sekar KC: Cerebrocostomandibular syndrome: Case report and literature review. Clin Pediatr (Phila) 1985;24:223-225. 131. Taguchi K: A new plastic operation for pectus excavatum: Sternal turnover surgical procedure with preserved internal mammary vessels. Chest 1975;67:606608. 132. Tanaka F, Kitano M, Shindo T, et al: [Postoperative lung function in patients with funnel chest]. Nippon Kyobu Geka Gakkai Zasshi 1993;41:2161-2165. 133. Tang Chen YB, Chen JS, Lee YC, et al: Revascularization of turnover sternum: A definitive treatment for intractable funnel chest. Microsurgery 1999;19:296-302. 134. Udoshi MB, Shah A, Fisher VJ, et al: Incidence of mitral valve prolapse in subjects with thoracic skeletal abnormalities-a prospective study. Am Heart J 1979;97:303-311. 135. Urschel HC Jr, Byrd HS, Sethi SM, et al: Poland's syndrome: Improved surgical management. Ann Thorac Surg 1984;37:204211. 136. Vanamo K, Peltonen J, Rintala R, et al: Chest wall and spinal deformities in adults with congenital diaphragmatic defects. J Pediatr Surg 1996;31:851-854. 137. von der Oelsnitz G: [Anomalies of the chest]. Z Kinderchir 1981;33:229-236. 138. Wada J, Ikeda K, Ishida T, et al: Results of 271 funnel chest operations. Ann Thorac Surg 1970;10:526-532. 139. Weber TR, Kurkchubasche AG: Operative management of asphyxiating thoracic dystrophy after pectus repair. J Pediatr Surg 1998;33:262-265. 140. Wechselberger G, Ohlbauer M, Haslinger J, Schoeller T: Silicone implant correction of pectus excavatum. Ann Plast Surg 2001;47:489-493.

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141. Weg JG, Krumholz RA, Harkleroad LE: Pulmonary dysfunction in pectus excavatum. Am Rev Respir Dis 1967;96:936-945. 142. Welch K: Satisfactory surgical correction of pectus excavatum deformity in childhood: A limited opportunity. J Thorac Surg 1958;36:697-713. 143. Welch K: Chest Wall Deformities. Philadelphia, WB Saunders, 1980. 144. Welch KJ, Vos A: Surgical correction of pectus carinatum (pigeon breast). J Pediatr Surg 1973;8:659-667. 145. WicksJD, Levine MD, Mettler FA Jr: Intrauterine sonography of thoracic ectopia cordis. AJR Am J Roentgen01 1981; 137:619-621. 146. Wieting R: Eine operative behandelte Herzmissbildung. Dtsch Z Chir 1912;114:293-295. 147. Williams AJ, Vauter G, Reid LM: Lung structure in asphyxiating thoracic dystrophy. Arch Path01 Lab Med 1984; 108:658-661. 148. Willital GH: [Indication and operative technique in chest deformities]. Z Kinderchir 1981;33:244252. 149. Wolf WM, Fischer MD, Saltzman DA, et al: Surgical correction of pectus excavatum and carinatum. Minn Med 1987;70:447-453. 150. Wynn SR, Driscoll DJ, Ostrom NK, et al: Exercise cardiorespiratory function in adolescents with pectus excavatum: Observations before and after operation. J Thorac Cardiovasc Surg 1990;99:41-47. 151. Yamaguchi M, Tsukube T, Ohashi H, et al: [Early and long-term results of sternocostal elevation combined with bridge external traction for funnel chest in children]. Nippon Kyobu Geka Gakkai Zasshi 1993;41:2341-2348.

T h e Nuss Procedure for Pectus Donald Nuss and Robert E. Kelly, Jr

MINIMALLY INVASIVE REPAIR The minimally invasive repair of pectus excavatum consists of a two-pronged approach: the surgical repair and an exercise and posture program. Surgical correction of pectus excavatum is accomplished by inserting a convex steel bar under the sternum with the convexity facing posteriorly. When the bar is in position, it is turned over 180 degrees, thereby correcting the deformity (see Figs. 59-18 to 59-27). The technique is possible because of the malleability and flexibility of the anterior chest wall; it requires no cartilage incision or resection and no sternal osteotomy. Because most of these patients lead sedentary lives and

have the classic "pectus posture," which aggravates the deformity, they are also given a set of breathing and posture exercises to do on a daily basis and are encouraged to participate in aerobic sports activities.

CLASSIFICATION AND TREATMENT ALGORITHM When pectus excavatum patients are evaluated for the first time, they are classified as having mild, moderate, or severe deformities. Patients with mild or moderate deformities are started on the exercise and posture program and re-evaluated at 12-month intervals to ensure that they have developed an exercise routine and are

922

PART

VI

THORAX History Physical exam

1/

Mild

m '

Severe

J.

Exercise program

f--

Moderate

J.

f--

Pulmonary function test CT scan Cardiac evaluation

+ I

Follow-up every 12 mo

Severe

J.

Minimally invasive repair

-

.

Clinical pathway for management of patients with

pectus excavatum.

doing the exercises correctly. Approximately 66% of patients are treated conservatively. Patients with severe deformities undergo a workup to determine whether they are candidates for surgery. The workup includes pulmonary function studies; a cardiology evaluation, including an electrocardiogram and echocardiogram; and a CT scan. For consistency, radiologists have suggested that the chest CT be performed during quiet respiration, not during maximal inspiration. Surgical correction is warranted if the patient has two or more of the following criteria: (1) progressive or symptomatic pectus excavatum; (2) restrictive disease, as determined by pulmonary function studies; (3) CT scan showing cardiac compression or displacement, pulmonary atelectasis, and a Haller CT index greater than 3.25; (4) cardiac abnormalities, including mitral valve prolapse or bundle branch block; (5) recurrent pectus excavatum after a failed repair.

SURGICAL TECHNIQUE Preoperative Checklist: Day before Surgery 1. Review studies and check for allergies, including allergy to metallic objects. 2. To calculate the length of the pectus bar required, measure the distance from the right to the left midaxillary line and subtract 2 cm from this measurement. The bar takes a shorter course than the tape measure and therefore needs to be shorter than the measurement (Fig. 59-19).

Patient Anesthesia, Preparation, and Positioning 1. General endotracheal anesthesia. 2. Insertion of thoracic epidural catheter by the anesthesiologist. Epidural analgesia is continued for 3 to 5 days (average, 3 days). 3. Insertion of indwelling bladder catheter. Catheter is removed on the first postoperative day when the patient is awake and oriented.

. . .

Measure the distance from the right to the left midaxillary line. The bar should be 2 cm shorter than the measurement. Bend the bar into the desired configuration, leaving a 2- to 4 c m flat section in the middle to support the sternum.

4. Nasogastric or orogastric tube is inserted during surgery and removed at the end of the procedure. 5. Antibiotic coverage (e.g., cefazolin x 5 days) is essential to minimize the risk of pneumonia with subsequent bar infection. 6. Both arms are abducted at the shoulder, and gel pads are used to prevent brachial plexus injury (see Fig. 59-19). Allow slight flexing at the elbows. 7. After draping, the Lorenz pectus support bar is bent into a semicircle, leaving the central 2-cm section flat to support the sternum (see Fig. 59-19). Bending the bar into an arch shape allows sustained load bearing of the bar. If the central flat section of the bar is too long, there will be undercorrection.

Patient Marking 1. The deepest point of the pectus excavatum is marked with a circle using a marking pen (Fig. 59-20). If the deepest point of the pectus is inferior to the sternum, the inferior end of the sternum is marked instead. This point sets the horizontal plane for bar insertion. 2. The intercostal spaces that are in the same horizontal plane as the deepest point of the pectus excavatum are marked with an X. These entry and exit points on each side of the sternum should be medial to the top of the pectus (costochondral) ridge (see Fig. 59-20).

CHAPTER

2.

3.

Mark the deepest point of the depression with a circle, mark the intercostal space medial to the top of the ridge with an X, and mark the incision site with a line. These marks should all be in the same horizontal plane. The thoracoscope is inserted two intercostal spaces below the incision site. I

-

*

3. Lines are drawn for the proposed incision sites on each lateral chest wall in the same horizontal plane (see Fig. 59-20).

Thoracoscopy and Tunnel Creation 1. A thoracoscope is inserted through the right lower lateral chest wall approximately two interspaces inferior to the proposed skin incision (see Fig. 59-20).

. - .

On each side, a deep subcutaneous tunnel is created from the anterior aspect of the lateral thoracic incisions to the intercostal spaces marked with an X, medial to the top of the ridge.

4.

5.

59

Congenital Chest Wall Deformities

923

A thorough inspection of the right hemithorax and mediastinum is performed, ensuring that there is no contraindication for repair. Then pressure is applied to the intercostal spaces marked for bar insertion to ensure that the external markings line up well with the internal anatomy. After confirming by thoracoscopy that the internal and external anatomy match up well, bilateral thoracic skin incisions are made, and a deep subcutaneous tunnel is raised anteriorlv toward the intercostal swace marked with an X, medial to the top of the pectus ridge (Fig. 59-21). Also, a pocket is created for the distal end of the pectus bar and stabilizer. Under thoracos~opiccontrol, the appropriate size Lorenz introducer is inserted through the right intercostal space at the top of the pectus ridge at the previously marked X (Fig. 59-22). The electrocardiogram volume is turned up so that the heartbeat is clearly audible. The pericardium is gently dissected off the undersurface of the sternum (see Fig. 59-22). The introducer is slowly advanced across the mediastinum under thoracoscopic guidance, with the point always facing anteriorly and in contact with the sternum. When thk substernal tunnel has been com~leted,the tip of the introducer is pushed through the contralatera1 intercostal space at the previously marked X and advanced out of the skin incision (Fig. 59-23).

Sternal Elevation and Bar Insertion 1. The introducer is used to elevate the sternum. The surgeon lifts the introducer on the right side, and the assistant lifts on the left side (see Fig. 59-23). The lifting is repeated until the sternum has been elevated out of its depressed position and the pectus excavatum has been corrected. An umbilical tape is attached to the

924

PART

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THORAX

.-• A, A Lorenz introducer is inserted into the subcutaneous tunnel on the right. Under thoracoscopic guidance, it is pushed through the right intercostal space marked with an X. B, Under thoracoscopic guidance, a transthoracic substernal tunnel is created by dissecting- the .pleura and pericardium off the undersurface of the sternum with the introducer. The introducer is pushed through the left intercostal space marked with an X and advanced out of the left lateral thoracic incision.

/'

-

.

The sternum is elevated out of its depressed position by lifting the introducer on each side while applying pressure to the lower costal margin. The lifting is repeated until the pectus excavatum is corrected.

. . .

After correcting the pectus excavatum, umbilical tape is attached to the end of the introducer, which is then slowly withdrawn from the chest, thereby pulling the umbilical tape through the transthoracic tunnel.

CHAPTER

. - .

The previously prepared pectus support bar is tied midance, is ~ u l l e d to the umbilical taDe and. under thoracoscovic " through the substernal tunnel with the convexity facing posteriorly. 1

2.

3. 4. 5.

,

.

introducer, which is slowly extracted, pulling the umbilical tape through the substernal tunnel (Fig. 59-24). The previously prepared pectus bar is tied to the umbilical tape and guided through the substernal tunnel using the tape for traction and the thoracoscope for vision. The bar is inserted with the convexity facing posteriorly (Fig. 59-25). When the bar is in position, it is rotated 180 degrees using the bar flipper (Fig. 59-26). If the bar requires further bending, it is turned over and molded where required, using the small Lorenz bar bender. If one bar is not enough, a second bar is inserted one interspace above or below the first one. Two bars give

-

.

When the bar is in position, it is rotated 180 degrees using the bar flipper.

I - .

59

Congenital Chest Wall Deformities

925

Severe pectus excavatum before surgery.

better and more stable correction, especially in older patients. 6. Slight overcorrection is necessary to prevent recurrence after the bar is removed (Figs. 59-27 and 59-28). 7. Some surgeons prefer to approach the mediastinal tunneling from the left rather than the right side. Other surgeons make a third incision over the xiphoid and then apply a towel clip to elevate the

The patient in Figure 59-27 after repair, showing slight overcorrection. A

*

I 926

PART

VI

THORAX

.-•

To prevent bar dis-

placement, a stabilizer with wire fixation suture is applied on the left. On the right side, heavy absorbable sutures (0 or 1 PDS) are placed around the bar and underlying rib. In addition, sutures are placed through the holes in the bar and stabilizer and in the underlying fascia.

sternum; others do a finger dissection under the sternum before inserting the introducer.

Bar Stabilization 1. Stabilization of the bar is absolutely essential for success. A stabilizer is inserted onto the left end of the bar and wired to the bar with No. 3 surgical steel wire (Fig. 59-29). If the bar does not seem stable, a second bar rather than a second stabilizer is probably required. 2. Heavy absorbable 0 or 1 PDS sutures are placed around the bar and underlying rib using an "endo-close" laparoscopic needle under thoracoscopic vision on the right side (see Fig. 59-29). Hebra et al.5 advocate placing a suture adjacent to the sternum. 3. Once the bar is stabilized, the incisions are closed in layers, and the pneumothorax is evacuated using the trocar and attached tubing or a chest tube with a "water-seal" system. 4. A chest radiograph is obtained before the patient is taken out of the operating room, to check for residual pneumothorax.

Postoperative Management 1. In the recovery room, the patient is kept well sedated for 1 to 2 hours to provide a smooth emergence from anesthesia. 2. The epidural cBtheter is left in place for 3 to 5 days.

3. The patient is discharged home on the fourth or fifth postoperative day. 4. Patients may return to school after 2 weeks but may not participate in sports for 6 weeks after surgery. 5. After 6 weeks, patients are encouraged to resume their pectus breathing and posture exercises and to participate in aerobic sports activities (e.g., soccer, basketball, swimming). 6. Heavy contact sports (e.g., boxing, football, ice hockey) are prohibited until bar removal.

Technique of Bar Removal (2 to 4 Years after Insertion) 1. General endotracheal anesthesia with 5 to 6 cm of positive end-expiratory pressure. 2. Position the patient supine, with both arms abducted at the shoulder. 3. Check radiographs to see where the stabilizers are. 4. Palpate to see whether the bar and stabilizers are palpable and close to the old scar. If they are not palpable, use C-arm fluoroscopy to determine the exact site of the hardware. 5. Use old scars for the incision site if possible. In most patients, only one incision is necessary if only one stabilizer was used. 6. Mobilize the bar end and stabilizers. Cut the wire in two places and remove it. 7. When the bar and stabilizer have been freed from the surrounding scar tissue, insert a bone hook through the hole in the inferior wing of the stabilizer and

CHAPTER

59

Congenital Chest Wall Deformities

927

extract it from the incision. Then extract the end of the bar, followed by the superior wing of the stabilizer. Slide the stabilizer off the bar. Insert an ortho~edicbone hook through " the hole in the end of the bar and apply gentle traction (Figs. 59-30 and 59-31). If the bar moves, turn the into the decubitus position and pull the bar out in a downward direction over the patient's back. Return the patient to the supine position, and close the incision. Keep the patient on positive end-expiratory pressure until the incision is closed. Bar "unbenders" have recently been developed and are useful in patients who have two stabilizers and require both right and left incisions.

Timing of Bar Removal

B

. - .

We advise that the pectus bar be left in place for 2 to 4 years (average age, 3 years). Patients are evaluated on an annual basis, and their growth and activity level are monitored. They are encouraged to do their pectus exercises and to participate in aerobic sports. Patients between the ages of 6 and 10 years often do not grow rapidly, and they tolerate the bar well for 3 or even 4 years. In contrast, teenagers who undergo a massive growth spurt may require bar removal after 2 years. We consider the exercise programs to be just as important as the surgery. Many children and adults have sedentary lifestyles and never perform aerobic activities; it is thus necessary to stimulate their cardiopulmonary systems because tidal volume is only 10% of total lung capacity. Deep breathing with breath-holding for 10 to 15 seconds and aerobic activities such as running (e.g., soccer, basketball) and swimming are vigorously

A, The bar and stabilizer are mobilized and delivered out of the incision. B, The stabilizer is removed by sliding it off the bar.

RESULTS Demographics As of December 2005, 785 patients had undergone primary Nuss procedures at our institution; 473 patients have had the bar removed, and 387 are more than 1-year post bar removal (Fig. 59-32). Since the original presentation,14 numerous important modifications have been made3 both to the surgical technique (e.g., routine use of thoracoscopy) and to the instruments to minimize risk and facilitate insertion and stabilization of the substernal support bar. These have markedly reduced the risks and complications and have been well documented in other publication~.~J~ A total of 1511 patients were evaluated for chest wall deformities in the 17-year period from 1987 through December 2005 (Table 59-4): , 785 had their initial minimally invasive procedure performed at our facility (primary repairs), and 67 had redo operations (initial operations done elsewhere). ,

The bar is removed by turning the patient onto his side (lateral decubitus position), inserting an orthopedic hook through the hole in the bar, and pulling it down over his spine. .

.

a

928

PART

VI

THORAX

Complication

.

Death Cardiac perforation Pneumothorax Requiring chest tube Requiring aspiration Pleural effusion requiring drainage Pericarditis Hemothorax (surgical) Pneumonia Drug reaction Horner's syndrome

Time Bar In-situ (mo) Excellent

-

.

Good

Fair

No. of Patients (%) 0 0 481 (51.2) 20 (2.5) 3 (0.3) 3 (0.3) 4 (0.5) 7 (0.9) 2 (0.2) 32 (4.0) 166 (21.1)

Failed

Results based on the amount of time the bar was left in place for patients 1 or more years post bar removal (N= 387)

COMPLICATIONS Early Complications4.6,7

The male-female ratio in patients undergoing repair was 4.7:l. The median age was 14.2 years, with a range of 22 months to 29 years. The median Haller CT index was 4.6 (range, 2.4 to 31). Cardiac compression was noted on echocardiography or CT scan in 654 of 785 patients (83%). Mitral valve prolapse was noted in 117 of 785 patients (14.9%). Resting pulmonary function testing was completed in 692 patients and demonstrated abnormalities in up to 42.3% of them.'

Operative Procedure, Analgesia, and Length of Stay

There were no deaths and no cardiac perforations during the 785 repairs performed at our institution (Table 59-5). Pneumothorax requiring chest tube drainage occurred in 20 repairs (2.5%); percutaneous aspiration only was required in 3 repairs (0.3%). Hemothorax requiring drainage occurred after 7 repairs (0.9%). Three pleural effusions required treatment by either chest tube or aspiration (0.3%). Pericarditis requiring treatment with indomethacin occurred after 4 repairs (0.5%),with one requiring pericardiocentesis. Pneumonia occurred after 2 repairs (0.2%), and medication reactions occurred following 32 repairs (4.0%). A total of 166 patients had transient Horner's syndrome at varying times during the thoracic epidural administration.

In 584 patients (74.4%),a single bar was inserted; two bars were inserted in 197 patients (25.1%). Blood loss in most patients was minimal (110 mL), with the exception of one patient who developed a hemothorax but did not require transfusion.12 Epidural analgesia was used for 3 days in the vast majority of patients. The median length of stay was 5 days.*O

Complication

I

Total number of patients evaluated Total number of minimally invasive (Nuss) procedures Total number of primary surgeries Total number of redo surgeries Prior Ravitch procedure Prior Nuss procedure Prior Leonard procedure

1278 685 633 52 28 24 2*

/

'Prior Leonard procedureswere also prior Ravitch procedures and were counted only once in the analysis.

Bar displacement Requiring revision Before stabilizer With stabilizers With wired stabilizers With PDS sutures Hemothorax Wound infection Bar infection Requiring early removal Bar allergy Overcorrection Recurrence

No. of Patients (%) 51/785 28/785 10/113 18/672 9/360 1/237 2/785 7/785 6/785 2/785 19/785 22/785 8/785

(6.5%) (3.5%) (8.8%) (2.6%) (2.5%) (0.4%) (0.2%) (0.9%) (0.7%) (0.2%) (2.4%) (2.8%) (1.0%)

CHAPTER

59

Congenital Chest Wall Deformities

929

Late Complications Fifty-one patients (6.5%) experienced bar displacement (Table 59-6); however, only 28 displacements (3.5%) warranted repositioning. Of these 28 displacements, 10 occurred before stabilizers were available, a period covering our first 113 repairs. After the introduction of stabilizers, the incidence of bar displacement dropped from 8.8% to 2.6%. When the bar and stabilizers were wired together, the incidence of bar displacement dropped to 2.5%. There has been only one bar displacement (0.4%) since we started combining the placement of a stabilizer on the left and the placement of PDS sutures around the bar and the underlying rib on the right. Bar infection occurred in six patients (0.7%), requiring early bar removal in two (0.2%). Nineteen patients had allergies to the bars.16 These presented as rashes in the area of the bar or the stabilizer, sterile abscesses at the incision site, pleural and/or pericardial effusions. Of 785 patients, 22 (2.8%) developed a moderate overcorrection of their deformity, and 4 (0.5%) developed a true carinatum deformity.

OVERALL RESULTS AND LONG-TERM FOLLOW-UP Patients are re-examined at 6 months postoperatively and then annually. Long-term assessments classify the postoperative results as excellent, good, fair, or failed. A result is considered excellent if thepatient experiences total repair of the pectus as well as resolution of any associated symp toms. A good result is distinguished by a markedly improved but not totally normal chest wall appearance and resolution of any associated symptoms. A fair result indicates a mild residual pectus excavatum without complete resolution of associated symptoms. A failed repair indicates recurrence of the pectus and associated symptoms or the need for another repair after bar removal. The initial cosmetic and functional results were excellent in 718 patients (91%), good in 64 (8%), fair in 1 (0.2%),and failed in 2 (0.25%).A total of 385 have had their bars out for more than 1 year, and 88 have had their bars out for less than 1 year. Among those whose bars were removed 1 or more years ago, the results were excellent in 79.8%, good in 14.9%, fair in 2.3%, and failed in 2.0%. Patients who did not comply with the exercise program and had their bars removed before puberty had higher recurrence rate. The length of time the bar was left in situ had a direct effect on the long-term outcome. The longer the bar stayed in, the better the results (see Fig. 59-32). The age of the patient also affected the long-term outcome, with the best results occurring in those 7 to 12 years old and 13'. to 18 years old (Fig. 59-33).2 In addition to the 785 primary operations, there were 67 successful remedial mihimally in-ive pectus repairs."

a

CONCLUSION The minimally invasive procedure provides good to excellent correction of pkctus excavatum in more than 90% of

.

Age of Patients at Primary Surgery (yr) Excellent

-

.

Good

Fair

Failed

Results based on age at surgery for patients 1 or more years post bar removal ( N = 276).

patients with no rib resection, no sternal osteotomy, minimal blood loss, and rapid return to normal activity.2,4,6,10-'2Studies have shown marked improvement in the patient's body image8.15 and have also shown improvement in pulmonary function s t u d i e ~ . ~ , ~

REFERENCES 1. Borowitz D, Cemy F, Zallen G, et al: Pulmonary function and exercise response in patients with pectus excavatum after Nuss repair. J Pediatr Surg 2003;38: 544547. 2. Coln D, Gunning T, Ramsey M: Early experience with the Nuss minimally invasive procedure. World J Surg 2002; 26:1217-1221. 3. Croitoru DP, Kelly RE Jr, Nuss D, et al: Experience and modification update for the minimally invasive Nuss technique for pectus excavatum repair in 303 patients. J Pediatr Surg 2002;37:437-445. 4. Fonkalsrud EW, Beanes S, Hebra A, et al: Comparison of minimally invasive and modified Ravitch pectus excavatum repair. J Pediatr Surg 2002;37:413-417. 5. Hebra A, Gauderer MW, Tagge EP: A simple technique for preventing bar displacement with the Nuss repair of pectus excavatum.J Pediatr Surg 2001;36:1266-1268. 6. Hebra A, Swoveland B, Egbert M, et al: Outcome analysis of minimally invasive repair of pectus excavatum: Review of 251 cases. J Pediatr Surg 2000;35:252-257. 7. Hyung JP, Seock Y, Cheol SL: Complications associated with the Nuss procedure: Analysis of risk factors and suggested measures for prevention of complications. J Pediatr Surg 2004;39:391-395. 8. Lawson ML, Cash TF, Akers RA, et al: A pilot study of the impact of surgical repair on disease-specific quality of life among patients with pectus excavatum.J Pediatr Surg 2003; 38:916-918. 9. Lawson M, Mellins R, Tabangin M, et al: Impact of pectus excavatum on pulmonary function before and after repair with the Nuss procedure. J Pediatr Surg (submitted for publication).

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10. Miller KA, Woods RK, Sharp RJ, et al: Minimally invasive repair of pectus excavatum: A single institution's experience. Surgery 2001;130:652-657. 11. Miller RA: Minimally invasive bar repair for redo correction. J Pediatr Surg 2002;37:1090-1092. 12. Molik KA, Engum SA, Rescorla FJ, et al: Pectus excavatum repair: Experience with standard and minimally invasive techniques. J Pediatr Surg 2001;36:324328. 13. Nuss D, Kelly RE Jr, et al: Repair of pectus excavatum. Pediatr Endosurg Innovat Techn 1998;2:205-221.

14. Nuss D, Kelly RE Jr, et al: A 10-year review of a minimally invasive technique for the correction of pectus excavatum. J Pediatr 1998;33:545-552. 15. Roberts J, Hayashi A, Anderson JO, et al: Quality of life of patients who have undergone the Nuss procedure for pectus excavatum: Preliminary findings. J Pediatr Surg 2003;38:779-783. 16. Saitoh C, Yamada A, Kosaka K, et al: Allergy to pectus bar for funnel chest. Plast Reconstr Surg 2002;110:719-721.

Congenital Diaphragmatic Hernia and Eventration Charles J. H. Stolar and Peter W. Dillon

HISTORY The earliest English language description of the gross anatomy and pathophysiology associated with congenital diaphragmatic hernia (CDH) in a newborn was by McCauley, an associate of Hunter, as reported in the Proceedings of the Royal College of Physicans, 1754203: The child was born in the lying-in-hospital in Brownlow Street on the 24th of August, 1752: and was a fully grown boy, remarkably fat and fleshy. He was the fifth child of a healthy young woman who was well during her pregnancy. The child, when first born, started and shuddered; so that the nurse apprehended his going into fits. He breathed also with difficulty and it was some time before he could cry; which when he did, there was something peculiar in its note. He seemed to revive a little in about half an hour and breathed more freely: but soon relapsed and died before he was quite an hour and a half old. Being informed of these particulars by the mother, the matron, and the nurse, I was desirous of examining the body .... I laid open the abdomen and found none of the intestines were contained in that cavity except part of the colon which was distended with meconium. Before I proceeded further with the dissection I sent to acquaint my ingenious friend, Dr. Hunter. We together dissected and examined this curious subject: and at the same time committed to writing the most remarkable appearances. When the sternum was raised, the stomach with the greatest part of the intestines, with the spleen, and part of the pancreas were found in the left cavity of the thorax; having been protruded through a discontinuation, or rather an aperture of the diaphragm, about an inch from the natural passage of the esophagus. From the extraordinary bulk of the parts contained in the left side of the thorax, the mediastinum, the heart, the esophagus, and the descending aorta were forced a considerable way to the right side of the thorax; because there was not the least mark of rupture or inflammation about the edges of the chasm: and because it is probable that

the diminished size of the left lobes of the lungs, and the heart and mediastinum being pushed to the right side, were gradually affected by the bulk and increase of the viscera. As the esophagus was pushed to the right side by the stomach and the bowels, in the cavity of the thorax it kept the same course and pierced the diaphragm not in the usual place, but considerably further to the right side: and the aperture through which it passed was backwards and to the right side with respect to that for the vena cava. I have preserved the heart and lungs to show the disproportioned sizes of the lobes. And I have dried and prepared the diaphragm with its connections to the vertebrae and sternum to show the preternatural aperture through which the bowels passed into the thorax; as also the passage of the esophagus to the right side of the diaphragm. These preparations were at the same time shown to the Society. Cooper,59in 1827, and Laennec,17' in 1834, not only reported clinical descriptions and gross pathology of CDH but also suggested that laparotomy might be the proper approach for reduction and correction of the , ~1847, ~ was the first to make the bedhernia. B o w d i t ~ hin side diagnosis of CDH and further emphasized the clinical criteria for diagnosis. Although Bochdalek's understanding of the embryology was incorrect, this congenital defect continues to carry his name.2We speculated that the hernia resulted from a posterolateral rupture of the membrane separating the pleuroperitoneal canal into two cavities. He also incorrectly speculated that the best way to repair the defect was through the bed of the 12th rib. The record is not clear as to whether this was actually attempted. The earliest, although unsuccessful, efforts to repair CDHs were by Nauman,2i0in 1888, and O'Dwyer, in 1890.227The first reports of successful repairs were in an adult by Aue,l2 in 1901, and a child by Heidenhain,132in 1905. The groundwork for treating CDH in the newborn period*was laid by Hedblom,l28 whose review of the reported cases as of 1925 showed that 75% of 44 infants diagnosed in the newborn period died. He suggested that

932

PART

VI

THORAX

Chest radiograph of an infant with a right-sided congenital diaphragmatic hernia demonstrating air-filled loops of intestine in the right hemithorax with contralateral displacement of the mediastinum. The infant has been cannulated for venoarterial extracorporeal membrane oxygenation.

earlier intervention might improve survival. Successful repair of CDH remained rare until 1940, when Ladd and Gross17"eported 9 of 16 patients surviving operative repair, the youngest being 40 hours old. It was not until 1946 that Gross113 reported survival of the first infant younger than 24 hours old after operative repair of the defect. Until the 1980s, the standard of care remained immediate neonatal surgery followed by postoperative resuscitative therapy (Fig. 60-1) .

EPIDEMIOLOGY AND GENETICS The reported incidence of CDH is estimated to be In the United between 1 in 2000 to 5000 births.46~107,120~238 States, approximately 1000 infants a year are affected with this condition, and in a recent study from Atlanta the birth prevalence was found to be 2.4 per 10,000 births.84 The incidence in stillborns is less well documented. Approximately one third of infants with CDH are stillborn, but these deaths are usually due to associated fatal congenital anomalies."0~238,312 When stillborns are counted with live births, females appear to be more commonly afflicted than males.46,104,238 Defects are more common on the left side, with approximately 80% being left sided and 20% right sided.

Bilateral CDH defects are rare and have a high incidence of associated anomalies.222 Infants with isolated CDH are more likely to be premature, macrosomic, and male; and about one third of affected infants may have associated major defects.84Women who are thin or underweight for their height may have an increased risk of having an infant with an isolated CDH.305 CDH is thought to represent a sporadic developmental anomaly, although a number of familial cases have been reported.46Jll,208 The expected recurrence risk in a first-degree relative has been estimated to be 1 in 45 or approximately 2%.lg3Structural chromosomal abnormalities have been identified in 9% to 34% of CDH infants and include trisomies, deletions, ~ , ~ 2 ~ chromosomes with and t r a n s l o ~ a t i o n s . ~ ~Specific deleted or translocated genes may be candidate loci for The combination of CDH and CDH de~elopment.l3,~2J97 an abnormal karyotype has been associated with a poor OUtcOme.134,141,321 The cause of a CDH is unknown. As with other embryopathies there is increasing evidence that CDH may be due to the exposure of genetically predisposed or susceptible individuals to environmentalfactors. Exposure to a number of pharmacologic agents and environmental hazards has been implicated in its development. These include insecticides and drugs such as phenmetrazine, thalidomide, quinine, cadmium, lead, and nitrofen.65,138,149,232,307 The clinical findings of vitamin A deficiency in CDH infants and the effects of vitamin A administration in nitrofeninduced pulmonary hypoplasia have strengthened the evolving hypothesis that alterations in retinoid-regulated target genes may be responsible for CDH development.112

ASSOCIATED ANOMALIES Any newborn with a major congenital anomaly, including infants with CDH, has an increased incidence of an additional malformation compared with the general population. Although previously thought to be low, the incidence of associated malformations in infants with a CDH ranges from 10% to 50%65,95,110,194,2073226,296,312 Skeletal defects have been noted in as many as 32% of CDH infants and include limb reduction and costovertebral defects.207,226,285 Cardiac anomalies have been found in 24% of infants. Cardiac hypoplasia involving the left ventricle and often associated with hypoplasia of the aortic arch is frequently described and can be confused with hypoplastic heart syndromes. However, the clinical significance is limited. Most cardiovascularmalformations involve the cardiac outflow tract such as ventricular septa1 defects, tetralogy of Fallot, transposition of the great vessels, double outlet right ventricle, and aortic ~oarctation.~~,206~284 Anatomic anomalies of the tracheobronchial tree have been found in 18% of patients with CDH and include congenital tracheal stenosis, tracheal bronchus, and trifurcated trachea.226 The incidence of associated malformations in stillborn infants with CDH is even higher. In one study 100% of stillborn infants with CDH had associated lethal anomalies.238Abnormalities noted in this stillborn group were predominantly neural tube defects and included anencephaly, myelomeningocele, hydrocephalus, and encephaloceles. Even in infants who survive to birth but die shortly thereafter, neural tube

CHAPTER

defects were the most common malformations noted. Cardiac defects were the second most common group and included ventriculoseptal defects, vascular rings, and coarctation of the aorta.284 Other midline developmental anomalies have also been reported and include esophageal atresia, omphalocele, and cleft palate. A number of syndromes have a CDH as a pathologic finding. These syndromes include trisomy 21, trisomy 18, trisomy 13, Frey's syndrome, Beckwith-Wiedemann syndrome, Goldenhar's syndrome, Coffin-Siris syndrome, Fryns syndrome, Meacham syndrome, and Kabuki syndrOme.71,83,134,166,223

60

Congenital Diaphragmatic Hernia and Eventration

933

and relies on the fusion of the two muscle groups in the final stages of development for its strength. Delay or failure of muscular fusion leaves this area weak, perhaps predisposing to herniation. Bochdalek first described this area of the posterolateral diaphragm in 1848, and it is for this reason that the most common site for CDH bears his name.

Lung Development

Fetal lung development is divided into five stages: embryonic, pseudoglandular, canalicular, saccular, and alveolar.'g Embryonic lung development begins during the third week of gestation as a derivative of the foregut and is marked by the formation of a diverticulum off of the caudal end of the laryngotracheal groove.35The trachea Diaphragmatic Development and the two primary lung buds form from this diverticuThe embryologic development of the diaphragm remains lum by the fourth week ofgestation. At 6 weeks, these lung incompletely understood and involves multiple, complex buds have further developed into defined lobar struccellular and tissue interactions. The fully developed tures. The pseudoglandular phase of lung development diaphragm is derived from four distinct components: takes place during the 7th to 16th weeks of gestation and involves lung airway differentiation. It is during this (1) the anterior central tendon forms from the septum transversum, (2) the dorsolateral portions form from the period that all bronchial airways develop. From the pleuroperitoneal membranes, (3) the dorsal crura evolve 16th to the 24th weeks of gestation, fetal lung developfrom the esophageal mesentery, and (4) the muscular ment enters the canalicular phase of growth. During this portion of the diaphragm develops from the thoracic period, airspace development occurs, as crude alveolar intercostal muscle groups. The precursors of diaphragair sacs begin to take shape. Type 1 pneumocytes begin to differentiate, and the precursors of type 2 pneumocytes matic structure begin to form during the fourth week of gestation with the appearance of the peritoneal fold from ultimately responsible for surfactant production begin to the lateral mesenchymal tissue. At the same time, the appear. Gas exchange becomes functionally possible at septum transversum forms from the inferior portion of this stage. Continued maturation of the crude alveolar airspaces the pericardial cavity. The septum transversum serves to takes place during the saccular phase of development separate the thoracic from the abdominal cavities and that extends from 24 weeks' gestation to term. During this eventually forms the central tendinous area of the fully time period there is continued remodeling of the airdeveloped diaphragm. It defines the rudimentary pleuroperitoneal canals and allows for the establishment of space dimensions and a maturation of surfactant synthesis capabilities.115 Mature, adult-like alveoli begin to appear mesenchymal tissue within these canals that ultimately shortly after birth.36337 Extensive alveolar maturation and results in pulmonary parenchymal development. multiplication then takes place from birth until approxiClosure of the pleuroperitoneal canals with the formamately 8 years of age, with a 10-fold increase in the tion of a pleuroperitoneal membrane occurs during the ~ ~ ~ ~ ~ ~ have number of functioning a l v e ~ l i . " ,Investigators eighth week of gestation. Several theories have been proproposed that alveolar formation may be completed by posed to explain the formation of this membrane and the 2 years of age.Zg0 subsequent development of a diaphragmatic structure. Pulmonary vascular development follows the stages Progressive growth of the pleuroperitoneal membrane has been one mechanism proposed for canal closure.62J52 of airway and alveolar growth and can be divided into two anatomic units based on associated airway structure. Other researchers have postulated that concurrent hepatic and adrenal organogenesis is crucial to this process.41,43,311 The term acinus describes the functional unit of the lung that includes the respiratory bronchioli, alveolar ducts, The involvement of a posthepatic mesenchyrnal plate in diaphragmatic formation has been proposed.l49 and alveoli-all structures that evolve during or after the The pleuroperitoneal folds extend from the lateral canalicular phase of lung development. Vascular development in this region proceeds concurrently with body wall and grow medially and ventrally until they fuse alveolar growth and multiplication. The preacinar strucwith the septum transversum and dorsal mesentery of tures include the trachea, major bronchi, and lobar the esophagus during gestational week 6. Complete closure of the canal takes place during week 8 of gestation. bronchi up to the terminal bronchioles. Preacinar vascuAnatomically, the right side closes before the left.212 lar development is completed by 16 weeks' gestational age.136,137,243 Muscularization of the diaphragm appears to develop from It is now recognized that pulmonary development is the innermost muscle layer of the thoracic cavity, although marked by a series of programmed events regulated by it has been proposed that the posthepatic mesenchymal , l ~ ~ genes such as the homeobox genes, nuclear tranplate is a possible source of muscular t i ~ s u e . ~ ~ master Posterolaterally, at the junction of the lumbar and costal scription factors, hormones, and growth factors. These muscle groups, the fibrous lumbocostal trigone remains processes involve genes regulating epithelial and as a small remnant of the pleuroperitoneal membrane endothelial interactions as well as temporal and spatial

934

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interactions of several hormones and growth factors. Early developmental transcription factors such as hepatocyte nuclear factor-3P and thyroid transcription factor-1 regulate pulmonary development from the foregut mesenchyme. Additional stimuli of pulmonary development involve the transforming growth factor-0 pathway, sonic hedgehog pathway, Notch-delta pathway, Wingless-Int pathway, and cytokine receptor pathways. Subsequent signal transduction control of organogenesis includes the apoptotic pathways, nuclear receptor pathways, and interleukin pathways. Hormones such as the glucocorticoids, thyroid hormone, and retinoic acid have been shown to regulate several of the crucial cellular interactions required for proper pulmonary organogenesis and differentiation.49 Although the pathways of normal pulmonary development have become clearer, little is known about the alterations in gene expression, growth factor interactions, and hormone levels associated with the pulmonary maldevelopment of the CDH lung. A number of factors have been found to be elevated in CDH lung specimens including epidermal growth factor, transforming growth factor*, vascular endothelial growth factor, insulin-like growth factor, tumor necrosis factor*, and glucocorticoid Other factors receptor gene expre~sion.114~2~0~229~263.272 such as sonic hedgehog expression, heme oxygenase-1, and endothelial nitric oxide levels reportedly are decreased. The importance of these findings remains to be determined.'71.294 Recently, advances in understanding the developmental defects in mammalian lung formation associated with CDH have come in the murine nitrofen model.50 The adoption of the nitrofen model of experimental CDH coincides with the theory that many developmental defects, including CDH, are embryopathies caused by toxin exposure. Nitrofen is an environmental toxicant, and its administration to pregnant mice results in offspring with pulmonary hypoplasia, diaphragmatic hernia defects, reduced airway branching, excessive muscularization of pulmonary vessels, surfactant deficiency, and respiratory failure at birth. The pulmonary hypoplasia induced by nitrofen is associated with alterations in a number of growth factors and developmental pathways , ~ ~ nitrofen model of CDH forin embryonic m i ~ e . 4 9The mation has dramatically changed the perception of this disease process as a simple mechanical defect in the diaphragm resulting in pulmonary compression and respiratory failure. Multiple studies now indicate that lung hypoplasia may precede diaphragmatic hernia formation and involves a number of pathways fundamental to the embryonic development of the lung.153 A number of physical factors may also affect pulmonary intrathoracic space growth and de~elopment.~'='Adequate is a prerequisite for normal pulmonary growth. Any intrathoracic or extrathoracic process that results in diminishment of the intrathoracic space and pulmonary parenchymal compression can lead to the development of structurally immature Other physical factors important in lung growth include the maintenance of normal fetal lung liquid and amniotic fluid dynamics.4,7.i,76,9~~21 1

PATHOLOGY Although the cause of CDH is uncertain, its consequences on pulmonary development and function are well documented. During the early development of the diaphragm, the midgut is herniated into the yolk sac. If closure of the pleuroperitoneal canal has not occurred by the time the midgut returns to the abdomen during gestational weeks 9 and 10, the abdominal viscera herniate through the lumbocostal trigone into the ipsilateral thoracic cavity. The resulting abnormal position of the bowel prevents its normal counterclockwise rotation and fixation. No hernia sac is Dresent if the event occurs before complete closure of the pleuroperitoneal canal, but a nonmuscularized membrane forms a hernia sac in 10% to 15%of CDH patients.lg9Although some claim the herniation can occur late in gestation or be intermittently present as a dynamic process, in most cases the defect is established by gestational week 12.3 The subsequent postnatal ~ r o b l e m srelate to the effects of the herniated viscera on the developing heart and lungs. The classic left-sided CDH features a 2.0- to 4.0-cm posterolateral defect in the diaphragm through which the abdominal viscera have been translocated into the hemithorax (Fig. 60-2). Herniated contents often include the left lobe of the liver, the spleen, and almost the entire gastrointestinal tract. The stomach is frequently in the chest, which results in some degree of obstruction at the

Schematic illustration of a left congenital diaphragmatic hernia showing translocation of abdominal viscera through a posterolateral aperture into the chest. (From Spitz L, Coran AG (eds): Rob & Smith's Pediatric Surgery. London, Chapman & Hall, 1996.)

CHAPTER

60

Congenital Diaphragmatic Hernia a n d Eventration

935

gastroesophagealjunction. This obstruction, in turn, causes greatly reduced. This finding was noted in both ipsilatdilatation and ectasia of the esophagus. Occasionally, the eral and contralateral pulmonary specimens.1° Alveolar development is severely affected, and it has been kidney may be in the chest tethered by the renal vessels. reported that few normal alveoli exist in the lungs at In instances of a right-sided defect, the large right term.234In addition, the changes in airway structure are lobe of the liver can occupy much of the hemithorax in quite variable. Infants requiring low ventilatory assisaddition to other abdominal viscera. The hepatic veins tance during treatment had the same airway muscle mass may drain ectopically into the right atrium, and fibrous as controls, whereas infants with prolonged ventilatory fusion between the liver and the lung has been reported. support had significantly greater muscle thickness Both of these anatomic findings can significantly comthroughout the conducting airways.44 plicate attempted surgical repair of the diaphragmatic The pulmonary vascular bed is distinctly abnormal in defe~t.l~~J~~ lungs from patients with CDH. A reduction in the total The diaphragmatic defect usually features a completely number of arterial branches in both the ipsilateral and open space between the chest and abdomen, although the contralateral pulmonary parenchyma has been some infants have a membrane of parietal pleura and reported.170J87 Structurally, significant adventitial and peritoneum acting as a hernia sac. This finding is to be medial wall thickening has been noted in pulmonary arterdistinguished from an eventration of the diaphragm, ies of all sizes in CDH lungs in association with abnormal which results from phrenic nerve or anterior horn cell muscularization of the small preacinar and intra-acinar degeneration. The muscle fibers of the diaphragm are arteriole~.26,2~6,"5 The physiologic consequence of this usually present. abnormal arterial muscularization may be an increased Elegant animal models by de Lorimier and Harrison susceptibility to the development of fixed and intractable have shown that long-term compression on the developpulmonary hypertension. No significant changes in puling fetal lungs by the herniation of abdominal contents monary venous structure have been identified resulting into the thoracic cavity results in pulmonary maldevelopfrom CDH development. Increased adventitial thickness ment and lung h y p o p l a ~ i a ~ ~(Fig. J 2 ~ 60-3). Unilateral of pulmonary veins has been noted in CDH infants but visceral herniation affects both ivsilateral and contralatappears to be postnatally derived perhaps as a result of eral pulmonary development, although hypoplasia is treatment or secondary to the pathology of pulmonary predictably more severe on the ipsilateral side. This is hypertension.*06 confirmed by an analysis of lung volumes and weights in 35 blood flow accounts for only 7% of cardiac human autopsy specimens and animal r n o d e l s . ~ 0 ~ 6 ~ J ~ ~ ~ ~Pulmonary output during normal fetal development, and pulmonary Because the process of CDH herniation occurs at the vascular resistance remains high. The fetus preferentially time of bronchial subdivision, it is at this stage that shunts oxygenated blood from the placenta through the lung development becomes compromised. Although all foramen ovale and ductus arteriosus in a right-to-left direcmajor bronchial buds are present in a CDH lung, the tion into the systemic circulation. At birth, a number of number of bronchial branches in the affected lung is hemodynamic changes take place that dramatically alter this circulatory profile. With the institution of breathing, pulmonary vascular resistance falls, as does pulmonary artery pressure allowing for an increase in pulmonary blood flow. Systemic vascular resistance and left atrial pressure rise causing the foramen ovale to close. Increased arterial oxygen tension induces spontaneous closure of the ductus arteriosus. Transition from a fetal to an adulttype circulatory pattern is accomplished. Persistent fetal circulation may develop if this process is interrupted. After birth and interruption of placental circulatory support, persistently elevated pulmonary vascular resistance results in increased pulmonary artery pressures and decreased pulmonary vascular blood flow. The increased vascular resistance results in right-to-left shunting of blood at either the atrial or the ductal levels with the delivery of unsaturated blood into the systemic circulation. As the blood flow in the shunt increases, the oxygen saturation in the systemic circulation falls and the mixed venous return to the right side of the heart becomes progressively desaturated. The resulting hypoxia further increases pulmonary vascular resistance and compromises pulmonary blood flow while increasing the right-to-left Operative photograph of a left congenital diaphragmatic hernia created in a fetal lamb. The posterolateral shunt flow. Severe and progressive respiratory failure defect can be seen looking from the abdomen into the chest. ensues. (From Spitz L, Coran AG (eds): Rob & Smith's Pediatric Surgery. Factors that contribute to the persistence of high pulLondon, Chapman & Hail, 1996.) monary vascular resistance in CDH lungs are thought to

936

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solid viscera in the thorax. The stomach may be small be the structural changes in decreased total arteriolar because of interference with fetal swallowing. If the cross-sectional area in the involved lungs and the increased muscularization of the arterial structures that diaphragmatic defect is on the right side, the liver can are present. In the postnatal period there is failure of the tamponade the hernia site and obscure the diagnosis. The diagnosis of CDH may be missed because intermitnormal arterial remodeling process further maintaining tent herniation of abdominal viscera into the thoracic the abnormal vascular resistance that may be only partly Additional exacer. ~ misinterpretation of the cavity has been r e p ~ r t e d The reversed by treatment inter~entions.2~~ bations of pulmonary vascular resistance may be induced fetal US scan can be caused by other diagnoses such as by the known stimulators of pulmonary hypertension, esophageal atresia and cystic lung anomalies. Functional including hypoxia, acidosis, hypothermia, and ~ t r e s s . 2 ~ ~information concerning fetal breathing can be obtained Alterations in the levels of various prostaglandins, by duplex Doppler examination of amniotic flow at the leukotrienes, catecholamines, and the renin-angiotensin fetal nares at the time of fetal US. A fetal tidal volume/ system have been implicated as mediators of this complex minute ventilation can be determined that may have a proces~?9~2~~ It can only be surmised at this time whether bearing on prognosis.l" In addition to diagnosis, prenatal US may also be of there is an exaggerated response to these stimuli by the benefit in predicting outcome by utilizing quantitative abnormal vascular structures of CDH lungs.60 techniques to estimate the severity of pulmonary hypoplasia of the fetal CDH lung. Threedimensional estimation of the fetal lung volume, calculation of the right lung area to DIAGNOSIS thoracic area ratio, and calculation of the lung to thoracic The diagnosis of a CDH is often made on a prenatal circumference ratio are three different measurements ultrasound (US) examination and is accurate in 40% to that appear to correlate with neonatal o u t ~ o r n e . l ~ ~ 2 ~ ~ ~ * 5 0 US can be limited by the poor acoustic contrast between 90% of cases.lsR Although considerable variation in detection rates have been reported, the mean gestational fetal lung and herniated viscera, position of the fetus, age at discovery is 24 weeks and has been reported as early and operator experience. As a result, prenatal magnetic as 11weeks.lo5The US mav be obtained for routine obstetric resonance imaging (MRI) evaluation is being used with care or because of suspicion concerning the presence of increasing frequency when obstetric sonography has polyhydramnios. Polyhydramnios has been reported presdetected a complex fetal anomaly and is ideally suited for ent in up to 80% of pregnancies with associated CDH.3 fetuses with a diaphragmatic hernia.l42J$6MRI can readThe mechanism of polyh~dramniosis thought to be due ily determine liver position in relation to the diaphragm to kinking of the gastroesophageal junction by transloand detect herniated liver into either hemithorax. It cation of the stomach into the thorax with resultant may also be used to more accurately assess lung volume foregut obstruction. The US diagnosis of a CDH is sugto determine pulmonary hypoplasia with subsequent gested by observing the stomach or fluid-filled loops of correlation to outcome.199.230,306 intestine in the fetal thorax at the same cross-sectional After birth, the spectrum of respiratory symptoms in an infant with a CDH is determined by the degree of pullevel as the heart (Fig. 6044, B). Additional US findings u dabsence e of the stomach suggestive of a ~ ~ ~ j n c l the monary hypoplasia and reactive pulmonary hypertension. in the abdomen and the presence of the liver or other The most severely affected infants develop respiratory

A

B

A, Ultrasound examination of a 28-week gestation fetus (twin B) in cross section demonstrating the fetal heart (FH) and stomach (ST) in the same plane. B, Ultrasound examination of the same fetus but in a sagittal plane demonstrating relationship of the stomach, liver, and heart.

CHAPTER

distress at birth, whereas a majority demonstrates respiratory symptoms within the first 24 hours of life. Classically, these infants have a scaphoid abdomen and an asymmetrical distended chest. The chest may become more distended as swallowed air passes into the stomach and intestines. Gastrointestinal distention further compresses pulmonary parenchyma and affects parenchymal ventilatory characteristics. It may lead to addition1 mediastinal compression with impairment of the contralateral lung. Because of the small size of the neonate's chest, breath sounds may or may not be present on the side of the defect. Mediastinal compression with shift into the contralateral thorax may cause deviation of the trachea away from the side of the hernia and also result in obstruction to venous return with the hemodynamic consequences of hypotension and inadequate peripheral perfusion. The signs of respiratory distress may include cyanosis, gasping, sternal retractions, and poor respiratory effort. The diagnosis of a CDH can be confirmed by a plain chest radiograph that demonstrates loops of intestine in the chest. The location of the gastric bubble should also be noted, and its position can be confirmed by placement of an orogastric tube. Rarely, a contrast study of the upper gastrointestinal tract is required. The chest radiograph shows angulation of the mediastinurn and a shifting of the cardiac silhouette into the contralateral thorax. Although minimal aeration of the ipsilateral parenchyma may be noted, chest radiographs are unreliable for estimating the degree of pulmonary hypopla~ia.~2J~O Once the diagnosis of a CDH is confirmed, additional radiographic and US examinations should be carried out to search for associated anomalies. Echocardiography and both renal and cranial US scans should be obtained. Although most CDHs present in the first 24 hours of life, 10% to 20% of the infants with this defect present later.20' These latter infants present with recurrent mild respiratory illnesses, chronic pulmonary disease, pneumonia, effusion, empyema, or gastric volvulus.

DIFFERENTIAL DIAGNOSIS The diagnosis of a CDH can be confused with a number of other congenital thoracic conditions, including eventration of the diaphragm, anterior diaphragmatic hernia of Morgagni, congenital esophageal hiatal hernia, congenital cystic disease of the lung, and primary agenesis of the lung. Diaphragmatic eventration has many causes but is seen in the newborn with birth trauma or WerdnigHoffmann disease. The eventrated diaphragm can rise as high as the third intercostal space and have the same physiologic consequencesas CDH. It can also be completely asymptomatic. The diagnosis is made by fluoroscopy or realtime US with the demonstration of paradoxic movement of the diaphragm. MRI is also useful in determining diaphragmatic structure. Morgagni hernias occur at the hiatus for the internal mammary arteries and are much less common than Bochdalek hernias. Affected infants can present as a gastrointestinal crisis because of incarceration or volvulus of the colon or small bowel and require immediate operative intervention.

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Congenital Diaphragmatic Hernia and Eventration

937

PROGNOSTIC FACTORS The search to determine clinically relevant prognostic factors that predict the outcome of infants with CDH has been frustratingly complex, contradictory, and for the most part unsuccessful. Many studies have attempted to examine both anatomic and physiologic parameters that relate to survival, but each has been hampered by its retrospective analysis in the presence of the continuing evolution of new therapies. Whereas consideration of multiple factors may influence one's clinical impression regarding survival potential of an infant with CDH, such an impression cannot be derived from one measurement alone.

Anatomic Factors With the ability to establish the diagnosis of CDH in utero as a result of the increased use of prenatal US, studies suggested that the antenatal diagnosis of a CDH before 24 weeks' gestational age was associated with a high mortality. Others have shown that antenatal diagnosis, regardless of timing, of an isolated CDH without other associated anomalies is not an indicator of outcome.317 A CDH associated with another significant anomaly still has a dismal prognosis. If a CDH is not detected by prenatal US but is subsequently diagnosed after birth, survival rates mav be excellent. It was also r e ~ o r t e dthat the presence of polyhydramnios was indicative of poor sunival.llY A number of studies, however, have refuted this observation and have shown that the presence of polyhydramnios has no predictive value on the eventual outcome of an infant with CDH.61,261,278 The position of the stomach has been proposed as a prognostic indicator by a number of investigators. Survival rates of infants with CDH with the stomach properly located below the diaphragm at the time of diagnosis have been reported to be as high as 100%but is only 30% when the stomach had herniated into the hes st.^^,^^,^^^ Other studies have shown no predictive value of such positioning.289 The side of the diaphragmatic defect may be somewhat predictive of outcome. It has been reported that patients with right-sided defects have a worse prognosis than those with left-sided defects.1°"2Y1 A recent study reported no differences in outcomes between the two sides.129 However, right-sided defects may not become evident in the newborn period and may present with very mild respiratory symptoms at a later age.64 A prenatal anatomic parameter that appears to have predictive correlation is the determination of the lung-tohead ratio (LHR).The ratio is determined from simultaneous sonographic measurements of the lung and head, and ratios less than 1.0 have been associated with poor 0utcomes.l64J8"~Y2Correlation with outcome was Independent of gestational age. Not all perinatal groups have found the LHR to be clinically h e l ~ f u l . l 3 ~ Analysis of cardiopulmonary structure including ventricular and great vessel dimensions in either the prenatal or postnatal period as well as determining function in the postnatal period may also be of prognostic importance.61.124 A number of indices have been reported,

938

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THORAX

The most commonly used calculation is the oxygenaincluding calculation of the cardioventricular index (left tion index (01). It is calculated by the formula: ventricli/right ventricle), the cardiovascular index (Ao/PA), and a modified McGoon index (the combined 0 1 = (MAP x Fio2/Pao2) diameter of hilar pulmonary arteries indexed to the A modified McGoon index less With conventional ventilatory therapy an OI less than descending a0rta).2*2,2~~ 0.06 had a survival rate of 9876, whereas an 0 1 greater than than or equal to 1.3 predicted mortality with a sensitivity 0.175 had no survivors.22The predictive powers of these of 85% and a specificity of 100%.An analysis of left ventricular mass combined with the simultaneous determination factors with such therapies as ECMO, high-frequency of fractional shortening has also been used to predict outoscillation (HFO), surfactant, and nitric oxide (NO) have come with an index of 1.2 associated with nons~rvival.2~~not been determined. These measurements may be difficult to obtain either in utero or postnatally and are heavily observer dependent. In additibn, no single measuremknt may giv6 enough Pulmonary Function Tests information to completely assess cardiopulmonary status The analysis of preoperative and postoperative pulin a CDH neonate.288 monarv function tests has been r e ~ o r t e dto have predictive value in identifying infants that might require ECMO therapy as well as identifying survivors. Initial Physiologic Parameters studies of respiratory function in infants with CDH uncovered thedetrimental changes in compliance measUnfortunately, there are few physiologic parameters that urements resulting from surgical repair and helped can be measured in the neonate to assess pulmonary support the hypothesis of medical stabilization and function other than Po2, Pco?, and pH. Thus, arterial Using the treatment blood gas analysis has been the cornerstone for attemptdelayed surgical inter~ention.2~~~2~2 strategies of delayed surgical repair and ECMO when necing to establish clinical predictive criteria. Early studies essary, infants did not require ECMO when their initial ~ survivors showed differences in pH and P C O between and nonsurvivors in response to therapeutic intervenpreoperative compliance measurement was greater than tions available at that time.3°s20gInfants with a low Pco, 0.25 mL/cm H20/kg and initial tidal volume was greater and a Po2 that was initially normal or improved with than 3.5 mL/kg. An improvement in the tidal volume of 4 mL/kg after repair correlated with survival.2y' mechanical ventilation had an excellent outcome, Studies have indicated that preoperative measurement whereas those infants who had high PCO?levels unreof functional residual capachy may predict fatal pulsponsive to mechanical ventilation did poorly. These monary hypoplasia.8 In addition, serial measurements of authors noted the importance of measuring both pretotal pulmonary compliance have been found useful in ductal and postductal blood gases to assess the degree of predicting outcome in high-risk infants.I5" right-to-left shunting. Although no single parameter has proven sufficient as Since these initial reports, investigators have derived a a prognostic factor in managing CDH infants, recent mulnumber of formulas using various blood gas components ticenter studies have shown that significant independent to predict outcome. The most basic concept is the alveopredictors of total mortality include prenatal diagnosis, lar-arterial oxygen gradient (Aado2) It is calculated by birth weight, low 1- and 5-minute Apgar scores, and rightthe formula: sided defe~t.56,267,*~~ Although initially used to determine entry criteria for extracorporeal membrane oxygenation (ECMO), its use has been superseded by the development of other indices. Using blood gas analysis and Pco2 levels in combination with ventilatory data, parameters were determined to predict outcome in CDH infants managed with convenTo do this, a ventilatory tional ventilatory technique~.2~.2~2~ index (VI) was calculated: VI = (RRx MAP x Paco2)

When the Pco2 could be reduced to less than 40 mm Hg with a ventilatory index less than 1000, all patients survived. A modified ventilatory index (MVI) was calculated by using peak inspiratory pressure (PIP) rather than mean airway pressure (MAP) : MVI = (RRx PIP x Paco,)

+

1000

In infants with an MVI less than 40, the survival rate was 96% using conventional therapy. All infants died if the MVI was greater than 80.22"

TREATMENT Success in the management of CDH has improved dramatically from 1929 when Greenwald and Steinerlll wrote, "For the patient in whom the hernia makes its appearance at birth, little or nothing can be done from a surgical standpoint." A number of innovative treatment strategies have been used, although consistent impact on overall survival is still difficult to obtain.

Prenatal Care The diagnosis of a CDH is being made with increasing frequency by prenatal US examination. This study may be initiated when a discrepancy between size and dates is noted. The prenatal diagnosis of CDH should be complemented by a careful search for other congenital anomalies, particularly those affecting the cardiovascular

CHAPTER

and nervous systems. Evaluation of fetal karyotype should be accomplished by amniocentesis or chorionic villus or fetal blood sampling. Currently, the standard of care is to support the fetus and mother while bringing them to delivery as close as possible to term. The advandiagnosis k in being able to properly tage of prepare and inform the parents about possible treatments and outcomes. The fetus and mother should be referred to an appropriate tertiary perinatal center where the full array of respiratory care strategies including NO, oscillating ventilators, and ECMO are immediately available. Anything less may potentially compromise the best possible outcome.262 Spontaneous vaginal delivery is preferred unless obstetric issues supervene. The mere diagnosis of a CDH is not an indication for elective cesarean section. At this time, fetal intervention with attempted in utero correction of the defect is investigational and highly experimental. Recent trials of fetal tracheal occlusion for CDH in an effort to promote antenatal lung growth have been abandoned because they did not show improved survival rates over contemporary conventional treatments.73,98,122.'23 Tracheal occlusion resulted in lung enlargement but did not reverse the pathologic process associated with pulmonary hypoplasia.l3l As discussed in the outcome section, the prognosis for isolated CDH is not as grave as popularly thought, and hence the rationale for jeopardizing the mother and fetus in the first place may need to be reevaluated. Although prenatal corticosteroids are used to enhance lung development in premature infants, the role of antenatal corticosteroid therapy in CDH patients remains undetermined. The rationale for such therapy to induce pulmonary maturation in a hypoplastic lung is based on Balanced animal studies and isolated case reports.100~161,200 against these observations is the growing evidence from premature infant studies that such drugs may also have adverse perinatal and long-term effects.160~270The true potential of this therapy in improving CDH outcomes awaits the results of a randomized prospective study.

Preoperative Care Resuscitation After the birth of the infant and confirmation of the diagnosis of CDH, all efforts should be made to stabilize the cardiorespiratory system while inducing minimal iatrogenic injury from therapeutic interventions. It is essential to consider that the CDH is a physiologic emergency and not a surgical emergency. The respiratory distress associated with a CDH in the newborns results from a combination of two factors previously discussed: uncorrectable pulmonary hypoplasia and potentially reversible pulmonary hypertension. The balance between these two factors determines the response to therapy and ultimately the outcome. Clinically, both are manifested by an increase in pulmonary vascular resistance and elevated pulmonary artery pressures, right-to-left shunting at the ductal and foramen levels, and progressive hypoxemia. Because there are no proven therapies to promote

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pulmonary growth at this time, therapeutic interventions are aimed at governing pulmonary vascular tone. Resuscitation begins with endotracheal intubation and nasogastric tube insertion. Ventilation by mask and Ambu bag is contraindicated to avoid distention of the stomach and intestines that may be in the thoracic cavity. Arterial and venous access should be acquired through the umbilicus. If the umbilical venous catheter can be passed across the liver into the right atrium, it can be useful for monitoring central venous pressures as well as obtaining mixed venous blood gas samples. Although the umbilical artery is excellent for monitoring systemic blood pressure and obtaining postductal arterial blood gas specimens, additional information can be obtained by monitoring arterial oxygen saturation in a pfeductal position either with a right radial arterial catheter or a transcutaneous saturation probe. An important part of the treatment algorithm is an attempted estimation as to whether the infant has enough lung capacity for meaningful gas exchange. It is important to consider this fact before exposing an infant and family to heroic treatment strategies. As in any neonatal resuscitation, meticulous attention must be paid to maintaining proper temperature regulation, glucose homeostasis, and volume status in the neonate in an effort to maintain adequate oxygen delivery. Any stressful stimulus can further exacerbate already elevated pulmonary pressures and lead to increased shunt flow and further systemic desaturation. Infants should be properly sedated, and any combination of agents, including midazolam (Versed), fentanyl, or morphine can be used. Muscle paralysis is strongly discouraged because of its untoward consequences on ventilatory mechanics and potential morbidity. Infants not "cooperating"with ventilator strategies generally need attention to their discomfort, not muscle paralysis. Systemic hypotension and inadequate tissue perfusion may be observed and reversed with intravenous fluid administration including crystalloid, blood products, and colloid. Cardiotonic drugs such as doparnine or dobutamine may be required. Metabolic acid-base disturbances are usually related to hypoperfusion and should be corrected by fluid management or bicarbonate administration. Metabolic acidosis can be reversed with bicarbonate administration if ventilation can be appropriately managed. Severe hypercapnia (Pco2 >70 mm Hg) should be managed by changing ventilator strategy.

Ventilation The type of mechanical ventilator needed for the infant with a CDH is a matter of personal and institutional preference. Most infants can be successfully managed with a simple pressure-cycle ventilator using a combination of high rates (100 breaths per minute) and modest peak airway pressures (18 to 22 cm H 2 0 and no positive end-expiratory pressure [PEEP]) or 'rower rates (20 to 40 breaths per minute) and higher pressures (22 to 35 cm H 2 0 , 3 to 5 cm PEEP). The goal of such ventilatory support is to maintain minute ventilation while obtaining a preductal Po2greater than 60 mm Hg (Sao, 90% to 100%) with a corresponding Pco2 of less than 60 mm Hg.

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pH and Pco2 levels have been shown to be important in modifying pulmonary vascular t0ne.2~~ The successful clinical manipulation of these parameters in therapeutic interventions in neonates with persistent pulmonary hypertension represents an initial treatment strategy86 It is now clear, however, that the extremes of hyperventilation with induced alkalosis should be avoided because such therapy compounds the pulmonary problems with serious iatrogenic injury.I62A respiratory strategy based on permissive hypercapnea and spontaneous respiration has proven to be quite successful.31 If conventional mechanical ventilatory techniques cannot reverse the hypoxemia or hypercarbia, high-frequency techniques using an oscillating ventilator may be required. This technique may be effective in removing carbon dioxide and temporarily stabilizing an infant in severe respiratory distress. When such techniques have been used as initial therapy, survival results have been quite

Pharmacology A broad spectrum of drugs and antihypertensive agents has been used in attempts to modify the pulmonary vascular resistance in infants with CDH and respiratory failure. Experience has been extrapolated from clinical trials of infants with persistent pulmonary hypertension of the newborn (PPHN) and other forms of neonatal respiratory failure. In the past, agents such as tolazoline, which exerts its effects through a-receptor blockade, had been utilized to lower pulmonary vascular resistance in the face of ~ , 2efficacy ~~ in hypoxemia and respiratory f a i l ~ r e . 2 ~ Its CDH infants was marginal. Other drugs, such as nitroprusside, isoproterenol, nitroglycerin, and captopril, have not been effective.38 The administration of various prostaglandin derivatives, including prostaglandin D2 (PGD2), prostaglandin El (PGEI), and prostacyclin, and of the cyclooxygenase inhibitor indomethacin has also been disapp~inting.~~~~'~~ New management strategies for treating persistent pulmonary hypertension now undergoing clinical evaluation include various calcium channel blockers, prostacyclin derivatives, endothelin receptor antagonists, and phosphodiesterase-5 inhibitors such as sildenafil.92,240

Surfactant Animal models have demonstrated that experimentally induced CDH lungs are surfactant deficient, but such results have not been replicated in human studies. Early reports in infants with CDH demonstrated alterations in ~ , 3 ~ ~ recent surfactant levels and ~ o m p o s i t i o n . 2 ~However, studies have indicated that the surfactant pool in infants with CDH is no different than control patients even in ~ J ~ ~may be infants requiring ECMO s ~ p p o r t . " J ~There alterations in synthetic and metabolic kinetics for individual components.53 In terms of improving respiratory function and outcomes, clinical and experimental investigations with surfactant administration have been mi~ed."J08J~~~2~6 A multicenter review of surfactant administration in CDH patients showed no overall benefit to its use and demonstrated a lower survival rate in

preterm infants compared to full-term infants.178At this time, there are no clinical data to support the administration of surfactant in the management of CDH infants.

Nitric Oxide NO is a potent mediator of vasodilatation and was originally identified as endothelialderived relaxing factor.145,289 Because it is a highly diffusible gas that is rapidly inactivated by binding to hemoglobin, it is particularly suited for administration to the pulmonary vasculature with mechanical ventilatory techniques. In clinical studies, NO was effective in improving oxygen saturation levels in In an neonates with respiratory failure due to PPHN.169,247 animal model of PPHN, NO decreased pulmonary artery pressures and increased arterial oxygen saturation without discernable side effects.lo3 Unfortunately, its effects in CDH infants with respiratory failure have been m i ~ e d . l , 8 0 , ~ ~ There , ~ ~ ~ , ~are 6 7 no data to show that NO administration improves survival or decreases the requirement for ECMO.97 The variable physiologic response to NO in these infants may be related to the method of its administration.155 NO administered through a nasal cannula has been utilized for the treatment of late pulmonary hypertension following extubation.'@ The exact role of NO in the treatment of pulmonary hypertension and respiratory failure in CDH infants has not been defined despite its widespread use.

Surgical Management Timing of Surgical Repair Historically, CDH was considered a surgical emergency. Infants were rushed to the operating room as soon as possible after birth in the belief that reduction of the abdominal contents from the chest would relieve the compression of the lungs. Frequently, after a brief postoperative honeymoon period marked by adequate gas exchange, progressive deterioration in the infant's respiratory status ensued with elevated pulmonary vascular resistance, right-to-left shunting, hypoxemia, and ultimately death due to respiratory failure. As management techniques for neonatal respiratory failure evolved, a period of medical stabilization and delayed surgical repair in an attempt to improve the overall condition of the infant with CDH was proposed.26-181 At the same time there was increasing evidence of the potential detrimental effects of early surgical repair on respiratory function.'" Since then, multiple single institutional studies have reported improved survival rates with delayed surgery as part of their treatment protocols, whereas others have found no changes in overall outcome.* Importantly, no study has shown a decrease in survival rates with this technique. Although-delayedsurgical repair is now widely practiced, there is no statistical evidence that supports this approach over immediate repair at this time.fl4

*See references 6, 31, 40, 48, 101, 109, 127, 224, 241, 246, 260, 313, and 320.

CHAPTER

The optimal timing of operative repair when employing a strategy of delayed repair also remains undetermined. The period of preoperative stabilization has varied from Some authors several days to several ~eeks.~O,22~,2~6,323 have reported waiting until the infant is successfully weaning off of mechanical ventilation and requiring low ventilator settings. Others follow the severity of pulmonary hypertension with serial echocardiographic examinations and wait until the hypertension has abated or at least s t a b i l i ~ e d . ~ ~ , l 2 ~

Operative Repair Most surgeons approach the defect through a subcostal incision, although the repair can be done through a thoracotomy incision as well. For rare cases in which

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reduction of the herniated contents is difficult because of an abnormally shaped liver or spleen, a combined approach can be used. Both thoracoscopic and laparoscopic techniques have been used to repair these defects.21,1738228,245,259,324 Ideallv suited for older infants with delayed presentation, minimally invasive techniques may have a higher incidence of technical and physiologic consequences in the n e ~ b o r n . ~ ~ f t i rdivision of the abdominal wall muscles and entrance into the abdominal cavity, the viscera are gently reduced from the defect and completely eviscerated for adequate visualization. The spleen dn the' left side and the liver on the right " are usually the last organs to be mobi~ . k).Mobilization lized from the chest cavity i ~ i 60-5A, can be difficult and must be done without injury to either organ. On the right side, the kidney and adrenal gland

A, Schematic drawing of an unreduced left congenital diaphragmatic hernia as seen from the abdomen. B, The same hernia but now reduced, demonstrating that the spleen is usually the last organ to be reduced from the chest cavity. Sutures have been placed for a primary repair. C, Completed primary repair of a left congenital diaphragmatic hernia. D, Repaired left congenital diaphragmatic hernia using prosthetic material. (From Spitz L, Coran AG (eds):Rob & Smith's Pediatric Surgery. London, Chapman & Hall, 1996.)

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may be found in the chest as well. Abnormal drainage of the hepatic veins on either side may complicate mobilization of the liver. Once the abdominal contents are reduced, the defect in the diaphragm in the posterolateral position can be examined. In 20% of patients, a hernia sac formed by parietal pleura and peritoneum is present and must be excised to minimize chances of recurrence.237 Usually, there is an anterior rim of diaphragm of varylng size. The posterior rim of diaphragm must be searched for in the retroperitoneal tissue, because it may be rolled up like a window shade by the peritoneum. The peritoneum must be opened over this fold and the diaphragmatic tissue mobilized. When tissue is adequate, a primary repair with interrupted nonabsorbable suture material can be performed (see Fig. 60-5C). In some cases, the posterior rim of tissue may disappear along the lateral chest wall. If enough diaphragmatic tissue exists anteriorly, it can be sutured directly to the body wall with sutures placed around the ribs. If the defect is too large to be closed in a primary fashion, a number of reconstructive techniques have been described using various nearby stxuctures,such as prerenal fascia, rib structures, and various thoracic and abdominal wall muscle flaps.22,1",255,266,304,310 If there is any chance that ECMO support might be required in the management of the infant, however, the use of complex reconstructive techniques requiring extensive tissue dissection is contraindicated because of the risk of bleeding. The use of prosthetic material to complete the diaphragmatic closure has gained widespread acceptance (see Fig. 60-5D). A floppy, tension-free diaphragmatic repair can be accomplished that may lessen the degree of intra-abdominal pressure when closing the abdominal wall.19 Besides the risk of infection, the major drawback to using a prosthetic patch closure is the risk of dislodgment and subsequent reherniation." Complications of prosthetic patch repair occur in approximately 10% to almost 50% of cases. Patients who develop a recurrent hernia present with bowel obstruction or respiratory distress or may be a~ymptomatic.~~,2~~ With the loss of intra-abdominal domain, abdominal wall closure may not be possible at all or may result in unacceptable intra-abdominal pressure (i.e., abdominal compartment syndrome) even after extensively stretching the abdominal wall. In these situations, simple closure of the skin can be accomplished with repair of the resultant ventral wall defect some months later. If the skin cannot be closed successfully, temporary closure using prosthetic material such as a silo can be used. Biologic closure should then be obtained as soon as safely possible in the postoperative period. Drainage of the chest cavity on the repaired side with a tube thoracostomy is not indicated except for active bleeding or uncontrolled air leak. It has been proposed that such a tube with even a small degree of negative suction may add to the barotrauma and pulmonary hypertension imposed by mechanical ventilation on a hypoplastic lung.a3 Additional surgical procedures at the time of the repair such as correction of the nonrotation as well as appendectomy are not indicated and should be avoided if ECMO is to be considered.

The repair of recurrent defects can present a formidable surg&il challenge. Since the most common organ involved in recurrent herniation is either the small or large bowel, intestinal adhesions to the disrupted diaphragm or intrathoracic organs may compromise attempted closure. Repair is most commonly approached through the abdomen but can be accomplished through a thoracotomy as well. If adequate diaphragmatic tissue is present, then primary reapproximation should be attempted. Otherwise, different techniques for mesh insertion have been tried.68,24a2254

Anesthesia To avoid the stresses of transport and sudden changes in ventilation parameters imposed by a trip to the operating room, a number of centers have adopted the policy of performing surgical repair of CDH infants in the neonatal intensive care unit. This change in location allows for the lowest degree of disruption in the neonate's environment. Anesthesia is achieved by intravenous narcotic and muscle relaxant techniques. With intravenous anesthetics, the infant ventilator can be used continuously rather than a conventional anesthesia machine.

Postoperative Management Postoperative management should continue the trends and goals established before the operative procedure. Ventilator support should be tailored to keep preductal Po2 levels at least above 80 mm Hg and Pco2 levels less than 30 to 35 mm Hg. Echocardiograms should be obtained routinely to assess pulmonary hypertension, shunt flow, and ventricular performance. Therapeutic interventions discussed previously may be employed if respiratory decompensation develops. Weaning from ventilator support should be slow and deliberate as tolerated by the infant. Meticulous attention to fluid status must be maintained, particularly in the immediate postoperative period. As a result of surgical intervention, these infants are often hypovolemic and frequently require extra volume administration over time.

Extracorporeal Membrane Oxygenation Even with recent advancements in treatment strategies, overwhelming respiratory failure requiring ECMO support occurs in 15% to 45% of CDH infants.l4~"7.*~*41 Initially, infants were placed on ECMO after developing respiratory failure following the immediate repair of the diaphragmatic defect. With the evolution of delayed surgical repair, ECMO is now considered a part of the preoperative stabilization process. Clinical criteria for determining ECMO *usein infants with CDH have been based on factors predictive of at least an 80% mortality rate with mechanical ventilation. A number of parameters have been proposed, including the calculation of the oxygenation index (01) and the alveolar-arterial oxygen difference [ (A - a) DO^]. For CDH

CHAPTER

60

patients the most common reason for the initiation of ECMO was an 0 1 of 40 or greater, and it is often considered for an OI as low as 25." Generally accepted criteria for initiating ECMO support for neonatal respiratory failure based on [ (A - a)DO,] criteria include a value of 610 or greater despite 8 hours of maximal medical management. It must be realized that such criteria continue to be institutional specific and that no calculations can replace clinical judgment and frequent bedside assessment. Failure to improve in the setting of severe pulmonary hypertension and progressive hypoxemia despite maximum medical intervention remains a valid qualifying criterion for ECMO support. Controversy still exists as to whether ECMO support should be offered to all infants with CDH and respiratory failure. The issue of severe pulmonary hypoplasia incompatible with life must be kept in mind when ECMO is being" considered. This intervention is successful when used to support an infant with a reversible process of pulmonary hypertension. However, it is not a treatment for those infants with irreversible hypoplasia. Differentiating these infants on clinical parameters can be quite difficult. A newborn with a CDH who is unable to reach a preductal oxygen saturation level of at least 90% or a markedly ~ unresponsive to any type of ventilaelevated P C Olevel tory intervention during the pre-ECMO course has a high likelihood of having irreversible hypopla~ia.2~Wn the other hand, others have proposed that all infants should be ECMO candidates. Although widely accepted as a treatment for the respiratory failure associated with CDH, the impact of ECMO on improving overall survival continues to be debated. Over the past decade a number of studies have demonstrated improved survival rates in CDH infants with ECMO However, other as part of the treatment ~trategy.57J0~23~2 institutions have either not noted any improvements resulting from ECMO or have been able to manage their . ~ ~ sur~ ~ ~ infants without it with equivalent s ~ c c e s sOverall vival rates of infants treated with ECMO vary from 34% to 87% and are clearly, dependent on a number of variables, including gestational age and birth weight, respiratory function, and the degree of pulmonary development As and associated pulmonary hyperten~ion."~~~,l65,185,276 conventional treatment strategies continue to improve, ECMO utilization and concomitant survival rates may decrease.14 A number of surgical issues are involved in the management of CDH infants while on ECMO. Both venovenous and venoarterial techniques have been reported to be equally effective in supporting patients while on bypass.82J7* With venovenous bypass, severe right-sided heart failure can be managed temporarily with a PGEl infusion to keep the ductus open until the pulmonary hypertension resolves or by converting to venoarterial support. The timing of the surgical repair of the defect in relation to ECMO support remains variable. As a result of the acceptance of delayed surgical repair as a treatment strategy, more than 90% of CDH infants requiring ECMO support are placed on bypass before undergoing surgical repair.I8O Surgical repair of the defect while on ECMO can then be accomplished but has been associated with hemorrhagic L

Congenital Diaphragmatic Hernia and Eventration

943

complications in 60% of the patient~.I7"~~' Survival rates after surgery on ECMO have varied from 43% to 80%.M23132316 TO minimize the risk of hemorrhagic complications a number of techniques have been proposed, including the use of heparin-bonded ECMO circuits, performance of the surgical repair just before expected decannulation, and aggressive management of the anticoagulant status of the infant, including the use of antifibrinolytic therapy. Because of the coagulation problems, less than 20% of infants are reportedly repaired while on ECM0.51 The majority undergo repair after the completion of ECMO. This delayed operative approach sometimes not occurring until several days after decannulation has been extremely successful,with survival rates of almost 80% and higher.I,81,26However,there are currently no acceptable studies comparing either pathway.

Outcome Survival rates (discharge to home) for infants born with an isolated CDH have improved dramatically over the past decade when compared with the historical values of Survival rates as high as approximately 50%.3,11"1",261,319 80% to 93% are being reached with current treatment modalities.7~31,85,182,308 Nevertheless, variation in survival rates remains high, representing significant institutional differences in management strategies and patient accrua1.1*,275Further complicating t h e interpretation of most studies has been the continued evolution of respiratory care and medical treatment strategies. In addition, the presence of associated anomalies such as congenital heart disease remains a significant risk factor for a poor outcome in these infants."J5*Zm With improved overall survival rates, a greater number of physiologically compromised infants are surviving beyond the neonatal period, and late death in approximately 10% of initial survivors been reported mostly due to the consequences of ~has ~ ~ persistent pulmonary hypertension or iatrogenic complications.1503248.257 Before the widespread use of ECMO and newer treatment modalities, long-term survivors of conventional mechanical ventilation were reportedly healthy and withStudies out clinically evident respiratory di~ease.l~J02.24' have now shown that CDH survivors may be at risk for a number of long-term morbidities such as chronic pulmonary growth failure, neurodevelopmental delay, gastrointestinal problems, and orthopedic issues. The probability of respiratory, nutritional, and musculoskeletal morbidity is higher in CDH infants treated with ECM0.50 Pulmonary issues are by far the most common longterm problems in infants surviving beyond the neonatal period. Pulmonary developmental studies have shown that alveolar multiplication continues for several years after birth. A normal number, howeveq is never achieved in CDH hypoplastic lungs. Over time the alveoli become emphysematous, and there is gradual remodeling of the pulmonary bed.2~mphysematouschanges may affect both lung fields, because the contralateral lung may herniate across the mediastinum. Studies have shown

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that even in infants with severe respiratory distress in the neonatal period lung volume will increase with time. However, pulmonary blood flow remains significantly decreased compared with the contralateral side, suggesting that vascular growth in severe cases does not match alveolar growth.217 Pulmonary function tests have been most useful in managing long-term survivors, because chest radiographs and ventilation-perfusion studies are almost always abnormal and therefore have had little influence on medical therapy. Although a number of infants may demonstrate compromised compliance early in their course, serial pulmonary function testing has demonstrated improved compliance over time associated with real lung growth.172 In long-term studies of survivors, many had normal pulmonary function tests In 30% to 50% of even with exercise testing.202,215,300.3'2 survivors there may be either obstructive or restrictive Increased bronchial hyperventilatory irnpairments.215~242~ reactivity has also been noted.l46,269 Treatment strategies for these patients have included the use of supplemental oxygen, bronchodilator therapy, corticosteroids, and diuretics. Clinically, chronic lung disease has been reported in CDH survivors, particularly in those requiring ECM0.63,'96,215 Whether this finding is related to the pathology of the disease or has been induced iatrogenically Regardless, ~~ owing to techniques of ventilation is ~ n c l e a r . 2 prolonged elevation in pulmonary artery pressure whether it results from pulmonary hypoplasia or bronchopulmonary dysplasia impacts long-term survival. Pulmonary artery pressures normalize in approximately 50% of all patients by 3 weeks of age but can remain elevated for months in as many as one third of surviving infants.81J48,258 This morbidity improves over time, and most survivors lead unaffected lives.172Jg" Studies have identified a number of nonpulmonary morbidities in CDH survivors with neurodevelopmental abnormalities being the most common. Developmental delay has been reported in a number of surviving infants.196 Abnormalities in both motor and cognitive skills have been identified.'j32279 Other neurologic problems reported include visual disturbances, hearing loss, seizures, abnormal cranial computed tomography (CT) and MRI, and abnormal electroencephalographic studies.63J43J96 Most studies have implicated ECMO as a factor in these neurologic problems, but CDH survivors treated without ECMO are also at ri~k.~,~"204,239 A high incidence of gastroesophageal reflux and foregut dysmotility has been found in CDH survivors (Fig. 60-6).63,93J961281,299Most infants have been managed with feeding regimen manipulations and prokinetic agents. Antireflux procedures have been reserved for medically unresponsive patients or those requiring gastrostomy tube placement for feeding purposes. Nutritional and growth-related problems have been found in a significant number of these survivors as we11.20 Long-term surveillance and aggressive nutritional management are required for these infants. Worrisome anecdotal reports are beginning to appear describing Barrett's esophagitis and chronic lung disease secondary to chronic gastroesophageal reflux.

Barium sulfate esophagogram in an infant with a left congenital diaphragmatic hernia demonstrating a dilated, ectatic esophagus. The stomach was oriented vertically and emptied slowly.

A number of skeletal disorders have been reworted. including chest wall defects (pectus anomalies) and s ~ o l i o s i s . ~ ~Treatment ,2~~,2~~ of these problems has included initial attempts at bracing followed by surgical correction. As interventional therapies have evolved, a new group of survivors has emerged with different patterns of longterm morbidities. Sicker infants who are physiologically compromised to varylng degrees are surviving in greater numbers. Resource management for these infants in the " future will be crucial as we attempt to determine and justify the impact of treatment strategies on survival rates and quality of life.z3l

Future Therapies Despite the advancements that have been made in treating infants with CDH, it still represents a frustrating and complex clinical problem. As the striking variance in survival rates attests, no currently employed therapeutic intervention or management strategy has emerged for widespread successful application. Even with the increasing success of current treatment strategies such as permissive hypercapnia, delayed operative repair, antihypertensive pharmacology, and advanced ventilatory techniques, a cohort of infants refractory to these interventions continue to be candidates for novel treatments. The concept of fetal surgical intervention evolved from the experimental observation in lambs that reduction of compressive forces on the lung resulted in continued pulmonary growth and development.2J1sAlthough technically and theoretically exciting, the clinical .trial of fetal diaphragmatic repair was disappointing.117 Significant problems were encountered with patient seleciion and- postoperative maternal management. A direct extension of these attempts at in utero repair was the observation that tracheal ligation accelerated

-

CHAPTER

fetal lung growth and reversed the alveolar hypoplasia and abnormal pulmonary vascular pattern in fetal lamb Tracheal occlusion and rat models of CDH.77,78,171,315 or PLUG therapy (plug the lung until it grows) resulted in improved oxygenation and ventilation after birth when compared with untreated control animals.130 These observations ultimately led to a randomized, clinical trial comparing fetal endoscopic tracheal occlusion to current standard postnatal care for severe congenital diaphragmatic hernia.122 Fetuses qualified for enrollment if they were between 22 and 27 weeks' gestational age and had liver herniated into the left chest with an LHR below 1.4. The 90-day survival rate for the tracheal occlusion group was 73%, and it was 77% for the control group. Because there was no difference in survival between the two groups, the study was closed after 24 patients were treated. Nonetheless, there are reports of continued application of this intervention in European centers.72 Future research will determine whether fetal intervention has a role in the treatment of CDH. Liquid ventilation techniques have been attempted in CDH infants while on ECMO (Fig. 60-7).233 After perfluorocarbon administration, significant increases were reported in Pao, levels and in static total pulmonary compliance measurements accompanied by a fall in Pace, levels. No adverse side effects were noted. Extensive studies are required to examine this newest form of ventilation before its efficacy can be judged. Based on the observations of fetal lung growth induced by tracheal occlusion, inducement of postnatal lung growth with static distention has also been investigated. During the course of the liquid ventilation experiments, pulmonary distention as a result of perfluorocarbon

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Congenital Diaphragmatic Hernia and Eventration

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administration was observed. Its use as a potential treatH ment to induce postnatal lung growth ~ ~ - C Dpatients was then reported.94,135f303 Preliminary studies have shown significant radiographic enlargement of the lung and improved gas exchange. The same results have also been achieved using intra-alveolar albumin admini~tration.673~75 Further study of this potential intervention is required. Lung transplantation has also been used anecdotally in the surgical treatment of CDH.ls4,zg7Both unilateral and bilateral transplants have been attempted. Currently, not enough experience exists to recommend this form of treatment. The potential role of pharmacologic augmentation of pulmonary growth and development is currently being investigated. The combined administration of thyrotropinreleasing hormone and glucocorticoid therapy has been studied in a chemically induced rat model of CDH, It is also known with positive effects on lung gro~th.2~3 that a number of growth factors are crucial to normal pulmonary development. It has been proposed that perhaps selected administration of one or several of these pharmacologic agents or growth factors may be able to reverse the pulmonary hypoplasia of CDH.3g-z83 Continued experimental work using the nitrofen model of CDH may uncover new candidates to promote lung growth and development either prenatally or after birth. - Finally, given the current wide-ranging survival rates at various institutions, an in-depth study and evaluation of current management techniques and outcomes must be made. The efforts of the CDH Study Group to interpret very hetereogeneous data is an encouraging beginning. Such a study might result in the refinement and consolidation of current practices into a universally effective treatment strategy.

FORAMEN OF MORGAGNI HERNIA

Chest radiograph of a left congenital diaphragmatic hernia being supported with extracorporeal membrane oxygenation. The lungs have been opacified with perflubron for liquid ventilation. The pulmonary hypoplasia can be appreciated. (Courtesy of R. B. Hirschl, MD.)

The anterior diaphragmatic hernia of Morgagni is located anteromedially on either side of the junction of the septum transversum and the thoracic wall. The defect occurs through the embryologic space of Larrey. Occasionally, bilateral Morgagni hernias communicate in the midline, constituting a large anterior diaphragmatic defect extending all the way across the midline from right to left. Typically a sac is present, and herniation of the colon or small bowel is usually discovered to the right or left of the midline. Morgagni hernias account for less than 2% of diaphragmatic defects. Although this defect may be observed in neonates, it usually presents more commonly in older children or adults. Associated anomalies may be present and include malrotation. An anterior midline deficiency in the diaphragm with or without the other elements of the pentalogy of Cantrell with free pericardial and peritoneal communication may allow herniation of intestine into the pericardium. The hernia is often discovered incidentally as a mass or airfluid level on a chest radiograph. A barium enema or a CT scan may confirm the diagnosis. Operative correction is easily performed through an upper transverse abdominal incision. The diaphragm is

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sutured to the underside of the posterior rectus sheath at the costal margin after reduction of the hernia and resection of the sac. Laparoscopic and thoracoscopic techniques have also been used to repair this defect.70~144,191,221

EVENTRATION OF THE DIAPHRAGM Eventration of the diaphragm may be either congenital or acquired. The congenital form may be indistinguishable from a diaphragmatic hernia with a sac, and symptoms are usually similar. The acquired lesion is probably due to paralysis of the phrenic nerve that may occur from injury during repair of congenital heart defects, and some of the so-called congenital forms may be acquired through birth injury (Erb's palsy). The diaphragmatic muscle is usually present in its normal distribution, but it is attenuated and inactive. If a rim of diaphragm is present with a central defect to cover the pleural and peritoneal membrane, the lesion is probably a diaphragmatic hernia, although such a distinction may be moot. There may be no symptoms whatsoever even in the presence of a large eventration, although the findings may range from wheezing, frequent respiratory infections, and exercise intolerance to extreme respiratory distress. Diagnosis is usually made on fluoroscopy of the chest. In such cases, the diaphragm moves paradoxically with respiratory motion. This paradoxic movement may be so marked that it results in severe compromise of gas exchange. Although pneumoperitoneum was used frequently in the past, CT or MRI is used more often today. A small eventration may be left untreated. Repair is indicated when a large functional deficit in the function of the ipsilateral lung on ventilation/perfusion studies is found in an apparently asymptomatic patient. In such cases, the compressed lung will not grow well. For the same reason, a large eventration should be repaired even when asympte matic. Repair may be performed either through the abdomen or the chest, but, in most cases, a low thoracotomy is recommended. Through this approach the diaphragm is best plicated with nonabsorbable interrupted 2-0 sutures. A radial or peripheral incision may also be made in the diaphragm and the edges overlapped and sutured. It is important to reef up and overlap the diaphragm so that it is taut, overcorrecting it somewhat, because invariably the muscle will stretch and the eventration will recur if this is not done. Diaphragmatic plication for acquired eventration is frequently necessary to wean infants from ventilatory support. Plication can also be accomplished by either a laparocoscopic or thoracoscopic approach.

REFERENCES 1. Adolph V, Flageole H, Perreault T, et al: Repair of congenital diaphragmatic hernia after weaning from extracorporeal membrane oxygenation. J Pediatr Surg 1995;30:349. 2. Adzick NS, Outwater KM, Harrison MR, et al: Correction of congenital diaphragmatic hernia in utero: IV. An early gestational fetal lamb model for pulmonary vascular morphometric analysis.J Pediatr Surg 1985;20:673.

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144. Hussong RL Jr, Landreneau RJ, Cole FH Jr: Diagnosis and repair of a Morgagni hernia with video-assisted thoracic surgery. Ann Thorac Surg 1997;63:1474. 145. Ignarro LJ, Buga GM, Wood KS, et al: Endotheliumderived relaxing factor produced and released from artery and vein is nitric oxide. Proc Natl Acad Sci U S A 1987;84:9265. 146. Ijsselstijn H, Tibboel D, Hop WJ, et al: Long-term pulmonary sequelae in children with congenital diaphragmatic hernia. Am J Respir Crit Care Med 1997;155:174. 147. Ijsselstijn H, Zimmerman LT, Bunt JE, et al: Prospective &luaGon of surfactant ~ o ~ ~ o s iint ibroncho~lveolar o~ lavage fluid of infants with congenital diaphragmatic hernia and of age-matched controls. Crit Care Med 1998;26:573. 148. IoconoJA, Cilley RE, Mauger DT, et al: Postnatal pulmonary hypertension after repair of congenital diaphragmatic hernia: Predicting risk and outcome. J Pediatr Surg 1999; 34:349. 149. Iritani I: Experimental study on embryogenesis of congenital diaphragmatic hernia. Anat Embryo1 (Berl) 1984; 169:133. 150. Jaillard SM, Pierrat V, Dubois A, et al: Outcome at 2 years of infants with congenital diaphragmatic hernia: A population-based study. Ann Thorac Surg 2003;75:250. 151. Janssen DJ, Tibboel D, Carnielli W, et al: Surfactant phos phatidylcholine pool size in human neonates with congenital diaphragmatic hernia requiring ECMO. J Pediatr 2003;142:247. 152. Jenkinson EL: Absence of half of the diaphragm (thoracic stomach; diaphragmatic hernia). AJR Am J Roentgenol 1931:26:899. 153. Jesudason EC: Challenging embryological theories on congenital diaphragmatic hernia: Future therapeutic implications for paediatric surgery. Ann R Coll Surg Engl 2002;84:252. 154. Kaiser JR, Rosenfeld CR: A population-based study of congenital diaphragmatic hernia: Impact of associated anomalies and preoperative blood gases on survival.J Pediatr Surg 1999;34:1196. 155. Karamanoukian HL, Glick PL, Wilcox DT, et al: Pathophysiology of congenital diaphragmatic hernia: VIII. Inhaled nitric oxide requires exogenous surfactant therapy in the lamb model of congenital diaphragmatic hernia. J Pediatr Surg 1995;30:1. 156. Karamanoukian HL, Glick PL, Wilcox DT, et al: Pathophysiology of congenital diaphragmatic hernia: X: Localization of nitric oxide synthase in the intima of pulmonary artery trunks of lambs with surgically created congenital diaphragmatic hernia. J Pediatr Surg 1995;30:5. 157. Karamanoukian HL, Glick PL, Zayek M, et al: Inhaled nitric oxide in congenital hypoplasia of the lungs due to diaphragmatic hernia or oligohydramnios. Pediatrics 1994; 94:715. 158. Katz S, Kidron D, Litmanovitz I, et al: Fibrous fusion between the liver and the lung: An unusual complication of right congenital diaphragmatic hernia. J ~ e d i a t Surg r 1998;33:766. 159. Kawadia V, Greenough A, Laubscher B, et al: Perioperative assessment of respiratory compliance and lung volume in infants with congenital diaphragmatic hernia: Prediction of outcome. J Pediatr Surg 1997;32:1665. 160. Kay HH, Bird IM, Coe CL, et al: Antenatal steroid treatment and adverse fetal effects: What is the evidence?J Soc Gynecol Invest 2000;7:269. 161. Kay S, Laberge JM, Flageole H, et al: Use of antenatal steroids to counteract the negative effects of tracheal occlusion in the fetal lamb model. Pediatr Res 2001;50495.

162. Kays DW, Langham MR Jr, Ledbetter DJ, et al: Detrimental effects of standard medical therapy in congenital diaphragmatic hernia. Ann Surg 1999;230:340. 163. Keller RL, Aaroz PA, Hawgood S, et al: MR Imaging of hepatic pulmonary fusion in neonates. AJR Am J Roentgenol 2003;180:438. 164. Keller RL, Glidden DV, Paek BW, et al: The lung-to-head ratio and fetoscopic temporary tracheal occlusion: Prediction of survival in severe left congenital diaphragmatic hernia. Ultrasound Obstet Gynecol 2003;21:244. 165. Keshen TH, Gursoy M, Shew SB, et al: Does extracorporeal membrane oxygenation benefit neonates with congenital diaphragmatic hernia? Application of a predictive equation. J Pediatr Surg 1997;32:818. 166. Killeen OG, Kelehan P, Reardon W: Double vagina with sex reversal, congenital diaphragmatic hernia, pulmonary and cardiac malformations-another case of Meacham syndrome. Clin Dysmorphol 2002;11:25. 167. Kinsella JP, Neish SR, Ivy DD, et al: Clinical responses to prolonged treatment of persistent pulmonary hypertension with low doses of inhaled nitric oxide. J Pediatr 1993;123:103. 168. Kinsella JP, Parker TA, Ivy DD, et al: Noninvasive delivery of inhaled nitric oxide therapy for late pulmonary hypertension in newborn infants with congenital diaphragmatic hernia. J Pediatr 2003;142:397. 169. Kinsella JP, Neish SR, Shaffer E, et al: Low-dose inhalational nitric oxide in persistent pulmonary hypertension of the newborn. Lancet 1992;340:819. 170. Kitagawa M, Hislop A, Boyden EA, et al: Lung hypoplasia in congenital diaphragmatic hernia: A quantitative study of airway, artery, and alveolar development. Br J Surg 1971;58:342. 171. Kitanox Kanai M, Davies P, et al: Lung growth induced by prenatal tracheal occlusion and its modifying factors: A study in the rat model of congenital diaphragmatic hernia. J Pediatr Surg 2001;36:251. 172. Koumbourlis AC, Stolar CJ, Stylianos S: Lung function in infants after repair of congenital diaphragmatic hernia [abstract]. Am Rev Respir Dis 1994;148:A548. 173. Krishna A, Zargar N: Laparoscopic repair of a congenital diaphragmatic hernia. Pediatr Surg Int 2002;18:491. 174. Kugelman A, Gangitano E, Pincros J, et al: Venovenous versus venoarterial extracorporeal membrane oxygenation in congenital diaphragmatic hernia. J Pediatr Surg 2003; 38:1131. 175. Kunaisaki SM, Chanh R, Fauza D, et al: Hypertonic enhancement of fetal pulmonary growth after tracheal occlusion. J Pediatr Surg, in press. 176. Ladd WE, Gross RE: Congenital diaphragmatic hernia. N Engl J Med 1940;223:917. 177. Laennec RTH, 1834, cited in Ravitch MM: Congenital diaphragmatic hernia. In Nyhus LM (ed): Hernia. Philadelphia, JB Lippincott, 1964. 178. Lally KP, Lally PA, Langham MR, et al: Congenital Diaphragmatic Hernia Study Group: Surfactant does not improve survival rate in preterm infants with congenital diaphragmatic hernia. J Pediatr Surg 2004;39:829. 179. Lally KP, Paranka MS, Roden J, et al: Congenital diaphragmatic hernia: Stabilization and repair on ECMO. Ann Surg 1992;216:569. 180. Lally KP, The CDH Study Group. The usk of ECMO for stabilization of infants with congenital diaphragmatic hernia-a report of the CDH Study Group. Presented at the 20th annual meeting of the Surgical Section of the American Academy of Pediatrics, Boston, October 2002.

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223. Neville HL, .Jaksic T, Wilson, .JM, et al: Congenital ~ i a ~ h r a ~ m Hernia a t k Study ~ r d u Fryns ~ : syndrome in children with congenital diaphragmatic hernia. J Pediatr Surg 2002;37:1685. 224. Nio M, Haase G, Kennaugh J, et al: A prospective randomized trial of delayed versus immediate repair of congenital diaphragmatic hernia. J Pediatr Surg 1994;29:618. 225. Norden MA, Butt W, McDougall P: Predictors of survival for infants with congenital diaphragmatic hernia. J Pediatr Surg 1994;29:1442. 226. Nose K, Kamata S, Sawai T, et al: Airway anomalies in patients with congenital diaphragmatic hernia. J Pediatr Surg 2000;35:1562. 227. O'Dwyer J: Operation for relief of congenital diaphragmatic hernia. Ann Surg 1890;11:124. 228. Ochoa de Castro A, Ramos MR, Calonge WM, et al: Congenital left-sided Bochdalek diaphragmatic hernia thoracoscopic repair--case report. Eur J Pediatr Surg 2003; 13:407. 229. Ohshiro K, Miyazaki E, Taira Y, et al: Upregulated tumor necrosis factor-alpha gene expression in the hypoplastic lung in patients with congenital diaphragmatic hernia. Pediatr Surg Int 1998;14:21. 230. Paek BW, Coakley FV, Lu Y, et al: Congenital diaphragmatic hernia: Prenatal evaluation with MR lung volumetrypreliminary experience. Radiology 2001;220:63. 231. Poley MJ, Stolk EA, Tibboel D, et al: The cost-effectiveness of treatment for congenital diaphragmatic hernia. J Pediatr Surg 2002;37:1245. 232. Powell PD, Johnstone JM: Phenmetrazine and fetal abnormalities. BMJ 1962;17:1327. 233. Pranikoff T, Gauger PG, Hirschl RB: Partial liquid ventilation in newborn patients with congenital diaphragmatic hernia. J Pediatr Surg 1996;31:613. 234. Pringle KC: Lung development in congenital diaphragmatic hernia. In Puri P (ed): Congenital Diaphragmatic Hernia. Basel, Karger, 1989. 235. Pringle KC, Turner JW, Schofield JC, et al: Creation and repair of diaphragmatic hernia in the fetal lamb: Lung development and morphology. J Pediatr Surg 1984; 19:131. 236. Purohit DM, Pais S, Levkoff AH: Effect of tolazoline on hypoxemia in neonatal respiratory distress. Crit Care Med 1978;6:14. 237. Puri P: Congenital diaphragmatic hernia. Curr Probl Surg 1994;31:787. 238. Puri P, Gorman WA: Natural history of congenital diaphragmatic hernia: Implication for management. Pediatr Surg Int 1987;2:327. 239. Rasheed A, Tindall S, Cueny DL, et al: Neurodevelopmental outcome after congenital diaphragmatic hernia: Extracorporeal membrane oxygenation before and after surgery.J Pediatr Surg 2001;36:539. 240. Rashid A, Ivy D: Severe paediatric pulmonary hypertension: New management strategies. Arch Dis Child 2005; 90:92. 241. Reickert CA, Hirschl RB, Schumacher R, et al: Effect of very delayed repair of congenital diaphragmatic hernia on survival and extracorporeal life support use. Surgery 1996;120:766. 242. Reid IS, Hutcherson RJ: Long-term follow-up of patients with congenital diaphragmatic hernia. J Pediatr Surg 1976; 11:939. 243. Reid L: Structural and functional reappraisal of the pulmonary artery system. In Scientific B& of Medicine Annual Reviews. University of London, Athlone Press, 1968. 244. Reyes C, Chang LK, Waffarn F, et al: Delayed repair of congenital diaphragmatic hernia with early high-frequency

oscillatory ventilation during preoperative stabilization.

J Pediatr Surg 1998;33:1010. 245. Richardson WS, Bolton JS: Laparoscopic repair of congenital diaphragmatic hernias. J Laparoendosc Adv Surg Tech A 2002;12:277. 246. Roberts JP, Burge DM, Griffiths DM: High-risk congenital diaphragmatic hernia: How long should surgery be delayed? Pediatr Surg Int 1994;9:555. 247. Roberts JD, Polaner DM, Lang P: Inhaled nitric oxide in persistent pulmonary hypertension of the newborn. Lancet 1992;340:818. 248. Rowe DH, Stolar CJ: Recurrent diaphragmatic hernia. Semin Pediatr Surg 2003;12:107. 249. Roye DP: Personal communication, 1992. 250. Ruano R, Benachi A, Martinovic J, et al: Can threedimensional ultrasound be used for the assessment of the fetal lung volume in cases of congenital diaphragmatic hernia? Fetal Diagn Ther 2004;19:87. 251. Rudolph AM, Yuan S: Response of the pulmonary vasculature to hypoxia and H+ ion concentration changes. J Clin Invest 1966;45:399. 252. Sakai H, Tamura M, Hosokawa Y, et al: Effect of surgical repair on respiratory mechanics in congenital diaphragmatic hernia. J Pediatr 1987;111:432. 253. Sakurai Y, Azarow K, Cutz E, et al: Pulmonary barotrauma in congenital diaphragmatic hernia: A clinicopathological correlation. J Pediatr Surg 1999;34:1813. 254. Saltzman DA, Ennis JS, Mehall JR, et al: Recurrent congenital diaphragmatic hernia: A novel repair. J Pediatr Surg 2001;36:1768. 255. Scaife ER, Johnson DG, Meyers RL, et al: The split abdominal wall muscle flap-a simple, mesh-free approach to repair large diaphragmatic hernia. J Pediatr Surg 2003;38:1748. 256. Scheffers EC, Ijsselstijn H, Tenbrinck R, et al: Evaluation of lung function changes before and after surfactant application during artificial ventilation in newborn rats with congenital diaphragmatic hernia. J Pediatr Surg 1994;29:820. 257. Schoeman L, Pierro A, Macrae D, et al: Late death after extracorporeal membrane oxygenation for congenital diaphragmatic hernia. J Pediatr Surg 1999;34:357. 258. Schwartz IP, Bernbaum JC, Rychik J, et al: Pulmonary hypertension in children following extracorporeal membrane oxygenation therapy and repair of congenital diaphragmatic hernia. J Perinatol 1999;19:220. 259. Shah AV, Shah AA: Laparoscopic approach to surgical management of congenital diaphragmatic hernia in the newborn. J Pediatr Surg 2002;37:548. 260. Shanbhogue LK, Tam PK, Ninan G, et al: Preoperative stabilisation in congenital diaphragmatic hernia. Arch Dis Child 1990;65(10 spec no) :1043. 261. Sharland GK, Lockhart SM, Heward AJ, et al: Prognosis in fetal diaphragmatic hernia. Am J Obstet Gynecol 1992;166(1 pt 1):9. 262. Shaw KS, Filiatrault D, Yazbeck S, et al: Improved survival for congenital diaphragmatic hernia, based on prenatal ultrasound diagnosis and referral to a combined obstetricpediatric surgical center. J Pediatr Surg 1994;29:1268. 263. Shehata SM, Mooi WJ, Okazaki T, et al: Enhanced expression of vascular endothelial growth factor in lungs of newborn infants with congenital diaphragmatic hernia and pulmonary hypertension. Thorax 1999;54:427. 264. Shehata SM. Sharma HS. van der Staak FH. et al: Remodeling of pulmonary arteries in human congenital diaphragmatic hernia with or without extracorporeal membrane oxygenation. J Pediatr Surg 2000;35:208. 265. Sigalet DL, Tierney A, Adolph V, et al: Timing of repair of congenital diaphragmatic hernia requiring extracorporeal membrane oxygenation support. J ~ e d i a t rsurg-1995; 30:1183. -

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266. Simpson JS, Gossage JD: Use of abdominal wall muscle flap in repair of large congenital diaphragmatic hernia. J Pediatr Surg 1971;6:42. 267. Skari H, Bjornland K, Frenckner B, et al: Congenital diaphragmatic hernia in Scandinavia from 1995 to 1998: Predictors of mortality.J Pediatr Surg 2002;37:1269. 268. Skari H, Bjornland K, Haugen G, et al: Congenital diaphragmatic hernia: A meta-analysis of mortality factors. J Pediatr Surg 2000;35:1187. 269. Skousgaard SG: Severe bronchial hyperreactivity as a sequel to congenital diaphragmatic hernia. Paediatr Anaesth 1998; 8:503. 270. Smith GN, Kingdom JC, Penning DH, et al: Antenatal corticosteroids: Is more better? Lancet 2000;355:251. 271. Solari V, Piotrowska AP, Puri P: Expression of heme oxygenase-1 and endothelial nitric oxide synthase in the lung of newborns with congenital diaphragmatic hernia and persistent pulmonary hypertension. J Pediatr Surg 2003;38:808. 272. Solari V, Puri P: Glucocorticoid receptor gene expression in the hypoplastic lung of newborns with congenital diaphragmatic hernia. J Pediatr Surg 2002;37:715. 273. Springer SC, Fleming D, Hulsey TC: A statistical model to predict nonsurvival in congenital diaphragmatic hernia. J Perinatol 2002;22:263. 274. Sreenan C, Etches P, Osiovich H: The western Canadian experience with congenital diaphragmatic hernia: Perinatal factors predictive of extracorporeal membrane oxygenation and death. Pediatr Surg Int 2001;17:196. 275. Stege G, Fenton A, Jaffray B: Nihilism in the 1990s: The true mortality of congenital diaphragmatic hernia. Pediatrics 2003;112:532. 276. Stevens TP, Chess PR, McConnochie KM, et al: Survival in early and late-term infants with congenital diaphragmatic hernia treated with extracorporeal membrane oxygenation. Pediatrics 2002;110:590. 277. Stevens DC, Schreiner RL, Bull MJ, et al: An analysis of tolazoline therapy in the critically-ill neonate. J Pediatr Surg 1980;15:964. 278. Stolar C, Dillon P, Reyes C: Selective use of extracorporeal membrane oxygenation in the management of congenital diaphragmatic hernia. J Pediatr Surg 1988;23:207. 279. Stolar CJ, Crisafi MA, Disco11YT: Neurocognitive outcome for infants treated with extracorporeal membrane oxygenation: Are infants with congenital diaphragmatic hernia different? J Pediatr Surg 1995;30:366. 280. Stolar CJ, Dillon PW, Stalcup SA: Extracorporeal membrane oxygenation and congenital diaphragmatic hernia: Modification of the pulmonary vasoactive profile. J Pediatr Surg 1985;20:681. 281. Stolar CJ, Levy JP, Dillon PW, et al: Anatomic and functional abnormalities of the esophagus in infants surviving congenital diaphragmatic hernia. Am J Surg 1990; 159:204. 282. Suda K, Bigras JL, Bohn D, et al: Echocardiographic predictors of outcome in newborns with congenital diaphragmatic hernia. Pediatrics 2000;105:1106. 283. Suen HC, Losty P, Donahoe PK, et al: Combined antenatal thyrotropin-releasing hormone and low-dose glucocorticoid therapy improves the pulmonary biochemical immaturity in congenital diaphragmatic hernia. J Pediatr Surg 1994;29:359. 284. Sweed Y, Puri P: Congenital diaphragmatic hernia: Influence of associated malformations on survival. Arch Dis Child 1993;69(1spec no):68. 285. Swietlinski J, Swist-Szulik K, Maruniak-Chudek I, et al: Spondylothoracic dysostosis associated with diaphragmatic hernia and camptodactyly. Genet Couns 2002; 13:309.

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286. Taira Y, Yamataka T, Miyazaki E, et al: Comparison of the pulmonary vasculature in newborn and stillborns with congenital diaphragmatic hernia. Pediatr Surg Int 1998;14:30. 287. Thebaud B, Azancot A, de Lagausie P, et al: Congenital diaphragmatic hernia: Antenatal prognostic factors. Does cardiac ventricular disproportion in utero predict outcome and pulmonary hypoplasia? Intensive Care Med 1997;23:10062. 288. Thibeault DW, Olsen SL, Truog WE, Hubbell MM: PreECMO predictors of nonsurvival in congenital diaphragmatic hernia. J Perinatol 2002;22:682. 289. Thorpe-Beeston JG, Gosden CM, Nicolaides KH: Prenatal diagnosis of congenital diaphragmatic hernia: Associated malformations and chromosomal defects. Fetal Ther 1989;4:21. 290. Thurlbeck WM: Postnatal human lung growth. Thorax 1982;37:564. 291. Touloukian RJ, Markowitz RI:A preoperative x-ray scoring system for risk assessment of newborns with congenital diaphragmatic hernia. J Pediatr Surg 1984;19:252. 292. Tracy TFJr, Bailey PV, Sadiq F, et al: Predictive capabilities of preoperative and postoperative pulmonary function tests in delayed repair of congenital diaphragmatic hernia. J Pediatr Surg 1994;29:265. 293. Turner GR, Levin DL: Prostaglandin synthesis inhibition in persistent pulmonary hypertension of the newborn. Clin Perinatol 1984;11:581. 294. Unger S, Copland I, Tibboel D, et al: Down-regulation of sonic hedgehog expression in pulmonary hypoplasia is associated with congenital diaphragmatic hernia. Am J Path01 2003;162:547. 295. Vacanti JP, Crone RK, Murphy JD, et al: The pulmonary hemodynamic response to perioperative anesthesia in the treatment of high-risk infants with congenital diaphragmatic hernia. J Pediatr Surg 1984;19:672. 296. van Dooren ME, Brooks AS, Tibboel D, et al: Association of congenital diaphragmatic hernia with limb-reduction defects. Birth Defects Res A Clin Mol Teratol2003;67:578. 297. Van Meurs KP, Rhine WD, Benitz WE, et al: Lobar lung transplantation as a treatment for congenital diaphragmatic hernia. J Pediatr Surg 1994;29:1557. 298. Vanamo K, Peltonen J, Rintala R, et al: Chest wall and spinal deformities in adults with congenital diaphragmatic defects. J Pediatr Surg 1996;31:851. 299. Vanamo K, Rintala RJ, Lindahl H, et al: Long-term gastrointestinal morbidity in patients with congenital diaphragmatic defects. J Pediatr Surg 1996;31:551. 300. Vanamo K, Rintala R, Sovijarvi A, et al: Long-term pulmonary sequelae in survivors of congenital diaphragmatic defects. J Pediatr Surg 1996;31:1096. 301. Vazquez WD, Cheu HW: Hemorrhagic complications and repair of congenital diaphragmatic hernias: Does timing of the repair make a difference? Data from the Extracorporeal Life Support Organization. J Pediatr Surg 1994;29:1002. 302. von Staak FH, de Haan AF, Geven WB, et al: Improving survival for patients with high-risk congenital diaphragmatic hernia by using extracorporeal membrane oxygenation. J Pediatr Surg 1995;30:1463. 303. Walker GM, Kasem KF, O'Toole SJ, et al: Early perfluorodecalin lung distension in infant? with congenital diaphragmatic hernia. J Pediatr Surg 2003;38:17. 304. Wallace CA, Roden JS: Reverse, innervated latissimus dorsi flap reconstruction of congenital diaphragmatic absence. Plast Reconstr Surg 1995;96:761. 305. Waller DK, Tita AT, Werler MM, et al: Association between prepregnancy maternal body mass index and the risk of having an infant with a congenital diaphragmatic hernia. Birth Defects Res A Clin Mol Teratol2003;67:73.

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306. Walsh DS, Hubbard AM, Olutoye 0 0 , et al: Assessment of fetal lung volumes and liver herniation with magnetic resonance imaging in congenital diaphragmatic hernia. Am J Obstet Gynecol 2000;183:1067. 307. Warkany J, Roth CB: Malformations induced in rats by maternal vitamin A deficiency. J Nutr 1948;35:1. 308. Weber TR, Kountzman B, Dillon PA, et al: Improved survival in congenital diaphragmatic hernia with evolving therapeutic strategies. Arch Surg 1998;133:498. 309. Weibel ER, Gomez DM: A principle for counting tissue structures on random sections.J Appl Physiol 1962;17:343. 310. Weinberg J: Diaphragmatic hernia in infants: Surgical treatment with use of renal fascia. Surgery 1938;3(4):78. 311. Wells LJ: Development of the human diaphragm and pleural sacs. Contr Embryo1 Carnegie Inst 1954;35:107. 312. Wenstrom KD, Weiner CP, Hanson JW, et al: A five year statewide experience with congenital diaphragmatic hernia. Am J Obstet Gynecol 1991;165:838. 313. West KW, Bengston K, Rescorla FJ, et al: Delayed surgical repair and ECMO improves survival in congenital diaphragmatic hernia. Ann Surg 1992;216:454. 314. WigglesworthJS, Desai R, Guerrini P: Fetal lung hypoplasia: Biochemical and structural variations and their possible significance. Arch Dis Child 1981;56:606. 315. Wilson JM, Difiore JW, Peters (2%Experimental fetal tracheal ligation prevents the pulmonary hypoplasia associated with fetal nephrectomy: Possible application for congenital diaphragmatic hernia. J Pediatr Surg 1993;28:1433. 316. Wilson JM, Bower LK, Lund DP: Evolution of the technique of congenital diaphragmatic hernia repair on ECMO. J Pediatr Surg 1994;29:1109.

317. Wilson JM, Fauza DO, Lund DP, et al: Antenatal diagnosis of isolated congenital diaphragmatic hernia is not an indicator of outcome. J Pediatr Surg 1994;29:815. 318. Wilson JM, Lund DP, Lillehei CW, et al: Congenital diaphragmatic hernia-a tale of two cities: Boston experience. J Pediatr Surg 1997;32:401. 319. Wilson JM, Lund DP, Lillehei CW, et al: Congenital diaphragmatic hernia: Predictors of severity in the ECMO era. J Pediatr Surg 1991;26:1028. 320. Wilson JM, Lund DP, Lillehei CW, et al: Delayed repair and preoperative ECMO does not improve survival in high-risk congenital diaphragmatic hernia. J Pediatr Surg 1992;27:368. 321. Witters I, Legius E, Moerman P, et al: Associated malformations and chromosomal anomalies in 42 cases of prenatally diagnosed diaphragmatic hernia. Am J Med Genet 2001; 103:278. 322. Wohl ME, Griscom NT, Streider DJ, et al: The lung following repair of congenital diaphragmatic hernia. J Pediatr 1977;90:405. 323. Wung JT, Sahni R, Moffitt ST, et al: Congenital diaphragmatic hernia: Survival treated with very delayed surgery, spontaneous respiration, and no chest tube. J Pediatr Surg 1995;30:406. 324. Yamaguchi M, Kuwano H, Hashizume M, et al: Thoracoscopic treatment of Bochdalek hernia in the adult: Report of a case. Ann Thorac Cardiovasc Surg 2002; 8:106. 325. Yamataka T, Puri P: Pulmonary artery structural changes in pulmonary hypertension complicating congenital diaphragmatic hernia. J Pediatr Surg 1997;32:387.

Cysts of the Lungs and Mediastinurn N. Scott Adzick and Diana L. Farmer

Familiarity with normal variations and potential pathologic abnormalities in the lung and mediastinum is necessary because questions frequently arise on evaluation of chest radiographs. The possibility of infection, respiratory difficulty, and airway obstruction from space-occupying lesions makes mandatory the expeditious evaluation and treatment of children with a mediastinal or pulmonary cystic mass. The prognosis of mediastinal and lung cysts in most children is good.

thymopharyngeal duct results in congenital cysts of the thymus.118 Prenatal lung development is described in Chapter 60, "Congenital Diaphragmatic Hernia and Eventration." A mixed lung lesion consisting of a combination of bronchogenic cyst, bronchopulmonary sequestration, and congenital cystic adenomatoid malformation suggests a common embryologic link for these malformations, but the precise embryologic causes are unknown.81

EMBRYOLOGY

CYSTIC LUNG LESIONS

Mediastinal and lung cysts are developmental in origin. Embryologic development pertinent to mediastinal masses is mostly related to the foregut and the thymus. The foregut is first recognizable as an epithelial-lined tube late in the third postconceptual week, by which time the respiratory groove (tracheal bud) is visible. Septation of the esophagus and the trachea occurs over the ensuing 2 weeks by a process of cephalocaudal growth of both structures, lateral infolding of the foregut, and caudocranial septation of the trachea and esophagus. During this interval, there is proliferation of foregut epithelium that almost completely obliterates the esophageal lumen before subsequent tubularization. Differentiation of both esophageal and tracheal epithelium is recognizable in the fourth week. The process is largely completed by day 32 to 34. It is presumed that incomplete tubularization after the epithelial proliferative phase results in foregut duplication cysts.l17 The thymus develops as paired primordia from the ventral third pharyngeal pouch. During the seventh postconceptual week, the primordia elongate caudad and ventromedially to their normal position anterior to the aortic arch. At that time, the two thymic lobes attach to each other by connective tissue but not parenchyma. Before complete descent, thymic primordia contain a thymopharyngeal duct, which is obliterated after complete descent. Incomplete descent may result in solid or cystic masses in the neck. Lack of obliteration of the

Diagnosis and Treatment The true incidence of cystic lung lesions is unknown because there are no population-based studies in the literature. Congenital cystic adenomatoid malformation was first described as a distinct pathologic entity by Chin and Tang in 1949." Before then, congenital cystic adenomatoid malformation was grouped under the general diagnosis of congenital cystic lung disease, along with bronche pulmonary sequestration, congenital lobar emphysema, and bronchogenic cyst. Prenatal diagnosis provides insight into the in utero evolution of fetal lung lesions such as congenital cystic adenomatoid malformation (CCAM), bronchopulmonary sequestration (BPS), and congenital lobar emphysema. Serial sonographic study of fetuses with lung lesions has helped define the natural history of these lesions, determine the pathophysiologic features that affect clinical outcome, and formulate management based on prognosis.1,34,86,112,128,131 A series of more than 175 prenatally diagnosed cases from the Children's Hospital of Philadelphia and the University o f TCalifornia, San Francisco, found that the overall prognosis depends on the size of the lung mass and the secondary physiologic derangement: a large mass causes mediastinal shift, hypoplasia of normal lung tissue, polyhydramnios, and cardiovascular compromise leading to fetal hydrops and death (Fig. 61-1).2

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A

B

A, Transverse ultrasonographic scan of the fetal thorax at 22 weeks' gestation. A large multicystic mass in the left hemithorax (open arrows) displaces the mediastinum to the right. H, heart. B, Sagittal ultrasonographic scan of the fetal thorax and abdomen shows an echogenic mass (open arrows) of the left hemithorax that flattens the left hemidiaphragm (D). A, aorta; Sp, spine. This lesion grew and resulted in fetal hydrops. Fetal surgical resection of the affected lobe was performed successfully at 23 weeks' gestation, delivery occurred at 35 weeks' gestation, and the infant survived.

Huge fetal lung lesions have reproducible pathophysiologic effects on the developing fetus. Esophageal comwression by the thoracic mass causes interference with fetal swallowing of amniotic fluid and results in polyhydramnios. Polyhydramnios is a common obstetric indication for ultrasonography, so a prenatal diagnostic marker exists for many large fetal lung tumors. Support for this concept comes from the absence of fluid in the fetal stomach in some of these cases, and the alleviation of polyhydramnios after effective fetal treatment.* The hydrops is secondary to vena caval obstruction and cardiac compression from large tumors causing an extreme mediastinal shift. Like CCAMs, a fetal BPS can also cause fetal hydrops, either from the mass effect or from a tension hydrothorax that is the result of fluid or lymph secretion from the BPS.2Hydrops is a harbinger of fetal or neonatal demise and manifests as fetal ascites, pleural and pericardial effusions, and skin and scalp edema. Although there is some association of both polyhydramnios and hydrops with fetal lung lesions, experience indicates that either can occur indewendentlv of the other. Smaller thoracic lesions can cause respiratory distress in the newborn period, and the smallest masses may be asymptomatic until later in childhood when infection, pneGmothorax, or malignant degeneration may occur. Large fetal lung tumors may regress in size on serial prenatal sonography illustrating that improvement can occur during fetal life.70,80,113In particular, many noncystic BPSs dramatically decrease in size before birth and may not need treatment after birth.2 However, fetal lung lesions that seem to disappear on prenatal ultrasound and are not seen on neonatal chest radiograph still require evaluation by chest CT scan, which will frequently detect a 1esi0n.l~~

Recently, fetal CCAM volume has been determined by sonographic measurement using the formula for a prolate ellipse (length x height x width x 0.52). A CCAM volume ratio (CVR) is obtained by dividing the CCAM volume by head circumference to correct for fetal size. A CVR greater than 1.6 is predictive of increased risk of hydrops, with 80% of these CCAM fetuses developing hydrops. The CVR may be useful in selecting fetuses at risk for hydrops and thus needing close ultrasound observation and possible fetal intervention." Serial CVR measurements have shown that CCAM growth usually reaches a plateau by 28 weeks' gestation. For fetuses at less than 28 weeks' gestation, the recommendation is twice-weekly ultrasound surveillance if the CYR is greater than 1.6 and initial weekly surveillance for fetuses with smaller CVR values. The finding that fetuses with hydrops are at very high risk for fetal or neonatal demise led to the performance of either fetal surgical resection of the massively enlarged pulmonary lobe (fetal lobectomy) for cystic/solid lesions or thoracoamniotic shunting for lesions with a dominant ~yst.2,~,~2 Lesions with associated hydrops that are diagnosed late in gestation may benefit from resection using an ex utero intrapartum therapy approach.53The fetus with a lung mass but without hydrops has an excellent chance for survival with maternal transport, planned delivery, and neonatal evaluation and surgery. Neonates with respiratory compromise due to a cystic lung lesion require prompt surgical resection, usually by lobectomy. In the most severe cases, ventilatory support with high-frequency ventilation or extracorporeal membrane oxygenation may be required. In asymptomatic neonates with a cystic lung lesion, we believe that elective resection is warranted because of the risks of infection

CHAPTER

and occult malignant tran~formation.7~ Malignancies consist mainly of pulmonary blastoma and rhabdomyosarcoma in infants and young children and bronchioloalveolar carcinoma in older children and adults.l5,31,89,106,132After confirmation of CCAM location by postnatal chest computed tomography (CT) with intravenous contrast, we recommend elective resection at 1 month of age or older. An experienced pediatric surgeon can safely perform a thoracotomy and lobectomy in infants with minimal risk of morbidity, and thoracoscopic resection has been perresection also maximizes compensatory f ~ r m e dEarly .~ lung growth; long-term follow-up has shown normal pulmonary function.66.71In contrast, we have usually followed patients with a tiny, asymptomatic, noncystic extralobar bronchopulmonary sequestration if we are confident of the diagnosis based on postnatal imaging studies. We do not favor the approach of catheterization and embolization for the treatment of larger bronchopulmonary sequestration lesions but instead opt for surgical resection.

Congenital Cystic Adenomatoid Malformation CCAM is characterized by an "adenomatoid" increase of terminal respiratory bronchioles that form cysts of various sizes. Grossly, a CCAM is a discrete, intrapulmonaiy mass that contains cysts ranging in diameter from less than 1.0 mm to over 10.0 cm. Histologically, CCAM is distinguished from other lesions and normal lung by (1) polypoid projections of the mucosa, (2) an increase in smooth muscle and elastic tissue within cyst walls, (3) an absence of cartilage (except that found i n "entrapped" normal bronchi), (4) the presence of mucus-secreting cells, and (5) the absence of inflammation.l22 Although the tissue within these malformations does not function in normal gas exchange, there are connections with the tracheobronchial tree, as evidenced by air trapping that can develop during postnatal resuscitative efforts. Cha has identified two histologic patterns of fetal CCAM: pseudoglandular and canalicular.26 Stocker defined three types of CCAM (types I to 111) based primarily on but this categorization has little clinical relcyst ~ize,122J2~ evance. Prenatally diagnosed CCAMs are divided into two categories based on gross anatomy and ultrasound findings.' Macrocystic lesions contain single or multiple cysts that are 5.0 mm in diameter or larger on prenatal ultrasound, whereas microcystic lesions appear as a solid echogenic mass on sonography. The overall prognosis for prenatally diagnosed lesions depends primarily on the size of the CCAM rather than on the lesion type, and the underlying growth characteristics are likely to be important. Resected large fetal CCAM specimens demonstrate increased cell proliferation and markedly decreased apoptosis compared with gestational-age-matched normal fetal lung tissue.z4 Examination of factors that enhance cell proliferation or down-regulate apoptosis in CCAM may provide further insights into the pathogenesis of this tumor and may suggest new therapeutic approaches. Fetal CCAMs that grew rapidly, progressed to hydrops, and required in utero resection showed increased platelet-derived growth factor (PDGF) gene expression and PDGF protein production

61

Cysts of the Lungs and Mediastinurn

957

compared with either normal fetal lung or term CCAM specimens.76 CCAM usually arises from one lobe of the lung, with the lower lobes being the most common site. Bilateral lung involvement is rare. CCAM lesions have an equal leftand right-sided incidence. For those children who are not diagnosed as a fetus or newborn, the usual clinical presentation is with infection in the CCAM area, probably due to failure of clearance of environmental bacterial pathogens. Other presentations include pneumothorax, reactive airway disease, and failure to thrive. There is no gender predominance. Associated anomalies in our experience are very uncommon.

Bronchopulmonary Sequestration A BPS is a mass of nonfunctioning lung tissue that is supplied by an anomalous systemic artery and does not have a bronchial connection to the native tracheobronchial tree. There are two forms of sequestration: extralobar and intralobar. Extralobar sequestrations are completely separate from the normal lung and are surrounded by a separate pleural covering, whereas intralobar sequestrations are incorporated into the normal surrounding lung. An extralobar sequestration may reside in the chest, within the diaphragm, or in a subdiaphragmatic location. Intralobar and extralobar sequestrations can occur simultaneously. An entire lung can be sequestered, and bilateral sequestrations have been reported but are very rare.8gBecause of the foregut derivation, communication between the esophagus or the stomach and a BPS may occur and, if suspected, should be delineated preoperatively by upper gastrointestinal series.121 Arterial blood supply to the BPS can arise from below or above the diaphragm, and venous drainage can be to either the pulmonary or the systemic venous circulation. The anomalous blood supply can result in high-output cardiac failure because of substantial arteriovenous shunting through the BPSlo4or bleeding with massive hemoptysis or hemothorax.log On prenatal ultrasonography, a BPS appears as a welldefined echodense, homogeneous mass. Detection by color flow Doppler of a systemic artery or arteries from the aorta to the fetal lung lesion is a pathognomonic feature of fetal BPS (Fig. 61-2).55 However, if this Doppler finding is not detected, then an echodense microcystic CCAM and a BPS can have an identical prenatal sonographic appearance. Ultrafast fetal magnetic resonance imaging (MRI) may help differentiate CCAM from BPS.Iw' Furthermore, there are prenatally diagnosed lung masses that display clinicopathologic features of both CCAM and sequestrationhybrid lesions-which suggests a shared embryologic basis for some of these lung masses.25,29,56The ability to differentiate intralobar and extralobar sequestration before birth is limited unless an extralobar sequestration is highlighted by a pleural effusion or is located in the abdomen (usually close to the left adrenal gland). There are no diagnostic hallmarks for the specific prenatal diagnosis of an intralobar sequestration. Extralobar BPS has a predominance in males (3:1), is more common on the left side, and can be associated

958

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VI

THORAX

By Doppler studies, a systemic artery (curved arrow) from the descending aorta (Ao) supplies the mass (*), consistent with the prenatal diagnosis of pulmonary sequestration.

with conditions such as congenital diaphragmatic hernia, vertebral deformities, and congenital heart disease. Approximately 5% of neonates with a congenital diaphragmatic hernia will have an extralobar BPS, which is usually an incidental intraoperative finding. An isolated, tiny noncystic extralobar BPS rarely requires treatment. An intralobar BPS is most commonly seen in the medial basal or posterior basal segments of the lower lobes, left side more frequent than the right side. Upper lobe involvement is present in only 10% to 15% of cases. For those cases that are not prenatally diagnosed, the usual postnatal presentation of an intralobar BPS is recurrent pneumonia and even abscess formation within the BPS; thus resection (usually by lobectomy) is warranted. It is mandatory to identify and ligate the feeding systemic arterial vessel(s), which usually is found within the inferior pulmonary ligament.

Congenital Lobar Emphysema Several causes for congenital lobar emphysema have been described,79but the fundamental mechanism is that the affected bronchus allows passage of air on inspiration but only limited expulsion of air on expiration leading to lobar overexpansion. Air trapping in the emphysematous lobe may be due to (1) dysplastic bronchial cartilages creating a ball-valve effect or a complete bronchial atre(2) endobronchial obstruction from inspissated sia35,133; mucus130or extensive mucosal proliferation and infolding54; (3) extrinsic compression of the bronchi from aberrant cardiopulmonary vasculature or enlarged cardiac chambers44;and (4) diffuse bronchial abnormalities that may or may not be related to infection.74

Careful preoperative bronchoscopy may help delineate an intrinsic obstructive lesion.35The most common site of involvement for congenital lobar emphysema is the left upper lobe (40% to 50%), followed by the right middle lobe (30% to 40%), right upper lobe (20%), lower lobes (I%),and multiple sites for the remainder. Barotrauma associated with the treatment of bronchopulmonary dysplasia in preterm infants can result in acquired ernphyscma in which multiple areas of hyperinflation may be present." Because of endotracheal tube positioning, right lower lobe involvement is common in these cases, which helps to differentiate acquired from congenital disease. Polyalveolosis or the polyalveolar lobe first described by Hislop and Reid has been found in some . ~ ~ total alveolar cases of congenital lobar e m p h y ~ e r n aThe number is increased severalfold in this condition, but the airways and arteries are normal for age in number, size, and structure. The polyalveolar lobe becomes overinflated and hyperlucent on chest radiography because of impaired air exchange in the affected lobe. Congenital lobar emphysema can be distinguished prenatally from other cystic lung lesions on ultrasonography by increased echogenicity and reflectivity compared with a microcystic C W and the absence of systemic arterial blood supply compared with a BPS.s,92Progressive enlargement of these lesions prior to 28 weeks' gestation may be due to fetal lung fluid trapping in the lobe analogous to the air trapping seen postnatally. Late in gestation, lobar emphysema may regress in the size and the character of the mass, rendering it indistinguishable from adjacent normal fetal lungg2Postnatal assessment is important because of the risk of postnatal air trapping in the emphysematous lobe. At the time of birth, the affected lobe may be radiopaque on chest radiography because of delayed clearance of fetal lung fluid. Prenatally diagnosed mainstem bronchial atresia results in massive lung enlargement, hydrops, and fetal death; ultrafast fetal M I R I demonstrates that the entire lung is involved and that there are dilated bronchi distal to the mainstem atresia.65 Congenital lobar emphysema is diagnosed at birth in about 25% of cases and by age 1 month in about 50%. The diagnosis is sporadic after 6 months of age. The earlier the onset of symptoms, the more likely the progression of lobar emphysema and the need for resection. Nevertheless, some infants have very mild symptoms that do not progress, and the emphysematous lobe remains stable and does not encroach on adjacent lung, so resection is not required in these cases.93 Besides chest radiography and CT (Fig. 61-3), a ventilation-perfusion scan can demonstrate delayed uptake and washout of the xenon radioisotope from the affected lobe and little blood flow through it. If the presentation is respiratory distress and pulmonary lobar hyperinflation, then the mainstay of management is resection of the emphysematous lobe. Positive-pressure ventilation may result in abrupt exaggerated air trapping in the lobe with sudden cardiopulmonary decompensation, so it is important for the surgeon to be present during anesthetic induction in the event that urgent thoracotomy is needed. At operation, the affected lobe will characteristically "pop out" through the thoracotomy wound. High-frequency ventilation,45 selective bronchial intubation+? and endoscopic decompression

CHAPTER

61

Cysts o f the Lungs and Mediastinum

959

which a retrospective review compared the 60-year experience before and after 1970. The best estimate of prevalence of mediastinal masses is provided by a retrospective pathology study of mediastinal masses from Victoria in Australia, which had an estimated pediatric population of 900,000. In that series, 50% of mediastinal masses were lymphoma followed by 20% of neurogenic origin, 8% foregut duplication cysts, and 6% teratomas.l16This prevalence is similar to the recent U.S. series (see Table 61-1).

Anatomic Considerations A clear understanding of the anatomic subdivisions of the mediastinum is useful in differential diagnosis and selection of diagnostic studies. The mediastinum is the central thoracic space bounded laterally by the right and left parietal pleura, anteriorly by the sternum, posteriorly by Chest CT scan from a neonate with congenital lobar the vertebral bodies to include the transverse processes, emphysema involving the right middle lobe. There are dilated superiorly by the thoracic inlet, and inferiorly by the airspaces in the right middle lobe with compressive atelectasis of the diaphragm. Although several classificationsfor subdividing right lower lobe. The mediastinum is shifted to the left, and a portion the mediastinum exist, the classic anatomic description is of the emphysematous lobe herniates across the midline posterior to used here.82 The value of any system of anatomic subdivithe heart (arrow). sion is to provide insight into the contents of that region, which simplifies differential diagnosis. The superior mediastinum is delimited by the thoracic inlet superiorly and the plane between the sterof the emphysematouslobeg6may be useful adjuncts in the nomanubrial junction and the inferior limit of the fourth preoperative management of patients with respiratory disthoracic vertebra inferiorly. The lateral boundaries are the tress. Long-term pulmonary growth and function after lobectomy for congenital lobar emphysema is e ~ c e l l e n t . ~ ~parietal pleurae. Normal anatomic contents of this s u b division are the thymus, .other lymphatic structures, and mesenchymal derivatives, including vasculature, diffusely found throughout the entire mediastinum. CYSTIC MEDIASTINAL LESIONS The anterior mediastinum is the zone posterior to the sternum, anterior to the pericardium, superior to the Clinical Features diaphragm, and inferior to the plane through the sternomanubrial junction. This space normally contains The clinical manifestations of mediastinal lesions are the mesenchymal derivatives, fat, and connective tissue. result of mass effects and are influenced by the location The middle mediastinum is delimited by the periof the lesion within the chest. Many are asymptomatic, cardium and origins of the great vessels. Therefore, its although the most important symptom of anterior and normal contents are the pericardium, heart, great vessels, middle mediastinal masses is respiratory distress, particulymphatics, and mesenchymal derivatives. larly in infants when noisy, stridorous breathing or cyanosis The posterior mediastinum is outlined by the periwhile feeding is observed.67 In older children, cough, chest pain, dyspnea, orthopnea, or, rarely, hemoptysis 0ccurs.2~ cardium and great vessels anteriorly, the vertebral column posteriorly, and, as in each of the prior subdivisions, the Respiratory distress may be life threatening in all age parietal pleurae laterally. Its contents include the trachea gro~ps.9,*0,67,98,~~ Rapid onset of respiratory distress or and main bronchi, esophagus, widely distributed lymphatic symptoms of superior vena caval obstruction suggest lymstructures, sympathetic nervous ganglia, descending aorta, Although rare, infected teratomas have been azygous venous system, and thoracic duct. reported to rupture into the bronchus, pleura, pulmonary Large masses or diffuse processes may transgress multiartery, and pericardium.20,94JlO Posterior mediastinal massks can be quite large and yet asymptomatic, often disple subdivisions. An additional caveat to aid in differential covered incidentally on a chest radiograph taken for other diagnosis is age. With the exception of posterior mediastinal neuroblastoma, mediastinal masses in young children indications. Less frequently, pain or symptoms of spinal are most likely to be developmental in origin. Mediastinal cord compression lead to r e ~ o g n i t i o n . ~ ~ J l ~ Reports from individual institutions regarding masses that are not cystic will also be mentioned. mediastinal masses may be biased by selection. If more recent series are compared with those published before 1967 (Table 61-l), an increase in malignancy, Diagnosis and Treatment particularly of lymphomas and neuroblastoma, is eviRecognition of cystic mediastinal masses may first occur on dent.l9,48,4g,51,67,100,110~114,115Such is the case in a single large The fetus who develops progressive fetal ultra~ound.6g~8"8~ institutional series from Walter Reed Army Hospital28 in

960

PART

VI

THORAX

Cyst/Neoplasm Neurogenic Tumors Neuroblastoma/ganglioneuroblastorna Ganglioneurorna Neurofibrorna Neurilemoma/schwannoma Paragangliorna (pheochromocytoma) Primitive neuroectodermal turnor/neurosarcoma

King et at.,

Simpson and Campbell,

Saenz et al.,

Cohen et al.,

Grosfeld,

1982e7

1991116

1993-

199128

199447

Total

%

16 9 4 1

32 14 3 3 2 2

13 8

50 14 2 5

227

33

105

62

201

677

20 17 4 6 1

1

Lymphomas Hodgkin's d~sease Non-Hodgkin's lymphoma Germ Cell Tumors Teratodermoid Benign Malignant Seminorna/ernbryonal carcinoma Mesenchymal Tumors Lymphangiorna/cystic hygroma Hernangioma Fibrorna/fibrosarcoma Liporna/Iiposarcoma/sarcoma Rhabdomyosarcoma Cysts Pericardial Bronchogenic Enteric Neurenteric/misc. cyst Thymic Lesions Thymic cyst Hyperplasia Thymoma Thymic carcinoma Miscellaneous Granulomas, abscess, fibrosis Total

188

121

nonimmune hydrops, cardiac failure, or mediastinal shift with compression of developing lung tissue may benefit from in utero decompression or resection of a cystic mediastinal lesion.84 For cystic mediastinal masses, the initial postnatal diagnostic study should be anteroposterior and lateral chest radiographs. A presumptive diagnosis can often be made based on the location of the lesion on the plain radiograph. CT has now largely replaced endoscopy and esophagograms as part of the preoperative evaluation. Several studies comparing contrast medium-enhanced CT to MRI suggest that CT is superior, given its ability to define calcification within a mass.13,5g MRI is useful if spinal involvement is in question or if vascular lesions are being considered. An esophagogram reveals the characteristic extrinsic mass effect of a foregut duplication cyst, but CT is probably the most useful study for this diagnosis. Echocardiography has value in defining the rare

intrapericardial teratoma in the neonate with an enlarged pericardial silhouette47 and can detect congenital heart disease if present. The goal of the preoperative diagnostic workup is to help define the optimal surgical approach. When the nature of a mediastinal mass is uncertain or if the potential of malignancy exists, a preoperative serum sample should be drawn for determination of alpha fetoprotein or P-human chorionic gonadotropin levels, particularly in the case of anterior mediastinal tumors. Similarly, urinary catecholamine catabolites should be obtained in suspect posterior mediastinal masses. Surgical resection at the time of diagnosis is the preferred treatment of benign mediastinal cysts and tumors. When indicated, thoracoscopic resection or biopsy can be performed with adequate results and minimal morLarge anterior mediastinal masses are best bidity.32~64,~~ approached through median sternotomy, and middle

CHAPTER

61

Cysts of t h e Lungs a n d Mediastinum

961

and posterior mediastinal masses are best approached through posterolateral thoracotomy.

a cosmetically unacceptable appearance. The cysts are lined with ciliated, respiratory epithelium; contain lymphocytes as well as normal thymic tissue; and often show inflammatory and granulomatous changes. Thymolipoma is a benign tumor, possibly hamartoma, of mixed fatty and ANTERIOR AND SUPERIOR MEDlASTlNUM thymic tissue. Resection results in diagnosis and cure. Thymomas are rare in children, accounting for less than The anterior and superior mediastinum contains the 1% of mediastinal tumors, with only 20 well-documented thymus, great vessels, and a network of lymphatic struccases of malignant thymoma in children in the literatures, as well as connective and adipose tissue. Lymphomas ture.61,72,103,1*6These tumors originate in the thymic are the most common tumors, followed by teratomas, epithelium and are usually aggressive.21 Treatment is germ cell tumors, cystic hygromas, and thymic lesions multimodal, but outcome is poor. (Fig. 61-4). Anterior mediastinal masses in infants are Although the thymus is located in the anterior and usually either a teratoma or a thymic enlargement. superior mediastinum, ectopic thymic tissue can be found Foremost in evaluation of masses of the anterior in the neck and posterior mediastinum as we11.7~12Jlg mediastinum is assessment of the risk of malignancy. Benign thymic hyperplasia is a physiologic enlargement of Malignant disease such as lymphoma generally presents the thymus gland no longer believed to cause respiratory in the older child, is often associated with systemic symp toms and adenopathy elsewhere, and is frequently embarrassment, although rapid enlargement has led some authors to recommend resecti0n.77,~07If necessary, a associated with symptoms of airway compromise. When short course of prednisone shrinks the normal thymus possible, the diagnosis should be sought from nonmediastigland and helps differentiate it from nonlymphoid medinal sources, such as bone marrow, pleural fluid, or other masses. MRI can also be h e l p f ~ l .Mediastinal ~~,~~ ~ ~ , ~astinal ~ nodal tissues, thus avoiding a general a n e s t h e t i ~ . " If radiation is of historical interest only because it had an a diagnosis is still lacking in the presence of airway comprounacceptably high association with thyroid carcinoma. mise, corticosteroid administration reduces the risk of Exploration is recommended only when malignancy open biopsy yet does not affect diagnostic accuracy. cannot be ruled out, as in benign nodular thymic hyperLymphomas are discussed in Chapter 35. plasia. Nodular thymic hyperplasia is usually asymptomatic and is usually recognized as a superior mediastinal mass on an incidental chest film. CT reveals a solid, asymmetrical, Thymus nonenhancing mass within a thymic lobe. Peripheral blood and bone marrow studies are normal. Operation in these Thymic cysts are seen in the anterior mediastinum and instances reveals a lymphoid mass within one lobe of the the neck (Figs. 61-5 and 61-6). They are usually asymptothymus with histologic compression of adjacent normal matic but can become infected or hemorrhagic or thymus. Analysis of lymphocytes in the mass reveals a produce symptoms owing to mass effects and can create

A

B

A 5-year-old boy presented with a superoanterior mediastinal mass noted to be separate from the pericardial silhouette on an anteroposterior chest film ( A ) . Lateral chest radiograph (B) reveals sternomanubrial prominence and a mass anterior to the trachea. This mass turned out to be a teratoma.

962

PART

VI

THORAX

B Fullness in the left neck led to these CT scans, which delineated a left thymic cyst anterior to neck vessels with extension into anterior mediastinum (A) at and below the level of the carina (B).

normal ratio of T and B lymphocytes. Today, most thymic lesions can be resected using thoracoscopic techniques.

Teratomas, Dermoid Cysts, and Germ Cell Tumors After lymphoma, teratomas are the most common tumors of the anterior mediastinum. They also have been reported .~~ in other subdivisions of the m e d i a s t i n ~ mTeratomas characteristically have both cystic and solid components and are derived from at least two and, most often, all three germ cell layers." Some controversy exists about the origin of teratomas because they may occur near or at the midline from brain to anus. One view is that they

Thymic cyst mobilized from the mediastinum in the same patient as in Figure 61-5 through sternotomy before removal of the cervical extension.

represent a mature form of extragonadal germ cell tumor.32 The other is that they arise from undifferentiated embryonic cells. The World Health Organization classifies are, by definiteratomas as germ cell variant~.~Wermoids tion, composed of ectodermal and mesodermal derivatives only. They are mature, benign masses often encased in a fibrous, thick cyst wall containing various skin appendages including hair or teeth. True teratomas can be some of the largest and most unusual tumors with malignant elements, particularly when diagnosis is delayed. In the young patient, teratomas are usually benign. Only 25% are malignant in all age gr0ups.l2~Because it is not always possible to determine if a tumor is fully mature preoperatively, alpha-fetoprotein and P-human chorionic gonadotropin levels should be obtained in all patients. When malignant elements are present, they are most commonly yolk sac in origin, currently termed endodermal sinus tumors.36 The signs and symptoms of extrapericardial teratomas are that of any compressive, anterior mediastinal mass, such as tachypnea or stridor. Although rupture of teratomas into adjacent structures has been reported, this is a rare e~ent.~*J29 Intrapericardial tumors are more common in neonates and young infants and present as low cardiac ~ u t p u tIntrapericardial .~ teratomas are invariably benign and arise in the sulcus between the origins of the aortic root and the main pulmonary artery. On chest radiograph and CT, the mass is generally asymmetrically placed in the anterior mediastinum, commonly with extension into the right or left hemithorax. Flocculent calcifications are often seen. Anterior mediastinal teratomas are generally best approached through a sternum-splitting incision. Despite their large size, the vascular supply is often scant. Exceptions are those tumors with malignant elements, in which preoperative

CHAPTER

aortography may reveal a posterior mediastinal teratoma with arterial supply from the aorta.60~62

MIDDLE MEDlASTlNUM In the classic anatomic description, the middle mediastinum is circumscribed by the pericardium.82As such, pericardial cysts may be the only true common middle mediastinal cysts. Pericardial cysts are benign, thinwalled, fluid-containing cysts lined with mesothelium. It is postulated that the pericardium forms from a series of disconnected lacunae in the mesenchyme that later coalesce to form the pericardial sac. Occasionally, one of these lacunae persists as a pericardial cyst. They are nearly always asymptomatic and are often discovered on routine chest films or at autopsy. The classic description is that of a cystic mass lying anteriorly in the chest at either cardiophrenic sulcus, although the right side is more common. Historically, thoracotomy was recommended to establish a definitive diagnosis. Currently, CT provides a sufficiently characteristic appearance to allow accurate diagnosis, thus allowing nonintervention unless the cyst is large. If the diagnosis is uncertain, these can be excised or unroofed thoracoscopically as well.

61

Cysts of the Lungs a n d Mediastinurn

963

inflammatory processes in children. Most common of these lesions is the spectrum of benign to malignant neurogenic tumors of the sympathetic nervous system. In the young, the most common tumor is a malignant neuroblastoma, and in the older child, the most common tumors are benign ganglioneuromas; both of these lesions are discussed in Chapter 28.

Foregut Duplication Cysts Foregut duplication cysts are reasonably common in pediatric specialty centers. The nomenclature of these lesions varies considerably. They can be subdivided clinically and pathologically into (1) enteric duplications and cysts (lined by intestinal epithelium), (2) bronchogenic cysts (lined by respiratory epithelium), and (3) neurenteric cysts (associatedwith vertebral anomalies or having a connection with the nervous system). Enterogenous is a confusing historical term and in various reports has included each of the aforementioned categories. The generic term fuvegut duplication cyst is a more accurate embryologic description with subdivision into bronchogenic or enteric cysts determined by the histology of the mucosa lining the cyst wall. In fact, all three endodermal derivatives may be found in the occasional foregut duplication, supporting a common embryologic derivation for foregut duplication cysts.

POSTERIOR MEDlASTlNUM The posterior mediastinum lies behind a plane passing in front of the tracheal bifurcation and extending posteriorly to the paravertebral sulci.82 The posterior mediastinum is the site of a heterogeneous group of cysts, neoplasms, and

~

~

cystS ~ ~

,

,

~

~

Bronchogenic cysts (Fig. 61-7) develop from abnormal budding of the tracheal diverticulum or ventral portion

A, Bronchogenic cyst. Central tracheobronchial compression with respiratory distress was demonstrated in this 15-month-old boy transferred to the intensive care unit in critical condition. He had been treated for a year for symptoms of asthma. B, Lateral view shows remarkable tracheal compression with tracheoesophageal separation confirmed by contrast agent in the esophagus.

~

964

PART

VI

THORAX

of the foregut. These cysts can be found in a variety of locations from paraesophageal to paratracheal, perihilar, or intraparenchymal?l depending on the level at which the abnormal budding occurred in the development of the foregut or tracheobronchial tree. It has been reported that about two thirds of bronchogenic cysts are located within the lung parenchyma, with the remainder in the mediastinum; but this distribution varies between different reports. Rarely, they can be found in remote locations, such as the tongue, neck, back, and even below the diaphragm.l~.40,51,1011127 Histologically, bronchogenic cysts are thin walled, lined with bronchial epithelium, and filled with mucus. They can be single or multiple and are white or pinkish. Cartilage has been reported in the wall of these cysts, and air-fluid levels may be present. The cysts have no predilection for the right or left side. Although they do not usually communicate with the tracheobronchial tree, they may do so from inception or the communication may be acquired from superinfection. Diagnosis in older children often results from identification of an incidental mass on chest radiograph obtained for an unrelated reason. Infants usually present with respiratory symptoms, and the mass may be obscured on plain film by associated atelectasis and infection (Figs. 61-8 and 61-9).37,7"120 In this case, the diagnosis can be delayed, but CT usually confirms the diagnosis. ~ r o n c h d ~ e ncysts i c have also been recognized on antenatal ultrasound5 and on esophagogram for other indications. The differential diagnosis includes foreign body, lobar emphysema, pneumonia, bronchial stenosis, and pneumothorax. Bronchogenic cysts should be excised to avoid the complications of infection, hemorrhage, or sudden death from rapid expansion under tension. A risk of malignant

Microscopically, this bronchogenic cyst wall is lined by ciliated respiratory epithelium and contains bronchial cartilage, characteristic of bronchogenic cysts and evidence that they are central bronchial developmental anomalies (in contrast to cystic adenomatoid malformation, which is a peripheral parenchymal anomaly).

transformation does exist, as malignancy has been reported in two adult patients with bronchogenic cysts and adenocarcinoma has been reported arising from a bronchogenic cyst in an 8-year-old girl.l25 Excision should be accomplished without injury to the bronchial or esophageal wall. Small cysts in the pulmonary hilum may not be visualized until the mediastinal pleura is opened. Cyst resection is usually straightforward, but occasionally limited parenchymal lung resection or lobectomy may be required. In the majority of patients, bronchogenic cysts are amenable to thoracoscopic resection."^^^ An error in recognition may lead to unnecessary resection of emphysematous lung tissue rather than removal of a cyst producing bronchial obstruction. Complete excision is recommended; recurrence 25 years after incomplete resection has been reported.105 Although there are reports of transbronchial drainage, we do not recommend that approach.95

Enteric Duplication Cysts

Urgent thoracotomy in the same patient as in Figure 61-7 showed a large unilocular cyst. It was aspirated of infected mucus to relieve bradycardia and then removed from its attachment to the posterior trachea. The microscopic appearance is shown in Figure 61-9.

Enteric cysts arise from failure of coalescence of vacuoles early in development of the foregut. They are lined by esophageal or gastric epithelium surrounded by smooth muscle. They have been called variously enterogenic or enterogenous cysts, esophageal cysts, enteric cysts, and esophageal duplications. Gastric mucosa is often seen, and intramural adrenal cortical rests have been reported.13qnteric cysts may be located throughout the posterior mediastinum and in the neck. Although most commonly integral to the wall of the esophagus, they may communicate with the lumen of the esophagus or exist completely separate from the structure of origin. A number of large thoracoabdominal enteric cysts have been reported, either ending blindly in the abdomen or

CHAPTER

connecting with the lumen of the stomach, jejunum, ileum, or pancreatic duct.5l,gg Biliary reflux during bronchoscopy was reported in a case of an enteric duplication cyst that penetrated the diaphragm and connected the carina with the biliary tree.73Thereis a 12%incidence of associated malformations. Most of these are additional enteric duplication^.^^ Two cases of prenatally diagnosed intrathoracic enteric duplication cyst associated with hydrops have been treated with placement of a thoracoamniotic shunt in ~ t e r o . ~ ~ In most series, enteric cysts are asymptomatic at presentation. Chest radiograph and CT are the mainstays of diagnosis (Figs. 61-10 to 61-12). Although ggmTc pertechnetate, abdominal ultrasound, barium swallow, or MRI may occasionally be useful adjunctive procedures, the goal of preoperative studies is less an attempt to make a definitive diagnosis than to provide information to aid in operative planning. Treatment consists of complete surgical excision either by thoracotomy or thoracoscopy. If necessary, as in long tubular duplications, the mucosal lining of a foregut duplication may be stripped, leaving the common muscular wall intact.lZ4

A

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Cysts of t h e Lungs a n d Mediastinum

965

Marsupialization is no longer recommended. These are benign lesions, and esophageal integrity should be preserved.

Neurenteric Cysts Neurenteric cysts are rare foregut duplications that also have connections to the spinal canal, sometimes with the dura. Although they most commonly present as intrathoracic masses, they may also present as an intraspinal mass. The coexistence of a cystic posterior mediastinal mass with adjacent hemivertebrae should raise suspicion of a neurenteric cyst as well as anterior rnyel~meningocele.~~ Neurenteric cysts are thought to form early in develop ment when the notochord and foregut are in apposition, either by failure of complete separation or by herniation of foregut endoderm intothe dorsal e c t ~ d e r m . ~ ~ , ~ ~ Histologically, neurenteric cysts have alimentary tract mucosa, well-developed muscle walls, and no serosa. Gastric mucosa may be present, so signs of inflammation and ulceration may occur.@Symptoms often include pain

B

A, Incidental finding of an asymptomatic mediastinal mass behind the cardiac silhouette on anterior chest radiograph (arrow). B, On lateral film, the lesion was located just inferior and posterior to the base of the heart (arrow) and adjacent to the esophagus.

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B

A and B, CT scan further delineates the lesion in the patient shown in Figure 61-10 (ring marker). CT is probably the most useful imaging approach for patients with mediastinal tumors.

or neurologic findings (or both). MRI is suggested when Miscellaneous Mesenchymal Cystic Tumors a posterior mediastinal mass is associated with vertebral Mesenchymal tumors may occur throughout the medianomalies. Prompt excision is indicated. Paraplegia and death owing to meningitis have been rep~rted.~~Althoughastinum and may compromise the airway. They originate some authors report leaving the neural connections from connective tissue, lymphatic tissue, smooth and intact, most recommend total excision with simultaneous striated muscle, fat, and blood vessels. As a group, laminectomy if necessary.l4~l6,38 they constitute less than 5% of mediastinal masses in Other miscellaneous entities enter into the differential children. diagnosis of rare posterior mediastinal cystic masses. Mesenchymal tumors derived from blood and lymph Anterior thoracic meningoceles are seen in older children vessels are the most common varieties in children, espeand are thought to be progressive degenerative lesions cially lymphangiomas (cystic hygroma). In most patients, associated with vertebral anoma1ies.l" MRI should distinlymphangioma presents as a superior or posterior mediguish this lesion from a neurenteric cyst. astinal extension of a cervical lesion; however, primary ~ ~ , tumors ~ mediastinal lymphangiomas do o ~ c u r .These grow by proliferation of endothelial cell-lined buds within tissue planes. Symptoms relate to the size and invasiveness of the tumors or relate to i n f e ~ t i o n Hemorrhage .~~,~~ into these tumors can cause obstruction from rapid increase in size. Diagnostic steps include CT with intravenous contrast material or MRI. Fibrous reaction and neovascularization may make surgical resection tedious, although it remains the best therapy. Sclerotherapy with OK-432 is under investigational use in the United States and has been shown to have dramatic results in other countries. The most common complication after surgical resection of mediastinal lymphangioma is lymphatic fluid leak. Treatment of this complication by aspiration, chest tube drainage, and fibrin glue application (if drainage alone fails) is usually effective. Lymphangiomas recur in at least 15%of cases after resection, so long-term follow-up is important. There have been rare reports of mediastinal hemangiomas. The preOperative findings revealed a single cyst with ferred treatment of hemangiomas is nonoperative when esophageal mucosal lining, and microscopic examination confirmed possible, including the use of pulse corticosteroids or the presence of esophageal mucosa. interferon-a.

-.

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Laryngoscopy, Bronchoscopy, and Thoracoscopy Bradley M . Rodgers and Eugene D. McGahren Ill

The ability to view the larynx and tracheobronchial tree directly in living subjects has long intrigued physicians. Bozzini, in 1806, is credited with being the first to design an instrument specially to visualize the larynx and upper a i r ~ a yHis . ~ hollow tube was illuminated by a wax candle whose light was reflected with a mirror down the axis of the instrument. Babington, in 1829, devised the laryngeal mirror, which used reflected light. Several physicians subsequently developed rigid tubes with reflected light for observation of the esophagus and proximal part of the stomach. The major breakthrough, however, in the evolution of endoscopy came in 1879 when Nitze developed a cystoscope with a distal lens illuminated by a heated platinum Shortly thereafter, Nitze adapted Thomas Edison's discovery of the incandescent light bulb to his telescopic instrument by placing a bulb with a miniature filament at the end of the tube. Kirstein developed a laryngoscope with a blade, similar to our modern Miller blade, that was illuminated by an incandescent bulb in the handle, and Chevalier Jackson modified this instrument by placing the bulb on the distal portion of the blade and adding a removable floor to the laryngo~cope.2~ The final significant advance in rigid endoscopic technology was development of the Hopkins rod-lens system. Hopkins constructed a rigid endoscopic telescope with a series of lenses separated by quartz glass that enormously improved transmission of light through the instrument and allowed more magnification and better image resolution than had ever before been possible. In turn, this development allowed for miniaturization of endoscopes, applicable for use in children, and recording of highresolution images on film and television. Hopkins was also instrumental in development of the early flexible fiber-optic endoscopes. In 1930 Lamm discovered that images could be transmitted through thin fiberglass threads that were oriented and bound tightly t0gether.2~A prototype flexible gastroscope using this fiber-optic technology was developed by Hopkins in 1954 and was first used clinically by Hirschowitz et al. in 1958.18Ikeda adapted this same technology to the development of a flexible fiber-optic bronchoscope in 1970.21

Subsequent refinement in this technology allowed the development of truly miniaturized flexible fiber-optic laryngoscopes and bronchoscopes, suitable for use in infants and children of any size. The history of the development of thoracoscopy, in significant measure, parallels that of airway and gastrointestinal endoscopy. In 1910 HansJacobaeus used Nitze's cystoscope to visualize the pleural space in patients with pulmonary tuberculosis.22 In that era, artificial pneumothorax was known to be effective in treating many patients with cavitary tuberculosis, and Jacobaeus quickly perfected techniques to perform "closed intrapleural pneumolysis" with the cystoscope and a galvanic cautery. Jacobaeus coined the term "thoracoscopy" and by 1921 was able to of show the utilitv of this ~ro'edure for the diagnosis " intrathoracic carcinoma by observation and direct biopsy.z3 Rodgers and Talbert used the Hopkins rod-lens tele&ope for~horacoscopyand suggested the use of this technique for lung biopsy for the diagnosis of pulmonary infiltrates in immunocompromised children and reported its successful application in this clinical setting in 1976.59

LARYNGOSCOPY Indications Laryngoscopy is used for both diagnostic and therapeutic purposes in pediatric patients. The most common indication for laryngoscopy in infants and children is for the evaluation of stridor.17a32The term stm'dor refers to a highpitched respiratory sound created by turbulence of airway gases. Laryngeal and supraglottic pathology usually creates inspiratory stridor, which may change in nature with different positions or certain activities. Tracheal narrowing is generally manifested as expiratory stridor. Most infants and children with persistent inspiratory stridor should undergo laryngoscopy to establish a precise anatomic diagnosis. Other common indications for diagnostic laryngoscopy in children include a change in cry or voice, acute respiratory distress, or repeated episodes

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of aspiration. Indications for therapeutic laryngoscopy in children include the treatment of congenital or acquired subglottic stenosis, laryngeal webs, laryngoesophageal clefts, and laryngeal papilloma. Laryngeal foreign bodies, though uncommon, can be a cause of sudden respiratory distress and are thus an important indication for emergency laryngoscopy.

Instrumentation A surgeon performing laryngoscopy in infants and children must be skilled in the use of both flexible and rigid endoscopes and must have a broad array of instrumentation available. Often, rigid and flexible instruments are used in conjunction with each other because each has advantages and disadvantages in certain clinical situations. The standard rigid laryngoscopes used in pediatric practice are open sided with blades varying between 8 and 13.5 cm in length. Illumination is provided by a high-intensity light source aimed down the blade from a prism in the handle of the instrument (Fig. 62-1). Certain specialized laryngoscopes, such as the pediatric Dedo laryngoscope, allow suspension laryngoscopy for more complex operative procedures. The anterior commissure endoscope has an 1lcm-long blade with a keel configuration of the distal portion (Fig. 62-2). This endoscope is helpful in exposing

Anterior commissures endoscope. This instrument has an 11-cm-longblade with a keel configuration of the distal portion (inset).Illumination is provided by a prism in the handle. This instrument may be suspended.

-

cmo

I

2

3

4

5

Pediatric rigid laryngoscopes. These instruments have blades ranging from 8 cm (A) through 13.5 cm (C) in length. Illumination is provided by a light prism in the handle of the instrument. These instruments may be suspended.

the anterior aspect of the larynx in small infants. In addition, the configuration of the blade allows abduction of the vocal cords for the diagnosis of a laryngoesophageal cleft. The flexible instruments used for laryngoscopyin infants and children vary in size from the 2.0-mm-outerdiameter ultrathin bronchoscope to the 3.6mm-outerdiameter pediatric bronchoscope. The ultrathin endoscope does not have an instrument or suction channel and has only tweway deflection of the tip, thus limiting its use to diagnostic examinations. The standard pediatric flexible bronche scope has two-way tip deflection and a suction or instrument channel. This endoscope can be used satisfacte rily to visualize the larynx in all but very small premature infants (
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Procedure Diagnostic laryngoscopy in infants and children may be performed either with sedation and topical anesthesia or with general anesthesia. Usually, patients undergoing rigid laryngoscopy are administered general anesthesia. All patients must be thoroughly monitored during the endoscopic procedures. Continuous electrocardiographic (ECG) and pulse oximeter monitoring should be performed to detect the hypoxia or bradycardia that is occasionally precipitated by these procedures. Anesthesia is induced with the mask, and if possible, the patient is not intubated before direct laryngoscopy. The patient is then positioned with the neck extended and the jaw slightly flexed. All the instruments anticipated for examination of the airway are sterilized and available in the operating room. he rigid laryngoscope is passed along the right border of the tongue until the epiglottis is visualized. The blade of the laryngoscope is passed under the epiglottis and used to elevate this structure to visualize the supraglottic larynx and vocal cords. Often, subglottic pathology can be appreciated from this vantage. With the endoscope in this position, movement of the larynx with respiratory effort & observed. In patients with laryngomalacia, the base of the epiglottis is often narrow ("omega shaped"), and the arytenoid processes coapt in the midline with inspiratory effort (Fig. 62-3). Frequently, visualization of the vocal cords is completely lost during inspiration in these patients. In cases of vocal cord paralysis, the affected cord will be noted to be in the midposition and will not abduct with insviration. After the cords have been evaluated, the glottic airway may be sprayed with lidocaine (4 mg/kg) to minimize laryngospasm as the rest of the examination proceeds. Use of the anterior commissure endoscove often allows for better visualization of the anterior aspect of the larynx, particularly in small infants. Passage of the narrow tip of this endoscope into the glot& opening allows forced abduction of the cords and visualization of the cords and the

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posterior laryngeal membrane, the area of a laryngoesophageal cleft. For many therapeutic procedures on the larynx, use of the suspension laryngoscope is essential because it allows binocular magnification of the larynx and unimpeded use of laryngeal surgical instruments. The square blade of the suspension laryngoscope is passed beneath the epiglottis, and the tip is elevated to expose the larynx and supraglottic airway. The suspension apparatus is supported on a Mayo stand placed over the patient's chest. For procedures involving the anterior aspect of the larynx, the anterior commissure endoscope may be suspended in similar fashion. If the preoperative diagnosis is laryngomalacia, the examination is often initiated with the flexible endoscope. This instrument is passed through the nose into the posterior of the pharynx. It is slowly advanced until the epiglottis is identified. Positioning the tip of the endoscopejust beyond the epiglottis on the posterior pharyngeal wall allows excellent visualization of the laryngeal airway and assessment of its dynamic function with respiratory effort. Assessment of laryngeal motion with the flexible endoscope is superior to that obtained with the rigid endoscope because there is no distortion of the larynx or supraglottic airway with the instrument itself.15 The flexible endoscope may be passed through the laryngeal mask airway (LMA) to visualize the glottis in patients under general anesthesia.2 In most instances, after complete evaluation of the larynx and supraglottic airway, a bronchoscopic examination is performed to rule out associated distal pathology.

Complications Complications of diagnostic laryngoscopy are rare, with the exception of exaggerated airway obstruction secondary to laryngeal edema. In situations in which diagnostic laryngoscopy is being performed in patients with severe airway obstruction, equipment should be available for emergency tracheostomv. Likewise. vreoverative discussions with the anesthesiologist should emphasize the potential need for intubation with a small (2.5 mm) endotracheal tube for emergency ventilation. The complications resulting from therapeutic laryngoscopy depend-on the procedure being performed. Perforation of the larynx or pharynx is a potential but uncommon complication after vigorous laryngeal dilation or the use of lasers or cryotherapy for the treatment of laryngeal or subglottic stenosis. The potential for hypoxia developing during the performance of laryngoscopy may through the suction be minimized by insdflating - oxygen .channel of the .flexible laryngoscope or &rough a tube placed in the comer of the mouth while using the rigid scope. Hoeve et al. recorded an overall complication rate of 1.9% in children undergoing rigid laryngobronchoscopy.~~ There was a 0.5% complication rate in infants younger than 3 months. Complications included hemorrhage (0.5%), cardiac arrhythmias (0.6%),subglottic edema (0.3%),and vneumothorax (1.2%). The com~licationof cardiac arrhythmia was eliminated with the use of pulse oximetry to monitor patients. Wood has reported a 2.9% complication rate with no mortality in a large series of children undergoing flexible laryngobronch~scopy.~~ L

Endoscopic appearance of the supraglottic area in a child with laryngomalacia. Note the "omega-shaped"epiglottis with a very narrow base. The arytenoids (asterisk) collapsed in the midline with inspiration.

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BRONCHOSCOPY Indications Bronchoscopy is used for both diagnostic and therapeutic purposes in the care of infants and children. Indications include stridor, persistent atelectasis, persistent cough, recurrent or persistent pneumonia, suspicion of an airway foreign body, assistance in intubation, assessment of endotracheal tube placement, bronchial toilet, airway bleeding, and postoperative or postextubation hoarseness or wheezing.47,"277fi Interventions undertaken with bronchoscopy may include removal of a foreign body or secretions, tracheostomy care, bronchoalveolar lavage, instillation of medications, laser therapy, balloon dilation or placement of stents for obstructing lesions, and transbronchial biopsy.8,39,",97,6".77 Relative contraindications to bronchoscopy may include a bleeding diathesis, hemodynamic instability, arrhythmias, hypoxemia, pulmonary The value hypertension, or potential airway 0bstruction.~~~~2 of the information to be gained from the bronchoscopic examination must always be weighed against the potential risks of the procedure.

Instrumentation Pediatric bronchoscopes are available as both flexible and rigid instruments. The initial and still standard pediatric flexible bronchoscope has an outer diameter of 3.5 to

3.7 mm with a 1.2-mm suction instrument port. Movement of the tip is bidirectional and has a range of 180 to 220 degrees. The suction port allows either instillation of fluids or oxygen or suctioning of airway mucus. However, the small size of the suction channel makes suctioning of tenacious mucus difficult and does not easily allow transbronchial biopsy. The smallest endotracheal tube that this bronchoscope can pass through is 4.5 mm. In patients without endotracheal tubes, however, this bronchoscope can usually be passed transnasally, even in infants as small as There is also a 2.8-mm flexible bronchoscope 700 g.10,74,75977 with a 1.2-mm suction port that has the capabilities of the 3.5-mm scope and is therefore preferable in smaller children.77 Smaller, ultrathin bronchoscopes with outer diameters of 2.7, 2.2, 2.0, and 1.8 mm are now commonly used. Suction channels of 0.7 to 0.8 mm are available in the 2.7- and 2.2-mm endoscope^.^^,^^,^^,^^ The 1.8-mm scope lacks a bidirectional tip. Endoscopes 2.2 mm and smaller can pass through a 2.5-mm endotracheal tube.4t The rigid pediatric bronchoscope consists of a rigid rod-lens telescope that is passed through an outer sheath. The sheath has an inner diameter of 3.5 to 7.5 mm and a length of 23 or 30 cm (Fig. 62-4). The telescope size used for any particular sheath must be chosen to maximize visualiiaiion while minimizing airway resistance." A special adapter allows for ventilation directly through the sheath. In addition, an instrument port allows passage of a catheter for irrigation or suctioning. Grasping and biopsy instruments are coupled directly to rigid telescopes

Pediatric rigid bronchoscopes. These instruments vary in size between 2.5 x 20 cm (A) and 6 x 30 cm (E). The rod-lens telescope is passed directly through the shaft of these instruments. The operative side channel (asttnisks) allows passage of suction and surgical instruments. The ventilator side channel (star) allows continuous ventilation during the procedure.

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B

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C

A, Optical forceps. 23, The peanut grasper is coupled to a long endoscopic telescope for direct, magnified vision for foreign body extraction. C, The magnified image allows precise positioning of the grasping forceps for safe foreign body removal.

to create optical forceps that can be passed through the sheath (Fig. 62-5). Even though rigid bronchoscope sheaths are labeled according to their minimal inner diameter, these sizes do not necessarily correlate with actual working sizes. Actual sizes for the Storz rigid bronchoscopes are included in Table 62-1. Care must be taken to choose a bronchoscope that is the appropriate size for the infant or child to be examined and that allows enough room within the sheath for the placement of telescopic instruments or catheters if necessary.

Nominal Size 2.5 x 3.0 x 3.5 x 4.0 x 5.0 x 6.0 x

20 20/26/30 20/26/30 30 30 30

Inside Diameter (mm) 3.5 4.3 5.0 6.0 7.1 7.5

Outside Diameter (mm)------4.2 5.0 5.7 6.7 7.8 8.2

Length (cm) 20 20/26/30 20/26/30 30 30 30

Adapted from Marzo SJ, Hotaling AJ: Trade-off between airway resistance and optical resolution in pediatric rigid bronchoscopy. Ann Otol Rhinol Laryngol 1995;104:282.

Procedure Before any bronchoscopic examination, a thorough history and physical examination should be performed. Particular attention should be paid to any abnormalities of the neck or spine that might make passage of the bronchoscope difficult, the position of the trachea in the neck, and any asymmetry in breath sounds. Frontal and lateral chest radiographs should be obtained in all patients to define the intrathoracic anatomy and pathology. A barium swallow may be helpful if vascular compression of the airway or gastroesophageal reflux is suspected. Cinefluoroscopy or inspiratory-expiratory chest radiographs may help confirm the presence and identify the location of a suspected airway foreign body. In some instances, computed tomography (CT) of the chest may aid in evaluation of the intrathoracic airway and surrounding structures. Once the bronchoscopic procedure begins, one must be prepared for emergency access to the airway by either endotracheal intubation or tracheostomy. A surgeon preparing to perform bronchoscopy must be familiar with all the available equipment, and the equipment must be in working order. Care must be taken in the maintenance of bronchoscopic equipment as well because inadequate cleaning or the development of cracks in the equipment may predispose to bacterial c o n t a m i n a t i ~ nThe . ~ ~ appropriate-sized equipment must be available for the size and needs of the child. If a foreign

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body is to be removed, it may be valuable to test the grasping equipment on a sample of the suspected object before commencing the pr0cedure.7~Virtually all bronchoscopic examinations are now undertaken with the use of video monitoring and recording with magnification. This facilitates visualization of the anatomv. ,, documentation for later review, comparisons of findings over time, and discussion with parents and caretakers.39 Flexible bronchoscopy can be performed at the bedside in an intensive care. unit set6ng. Preoxygenation is imperative. Sedation is usually supplemented with an antisialagogue such as atropine to minimize reflex bradycardia. a to~icalanesthetic such as lidocaine to anesthetize the pharydx and upper airway, and anxiolytics. Steroids may be helpful to minimize postprocedure edema.37.41.47 The bronchoscope is passed transnasally in a nonintubated patient. In a ventilated patient, an appropriately sized bronchoscope can be passed directly through the endotracheal tube. In some instances, the flexible bronchoscope may be introduced through a T-adapter, thus allowing continuation of ventilation or administration of supplemental oxygen during the procedure. Ventilation cannot be accomplished through the flexible bronchoscope; therefore, the patient must be able to breathe spontaneously around the scope or must be mechanically ventilated while the bronchoscope is manipulated though the T-adapter. This is not an insignificant limitation because the normal infant airway is only approximately 5 mm in diameter and resistance to airflow increases inversely with the fourth power of the radius. In addition, the noimal ventilatorv cvcle allows twice the time for expiration as for inspiration. The LMA has proved to be a particularly useful adjunct to flexible bronchoscopy, although rigid bronchoscopy may be accomplished through the LMA as well. The LMA provides a leakless anesthesia circuit for bronchoscopic examination. It allows airway support with positive pressure, COP monitoring, assisted ventilation, and anesthetic delivery without leakage into the surrounding environment. The LMA also allows the use of larger fiber-optic instruments than would be possible with a transnasal or endotracheal tube approach. This, in turn, allows the use of larger suction chambers. Finally, the LMA facilitates examination in patients with anatomic limitations such as micrognathia or a rigid neck and may facilitate securing of a difficult airway by allowing easier passage of a flexible bronchoscope over which an endotracheal tube may be placed. Potential contraindications to use of the ~ k f Afor bronchoscopy include gastroesophageal reflux, a full stomach, or poor pulmonary ~ompliance.2,~~.~~~~ In the presence of a partially occluding bronchoscope, "breath stacking" may occur with an accumulation of carbon dioxide.2Fhus, examinations with the flexible bronchoscope, including suctioning of mucus, should be limited to 30 to 45 seconds.76ECG, pulse oximetry, and possibly end-expiratory COBmonitoring should be performed during the entire procedure." To compensate for the occlusive effects of the flexible bronchoscope, supplemental oxygen can be administered through the suction port or through a catheter in the opposite nares when an ultrathin scope without a suction port is 8

,

being used. In the setting in which mucus is being removed, saline or mucolytic agents may be instilled through the suction port t o allow removal of thicker secretions. If a mucous plug is particularly tenacious and cannot be suctioned through the port, it can sometimes be suctioned against the tip of the bronchoscope and then removed by carefully withdrawing the scope from the airway. It is important that team members, other than the bronchoscopist, be involved in monitoring the child's progress because "bronchoscopist hypnosis"
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be helpful for specific lower airway evaluation^.^^ After the airway is inspected, any appropriate manipulations are completed. Should ventilation become difficult, the telescope may be removed and ventilation can continue through the unobstructed bronchoscope sheath. Images may be projected onto a monitor by placing a video camera on the telescope eyepiece. During the course of the procedure, care must be taken to evaluate the dynamics of the airway and anatomic variations. Removal of various sizes and types of foreign bodies requires the availability of a variety of grasping instrument^.^ Generally, removal of the object from the airway requires removal of the entire bronchoscope apparatus because most foreign bodies will not pass through the bronchoscope sheath. If a foreign body is particularly friable, such as an aspirated peanut, it may be helpful to pass a Fogarty balloon catheter through the access port or through the sheath and beyond the object. Care must be taken to not break the balloon. The balloon is then inflated, the object is withdrawn into the sheath, and the entire apparatus is removed.28 The airway should always be reexamined to rule out any residual foreign body fragment and to suction any mucus and secretions that have accumulated in the airway beyond the foreign body. Although all procedures should be performed in an efficient manner, time is usually not as limiting a factor during rigid bronchoscopy as it is during flexible bronchoscopy because of the ability to ventilate through the sheath. At the end of the procedure, the endoscope is removed under direct vision. An endotracheal tube can then be placed if necessary, a preexisting tracheostomy may be replaced, or the patient may be observed breathing spontaneously.

Complications Significant complications of flexible and rigid bronchoscopy are uncommon but may include hypoxia, hypercapnia, bradycardia, laryngospasm, pneumothorax, subglottic or other airway edema, bleeding, fever, The most serious comand nosocomial infection.*2,48,71,75 plications appear to occur in small infants undergoing bronchoscopy. In one series of 132 infants younger than 1 month undergoing rigid bronchoscopy, pneumothorax developed in 5 , bronchial disruption in 1, and pulmonary artery disruption in 1. Each of these injuries was treated successfully.31

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for empyema.l4,26,55The procedure remains our technique of choice for biopsy of mediastinal lesions, particularly lyrnph0mas.~2Certain mediastinal lesions, such as bronchogenic or duplication cysts, can be completely excised via thoracoscopy, thus avoiding a thoracotomy in these patients.46~55The technique remains quite useful for pulmonary biopsy, both in immunocornpromised and in otherwise normal children with undiagnosed pulmonary infiltrates or nodules.6 It is also useful in the treatment of many pleural disorders, such as spontaneous pneumothorax and c h y l o t h ~ r a x . ~Recent ~ , ~ ~ reports have demonstrated its usefulness and safety in performing anatomic lobectomies in children." Several authors have now described repair of esophageal atresia, with and without tracheoesophageal fistula, with thoracoscopic techniques.3,33,62 Techniques have been developed for closure of diaphragm hernias and for occlusion of the ductus arteri~sus.~~~~Vericardial windows may be created to drain chronic pericardial effusions. Thoracoscopy has been used to achieve exposure for spinal diskectomy in The role of the robot children with thoracic scoli~sis.~g in pediatric thoracoscopy is in the early stages of definition.9.20 The range of motion of the instruments with the robot may facilitate working in very small spaces.

Instrumentation For thoracoscopy in children, 3-, 5-, or 10-mm Hopkins rod-lens telescopes may be used. We have preferred the Odegree telescopes, although other authors have described using the 30- and 70-degree telescopes in certain circumstances.54 In small infants, the 3-mm endoscopic telescope may be useful (Fig. 62-6). The telescopes and operating instruments are passed through transthoracic trocars, which may be valved, as those used for laparoscopy, or unvalved. We have found the Innerdyne expandable trocar useful in children because its radial expansion allows placement of a 5- or 10-mm trocar in small children without the hazard of intercostal vessel or nerve injury (Fig. 62-7). The operating instruments are, for the most part, 3 or 5 mm in diameter with insulated shafts for the use of cautery. We have preferred the reusable instruments and have chosen them to duplicate the types of instruments that we would use for an open thoracotomy (Fig. 62-8). The endoscopic GIA stapler is useful for obtaining lung biopsy samples and for excising cysts of the lung, but this instrument must be passed through a 12-mm trocar and must have 5 cm within the pleural space to fully open the anvil, thus limiting the usefulness of this instrument in small children.

Indications When originally described for use in children, thoracoscopy was proposed as a method for obtaining pulmonary biopsy samples in patients who were immunocompromised.59 With further refinements in the technique and the development of better instrumentation, there are now many diagnostic and therapeutic indications for thoracoscopy in children. In our own series, the most common indication for thoracoscopy has become pleural debridement

Procedure Successful performance of thoracoscopy in children requires careful attention to patient selection and preoperative imaging. In children with mediastinal pathology, special imaging studies such as CT or magnetic resonance imaging are helpful in defining the relationship of the pathology to other mediastinal structures and determining the most direct approach to the lesion. For lung

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biopsy, frontal and lateral radiographs usually suffice to localize the area of pathology. Patients undergoing thoracoscopy for biopsy of parenchymal nodules must be carefully selected on the basis of preoperative CT scans. Nodules further than 1 cm from the visceral pleura may be difficult to identify at the time of thoracoscopy, and preoperative localization techniques

such as transthoracic wire placement or tattooing may ~ ~patients ~ ~ , ~ with pleural effusions be very h e l p f ~ 1 . 4In or empyema who are being considered for thoracoscopic drainage and dkbridement, transthoracic ultrasound or thoracic CT can help localize the area of largest loculation, into which the initial trocar should be placed.

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Thoracoscopic instruments. A, All of the following instruments have 5-mm shafts that are insulated: A, Babcock forceps; B, Right-angle dissector; C, Metzenbaum scissors; D, Allis forceps. B, Different handle configurations are available for all these instruments, depending on their expected use and operator preference.

Thoracoscopic procedures in children may be performed with the use of either intravenous sedation and regional anesthesia or general anesthesia." Procedures that may be performed rapidly and with little manipulation of the visceral pleura, such as talc pleurodesis or lung biopsy, may be successfully completed with regional anesthesia induced by intercostal nerve blocks.

More prolonged and complicated procedures are best performed with general anesthesia. Unilateral ventilation, with contralateral mainstem intubation, is helpful for cases requiring extensive mediastinal dissection. Patients should be monitored thoroughly during these procedures with continuous EGG monitoring as well as pulse oximetry. Instruments should be available in the operating room

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for performing an emergency thoracotomy if needed for control of bleeding. The patient is positioned on the operating table to facilitate the approach to the area of pathology. Procedures involving lung biopsy or pulmonary resection are performed with the patient in a full lateral decubitus position to allow access to all pulmonary lobes and fissures. Lesions in the posterior mediastinum are best accessed by rolling the patient forward from the true lateral decubitus position, whereas anterior mediastinal lesions are best approached by rolling the patient posteriorly. The initial trocar is usually placed in the midaxillary line in the fifth or sixth intercostal space. Placement of subsequent trocars then depends on the accessibility of the pathology. Generally, the trocars for the operating instruments are placed on either side of the telescope in a triangular configuration, with the telescope at the apex. Pleural dkbridement for empyema is accomplished with large grasping forceps and pressure irrigation. Denser adhesions are divided with the cautery. Lung biopsy specimens were initially obtained with the cup biopsy forceps, with a fragment of pulmonary parenchyma sheared off as the forceps were withdrawn through the trocar. However, this technique pt-ovided no pneumostasis or hemostasis. Tissue coagulation instruments are now available in 5-mm diameters and appear to provide excellent pneumostasis and hemostasis for lung biopsy.6gIn larger children, use of the endoscopic GIA stapler allows large wedge biopsy specimens to be obtained safely. Mediastinal lesions may be biopsied or resected by opening the parietal pleura overlying the lesion and dissecting the lesion with blunt and sharp techniques. Exposure of mediastinal lesions being considered for resection may be improved by instilling COBinto the chest under low pressure (4 to 6 mm Hg) to collapse the ipsilateral lung. Hemostasis is usually achieved with the electrocautery, although metallic clips may be used for larger vessels. We have used a core biopsy needle passed directly across the chest wall and positioned under direct vision to obtain deeper specimens after biopsy of the superficial portion of mediastinal lymph nodes with the cup forceps. Patients with chylothorax may be treated by ligation or clipping of the thoracic duct along with the adjacent tissue behind the esophagus , 2 ~ ,duct ~ ~ may also be dissected at the aortic h i a t ~ s . ~ The individually and occluded with metallic clips. In the event of more diffuse lymphatic leakage, ligation of the thoracic duct may be followed by the application of fibrin glue to the region of leak.13 Patients undergoing thoracoscopy for pneumothorax may have a complete pleural abrasion after division of pleural adhesions with the cautery. We have used a piece of Marlex mesh held in grasping forceps to perform the abrasion. In some cases an apical pleurectomy may be performed by incising the parietal pleura over the sixth rib laterally and bluntly dissecting the pleura from the upper half of the hemithorax. Talc pleurodesis may be performed in selected patients by dusting USP pure talc on the visceral and parietal pleural surfaces throughout the entire hemithorax. We have preferred to leave a chest tube in place after removal of the trocars, although some authors have not used tubes if the visceral pleura has not been violated during the pr0cedu1-e.~~

Complications Complications of thoracoscopy are in large part determined by the procedure performed and the medical condition of the patient. The majority of the complications, as well as all of the mortality, reported in children undergoing thoracoscopy has occurred in mechanically ventilated patients undergoing thoracoscopic lung biopsy for diffuse pulmonary infiltrates.53 The incidence of prolonged bronchopleural fistula is highest in this group of patients, and this may complicate their respiratory management. Hemorrhage requiring transfusion is a rare complication of thoracoscopy, even in patients who are thrombocytopenic as a result of chemotherapy. Preoperative correction of coagulation abnormalities minimizes the risk for this complication. As with any biopsy procedure, false-negative biopsy results are occasionally reported with thoracoscopy. We believe that the addition of visually directed core needle biopsy to superficial nodal biopsy has minimized the frequency of this problem. Occasionally, lesions visible by radiographic studies cannot be localized by thoracoscopy. This appears to be particularly true for pulmonary parenchymal nodules. A surgeon performing thoracoscopy has limited ability to "palpate" the pulmonary surface, and it is often difficult to locate lesions situated deep within the pulmonary parenchyma. Occasionally, collapsing the ipsilateral lung with unilateral pulmonary ventilation will make these deeper lesions more evident. Various techniques of preoperative marking of these lesions have been described to aid in their localization. In general, thoracoscopy has proved to be a highly accurate and very safe procedure. The overall results are quite comparable to those with open thoracotomy, but with less postoperative morbidity. Endoscopic techniques for visualization of the airway and intrathoracic structures have assumed a critically important role in the management of children. Newer uses of these techniques have been developed as the technology has been refined. It is incumbent on pediatric surgeons to be familiar with these techniques and facile in their performance.

REFERENCES 1. Arca MJ, Barnhart DC, Lelli JL, et al: Early experience with minimally invasive repair of congenital diaphragmatic hernias: Results and lessons learned. J Pediatr Surg 2003;38:1563. 2. Badr A, Tobias J, Rasmussen GE, et al: Bronchoscopic evaluation facilitated by the laryngeal mask airway in pediatric patients. Pediatr Pulmonol 1996;21:57. 3. Bax KN. van der Zee DC: Feasibilitv of thoracoscoaic reaair of esophageal atresia with distal fistula. J Pediatr Surg 2002; 37:192. 4. Black RE, Johnson DG, Matlak ME: Bronchoscopic removal of aspirated foreign bodies in children. J Pediatr Surg 1994; 29:682. 5. Bozzini PH: Lichteiter, eine Erfindung zur Anschauung innerer Teile und Krankheiten. J Prak Heilk 1806; 24:107. 6. Burns RC, McGahren ED, Rodgers BM: Thoracoscopic approach to pulmonary parenchymal lesions. Pediatr Endosurg Innov Tech 2001;5:141. 1

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7. Burns RC, McGahren ED, Rodgers BM: Thoracoscopy in the management of chylothorax. Pediatr Endosurg Innov Tech 2001;5:153. 8. Cohen S, Pine H, Drake A: Use of rigid and flexible bronchoscopy among pediatric otolaryngologists. Arch Otolaryngol Head Neck Surg 2001;127:505. 9. Drasin T, Gracia C, Atkinson J: Pediatric applications of robotic surgery. Pediatr Endosurg Innov Tech 2003; 7:377. 10. Fan LL, Sparks LM, Fix EJ: Flexible fiberoptic endoscopy for airway problems in a pediatric intensive care unit. Chest 1988;93:556. 11. Gaafar HA. The fiberoptic bronchoscope in the diagnosis and investigation of laryngeal disorders. Clin Otolaryngol 1983;8:103. 12. Godfrey S, Springer C, Maayan C, et al: Is there a place for rigid bronchoscopy in the management of pediatric lung disease? Pediatr Pulmonol 1987;3:179. 13. Graham DD, McGahren ED, Tribble CG, et al: Use of videoassisted thoracic surgery in the treatment of chylothorax. Ann Thorac Surg 1994;57:1507. 14. Grewal H, Jackson RJ, Wagner CW, Smith SD: Early videoassisted thoracic surgery in the management of empyema. Pediatrics 1999;103:63. 15. Handler SD: Direct laryngoscopy in children: Rigid and flexible fiberoptic. Ear Nose Throat J 1995;74:100. 16. Hasagawa S, Hitomi S, Murakawa M, et al: Development of an ultrathin fiberscope with a built-in channel for bronchoscopy in infants. Chest 1996;110:1543. 17. Hawkins DB, Clark RW: Flexible laryngoscopy in neonates, infants, and young children. Ann Otol Rhinol Laryngol 1987;96:81. 18. Hirschowitz BI, Curtis LE, Peters CW, et al: Demonstration of a new gastroscope, the fibergastroscope. Gastroenterology 1958:35:50. 19. Hoeve LJ, Rombout J, Meursing AEE: Complications of rigid laryngobronchoscopy in children. Int J Pediatr Otorhinolaryngol 1993;26:47. 20. Hollands CM, Dixey LN: Robotic-assisted esophagoesophagostomy. J Pediatr Surg 2002;37:983. 21. Ikeda S: Flexible bronchofiberscope. Ann Otol Rhinol Laryngol 1970;79:916. 22. Jacobaeus HC: Uber die Moglichkeit die Zystoskopie bei Untersuchung seroser hohzungen Anzuwenden. Munch Med Wochenschr 1910;40:2090. 23. Jacobaeus HC, Key E: Some experiences of intrathoracic tumors, their diagnosis and their operative treatment. Acta Chir Scand 1921;53:573. 24. Kent RB 111, Pinson TW: Thoracoscopic ligation of the thoracic duct. Surg Endosc 1993;7:52. 25. Keohane JD, Forte V, MacPherson B: Pressure, flow, and resistance characteristics of the pediatric Storz-Hopkins bronchoscopes. Otology 1991;20:155. 26. Kern JA, Rodgers BM: Thoracoscopy in the management of empyema in children. J Pediatr Surg 1993;28:1128. 27. Koltai PJ, Nixon RE: The story of the laryngoscope. Ear Nose Throat J 1989;68:494. 28. Kosloske AM: The Fogarty balloon technique for the removal of foreign bodies from the tracheobronchial tree. Surg Gynecol Obstet 1982;155:72. 29. Lamm H: Biegsame optische Cerate. Z Instrumentenkunde 1930;30:579. 30. LeBret E, Folliquet TA, Laborde F:Videothoracoscopic surgical interruption of patent ductus arteriosus. Ann Thorac Surg 1997;64:1492. 31. Lindahl H, Rintala R, Malinen L, et al: Bronchoscopy during the first month of life. J Pediatr Surg 1992;27:548.

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32. Lis G, Szczerbinski T, Cichocka-Jarosz E: Congenital stridor. Pediatr Pulmonol 1995;20:220. 33. Lobe TE, Rothenberg SS, WaldschmidtJ, et al: Thoracoscopic repair of esophageal atresia in an infant: A surgical first. Pediatr Endosurg Innov Tech 1999;3:141. 34. Martinot A, Closset M, Marquette CH, et al: Indications for flexible versus rigid bronchoscopy in children with suspected foreign-body aspiration. Am J Respir Crit Care Med 1997;155:1676. 35. Marzo SJ, Hotaling AJ: Trade-off between airway resistance and optical resolution in pediatric rigid bronchoscopy. Ann Otol Rhinol Laryngol 1995;104:282. 36. McGahren ED, Kern JA, Rodgers BM: Anesthetic techniques for pediatric thoracoscopy. Ann Thorac Surg 1995; 60:927. 37. Mehrishi S, Raoof S, Mehta AC: Therapeutic flexible bronchoscopy. Chest Surg Clin North Am 2001;11:657. 38. Muntz HR: Therapeutic rigid bronchoscopy in the neonatal intensive care unit. Ann Otol Rhinol Laryngol 1985;94:462. 39. Nicolai T: Pediatric bronchoscopy. Pediatr Pulmonol 2001; 31:150. 40. Nitze M: Eine neue Boebachtungs und Untersuchungsmethode fur Harnblase. Wien Med Wochenschr 1879; 24:650. 41. Nussbaum E: Usefulness of miniature flexible fiberoptic bronchoscopy in children. Chest 1994;106:1438. 42. Nussbaum E: Pediatric fiberoptic bronchoscopy. Clin Pediatr (Phila) 1995;34:430. 43. Nussbaum E, Zagnoev M: Pediatric fiberoptic bronchoscopy with a laryngeal mask airway. Chest 2001;120:614. 44. Ozcan C, McGahren ED, Rodgers BM: Thoracoscopic treatment of spontaneous pneumothorax in children. J Pediatr Surg 2003;38:1459. 45. Partrick DA, Bensard DD, Teitelbaum DH, et al: Successful thoracoscopic lung biopsy in children utilizing preoperative CT-guided localization. J Pediatr Surg 2002;37:970. 46. Partrick DA, Rothenberg SS: Thoracoscopic resection of mediastinal masses in infants and children: An evaluation of techniques and results. J Pediatr Surg 2001;36:1165. 47. Perez CR, Wood RE: Update on pediatric flexible bronchoscopy. Pediatr Clin North Am 1994;41:85. 48. Picard E, Schwartz S, Goldberg S, et al: A prospective study of fever and bacteremia after flexible fiberoptic bronchoscopy in children. Chest 2000;117:573. 49. Pollock ME, O'Neal KO, Picetti G, Blackman R: Results of video-assisted exposure of the anterior thoracic spine in idiopathic scoliosis. Ann Thorac Surg 1996;62:818. 50. Puhakka H, Kero P, Valli P, et al: Pediatric bronchoscopya report of methodology and results. Clin Pediatr (Phila) 1989;28:253-257. 51. Rimell FL, Shapiro AM, Mitskavich MT, et al: Pediatric fiberoptic laser rigid bronchoscopy. Otol Head Neck Surg 1996;114:413. 52. Rodgers BM: Thoracoscopy. In Holcomb GE (ed): Pediatric Endoscopic Surgery. Norwalk, CT, Appleton & Lange, 1993. 53. Rodgers BM: Pediatric thoracoscopy: Where have we come and what have we learned. Ann Thorac Surg 1994;56:704. 54. Rodgers BM: Instrumentation and technique for pediatric thoracoscopy. Pediatr Endosurg Innov Tech 2001;5:93. 55. Rodgers BM: The role of thoracoscopy in pediatric surgical practice. Semin Pediatr Surg 2003;12:62. 56. Rodgers BM, McGahren ED: Endoscopy in children. Chest Surg Clin North Am 1993;3:405. 57. Rodgers BM, Moazam R, Talbert JL: Endotracheal cryotherapy in the treatment of refractory airway strictures. Ann Thorac Surg 1983;35:52.

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58. Rogers DA, Philippe PG, Lobe TE, et al: Thoracoscopy in children: An initial experience with an evolving technique. J Laparoendosc Surg 1992;2:7. 59. Rodgers BM, Talbert JL: Thoracoscopy for diagnosis of intrathoracic lesions in children. J Pediatr Surg 1976; 11:703. 60. Rothenberg SS: Thoracoscopic repair of tracheoesophageal fistula in newborns. J Pediatr Surg 2002;37:869. 61. Rothenberg SS: Experience with thoracoscopic lobectomy in infants and children. J Pediatr Surg 2003;38:102. 62. Rothenberg SS, Chang JH, Toews WH, Washington RL: Thoracoscopic closure of patent ductus arteriosus: A less traumatic and more cost-effective technique. J Pediatr Surg 1995;30:1057. 63. Schellhase D: Pediatric flexible airway bronchoscopy. Curr Opin Pediatr 2002;14:327. 64. Selim M, Mowafi H, Al-Ghamdi A, et al: Intubation via LMA in pediatric patients with difficult airways. Can J Anaesth 1999;46:891-893. 65. Shinwell ES: Ultrathin fiberoptic bronchoscopy for airway toilet in neonatal pulmonary atelectasis. Pediatr Pulmonol 1992;13:48. 66. Silberman HD: The use of flexible fiberoptic nasopharyngolaryngoscope in the pediatric upper airway. Otolaryngol Clin North Am 1978;11:365. 67. Stringel G, TeixciraJA: Thoracoscopic ligation of the thoracic duct. J Soc Laparoendosc Surg 2000;4:239. 68. Swanson KL, Prakash UB, Midthun DE, et al: Flexible bronchoscopic management of airway foreign bodies in children. Chest 2002;121:1695.

69. Tirabassi MV, Banever GT, Tashjian DB, et al: Use of energy devices in thoracoscopy: Quantification of lung-sealing capacity. Pediatr Endosurg Innov Tech 2003;7:267. 70. Tunkel DE, Fisher QA: Pediatric flexible fiberoptic bronchoscopy through the laryngeal mask airway. Arch Otolarygol Head Neck Surg 1996;122:1364. 71. Wain G: Rigid bronchoscopy: The value of a venerable procedure. Chest Surg Clin North Am 2001;11:691. 72. WaldhausenJH, Shaw DW, Hall DG, et al: Needle localization for thoracoscopic resection of small pulmonary nodules in children. J Pediatr Surg 1997;32:1624. 73. Wong K, Lai S, Lien R, et al: Retrieval of bronchial foreign body with central lumen using a flexible bronchoscope. Int J Pediatr Otorhinolaryngol 2002;28:253. 74. Wood RE: Spelunking in the pediatric airways: Explorations with the flexible fiberoptic bronchoscope. Pediatr Clin North Am 1984;31:785. 75. Wood RE: Pitfalls in the use of the flexible bronchoscope in pediatric patients. Chest 1990;97:99. 76. Wood RE: Flexible bronchoscopy in infants. Int Anesthesiol Clin 1992;30:125. 77. Wood RE: The emerging role of flexible bronchoscopy in infants. Clin Chest Med 2001;22:311. 78. Wood RE, Azizkhan RG, Lacey SR, et al: Surgical applications of ultrathin flexible bronchoscopes in infants. Ann Otol Rhino1 Laryngol 1991;100:116. 79. Wood RE, Gauderer MWL: Flexible fiberoptic bronchoscopy in the management of tracheobronchial foreign bodies in children: The value of a combined approach with open tube bronchoscopy. J Pediatr Surg 1984;19:693.

Lesions of the Larynx, Trachea, and Upper hrway Dana Mara Thompson and Robin T. Cotton

Lesions of the upper airway, namely, the larynx and trachea, can cause life-threatening airway obstruction. The etiology of obstructive airway disease is often multifactorial and includes anatomic, congenital, and inflammatory problems, many of which are managed by surgical intervention. A variety of clinical signs and symptoms are associated with airway obstruction. Signs of acute airway obstruction are stridor, respiratory distress, apnea, cyanosis, pallor, tachypnea, use of accessory muscles of respiration and retractions, and mental status changes. Chronic airway obstruction may have similar signs and symptoms, and long-term complications of airway obstruction and hypoxia, such as failure to thrive, poor weight gain, pulmonary hypertension, and pectus excavatum, may develop. Regardless of whether the airway is acutely or chronically obstructed, stridor is the most useful noninvasive clinical examination finding for determining the location of the obstruction in the airway. Stridor occurs as a result of turbulent airflow through a narrowed lumen and is present in virtually all children with airway obstruction, except those on the brink of complete asphyxia. The phase of respiration in which stridor is heard will help an astute examiner better determine the location of the lesion. Inspiratory stridor typically occurs with obstructive lesions above the glottis, such as laryngomalacia and vocal cord paralysis. Biphasic stridor is heard with a fixed obstruction below the glottis, in the subglottis or trachea. Expiratory stridor usually represents an obstruction in the intrathoracic airway, such as tracheomalacia. Obstructive lesions of the airway may be mistakenly diagnosed as asthma on the basis of a respiratory "wheeze"; therefore, a high index of suspicion and correlation with other clinical examination findings are essential to not overlook a potentially critical or surgically correctable cause of airway obstruction. Endoscopic evaluation of the airway has revolutionized the diagnosis and management of an obstructed airway. Endoscopic evaluations are divided into those done with the patient awake and those done under sedation or general anesthesia. Flexible fiber-optic nasopharyngoscopy and laryngoscopy are performed with the child awake. This technique permits safe, rapid examination of the

nose, hypopharynx, supraglottis, and glottis in virtually all children, despite age or lack of cooperation. The awake state allows for evaluation of the dynamics of supraglottic tone, vocal fold mobility, and the impact of fixed obstructing lesions of the larynx. Examination under the influence of sedation or general anesthesia can alter the findings, and therefore a significant cause of airway obstruction, particularly pharyngomalacia, laryngomalacia, and vocal cord paralysis, could be overlooked. Direct examination of the airway under general or sedated anesthesia remains the mainstay for diagnosis and confirmation of lesions that obstruct the airway, especially those below the glottis that cannot be accurately evaluated by awake fiber-optic examination. Airway endoscopy confirms the presence of suspected laryngotracheal pathology such as subglottic stenosis and tracheal stenosis. The goal of evaluation and management of any airway obstruction caused by laryngeal or tracheal disease is to establish and maintain a safe and stable airway. The number of children who require surgical intervention for airway obstruction has increased, in part because of the development of long-term intubation and ventilation techniques in the 1960s that allowed increased survival rates in critically ill premature newborns. As a result of long-term intubation, these infants were able to survive, but an entirely new spectrum of long-term health problems developed, including those of the airway and in particular the larynx and trachea.

AIRWAY PATHOPHYSIOLOGY AND DIAGNOSTIC CONSIDERATIONS The larynx is the entry point for air into the trachebronchial tree and respiratory system. Without a functioning larynx, the remainder of the respiratory system is compromised. The phylogenetic purposes of the larynx are respiration and protection of the lower airway from aspiration. Voice is an evolutionary and secondary function of the larynx. The pediatric airway differs from the adult airway in structure and function. An infant's larynx is about a

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third its adult size and measures approximately 7 mm in the sagittal dimension and 4 mm in the coronal plane. The vocal cords are 6 to 8 mm long. The subglottic space is approximately 4.5 mm across; it is bounded by cricoid cartilage, the only complete ring of cartilage in the upper airway, and is the narrowest portion of the upper airway. Therefore, only 1 mm of mucosal edema in this portion of an infant's airway can obstruct the airway by 40%. As the airway space and dimensions grow with age, mucosal edema causes less compromise of the airway. The cartilaginous framework of the larynx and trachea is softer and more pliable in infancy. This can lead to a tendency to collapse under external compression or air pressure gradients and may result in airway obstruction as seen in laryngomalacia and tracheomalacia. As the infant grows and the cartilage matures, symptoms of these conditions often spontaneously improve and resolve without intervention. In an infant, the larynx sits high in the neck at the level of vertebrae C2 and C3, directly behind the nose, with approximation of the velum, tongue, and epiglottis functionally separating respiration from swallowing. Because neuromuscular function for airway protection is not fully developed at this stage, this intended anatomic relationship allows the infant to safely breathe and feed at the same time without aspirating. As a result of this anatomic relationship, however, any obstruction of the nasal cavity can cause significant obstruction of the airway, which also causes feeding difficulty. In conjunction with neuromuscular maturation, the position of the larynx descends in the neck. By the age of 2 years, the larynx descends to C4, thereby creating less of a functional separation between the functions of breathing and swallowing. By 6 years of age, the larynx has descended to its adult location directly behind C6. Airway and swallowing symptoms tend to be exaggerated if neuromuscular function is compromised or has not matured in conjunction with descent of the larynx.

Tracheotomy Technique The technique of pediatric tracheotomy preferred by the authors is as follows. The patient is taken to the operating room and the airway secured with an endotracheal tube. Because the typical landmarks for tracheotomy may be difficult to identify as a result of the small size of the larynx and cricoid, tracheotomy in the emergency setting is best done with a secured airway either by intubation or by rigid bronchoscopy. A vertical incision is made over the midline of the neck, its superior extent at the cricoid cartilage. Subcutaneous fat is removed with electrocautery, and the fascia is divided in layers in the midline. The strap muscles are separated at the raphe, and the thyroid isthmus is divided with electrocautery. Vertical 4 0 nonabsorbable "stay sutures" are placed through the third and fourth tracheal cartilage rings on the right and left sidesjust off the midline and tied loosely. Gentle tension is applied to these sutures to elevate the tracheal rings, and then the airway is entered with a blade in the midline between the third and fourth rings. As seen in Figure 63-1, the stoma is created by placing 4-0 chromic gut sutures through the cut edge of,the trachea and sewing them to skin. The suggestion by some authors that this

TRACHEOTOMY Tracheotomy is a means of managing severe airway obstruction caused by nearly all of the airway lesions discussed in this chapter. As mentioned earlier, the number of children who require surgical intervention for airway obstruction has increased, partly as a result of the development of longterm intubation and ventilation techniaues in the 1960s that allowed criticallv ill premature newborns to survive.

major indications for long-term tracheotomy in children are airway obstruction, ventilatory support, and pulmonary toilet. Most children with tracheotomy tubes in place for airway obstruction undergo the procedure as very young infants, either for acquired subglottic stenosis related to prolonged endotracheal intubation or for congenital lesions that compromise the airway. Because of the morbidity and the psychosocial and developmental implications of tracheotomy in a child, all alternative interventions should be explored before proceeding to tracheotomy.

A

J

P"

I"

/ /

B

-' A, Placement of stay suture. B, Creation of immediate

stoma

CHAPTER

technique fashions a more "permanent" stoma and may result in a persistent tracheocutaneous fistula after decannulation has not been substantiated. Because the major sources of mortality in pediatric patients undergoing tracheotomy are accidental decannulation or inability to replace an obstructed tube, the authors believe that the added margin of safety, particularly in the first few days, is justification for the approach outlined. In addition, pediatric tracheotomies are rarely short term, and even without the skin sutures, the tract tends to epithelialize over time. The endotracheal tube (or bronchoscope) is withdrawn, an appropriately sized tracheotomy tube is inserted, and ventilation is ensured bilaterally. As seen in Figure 63-2, the previously placed stay sutures are labeled for each of the right and left sides and then taped to the anterior chest wall to serve as emergency traction lines in the event of accidental decannulation. The tracheotomy tube is secured around the neck with cotton twill ties. A tracheotomy tube, particularly if it does not have an inner cannula, should not be directly sewn to the skin of a child. If a significant life-threatening mucous plug obstructs the tracheotomy tube, particularly in the immediate postoperative period when the tract has not been fully established, having a tube secured to the skin presents a delay in urgent removal and replacement with a patent clean tube. Ideally, the position of the tracheotomy tube is evaluated by passing a telescope through the glottis, alongside the tracheotomy tube. This allows the surgeon to ensure that the tip of the tracheotomy tube is proximal to the carina. This technique also permits the surgeon to evaluate the fit of the tracheotomy tube within the lumen of the trachea. This relationship is ideally collinear and concentric without any rubbing or encroachment on the anterior or posterior tracheal wall. If assessment by this method is not possible, a flexible bronchoscope can be passed through the tracheotomy tube to ensure that the tip is proximal to the carina. The tracheotomy tube is changed and the stay sutures are removed in 5 days once the tract has been established. These patients should be managed in a monitored hospital setting, at least until

Labeling stay sutures.

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the tract has been established, a successful change of the tracheotomy tube has occurred, and appropriate education is given and understood by at least two caregivers.

Tracheotomy Complications Perioperative, postoperative, and long-term complications of tracheotomy may develop, many of which can occur whenever a tracheotomy tube is in place. Perioperative complications after tracheotomy tube placement include pneumothorax and major vessel bleeding, particularly from the innominate artery. A chest radiograph should be performed at the end of the procedure to assess for the possibility of pneumothorax or pneumomediastinum. The most common immediate postoperative complications can be life threatening and include mucous plugging and accidental decannulation. The diameter of tracheotomy tubes for children is significantly smaller than those for adults, so any occlusion of the tube by mucus easily leads to complete airway obstruction, particularly in a child who is totally dependent on the tracheotomy to breathe. Likewise, the stoma into the airway for the tracheotomy tube is much smaller in a child. If the tube accidentally dislodges, the increased work of breathing causes further collapse and a "sucking" in closure at the stoma that makes it both difficult to breathe through and challenging to replace the tube. This effect is particularly dramatic in the immediate postoperative period, when the stoma has not fully matured. Because these complications are life threatening, every precaution should be taken to ensure that the tracheotomy tube is patent, carefully suctioned, and at the same time secure around the neck to prevent accidental decannulation. Any child with a tracheotomy tube for a prolonged period is at risk for a minor or major complication. As in the immediate postoperative period, mucous plugging and accidental decannulation are the most serious and life-threatening complications that can occur. Accidental decannulation remains a major concern throughout the time that a child has a tracheotomy tube. It is particularly concerning when a young child develops the manual dexterity to remove the tracheotomy tube. Accidental removal could prove to be a fatal event in a child with nearly total obstruction of the airway above the tracheotomy tube. Though not universally adopted, many caregivers recommend a home apnea monitor or a pulse oximeter to assist caregivers in detecting such a situation. In some cases the child will still be able to breathe comfortably through the stoma, and care should be taken to replace the tube rapidly, but safely. Hastily performed insertion of the tracheotomy tube may result in placement of the tube in a false tract and lead to airway compromise when none existed. We recommend that a tracheotomy tube one size smaller be readily available to the caregiver. Complications related to local infection of either the skin or soft tissue surrounding the stoma (cellulitis), tracheal mucosa (tracheitis), or tracheal cartilage (chondritis) may occur. By adapting the skin directly to the cut edge of the tracheal cartilage, epithelialization of the tract is accelerated and healing promoted. Nevertheless, local

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infections may develop in some patients after the perioperative period. Typically, these individuals have some underlying predisposition to breakdown and bacterial invasion, such as drug-induced immunosuppression, primary immunopathy, or diabetes. Treatment consists of local antimicrobial packing, frequent dressing and cannula changes, and systemic antibiotics. The choice of antibiotics is dictated by culture results. Staphylococcal and pseudomonal infections are frequently seen in the intensive care unit setting. Aggressive infections leading to chondritis with breakdown of the wound, exposure of the great vessels, and extension of infection into the mediastinum are rare. Suprastomal collapse and granuloma formation are nearly universal consequences of the presence of a tracheotomy tube, but the degree of obstruction caused is quite variable. Although some authors recommend routine removal of this tissue at regular intervals, this is not necessary in all patients. Overly aggressive removal of granulomas leads to more frequent recurrence, further arguing against routine excision.82 Granulomas that completely obstruct the suprastomal airway require removal because of the potential for complete airway obstruction if the tube becomes blocked or displaced, as well as to preserve phonation. Parents are usually the first to note symptoms or findings that may suggest significant suprastomal granuloma formation. Most common are progressive loss of voice and difficulty changing the tracheotomy tube. Voice loss occurs because the granuloma prevents the passage of air around the tracheotomy tube that is required to vibrate the vocal cords for voice production. The most lethal of late tracheotomy complications is erosion of the innominate artery at the level where the artery crosses the anterior tracheal wall. This complication can occur as a result of increased pressure from the tip of the tracheotomy tube against the anterior tracheal wall, which leads to the formation of granulation tissue, weakening of cartilage, and eventual erosion if not identified. Rigid and inappropriately curved tubes may contribute to this complication, thus emphasizing the importance of appropriate tracheotomy tube selection. Often, sentinel bleeding of bright red blood will alert the clinician to impending arterial rupture. For this reason, even small amounts of suctioned blood should be evaluated fully by flexible endoscopy. In the same manner that the anterior wall of the trachea can erode from the continued pressure of a tracheal cannula, the posterior wall can break down as well. This is rare as a late complication, although the presence of an indwelling nasogastric tube worsens the situation by trapping the posterior wall between two rigid foreign bodies. The diagnosis is suspected in patients with unexplained recurrent pneumonia or pneumomediastinitis. In a ventilated patient, eructation will occur with each inspiratory breath. This complication is traditionally managed by an open surgical procedure with the interposition of healthy muscle between the trachea and esophagus. With increased surgical experience, improved surgical techniques, identification and management of comorbid conditions that affect outcomes, and improvement in postoperative care, the indications for airway expansion

surgery have been extended to patients with laryngotracheal stenosis as the primary definitive operation, thus avoiding tracheotomy for many of the airway lesions that may have traditionally required a tracheotomy for initial management.29.34.101,lo5

LESIONS OF THE LARYNX AND SUBGLOTTIS Laryngomalacia Laryngomalacia is the most common laryngeal anomaly and cause of stridor in infancy. The clinical manifestation is inspiratory stridor that is worse with feeding, agitation, and supine position. The symptoms are usually present at birth or shortly thereafter. Symptoms peak at 6 to 8 months and usually resolve between 18 and 24 months of age.44 Mild forms of the disease are characterized by inspiratory stridor only. Those with moderate disease usually have feeding problems because it can be difficult for infants to coordinate the "suck-swallow-breathe" sequence in the setting of airway obstruction. Many of these infants have gastrointestinal reflux disease (GERD) and benefit from antireflux treatment and rneasures.30,7" Several factors account for this. First, the increased intrathoracic airway pressure from the proximal airway obstruction promotes reflux. Second, the immature reflexes that regulate esophageal motility cause poor esophageal clearance. Third, GERD in this patient population, like other infant populations with airway problems and apnea, may be related to frequent relaxation events of the lower esophageal sphincter.83 Infants with severe laryngomalacia experience lifethreatening complications of airway obstruction that can lead to pectus formation, failure to thrive, chronic hypoxia, pulmonary hypertension, and cor pulmonale. These patients require surgical interventi~n.~"~~.~~.~~~ The diagnosis is suspected by auscultation of the stridor, but it must be confirmed by flexible laryngoscopy. This examination must be done with the infant awake to demonstrate the cyclic collapse of supraglottic tissues into the laryngeal inlet. The influence of general anesthesia can obscure these findings. Other typical findings are an omega-shaped epiglottis and forward-prolapsing arytenoid cartilage obstructing airflow and complete view of the vocal folds. This examination is also done to exclude other significant supraglottic pathology. The etiology of this condition is multifactorial. Proposed theories include abnormal airway anatomy,"G5 immature cartilage formation, and neurologic disorders. Laryngomalacia is usually a self-limited disease that rarely requires surgical intervention. Surgical intervention is recommended for infants in whom life-threatening episodes of airway obstruction or complications of hypoxia develop. Tracheotomy was the treatment of choice for this condition until the mid-1980s, when techniques of ~~~~~,~~ supraglottoplasty were i n t r o d u ~ e d . Tracheotomy bypasses the site of laryngeal obstruction until the condition resolves spontaneously, generally after 18 to 24 months. Tracheotomy can be avoided by performing supraglottoplasty. This is accomplished by microsurgical removal of

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Laryngomalacia before (A) and after (B) supraglottoplasty.

the redundant prolapsing tissue seen in the area of the cuneiform cartilage and release of the aryepiglottic folds tethering the position of the epiglottis (Fig. 63-3).110 Long-term results with this approach have generally been excellent, with symptom reversal in 80% to 100% of cases.43,5l,fil,6"81,9fi,ll~ Some authors report that as many as 50% of patients will require additional airway procedures, either revision supraglottoplasty or tracheotomy.63,96 Supraglottic stenosis is the most severe complication of this operation and can occur after overzealous removal of tissue or failure to control for acid reflux disease. Although supraglottoplasty is a superior alternative to tracheotomy, in most circumstances some children with multiple medical comorbid conditions, particularly those with severe neurologic impairment or syndromes that involve the airway, are better initially managed with a tracheotomy.22

Laryngeal Atresia and Webs Laryngeal webs are congenital (Fig. 63-4) or acquired (Fig. 63-5). Congenital laryngeal webs and atresia are rare

and may be associated with velocardiac facial syndrome. The embryologic origin is failure of recanalization of the larynx during prenatal development. An atresia or web of sufficient size will be manifested at birth as aphonia and rapid asphyxiation if not immediately addressed. A thin web with a small residual airway may be ruptured by intubation. Thick webs and atresia make emergency intubation by standard techniques difficult, if not impossible. In this setting, survival of the infant may be dependent on securing the airway with urgent tracheotomy. Surgical management of thick webs and atresia requires a tracheostomy tube until surgical intervention is performed.67 Surgical correction usually requires laryngofissure with open airway division of the atretic region and resection of excess cartilage of the cricoid ring if present. A costal cartilage graft to the anterior cricoid may be necessary, similar to laryngotracheal reconstruction for subglottic stenosis. Timing of reconstruction is dependent on many factors, including the age of the child and surgeon experience. Thin and moderate anterior webs are manifested as aphonia or a weak cry at birth without obstructive

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airway symptoms. The primary goals of management are to provide a patent airway and achieve good voice quality. This is challenging because the vocal cords have a tendency for fibrosis and granulation tissue formation after surgical interventions. Traditionally, the treatment of choice for these thin and moderate laryngeal webs is laryngofissure and placement of a stent or keel when the surgeon believes that the child has grown appropriately, generally after 12 months of age. A recent report suggests that select laryngeal webs can be managed with endoscopic lysis and off-label (Food and Drug Administration) topical mitomycin C application, even in infants younger than 1 year.100 This technique may allow congenital webs to be successfully managed at a younger age. However, longterm outcomes of this technique are not available, and it is unknown whether infants treated by this method eventually need laryngotracheal reconstruction to maintain a patent airway. Long-term results of the management of webs depend on the severity of the original lesion. Surgically treated thin webs often heal with minimal disruption of phonation, whereas thicker plates with associated subglottic stenosis have less satisfactory results.7 Acquired laryngeal webs are also uncommon. Such webs are usually caused by direct laryngeal trauma in which the medial surfaces of both vocal cords are disrupted and they heal together and form a web. This is most commonly encountered in the management and treatment of laryngeal papillomas, particularly in the setting of laryngopharyngeal reflux.42

Vocal Cord Immobility: Vocal Cord Paralysis and Vocal Cord Fixation Vocal cord movement requires intact neurologic function of the vagus nerve and free rotation of the cricoarytenoid joint. The action of abduction of the vocal cords from the midline opens the glottic inlet for airflow into the tracheobronchial tree. Airflow is restricted if vocal cord abduction does not occur. Vocal cord immobility is caused by failure of the vocal cords to abduct. The two primary causes of vocal cord immobility are vocal cord paralysis and vocal cord fixation. Both can be congenital or acquired. Injury to the vagus nerve anywhere along its course from the cranial nucleus to the thoracic cavity causes neurogenic vocal cord paralysis. Acquired immobility is usually caused by a stretch injury, pressure encroachment, an inflammatory insult, or trauma or sectioning of the nerve itself; the cricoarytenoid joint is mobile, but neuromuscular function is compromised. A congenital, traumatic, or inflammatory process in the cricoarytenoid joint causes vocal cord fixation; the cricoarytenoid joint is fixed, but neuromuscular function is intact. Fixation and paralysis can coexist. Regardless of the etiology of immobility, failure of one or both of the vocal cords to abduct can lead to stridor and airway obstruction. Unilateral vocal cord immobility causes stridor but not often airway obstruction. Bilateral vocal cord immobility limits airflow through the glottis and frequently causes severe airway obstruction requiring an artificial airway. Some infants and children have mild symptoms

that occur only during periods of upper respiratory tract infection and may not require a tracheotomy. Most children with bilateral vocal cord immobility require tracheotomy early in the course of the disease, before definitive surgical therapy. Because it is bilateral immobility that most commonly leads to airway obstruction, the discussion of surgical treatment is limited to management of bilateral immobility. Management of airway symptoms of bilateral vocal cord paralysis (BVCP) is based on the etiology and site of involvement along the vagus nerve. In neonates and infants, BVCP may have a central etiology and is most commonly associated with a Chiari malformation or hydrocephalus. The caudal displacement of the brainstem seen in a Chiari malformation causes pressure on the brainstem and on the vagus nerve and its nucleus. Recognition plus diagnosis of this compression is important to prevent other complications of a Chiari malformation. BVCP may be relieved once the Chiari malformation is decompressed. Hydrocephalus leads to increased compression of the fourth ventricle, as well as compression of the vagus nerve and nucleus. Decreasing intracranial pressure by shunt placement is Infants with a central etiology of BVCP often ~urative.~~,lO~ who fail to improve with central decompressive procedures require a tracheotomy for airway safety. These groups of patients are also often prone to the eventual development of other lower cranial nerve problems and aspiration that keep them tracheotomy tube dependent and not good candidates for surgcal procedures to achieve decannulation. If the vagal nerve is intact and the cause of BVCP is a localized insult to the vagal nerve such as a stretch injury from obstetric trauma, infection, or extrinsic compression, an observational period is often warranted if there are no acute symptoms of airway obstruction. The paralysis is frequently transient in these patients, who are otherwise healthy. If the cause of vocal cord paralysis is traumatic as a result of direct nerve injury and function is not expected to return, a tracheotomy is required until another procedure can be performed to expand the glottic opening. This situation may be seen in "fixed wire" neck trauma57 with nerve injury or in patients with injury as a complication of thyroid or cardie thoracic surgery. Bilateral vocal fold immobility secondary to fixation occurs when the synovial joint surfaces of the cricoarytenoid joint become fixed, thereby preventing vocal fold abduction or adduction. In this setting, the vagal nerve is usually fully functional and physically intact. The most common cause of fixation of the joint is some type of direct trauma to the joint area itself, such as intubation or neck trauma in which the cricoarytenoid joint is dislocated. Once the joint is injured, an inflammatory process occurs and causes fixation of the joint. Juvenile rheumatoid arthritis can also result in bilateral immobility. Rarely is it congenital. Regardless of the cause of vocal fold immobility, surgical approaches for treatment in children are similar. The fact that a wide variety of surgical approaches are available suggests that no single procedure is ideal. The goal is to open the posterior glottic airway enough to allow for adequate airflow without exposing the patient to an increased risk for the complications of aspiration or a debilitating change in voice. The procedures described

CHAPTER

are often performed after the airway has been secured and is stable with a tracheotomy tube, although surgery can be primary with the goal of avoiding a tracheotomy. The decision to perform definitive primary surgery depends on the acuity of the airway obstruction, the age of the child, and the ability to protect the airway against aspiration. Repositioning and removal of structures and tissue in the posterior glottis, namely, the arytenoid cartilage and mucosa, are well-described techniques of opening the airway in the setting of bilateral vocal cord immobility. Such techniques include arytenoid lateralization, arytenoidopexy, partial arytenoidectomy, and cordotThese procedures can be performed alone omy.10,28,7"97 or in combination. The surgical approach can be external through a laryngofissure, endoscopic with the use of a COP laser, or a combination of both. Endoscopic C 0 2 laser removal of the vocal process of the arytenoid and a portion of the posterior vocal cord has been successfully used in some series.28 The management challenge with this technique is treatment of postoperative granulation tissue formation, which may lead to airway obstruction.80 Recent meta-analysis and retrospective studies evaluating the outcomes of surgically managed BVCP in children suggest that laryngofissure with partial arytenoidectomy combined with a vocal cord lateralization procedure results in the highest decannulation rates when compared with C 0 2 arytenoidectomy and cordotomy procedures or These same studies arytenoidopexy procedures a10ne.ll.~~ conclude that open external procedures appear to be more effective as first-line treatment of pediatric BVCP, with arytenoidopexy with or without partial arytenoidectomy offering an attractive first-line surgical option. They also conclude that C 0 2 laser procedures, though being less successful as a primary procedure, are effective for revision. Although these procedures have been effective in achieving decannulation and maintaining airway patency, long-term outcomes on aspiration and voice are not documented. Posterior graft laryngotracheoplasty is another effective technique to open the posterior glottis.32J08 Through a laryngofissure with extension into the first two rings of the trachea, the posterior cricoid lamina is incised and distracted to separate the arytenoid cartilage. Inserting a costal cartilage graft into the distracted posterior cricoid lamina stabilizes the position of the arytenoid cartilage. Although published series of this prdcedure are small, the decannulation rate after posterior approaches is near loo%." Endoscopic posterior cricoid split and rib graft insertion has been successfully accomplished in a few children with posterior glottic and subglottic stenosis.47

Recurrent Respiratory Papillomatosis Recurrent respiratory papillomatosis (RRP) is the expression of human papillomavirus (HPV) infection in the mucosa of the upper aerodigestive tract. Papillomas involving the larynx are the most common laryngeal tumor in children, and the larynx is the most frequent site of occurrence in the aerodigestive tract (Fig. 63-6). RRP of childhood tends to occur in clusters and has an

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Laryngeal papilloma obstructing the glottis

incredible propensitv for recurrence. The clinical manifestation of laryngeal papilloma is progressive airway obstruction and dysphonia that may progress to aphonia. RRP is most commonly associated with HPV-6 and HPV-11. Subtypes 16 and 18 are only rarely associated with RRP but, if present, have a higher risk for malignant transformation. These viral particles are present in adjacent and clinicallv normal siies of the res~iratorvtract but are expressed primarily in anatomic locations of juxtaposed epithelium, hence the high predilection for the vocal cords.53 The other common location is at an area of mucosal injury, such as a tracheotomy site.53The vector of transmission is controversial. Pediatric RRP and vaginal condyloma acuminatum are both caused by HPV subtypes 6 and 11, thus leading the majority of researchers to believe that vertical transmission from mother to child is taking place in most cases. Though unusual, vertical transmission to children born by cesarean section of mothers with vaginal warts has alsb been documented.90 The natural course of RRP is extremely variable, with no obvious patient-related risk factors to aid in prognosis. The estimated mean number of procedures per child for the disease is 19.7, with an average of 4.4 procedures per year. Many cases have been seen to regress spontaneously in adolescence, but others progress to extensive disease involving the trachea and pulmonary parenchyma, with a high fatality rate from untreatable airway obstruction or pulmonary complications. Even more uncommonly, the papilloma may undergo malignant degeneration to squamous cell carcinoma. For this reason, interval histologic examination of the removed tissue is important. Pediatric RRP continues to be an extremely difficult management problem. The goal of surgical treatment is to maintain a patent airway while providing a usable voice and to prevent spread of disease into the distal airway. Although the mainstay of surgical management has traditionally been the COP laser, newer surgical techniques have demonstrated efficacy in the management of pediatric RRP, including powered instrumentation, the laryngeal shaver,75 and the pulsed dye laser.2%egardless of the surgical technique used, scarring, stenosis, and web formation in the larynx are complications that occur despite careful endoscopic removal of the disease. 1

L

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The papilloma should be removed down to the level of the vocal cord mucosa, but the cords themselves should not be incised. When working in the anterior commissure, bilateral resection should not be done to avoid web formation. Even in experienced hands, the incidence of minor scarring in the anterior glottis may be as high as 25%.l04 Aggressive resection beyond that necessary to maintain a safe airway will not improve the long-term prognosis for remission but may contribute to late morbidity. The role of tracheotomy in the surgical management of laryngeal papilloma is controversial. Most surgeons try to avoid tracheotomy if possible. The mucosal injury at the tracheotomy site encourages the growth of papilloma outside the larynx, possibly increasing the probability of distal spread of the disease. The rate of tracheal spread in patients requiring tracheotomy has been reported to be as high as 50%.16It is quite possible, given the variable degree of aggressiveness of RRP, that patients who have distal spread of disease represent a subset with a predetermined propensity for dissemination beyond the larynx and would require a tracheotomy regardless. Patients in whom life-threatening airway obstruction develops as a result of aggressive disease within or beyond the larynx that cannot be managed by endoscopic procedures should have a tracheotomy placed until the disease can be controlled with further surgical intervention and adjunctive therapy. If a tracheotomy is placed, the clinician should make an effort to decannulate whenever possible. None of the many adjunctive therapies described for the management of RRP has convincingly changed the outcome of the disease course. The most common adjuvant medical therapies used for pediatric RRP are intei-feron alfa-2a, retinoic acid, and indol-3-carbinol/diindolylmethane (I3C/DIM). The most recently introduced adjunctive therapy is cidofovir, an acyclic nucleoside phosphonate derivative with antiviral activity that is used for the treatment of cytomegalovirus retinitis in patients with acquired immunodeficiency syndrome. Off-label use of cidbfovir injected directly into the region after removal of laryngeal papilloma has demonstrated efficacy in selected patients. In addition, promising research is being conducted to develop a vaccination for pediatric RRP.

Congenital subglottic stenosis with an elliptically shaped cricoid.

cricoid cartilage. The definition of what may be congenital or acquired stenosis can be somewhat arbitrary because secondary soft tissue stenosis and scarring from injury may develop in children with congenital subglottic stenosis and thereby result in an acquired stenosis. This most commonly occurs with prolonged intubation, so the true incidence of congenital subglottic stenosis is difficult to determine. Of the areas involved in stenosis, the subglottis is the most common. Most subglottic stenoses that require surgical management are acquired. An example of acquired stenosis is seen in Figure 63-8. The principles of surgical management discussed are applicable to congenital and acquired disease. Acquired subglottic stenosis became much more common after 1965 with the introduction of prolonged endotracheal intubation and ventilation of neonates.64 As the survival of very-low-birth-weightinfants increased, so did the number of patients with secondary laryngotracheal stenosis. It was recognized that acquired stenosis was more severe than congenital subglottic stenosis and a much more difficult management problem.45 Fortunately, advances in the technique of endotracheal intubation and tube stabilization along with the implementation of softer

Laryngotracheal and Subglottic Stenosis Laryngotracheal stenosis may be characterized by etiology and area involved. Areas of involvement include the supraglottis, glottis, subglottis, and upper part of the trachea. A single area or multiple areas can be involved. Stenosis of the larynx is congenital (Fig. 63-7) or acquired (Fig. 63-8). Congenital stenoses are believed to be the result of failure or incomplete recanalization of the laryngeal lumen by the 10th week of gestation. Congenital subglottic stenosis is histopathologically divided into membranous and cartilaginous stenosis (Table 63-1). Congenital stenosis is considered to exist when the lumen of the cricoid region of the airway measures less than 4 mm in a full-term infant or 3 mm in a premature infant with no previous history of intubation. As seen in Figure 63-7, the typical appearance of a congenital cartilaginous stenosis is that of an elliptically shaped

Acquired subglottic stenosis

CHAPTER

1 Cartilaginous Stenosis

Soft Tissue Stenosis

Cricoid cartilage deformity Granulation tissue Normal shape Submucosal fibrosis Small for infant's size Submucosal gland hyperplasia Abnormal shape Large anterior lamina Large posterior lamina Generalized thickening Elliptical shape Submucous cleft Other congenital cricoid stenoses Trapped first tracheal ring

I

materials for endotracheal tubes have decreased the incidence of tracheal/laryngotracheal stenosis in surviving neonates to 0.9% to 8.3%.78With the proliferation of lifesaving advancements in medicine and surgery, children survive disease processes in which survival was not likely 20 years ago. Other chronic diseases also develop as a result of treatment, with subglottic stenosis being one of them. The numbers of toddlers, children, and adolescents in whom stenosis of the larynx is now developing has increased, but the exact percentages are unknown. The stenosis can be soft or firm and is commonly a combination of both. Causes of soft tissue stenosis are submucosal mucous gland hyperplasia, ductal cysts, fibrous and granulation tissue, and laryngopharyngeal reflux of gastric acid causing mucosal edema. Firm stenoses are usually associated with an abnormally shaped or thickened cricoid cartilage or mature scar tissue. The Cotton-Myer grading system is most widely used for documentation of the degree of obstruction (Fig. 63-9). Endotracheal tube sizing has become the most widely used means of grading and assessing the degree of ~ t e n o s i s . ~ ~ Successful laryngotracheal reconstructive surgery requires a carefully formulated plan that includes identification

Cotton-Myer subglottic stenosis grading system.

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and management of significant medical comorbid conditions that have the potential to contribute to poor outcomes. The plan also requires accurate identification of the type of stenosis and all areas of the larynx and upper trachea involved because the stenosis can be multilevel and require more than one type of intervention. The treatment plan is custom tailored to the specific patient and that ~atient'smedical comorbid conditions and anatomic problems. The treatment plan is best formulated by a multidisciplinary team approach, including the pediatric otolaryngologist, pediatric surgeon, pulmonologist, gastroenterologist, anesthesiologist, intensivist, and appropriate allied health personnel. Any laryngeal stenosis can be effectively managed by placement of a tracheotomy. The morbidity plus mortality associated with tracheotomy tube placement has encouraged advancements in laryngotracheal reconstructive procedures to either avoid tracheotomy tube placement or achieve decannulation. Associated medical comorbid conditions, particularly cardiopulmonary disease and GERD, must be addressed, stabilized, and managed before considering surgical intervention. Children who require significant ventilatory or medical support are not good candidates for laryngotracheal reconstruction. Evaluation of swallowing function is essential to help determine the ability to protect the airway and the risk for aspiration so that preoperative and perioperative accommodations can be made to minimize the complications of aspiration. Patients with significant aspiration are not usually good candidates for laryngotracheal reconstruction. The influence of gastroesophageal reflux on laryngotracheal stenosis and wounds cannot be overemphasized. GERD is an etiologic factor in acquired subglottic stenosis. Clinical and animal studies demonstrate that the presence of acid in the region of the larynx negatively affects healing. 31,3"58,62,95,107 Perioperative and postoperative aggressive medical and sometimes even surgical antireflux therapy95 is recommended in the setting of laryngotracheal reconstructive surgery. Prospective and retrospective studies evaluating long-term outcomes of reflux control in such surgery are not available. Surgical management of laryngotracheal stenosis is individualized to the patient, and no operative approach is exactly the same for all cases. Each individual patient has multiple variables that must be considered, including the location and extent of the stenotic area, medical comorbidity, airway protection and swallowing function, age, and weight. Surgical options include endoscopic techniques, expansion surgery, and resection surgery. The methods used are dependent on the degree and location of the stenosis. In general, grade I stenosis is usually managed by endoscopic techniques. Grade I1 stenosis may be approached with either endoscopic or open techniques, depending on the location and extent of the lesion. Grade I11 and IV lesions almost always require open surgcal reconstruction. Grade I and I1 stenosis can be approached with endoscopic techniques. COPand potassium-titanyl-phosphate (KTP) lasers, because of their precise tissue characteristics, are the most widely used modalities. The laser is useful for treating early intubation injury with granulation tissue

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formation, subglottic cysts, thin circumferential webs, and crescent-shaped bands. Factors predisposing to failure of endoscopic laser treatment of subglottic stenosis are previous failed endoscopic procedures, significant loss of the cartilagnous framework, thick circumferential cicatricial scarring greater than 1 cm in vertical dimension, and posterior commissure involvement. A complication of laser treatment of subglottic stenosis is exposure of perichondrium or cartilage and subsequent perichondritis and chondritis, which may lead to further scar formation. Open surgical reconstruction is recommended when endoscopic methods to establish a patent airway are inappropriate or have failed. An anterior cricoid split is considered one of the expansion surgical techniques. It is used predominantly in a neonate with anterior subglottic narrowing who fails multiple attempts at extubation despite adequate pulmonary reserve. In this setting the laryngotracheal problem is due to narrowing at the level of the cricoid cartilage, and the airway lumen expands and decompresses once the anterior cricoid cartilage is divided in the midline. The endotracheal tube is left in place for 5 to 10 days. Dexamethasone sodium phosphate is initiated 24 hours before extubation and continued for 5 days after extubation. This technique leads to successful extubation in 66% to 78% of patients.lg As seen in Table 63-2, before considering the use of this technique in a neonate, several clinical criteria must be met to increase the probability of successful extubation after an anterior cricoid split. In the authors' hands, this technique has been replaced by an anterior cricoid split with the placement of a small auricular cartilage graft followed by endotracheal intubation for 7 days. Outcomes comparing decannulation rates of cricoid split versus cricoid split ~ t placement h of an auricular cap graft have not been formally reviewed. Multiple open procedures to expand a stenosed airway have been described. These procedures and their applications have evolved over the past 30 years. Since the introduction of laryngotracheal reconstruction with cartilage interpositional grafting in 1972 with placement of a cartilage graft between a split anterior cricoid and upper trachea,lg this method has become one of the most common techniques of expanding stenotic airway segments. Anterior grafting alone is typically used for grade I1

Extubation failure on at least two occasions secondary to subglottic laryngeal pathology Weight greater than 1500 g No ventilator support for at least 10 days before repair Supplemental 0, requirement less than 30% No congestive heart failure for 1month before repair No acute respiratory tract infection No antihypertensive medication for 10 days before repair

and I11 stenosis that does not involve the posterior glottis or subglottis. If there is posterior glottic or subglottic involvement in addition to the anterior stenosis, the posterior cricoid plate lamina is split with or without placement of an interpositional graft, depending on the degree of stenosis. This problem is more commonly seen in grade 111 and IV stenosis. Partial cricotracheal resection has evolved into another option for the surgical management of selected ~ 9 3operation ~~~~~02 grade 111 and IV s t e n o ~ i s . 3 R ~ ~ ~ ~In~ this the stenotic region of the anterior cricoid plate-and any involved tracheal stenotic segment are resected, and the trachea is mobilized to allow for an end-to-end anastomosis. The posterior trachea and trachealis muscle are anastomoied to the posterior cricoid plate and its mucosa. The anterior mobilized trachea is then sewn into the removed segment of the cricoid and secured to the thyroid cartilage (Figs. 63-10 and 63-11 ) .382R5393298 The traditional approach to laryngotracheal reconstructive surgery involves several stages of r e c o n ~ ~ c t i o n ~ ~ ~ ~ ~ ~ 2 0 when an expansion operation is performed, and a stent (Silastic sheeting or Teflon) is placed to stabilize the reconstruction. The stent is left in place above the tracheotomy tube (suprastomal stent) for 1 to 6 weeks. After removal of the stent and once the surgical site has healed with a patent subglottis, the tracheotomy tube is downsized until the child tolerates and is able to breathe around a plugged tracheotomy tube. Once this is accomplished, the tracheotomy tube is removed. This process of reconstruction and decannulation can take weeks to several months. The morbidity and potential mortality associated with a tracheotomy tube are well

Cricotracheal resection. A, Resection of the anterior cricoid with a mucosal incision in the posterior cricoid. B, View of resection of a scarred airway with preservation of the recurrent laryngeal nerve. C, Resection complete with a cuff of posterior tracheal mucosa.

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. -.

Reanastomosis o f a resected airway. A, Detensioning suture. B, Mobilization o f the trachea. C, Posterior anastomosis complete; anterior anastomotic sutures placed. D,Anastomosis complete.

recognized in children and have been discussed earlier in this chapter. With staged reconstruction and stent placement the child is left with little or no airway above the tracheotomy tube, which is life threatening if the tube accidentally falls out or is occluded. Long-term stenting carries the additional morbidity of granulation tissue formation, infection, dislodgment of the stent, dysphagia, and aspiration. To address these risks and circumvent some of these problems, single-stage laryngotracheal reconstruction (SSLTR) evolved. In the authors' hands, staged procedures are still performed in children with compromised pulmonary reserve, in those with complex multilevel stenosis that requires prolonged stenting, or in children in whom sedation is likely to be problematic. SSLTR involves surgical correction of the stenotic airway with a short period of endotracheal intubation, thus avoiding the need for prolonged laryngotracheal stenting and tracheotomy tube dependency. The airway must have adequate cartilaginous support to consider SSLTR as a surgical option. SSLTR requires comprehensive understanding of the principles of airway reconstruction and extensive experience on the part of the surgeon, anesthesiologist, intensivist, and nursing staff. Postoperative care of these patients can be complicated.34,37s48The experience at our institution with 200 SSLTR cases showed that reintubation was required in 29% and postoperative tracheostomy in 15%. The overall decannulation rate was 96%. It was also found that the use of anterior and posterior costal cartilage grafting, age younger than 4 years, sedation for more than 48 hours, leak pressure around the endotracheal tube greater than 20 cm H 2 0 , and moderate/severe tracheomalacia significantly increased the rate of reintubation. The duration of stenting did not affect outcomes. Children with anterior and posterior grafts and those

with moderate or severe tracheomalacia were more likely to need a postoperative tracheostomy. SSLTR can be effectively used for the treatment of pediatric laryngotracheal stenosis; however, diligent preoperative assessment of the patient's comorbid conditions and airway, meticulous pdstoperative care, and surgical skill and experience are important to the success of this operation. The ultimate goal of laryngotracheal reconstruction is tracheotomy decannulation or prevention. The rate of decannulation varies with the severity of stenosis and the method of reconstruction. Surgical management of pediatric subglottic stenosis is challenging. Multiple operations mav be reauired to achieve eventual extubation or decannulation, and there is no specific model to predict the outcome of pediatric airway reconstructive surgery. Review of the experience at our institution shows that decannulation rates for double-staged laryngotracheal reconstruction for Cotton-Myer grades 11,111, and IV are 95%, 74%, and 86%, respectively. SSLTR decannulation rates for Cotton-Myer grades 11,111, and IV are loo%, 86%, and 100%. Our experience is that children with Cotton-Myer grade I11 or IV disease represent a significant challenge, and refinements of technique are needed to address this subset of children. Children with grade IV stenosis are the most difficult group to obtain good results with surgical management. We have found that refinements in surgical technique plus the application of cricotracheal resection as the primary operation for grade IV stenosis has improved decannulation rates from 67% in the 1980s to 86% in the 1 9 9 0 ~ . ~ ~ Our experience also shows that patients who undergo cricotracheal resection have higher decannulation rates than do those who undergo la@ngotracheal reconstruction with anterior and posterior costal cartilage grafting (92% versus 81%). Cricotracheal resection patients are

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less likely to need additional open procedures to achieve decannulation (18% versus 46%)." Patients with grade IV stenosis and involvement of other areas of the larynx and trachea often require extended cricotracheal resection with the application of cartilage grafting or posterior cricoid and arytenoid procedures.

Hemangioma Subglottic and tracheal hemangiomas are benign congenital vascular malformations derived from mesodermal rests. The lesions are relatively uncommon and account for 1.5%of all congenital laryngeal anomalies, with a 2:l female p r e p ~ n d e r a n c ePatients .~~ are usually asymptomatic at birth but have stridor within the first few months of life; 85% are identified in the first 6 months,14and 50% have cutaneous hemangiomas present at the time of diagnosis.56 Asymmetric subglottic narrowing is the classic finding on soft tissue neck radiographs. Endoscopic diagnosis is usually made without biopsy because of the lesion's typical appearance of a compressible, asymmetric, submucosal mass with bluish or reddish discoloration most often found in the posterolateral region of the subglottis (Fig. 63-12). Subglottic and tracheal hemangiomas have a rapid growth phase that slows by 12 months, followed by slow resolution over the subsequent months to years. Most show complete resolution by 5 years. However, subglottic hemangiomas are associated with 30% to 70% mortality when left untreated." Therapeutic and surgical management of this problem is directed at maintaining the airway while minimizing potential long-term sequelae of the treatment itself. Current management options include partial laser excision, open surgical resection, systemic or intralesional steroids, systemic interferon alfa-2a, and tracheotomy. Bypassing the obstructing lesion with a tracheotomy plus waiting for the expected involution provides the optimal anatomic result and is considered by many to be the standard of care by which all other treatment options need to be measured. However, as previously discussed in this chapter, there are risks associated with a tracheotomy, as well as the delay in speech and language that is routinely

encountered when children require a tracheotomy at a young age. Early methods of treatment that are no longer used because of associated morbidity include external beam radiation, radium and gold implants, and sclerosing agents. Systemic corticosteroids for the treatment of subglottic hemangiomas were introduced in 1969 by Cohenl5 and are used as both primary and adjuvant therapy. Steroids decrease the size of the hemangioma and accelerate involution by an unknown mechanism. They are thought to decrease hemangioma size by blocking estradiol-induced growth40 or by directly increasing capillary sensitivity to vasoconstrictors. Corticosteroid therapy, with or without tracheotomy, has been shown to be successful in 82% to 97% of cases. However, whether the period of tracheotomy cannulation is decreased is unknown.g1The risks associated with long-term steroid use include growth retardation, a cushingoid face, and increased susceptibility to infection, including life-threatening Pneumocystis carinii pneumonia.3 Using an alternateday dosing regimen in the smallest possible doses may reduce these effects. Recent reports suggest that systemic steroids followed by short-term intubation after diagnostic bronchoscopy can be used as a safe and effective alternative in the management of obstructive pediatric subglottic hemangiomas.2 Other@ report successful avoidance of tracheotomy by endoscopic intralesional injection of corticosteroids into the hemangioma, with or without short-term intubation. Endoscopic surgical management with the C 0 2 laser .~~ was first reported in 1980 by Healy and c o l l e a g ~ e sSince its introduction, the C 0 2 laser alone or in combination with steroids or tracheotomy has become a standard therapy. Isolated unilateral subglottic hemangiomas are usually the best type and location for C 0 2laser treatment. In carefully selected patients, partial resection of the hemangioma with the C 0 2laser, with or without the addition of systemic . ~ ~ reports show that the corticosteroids,is s u c c e s s f ~ lRecent KTP laser is a good tool for the management of subglottic hemangiomas and has a low incidence of complications.52~60 The KTP laser is preferentially absorbed by hemoglobin, thus making this laser system well suited for the treatment of vascular tumors such as a hemangioma. Long-term outcomes of this technique are not available.

. -. hemangioma.

suibglottic

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less likely to need additional open procedures to achieve decannulation (18% versus 46%).33Patients with grade IV stenosis and involvement of other areas of the larynx and trachea often require extended cricotracheal resection with the application of cartilage grafting or posterior cricoid and arytenoid procedures.

Hemangioma Subglottic and tracheal hemangiomas are benign congenital vascular malformations derived from mesodermal rests. The lesions are relatively uncommon and account for 1.5% of all congenital laryngeal anomalies, with a 2:l female p r e p ~ n d e r a n c ePatients .~~ are usually asymptomatic at birth but have stridor within the first few months of life; 85% are identified in the first 6 months,14and 50% have cutaneous hemangiomas present at the time of diagnosis? Asymmetric subglottic narrowing is the classic finding on soft tissue neck radiographs. Endoscopic diagnosis is usually made without biopsy because of the lesion's typical appearance of a compressible, asymmetric, submucosal mass with bluish or reddish discoloration most often found in the posterolateral region of the subglottis (Fig. 63-12). Subglottic and tracheal hemangiomas have a rapid growth phase that slows by 12 months, followed by slow resolution over the subsequent months to years. Most show complete resolution by 5 years. However, subglottic hemangiomas are associated with 30% to 70% mortality when left untreated.56 Therapeutic and surgical management of this problem is directed at maintaining the airway while minimizing potential long-term sequelae of the treatment itself. Current management options include partial laser excision, open surgical resection, systemic or intralesional steroids, systemic interferon alfa-2a, and tracheotomy. Bypassing the obstructing lesion with a tracheotomy plus waiting for the expected involution provides the optimal anatomic result and is considered by many to be the standard of care by which all other treatment options need to be measured. However, as previously discussed in this chapter, there are risks associated with a tracheotomy, as well as the delay in speech and language that is routinely

encountered when children require a tracheotomy at a young age. Early methods of treatment that are no longer used because of associated morbidity include external beam radiation, radium and gold implants, and sclerosing agents. Systemic corticosteroids for the treatment of subglottic hemangiomas were introduced in 1969 by Gohen15 and are used as both primary and adjuvant therapy. Steroids decrease the size of the hemangioma and accelerate involution by an unknown mechanism. They are thought to decrease hemangioma size by blocking estradiol-induced growth40 or by directly increasing capillary sensitivity to vasoconstrictors. Corticosteroid therapy, with or without tracheotomy, has been shown to be successful in 82% to 97% of cases. However, whether the period of tracheotomy cannulation is decreased is unknown." The risks associated with long-term steroid use include growth retardation, a cushingoid face, and increased susceptibility to infection, including life-threatening Pneumocystis cannii pneumonia.3 Using an alternateday dosing regimen in the smallest possible doses may reduce these effects. Recent reports suggest that systemic steroids followed by short-term intubation after diagnostic bronchoscopy can be used as a safe and effective alternative in the management of obstructive pediatric subglottic hemangiomas.2 Others66report successful avoidance of tracheotomy by endoscopic intralesional injection of corticosteroids into the hemangioma, with or without short-term intubation. Endoscopic surgcal management with the COBlaser .~~ was first reported in 1980 by Healy and c o l l e a g ~ e sSince its introduction, the COBlaser alone or in combination with steroids or tracheotomy has become a standard therapy. Isolated unilateral subglottic hemangiomas are usually the best type and location for C 0 2 laser treatment. In carefully selected patients, partial resection of the hemangioma with the GO2laser, with or without the addition of systemic Recent reports show that the corticosteroids,is succe~sful?~ KTP laser is a good tool for the management of subglottic hemangiomas and has a low incidence of complications.5*~60 The KTP laser is preferentially absorbed by hemoglobin, thus making this laser system well suited for the treatment of vascular tumors such as a hemangioma. Long-term outcomes of this technique are not available.

Sulbglottic

hemangioma.

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Interferon alfa-2a has been used recentlv in children with obstructing hemangiomas that were unresponsive to laser or corticosteroid therapy (or both), and it has achieved 50% or greater regression of the lesion in 73% of patients.74 1nte;feron alfa-2a requires prolonged therapy because it does not promote involution but inhibits proliferation by blocking various steps in angiogenesis. The potential side effects, which include neuromuscular impairment, skin slough, fever, and liver enzyme elevaits use to larger, potentially fatal lesions. t i ~ nlimit , ~ ~ Despite the more widespread use of steroids and other treatment modalities, the ieauirement for tracheostomv has remained unchanged over the last 20 years. The use of laser therapy does not appear to confer any additional therapeutic benefit over and above tracheostomy alone in brhging about resolution of subglottic hemangioma. Systemic steroids may reduce the size of the hemangioma but are associated with multiple adverse effects. The decision to use the aforementioned techniques must therefore be made in light of these observations.13 To avoid the complications and provide more definitive treatment, the topic or it can extend to the carina and even into the mainstem of open surgical excision has been revi~ited.l3,29~~2,88,8~~~~~,~~5 bronchi. Multiple classification systems have been used The surgical technique is similar to SSLTR. The airway is to describe laryngeal clefts. Independent of the numberopened at the level of the cricoid cartilage, followed by ing system used, it is useful to differentiate the length of submucosal dissection with excision of the hemangioma. the cleft as laryngeal (interarytenoid only, partial cricoid, Because an associated moderate subglottic stenosis is or complete cricoid) and laryngotracheoesophageal often present, an anterior cartilage graft is usually placed (extending into the cervical trachea or the intrathoracic and the patient is intubated for 2 to 3 days. A recent study concluded that surgery for severe subglottic hemangioma trachea). Patients with a laryngeal cleft or LTEC have congenital is a reliable technique in selected patients and should be circuconsidered for cor6coresistant or corti~ode~endent, inspiratory stridor, cyanotic attacks associated with feeding, lar or bilateral hemangiomasl'J1and large life-threatening aspiration, and recurrent pulmonary infections. As the length of the cleft increases, so does the severity of syrnp hemangiomas.ZgThe early experience of single-stage excitoms, with aspiration present in 100% of patients with sion suggests that this technique is an exciting and LTECs. Although radiographic contrast studies may suggest promising surgical alternative, and more widespread a d o p aspiration, the best single study for identifying a laryngeal tion of it may be the best way of further improving the cleft is careful endoscopic examination with a high degree outcome of patients with subglottic hemangioma.13 of suspicion on the part of the endoscopist. The arytenoids need to be parted to obtain adequate visualization because the clefts may be obscured by redundant esophageal Laryngeal and Laryngotracheoesophageal Clefts mucosa prolapsing into the glottic and subglottic lumen. Most clefts that are limited to the supraglottic larynx do not Congenital laryngeal and laryngotracheoesophageal require surgical intervention. The anatomic depth of these clefts (LTECs) are rare conditions that can be charactersmall clefts reaches to the interarytenoid level and stops at ized by. a -posterior midline deficiency in separation of the vocal processes. Treatment methods include evaluation the larynx and trachea from the hypopharynx and and treatment of gastroesophageal reflux and swallowing esophagus (Fig. 63-13). The incidence is less than 0.1%, therapy.26 When surgical intervention is required for these and the majority of cases may be sporadic or associated smaller clefts, the authors prefer an open repair, although with a syndrome. There is a strong association with other some advocate endoscopic r e a ~ i r . ~ ~ ~ ~ anomalies (56%), most commonly tracheoesophageal Surgical repair is required for all laryngeal clefts that fistula in 20% to 27%.26 Six percent of children with a extend below the vocal cords. An anterior approach tracheoesophageal fistula have a coexisting laryngeal cleft. through a laryngofissure is the standard technique, and it Of the children with a tracheoesophageal fistula, the . provides excellent exposure of the entire defect without laryngeal cleft goes undetected in three quarters until perrisk to the laryngeal innervation. Complete LTECs that sistent aspiration, despite successful tracheoesophageal extend to the carina may require a posterolateral approach fistula repair, prompts further investigation.26 Laryngeal to allow for two-layer closure or an anterior approach with clefts or LTECs are often associated with a syndrome, most the use of either cardiopulmonary bypass or extracorporal commonly Opitz-G syndrome, the VATER association circulation. In most circumstances, a tracheotomy is (vertebral defects, imperforate anus, tracheoesophageal present before or placed at the time of reconstructive fistula, radial and renal dysplasia), the VACTERL associasurgery. However, single-stage repair with endotracheal tion (vertebral, anal, cardiac, tracheal, esophageal, renal, and limb anomalies), and Pallister-Hall syndrome.25 intubation used as a short-term stent is increasingly being performed and preferred by the authors for clefts extendThe degree of clefting may be relatively minor and ing to the midtrachea. involve only failure of interarytenoid muscle development,

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TRACHEAL LESIONS Tracheomalacia Tracheomalacia is a condition in which the tracheal wall cartilage is soft and pliable. The cardinal symptom of tracheomalacia is stridor with increased respiratory effort that leads to dynamic collapse of the airway. Tracheomalacia is primary or secondary, with the etiology of primary tracheomalacia being unknown. It is a common cause of stridor in infancy. Primary tracheomalacia differs from laryngomalacia in that the phase of stridor occurs during expiration; however, laryngomalacia and tracheomalacia can coexist, and the child may have both inspiratory and expiratory stridor. Most infants with primary or isolated tracheomalacia outgrow the condition by 18 months of age. Secondary tracheomalacia occurs as a result of another coexisting condition. The most common congenital conditions that cause secondary tracheomalacia are extrinsic compression of a vascular anomaly, such as a vascular ring or innominate artery (Fig. 63-14), and tracheoesophageal fistula, in which the malacia is opposite the fistula site located on the posterior tracheal wall. Tracheomalacia may also develop in infants who require long-term ventilatory support with high-pressure endotracheal tubes or cuffed tracheotomy tubes. There is no good treatment for severe or life-threatening tracheomalacia other than bypassing and stenting the area with a tracheotomy tube. Methods of endotracheal stenting with angioplasty and Palmaz stents have been attempted with varied success, and the authors prefer the use of a tracheotomy tube.

Congenital Tracheal Stenosis Congenital tracheal stenosis is a rare, potentially lifethreatening anomaly that usually involves complete cartilaginous tracheal rings and over the years has

Secondary tracheomalacia from compression of the innominate artery.

proved to be difficult to treat. In 1964, Cantrell and Guild12 classified congenital tracheal stenosis into three categories: long-segment stenosis with generalized hypoplasia (22%), funnel-like stenosis (37%),and segmental stenosis (41%) . Associated anomalies in children with congenital tracheal stenosis are common, with 24% having coexistent cardiovascular anomalies, including a pulmonary artery sling.9 Children with congenital tracheal stenosis usually have a history of biphasic stridor and possibly acute respiratory distress. Anteroposterior radiographs are strongly recommended at the initial evaluation, but a definitive diagnosis is best obtained with endoscopy (Fig. 63-15). Recent advances in threedimensional magnetic resonance imaging provide an alternative for diagnosis and follow-up. Additionally, magnetic resonance imaging, contrastenhanced computed tomography, or echocardiography is frequently needed to identify associated cardiovascular abnormalities. Over recent years, tremendous progress has been made in the treatment of congenital tracheal stenosis. Segmental resection with primary anastomosis has been shown to be the treatment of choice for stenoses involving up to 50% of the trachea. However, the large number of procedures advocated for the treatment of long-segment stenosis indicates that none has proved to be universally successful. Findings from our institution reiterate that nonoperative management of complete tracheal rings may be appropriate in selected patients. A retrospective stud~Qstimatedthat up to 10% of patients with complete tracheal rings will not require tracheoplasty. Selected patients must be asymptomatic or have minimal symptoms and demonstrate tracheal growth over serial examinations; the rate of growth, however, is left to be determined. Anterior tracheoplasty with pericardium was first described by Idriss and colleagues in 1984.46Since then, reported results of this technique reveal survival rates of 47% to 76% in larger series.24 Costal cartilage grafting for augmentation has had similar resultslo3in a

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smaller number of patients. Other augmentation materileft of the trachea was a normal finding in children, as als that have been tried include esophageal wall, rib, dura, seen on aortography in 96% of patients.94 and periosteum. Vascular compression of the tracheobronchial tree has Slide tracheoplasty, as described by Tsang and colan overall incidence of 3%. The most common sympto1eagues:g involves transverse division of the trachea in the matic true vascular ring is a double aortic arch, which middle of the stenosis and longitudinal incisions of the occurs if the fourth branchial arches and the dorsal aortic anterior portion on one end and the posterior portion on root persist on both sides. In 1 in 2500 persons, the left arch the other; the two ends slide over each other, thereby halvhas an atretic segment, but the right arch persists. A righting the length and doubling the diameter. In its original sided arch with a descending right aorta does not cause description, slide tracheoplasty was used for funnel-shaped airway compromise. However, if there is an associated left stenoses. This technique has evolved and has now become ductus or an aberrant left subclavian artery, a loose vascular the preferred surgical approach for tracheal stenosis ring is formed that generally results in less airway compre regardless of the length of narrowing (Fig. 63-16).21,84 mise than a true double aortic arch does. Because of the Tracheal homograft reconstruction should be considassociated airway compression of the lower trachea and ered only if other methods are not applicable The 83% right main bronchus, a pulmonary artery sling is the most success and survival rate reported with this technique49xjO symptomatic of the noncircumferential vascular anomalies has not stood the test of time. and occurs when the left sixth arch resorbs and the left pulmonary artery arises as a large collateral artery from the right pulmonary artery and passes between the esophagus and trachea to perfuse the left lung. This anomaly Tracheobronchial Vascular Compression commonly results in significant compromise of the right Vascular compression of the tracheobronchial tree has mainstem bronchus and airway symptoms. In addition, been the subject of much discussion since 1945, when 30% of patients with pulmonary artery slings have associthe first successful operation for a double aortic arch was ated complete tracheal rings4 The aberrant right described. A 1963 report27 reviewed 104 cases and coined subclavian artery is the most common mediastinal vascular the term "reflex apnea" to describe the episodic apnea anomaly. However, because of its retroesophageal course, associated with airway vascular compression. This series affected individuals may have dysphagia, but rarely symptu was reviewed and updated in 1969,70with successful medmatic airway compromise. Innominate artery compression ical management reported in 86.3% of 285 cases. of the trachea is not associated with a true vascular anomaly. Initial indications for surgical management included The innominate artery normally passes from its origin on the reflex apnea and recurrent bronchopulmonary infecaortic arch left of midline, across the anterior surface of tions, and these indications were expanded into absolute the trachea, to the right side. It has been hypothesized that and relative criteria." Relative criteria included failure of in patients who are symptomatic, the innominate artery is medical management, greater than 50% compression of more taut than normal and the tracheal cartilage is unusuthe tracheal lumen, and associated airway and lung ally compliant and more easily compressed or that abnormalities. Further definition of indications was dilatation of other structures, such as the heart, esophagus, reported in 1975,when 60 children who were operated on or thymus, causes mediastinal crowding. for innominate artery compression of the trachea were Respiratory compromise from tracheobronchial vascompared with 30 children who did not undergo surgery; cular compression is potentially life threatening but can it should be noted that the appropriateness of surgical cause subtle symptoms. A high index of suspicion is required to make the diagnosis. Patients with significant intervention was based not on the severity of compression vascular compression are usually identified early because seen at endoscopy or radiographically but on the severity of symptoms." Discontinuation of the word "anomalous" of the presence of stridor, chronic cough, recurrent was recommended in 1981 when it was reported that an bronchitis and pneumonia, difficulty feeding and failure origin of the innominate artery partially or totally to the to thrive, and occasionally reflex apnea. Reflex apnea has

transverse section of the trachea, with a proximal segment of the rings split posteriorly and the distal segment split anteriorly. Sliding of the two portions together doubles the circumference and halves the length.

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been described as a reflexive respiratory arrest of variable duration that is secondary to the stimulation of vagal afferent nerve fibers during swallowing and other forms of transient intrathoracic pressure changes, and it can be fatal. Chest radiographs may provide some evidence of tracheal compression, and a barium esophagograrn can show relatively characteristic filling defects that correspond to the various types of vascular compression. However, once vascular compression is suspected, the diagnostic modality of choice is magnetic resonance imaging, which will clearly demonstrate the mediastinal vascular anatomy, as well as the size of the lower airway. Spiral computed tomography may be a useful adjunct o r alternative to magnetic resonance imaging."5.Uthough today the diagnosis of vascular compression is usually known before undergoing endoscopy, bronchoscopy also reveals characteristic findings of compression, depending o n the type of vascular ring or sling. Bronchoscopy provides immediate visual assessment of the surgical results that can be achieved with relief of the compression and the degree of residual tracheomalacia present. Nonsurgical management may be effective for the majority of cases of innominate artery compression and loose vascular rings and slings that are mildly symptomatic. In contrast, moderately to severely symptomatic patients usually require surgical repair. Absolute indications for surgical treatment include reflex apnea, failure of medical management of severe respiratory distress after 48 hours, and prolonged intubation. Relative criteria include repeated episodes of lower respiratory tract infection, exercise intolerance, significant dysphagia with failure to thrive, o r coexisting subglottic stenosis, asthma, cystic fibrosis, o r previous tracheoesophageal repair. Innominate artery compression is relieved by aortopexy o r reimplantation, with success rates of 93% to 100% and n o reports of operative mortality o r long-term morbidity.' Occasionally, aortopexy sutures can loosen and the procedure needs to be revised. The results of surgical treatment of vascular rings are also encouraging, with 70% to 92% obtaining complete resolution of symptoms." double aortic arch requires surgical division of the smaller of the two arches. The ductus arteriosus o r aberrant subclavian artery is divided in the case of a right aortic arch with a left ductus arteriosus o r an aberrant left subclavian artery. In patients with severe tracheobronchial compression, residual tracheomalacia may persist for a variable period, and occasionally a tracheotomy is required to stent the malacic segment. A pulmonary artery sling is corrected by dividing the aberrant left pulmonary artery at its origin and reimplanting it anterior to the trachea. Coexisting complete tracheal rings need to be addressed at the same operation either by resection and end-to-end anastomosis o r with a slide tracheoplasty.

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49. Jacobs JP, Elliott MJ, Haw MP, et al: Pediatric tracheal homograft reconstruction: A novel approach to complex tracheal stenoses in children. J Thorac Cardiovasc Surg 1996;112:1549-1558,discussion 1559-1560. 50. Jacobs JP, Haw MP, Motbey JA, et al: Successful complete tracheal resection in a three-month-old infant. Ann Thorac Surg 1996;61:18241826, discussion 1827. 51. Jani P, Koltai P, Ochi JW, et al: Surgical treatment of laryngomalacia. J Laryngol Otol 1991;105:1040-1045. 52. Kacker A, April M, Ward RF: Use of potassium titanyl phosphate (KTP) laser in management of subglottic hemangiomas. Int J Pediatr Otorhinolaryngol 2001;59:15-21. 53. Kashima H, Mounts P, Leventhal B, et al: Sites of predilection in recurrent respiratory papillomatosis. Ann Otol Rhinol Laryngol 1993;102:580-583. 54. Lane RW, Weider DJ, Steinem C, et al: Laryngomalacia. A review and case report of surgical treatment with resolution of pectus excavatum. Arch Otolaryngol 1984;110:546-551. 55. Lee KH, Yoon CS, Choe KO, et al: Use of imaging for assessing anatomical relationships of tracheobronchial anomalies associated with left pulmonary artery sling. Pediatr Radio1 2001;31:269-278. 56. Leikensohn JR, Benton C, Cotton R: Subglottic hemangioma. J Otolaryngol 1976;5:487-492. 57. Link DT, Cotton R: The laryngotracheal complex in pediatric head and neck trauma: Securing the airway and management of external laryngeal injury. Facial Plast Surg Clin North Am 1999;7:133-144. 58. Little FB, Koufman JA, Kohut RI, et al: Effect of gastric acid on the pathogenesis of subglottic stenosis. Ann Otol Rhinol Laryngol 1985;94:516-519. 59. Macdonald RE, Fearon B: Innominate artery compression syndrome in children. Ann Otol Rhinol Laryngol 1971; 80:535-540. 60. Madgy D, Ahsan SF, Kest D, et al: The application of the potassium-titanyl-phosphate (KTP) laser in the management of subglottic hemangioma. Arch Otolaryngol Head Neck Surg 2001;127:47-50. 61. Marcus CL, Crockett DM, Ward SL: Evaluation of epiglottoplasty as treatment for severe laryngomalacia. J Pediatr 1990;117:706-710. 62. Maronian NC, Azadeh H, Waugh P, et al: Association of laryngopharyngeal reflux disease and subglottic stenosis. Ann Otol Rhinol Laryngol 2001;110:606-612. 63. McClurg FL, Evans DA: Laser laryngoplasty for laryngomalacia. Laryngoscope 1994;104:247-252. 64. McDonald IH, Stocks JG: Prolonged nasotracheal intubation. A review of its development in a paediatric hospital. Br J Anaesth 1965;37:161-173. 65. McSwiney PF, Cavanagh NP, Languth P: Outcome in congenital stridor (laryngomalacia). Arch Dis Child 1977;52: 215-218. 66. Meeuwis J, Bos CE, Hoeve LJ, et al: Subglottic hemangiomas in infants: Treatment with intralesional corticosteroid injection and intubation. Int J Pediatr Otorhinolaryngol 1990; 19:145-150. 67. Milczuk HA, Smith JD, Everts EC: Congenital laryngeal webs: Surgical management and clinical embryology. Int J Pediatr Otorhinolaryngol 2000;52:1-9. 68. Moes CA, Izukawa T, Trusler GA: Innominate artery compression of the trachea. Arch Otolaryngol 1975;101: 733-738. 69. Monnier P, Lang F, Savary M: Partial cricotracheal resection for pediatric subglottic stenosis: A single institution's experience in 60 cases. Eur Arch Otorhinolaryngol 2003; 260:295-297. 70. Mustard WT, Bayliss CE, Fearon B, et al: Tracheal compression by the innominate artery in children. Ann Thorac Surg 1969;8:312-319.

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71. Myer CM 31-4 O'Connor DM, Cotton RT: Proposed grading system for subglottic stenosis based on endotracheal tube sizes. Ann Otol Rhinol Laryngol 1994;103: 319-323. 72. Naiman AN, Ayari S, Froehlich P: Controlled risk of stenosis after surgical excision of laryngeal hemangioma. Arch Otolaryngol Head Neck Surg 2003;129:1291-1295. 73. Narcy P, Contencin P, Viala P: Surgical treatment for laryngeal paralysis in infants and children. Ann Otol Rhinol Laryngol 1990;99:124128. 74. Ohlms LA, Jones DT, McGill TJ, et al: Interferon alfa-2a therapy for airway hemangiomas. Ann Otol Rhinol Laryngol 1994;103:1-8. 75. Parsons DS, Bothwell MR: Powered instrument papilloma excision: An alternative to laser therapy for recurrent respiratory papilloma. Laryngoscope 2001;lll: 14941496. 76. Pollack IF, Kinnunen D, Albright AL: The effect of early craniocervical decompression on functional outcome in neonates and young infants with myelodysplasia and symptomatic Chiari I1 malformations: Results from a prospective series. Neurosurgery 1996;38:703-710,discussion 710. 77. PolonovskiJM, Contencin P, Francois M, et al: Aryepiglottic fold excision for the treatment of severe laryngomalacia. Ann Otol Rhinol Laryngol 1990;99:625-627. 78. Ratner I, Whitfield J: Acquired subglottic stenosis in the very-low-birth-weight infant. Am J Dis Child 1983;137: 40-43. 79. Remacle M, Bodart E, Lawson G, et al: Use of the C0,laser micropoint micromanipulator for the treatment of laryngomalacia. Eur Arch Otorhinolaryngol 1996;253:401-404. 80. Rimell FL, DoharJE: Endoscopic management of pediatric posterior glottic stenosis. Ann Otol Rhinol Laryngol 1998; 107:285-290. 81. Roger G, Denoyelle F, Triglia JM, et al: Severe laryngomalacia: Surgical indications and results in 115 patients. Laryngoscope 1995;105:1111-1117. 82. Rosenfeld RM, Stool SE: Should granulomas be excised in children with long-term tracheotomy? Arch Otolaryngol Head Neck Surg 1992;118:1323-1327. 83. Rudolph CD, Mazur LJ, Liptak GS, et al: Guidelines for evaluation and treatment of gastroesophageal reflux in infants and children: Recommendations of the North American Society for Pediatric Gastroenterology and Nutrition. J ~ e d i a t Gastroenterol r Nutr 2001;32(~6$~l 2): SlS31. 84. Rutter MJ, Cotton RT, Azizkhan RG, et al: Slide tracheoplasty for the management of complete tracheal rings. J Pediatr Surg 2003;38:928-934. 85. Rutter MJ, Hartley BE, Cotton RT: Cricotracheal resection in children. Arch Otolaryngol Head Neck Surg 2001;127: 289-292. 86. Rutter MJ, Willging JP, Cotton RT: Nonoperative management of complete tracheal rings. Arch Otolaryngol Head Neck Surg 2004;130:450-452. 87. Seid AB, Park SM, Kearns MJ, et al: Laser division of the aryepiglottic folds for severe laryngomalacia. Int J Pediatr Otorhinolaryngol 1985;10:153-158. 88. Seid AB, Pransky SM, Keams DB: The open surgical approach to subglottic hemangioma. Int J Pediatr Otorhinolaryngol 1991;22:85-90. 89. Seid AB, Pransky SM, Kearns DB: The open surgical approach to subglottic hemangioma. Int J Pediatr Otorhinolaryngol 1993;26:95-96.

90. Shah K, Kashima H, Polk BF, et al: Rarity of cesarean delivery in cases of juvenile-onset respiratory papillomatosis. Obstet Gynecol 1986;68:795-799. 91. Shikhani AH, Jones MM, Marsh BR, et al: Infantile subglottic hemangiomas. An update. Ann Otol Rhinol Laryngol 1986;95:336-347. 92. Sie KC, McGill T, Healy GB: Subglottic hemangioma: Ten years' experience with the carbon dioxide laser. Ann Otol Rhinol Laryngol 1994;103:167-172. 93. Stern Y, Gerber ME, Walner DL, et al: Partial cricotracheal resection with primary anastomosis in the pediatric age group. Ann Otol Rhinol Laryngol 1997;106:891-896. 94. StrifeJL, Baumel AS, Dunbar JS: Tracheal compression by the innominate artery in infancy and childhood. Radiology 1981;139:73-75. 95. Suskind DL, Zeringue GP 3rd, Kluka EA, et al: Gastroesophageal reflux and pediatric otolaryngologic disease: The role of antireflux surgery. Arch Otolaryngol Head Neck Surg 2001;127:511-514. 96. Toynton SC, Saunders MW, Bailey CM: Aryepiglottoplasty for laryngomalacia: 100 consecutive cases.J Laryngol Otol 2001;115:35-38. 97. Triglia JM, Belus JF, Nicollas R: Arytenoidopexy for bilateral vocal fold paralysis in young children. J Laryngol Otol 1996;110:1027-1030. 98. Triglia JM, Nicollas R, Roman S: Primary cricotracheal resection in children: Indications, technique and outcome. Int J Pediatr Otorhinolaryngol 2001;58:17-25. 99. Tsang V, Murday A, Gillbe C, et al: Slide tracheoplasty for congenital funnel-shaped tracheal stenosis. Ann Thorac Surg 1989;48:632-635. 100. Unal M: The successful management of congenital laryngeal web with endoscopic lysis and topical mitomycin-C. Int J Pediatr Otorhinolaryngol 2004;68:231-235. 101. Van Den Abbeele T, TrigliaJM, Lescanne E, et al: Surgical removal of subglottic hemangiomas in children. Laryngoscope 1999;109:1281-1286. 102. Walner DL, Stern Y, Cotton RT: Margins of partial cricotracheal resection in children. Laryngoscope 1999;109: 1607-1610. 103. Weber TR, Eigen H, Scott PH, et al: Resection of congenital tracheal stenosis involving the carina. J Thorac Cardiovasc Surg 1982;84:200-203. 104. Wetmore SJ, Key JM, SuenJY: Complications of laser surgery for laryngeal papillomatosis. Laryngoscope 1985;95: 798-801. 105. Wiatrak BJ, Reilly JS, Seid AB, et al: Open surgical excision of subglottic hemangioma in children. Int J Pediatr Otorhinolaryngol 1996;34:191-206. 106. Yamada H, TanakaY, Nakamura S: Laryngeal stridor associated with the Chiari I1 malformation. Childs Nerv Syst 1985;1:312-318. 107. Yellon RF, Goldberg H: Update on gastroesophageal reflux disease in pediatric airway disorders. Am J Med 2001;lll (Suppl 8A):78S-84s. 108. Younis RT, Lazar RH, Astor F: Posterior cartilage graft in single-stage laryngotracheal reconstruction. Otolaryngol Head Neck Surg 2003;129:168-175. 109. Zalzal GH, Cotton KT, McAdams AJ: Cartilage graftspresent status. Head Neck Surg 1986;8:363-374. 110. Zalzal GH, Anon JB, Cotton RT: Epiglottoplasty for the treatment of laryngomalacia. Ann Otol Rhinol Laryngol 1987;96:72-76.

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Infections and Diseases of the Lungs, Pleura, and Mediastinurn Pramod S. Puligandla and Jean-Martin Laberge

LUNG INFECTIONS

Community-Acquired Bacterial Pneumonia

Pulmonary infections affect children of all ages. Although the majority of mild to moderate infections can be treated effectively on an outpatient basis, there are still those patients who require hospitalization for treatment. The availability of vaccines and the use of a larger arsenal of antibiotics have decreased the incidence of severe lung infections and their complications. Indeed, empyema and lung abscess are presently less common sequelae of pulmonary infections. However, there has been a concurrent increase in the use of immunosuppressive medications and intensive chemotherapy that predisposes this population of patients to increased risk. Adjunctive techniques, including bronchoalveolar lavage and lung biopsy, are being required more frequently in immunocompromised patients to guide therapy and direct management.

Streptococcus pneumoniae

Streptococcus pneumoniae is a major cause of morbidity and mortality around the world. It is the most common pathogen in infants and children and is responsible for approximately 500,000 cases of pneumonia per year in the United States.356 Worldwide, uw to 3 million deaths per year occur as a result of pneumonia, with the majority of these cases occurring in developing countries and he as a result of S. pneumoniae i n f e c t i ~ n . ~ I " l ~ Tincreasing antibiotic resistance of this species over the past several years has led to changes in empirical therapy that may not be as effective.185~260~~58 S. pneumoniae is a gram-positive coccus that is part of the normal flora in children and adults. Colonization rates, particularly of the nasopharyngeal mucosa, appear to decrease with age and are an important factor in the development of infection.356 The simptoms of infection include fever, productive cough, tachypnea, dyspnea, Epidemiology malaise, and occasional emesis. On physical examination, patients have hypoxia and decreased breath sounds Previous estimates of the incidence of respiratory infections with crackles over the affected area. Radiographically, were based on studies from the 1980s and early 1990s pneumococcal infections can be lobar, multilobar, or from Europe and the United These reports sometimes segmental (Fig. 6 4 1 ) , and up to 40% of these indicated that the incidence of respiratory infections patients will also have pleural fluid. The treatment of was highest for younger children (6 months to 5 years) this infection, most often performed on an outpatient and decreased with age. More recent data support these basis, is complicated by bacterial r e s i ~ t a n c e . " - ~ ~ ~ , ~ ~ previous findings.'5*'47,253.408 The incidence of respiratory For patients infected with a strain demonstrating low to infections for children younger than 5 years of age is 3.0 to intermediate resistance, penicillin and other p-lactam 3.6/100. From an etiologic standpoint, several studies have antibiotics are still effective. Cephalosporins may be used identified both Strqbtococcuspneumoniae and viral agents as in~ cases of high resistance or if there is no clinical the most common causes of respiratory i n f e ~ t i o n s . 2 ~In~ 9 ~ ~ improvement with conventional The introterms of age, respiratory syncytial virus (RSV) prevails in duction of new heptavalent conjugate vaccines has young children (<2 years) with a larger proportion of ~ , ' ~ ~vaccines impacted on the severity of d i s e a ~ e . ~These community-acquired pneumonia being attributable to S. pneumoniuefor children older than 2 years of age.247,253,341 appear to be safe and effective, potentially reducing the number of cases of pneumococcal pneumonia by 50,000 No causative agent may be identified in up to 40% to 60% to 300,000 per year.357 of community-acquired ~ n e u m 0 n i a . l ~ ~ ,

.

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A Chest radiograph of a 1.5-year old boy with fever and dyspnea shows a typical round pneumonia of the superior segment of the lower lobe; an air bronchogram can be seen within the opacity A, Anteroposterior view. B, Lateral view.

Haemophilus influenzae This small, encapsulated gram-negative bacillus is a common cause of community-acquired pneumonia.l37.253,4m Over 95% of invasive cases of Haemophilus are caused by the type B strain. Infections with Haemophilus usually occur in the winter and spring. The clinical presentation includes fever, tachypnea, elevated white blood cell count, and the presence of unilateral consolidation with pleural effusion on chest radiographs. Extrapulmonary rnanifestations, such as meningitis and epiglottitis, are more common with this organism. Treatment is based on the susceptibility of these bacteria to p-lactam antibiotics. Cephalosporins can be used for those strains producing p-la~tamase.2~~ The overall incidence of this species causing significant infections has been dramatically reduced with the introduction of the Haemophilusvaccine, although a recent report has linked this immunization with the development of type 1 diabetes in children.75 Secondary transmission of invasive Haemophilus may still be significant in the household or day-care setting81 In such cases, prophylaxis with rifampin may be needed for high-risk children or if elimination of nasopharyngeal carriage is desired.8'

Staphylococcus aureus These ubiquitous gram-positive cocci are commonly found on the skin and nasal mucosa, with 20% to 30% of the population being normal carriers of this bacterium.81 S. aureus produces toxins and enzymes that form the basis of the lesions produced by this pathogen-a pyogenic exudate or an ab~cess.81."~Staphylococcal infections

are usually progressive, occurring in infancy and early childhood. Primary pneumonias occur during the winter and spring. patients-often present with fever a n d rapidly develop respiratory symptoms. Clinical and radiologic deterioration quickly ensues if the infection is left untreated. Radiographically, primary pneumonias display unilateral lobar consolidation. Secondarv infection/ pneumonia usually involves a prolonged febrile illness and is often accompanied by positive blood cultures.81 These infections usually present as diffuse bilateral infiltrates on chest radiographs. Staphylococcal pneumonias are often associated with pleural effusion^,"^^^ empyelung absce~ses,~4,405 or p n e u r n a t o c e l e s ~ ~ ~ ~ ~ ~ ~ ma~,~~,l75,1~* during the heaGng phase. Such lesions require followup until complete resolution (see later). Treatment involves the use of appropriate antistaphylococcal antibiotics. If penicillin allergy exists, other agents, including vancomycin, clindamycin, and macrolides, may be used.126,220,240 The duration of treatment is usually 3 to 4 weeks, with fevers persisting for up to 2 weeks after the institution of therapy.

Mycoplasma and Chlamydia Mycoplasma pneumoniae and Chlamydia pneumoniae are unique pathogens that can cause respiratory infections in children of all ages. However, such infections are usually found in children of school age or 0lder.l~~,267,297 These organisms represent clinically significant causes of atypical pneumonia. M. pneumoniae and C. pneumoniae have similar seroepidemiologic characteristics.2",296,383 Infection is spread by person-to-person contact and usually

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involves a 1- to 2-week incubation period. The presentation of atypical pneumonias is very similar to that of an RSV infection. There is gradual onset of symptoms, including sore throat, hoarseness, and rhiniti;, with or without fever. These upper respiratory tract symptoms progress to the lower respiratory tract over several days and include cough, pleuritic chest pain, rales, and rhonchi. Mycoplasma can also produce fever, chills, headache, and myalgias. Classically, these infections display interstitial infiltrates with unilateral subsegmental distribution, but this can be highly variable.121 The diagnosis is usually made on clinical grounds based on the history and physical examination. Other adjunctive tests including polymerase chain reaction (PCR), culture, and serology can also be used to confirm the diag.nosis.8*J33,156 " Macrolides (erythromycin, clarithromycin) are the mainstay of therapy for these infections.l35.153?267New azalide (azithromvcin) medications have been shown in a number of studies to be as effective as standard macrolide antibiotics but with a much shorter course of therapy, usually 5 days.157.2l9 i

r

Mycobacterium tuberculosis Tuberculosis infection in childhood almost invariably results from infection spread by an adult with active pulmonary disease.99~100J83When adult tuberculosis is properly controlled, the incidence of childhood tuberculosis is significantly reduced as well.100,146Indeed, the aggressive treatment of infection during the early stages of disease can have a major impact on morbidity and disseminated infection in the future.l83,354In North America, surgical complications of tuberculosis have been dramatically reduced secondary to effective medical therapy and intensive follow-up. Recent reports120J36,191 on the epidemiology of tuberculosis in developed nations have common themes: (1) immigrants and their children have the highest incidence of tuberculosis, (2) more serious disease is occurring in young children, and (3) skin testing and screening play an important role in identifying children with tuberculosis. The emergence of antibioticresistant strains of tuberculosis is a problem for the future and reflects the changes in the organism within the community as a whole.4J903272,328 Childhood tuberculosis differs from the adult form because primary pulmonary tuberculosis is a disease of the lymphatic system, the "primary complex."gg Primary tuberculosis results in secondary damage to the lungs through obstruction or damage to the large airways leading to atelectasis, chronic infection, and bronchiectasis.173 infections heal without residual lesions in ~ o s primary t the lung other than the Ghon complex (calcium deposit in a mediastinal or hilar lymph node). The healing of the primary lesion is believed to be associated with a positive host-organism balance, which has been attributed to either a strong natural host resistance or to a small initial inoculating dose.173If defense mechanisms are unable to control the primary infection, tuberculous pneumonia progresses with caseation, often accompanied by pleural effusion.173The clinical manifestations include fever, dysp nea, and cough. Suspicion for tuberculosis should be raised in any child with chronic cough, history of contact

1003

with an adult with tuberculosis, failure to thrive, or inability to recover from infection despite adequate treatrnent.lOOJ71 The diagnosis of tuberculosis is established by cultures of M. tuberculosis, obtained from sputum, bronchial washings, gastric aspirates, or other infected materia1.230,231,320 Recently, a reliable urine test for tuberculosis using PCR has also been introduced.231,302 In children, a positive tuberculin skin test indicates disease requiring antituberculous therapy.'15 The tuberculin test may be negative in immunosuppressed children, in those who are severely malnourished, or in those who have disseminated tuberOther factors that may culosis, who often are anergi~.ll5~50 lead to misdiagnosis include the interobserver reliability of test interpretation, repeated skin testing, particularly in high incidence populations, and the use of cortico~~,~~~ steroids at the time of t e ~ t i n g . Anti-tuberculous therapy may be indicated when the disease is suspected in such patients, because cultures may take several weeks to become positive. It is now evident that the absorption of anti-tuberculous drugs in adults may be impaired by a number of factors, including food consumption, regardless of the immune status of the patient.138-284,304There is a paucity of this type of data for children, but drug monitoring may be indicated to ensure that proper tissue levels are being delivered. Furthermore, standard medications, such as rifampin, isoniazid, ethionamide, ethambutol, and pyrazinamide can cause hepatotoxicity.*73 Currently, surgery is required only for pulmonary tuberculosis in which significant damage to a localized area of the lung has occurred. In contrast to adults, this usually involves the lower lobes in children. The operation should be conservative, usually consisting of a wedge resection, segmental resection, or lobectomy."g~130J62~94 The indications for surgical intervention in childhood tuberculosis include (1) major airway obstruction by extraluminal lymph nodes, (2) chronic airway compromise, (3) airway obstruction by intraluminal material, (4) posttuberculosis pulmonary destruction with or without fungal superinfection, (5) chronic cavitary lesions, and ( 6 ) tuberculosis-induced bronchiectasis.

Atypical Mycobacteria Atypical mycobacterial species were first identified in the 1950s.72 The incidence of these infections was relatively stable until the 1980s. when an increase in incidence concurred with the human immunodeficiency virus (HIV) epidemic.243 Many more organisms are being identified owing to more sophisticated culture techniques as well as to the increased number of immunocompromised patients.2,NG The most common presentation of atypical mycobacterial infections is cervical lymphadenitis.*,22,313The incidence of pulmonary infections with nt is atypical mycobacteria in i m m u n o ~ o m ~ e t e patients low,l03,273 but it is frequently observed in patients with and in patients infected with cystic fibrosis110,145,23g,278 HIV9'3,180,184,295(see later). The most common subtypes responsible for pulmonary infection include ~ ~ c o b a c t e & m avium complex. Other important species include M. kansasii, M. abscessus, M. xenopi, and M. malmoen~e.~ Clinically, immunocompetent patients may have minimal symptoms or present with fatigue and chronic cough

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with wheezing. The diagnosis may be suspected on chest radiographs and high-resolution computed tomography (CT),2,154,178which demonstrate fibrocavitary lung disease, particularly at the apices of the lung. Nodular, interstitial may also be preslung disease and even bronchie~tasisl~~ ent. The laboratory diagnosis of atypical mycobacteria can be made with sputum samples using PCR,57 highperformance liquid chromatography,61 or DNA probe techniq~es."-3~~~ The relapse of infection after treatment was a common occurrence in the pre-macrolide era because anti-tubercular medications are less potent against atypical mycobacteria than tuberculosis. Thus, many patients required surgical excision of affected regions of the lung. However, with the development of macrolides (erythromycin, clarithromycin), azalides (azithromycin) , and newer nonmacrolide antibiotics (ciprofloxacin), surgery is rarely indicated for pulmonary disease.2 In contrast, atypical mycobacterial cervical lymphadenitis is best treated by surgical excision of the affected lymph nodes, with antibiotic treatment reserved for patients with unresectable lesions or disseminated disease.

Viral Infections Bronchiolitis Bronchiolitis is a major cause for hospital admission in young children. The most common cause of bronchiolitis is RSV, which accounts for up to 125,000 admissions and 200 to 500 deaths per year in the United States.333 Other pathogens that have been implicated with bronchiolitis include parainfluenza viruses, influenza viruses, and aden o v i r u ~ e s Peak . ~ ~ ~times for infection occur during the early winter through the spring, with the mode of transmission being direct contact. The peak incidence of infection occurs between the ages of 2 and 6 months.3g' Initially starting as an upper respiratory tract infection with rhinorrhea, cough, and low-grade fever, lower respiratory symptoms progress rapidly over the next 24 to 48 hours. At this time, patients may demonstrate tachypnea, retractions, and wheezing. High fever is not uncommon, and young infants may also present with apnea. Transcutaneous oxygen saturations may fall below 95%, but these measurements may not necessarily correlate with clinical findings. Radiographically, patients exhibit hyperinflation, interstitial pneumonitis, and occasionally pleural thickening. Acquired lobar emphysema occasionally develops (Fig. 642). Lung resection rarely may be indicated, but in most patients the hyperinflation resolves with time. Several patient populations are at increased risk for RSV.3W These include premature infants, patients younger than 6 weeks of age, and children with chronic lung or congenital heart disease. Aboriginal populations are also at increased risk of the disease.236 RSV is shed by both symptomatic and asymptomatic children,l52with the rate of shedding decreasing with age.151 However, immunocompromised patients can shed virus for even longer periods of time, regardless of age.lg9Overall, the mortality from RSV is approximately 1% but can rise to 4% for A presumptive diagnosis of those patients at ri~k.l67,~~39"7

A, Chest radiograph in a 3-year-old child with acquired lobar emphysema secondary to pneumonia with respiratory syncytial virus. B, CT scan of chest reveals collapsed upper lobe and emphysematous middle lobe.

bronchiolitis can often be made on the clinical presentation and is supported by radiographic impressions. Confirmation of infections requires a nasopharyngeal aspiTreatment rate using a rapid immunosorbent assay.1gz4g.1m for bronchiolitis is generally supportive with supplemental oxygen, maintenance of hydration, and close monitoring.l"S281 In severe infection, particularly in atrisk populations, mechanical ventilation may be required. Interruption of transmission is paramount to prevent epidemics on the hospital wardsW6; thus, strict hand washing and the segregation of affected patients is also very important. Bronchodilators and inhaled corticosteroid medications have a limited role in the overall treatment plan but may provide temporary symptomatic relief.322 Antiviral therapies have not been as successful as anticipated but are still used for treatment in immunoVaccinations against RSV compromised patient~.I76,20',~~~ should be provided to high-risk children.Z88 Most infections are self-limited, but there is increasing evidence to

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1005

immunosorbent assay can also be used to confirm cases that are equivocal after radiologic investigations. Medical therapy with mebendazole has been recommended for vatients with small cvsts or asvmvtomatic disease.lg2 Patients with secondarily infected or symptomatic/ Parasitic Infections enlarging cysts will usually require pulmonary resection.35J96.317~372 There is some evidence that primary Echinococcus surgical resection of large or complicated hydatid cysts may decrease postoperative complications and shorten Echinococcus hydatid disease is a parasitic tapeworm infechospital stay.192 For the surgical management of hydatid tion of sheep and dogs that is transmissible to humans. cysts, gentle manipulation of lung tissue, careful control Infections are common in Egypt, the Middle East, and of cyst contents to avoid spillage, and a parenchyma-sparing Australia. Once rare in North America, hydatid disease approach is recommended. Percutaneous drainage of these has been diagnosed in several patients living in the southwestern United Stateslo2 and northern Canada.216,*58 cysts has been described but with only partial success.21 Cysts occur in the liver, spleen, and lungs. Most patients who present with pulmonary disease are children. These cysts should be removed because 30% of these The lmmunocompromised Patient lesions may eventually rupture," producing pleural effus i o n s , l ~ r o n c h i a lseeding, and occasionally acute Pediatric Cancer Patient anaphyla~is.~~6~196~365 Some children with hydatid lung Overall, cure rates for all types of childhood cancers have disease are asymptomatic, whereas others experience a exceeded 60%.*6Vhissignificant improvement has been nonproductive cough. Chest radiographs typically the result of improved chemotherapy regimens, improved demonstrate a single large pulmonary nodule or a large agents, and increased intensity of therapy. A persistent cyst(s) with an air-fluid level (Fig. 643). CT and magobstacle for these patients, however, is the threat of infecnetic resonance imaging (MRI) are also being used to tious complications. Indeed, the single most important provide more detail or to identify occasional lesions factor contributing to the risk of infection is the degree that are not apparent with conventional radiography of neutropenia. Neutrophil counts below 0.5 x 10g/L place despite the presence of symptoms. A serum enzyme-linked support a link between previous RSV infections and the development of childhood asthma.244,369

,

Echinococcal cyst in a 4year-old American Indian boy whose family lived in a sheep-herding area and owned several dogs. Large, homogeneous, spherical mass is visible in the right lung in the posteroanterior radiograph (A). At wedge resection (B), the opened cyst contained proglottids with scolices and booklets. The boy recovered without complications. (Inset, ~400.)

L

1006

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THORAX

mycoses in immunocompromised patients, and (2) reactivation of latent infections with Histoplasma, Coccidioides, and Blastomv~es.~~ The lung is the most common site for an invasive infecThe most common portal of tion with Aspergzll~s.2~~,~~5 entry for this fungus is the upper airway. Indeed, hospital epidemics have occurred secondary to the inhalation of shed spores from contaminated air-conditioning units and from nearby building construction or renovation sites.20 However, the incidence of such infections can be reduced with the use of laminar flow and high-efficiency filters.44 Asperg.lllus infections can be rapidly invasive. Necrosis and hemorrhage result from the invasion and thrombosis of pulmonary arteries and veins. This in turn leads to the development of cavitary lesions. Plain chest radiographs ark not as sensitive-for Aspergillus as CT scans Bacterial Infections because these infections may present as either diffuse Bacterial infections represent the most common cause of infiltrates or nodular disease (Fig. 644) .74Amphotericin pulmonary infection early in the course of chemotherapy. B is the treatment of choice,350 and the effectiveness of Several factors, including bacteremia, aspiration, ciliary therapy may be gauged by the recovery of white blood dysfunction, decreased pulmonary toilet, impaired mucosal cells and granulocytes. Because the response of pulbarriers, and endotracheal intubation may predispose pedimonary aspergillosis to amphotericin B alone can be as atric cancer patients to pulmonary infe~tions.~0~380low as 5%,70 the surgical resection of localized disease may Deficiencies in immunoglobulins as a result of immunobe required if no clinical improvement is observed.95~404 suppression also place these patients at risk of infection New lipophilic amphotericin may have improved efficacy by encapsulated bacteria, such as S. pneumoniae and over the standard preparation.228 In bone marrow transHaemophilus, owing to improper opsonization.225The risk plant patients, the-incidence of Aspergillus infection can of infection in bone marrow transplant patients has been be as high as The diagnosis of aspergillosis reported to be in the range of 12% to 15% within the may be difficult in these patients because of concurrent first 100 days after transplant.:74,87,235 prdblems such as graf6versus-host disease (GVHD). Overall, gram-negative bacilli are the most common The presence of Asperg.lllus in sputum samples of bone pathogens responsible for pulmonary infection in pedimarrow transplant patients is highly suggestive of infection, atric cancer patients. The most common gram-negative species include Pseudomonas, Klebsiella, and Enterobacter Patients with gram-negative infections present with early pulmonary infiltrates, which can be sufficiently treated with p-lactams, cephalosporins, and/or aminoglycosides. Pseudomonas infections generally require double antibiotic coverage. Infiltrates persisting longer than 7 days of treatment are usually due to these same species that possess intrinsic antibiotic resistance, necessitating a change to the treatment protocol. Gram-positive infections usually involve Staphylococcus, S. pneumoniae, and streptococcal (group A) species389for which p-lactams, cephalosporins, and vancomycin are usually sufficient for treatment. Listeria usually produces late and refractory infiltrates. Nocardial infections are uncommon but can be very severe, with a propensity for spread to the central nervous system.289Sulfonamides are the treatment of choice for this organism. patients at significantly increased risk of bacterial infection.l",318 If the duration of neutropenia is prolonged, the incidence of fungal infections is also increased.Zg0~"8~3389 The lung is the most common site of opportunistic infection in the immunocompromised cancer patient.269 The incidence of pneumonia in this population ranges from 0.5% to lO%.l23 The mechanism of infection is either from the aspiration of pathogens from the upper airway into the tracheobronchial tree or by hematogenous spread. The immune system can be affected in many different ways depending on the type, duration, and intensity of chemotherapy. Indeed, combination chemotherapy can impair multiple different facets of the immune response as a result of the different mechanisms of action of these medications.

Fungal Infections Fungal infections represent a common cause of mortality in highly immunocompromised patients. Indeed, there has been an increase in the incidence of invasive fungal infections, particularly in those patients with protracted neutropenia and in those patients receiving prolonged corticosteroid or antibiotic therapy.226.2" There are two major patterns to fungal infection: (1) opportunistic infections with Aspergillus and Candida, the two most common

. -. 1

,

Left upper lobe aspergilloma with diffuse bilateral

lung infiltrates in a 17-year-old patient with acute lymphoblastic leukemia undergoing intensive chemotherapy.

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Infections a n d Diseases of the Lungs, Pleura, a n d Mediastinum

but in equivocal cases a lung biopsy may be required to confirm the diagnosis. Candida is the most common fungal organism responsible for infection in immunocompromised patients.ZY1 The oral cavity is the major site of infection. Although the lung is not usually involved with Candida, it is the Spread most common site of invasive infe~tions.ll3J6~~3~~ to the lung may occur hematogenously or from the aspiration of contaminated oropharyngeal secretions. Plain chest radiographs are usually nonspecific. Bronchoalveolar lavage can be useful in confirming the diagnosis, but often a lung biopsy is required. The treatment of invasive candidal infections is evolving.ZR3 The azoles fluconazole and itraconazole are the standards of therapy against most species of Candida,Zm yet certain strains of Candida have specific, intrinsic resistance to either the azoles and/or amphotericin. Newer classes of antifungal agents such as the echinocandins (caspofungin), which affect fungal wall synthesis, are effective in cases of resistance, if standard therapies are ineffective or if the side effects of standard medications are limiting treatment.g4.282 However, it is clear that if the candidal infection is left untreated the prognosis of patients is uniformly poor.ZR9

Viral Infections Viral infections are uncommon in cancer patients except if the patients are severely immunocompromised. The susceptibility to viral infection depends on the extent to which host defense mechanisms have been affected. For example, cellular immunity can predispose patients to infection with the herpesvirus family, such as cytomegalovirus (CMV). The *incidence of 'cMV infection varies with the underlying disease process. It is more prevalent in patients with allogeneic rather than autolo~ ~ infection is usually gous bone marrow t r a n ~ p l a n t . 2This the result of the reactivation of a latent infection and presents as fever, headache, malaise, and myalgias and may precede the pneumonitis by 1 or 2 weeks. Radiographs are nonspecific, demonstrating diffuse, nodular, or atelectatic changes within the lung.79 The diagnosis of CMV may be confirmed by bronchoalveolar lavage with cytology or PCR on the recovered specim e n ~ . " ~Treatment * ~ ~ ~ includes the use of ganciclovir and irnmun~globulins.~~~~~~~ In bone marrow transplant patients, interstitial pneumonias are caused by CMV up to 50% of the time.Z52 The risk of CMV infection appears to be increased in patients who have concurrent GVHD, who receive frequent transfusions, or who receive methotrexate or antithymocyte medication^.^^ Varicella pneumonia is rare in immunocompetent patients. Thirty percent of patients who have visceral involvement may develop pneumonia.269 This can increase to 80% if they are receiving concurrent chemotherapy. Radiographically, these patients will present with diffuse bilateral fluffy infiltrates. If patients have been exposed to varicella, chemotherapy should be stopped for the period of incubation (up to 21 days). Passive immunization with varicella-zoster immune globulin should be administered at this time. The treatment of active infection includes acyclovir. Herpesvirus infections are usually rare unless there is concomitant

.

1007

gingivostomatitis. RSV infection can be very problematic in bone marrow transplant patients owing to their decreased T-cell-mediated immunity. Up to 80% of immunocompromised patients with RSV infections can progress to life-threatening infection. Only supportive treatment can be offered; therefore, preventive immunization is recommended for high-risk patients.3Y3

Pneumocystis jiroveci (carinii) This unusual organism has properties of protozoa (susceptible to trimethoprim) as well as fungi (based on RNA studies) and is seen almost exclusively in patients who are immunocompromised. Routine prophylaxis has dramatically reduced the incidence of this infection.79 Infection with Pneumocystis is usually the result of the reactivation of latent disease. The risk of infection is dependent on the level of immunosuppression, but bone marrow transplant patients and patients receiving corticosteroids are at particular risk. Patients usually complain of a fever, dry cough, and dyspnea. Progressive disease may present as hypoxia and respiratory distress. Radiographically, fulminant disease presents as bilateral hilar infiltrates that extend to the periphery of the lung (Fig. 645). The diagnosis is confirmed by histology and cytology that identifies tropho zoite cysts recovered by bronchoalveolar lavage.Zgg Trimethoprim/sulfamethoxazole (TMP/SMX) is the mainstay of treatment and prophylaxis.12 Corticosteroids and supplemental oxygen are also useful for patients with severe infections. If no response occurs within 72 hours, a lung

Pneumocystis jiroueci (carinii) pneumonia in a 5-year-old girl receiving chemotherapy for acute lymphocytic leukemia. Diffuse interstitial infiltrates are seen in both lungs. Biopsy of the lingula (note staples) demonstrated P jiroueci (can'nii).A Swan-Ganz catheter is positioned in the right inferior pulmonary artery. Although her leukemia was in remission, the child died of respiratory failure from the pulmonary disease. (Currently with antibiotic prophylaxis, early institution of empirical therapy, and diagnostic confirmation by bronchoalveolar lavage, such an outcome would be unusual.)

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biopsy is indicated. Mortality approaches 100% for untreated patients. Aerosolized pentamidine may also be used if myele suppression or rash occurs secondary to TMP/SMX adrninistration."j6

Pediatric HIV Patient The early diagnosis of HIV infection has translated into p r e longed sunival.'8Wcute pneumonia is the most common severe infection in HIV-infected children in the United States.'" In developing countries, particularly in subSaharan Africa, respiratory infections are one of the most common causes of illness, hospitalization, and mortality in HIV-infected children.141 The introduction of highly active antiretroviral therapy (HAART) in 1997 has dramatically improved the survival of HIV-infected adult patientsvn developed nations through the "reconstitution of the immune system."22Vhe efficacy of this therapy in children has also been demonstrated, particularly for those patients with severe immunosuppression.375 Interestingly, despite the effect of HAART on the natural history of HIV infection, there is conflicting evidence regarding its impact on the risk of developing bacterial pneumonia.%%403 The most common organisms responsible for bacterial pneumonia in HIV-infected patients are S. pneumoniae, S. aureus, group A P-hemolytic Streptococcus, H. injluenzae type b, Salmonella, and Pseud~monas.'~~ The clinical features of respiratory infections in children with HIV are similar to those with normal immune systems. However, patients with decreasing CD4+ counts, severe immunosuppression, and previous acquired immune deficiency syndrome (A1DS)defining respiratory infections are more 2~~ likely to develop acute p n e ~ m o n i a s . l ~ ,Furthermore, these patients may be predisposed to recurrent infection and its sequelae, including bronchiectasis, abnormal lung parenchymal architecture, and bullous lung disease.ZRThe diagnosis of pneumonia in HIV-infected children is based on clinical and radiographic findings. However, it is very important that opportunistic and atypical infections be excluded in this population of patients. Furthermore, the differential diagnosis of pulmonary infiltrates for these patients also includes noninfectious causes such as non-Hodgkin's lymphoma, the incidence of which may be increased with the institution of HAART.141-40" lung biopsy may be required to confirm a diagnosis in these patients. The prevention of infection plays a key role in the management of these patients and includes the routine immunization against Haemophilus and pneumococci as well as prophylactic TMP/SMX for Pneumocystis.~~7 Treatment should be initiated against the specific pathogen as soon as possible, but empirical therapy (cefotaxime or ceftriaxone) may be instituted while waiting for culture results.

Pneumocystis jiroveci (carinii) Pneumocystisjiroueci (cam'nii) infection is the most common AIDSdefining illness in children younger than 1 year of age."O The mortality with this infection is higher in children than in adults despite higher CD4+ levels.13

The incidence of Pneumocystis pneumonia, however, has decreased with the introduction of TMP/SMX prophylactic therapy.' Although there are currently insufficient data for children. recent adult series have demonstrated minimal recurrence of Pneumocystis pneumonia with the discontinuation of prophylaxis in patients with a good response to HAART therapy.323,395 Currently, Pneumocystis prdphylaxis is still recommended for (1).HIV-expdsed infants, starting at 4 to 6 weeks of age until infection is disproven; (2) for all HIV-infected infants younger than 1 year of age regardless of CD4+ count; and (3) all HIV-infected children if their CD4+ counts are below age-specific thresholds.' The clinical presentation of Pneumocystis . -pneumonia includes the rapid onset of dyspnea, tachypnea, and hypoxemia with dough and fever. Increases in serum lactate dehydrogenase may support the diagnosis. Radiographs commonly demonstrate hyperinflation and peribronchial thickening that can progress to diffuse alveolar infiltrates. ~ronchoalveolarlava& " or deep tracheal suctioning with balloon urinary catheters often confirms the diagnosis of Pneumocystis pneumonia, but lung biopsy may sometimes be required. TMP/SMX, in conjunction with corticosteroids and supplemental oxygen in severe cases, is the mainstay of treatment.

Lymphoid Interstitial Pneumonitis Lymphocytic or lymphoid interstitial pneumonitis (LIP) is a chronic lymphocytic infiltrative process seen in children with molder than 2 years bf age and represents another AIDSdefining illness. Epstein-Barr virus has been implicated in its pathogenesis. LIP has been estimated to occur in 20% to 30% of vertically transmitted cases of HIV in the United States and Patients often present with an insidious onset of respiratory symptoms that may be confused with tuberculosis. Other clinical findings include fever, digital clubbing, asymptomatic parotid swelling, symmetrical lymphadenopathy, and hepatomegaly. The clinical course is benign but may predispose patients to bacterial and viral pneumonias, bronchiectasis, and bullous lung " disease.l41~'86 Plain radiographs can 'demonstrate persistent reticulonodular infiltrates and hilar adenopathy that can be better appreciated by CT (Fig. 646). Lung biopsy is usually necessary to confirm the diagnosis and demonstrates significantly altered pulmonary architecture with an infiltration of CD8+cells.141Systemic corticosteroid administration over 4 to 6 weeks usually leads to resolution of the infiltrates. HAART has been shown to improve the clinical course of LIP and may reduce the prevalence of chronic lung disease associated with it.

Tuberculosis The increase in the incidence of tuberculosis in children in developed countries has paralleled the increase of the disease in HIV-infected adults, the primary source of transmission to children.34gThe clinical features of tuberculosis in HIV-infected children are similar to those in immunocompetent patients but with a predilection for rapid progression and extrapulmonary and/or disseminated disease.'j6Radiographs often demonstrate lobar or

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Infections a n d Diseases of the Lungs, Pleura, a n d Mediastinurn

A

1009

B

A 3-year-old child who recently immigrated from Africa presented with a history of weakness and coughing, having been treated for pulmonary tuberculosis 2 years previously. Respiratory distress worsened, and intubation was required. A, Plain radiograph demonstrates a lung infiltrate with an alveolar pattern. B, Diffuse consolidation with air bronchogram especially in the right lower lobe can be appreciated on CT. HIV was suspected and later confirmed. Bronchoscopy and bronchoalveolar lavage were not diagnostic. Lung biopsy revealed lymphoid interstitial pneumonitis. He was treated with corticosteroids and triple antiretroviral therapy and rapidly recovered.

diffuse infiltrates and atelectasis from bronchi compressed by hilar adenopathy. If a child is found to have tuberculosis, HIV testing should be undertaken. The diagnosis of tuberculosis is based on the clinical, epidemiologic, and radiographic data available.6 The early morning gastric aspirate of retained overnight secretions is the best noninvasive culture technique for tuberculosis and may provide a better yield than more invasive procedures, such as bronchoalveolar lavage and bronchoscopy." The tuberculin skin test is still a valuable diagnostic aid in all HIV-infected children and should be performed every 9 to 12 m0nths.5J~~ Prevention is key, and a clear determination of the tuberculosis status of all adults in the household is essential. Currently, vaccination of HIVinfected children with bacille Calmette-GuCrin is contraindicated in the United States owing to the risk of disseminated disease.40 However, in endemic areas, the World Health Organization has recommended the vaccine for asymptomatic HIV-infected children.286 For patients with significant exposure, isoniazid, regardless of skin test result, is indicated. If a repeat PPD test in 3 months is negative, the medication can be stopped. Treatment of active infections includes a multiple-agent regimen.337j348 Care must be taken to watch for interactions between antiretroviral and antituberculous medication^.^

Atypical Mycobacterial Infections Several species of atypical mycobacteria are clinically significant in patients with HIV. These include M. avium, M. intracellulare, M. lep-aemum'um, and M. scrofulaceum. These bacteria represent a major source of morbidity for HIV-infected children and usually cause systemic infection later in the course of AIDS. Previously, patients infected

with atypical mycobacteria had a 9- to 11-month life e x p e ~ t a n c y , ~but ~ ~ ,with ~ ~ 2 the advent of more effective treatments for HIV and atypical mycobacteria the disease is less common and the prognosis is better. Indeed, the incidence of disseminated nontuberculous mycobacterial infections appears to be decreasing in the era of HAART in a d ~ l t s . 9 6 , 2Controversy ~ ~ , ~ ~ ~ exists as to whether prophylactic therapy against opportunistic infections should be discontinued for patients responsive to this t h e r a ~ y . ~ O O , ~ ~ ~ In the pediatric population, clinical trials evaluating the effects of HAART on atypical mycobacteria infection have yet to be conducted. Thus, prophylaxis is still recommended for pediatric patients with disseminated disease." The clinical presentation of these patients usually involves failure to thrive, abdominal pain, and fatigue rather than respiratory symptoms. Patients may also have leukopenia, thrombocytopenia, and an increased serum lactate dehydrogenase. The diagnosis is made through blood culture or biopsy of a normally sterile site, including bone marrow and lymph nodes. Investigations must also eliminate the possibility of tuberculosis infection. Prevention of infection is accomplished through protection of the immune system with effective antiretroviral therapy. Primary prophylaxis with clarithromycin or azithromycin is based on CD4+ counts specific for age.5 Treatment of active infections can be accomplished with clarithromycin, ethambutol, ciprofloxacin, or azithromycin. Macrolides inhibit the metabolism of many antiretroviral medications.

Viral Infections CMV infection can present as chronic interstitial pneumonitis and is usually accompanied by retinitis, hepatitis,

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or colitis. It often occurs in severely immunosuppressed patients. Respiratory symptoms include nonproductive cough, dyspnea, and hypoxemia. Pneumonitis may be associated with concurrent Pneurnocystis infection. Radiographic findings include diffuse interstitial infiltrates. The diagnosis of CMV infection is made by identifying viral inclusions in urine, bronchoalveolar lavage, or biopsy specimens. However, the differentiation between active infection and asymptomatic viral shedding in HlV-infected patients is difficult and may complicate management regimens.396The preferred treatment is ganciclovir, particularly if gastrointestinal or retinal involvement is also identified.

Fungal Infections Systemic fungal infections are uncommon in HIV, because, more c o m ~ o n ,l .y ,these infections involve the skin or mucosa. Pulmonary mycoses are being identified with some frequency in children with HIV owing to impaired T-cell immunity. Histoplasmosis is uncommonly reported in this group of patients. A primary pulmonary focus may progress rapidly to disseminated disease and become fatal if left untreated. Severe disease presents as fever, hepatosplenomegaly, pancytopenia, reticulonodular lobar infiltrates, and the occasional progression to septic shock. The diagnosis is based on cultures of bronchoalveolar lavage samples or lung biopsy. Treatment involves the use of intravenous amphotericin B. Children with primary pulmonary disease should receive itraconazole for prophylaxis in the hopes of preventing disseminated disease. C7yptococcw and Coccidioides infections are usually associated with disseminated infection, and 50% of these patients have concurrent pulmonary infection. Cryptococcal infections present as fever, headache, pulmonary infiltrates, and confusion in disseminated disease. The diagnosis is made through sputum, blood, or cerebrospinal fluid cultures and the direct examination of cerebrosvinal fluid with India ink or latex agglutination. Treatment includes amphotericin B followed by fluconazole after 2 weeks. Coccidioidomycosis usually presents as disseminated disease affecting the lungs, brain, and skin. Fever, weight loss, cough, and an altered level of consciousness are often present. The diagnosis is made from sputum, bronchoalveolar lavage, or lung biopsy specimens. Acute infections are managed with amphotericin B, but recurrence is common, thus mandating prophylactic therapy is another uncommon with fluconazole. Aspergillosis - infection that usually presents as pulmonary disease and sinusitis. These patients experience fever, cough, dyspnea, and pleuritic chest pain. Sputum analysis, bronchoalveolar lavage, and occasionally lung biopsy are required to confirm the diagnosis. Amphotericin B is the treatment of choice, although newer azoles and the echinocandins Long-term have also been shown to be effecti~e.ls~,~O~ suppressive therapy with itraconazole may also be re4uired.335,336 The immunocompromised pediatric patient is under the constant threat of infection. These patients require constant surveillance and aggressive management strategies. For patients with pulmonary infiltrates, broad-spectrum

antibiotics should be started promptly. If no response is observed over the next 48 to 72 hours, a change in the antibiotic regimen and possibly the addition of amphotericin B and TMP/SMX may be indicated. For persistent lung infiltrates, either bronchoalveolar lavage, but more likely lung biopsy, should be performed. The results of lung biopsy for patients with persistent lung infiltrates have been shown to impact on the management of these patients up to 90% of the time.206

Cystic Fibrosis Cystic fibrosis (CF) is the most common autosomal recessive disease affecting whites and occurs in approximately 1 in 3,400 live births.25gAlmost 30,000 people are affected 2 ~ ~ prognosis for this disease has in the United S t a t e ~ . The improved considerably oveE the past 30 years but has plateaued since the mid 1990s.The current life expectancy for patients with CF is over 30 years of age. It is characterized by thick, inspissated mucus, chronic infection, and neutrdvhil-dominated inflammation of the a i r w a ~ s . 2 ~ ~ The cystic fibrosis transmembrane conductance regulator (CFTR) is a cyclic adenosine monophosphate-dependent chloride channel located on chromosome 7q21-31.1g3 Mutations in CFTR are responsible for the clinical manifestations of the disease. Several hypotheses have been proposed. One hypothesis suggests that the loss of W R as an ion channel in CF decreases fluid vroduction and ~ ~ leads to impaired enhances sodium a b ~ o r p t i o n .This ciliary function and mucus transport. Others believe increased sodium in the air-surface laver inactivates antimicrobial defensins and impairs lung defenses, including intraluminal killing of ingested bacteria.I4' Sodium is also thought to allow for increased bacterial binding to the airway epithelia, particularly Pseudornonas, in homozygous patients. Furthermore, there also appears to be dysregulation of the inflammatory cascade in CF -patients, leading to chronic inflammation.'" The clinical signs and symptoms of CF can vary widely. Patients may be relatively asymptomatic, present with chronic illness and failure to thrive, or complain of acute, recurrent exacerbations of pulmonary disease. However, the usual presentation is Gth the progression of a nonproductive cough to a loose productive cough with copious, purulent secretions. Classic physical findings include a barrel chest, rales, rhonchi, and digital clubbing with occasional cyanosis. Although initial pulmonary function tests demonstrate obstructive patterns, disease progression leads to the development of restrictive lung disease. The diagnosis of CF is confirmed with sweat tests (elevated chloride) or with the identification of mutations in C%TR, the most common being AR508. In the first decade of life, the most common organism isolated from CF patients is S. aureus (40%),followed by H. influenzae (15%).Zg9Pseudornonas is usually the first pathogen isolated in children younger than 1 year of age, and over 80% are infected with this organism by 18 years of age.59 Clinically, Pseudornonas is the most important pathogen in CF. These bacteria are able to form biofilms that enable them to avoid normal clearance mechanisms and the penetration of antibiotic^.^^ Pseudornonas also

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Infections and Diseases of the Lungs, Pleura, and Mediastinurn

produces exotoxins that contribute to its virulence, increasing the viscosity of secretions and further impairing ciliary transport.346 Burkholden'a cepacia is an organism with intrinsic antibiotic resistance. Patients infected with this organism present with high fevers, rapid pulmonary deterioration, and sometimes death. Viral infections may pose a special problem, particularly in young children, in whom they may predispose to secondary infection, the need for mechanical ventilation, and oxygen dependence.lZ RSV prophylaxis has been recommended for these infants.s1 The cornerstone of medical therapy for pulmonary disease in CF patients is the aggressive use of intravenous, oral, and nebulized antibiotics. Indeed, the increased life span of CF patients can be attributed directly to the development of effective antipseudomonal medications. Maintenance therapy is designed to prolong the period between pulmonary exacerbations with Pseudomonas. Recent phase I11 clinical trials have demonstrated the effectiveness of nebulized tobramycin.301 Macrolides are also effective because they possess anti-inflammatory properties and help to prevent biofilm f0rmation.l~~f326 The clearance of abnormal secretions is of paramount importance and includes regular chest physiotherapy and postural drainage. Mucolytic agents such as Nacetylcysteine and DNase can help mobilize thick inspissated secretions in CF patients.299,30°Attempts to reduce the inflammatory response with corticosteroids or other anti-inflammatory medications have been complicated by the side effects of these medications. Adequate nutritional support and early treatment of pancreatic insufficiency is another critical area for the medical therapy of patients with CF. Significant malnutrition may already be evident at the time of diagnosis in neonates and young children, even if they are asymptomatic. The imbalance between the increased energy needs of infants for growth and their impaired ability to achieve adequate nutritional intake can predispose to pulmonary compliIndeed, gains in both height and ~ations.2~ ~ ~ ~ 2long-term ~ weight have been demonstrated in infants treated earlier for their pancreatic insufficiency,llg and recommendations are in place to help guide clinicians with regard to nutritional requirements and surveillance for children with cystic fibrosis.50 Pediatric surgeons may be involved in the care of these patients in several ways as they get older. Implantable Infuse-A-Ports are useful to provide intravenous access for patients who frequently require antibiotics for pulmonary exacerbations. Nutritional management may require the use of a gastrostomy. Pulmonary complications of CF such as bronchiectasis, massive hemoptysis, and pneumothorax are discussed later in this chapter, and gastrointestinal and hepatic complications are discussed in other chapters. Lung transplantation remains the ultimate resort for patients with end-stage pulmonary disease. Approximately 1200 patients from the United States, Canada, England, and France have undergone transplant for this reason.298 Bilateral, sequential lung transplantation is the preferred approach for children with CF. Although long-term survival is still a problem for most patients, 1- and 2-year survival rates between 65% and 85% have

1011

been reported.32,112,249,351However, the optimal time to provide the maximal benefit from transplant is still unclear. Gene therapy, unfortunately, has not progressed beyond phase 1 trials despite the gene being identified over 10 years ago.lg3The main limitation to progress has been due to the development of inflammatory reactions to the lipid and viral vectors used to transmit the functioning CFTR gene to airway epithelial cells.lsgMore research to appropriately deliver such a therapy is being actively undertaken.

Chronic and Recurrent Pneumonia Pneumonias are a common cause of illness and hospitalization in children. The difference between recurrent or persistent pneumonias is often difficult to make. Indeed, there is no uniform definition for these types of pneumonias, and radiographic abnormalities may persist for several weeks to months before true resolution is observed. Optimally, the diagnosis of recurrent pneumonia should only be made after complete resolution of the index infection, but this is often difficult. By definition, recurrent pneumonias are pulmonary infections that occur twice in 1 year or as three episodes over any time frame.385 Several authors have tried to iden* the most common causes of recurrent pneumonia in children.'6.159,23*,279 Interestingly, unlike acute pneumonias, an underlying cause may be identified in chronic or recurrent pneumon i a ~up to 92% of the time. To many, asthma is the most common cause of recurrent pneumonia, followed by aspiration. Broadly, pneumonias may be classified into those that affect a single region of the lung and those that affect multiple areas.37gAbnormalities that affect single regions of the lung include those processes causing intraluminal obstruction (foreign body, bronchial tumor), extraluminal compression (tuberculosis, sarcoidosis, tumors, and vascular rings), or structural abnormalities of the lung (tracheal bronchus, localized bronchiectasis, congenital cystic adenomatoid malformation) .37gAbnormalities causing pneumonia in several regions of the lung include recurrent micro-aspiration, asthma, immune deficiency syndromes, mucociliary dysfunction (cystic fibrosis), structural abnormalities (bronchomalacia, WilliamsCampbell syndrome), bronchopulmonary dysplasia, and other rare diseases such as Wegener's granulomatosis and idiopathic pulmonary fibrosis.379 Other causes of recurrent lung infiltrates exist, such as the acute chest syndrome in patients with sickle cell disease (Fig. 647). Clinical evaluation of patients with chronic or recurrent pneumonias requires a thorough history and physical examination. The frequency, duration, and severity of previous infections, and the circumstances surrounding them, must be fully detailed. Associated symptoms such as wheezing, weight loss, and fever are also important details. The timing of the onset of symptoms, especially in the context of congenital malformations or genetic diseases such as cystic fibrosis can help narrow the differential diagnosis. The family history also provides valuable information. During the physical examination, a thorough assessment of the growth and development of the

1012

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THORAX Acute chest syndrome in sickle cell disease. A 5-year-old girl known to have hemoglobin S/P-thalassemia presented with nasal congestion, cough, and chest pain. The initial chest radiograph was normal (not shown); she was admitted for intravenous hydration and analgesia. Antibiotics were started when she became febrile. She became increasingly tachypneic and hypoxic. A, Two days after admission, the chest radiograph shows airspace disease mostly in the left lower lobe. B, On day 5 of the admission there is a complete opacification of the left hemithorax, with increased airspace disease in the right base. C,Four days later, after exchange transfusion, there is marked improvement.

child is necessary. Evaluation of a recent chest radiograph and the review of radiographs surrounding previous episodes of pneumonia may provide some details that may help direct management and investigations. The clinical status of the child will dictate the urgency of subsequent examinations. The need for supplemental oxygen or respiratory support can often be assessed by the physical examination in conjunction with pulse oximetry and blood gas analysis. Patients with a localized pneumonia may require bronchoscopy for foreign body removal or to assess for bronchial tumors and structural abnormalities. High-resolution CT of the chest may help to identify parenchymal lung lesions as well as intrinsic and extrinsic causes of bronchial obstruction. Patients with multifocal pneumonias may require an upper gastrointestinal series and pH probe to rule out aspiration, pulmonary function tests to assess for asthma,

or investigation for immunodeficiencies and other systemic diseases.

Bronchiectasis First described by Laennec in 1819,56bronchiectasis is the irreversible dilatation of the airways secondary to the inflammatory destruction of bronchial and peribronchial tissue. In the 1940s and 1950s, bronchiectasis was a leading cause of pulmonary resection in children.306 Currently, it has become an uncommon disease in developed countries and predominantly limited to the pediatric population. However, the incidence of and morbidity secondary to bronchiectasis is still a problem in developing countries and certain indigenous populations in developed nations (aboriginal peoples of Alaska and Australia

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and Samoans) .303The overall decrease in morbidity and mortality from this disease is the result of improvements in antibiotic therapy and vaccinations against common pathogens such as S. pneumoniae.

Pathogenesis and Etiology The pathogenesis of bronchiectasis follows three progressive stages. Initially, there is destruction of the ciliary epithelium, which is replaced with cuboidal squamous epithelium. In the early stages of disease (cylindrical bronchiectasis), there is localized damage to the elastic tissue of the airway in addition to edema and inflammation. Later in the disease (saccular bronchiectasis), the damage involves the muscle layers and cartilage of the airways, with anastomoses forming between pulmonary and bronchial arteries in the areas of saccular dilation. There is also evidence to support a host-mediated component to local tissue damage. Numerous diierent hypotheses regarding the develop ment of bronchiectasis have been proposed.gl~"g It is clear that infection is the most common cause of bronchiectasis and is the only theory that has been supported by animal studies (Fig. 64-8).56 Bronchiectasis may not result from the index infection but is usually the result of concomitant or subsequent infection with many agents such as tuberculosis v i r ~ s e s , 4 certain l , ~ ~ ~ fUngi,262and, occaand histoplasmo~is,3~~ Historically, measles and pertussis sionally, My~oplasrna.~~~ infections were also linked to the subsequent development

1013

of bronchiectasis.l87~330Cystic fibrosis is the most common genetic cause of bronchiectasis; here it occurs secondary to infection and bronchial obstruction with inspissated mucus. Other causes include congenital absence of supportive airway cartilage (Williams-Campbell syndrome) ,400 tracheomegaly, Marfan ~yndrome,~~W~-antitrypsin defibody aspiration>l* ciliary abnormalities c i e n ~ y , 3foreign ~~ (Kartagener's syndrome),4323" immunodeficiencies (IgA),164 asthma,lOs and right middle lobe syndrome.33.38'

Clinical Manifestations and Investigation Most patients present during the preschool years with cough, profuse sputum, wheezing, and chest pain. Up to 50% may have digital clubbing, which is reversible. Bronchiectasis, demonstrated by bronchial dilation, bronchial thickening, or a signet-ring sign, may be apparent on plain radiographs. Lung scintigraphy has been suggested as a valuable adjunctive test for patients with b r o n ~ h i e c t a s i s . 2This ~ , ~ ~technique allows for the identification of diseased areas of the lung that may not have been apparent on plain chest radiographs and could be used to plan surgical resections instead of bronchograhigh-resolution CT of the chest has ~ h y . 2However, ~~ replaced bronchography to document the pattern and severity of disease.155343 Findings include cylindrical or saccular dilatation of bronchi, pooling of secretions, and bronchial thickening (Fig. 649). However, acute suppurative infections of the lung may cause reversible dilatation of the bronchi that may be confused with bronchietasis.306 The distribution of bronchiectasis may give insight into the underlying cause. Patients with tuberculosis have generally unilateral involvement, whereas patients with CF and viral-induced disease have involvement of the upper lobes and lower lobes, respectively.

Therapy The treatment of bronchiectasis focuses on identifying and treating the underlying causes in addition to postural

Bronchial obstruction

Atelectasis and infection

walls

W

Diagrammatic representation of factors influencing the pathogenesis of bronchiectasis.

. A . a CT scan of the chest of a 10-year-old girl with cystic fibrosis. Preoperative ventilation-perfusion scanning revealed no function of this bronchiectatic lobe. The patient underwent an upper lobectomy.

-

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drainage techniques and chest physiotherapy. Antibiotic therapy is essential for acute exacerbations, whereas adequate nutritional support, with pancreatic enzyme replacement for patients with cystic fibrosis, is needed to prevent failure to thrive from recurrent infections and pulmonary exacerbations. Bronchoscopy has also been used to temporarily help alleviate bronchial obstruction or to due to foreign bodiesg7and inspissated ~ecretions~~2 aid in the preoperative or diagnostic evaluation of chronic lung i n f e c t i ~ n . ~ ~ l ~ * Although the frequency of surgical therapy for bronchiectasis has declined over the past several years, there are still those patients who do not respond to medical therapy and would benefit from surgical resection. The main indications for surgery include401:(1) localized disease with severe and debilitating symptoms, such as profuse sputum, fetid breath, and severe cough that significantly impacts quality of life; (2) life-threatening hemorrhage from localized disease; (3) resectable disease in the context of failure to thrive; and (4) resectable disease in an area of recurrent lower respiratory tract infections. Lesser indications for surgery include bilateral or nonlocalized disease or patients with only mild-to-moderate symptoms. The outcome of pediatric patients undergoing surgical resection has generally resulted in the cessation or improvement of clinical symptoms in the majority of patients. Indeed, data from older pediatric series demonstrated that almost three fourths of patients improved after surgery and experienced minimal morThis success has also been reflected in bidity.355.3g0,401 recent combined reports assessing both children and adults and those patients with nonlocalized and bilateral disease.",36,191,2fl In these series, segmentectomy, lobectomy, and pneumonectomy (with or without additional segmentectomy or lobectomy) were performed. In a combined total of 581 patients among these series, over 80% were asymptomatic or improved after a median follow-up of 4 years. Mortality ranged from 0% to 1.7%, and the surgical morbidity, including atelectasis, persistent air leak, empyema, bronchopleural fistula, and postoperative hemorrhage, ranged from 8% to 17%. In one pediatric series of 33 patients,150 the mortality and morbidity rates for similar types of operations were 2.8% and 17.6%, respectively. Only 11.7% of patients in this series did not benefit from the surgical procedure. In 2003, Rothenberg reported on his experience of thoracoscopic lung resection in 45 infants and children311 over a 7-year period. Twelve of these patients had localized but severe bronchiectasis. No mortality and only one intraoperative complication (in a patient with left lower lobe bronchiectasis) occurred in this series, indicating the feasibility of such techniques in children. The common themes for the successful operative management of bronchiectasis are careful patient selection, preoperative evaluation, and surgical technique, as well as an attempt to completely resect all diseased lung tissue.

Pulmonary Hemorrhage and Hemoptysis The causes of pulmonary hemorrhage and hemoptysis are wide ranging and may be classified according to the

age of the patient or on the basis of underlying lung disease.46In neonates, prematurity, pulmonary edema, respiratory distress syndrome, intracerebral bleeding, coagulopathy, and metabolic disorders can lead to pulmonary hemorrhage. For patients with chronic lung disease, bronchiectasis secondary to cystic fibrosis is the most common cause in the pediatric population. However, cavitary lung lesions, tuberculosis, neoplasms, retained foreign bodies, and frequent airway manipulation can lead to symptomatic hemorrhage. In otherwise normal patients, massive hemoptysis may be secondary to hemangiomas, congenital arteriovenous malformations, intralobar pulmonary sequestration, bronchopulmonary foregut malformations, unilateral pulmonary artery agenesis (due to the development of collaterals), and Ehlers-Danlos syndrome. Massive hemoptysis is defined in children as the expectoration of at least 240 mL of blood in 24 hours or recurrent episodes involving substantial amounts of blood (>lo0 mL/day) over days to weeks.362 It occurs in approximately 1% of patients with CF and is more frequent in those patients with severe lung disease.lz4 Most of these patients are older than the age of 10 years. The pathogenesis is related to the enlargement and tortuosity of the bronchial arteries and the multiple anastomoses that form between these vessels and the pulmonary arteries (Fig. 6410) .407Nonbronchial arteries may also form collaterals with the bronchial circulation or enter the lung through granulation tissue. Most episodes of major hemoptysis resolve spontaneously, but sedation and the discontinuation of medications that impair coagulation should be initiated. Hemoptysis usually indicates deteriorating lung function, and thus antibiotics may be used at this time to treat underlying infection. Vasopressin, endobronchial balloon tamponade, selective mainstem intubation, and topical a-adrenergic agonists have also been used.Z1 Bronchial artery embolization has emerged as a highly successful nonsurgical intervention for the short-term control of hemoptysis.177 Several series have demonstrated that this technique is safe and effective for the control of massive hemoptysis."~s6~41°However, up to 20% of these patients require repeated embolization. Failure of embolization is mainly attributable to nonbronchial colwith the lateral~.",~ogBronchoscowv can be used to h e l ~ preoperative localization of bleeding. Surgery with lobectomy may be lifesaving for patients who fail embolization or for those patients with fkminant, massive hemoptysis. ' i

Complications of Pneumonia Pneumatocele Pneumatoceles are small, thin-walled structures consisting of single or multiple cysts within an air-lined cavity secondary to alveolar and bronchiolar necrosis. These abnormalities are seen frequently as a consequence of infection by S. aureus, group A Streptococcus, and occasionally H. influenzae. Pneumatoceles secondary to S. aureus infections may be identified early in the disease process and occur in up to 80% of patients.*03 Pneumothorax and pyopneumothorax are complications resulting from the

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A

1015

B

A, Arteriogram obtained to identify the cause of hemoptysis in a 10-year-old girl with cystic fibrosis. Note the tortuous bronchial artery. B, After successful Gelfoam embolization, the peripheral branches of the artery are not visualized.

rupture of infected pneumatoceles.334 These lesions can be difficult to distinguish from congenital cysts of the lung. However, pneumatoceles are prone to spontaneous resolution whereas congenital abnormalities should not involute. Follow-up of chest radiographs are required until the resolution of the pneumatocele, and a CT scan may be useful in suspicious instances (Fig. 6 4 11) .

Lung Abscess A pulmonary abscess develops when a localized infection in the lung parenchyma becomes necrotic and then cavitates. Classically,pulmonary abscesses were classified into primary (occurring in healthy children) or secondary (occurring in otherwise compromised children).ze However, it is now clear that lung abscesses occur almost exclusively in areas of pneumonia.27 When appropriate antibiotic therapy is administered early, the frequency of lung abscesses decreases considerably. Abscesses developing in immunocompromised, severely ill, or occasionally very young patients have recently become a more frequent problem. Occasionally, congenital bronchogenic or pulmonary cysts may become secondarily infected. These lesions may be indistinguishable from lung abscess on chest radiographs (see Fig. 6 4 1 1C and Fig. 6412).

History In the 17th century, Bonet described two patients whom he cured of lung abscess by external drainage.165In the 1930s, Neuhoff and TourofP68 reported good results with one-stage surgical drainage of acute putrid abscess of the lung. A two-stage procedure, the first step to induce pleural symphysis, was used by Welch,3gl with a mortality rate of 40%. The treatment of lung abscess by resection in the early 1940s gave way to almost total reliance on antibiotics, which is still the approach now.306

Pathogenesis The aspiration of gastric contents is a leading cause of chronic pneumonia and lung abscess in children,27

particularly in those with neurologic deficits.sfioAspiration may occur acutely during trauma, anesthesia, or epileptic seizures or in those children with severe gastroesophageal reflux. Patients with repaired esophageal atresia or esophageal dysmotility are also at risk of a~piration."~ The aspiration of foreign bodies, including blood or tissue after tonsillectomy, were previously common antecedents of lung abscess.27,"fi Such abscesses are now infrequent because they are prevented by prompt bronchoscopic removal of foreign objectsgi and by endotracheal intubation and pharyngeal packing, which protects against aspiration during operations on the oropharynx. Lung abscess is an occasional complication of bacterial pneumonia and is much less frequent in the pediatric population than in adults.36oThe most common causative organisms are anaerobes," followed by S. aureus, Pseudomonas, streptococcalspecies, pneumococci, and occasionally H. influenzae. Other bacteria implicated in lung abscess include Klebsiella, Eschen'chia coli, Peptostreptococcus, and Peptococcus. Children with cellular or humoral immune deficiencies, either congenital or acquired, are occasionally unable to eradicate a pulmonary infection despite appropriate antibiotics, leading to inflammation, the breakdown of pulmonary parenchyma, and eventual abscess formation. Histologically, a lung abscess may be identified 18 to 36 hours after the inciting event but may only be apparent on chest radiographs after 7 days.27 When a lung abscess occurs in infants, an underlying congenital anomaly, such as a bronchogenic cyst or congenital cystic adenomatoid malformation, should be suspected (see Fig. 6 4 1 1).84These lesions require resection but initial treatment with antibiotics with or without drainage is usually indicated. The position of the child at the moment of aspiration determines the location of the lung abs~ess.")~ In supine patients, the superior segments of the lower lobes are most often involved. If the child is on the right side, the right upper lobe is at risk; if the child is on the left side, the apical posterior segment of the left upper lobe may be the site. The upright child aspirates into basilar segments of the lower lobes. The distribution of lung abscesses in various lobes and segments in children is similar to

1016

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A, A 5-year-old child presented with a right lower lobe pneumonia that responded to Intravenous antibiotics. B, During outpatient monitoring, small cysts were noted 6 weeks later and appeared to coalesce in a larger pneumatocele on this radiograph, taken 11 weeks after the initial study. Follow-up was recommended. C, At 14 years of age, the patient presented with a new episode of infection with a large air-fluid level and some smaller ones. Intravenous antibiotics were required for more than 2 weeks. CT confirmed the presence of three cysts. Six weeks later a right lower lobectomy was performed and microscopic examination confirmed a type I congenital cystic adenomatoid malformation.

that in adults. Lung abscesses often occur at the periphery of a segment or lobe, making them amenable to external drainage procedures.

Diagnosis The most common symptoms caused by lung abscess include fever, cough, chest pain, anorexia, productive sputum, weight loss, malaise, hemoptysis, and chills. Purulent sputum may be easily obtained from older children to help with a bacteriologic diagnosis; younger patients usually swallow their secretions. Putrid sputum is characteristic of an anaerobic abscess. The affected area of the chest may be dull to percussion and have decreased breath sounds. Leukocytosis is common. Patients may also present with restrictive lung disease patterns from the enlarging abscess or secondary to pleuritic chest pain. The diagnosis of lung abscess is established by a chest radiograph that shows a cavity, commonly with an air-fluid level (see Fig. 6412). An abscess should be distinguished

from pneumatocele, a localized collection of intrapulmonary air that usually does not have an air-fluid level, and from empyema with an air-fluid level. CT has become a valuable adjunct in the diagnosis and characterization of lung disease in complicated pneumonia, revealing pathology that may not be apparent on plain chest radiographs.lol

Treatment A specific bacteriologic diagnosis should be established before treatment whenever possible. Diagnostic bronchoscopy with direct aspiration of purulent fluid from the parent bronchus should be performed, except in those older children who are able to induce a satisfactory sputum sample. The needle aspiration of a peripheral abscess cavity under imaging guidance to isolate bacterial species and drain collections has been used with moderate su~cess.2~Vsolation of the causative organism is possible with this technique even if patients are concurrently receiving antibiotic therapy.

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1017

This may take from 1 to 6 months.28 The most effective antibiotic for the treatment of lung abscess has been clindamycin. Aminoglycosides are usually recommended for coliform bacteria. If Pseudomonas is strongly suspected, then an appropriate p-lactam with an aminoglycoside is recommended."O Medical therapy for lung abscesses is frequently unsuccessful in neonates and immunocompromised children, in whom the mortality approaches 20%.391Percutaneous catheter drainage of the abscess may be helpful in acutely ill children,"".O99.3R6.41' particularly for those who experience rapid progression of the disease despite maximal antibiotic therapy. The complications related to percutaneous techniques occur occasionally and include pneumothorax, hemothorax, incomplete drainage, and ~ ~ ~ ~ ~resection ~ of the bronchopleural f i s t ~ l a s . 2Surgical lung abscess by segmental resection or lobectomy is recommended for the chronic, large, and thick-walled abscesses or for those few patients who do not respond to intensive antibiotic therapy or percutaneous d ~ - a i n a g e . ~ ~ , z ~ ~ Other indications for resection include chronic abscesses lasting longer than 3 months, persistent significant hemoptysis, bronchial stenosis, significant bronchiectasis, and massive pulmonary necrosis.

Empyema

History Even during the ancient times of Hippocrates, Paul of Aegina, and Fabricius, empyema was a known complication that followed pulmonary infections and required external drainage for cure. In the 16th century, Park manually evacuated a putrid hematoma from the pleural cavity of a French soldier.165 Formal decortications were performed by Kuster in 1889 and Fowler in 1891.E5 Until the antibiotic era, discussions of therapy for empyema largely centered on the relative advantages of open drainage, various types of closed drainage, and the optimal time for the use of these measures.93

Definition and Pathogenesis B Lung abscess after aspiration in an infant. A, A thick-walled cavity is present on the anteroposterior supine view. B, An air-fluid level is visible on the lateral decubitus view.

The preferred treatment of lung abscess is appropriate intravenous antibiotic therapy and drainage. Satisfactory drainage can usually be accomplished by chest physiotherapy with postural drainage and percussion and by occasional bronchoscopic aspiration. For children who are unable to cough adequately, therapeutic bronchoscopy or transbronchial drainage may be necessary. Intravenous antibiotics are recommended for 2 to 4 weeks, followed by oral antibiotics for a total treatment period of 6 to 8 weeks. Antibiotics are discontinued when the child is symptom free and the chest radiographs are clear.

An empyema is the accumulation of purulent fluid in the pleural cavity and complicates pneumonia in up to 30% of children.359 It may also occur after trauma, neoplastic processes, intrathoracic esophageal perforation, or surgeries on the chest. Normally, the pleural membranes are permeable to liquid and a small amount of fluid exists between the visceral and parietal pleura to minimize friction during respiration. When the adjacent lung is healthy, the pleural cavity is generally resistant to infection. Empyema, once established, exhibits three characteristic stages67.314: (1) an exudative or early stage when the fluid is thin and of low cellular content; (2) an intermediate or fibrinopurulent stage during which large numbers of polymorphonuclear cells and fibrin are deposited in the pleural space, progressively impairing lung expansion and leading to the formation of fluid loculations; and (3) a final stage or organizing empyema during which a thick exudate forms and fibroblasts invade the fibrinous peel. The empyema may be diffuse and involve the entire

1018

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THORAX

pleural space, or it may be localized and encapsulated in an interlobar, diaphragmatic, or paramediastinal location. Currently, the most common organisms in childhood empyema are S. pneumoniae, S. aureus, and H. influen~ae.l2~ Other streptococci, mixed oral flora, and anaerobes have also been classically associated with the development of empyema. The changes in bacteriology are likely due to changing antibiotic resistance patterns. However, the incidence of empyema may be increasing,l0"292 and the virulence of the causative organisms appears to impact the natural course and, ultimately, the management of these patients.241 Tuberculous empyema is much more rare than effusion and is associated with a high bacterial load within the pleural space. Mycobacterial resistance is a problem in this situation owing to the poor pleural penetration of standard chemotherapeutic agents.174

Clinical Manifestations and Diagnosis The symptoms of empyema in a child are usually those of a short history of pulmonary infection followed by respiratory distress, fever, and cough. Chest or shoulder pain coupled with abdominal pain, distention, and ileus may intensify the respiratory difficulty. The radiographic appearance often includes bilateral pulmonary involvement with pneumatoceles occasionally identified within the lung. Haziness of a hemithorax may represent either pulmonary consolidation or pleural fluid. In the early exudative phase, the pleural fluid flows freely along the lateral chest wall on decubitus views (Fig. 6413). In advanced empyema, the exudate is a solid mass of fibrin and does not move with changes in position. In the intermediate fibrinopurulent stage, loculations typically develop (see Fig. 6413C). Air-fluid levels within the loculations suggest the presence of anaerobes in the pleural contents. Thoracentesis may provide valuable information on the quality of pleural fluid. The progression to advanced-stage empyema may be suspected if the fluid demonstrates any of the following characteristics after diagnostic thoracentesis: (1) gross pus, (2) pH < 7.0, (3) lactate dehydrogenase > 1000 U/mL, (4) glucose < 40 mg/dL, and (5) bacteria visible on Gram stain.

Treatment Primary therapy for empyema is the administration of high-dose intravenous antibiotics. Effective drainage of the pleural space also speeds the resolution of the empyema. Fluid that layers in the decubitus position may be amenable to chest tube drainage alone. Loculated fluid collections may not be sufficiently drained in such a manner, and the optimal managemen.t of these patients is still debated. Fibrinolytic therapy was recommended as early as the 1940s to improve the drainage of pleural fluid.3" Currentlv. ,, the use of fibrinolvtics remains controversial. Cameron and Davies64 reviewed the four randomized trials involving patients aged over 14 years conducted to date52,j"88,371and concluded that fibrinolytic therapy conferred significant benefit (shorter lengths of stay, increased chest tube drainage) without morbidity when compared with saline controls. However, routine use of this therapy could not be recommended owing to

the small numbers of patients involved in this metaanalysis. Several retrospective case series in children have also demonstrated inkeased pleural drainage with the use and streptokinase,76.2" with an average of ~rokinase20~,2~l 20% failure rate of therapy. Recombinant tissue plasminogen activator (alteplase) may provide even more effective drainage but has not been extensively evaluated thus far.394 Thomson and colleagues, in the only randomized trial in children to date,-assessed the efficacy of .~~~ urokinase in 60 children with e m ~ y e m a Although a significantly shorter length of stay was noted in the treatment group, control group patients had a much longer duration of prehospital illness (9 versus 5 days). Interestingly, this study also demonstrated a shorter length of stay for those patients receiving smaller-caliber chest tubes. In the end, there is evidence to support the use of fibrinolysis as an adjunctive therapy for children with complicated pleural effusions or empyema. The major reported complications with fibrinolytic therapy, including anaphylactic/allerplc reactions (with streptokinase), chest pain, hemorrhage, and bronchopleural fistula occurred rarely in these reports. Urokinase is no longer available on the market, whereas alteplase is very expensive. Decortication has been recommended in the treatment of complicated pleural effusions and empyema not responsive to medical therapy and attempts at pleural drainage. Indeed, using an empyema score, Hoff and colleagues demonstrated shorter and less complicated hospital stays for patients undergoing thoracotomy, particularly in severe disease.16Wideo-assistedthoracosco~ic surgery (VATS) is an excellent alternative to thoracotomy for this purpose and has been advocated by many as a primary intervention in pediatric patient~.77,104,14~,204,229,352 Given that patients with nonlocuiated effusions (stage 1) tend to recover with appropriate antibiotic therapy and chest tube drainage,67 VATS may play more of a role in late-stage empyema. Chen and colleagues7l noted that 70% of these patients eventually required surgery and that delay to surgical treatment increased length of stay. Patients in this series who were treated with VATS experienced the shortest lengths of stay, despite later intervenkon. Gates and colleagues systematically reviewed the English and Spanish language literature from 1987 to 2002 to determine the most effective treatment strategy for pediatric patients with empyema.l% In their analysis of 44 studies involving 1369 patients, only the length of stay could be shown to be statistically shorter for those patients treated by either thoracotomy or VATS. Unlike in adults for whom the American College of Chest Physicians has established guideline^,'^ treatment algorithms for pediatric patients with empyema vary widely and are often institution based. Interestingly, in a study from the Arkansas Children's Hospital,l22 a clinical pathway for the appropriate management of childhood empyema has been developed (Fig. 6414). In this prote col, if an empyema is identified on chest radiographs it is then assessed by ultrasound for the presence of loculations. If loculations are identified, early VATS is advocated. The results of this pathway have demonstrated significantly reduced lengths of stay and hospital costs when compared with the national children's database. However, others maintain that antibiotics and chest tube drainage

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Infections a n d Diseases of the Lungs, Pleura, a n d Mediastinum

1019

C A and B, An 11-year-old boy presented with left-sided pleuritic pain and fever. A, Chest radiograph shows a large left-sided effusion with mediastinal shift. B, Because of concern about an underlying malignancy, a CT scan was obtained that showed a large nonloculated fluid collection, with a collapsed lower lobe; fluid can be seen in the fissure. A chest tube was inserted and drained 400 mI, of serous fluid, with a lactate dehydrogenase of 4000 U/L, thus qualifying it as a fibrinopurulent empyema. There were no bacteria on Gram stain, but cultures grew Streptococcus. The patient improved with intravenous antibiotics, and the chest tube was removed 8 days later. Cand I), A 3-year-old girl had a more fulminant course. Loculations (arrow) and debris in the pleural fluid were evident on ultrasound in C. Despite early thoracoscopic drainage, she developed lung necrosis (seen on CT with intravenous contrast in D) with a persistent air leak, requiring 10 days in the intensive care unit and 1 month in hospital.

1020

PART

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THORAX ( ~ ~ 1 t i cpitI~\\,:i~ ~11 tor

Symptoms: cough, dyspnea, fevers

management of empyema in children. (From Finck C, Wagner C, Jackson R, Smith S: Empyema: Development of a critical pathway. Semin Pediatr Surg 2002;11:25-28,with permission.)

CXR - ?effusion

Yes

No

Obtain ultrasound iiLoculated

Treat underlying condition Pneumonia/antibiotics

Yes

4 VATS drainage

Thoracentesis

\

Yes

\

NO

Tube thoracostomy remove chest tube when < 50 mllday

Follow-up 4-6 weeks with CXR

are still the most cost-effective strategies for the treatment of empyema.248 Because of the lack of any prospective studies, there is a need for a multicenter, prospective, and randomized trial to answer ongoing questions regarding the best treatment of pediatric patients with empyema.

PEDIATRIC SPONTANEOUS PNEUMOTHORAX Primary spontaneous pneumothorax is defined as a pneumothorax occurring secondary to apical blebs or bullae It can without evidence of other lung pathology.293,332,3'J9 also occur in term neonates without any risk factors. In contrast, secondary spontaneous pneumothoraces occur in the context of underlying lung disease, such as cystic fibrosis or P jiroveci (carinii) pneumonia. Other lung infections, bronchiolitis, asthma (even mild), connective tissue disorders, congenital cystic adenomatoid malformations, and traumatic lung contusions are risk factors.8~."4~"? The incidence of primary spontaneous pneumothorax is estimated to be 7.4 to 18 per 100,000boys

Follow-up 4-6 weeks with CXR

and 1.2 to 6.0 per 100,000 girls in the United state^.^^"^^" Typically, the patient is a thin, lean adolescent who presents with an acute onset of ipsilateral pleuritic chest pain and nonproductive cough. Most patients are clinically stable on initial assessment. However, a small number may present in fulminant distress, including hypotension and respiratory failure, secondary to a tension pneumothorax. Other clinical findings in patients with pneumothorax include tachypnea and tachycardia. Chest radiographs confirm the diagnosis and may identify a secondary pathologic process within the lung. Expiratory films may be helpful to identify small pneumothoraces. Different methods are available to quantitate the size of the pneumothorax, because this factor is most likely to influence subsequent management. Indeed, a Light Index has been described that compares the diameter of the lung to the ipsilateral hemithorax as a means of quantitating the size of the pneumothora~.?2~227'1 Patients who present with an acute pneumothorax require supplemental oxygen and intravenous access. For those few patients presenting with a tension

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Infections and Diseases of the Lungs, Pleura, and Mediastinurn

pneumothorax, immediate needle decompression in the second intercostal space (midclavicular line) is necessary even before chest radiograph confirmation, followed by the prompt placement of a chest tube. A pneumothorax of less than 15% can often be managed by observation with or without supplemental oxygen, especially if the initial symptoms occurred more than 24 hours before presentation. Needle aspiration and the insertion of small pleural drains has also been used,2g3but the Delphi Consensus Statement (2001) does not support the routine use of needle decompression in this instance.10 Heimlich valves connected to the pleural drain allow for outpatient management of small pneumothoraces in compliant patients. Large pneumothoraces require the placement of a chest tube with underwater seal and drainage. An air leak that persists for more than 5 to 7 days may require further intervention, or at least confirmation that the For most chest tube in place is functioning pr0perly.2~~ young children (<8 years), and those with asthma as a predisposing factor, chest tube drainage is sufficient for treatment. However, adolescents with spontaneous pneumothorax have been reported to have-a recurrence rate Interestingly, in one adult of up to 40% to 60%.80,2g3,332 series, small drains were associated with a higher recurrence rate of pneumothorax (33%) than either observation alone (17%) or large-bore chest tubes (6%).381In the end, symptomatology should direct further investigation and treatment. CT is more sensitive at detecting blebs and bullae than normal radiographs, but it is unclear if its routine use for spontaneous pneumothorax ultimately changes management.25"33"338Some authors advocate the use of CT after the index mesentation. whereas others wait for a recurrence before further investigation.lg7No firm consensus has been established for the role of imaging in spontaneous pneumothorax. The indicaGons for surgical management include recurrence, persistent air leak, bilateral disease, and possibly the presence of large bullae. VATS appears to be superior to standard thoracotomy with respect to postoperative pain and complications in several series.1683387 Transaxillary mini-thoracotomy is a viable alternative to VATS and has certain advantages, particularly in the context of poor visualization and the Dresence of dense adhesions.l69,332,339 For pleurodesis, thoracoscopic pleural abrasion and talc poudrage are effective techniques.65.367 Apical pleurectomy can be easily performed through a transaxillary incision. For bilateral disease. both VATS and transaxillary mini-thoracotomy are effective and can be used as a Despite similar results in single-stage 0peration.2~~,~= outcome, VATS has become more popular among surgeons for the treatment of spontaneous pneumothorax The even though some controversy persists.g8,H1,1g7~387 recurrence rate with VATS ranges from 2% to 14%, although this does appear to decrease with increasing experience.l0"1"~179,2fi3For transaxillary mini-thoracotomy, the recurrence rate has been reported to be as low as 2%.105,197 All in all, both VATS and transaxillary thoracotomy are effective in the treatment of spontaneous pneumothorax. Furthermore, the guidelines for the treatment of spontaneous pneumothorax are often extrapolated from adult series, and randomized trials in the pediatric population are clearly warranted.

1021

Pneumothoraces in patients with cystic fibrosis are more difficult to treat because the air leak frequently persists. The use of a higher negative pressure (20 to 25 cm H 2 0 ) may be helpful. If this fails, thoracoscopic talc poudrage367 or other sclerosing agent@ are required to achieve pleurodesis and prevent recurrence. Pleurectomy is usually avoided to facilitate pneumonectomy should lung transplantation become necessary.

INTRATHORACIC ACCESS AND PROCEDURES Chest Tube Insertion in the Newborn for Pneumothorax In preparation of chest tube insertion, the infant is placed in an oxygen hood or, if intubated, maintained on ventilator support, restrained, and monitored via pulse oximetry and electrocardiography. A surgical headlamp or an overhead light source of similar quality should be available. The procedure is performed with sterile technique (mask, cap, gown, and gloves). In addition to sterile instruments (scalpel, mosquito clamps, Adson forceps, needle holder, fine scissors) and drapes, No. 8 and No. 10 French catheters, a sterile connector, 3-0 and 4 0 nonabsorbable suture on curved swedged-on needles, and an infant-sized underwater seal drainage system should be readily available. The chest wall is prepared with an iodophor solution and draped with sterile towels. The skin is infiltrated with lidocaine via a 25gauge needle placed lateral to the nipple in the anterior axillary line over the fourth rib. Injury to the nipple and underlying breast tissue should be avoided. A 3- to 4 m m incision is made with a No. 11 scalpel blade. A mosquito clamp is placed through the incision and used to spread the subcutaneous tissues. It is advanced upward over the rib and used to spread the intercostal muscles above the incision, which requires firm pressure, and then passed into the pleural cavity. This method produces a "tunnel" so that the entrance into the pleural cavity is superior to the level of the skin incision. Entry into the pleural space is heralded by reduced resistance and is usually followed by the sound of escaping air. The tip of the No. 8 French chest tube is placed in the end of the curved mosquito clamp, and the tube is advanced into the pleural cavity (Fig. 6415). An alternative is to use a trocar inside the chest tube to guide the latter through the tunnel. With this technique, it is safer to withdraw the tip of the trocar by a few millimeters and to place a large clamp on the tube 5 cm proximal to the tip to avoid uncontrolled penetration and injury to the mediastinal structures. The tube is advanced superiorly and anteriorly 3 to 4 cm, being certain that all of the holes in the tube are intrapleural, yet avoiding a tube that is too far and kinks after reaching the mediastinum. The tube is then sutured in place with a 3 4 nonabsorbable purse-string suture. Povidone-iodine (Betadine) ointment is placed at the tube-skin interface, and the tube is secured. The connecting tube is attached to an underwater seal, and the water level is observed to ensure fluctuation with respiration. The system may be set at 10 cm H 2 0 of negative

1022

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THORAX

.

-

.a

Chest tube insertion in the

newborn for pneumothorax. A, Preferably a small hemostat is inserted through a small incision in the anterior or midaxillary line and is tunneled upward, entering the chest above the next rib. The chest tube is inserted and secured with a suture ligature. Several knots should be placed after each circumferential pass of the thread to avoid any slippage. B, A trocar can be used as an alternative method of tube insertion, as long as the trocar i~withdrawn by a few millimeters within the tube; this technique allows easier guidance of the tube, for exarnple, if it has to be placed posteriorly and inferiorly to drain an effusion.

pressure if necessary, remembering that a high negative pressure will add to the positive pressure applied by a ventilator and may lead to barotrauma. A disposable infant Pleur-Evac system is highly effective and easily managed in the neonatal intensive care unit. A chest radiograph is obtained to determine the location of the tube, to ensure that all the holes are intrapleural, and to check that tube placement was effective in expanding the collapsed lung. A lateral chest radiograph may be obtained to determine whether the tube is in an anterior or a posterior location. A superior and anteriorly placed tube most effectively evacuates pneumothorax. Excessive bubbling indicates a continued source of air leak from the injured lung, a bronchopulmonary fistula, or most commonly a leak in the system. The most frequent complications related to chest tube insertion are (1) injury to the intercostal vessels during insertion and (2) lung perforation caused by the clamp

or tube. If there is excessive bleeding and continued significant air leak, surgical correction is required. Injury to mediastinal lymphatic, venous, and nervous structures' has also been described. Kits are available that allow the Seldinger technique to be used to rapidly and safely place a small chest tube in infants. A needle is inserted in the pleural cavity and a guidewire passed. The needle is removed, and a dilator is passed over the wire, followed by a pigtail catheter.

Chest Tube Care and Removal After insertion for pneumothorax a chest tube usually drains little fluid after the air is evacuated. In infants who do not require mechanical ventilation, when there is no further bubbling in the water seal chamber and the lung is fully expanded for 24 to 48 hours, the suction, if utilized,

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Infections and Diseases of the Lungs, Pleura, and Mediastinurn

is removed and the tube left only on an underwater seal. If the pneumothorax does not reaccumulate in 12 to 24 hours, it is probably safe to remove the tube. The tube should be removed rapidly and the tube site sealed with petroleum gauze dressing to prevent air from entering the chest. An additional chest radiograph is usually obtained to be sure that there is no recurrence of the pneumothorax. It is probably safer to leave the chest tube in place for longer periods if the infant requires mechanical ventilation, especially if high peak inspiratory pressure and/or positive end-expiratory pressure is necessary.

Chest Tube Insertion in Older Children Pneumothorax in older children is usually encountered in patients with spontaneous rupture of an emphysematous bleb, asthma, cystic fibrosis, and after blunt, or, occasionally, penetrating chest wall trauma. A tube thoracostomy is required in symptomatic patients. Chest tube insertion in older infants and children may also be required for pleural effusions from a variety of causes, including chylothorax; traumatic hemothorax; lymphoma; inflammation as a result of bacterial, fungal, and viral pneumonia; empyema; and other causes. Insertion of a chest tube in these patients follows the same pattern of sterile techniques and preparation described in the management of neonates. Infants and toddlers can be premedicated with intravenous fentanyl (1.0 pg/kg) and midazolam (0.1 mg/kg) as part of a conscious sedation protocol. Alternatively, ketamine (1.0 mg/kg) with or without midazolam provides excellent analgesia and sedation while preserving respiration reflexes and cardiac parameters throughout the duration of the procedure. Children are kept in the supine position with a small roll under the affected hemithorax to elevate the area. The ipsilateral arm is positioned superiorly and laterally. The chest tube size is determined by the child's weight and whether the problem is a pneumothorax, a transudate, or an exudate (Table 641). After sterile preparation, a local anesthetic, and placement of a small skin incision, the appropriate-sized tube is inserted in the third or fourth interspace in the anterior to midaxillary line and positioned upward and anteriorly for pneumothorax. If the patient has an effusion, the location should be determined by correlating the physical examination (e.g., dullness to percussion and diminished tactile fremitus) with the findings on chest radiograph,

Patient Weight (kg) <3 3-8 8-15 16-40 >40

Size (French) Pneumothorax Transudate &lo 10-12 12-16 16-20 20-24

8-10 10-12 12-16 16-20 24-28

Exudate 10-12 12-16 16-20 20-28 28-36

1023

ultrasound, and/or chest CT. A 20-gauge needle or angiocatheter may be insertedjust at the level of transition of percussion sounds (from tympanic to dull) to locate the effusion. The chest tube can then be inserted as noted earlier and positioned inferiorly and posteriorly. The chest tube should not be placed below the level of the seventh rib to avoid injury to the spleen, liver, or diaphragm.

Lung Biopsy Open-lung biopsy is usually obtained early in the diagnostic evaluation of diffuse pulmonary disorders in children and is generally preferred to a percutaneous transthoracic needle biopsy for establishing the diagnosis. Needle lung biopsies are fairly reliable and accurate; however, pneumothorax or hemothorax occur in approximately one third of patients. Larger specimens are obtained by open lung biopsy for cultures and histologic study as well as special staining and occasionally for electron microscopy. It is easier to avoid air leaks and to secure complete hemostasis with open wedge biopsy. Pneumothorax is prevented by the routine use of a chest tube. The mortality after surgery is rarely a result of the procedure; death, when it occurs, is almost always caused by the patient's underlying disease. A tissue diagnosis is established in almost all patients after open-lung biopsy and influences subsequent therapy in over 90%.Z0"he preoperative diagnosis is confirmed in approximately 60% of patients and corrected in over 35%. Moreover, the differential diagnosis is often between infectious, neoplastic, or inflammatory processes such as bronchiolitis obliterans with organizing pneumonia (BOOP) or lymphoid interstitial pneumonitis. Because inflammatory processes require tissue for diagnosis and are treated with corticosteroids, a lung biopsy is essential to confirm the diagnosis (Fig. 6416; see also Fig. 646). Children who must undergo open-lung biopsy may be poor risks for surgery and anesthesia. They are often immunosuppressed with spreading pulmonary infiltrates and impending respiratory failure. Biopsy should be performed early, when indicated, rather than after respiratory failure has supervened and the child is dependent on a ventilator. However, even for patients with persisting or undiagnosed respiratory failure, lung biopsy ?till leads to significant changes in management despite a higher incidence of complications, mainly as air leak (45%). Careful preoperative review of chest radiographs is essential to identify the optimal site for biopsy; sometimes two different areas should be sampled, one heavily infiltrated and the other less involved. Preoperative discussion with the pathologist is invaluable. A small anterior thoracotomy incision with the biopsy performed using a stapler device is safe and expeditious; in smaller children, a Lahey clamp allows an adequate biopsy specimen through a smaller incision, especially if the lung parenchyma is stiff and cannot be brought out through the incision (Fig. 6417). Alternatively, a transaxillary incision may provide adequate access to lung tissue desired for lung biopsy. In experienced hands there is minimal mortality or morbidity from open-lung biopsy in spite of the patient population. In patients large enough

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A

B

A 17-year-old boy with stage IV Hodgkin's disease underwent radiotherapy and autologous bone marrow transplantation. A, On routine surveillance CT, bilateral focal airspace disease was seen, mostly in the superior segments of the lower lobes. Lung biopsy revealed bronchiolitis obliterans. He was treated with corticosteroids, and a repeat scan 3 months later (B) showed a near-complete resolution.

to allow the use of endoscopic stapling devices, lung biopsy can also be performed by thoracoscopy, with similar risks and complications to the open procedures (see Chapter 62).

CHYLOTHORAX The escape of chyle into the mediastinum from a defective thoracic duct and thence into one or both pleural spaces is a welldescribed entity. Historical perspectives on chylothe rax and its management include the evolution of the knowledge of anatomy and physiology of the thoracic duct, the development of the science of nutrition, and progress in thoracic surgery. Of note, Blalock reported in 1937 the experimental occlusion of the superior vena cava could produce chylothorax, which was prevented by prior ligation of the thoracic duct.45 A decade later, Lampson was Considerations of the first to use this treatment ~linically."~ therapy focus on causative factors and include dietary modification and octreotide to decrease thoracic duct flow, thoracentesis and/or thoracostomy drainge to relieve respiratory embarrassment and promote pleural sealing, and surgical ligation of the disrupted duct or pleuroperitoneal shunting when conservative measures fail.

Etiology A, An open-lung biopsy can be done with minimal morbidity using a small anterior thoracotomy. B, The lingula can be grasped easily and provides an adequate specimen in patients with diffuse lung infiltrate; in small children (or when a stiff lung cannot be brought outside the chest wall) a Lahey clamp is used to obtain the biopsy specimen instead of a linear stapler. After the lung tissue above the Lahey clamp is cut sharply with a scalpel, a continuous U suture is passed underneath the clamp, the clamp is released, and the suture is tightened and brought back as a simple continuous stitch. This provides excellent hernostasis and prevents air leaks.

Effusion of chylous fluid into the thorax may occur spontaneously in newborns and has usually been attributed to congenital abnormalities of the thoracic duct or trauma from delivery.47 However, the occurrence of chylothorax in most cases cannot be related to the type of labor or delivery and lymphatic effusions may be discovered prenatally.ll8.233Chylothorax is the leading cause of pleural effusions in neonates.92 Chylothorax in older children is rarely spontaneous and occurs almost invariably after trauma or cardiothoracic

CHAPTER

64

Infections a n d Diseases of the Lungs, Pleura, a n d Mediastinum

1025

Thoracic duct

Collaterals

,

innominate vein

5 6

Thoracic duct Chest radiograph of 4year-old girl with bilateral extensive lymphangioma and chylothorax. Note hazy appearance of fluid and major compression of the left lung.

surgery; however, some patients with thoracic lymphangioma may present in this older age group Cisterna chyli Operative injury may be in part a (Fig. 6418).4',48,215,'61 result of anatomic variations of the thoracic duct. Trauma leading to hyperextension of the spine with rupLeft lumbar ture of the duct from stretching has been reported with trunk high diving, wrestling, and other such a~tivities.2~5932~ Extensive bouts of coughing have been reported to cause rupture of the thoracic duct, which is particularly vulnerable when full following a fatty meal.310 Neoplasms, Schematic representation of most common particularly lymphomas and neuroblastomas, have occaanatomic arrangement of the thoracic duct. (From DeMeester R, sionally been noted to cause obstruction of the thoracic dUCt.107,2.54 LymphangiomatoSiSor diffuse lymphangiectasia Lafontaine E: The pleura. In Sabiston DC, Spencer FC [eds]: Gibbon's Surgery of the Chest, 4th ed. Philadelphia, WB Saunders, may produce chylous effusion in the pleural space and peritoneal cavity. Other causes include mediastinal 1983, reprinted with permission.) inflammation, subclavian vein or superior vena caval thrombosis, misplaced central venous catheters, and child abUSe.42,62,92, 148,2j1,373 arch and into the posterior neck to the junction of the subclavian and internal jugular veins. Many variations are present in the entire ductal system, Anatomy and Pathophysiology and the typical course of the thoracic duct is present in The thoracic duct develops from outgrowths of the juguonly approximately 50% of individuals.90~310The most lar lymphatic sacs and the cisterna chyli. During common variations are a double system originating from embryonic life, bilateral thoracic lymphatic channels are the cisterna or a multiple ductal pattern at the level of present, each attached in the neck to the corresponding the diaphragm. In the chest a rich collateral system origjugular sac. As development progresses, the upper third inates from intercostal spaces, the posterior mediastinum, of the right duct and the lower two thirds of the left duct and visceral lymphatics, which communicate freely with involute and close. The wide variation in the final the main duct via collecting trunks. anatomic structure of the main ductal system attests to The thoracic duct contains smooth muscle in the wall the multiple communications of the small vessels comthat is capable of contracting with sufficient force to prising the lymphatic system. The thoracic duct originates propel lymph upward toward the jugular venous junction in the abdomen at the cisterna chyli located over the at a rate of 50 to 200 mL/hr.lVhe rate of lymph flow in second lumbar vertebra (Fig. 64-19). The duct extends the thoracic duct varies widely and relates to the volume of fat ingestion, scar tissue in the mediastinum, presence into the thorax through the aortic hiatus and then passes of portal hypertension, and other factors. The flow of upward into the posterior mediastinum on the right before shifting toward the left at the level of the fifth thochyle superiorly into the subclavian vein is enhanced by the racic vertebra. It then ascends posterior to the aortic presence of valves in the thoracic duct, portal pressure,

1026

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and the differential gradient between the negative intrapleural pressure and the positive intra-abdominal pressure.45.'" Conversely, increasing the intrathoracic pressure through the use of positive end-expiratory pressure has been shown to decrease by half the flow of chyle in the thoracic duct. The chyle contained in the thoracic duct conveys approximately three fourths of the ingested fat from the intestine to the systemic circulation. The fat content of The large fat molchyle varies from 0.4 to 4.0 g/dL.45,310 ecules absorbed from the intestinal lacteals flow through the cisterna chyli and superiorly through the thoracic duct.'?' Total protein content of thoracic duct lymph is also high. Nutritional complications were a major source of mortality from chylothorax in the era preceding parenteral nutrition. Other than nutrients, the thoracic duct carries white blood cells (primarily lymphocytes [T cells] )-2000 to 20,000 cells/mL. Eosinophils are also present in higher proportion than in c&culating blood. Loss of lymphocytes through a thoracic duct in fistula may lead to an immunocompromised state13Y; fact, external drainage of the thoracic duct was used as an adjunct to imm~nosuppression in the early era of organ transplantation. Chyle appears to have a bacteriostatic property, which accounts for the rare occurrence of infection complicating chylothorax.

Clinical Manifestations Birth trauma was formerly thought to be the cause of many neonatal chylothoraces, but the increasing use of prenatal ultrasonography has changed the perspective. Non-iatrogenic chylothorax occurring in young children is usually related to congenital anomalies of the chyliferous vessels, cisterna chyli, or the thoracic duct itself. Most of these chylothoraces result from intrapleural leakage from dilated and thin-walled intercostal, diaphragmatic, or accessory mediastinal lymphatics. When there is lymphatic overload, these alternate lymphatics may dilate considerably to eventually become transudative lymphatic varices. In other cases, subpleural lymphatics may rupture into the pleural cavity, as in certain cardiac anomalies (e.g., total anomalous pulmonary venous return). The accumulation of chyle in the deural space from a thoracic duct leak may occur rapidly and produce pressure on other structures in the chest, causing acute respiratory distress, dyspnea, and cyanosis with tachyinea. In the fetus, a pleural effusion may be secondary to generalized hydrops but a primary lymphatic effusion (idiopathic, secondary to subpleural lymphangiectasia, pulmonary sequestration, or associated with syndromes such as Down, Turner's, and Noonan's) can cause mediastinal shift and result in hydrops or lead to pulmonary hypopla~ia.~~~,2" Postnatally, the effects of chylothorax and the prolonged loss of-chyle may include malnutrition, hypoproteinemia, fluid and electrolyte imbalance, metabolic acidosis, and immunodeficiency. In a neonate, symptoms of respiratory embarrassment observed in combination with a pleural effusion strongly suggest chylothorax. The involved side presents characteristic findings of intrapleural fluid with respiratory lag, dullness on percussion, diminished breath sounds, and

shift of the mediastinum. Fever is not common. Chest radiographs typically show massive fluid effusion in the ipsilateral chest with pulmonary compression and mediastinal shift. Bilateral effusions may also occur. Aspiration of the pleural effusion reveals a clear strawcolored fluid in the fasting patient, which becomes milky after feedings. Analysis of the chyle generally reveals a total fat content of more than 400 mg/dL (or triglyceride level greater than 110 mg/dL) and a protein content of more than 5 g/dL. In a fetus or a fasting neonate, the most useful and simple test is to perform a complete blood cell count and differential on the fluid; when lymphocytes exceed 80% or 90% of the white blood cells, a lymphatic effusion is confirmed; the differential can be compared with that obtained from the blood cell count, in which lymphocytes rarely represent more than 70% of white blood cells. Most cases of traumatic chylothorax develop after thoracic operations, in particular, repair of patent ductus arteriosus, coarctation of the aorta, and Blalock-Taussig shunt.z7l Injury to the thoracic duct in the left chest is particularly common during secondary thoracotomies for correction of lesions in the descending aorta or esophagus just inferior to the arch. If lymphatic drainage is noted at operation, the proximal and distal ends of the thoracic duct should be ligated.Z7l A period of days or weeks may elapse between trauma or surgery and the development of a symptomatic chylothorax. As chyle accumulates in the pleural space from a thoracic duct leak, progressively more pronounced respiratory symptoms develop as pulmonary compression becomes more severe. Dyspnea, tachypnea, and eventually arterial desaturation with cyanosis can develop. Nutritional deficiency is a late manifestation of chyle depletion and occurs when dietary intake is insufficient to replace the thoracic duct fluid loss.

Therapy Whereas small quantities of short-chain fatty acids are absorbed through the portal venous circulation, 80% to 90% of all fat absorbed from the gut is transported by way of the thoracic duct in the form of chylomicrons. Thus, feedings restricted to medium- or short-chain triglycerides theoretically result in reduced lymph flow in the thoracic duct and may enhance spontaneous healing ~ ~ 2 ~ ~ it has been of a thoracic duct f i s t ~ l a . 1 ~However, shown that any internal feeding, even with clear fluids, significantly increases thoracic duct flow.221 Therefore, for patients who experience large chylous fluid losses, withholding oral feedings and providing total parenteral nutrition is preferred." For patients who are already on mechanical ventilation, the addition of positive end-expiratory pressure can further decrease the lymphatic flow. Recently, somatostatin or its analogue octreotide have These agents been found useful in several report~.~~,~"22l decrease gastric, pancreatic, and intestinal secretions and have become an important tool in the management of pancreatic and intestinal fistulas. Because of its short half-life, somatostatin requires a continuous intravenous infusion, whereas the synthetic analogue octreotide can be given subcutaneously every 8 hours, starting at a dose

CHAPTER

64

Infections and Diseases of the Lungs, Pleura, and Mediastinurn

of 10 to 20 ~ g / k g / d a y . ~ 3Continuous infusions of octreotide at 1 to 4 pg/kg/hour may be more effective. It has been used as a rescue after failed surgeV3 and even as the first-line treatment without diet modification.2z4 If nonoperative management is effective, external intake should be reinstituted first with mediumchain triglycerides, followed by a normal diet for age after 2 weeks. Cultures of chylous fluid are rarely positive; providing long-term antibiotics during the full course of chest tube drainage is not considered necessary. Thoracentesis is used for diagnosis and may be sufficient to relieve spontaneous chylothorax in occasional infants with the dietary measures described; however, chest tube drainage will be necessary for the majority. Furthermore, tube drainage allows quantification of the daily chyle leak and promotes pulmonary reexpansion, which may enhance healing. Chylothorax in newborns Because ~~~2~ identifying ~~~~ usually ceases ~ p o n t a n e o u s l y . 2 ~ the actual site of the fluid leak is difficult, surgery is often deferred for several weeks. Similarly, most cases of traumatic injury to the thoracic duct can be managed successfully by chest tube drainage and replacement of If drainage persists in quantithe protein and fat l0ss.2~~ ties beyond the tolerance of the infant or child and shows no evidence of diminishing, or if it persists after 2 to 3 weeks without decreasing, ligation of the thoracic duct on the side of the effusion may be necessary. Standard contrast lyrnphangiography has been abandoned, but isotope lyrnphangiography using technetium-99m colloid, or other markers, may be helpful in identifying the site of the fistula.lg4 Occasionally the chylous fluid may enter the pericardial sac and cause ~hylb~ericardial ta'mponade, in which case pericardiocentesis should provide immediate relief. Although bilateral spontaneous chylothorax in newborns is uncommon, it can produce fatal respiratory distress unless recognized and drained promptly. When chylothorax remains resistant despite prolonged chest tube drainage and total parenteral nutrition, thoracotomy or thoracoscopy on the ipsilateral side may be necessary.48~329The decision whether to continue with conservative management or to undertake surgical intervention should be based on the nature of the underlying disorder, the duration of the leak, the daily volume of fluid drainage, and the severity of nutritional and/or immunologic depletion. Several authors have suggested that patients in whom the chest tube drains more than 100 mL/year of age/day or 10 mL/kg/day without slowing down after 10 to 20 days should undergo surgery. Although this is not an absolute indication, one should remember that loss of lymphocytes may lead to overwhelming bacterial or fungal infections, thus explaining the majority of deaths from chylothorax in the current era.232212222 The ingestion of 60 mL of cream 30 minutes before surgery may facilitate the identification of the thoracic duct and the fistula. When identified, the draining lymphatic vessel should be suture ligated above and below the leak with reinforcement by a pleural or intercostal muscle flap. Meticulous dissection of the thoracic duct with isolation of the fistula is often not feasible. When a leak cannot be identified with certainty, or when multiple leaks originate from the mediastinum, ligation of all the tissues surrounding the aorta at the level of the

1027

hiatus provides the best results. Fibrin glue and argonbeam coagulation have also been used as an adjunct for ill-defined areas of leakage or incompletely resected lympangi0mas.2~~ Thoracoscopy has been used in larger patients to avoid t h o r a c o t ~ m y The . ~ ~ ~leak, if visualized, can be ligated, clipped, or sealed with fibrin glue. If the leak cannot be identified, pleurodesis can be accomplished with talc or other sclerotic agents under direct vision through the thoracoscope, but this technique should probably be avoided in infancy because of the consequences on lung and chest wall growth. If there is concomitant chylopericardium, a pericardial window can be fashioned. Because thoracoscopy is less invasive, some surgeons advocate early intervention, as early as 5 to 10 days. This approach may be indicated in conditions where the failure rate of conservative management is higher, such as superior vena cava thrombosis or problems associated with increased right-sided heart pressures. Pleuroperitoneal shunts have been used for refractory chylothorax in which a leak has not been identified and in those patients who do not respond to initial nonoperative management, especially if they have a higher This approach has been used with occaoperative ri~k.26~ sional success both in patients with congenital anomalies of the thoracic duct or lymphangiomas or in patients who have persistent drainage after cardiac surgery.307 A Denver double-valve shunt system is the type most commonly employed; it may be totally implanted under local anesthesia and allows the patient or parent to pump the valve to achieve decompression of the pleural fluid into the abdominal cavity, where it is reabsorbed. An externalized pumping chamber was found to be superior in smaller infants.402 It may offer the least invasive treatment for neonates or infants who develop a refractory chylothorax after surgery for complex cardiac malformations, as long as right-sided heart pressures are below 25 cm H 2 0 . Overall, most patients with chylothorax can be cured with conservative measures, nutritional support, and occasional operative intervention. Patients with diffuse lymphatic malformations remain a challenge.

MEDIASTINAL INFECTIONS Acute Mediastinitis Acute mediastinitis occurs as a result of contamination and/or soilage of the mediastinal space secondary to the trauma or perforation of either the trachea or esophagus. Rarely, mediastinitis can develop from a descending retropharyngeal or cervical abscesses1" or the rupture of suppurative mediastinal lymph nodes. Infection within the mediastinum can disseminate quickly because this space contains no anatomic barriers to the spread of infection. Clinically, acute mediastinitis is heralded by high fever, chest pain, dyspnea, cyanosis, and marked tachycardia as well as a significant leukocytosis. In neonates, the signs and symptoms may be subtle, including lethargy, fever, apnea, temperature instability, and leukopenia. The management of mediastinitis includes

1028

PART

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THORAX

hemodynamic support, the prompt administration of intravenous antibiotics, and mediastinal drainage. Drainage may be particularly important in the context of a mediastinal abscess or continued leak/contamination from a perforated esophagus. Cervical, transthoracic, retropleural, or anterior approaches may be utilized to facilitate drainage, depending on the location of abscess or leakage.

Infections After Median Sternotomy Although the incidence of sternal wound and mediastinal infections after median sternotomy is low, these infections can have devastating implications on the postoperative course of these patients. In adult series, sternal wound infections have been shown to occur in up to 20% of patients,'34 whereas the incidence of mediastinitis ranges from 1% to 2%.m0Tortoriello and colleagues reviewed their experience with mediastinitis after pediatric cardiac surgery over 15 years at the Texas Children's Hospital.366 Only 15 pediatric patients in their series of 7616 patients developed mediastinitis (0.2%). The only mortality in this series was secondary to a fulminant fungal mediastinitis after orthotopic heart transplantation. The most common infective organism was S. aureus, a finding supported by other reviews.2" Other organisms included Pseudomonas and Candida. Deep sternal infections may also be caused by gram-negative enteric flora and anaerobes. The early identification and aggressive treatment of mediastinal infections is required. Clinically, patients present with local erythema, fluctuance, purulent drainage, sternal instability, fever, and leukocytosis. These features may only be apparent after the first postoperative week. Indeed, the median time for diagnosis of sternal wound complications was 14 days postoperatively in the Texas Children's series.'" CT and gallium scanning has been useful in identifying deep sternal infections as well as sternal osteomyelitis. Controversy still exists regarding the optimal modalities that may be used to treat mediastinitis in sternotomy patients. Standard management strategies including debridement and antibiotic irrigation have evolved to the liberal use of omentall7 and rotational muscle flaps.'4,1*7J4' The results with these new techniques have generally been good, and an aggressive approach to the management of sternal wound complications is recommmended.366

Granulomatous and Sclerosing Mediastinitis This invasive and compressive process results from the enlargement of mediastinal and hilar lymph nodes secondary to tuberculosis or fungal diseases such as h i s t ~ p l a s m o s i s . ~a) review ~n of 180 cases, Schowengerdt demonstrated that ongoing enlargement or suppuration of these lymph nodes would lead to the compression, invasion, and fibrosis of mediastinal structure^."^ The superior vena cava syndrome and pulmonary vascular and bronchial obstruction have also been ascribed to this process. CT and MRI are often used to fully delineate the

extent of disease,276 but biopsy is often required to confirm the diagnosis. The course of this disease is generally mild and may be treated medically. Symptoms related to the compression of mediastinal structures usually subside with control of the underlying tubercular or fungal infection.

REFERENCES 1. 1995 Revised guidelines for prophylaxis against Pneumocystis can'nii pneumonia for children infected with or perinatally exposed to human immunodeficiency virus. MMWR Recomm Rep 1995;44:1. 2. Diagnosis and treatment of disease caused by nontuberculous mycobacteria. Am J Respir Crit Care Med 1997;156 (Supp1):Sl. 3. Antiretroviral therapy and medical management of pediatric HIV infection. Pediatrics 1998;102:1005. 4. Guidelines for surveillance of drug resistance in tuberculosis. Int J Tuberc Lung Dis 1998;2:72. 5. 1999 USPHS/IDSA guidelines for the prevention of opportunistic infections in persons infected with human immunodeficiency virus. MMWR Recomm Rep 1999;48:1. 6. Diagnostic standards and classification of tuberculosis in adults and children. Am J Respir Crit Care Med 2000; 161:1376. 7. Policy statement: Recommendations for the prevention of pneumococcal infections, including the use of pneumococcal conjugate vaccine (Prevnar), pneumococcal polysaccharide vaccine, and antibiotic prophylaxis. Pediatrics 2000;106:362. 8. Survival after introduction of HAART in people with known duration of HIV-1 infection. Lancet 2000;355:1158. 9. Updated guidelines for the use of rifabutin or rifampin for the treatment and prevention of tuberculosis among HIV-infected patients taking protease inhibitors or nonnucleoside reverse transcriptase inhibitors. Centers for Disease Control and Prevention. MMWR 2000;49:185. 10. American College of Chest Physicians Delphi consensus statement on management of spontaneous pneumothorax. Chest 2001;119:148. 11. Abadco DL, Steiner P: Gastric lavage is better than bronchoalveolar lavage for isolation of MycohactPrium tuhmculosis in childhood pulmonary tuberculosis. Pediatr Infect Dis J 1992;11:735. 12. Abman SH, Ogle JW, Butler-Simon N, et al: Role of respiratory syncytial virus in early hospitalizations for respiratory distress of young infants with cystic fibrosis. J Pediatr 1988; 113:826. 13. Abrams EJ: Opportunistic infections and other clinical manifestations of HIV disease in children. Pediatr Clin North Am 2000;47:79. 14. Abuzaitoun OR, Hanson IC: Organ-specific manifestations of HIV disease in children. Pediatr Clin North Am 2000;47:109. 15. Acevedo D: Motor control of the thoracic duct. Am J Physiol 1943;139:600. 16. Adam KA: Persistent or recurrent pneumonia in Saudi children seen at King Khalid University Hospital, Riyadh: Clinical profile and some predisposing factors. Ann Trop Paediatr 1991;11:129. 17. Aeba R, Katogi T, Moro K, et al: Omental flap for mediastinitis after median sternotomy in asplenia syndrome and gut malrotation. Thorac Cardiovasc Surg 2000;48:243. 18. Agrawal RL, Jain SK, Gupta SC, et al: Hydropneumothorax secondary to hydatid lung disease. Indian J Chest Dis Allied Sci 1993;35:93.

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19. Ahluwalia GS, Hammond GW: Comparison of cell culture and three enzyme-linked immunosorbent assays for the rapid diagnosis of respiratory syncytial virus from nasopharyngeal aspirate and tracheal secretion specimens. Diagn Microbiol Infect Dis 1988;9:187. 20. AisnerJ, Schimpff SC, Bennett JE, et al: Aspergillus infections in cancer patients: Association with fireproofing materials in a new hospital. JAMA 1976;235:411. 21. Akhan 0 , Ozmen MN, Dincer A, et al: Percutaneous treatment of pulmonary hydatid cysts. Cardiovasc Intervent Radiol 1994;17:271. 22. Albright JT, Pransky SM: Nontuberculous mycobacterial infections of the head and neck. Pediatr Clin North Am 2003;50:503. 23. Allen EM, van Heeckeren DW, Spector ML, et al: Management of nutritional and infectious complications of postoperative chylothorax in children. J Pediatr Surg 1991;26:1169. 24. Alvarez JRF, Kalache KD, Grauel EL: Management of spontaneous congenital chylothorax: Oral medium-chain triglycerides versus total parenteral nutrition. Am J Perinatal 1999;16:415. 25. Andrews J, Nadjm B, Gant V, et al: Community-acquired pneumonia. Curr Opin Pulm Med 2003;9:175. 26. Armstrong DS, Grimwood K, Carlin JB, et al: Lower airway inflammation in infants and young children with cystic fibrosis. Am J Respir Crit Care Med 1997;156:1197. 27. Asher MI, Leversha AM: Lung abscess. In Chernick V, Boat TF (eds): Kendig's Disorders of the Respiratory Tract in Children, 6th ed. Philadelphia, WB Saunders, 1998. 28. Asher MI, Spier S, Beland M, et al: Primary lung abscess in childhood: The long-term outcome of conservative management. Am J Dis Child 1982;136:491. 29. Ashford NS, Buxton-Thomas MS, Flower CD, et al: Aerosol lung scintigraphy in the detection of bronchiectasis. Clin Radiol 1988;39:29. 30. Ashour M, A1 Kattan K, Rafay MA, et al: Current surgical therapy for bronchiectasis. World J Surg 1999;23:1096. 31. Aujard Y, Fauroux B: Risk factors for severe respiratory syncytial virus infection in infants. Respir Med 2002; 96(Suppl B):S9. 32. Aurora P, Whitehead B, Wade A, et al: Lung transplantation and life extension in children with cystic fibrosis. Lancet 1999;354:1591. 33. Ayed AK: Resection of the right middle lobe and lingula in children for middle lobe/lingula syndrome. Chest 2004; 125:38. 34. Backer CL, Pensler JM, Tobin GR, et al: Vascularized muscle flaps for life-threatening mediastinal wounds in children. Ann Thorac Surg 1994;57:797. 35. Balci AE, Eren N, Eren S, et al: Ruptured hydatid cysts of the lung in children: Clinical review and results of surgery. Ann Thorac Surg 2002;74:889. 36. Balkanli K, Genc 0 , Dakak M, et al: Surgical management of bronchiectasis: Analysis and short-term results in 238 patients. Eur J Cardiothorac Surg 2003;24:699. 37. Ball P: Therapy for pneumococcal infection at the millennium: Doubts and certainties.Am J Med 1999;107(Suppl):77S. 38. Ball WS Jr, Bisset GS 111, Towbin RB: Percutaneous drainage of chest abscesses in children. Radiology 1989; 171:431. 39. Barben J, Robertson D, Olinsky A, et al: Bronchial artery embolization for hemoptysis in young patients with cystic fibrosis. Radiology 2002;224:124. 40. Bass JB Jr, Farer LS, Hopewell PC, et al: Treatment of tuberculosis and tuberculosis infection in adults and children. American Thoracic Society and the Centers for Disease

41. 42. 43.

44. 45. 46.

47. 48. 49. 50. 51. 52.

53.

54. 55. 56.

57. 58. 59. 60. 61. 62.

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Pizzo PA, Parillo JE (eds): Respiratory Disease in the Immunocompromised Host. Philadelphia, JB Lippincott, 1991. Welch KJ: Bronchiectasis. In Ravitch MM, Welch KJ, Benson CA, et a1 (eds): Pediatric Surgery, 3rd ed. Chicago, Year Book Medical Publishers, 1979. Welch KJ: Lung abscess. In Ravitch MM, Welch KJ, Benson CA, et a1 (eds): Pediatric Surgery, 3rd ed. Chicago, Year Book Medical Publishers, 1979. Welliver RC: Review of epidemiology and clinical risk factors for severe respiratory syncytial virus (RSV) infection. J Pediatr 2003;143(Suppl):S112. Welliver RC: Respiratory syncytial virus infection: Therapy and prevention. Paediatr Respir Rev 2004;5(Suppl A):S127. Wells RG, Havens PL: Intrapleural fibrinolysis for parapneumonic effusion and empyema in children. Radiology 2003;228:370. Weverling GJ, Mocroft A, Ledergerber B, et al: Discontinuation of Pneurnocystis carinii pneumonia prophylaxis after start of highly active antiretroviral therapy in HIV-1 infection. EuroSIDA Study Group. Lancet 1999; 353:1293. Whitley RJ, Jacobson MA, Friedberg DN, et al: Guidelines for the treatment of cytomegalovirus diseases in patients with AIDS in the era of potent antiretroviral therapy: Recommendations of an international panel. International AIDS Society-USA. Arch Intern Med 1998;158:957. Whyte KF, Williams GR: Bronchiectasis after mycoplasma pneumonia. Thorax 1984;39:390. Wigglesworth FW: Bronchiectasis: An evaluation of present concepts. McGill Med J 1955;24:189. Wilcox DT, Glick PL, Karamanoukian HL, et al: Spontaneous pneumothorax: A single-institution, 12-year experience in patients under 16 years of age. J Pediatr Surg 1995;30:1452. Williams HE, Landau LI, Phelan PD: Generalized bronchiectasis due to extensive deficiency of bronchial cartilage. Arch Dis Child 1972;47:423.

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401. Wilson JF, Decker AM: The surgical management of childhood bronchiectasis: A review of 96 consecutive pulmonary resections in children with nontuberculous bronchiectasis. Ann Surg 1982;195:354. 402. Wolff AB, Silen ML, Kokoska ER, et al: Treatment of refractory chylothorax with externalized pleuroperitoneal shunts in children. Ann Thorac Surg 1999;68:1053. 403. Wolff AJ, O'Donnell AE: Pulmonary manifestations of HIV infection in the era of highly active antiretroviral therapy. Chest 2001;120:1888. 404. Wong K, Waters CM, Walesby RK: Surgical management of invasive pulmonary aspergillosis in immunocompromised patients. Eur J Cardiothorac Surg 1992;6:138. 405. Wong KS, Chiu CH, Yeow KM, et al: Necrotising pneumonitis in children. Eur J Pediatr 2000;159:684. 406. Wood JR, Bellamy D, Child AH, et al: Pulmonary disease in patients with Marfan syndrome. Thorax 1984;39:780. 407. Wood RE: Hemoptysis in cystic fibrosis. Pediatr Pulmonol 1992;8:82. 408. Wubbel L, Muniz L, Ahmed A, et al: Etiology and treatment of community-acquired pneumonia in ambulatory children. Pediatr Infect Dis J 1999;18:98. 409. Yoon W, Kim JK, Kim YH, et al: Bronchial and nonbronchial systemic artery embolization for life-threatening hemoptysis: A comprehensive review. Radiographics 2002;22:1395. 410. Yu-Tang GP, Lin M, Teo N, et al: Embolization for hemoptysis: A six-year review. Cardiovasc Intervent Radio1 2002;25:17. 411. Zaia JA: Prevention and management of CMV-related problems after hematopoietic stem cell transplantation. Bone Marrow Transplant 2002;29:633. 412. Zuhdi MK, Spear RM, Worthen HM, et al: Percutaneous catheter drainage of tension pneumatocele, secondarily infected pneumatocele, and lung abscess in children. Crit Care Med 1996;24:330.

Harry Lindahl

HISTORY The first person to perform esophagoscopy was Kussmaul in 1870, who used a hollow rigid tube with a reflected light for illumination. His patient was a professional sword swallower.22 Mikulicz introduced the gastroscope in 1881. His instrument consisted of several small optical units coupled with articulated joints. In 1897, Kelling invented a flexible metal esophagoscope; and in 1898 he invented a gastroscope, the lower third of which could be flexed to 45 degrees. The gastroscope also featured an objective window that could be rotated 360 degrees. Kelling used a miniature electric bulb and a prism for lighting. In 1936, Schindler worked with Wolf, an optical physicist and manufacturer, to design a semi-flexible gastroscope that incorporated a rubber finger at the working end. The system contained more than 48 lenses and used an electric bulb for illumination.22 Hirschowirz and coworkers developed flexible fiberglass gastroscopes in 1958 for endoscopy of the upper gastrointestinal tract. During the past 10 to 15 years flexible video endoscopes have surpassed the use of fiber endoscopes. Video endoscopes are at present available from major manufacturers in sizes enabling upper gastrointestinal endoscopy even in small premature infants.'2

EVALUATION OF ESOPHAGEAL ANATOMY AND FUNCTION Radiographic Imaging Esophageal length, diameter, and contour are best evaluated by radiographic imaging with intraluminal barium. Whenever esophageal perforation is suspected, however, a water-soluble contrast medium such as Hypaque or an iso-osmotic agent such as Omnipaque (Amersham Health, Buckinghamshire, UK) is preferred over barium. The possibility of leaking barium into the mediastinum through an esophageal perforation should be avoided.

The esophagogram provides limited accuracy for locating the junction of esophagus and stomach in relation to the diaphragmatic hiatus. Esophagoscopy is more useful in determining the presence or absence of an intra-abdominal length of esophagus, and esophageal manometry is necessary for evaluating function of the lower esophageal sphincter.

Esophagoscopy Direct visualization and mucosal biopsy through an esophagoscope are the only accurate means of evaluating mucosal changes in the esophagus. The normal esophageal mucosa has a flat, shiny surface with a pattern of fine vessels. Esophageal contour can be inspected during endoscopic examination because the normal curvature of the thoracic spine is reflected in the curvature of the esophagus. Extrinsic pulsations from the aortic arch are usually seen easily in the upper third of the esophagus. With slight air insufflation, the point of diaphragmatic closure is easily identified at the lower end, and the junction between the flat esophageal and the more reddish and velvety gastric mucosa is normally below the level of diaphragmatic closure. This gastroesophageal junction forms an undulating circle that is usually easy to identify. Mucosal biopsy is necessary to evaluate submucosal and subtle surface changes. Advanced degrees of inflammation are obvious by visual inspection, and the deeper changes can often be inferred. The usefulness of open-channel esophagoscopy, the forerunner of all upper gastrointestinal endoscopy, is now limited almost exclusively to the removal of esophageal foreign bodies.

Pressure Monitoring Intraluminal recording of esophageal pressure dynamics is currently the most accurate way to evaluate esophageal motility. Observation of peristalsis during radiographic

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contrast study is less reproducible and certainly less quantifiable, although information about coordination of peristalsis, esophageal spasm, and completely uncoordinated esophageal contractions is easily seen radiographically. Early pressure recording techniques used intraesophageal balloons. Water-perfused catheters with that are pulled back multiple pressure recording through the length of the esophagus during the recording have supplanted this technique. More sophisticated techniques incorporate circular ports to calculate radial pressure vectors during the pull-back.23 Esophageal manometry is considered essential for the study of several esophageal disorders in adults. Achalasia, diffuse esophageal spasm, and nonspecific motor disorders are conditions identified by manometry, and some surgeons think that manometry is an important means in the selection of patients for antireflux surgery.24 Manometry has been applied much less widely in infants and children. Patient cooperation is required for a good study. Infants and children seldom tolerate esophageal-pressure recording probes without sedation, and the sedation itself may alter interpretation of the study results. Moreover, the motility disorders identified by manometry in adults are much less common in children. Finally, data from motility studies in children, with the exception of the few with achalasia, have seldom produced significant changes in surgical management.18 x

u

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esophagitis,26 and convincing data suggest that bile, combined with acid reflux, is the critical factor in the development of Barrett's mucosal dysplasia in the lower e~ophagus.2~ Esophageal bile detection is difficult and uncertain with pH monitoring because the mixture of acid with alkaline bile is often recorded in the neutral range by pH monitoring. The presence of bile and acid reflux is thus masked unless bile acids are measured directly from F tric aspirates. Technical improvements have allowed the , direct and continuous measurement of bile in the esophagus independent of pH.*

INDICATIONS AND APPLICATIONS OF ESOPHAGOSCOP'~ Esophagoscopy is performed for either diagnostic or therapeutic indications. For diagnostic endoscopy the flexible adequate-size video endoscope is superior. For some therapeutic procedures the open-tube rigid esophagoscope still has its advantages. Esophagoscopy is an unpleasant procedure and should preferably be performed in children under general anesthesia with endotracheal intubation. Therapeutic esophagoscopy should always be performed under general anesthesia with endotracheal intubation. In units where safe anesthesia cannot be guaranteed, therapeutic esophagoscopy should not be done.

Eighteen to 24-Hour pH Monitoring Reflux of gastric acid into the esophagus is thought to be the most common cause of esophageal inflammation, and evaluation of the presence and severity of reflux esophagitis is the most common reason for esophagoscopy in children. In situations in which some quantification of reflux is important, the 24hour esophageal pH study is suggested.I4Several authors have described the technical aspects of performing esophageal pH studies in children.3.*9Normal values for infants and children have also been documented.11~2RHowever, pH monitoring only measures acid reflux, and, recently, there has been a study showing the irreproducibility of serial pH measurings.17 Esophageal pH studies seldom provide the major basis for decisions on esophageal reflux surgery in children, but esophageal pH data can provide important corroboration for complex clinical situations that are suggestive but not diagnostic of reflux disease. These situations are primarily associated with respiratory complications of presumed reflux, which is not confirmed by barium esophagogram or by esophagoscopy with biopsy. Whereas esophagitis is the most common complication of gastroesophageal reflux in adults, respiratory complications of reflux without significant esophagitis are much more common in infants and children. Thus, esophageal pH monitoring is often important in the management of such children.'()

Bile Reflux Detection Reflux of bile into the esophagus has been implicated as a synergistic factor in the development of reflux

Diagnostic Evaluation Suspicion of Gastroesophageal Reflux The suspicion of gastroesophageal reflux is probably the most common cause of diagnostic esophagoscopy in children. The examination is performed to evaluate the presence or severity of reflux esophagitis. However, inflammation of the esophageal mucosa and submucosa is not reliably diagnosed endoscopically in the absence of mucosal ulcerations or erosions. The macroscopic appearance of the esophageal mucosa is difficult to interpret, and therefore the diagnosis and grading of esophagitis depends on mucosal biopsy.20 The more advanced degrees of esophagitis are easily recognized. Normally, a fine vascular pattern can be seen just below the mucosal surface (Fig. 65-1). Loss of this superficial vascular pattern, along with erythema, erosions, ulcerations, or nodularity, is associated with varying degrees of biopsy-proven esophagitis. Additional signs of esophagitis include mucosal bleeding on contact, white plaques of various configurations surrounded by an erythematous border, and a cobblestone appearance of the mucosa. Narrowing of the lumen caused by stricture is a complication of long-standing untreated severe esophagitis. Esophagoscopy for suspicion of gastroesophageal reflux must include gastroduodenoscopy to evaluate possible gastric mucosal lesions and to rule out pyloric or duodenal obstruction. Retrograde view of the cardia gives information of hiatal hernia and the angle of His,

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Normal cardia of a 7-month old boy as seen from mucosa: a oattern of fine vessels can be above. Normal esoohacreal <> seen under the mucosa. L

Cardia of a 10-yea~uldboy with portal vein thrombosis 3 months after a successful Rex shunt. The His angle is normal. Submucous veins are still prominent after 10 years of portal vein hypertension.

which are factors affecting gastroesophageal reflux (Figs. 65-2 and 65-3).

Dysphagia Dysphagia may be associated with esophagitis, esophageal foreign body, congenital or acquired stricture, congenital malformations, benign tumors, structural disease of the esophageal wall, or functional disorders. Endoscopic evaluation gives information of anatomic defects (e.g., stricture) but nothing of functional disorders.

Corrosive Injury Indications for esophagoscopy after caustic ingestion are controversial in children. Also, the preferred timing of endoscopy varies. I prefer to perform esophagoscopy within 24 hours of ingestion of caustic liquid in symptomatic patients. Patients without symptoms, that is, those who can swallow without difficulties and pain, do not need endoscopy. Flexible endoscopes instead of rigid instruments should be used to assess the severity of mucosal injury. In severe cases even in older children the use of a neonatal video endoscope of 5 to 6 mm in diameter can be useful because it causes less trauma than a larger instrument. Endoscopy should always be performed with complete visual control. The instrument must never be pushed blindly forward because this may cause esophageal perforation, especially in cases with full-thickness injury. Circumferential damage is not a

Inversion endoscopy of the cardia o f a &year-old boy with esophageal atresia and fundoplication. The fundoplication has partially slipped into the chest.

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contraindication of passing the endoscope, provided it can be done in full visual control. In circular damage it is advisable to pass a silicone tube to the stomach because this enables enteral feeding and also facilitates dilatation of the following stricture. The diagnosis of full-thickness injury cannot be made with endoscopy. It is a clinical diagnosis, in which the knowledge of the nature and amount of ingested material, the patient's clinical condition, and the laboratory parameters are more important than endoscopic findings.

Upper Gastrointestinal Bleeding Upper gastrointestinal bleeding is rare in children. Severe esophagitis, variceal bleeding, Mallory-Weiss lesion, or bleeding from mucosal lesions of the stomach or duodenum are the causes. The best way to diagnose these is upper gastrointestinal endoscopy. Endoscopy for acute upper gastrointestinal hemorrhage is technically demanding and should only be performed by an experienced endoscopist. Bleeding from esophageal varices can be anticipated from a palpable large spleen. The cause can be either portal vein thrombosis or liver cirrhosis, which in children is usually caused by biliary atresia. If variceal bleeding is suspected, preparation for acute sclerotherapy or ligation of the varices should be made. Severe esophagitis causing significant blood loss is very rare but easily detected in endoscopy. Mallory-Weiss tear occurs even in neonates and is best seen in inversion endoscopy from the stomach side of the cardia. Often Mallory-Weiss tear appears as a local hematoma in the cardia, which hides the actual tear.

Trauma The most common cause of esophageal disruption is iatrogenic. Most often it results from esophageal dilatation or the dilatation is other therapeutic instrumentation.l"f performed under endoscopic control, the perforation is usually easily diagnosed in the same endoscopy. There should be no perforations associated with diagnostic esophagoscopy. Both blunt and penetrating forces can cause esophageal disruption or perforation. Compression injuries to the chest more commonly disrupt the airway, but an air-filled esophagus may also be disrupted. In these cases esophagography with water-soluble contrast medium provides the best approach to diagnosis of esophageal perforation if the patient is conscious and a swallowing study can be performed. Flexible esophagoscopy can identify major tears or complete disruption, but a small crack in the wall after stricture dilatation may not be apparent without contrast radiographic imaging.

Anastornotic stricture of a (i-month-oldboy with esophageal atresia.

The unyielding, ribbed esophageal wall associated with cartilaginous rings is striking to view with a flexible scope. Tracheoesophageal fistulas are best seen with tracheoscopy and are usually invisible from the esophageal side. Figure 65-4 shows the anastomotic stricture of a patient with esophageal atresia.

FoNow-up of Congenital Upper Gastrointestinal Anomalies Operated congenital upper gastrointestinal anomalies carry a significant risk of late esophageal pathology. Complications of gastroesophageal reflux, esophagitis, gastric metaplasia, and even adenocarcinoma have been reported. Many of the patients are asymptomatic, even when harboring gastric metaplasia. To prevent irreversible premalignant mucosal changes, routine follow-up esophagoscopy of corrected upper gastrointestinal anom. l ~ - ~ ~ endoscopy alies should be c o n ~ i d e r e d . l z J ~ Follow-up of a 3-year-old boy with esophageal atresia and gastric tube is shown in Figure 65-5. Esophageal atresia anastomosis is evident in a 22-year-old woman in Figure 65-6.

Therapeutic Applications Stricture Dilatation

Anatomic Abnormalities Anatomic abnormalities of the esophagus, such as congenital stenoses, cartilaginous rings in the esophageal wall, leiomyomas, and cystic duplications are usually first identified radiographically and then confirmed endoscopically.

Balloon dilatation with or without a guidewire and with either fluoroscopic or endoscopic control is the treatment of choice for strictures. Localized anastomotic strictures are commonly managed with balloon dilatation either under fluoroscopic control or using direct endoscopic

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Pseudocardia of a patient with esophageal atresia. The esophagus has been reconstnicted with retlustemal reversed gastric tube.

visualization. Long or tight and tortuous strictures require the passage of a guidewire either endoscopically or under fluoroscopic control. The choice whether to dilate under fluoroscopic or endoscopic control depends on the preference and experience of the unit. The use of

Vi~~alization The balloon dilatator can also be introduced with endoscopic control. Small-caliber dilatators fit the endoscope working channel and can be directly pushed into the stricture. Larger caliber balloons usually require separate passing of the guidewire through the working channel of the scope into the stricture. After that, the endoscope is removed and the dilator is passed over the wire as in fluoroscopic assisted dilatation. The dilatation procedure can be inspected if the endoscope is passed beside the dilator to have a direct view of the stricture. The advantage of this method is that the extent of inflammation can be assessed and biopsy can be done, balloon dilatation can be monitored through the flexible esophagoscope, and any cracking or mucosal damage can be evaluated after the balloon is withdrawn. Figure 65-4 shows the anastomotic stricture of a patient with esophageal atresia.

Dilatation with a Guidewire Left In Situ In difficult strictures requiring multiple dilatations this technique is helpful. A gastrostomy is required. A guidewire is passed from the upper esophagus through the flexible scope into the stomach. The intragastric portion is then recovered with an endoscope through the gastrostomy opening. With the use of this guidewire, balloon dilators can be pushed to the stricture either from below or from above. After dilatation the guidewire can be replaced with a nasogastric tube, which is tied to the gastrostomy tube. In the next session the nasogastric tube can be used to lead the guidewire from the nose through the gastrostomy, making repeated dilatations easy and safe.

Gastrostomy Tube or Button Insertion Esophageal atresia anastomosis in a 22-year-old woman.

Flexible gastroscopy is an essential component of the retrograde "pull" technique for percutaneous placement of

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gastrostomy tubes or gastrostomy button^.^ Details of the technique are well described in the supply kits for these devices. Previous upper-abdominal surgery is a relative contraindication to endoscopic placement of gastrostomy devices because adhesions may prevent apposition of the stomach with the anterior abdominal wall when it is filled with air through the gastroscope. Tubes have actually traversed the colon or small bowel en route to the stomach because of adhesions limiting direct contact between the stomach and parietal peritoneum. With the "pull" technique, a percutaneously placed guide string or flexible wire is endoscopically retrieved from the stomach. The use of a basket snare through the instrument channel of the gastroscope is the simplest way to retrieve the guidewire up through the esophagus and out the mouth. The tube is then attached at its tapered, muscle-penetrating end and pulled retrograde down the esophagus, across the stomach, and out the anterior abdominal wall. The final position of the flared end in the stomach should be monitored by direct inspection through the gastroscope to make certain the gastric wall is pulled up snugly against the parietal peritoneum. I prefer to make the first tube or button change with endoscopic control to ensure that the end of the tube or button is inside the stomach. Separation of the stomach and anterior peritoneum has happened, resulting in feeding into the peritoneal cavity, which is a potentially lethal complication.

Foreign-Body Removal Effective management of esophageal foreign bodies requires familiarity and skill in the use of several different extraction techniques. Many esophageal foreign bodies that are not sharp and not embedded in the mucosa as a result of long-term residence can be removed with a contrast medium-filled balloon catheter under fluoroscopic control. Coins account for most of these problems. In a series of 415 cases,21 76% were caused by coins; the catheter removal technique was successful in 91%.Foreign bodies that are stuck at the cricopharyngeus sphincter can often be removed using a long-bladed laryngoscope and Magill forceps.9 There are also other minimally invasive techniques for removing coins.4 Esophagoscopic removal is considered necessary when the foreign body seems imbedded, has sharp points or corners, or is soft and fragmented and may Gesent a risk for aspiration during balloon extraction. However, depending on the experience of the unit, esophagoscopic removal using an open channeled esophagoscope can also be used in simple coin removals. Impacted organic matter is best removed using the rigid open-channel esophagoscope. Chunks of meat and other debris are usually lodged above a stricture, making advancement into the stomach with a bougie difficult or even dangerous. Large extraction forceps can be introduced through the rigid scope, allowing several passes of the instrument without removal of the scope sheath with each fragment. Large, sharp objects also are more safely manipulated into the protecting sheath of

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the open-channel scope. This prevents contact with the esophageal wall during extraction of the foreign body and scope as a unit. In all extractions with the openchannel esophagoscope the use of optical forceps from a rigid pediatric bronchoscope can be helpful, because it provides a magnified view. Small, imbedded objects can sometimes be handled with the flexible scope and the appropriate alligator, cup, or tack forceps or various grasping wires or baskets. Open safety pins pointing upward are easily extracted by grasping the spring loop with a tack forceps, passing the entire pin into the stomach for a turnaround, and then extracting the pin with the open point downward as it is removed as a unit with the scope.

Injection Sclerotherapy Injection sclerotherapy for esophageal varices is done with the flexible esophagoscope and the flexible needle injector. We have -used intravariceal injection with 3% sodium tetradecyl sulfate. The injection volume has been 0.5 to 1.0 mL per varicose vein, with a total volume of 2.0 to 3.0 mL per session. In more than 25 years of experience I haveseen no complications associated with the sclerosant, nor has there been any need for blood transfusions because of the injection. There are few randomized controlled trials of the effect of injection sclerotherapy. In a series of 100 children with varices, randomized for prophylactic sclerotherapy, good elimination of varices was achieved in the sclerotherapy group, but this did not improve survival.' Endoscopic variceal ligation with small rubber bands has been developed asvan alternative to endoscopic variceal sclerosis, and the effectiveness and complication rates for the two techniques were similar in a randomized trial in adults.6 Ligation of varices is gaining popularity also in the pediatric age

lntraluminal Laser Therapy Intraluminal laser ablation of esophageal lesions is used in adults.30 Flexible optical fibersfor cutting, sclerosing, or ablating lesions are available for passage through the instrument channel of a fiberscope, but clinical applications in infants and children are currently so rare that most pediatric surgical units do not maintain the necessary equipment or expertise. Endoscopic laser applications can be a possibility for future development.

INSTRUMENTATION Flexible Fiberoscopy The flexible video end-viewing gastroscope is the instrument of choice for esophagoscopy in infants and children. Excellent videoscopes in pediatric sizes are now available from several major manufacturers of endoscopic equipment. For routine diagnostic and therapeutic applications, the endoscopes are equipped with at least one channel for suction and instrumentation. The gastroscopes also include positive-pressure insufflation and

\

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the capability to flush and clear the lens without withdrawal of the scope. Four-way directional controls for the viewing tip are standard. The video picture can be tape recorded, and both paper and digital pictures can be obtained with modern equipment. The external diameter of most pediatric videoscopes with these features ranges from 6.0 to 9.0 mm. Guidelines for sterilization of fiberscopes are now fairly rigid. Automatic sterilizers are available from the manufacturers to facilitate cleaning and decontamination. Accessory instrumentation for passage through the long working channel of the scopes includes various biopsy and foreign-body forceps, graspers, baskets, flexible injectors, magnets, diathermy loops, and laser optical fibers.

Rigid, Open-Channel Endoscopy The use of a rigid, open-channel instrument in the esophagus still has a few specific indications. The large working channel of the open, rigid scope allows safe removal of large, sharp, pointed foreign bodies because the sharp edges of the foreign body can be partially drawn into the scope for protection during withdrawal. Large organic foreign bodies are also more easily removed. The large working channel allows several passes with much larger extractors than could be used otherwise, and the larger graspers lessen the break up and fragmentation that complicate manipulation with flexible instruments. For better visualization, the rigid Hopkins optical rod of the rigid bronchoscope can be used. The use of rigid optical foreign-body forceps of the bronchoscope often facilitates foreign-body removal.

PATIENT PREPARATION, SEDATION, AND PAIN CONTROL Even flexible esophagoscopy is an unpleasant procedure in children. Therefore, I prefer general anesthesia with airway intubation. It provides a more controlled and, in many cases, a safer environment for esophagoscopy than sedation. General anesthesia is mandatory in children for the management of foreign-body extraction, stricture dilatation, injection sclerotherapy, or variceal ligation. It might seem that general anesthesia would involve increased risk, but the reverse is usually the case. Intravenous sedation and a forceful endoscopy in an agitated or uncooperative child without airway control can invite disaster from respiratory depression and cardiovascular collapse. Aspiration is also an increased risk in procedures such as injection sclerotherapy or evaluation of acute bleeding, in which irrigation fluid or blood may reflux back into an unprotected airway. General anesthesia minimizes psychic trauma, increases the safety of the manipulation, and makes endoscopy much easier for the surgeon. I have no personal experience with esophagoscopy under conscious sedation without general anesthesia. However, some clinicians still use this approach. The usual agents for intravenous sedation include a short-acting central nervous system depressant of the benzodiazepine

class combined with a narcotic. Dosages are titrated to effect, within predetermined limits. A topical anesthetic spray of the hypopharynx is helpful before introduction of the endoscope. Continuous monitoring of heart rate and oxygen saturation and intermittent monitoring of blood pressure during the procedure and for an appropriate interval afterward are mandatory. Oxygen, bag, mask, and an intravenous narcotic antagonist should be available at the bedside during the procedure. Esophagoscopy under sedation should not be performed outside of an endoscopy suite that is equipped for resuscitation and cardiorespiratory support. An exception can be made, of course, for procedures required in an intensive care unit where similar supportive facilities are available. Trained personnel, as well as appropriate facilities and equipment, are essential for making the procedure maximally productive and safe. Some cooperative teenagers can undergo endoscopy without sedation, using only topical anesthetic spray of the pharynx. In selected patients this provides better cooperation than endoscopy under sedation.

TECHNICAL CONSIDERATIONS Before use, all equipment must be checked to ensure that it is in working order. The lens focus on the flexible endoscope must also be adjusted before insertion, and the video endoscope must be white balanced. The control element of the flexible scope is held in the notch between thumb and fingers of the left hand. The upward-pointing second and third fingers operate the suction and insufflation controls, and the fourth and fifth fingers stabilize the endoscope. The left thumb is used to control the north and south movement, and the right hand stabilizes the distal scope at the mouth, controls insertion, and provides lateral movement by rotational changes. Fine adjustments in east and west orientation of the tip can be made with the lateral adjustment control wheel. To protect the flexible scope, a mouthpiece is inserted between the anterior teeth.

Flexible Endoscopy with General Anesthesia Flexible videoendoscopy under general anesthesia is simpler in every respect except for insertion of the scope through the cricopharyngeus. The anesthetized patient does not swallow, either voluntarily or involuntarily. The patient is placed supine. The endoscopist stands at the head of the patient on the right side of the table. The endoscope is passed under visual control behind the larynx to the esophagus. If the larynx lies tightly against the back wall of the hypopharynx, the anesthetist can be asked to gently lift the angle of the jaw. A small jet of air can be introduced from the level of the pyriform sinus to open the cricopharyngeus. The tip of the endoscope is then advanced under vision into the orifice that comes into view. Once through the cricopharyngeus, the endoscope is adjusted so that the lumen of the esophagus is straight ahead. Observations are made during advancement and withdrawal of the endoscope. In evaluation of esophagitis

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or caustic injury, it is important to record the condition of the mucosa before the endoscope has passed over it.

Flexible Endoscopy with Intravenous Sedation or Without Sedation Intravenous sedation rarely provides total cooperation of the child undergoing endoscopy. The examination must be comprehensive but brief. This requires gentleness, precise manipulation, no unnecessary or false maneuvers, and considerable experience on the part of the endoscopist. In larger patients without sedation and those only lightly sedated, the introduction of the endoscope is best performed when the patient is sitting. After the introduction of the endoscope through the cricopharyngeus sphincter, the patient is usually placed in the left lateral position with the head slightly extended. A smooth introduction greatly reduces fear of and resistance to the procedure. Many endoscopists prefer blind intubation of the cricopharyngeus, accomplished by pressing the tongue forward with the index and middle fingers of the left hand while the right hand advances the scope during a swallow. However, introduction under direct vision through the scope offers more precise placement. A swallow can sometimes be initiated in a child by squirting water into the pharynx through the lens-washing system.

Rigid Endoscopy with Open-Channel Viewing Rigid endoscopy in a child should always involve general intubation anesthesia to minimize trauma and the risk for perforation. The supine position, with the neck forward and the head extended, is satisfactory for most examinations. The open-channel rigid esophagoscope is introduced under direct vision into the back of the pharynx with the lip of the beveled portion anterior. This lip is then used to elevate the larynx gently and to open the cricopharyngeus. The patient's mandible and maxilla are supported with the endoscopist's left hand; the thumb and index finger hold the esophagoscope as if holding a billiard cue. The right hand manipulates the scope as it would a cue. The scope should not be advanced unless the lumen of the pharynx or esophagus is clearly visualized straight ahead. If the cricopharyngeus does not open up with elevation by the lip of the scope against the posterior portion of the larynx, the esophageal lumen should be identified by passage of a soft suction catheter through the scope as a lumen finder. The scope is then passed over this catheter into the upper esophagus under direct vision. A view of the esophageal lumen should be maintained as the scope is advanced through the gastroesophageal junction into the stomach. More detailed inspection can then be obtained as the scope is withdrawn.

COMPLICATIONS Esophagoscopy involves risks associated with sedation or anesthesia in addition to the risk for direct instrumental

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perforation of the pharynx, esophagus, or stomach. Drug reactions, tracheobronchial aspiration, and hypoxic brain damage are all potential and almost entirely preventable complications associated with upper gastrointestinal endoscopy. Instrumental perforation should be entirely preventable; unfortunately, this complication still occurs. Before flexible endoscopy, the more common sites for perforation involved the posterior pharynx in children who were restrained and were examined while awake. Esophagoscopy associated with the dilatation of tight strictures still carries a greater risk for perforation than does a purely diagnostic procedure, but reliable figures on the incidence of instrumental perforation are not available for children. Even for simple diagnosis, the risk for perforation in the presence of severe esophagitis, whether from reflux or from caustic ingestion, must be greater than that in a patient with an esophagus that is not inflamed. The predominant use of flexible instruments in recent years is a major factor in reducing and almost eliminating instrumental perforation in children. As long as a magnified view of the esophageal lumen is maintained throughout the procedure, perforation remains unlikely. During the 10-year period 19942003 there were 6418 esophagoscopies or upper gastrointestinal endoscopies performed by pediatric surgeons in Helsinki University Children's Hospital. Esophageal dilatation was performed in 386 sessions. There were two perforations, both related to dilatation of anastomotic stricture after esophageal atresia repair. Both required surgical correction. There was no mortality associated with the perforations, but in one patient several operations were required to preserve the patient's esophagus. During the same period, esophagoscopy and extraction of esophageal foreign body was performed on 140 patients and sclerotherapy of esophageal varices was performed in 102 sessions. There were no surgical complications associated with these procedures, nor have there been esophageal perforations associated with diagnostic esophagoscopies.

REFERENCES 1. Celinska-Cedro D, Teisseyre M, Woynarowski M, et al: Endoscopic ligation of esophageal varices for prophylaxis of first bleeding in children and adolescents with portal hypertension: Preliminary results of a prospective study. J Pediatr Surg 2003;38: 1008-1011. 2. Champion G, Richter JE, Vaezi MF, et al: Duodenogastroesophageal reflux: Relationship to pH and importance in Barrett's esophagus. Gastroenterology 1994; 107:747. 3. Evans DF, Haynes J,Jones JA, et al: Ambulatory esophageal pH monitoring in children as an indicator for surgery. J Pediatr Surg 1986;21:221. 4. Gauderer MW, DeCou JM, Abrams RS, et al: The penny pincher: A new technique for fast and safe removal of esophageal coins. J Pediatr Surg 2000;35:276-278. 5. Gauderer MW: Percutaneous endoscopic gaatrostomy 20-years later: A historical perspective. J Pediatr Surg 2001; 36:217-219.

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6. Gimson AE, Ramage JK, Panos MZ, et al: Randomised trial of variceal banding ligation versus injection sclerotherapy for bleeding oesophageal varices. Lancet 1993;342:391. 7. Gon~alvesMEP, Cardoso SR, Maksoud JG: Prophylactic sclerotherapy in children with esophageal varices: Longterm results of a controlled prospective randomized trial. J Pediatr Surg 2000;35:401-405. 8. Hall RJ, LillyJR, Stiegmann GV: Endoscopic esophageal varix ligation: Technique and preliminary results in children. J Pediatr Surg 1988;23:1222. 9. Janik JE, Janik JS: Magill forceps extraction of upper esophageal coins. J Pediatr Surg 2003;38:227-229. 10. Johnson DG, Syme WC, Matlak ME, et al: Gastrooesophageal reflux and respiratory disease: The place of the surgeon. Aust NZ J Surg 1984;54:405. 11. Jolley SG, Johnson DG, Herbst J,et al: An assessment of gastroesophageal reflux in children by extended pH monitoring of the distal esophagus. Surgery 1978;84:16. 12. Koivusalo A, Rintala R, Lindahl H: Gastroesophageal reflux in children with a congenital abdominal wall defect. J Pediatr Surg 1999;34:1127-1129. 13. Lindahl H, Rintala R, Sariola H: Chronic esophagitis and gastric metaplasia are frequent complications of esophageal atresia. J Pediatr Surg 1993;28:1178-1180. 14. Meyers WF, Roberts CC, Johnson DG, et al: Value of tests for evaluation of gastroesophageal reflux in children. J Pediatr Surg 1985;20:515. 15. Moghissi K, Pender D: Instrumental perforations of the oesophagus and their management. Thorax 1988;43:642. 16. Myer CM 111, Ball WSJr, Bisset GS 111: Balloon dilatation of esophageal strictures in children. Arch Otolaryngol Head Neck Surg 1991;117:529. 17. Nielsen RG, Kruse-Andersen S, Husby S: Low reproducibility of 2 x 24hour continuous esophageal pH monitoring in infants and children: A limiting factor for interventional studies. Dig Dis Sci 2003;48:1495-1502. 18. Opie JC, Chaye H, Fraser GC: Fundoplication and pediatric esophageal manometry: Actuarial analysis over 7 years. J Pediatr Surg 1987;22:935.

19. Schalamon J, Lindahl H, Saarikoski H, et al: Endoscopic follow-up in esophageal atresia-for how long is it necessary?J Pediatr Surg 2003;38:702-704. 20. Schapiro M: Flexible fiberoptic esophagoscopy. In Berci G (ed): Endoscopy. New York, Appleton-Century-Crofts, 1976. 21. Schunk JE, Harrison AM, Corneli HM, et al: Fluoroscopic Foley catheter removal of esophageal foreign bodies in children: Experience with 415 episodes. Pediatrics 1994;94:709. 22. Spaner SJ, Warnock GL: A brief history of endoscopy, laparoscopy and laparoscopic surgery.J Laparoendosc Adv Surg Tech A 1997;7:369-373. 23. Stein HJ, DeMeester TR, Naspetti R, et al: Three-dimensional imaging of the lower esophageal sphincter in gastroesophageal reflux disease. Ann Surg 1991;214:374. 24. Stein HJ, DeMeester TR: Indications, technique, and clinical use of ambulatory 24hour esophageal motility monitoring in a surgical practice. Ann Surg 1993;217:128. 25. Stein HJ, Hoeft S, DeMeester TR: Functional foregut abnormalities in Barrett's esophagus. J Thorac Cardiovasc Surg 1993;105:107. 26. Stoker DL, Williams JG: Alkaline reflux oesophagitis. Gut 1991;32:1090. 27. Vanamo K, Rintala RJ, Lindahl H, et al: Long-term gastrointestinal morbidity in patients with congenital diaphragmatic defects. J Pediatr Surg 1996;31:551-554. 28. Vandenplas Y, Goyvaerts H, Helven R, et al: Gastroesophageal reflux, as measured by 24hour pH monitoring, in 509 healthy infants screened for risk of sudden infant death syndrome. Pediatrics 1991;88:834. 29. Vandenplas Y Esophageal pH monitoring: Methodology, indication and interpretation. Eur J Pediatr Surg 1991;1:67. 30. Weston AP: Use of lasers in Barrett's esophagus. Gastrointest Endosc Clin North Am 2003;13:467-481.

,

Caustic Strictures of the Esophagus -

--

-

-

Alastair J. W. Millar, Alp Numanoglu, and Heinz Rode

HISTORICAL NOTE

morbidity is often devastating and can be associated with Corrosive ingestion is a disease of the industrial age.75 lifelong consequences. Comprehensive statistics dating The tragic consequences of ingesting caustic substances back to the 1970s indicate a decrease in the incidence of and the evolution of treatment methods have been well ingestion; however, in developing countries, the many summarized by Tucker et al.11" Esophageal dilatation of the reports of esophageal replacement procedures bear witness resulting stricture, initially using blind bougie dilatation to this serious worldwide public health problem.2.11~4"i"x6 through the mouth, has changed little in principle but This is particularly true in areas where corrosive substances greatly in practice as a result of technologic advance~.~"~6are available in containers that are not childproof or Development of the distally lighted esophagoscope, where such substances have been decanted from larger introduction of string-guided retrograde dilatation via containers for use in homes.j5 There is still a great need gastrostomy, and improvements in general medical and for adult education and for legislation to ensure correct nutritional support have nearly eliminated early morlabeling and safe packaging and to restrict the strength tality."),l():4.'l!)."7 Based on experimental evidence, the use and availability of caustic agent~.2"1~,12:~ of steroids and antibiotics became widespread in the 1950s Approximately 20% of ingestions of caustic substances and 1960s in an attempt to reduce the incidence of stricture Early result in some degree of esophageal inj~ry.">~),ii by inhibiting inflammation, scar formation, and infecmanagement strategies for ingestion are now well defined, tion. 16,lX,21.24.ii2,.i6.67,70,Y9 However,mortalim still occurs from particularly the use of fiber-optic endoscopy to assess the pharyngeal and laryngeal burns resulting in edema and ever, extent and severity of i n j ~ r y . ~ ~ ~ ~ J 2 W o wcontroairway obstruction, massive ingestion with perforation, versy still surrounds the use of steroids, antibiotics, and and complications after stricture dilatation or surgical esophageal stents and the timing, frequency, and method bypass of an irreversibly damaged esophagus.4.9~31~,"'48,4*7g of esophageal dilatation in the prevention and management of caustic strictures. Indications for definitive esophageal surgery or bypass and the type of procedure to use are also subjects of ongoing debate.31 EPIDEMIOLOGY The ingestion of corrosive substances remains a major health hazard in children, despite aggressive educational programs aimed at both children and adults, preventive labeling and packaging, and even legislation limiting the strength and availability of caustic SUbStanCeS.26,7.i.~~)~S~~2Z,~~91)~22,~23 In rural areas and in developing countries, caustic soda in both crystal and liquid form is used in home industry for soap making, fruit drying, and container cleaning on farms. In addition, the availability of innumerable over-the-counter caustic cleaning agents virtually ensures that children will continue to be at risk. The most distressing aspect is that the majority of ingestions occur in children younger than 3 years and are entirely preventable. Boys are more frequently i n v o l v e d . 2 ~ ~ 2 ~ ~ingestion ~ o x i c in children older than 5 years is suspect, and ingestion in adolescents (where girls predominate) is usually intentionalMji7";in these cases, larger volumes and more potent corrosive and caustic materials tend to be used. Although mortality is rare,

CAUSE Strong alkalis that are sold in both liquid and granular form are the principal cause of severe injury (Table 68-1).2" Household bleach, dishwasher detergents, and other cleaning agents, all of which are moderately alkaline, are the most frequent corrosive material ingested. However, these bums are usually limited to the esophageal mucosa, without extensive necrosis or subsequent stricture formation.26,e A wide variety of caustic substances can cause direct injury to living tissues and particularly to moist mucous membranes, including corrosives such as potassium and sodium hydroxide (lye) and phenols; reducing agents such as hydrochloric and nitric acids; desiccants such as sulfuric acid; oxidizing agents such as chromic acid, sodium hypochlorite, and potassium permanganate; and protoplasmic poisons such as acetic and formic a~ids.~'.O':J"The physical form of the substance ingested and its pH play a

CHAPTER

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Caustic Strictures of the Esophagus

1083

and alkaline substances differs considerably. With acid ingestion, coagulation necrosis of the musoca, hard eschar formation, and usually limitation of acid penetration through the mucosa occur. With alkali ingestion, tissue Caustic Commercially penetration with liquefactive necrosis is followed by Substance Type Available From -destruction of the epithelium and submucosa, which may Acids Sulfuric Batteries extend through the muscle layer.1".9"fi1A friable disIndustrial cleaning agents colored eschar develops, under which tissue destruction Metal plating continues until the alkali is neutralized. The esophagus is Oxalic Paint thinners, strippers damaged principally at the areas of holdup: the cricophaMetal cleaners ryngeal area, the midesophagus where it is crossed by the Hydrochloric Solvents aortic arch and left mainstem bronchus, and immediately Metal cleaners Toilet and drain cleaners above the esophagogastric junction. Immediate spasm Antirust compounds and disorganized motility occur; these events may result Phosphoric Toilet cleaners in delayed emptying and even gastric reg~rgitation.~' Alkali Sodium hydroxide Drain cleaners Hemorrhage, thrombosis, and marked inflammation Potassium hydroxide Oven cleaners with edema may be seen in the first 24 hours after injury. Washing powders Depending on the degree of burn, inflammation may Sodium carbonate Soap manufacturing extend through the muscle layer until perforation occurs. Fruit drying on farms After 48 hours, there is evidence of thrombosis of submuAmmonia Commercial ammonia Household cleaners cosal vessels, which gives rise to local necrosis and gangrene. Ammonium hydroxide Bacterial contamination leads to the development of small Detergents, Sodium hypochlorite Household bleach, bleach cleaners intramural abscesses, which may extend to the mediSodium polyphosphate Industrial detergents astinum with full-thickness injury.'Ufter several days, Condy's Potassium Disinfectants, hair dyes necrotic tissue is sloug.hed, ed;ma decreases. and neovascrystals permanganate cularization begins. This early reparative or subacute phase is evident from the end of the first week through the second week after injury. Scar formation begins in the third substantial role in the site and type of postingestion week, when fibroblast proliferation replaces the submuesophageal injury, with a pH greater than 12 or less than cosa and muscularis and stricture formation commences. 1.5 being associated with severe corrosive injurie~.10."~~""6*~7s Mucosal re-epithelialization begins during the third week Crystalline drain cleaners in the form of concentrated and is usually complete by the s&th weekr~tis during this sodium hydroxide tend to adhere to the oropharynx or period that adhesions may form, narrowing or obliterating become lodged in the upper esophagus, where injury is the esophageal lumen. The end result may be a fibrotic most severe."2.4-4."")-127Highly concentrated caustic liquids stricture and a shortened e s o p h a g u s . l ~ fthe injury is usually pass rapidly through the oropharynx and cause transmural, necrosis may extend to the surrounding injury to the entrance of the esophagus, the midesophagus, mediastinum, leading to mediastinitis, or in an anterior and immediately proximal to the esophagogastricjunction. direction into the trachea, giving rise to tracheoesophageal Unlike alkaline solutions,which do not have much taste, or even aortoesophageal fist~las.".").~"~~ strong acids are bitter, burn on contact, and are usually Steroids have been used to modify the inflammaexpectorated. However, when swallowed, they pass rapidly tory response both at the site of the burn and in the through the esophagus and cause the most substantial deeper tissues, with the ultimate goal of less extensive damage in the antrum of the stomach. The injury tends ~ c a r r i n g . ~ 8 , " ~ " , ~ ~ , ~ ~ , ~ ~ )the W oextent w e v e rof , the initial to be worse when the stomach is empty.:)l The duodenum injury largely determines the outcome of the healed injury; and proximal small intestine are relatively protected by this can range from mucosal re-epithelialization,with loss pyloro~pasm.'"~2~"~~0~ Ferrous sulfate as tablets (Clinitest) of esophageal glands and some submucosal fibrosis but or capsules may also induce caustic injury to the esophapreservation of the muscularis, to complete replacement of gus or stomach.l!) Disk batteries contain concentrated the esophageal wall by fibrous t i s s ~ e .Once ~,~~ the muscle potassium or sodium hydroxide, but they rarely lodge in of the esophagus has been destroyed, it cannot regenerate; the esophagus because of their small size.'"f charged, at that point, maturation of the fibrous replacement with these batteries may also cause injury to adjacent mucosa epithelialization of the luminal surface is the only "positive" because of hydrolysis at the negative electrode. 0utcome.2~Reduction of scar tissue formation by induced inhibition of intermolecular covalent bonding of' collagen with lathyrogens and mitomycin C has been demonstrated experimentally but not clinically.'l,"-~',44 PATHOPHYSIOLOGY u

Much of what is known about the pathology of caustic injury in children has been derived from adult experience with self-inflicted injury and experimental studies in animals.3x..i:+.57,64,66,65j,78,Y7,106 Injury to mucosal surfaces occurs within seconds after contact with a strong acid or alkali..3~~""he nature of the injury caused by acidic

.

CLINICAL PRESENTATION Most infants and children who ingest caustic substances present with few symptoms or Only approximately one quarter have substantial objective evidence

1084

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of corrosive inge~tion.~"7~ The extent and severity of injury depend on the concentration and form of the ingested substance. Crystalline alkalis tend to adhere to moist surfaces and cause immediate pain; in this case, orophaGrade Description ryngeal burns and primarily upper esophageal injury result. 0 Normal Esophageal burns in the absence of objective oropharynI Edema and hyperemia of mucosa geal evidence may occur in a small percentage (510%)of Ila Friability: hemorrhage; erosion blisters, exudates, patients and should not deter the clinician from taking or whitish membranes; superficial ulcers the appropriate diagnostic steps. However, most patients Ilb Grade Ila plus deep, discrete or circumferential with extensive oropharyngeal injury present with substanulceration tial esophageal damage; esophageal injury is unlikely if llla Small scattered areas of necrosis; areas of brownish only the tongue and soft palate are involved.I,40,43,77 black or gray discoloration lllb Extensive necrosis The viscosity and specific gravity of corrosive acids are lower than those of liquid alkalis. As a result, acid ingestion is associated with rapid transit through the esophagus; thus, this organ may be largely spared. Damage occurs primarily in the antrum of the stomach because of the patients with a history of ingestion require endoscopy. pooling of swallowed acid proximal to the pylorus, which Some advocate endoscopy only in symptomatic patients.Ws74 goes into spasm on contact with the ingested a~id.~9,62,97,113 Technetium-labeled sucralfate radioisotope scanning Obvious signs and symptoms of injury may be evident, of the esophagus has been used successfully as a screenwith inflammatory mucosal edema in the oropharyngeal ing device, with lack of sucralfate adherence indicating area and severe pain in the mouth and in a retrosternal the absence of significant injury." Using endoscopy directi0n.2~2~~ This is often associated with agitation and findings to grade the severity of the injury, one can predict tachycardia. Drooling and inability to swallow indicate the long-term outcome, particularly with regard to subsevere posterior pharyngeal or upper esophageal injury.rn0.90 sequent stricture formation; however, it is sometimes Acute obstruction of the upper airway may result from difficult in practice to obtain an accurate assessment posterior pharyngeal and laryngeal edema caused by An attempt is made to visualize the (Table 68-2).37,m254 spillage of the caustic agent into the upper airway.54Jl" entire upper gastrointestinal tract, but identifying cirConcentrated ammonia fumes may be inhaled, causing cumferential or grade I11 injuries provides sufficient nasopharyngeal edema and leading to respiratory injury.54 information to initiate treatment protocols; attempts Although rare, esophageal perforation with mediastinitis, at further visualization are unnecessary and potentially peritonitis, and shock may occur.9~90 d a n g e r o ~ s Perforation . ~ ~ ~ ~ ~ in this situation is a severe complication that may be accompanied by mediastinitis and even mortality. In the presence of visual evidence of a pharyngeal burn with stridor, early esophagoscopy is INITIAL MANAGEMENT AND DIAGNOSIS contraindicated because of the risk of aggravating the Initial management is directed at maintaining an adequate airway 0bstruction.l2~Indirect fiber-optic laryngoscopy is airway and oxygenation and ensuring cardiovascular stauseful to assess the upper airway.g0Esophagoscopy may bility. A few patients may require immediate intervention be done at the same time if intubation is required, or it to maintain the airway. Once respiratory and hemodymay be done later, when edema of the upper airway has namic stability has been achieved, the noxious agent, its resolved. Initial radiographic studies should be restricted composition and concentration, and the circumstances to the neck, chest, and abdomen if aspiration or respiof ingestion should be investigated. Although the careratory burn is suspected. If fever, systemic sepsis, and giver should be able to identify the ingested substance, upper abdominal signs are present, perforation may have this information is often lacking. Many health regions occurred, and a water-soluble contrast esophagogram may have poison centers where detailed product information ~) be useful to provide evidence of p e r f o r a t i ~ n .A~ contrast is available.l17 In cases of caustic ingestion, inducing esophagogram is usually done after 10 to 14 days, when vomiting or encouraging the ingestion of any liquid is an assessment of the entire esophagus and upper gastroincontraindicated because the alkali is mostly neutralized testinal tract can identify the extent of injury and may by gastric acids, and the consequences of acid regurgitahelp in choosing the appropriate therapy (Fig. 68-1).71 tion may cause further injury. Also, inhaled or aspirated vomitus may introduce corrosive matter into the upper airway, leading to acute inflammation and edema with TREATMENT airway obstruction. Because the history and physical examination are unreIf a known mild irritant, such as hypochlorite bleach, has liable in assessing the degree of esophageal involvement, been ingested without evidence of injury, treatment can be endoscopic examination of the oropharynx and upper e~pectant.~3,",~28 If the substance ingested is not known gastrointestinal tract is crucial.' Fiber-optic endoscopy and symptoms are apparent, endoscopy is indicated."~37,92~96 is both accurate and safe, especially when done within For patients with first-degree burns (grade I injury), no 24 to 48 hours after i n g e ~ t i o n . ~ , ~ 0 ~ 9 j , ' 2Unnecessary 7-*28 specific treatment is necessary. Liquid oral intake is inititreatment is avoided when esophageal injury can be ated and extended to solids. If solid foods are tolerated, excluded; however, there is still debate about which the child can be discharged. Clinical follow-up at 2 to

CHAPTER

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Caustic Strictures of t h e Esophagus

1085

use of very high dose steroids (dexamethosone 1 mg/kg for 4 to 6 weeks) has been a d v o ~ a t e d . * 2 ,However, *~~~ the number of patients in these studies was small, and morbid conditions, such as mycotic infection of the esophagus, osteitis, peptic ulceration, and osteoporosis, were significant. For patients with severe injuries, a nasogastric tube may be passed for early feeding purposes. In patients who are unable to swallow, the tube can be used for enteral feeding, to serve as a guide for prograde dilatation,and, to some degree, to maintain patency of the esophageal lumen. In most cases, oral feeding commences as soon as the patient is able to swallow saliva. If dysphagia occurs, an esophagogram can identify the extent of involvement. Concomitant use of antifungal agents, antacids, and acidsecreting inhibitors (H2receptor blockers or proton pump inhibitors) is widespread, but their efficacy has not been proved.g~,96~103,123

COMPLICATIONS OF INJURY AND TREATMENT If a stricture is demonstrated on contrast radiography done 10 to 14 days after injury, a program of dilatation is commenced (Fig. 68-2).g6Various methods can be used,

Localized stricture from ingestion of caustic crystals in a 4year-old. The patient was managed successfully by local resection and primary esophageal anastomosis.

3 weeks is indicated, and contrast examination is done if residual clinical symptoms of dysphagia are noted. Patients with moderate (grade IIa) or severe (grade IIb and 111) injuries require further treatment aimed at .~~ most the prevention of stricture f ~ r m a t i o n Although patients with grade IIa injuries recover completely, close follow-up is required, and endoscopy and dilatation must be done as prophylactic measure^.^^^^^ Major controversy surrounds the treatment options for severe injuriesnamely, the use of steroids and antibiotics, esophageal stents, and esophageal dilatation.ll* Grade IIIb injuries are rare in the pediatric age group and usually occur in adolescents attempting suicide. These injuries may require immediate and aggressive surgery if extensive necrosis and perforation are present, especially if the stomach is also invol~ed."3"~~ The use of systemic steroids is based on the knowledge that they inhibit the inflammatory response, which is However, in clinbacked by animal experiments.16,18~52,53,111 ical trials using a variety of dosing regimens, no statistical difference in the prevention of stricture formation was evident.5J20 Extensive retrospective reviews have also failed to show any significant benefit of steroid therapy for patients with severe injuries.38xgO More recently, the

A

B

A, Early esophagogram after caustic ingestion. B, Several areas of'full-thickness ulceration progressed to extensive strictures, which required esophageal bypass.

1086

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VI

THORAX

ranging from mercury-filled bougies, flexible-graded bougie dilatation, guidewire-directed metal olives (Eder-Puestow system), or various balloon dilators." Dilatation should always be attempted with great care. Initial passing of bouges for prograde dilatation should never be done blindly. If there are several strictures and visualization is difficult, it is much safer to place a transesophageal string, which is then used to guide the dilators either retrograde through the gastrostomy or antegrade through the mouth.' lYThis is best done by initially passing a soft-tipped, flexible guidewire into the distal esophagus through a ga~trotomy.~~.ll~ Easy access to the gastroesophageal orifice is gained by advancing a polyvinyl chloride endotracheal tube up the lesser curve through the gastrotomy." For satisfactory dilatation of a stricture, a general anesthetic is required in the early stages to protect the airway. To be effective, dilatations should be done at least once a week, commencing with catheters that are one or two French sizes smalle; than the estimated diameter of the stricture. It is generally prudent not to dilate more than two to three sizes larger than the size of the first dilator meeting resistance. Initially, dilatation should be continued as long as esophageal healing and a progressive increase in esophageal caliber are noted, along with re-establishment of normal feeding. Poor prognostic factors are delay in presentation, extensive grade I11 injury, ongoing esophageal ulceration, a densely fibrotic stricture that cracks on dilatation, a stricture longer than 5 cm, and inadequate lumen patency despite repeated dilata~ .data ~ support the tions over a 9- to 12-month p e r i ~ d .No routine use of prophylactic antibiotics; however, if systemic infection or transmural necrosis occurs, appropriate antibiuring otic therapy should be c ~ m m e n c e d . ~ ~ . ~ " ~ Wrecovery, it is essential to provide adequate nutrition; in most cases, the gastrointestinal tract can be used, with access through the nasogastric tube or by placement of a feeding gastrostomy or jejunostomy tube. If dilatation fails and a dense stricture develops, it requires treatment." As with other benign esophageal strictures, the incidence and severity of gastroesophageal reflux must be investigated and excluded as a contributing cause Gastroesophageal ,~~,~~ reflux of the persisting s t r i ~ t u r e . 2 ~ should be managed surgically, if necessary, before definitive procedures are attempted.I0l Localized strictures may be resected with an end-to-end anastomosis. the whole esophagus must first be carefully assessed endoscopically to confirm that the stricture is localized, because the fibrotic injury may be much more extensive than is evident on radiography.9." A healthy color of the esophageal mucosa and distensibility with air insufflation at esophagoscopy are useful signs when assessing the esophagus. Local injection of steroids (1% triamcinolone acetate) into short strictures has had some success when combined with dilatation but has not been assessed prospectively.13.20,42.5668,80 Some investigators advocate the use of esophageal stenting by means of an indwelling nasogastric t~be.2~,"3,"The lumen is maintained, and adhesion of de-epithelialized areas of the esophagus is prevented; simultaneously, tube feedings can be given. Over the years, various types of

stents have been used (e.g., silicone, polytetrafluoroethylene) .1412739344.8,1*5If used, stents should remain in place for at least 6 weeks, at which time epithelial healing should be complete and fibrosis will have begun to mature. However, in many cases, these tubes are not well tolerated; they may gastroesophageal reflux, and if an extensive inflammatory response through the muscle occurs, the stent must be in place for much longer to be effective. Stents have also been used in the management of esophageal fistulas resulting from caustic injury or dilatation therapy, mainly as a temporizing measure before surgical repair or esophageal bypass (Fig. 68-3).87

LONG-TERM OUTCOME Extensive caustic injury may heal without stricture or may respond to the various prophylactic and therapeutic measures outlined. However, residual motility dysfunction can be expected, and an achalasia-like picture has been described,B344j.85 Carcinoma of the previously injured esophagus is a real risk, but the disease has a latency period of 15 to 40 years.8,'*,15,46,58,69,73,96,118 Also, Barrett's esophagus has

ow ever.

-

-

A

B

A, Contrast esophagogram of a persistent caustic stricture of the midesophagus, with esophageal shortening and marked gastroesophageal reflux (arrow). £3, This resolved after antireflux surgery and dilatation.

CHAPTER

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Caustic Strictures of the Esophagus

1087

been observed following lye-induced i n j ~ r y .Thus, ~ ~ ~ ~ used ( ~ for less extensive but persistent strictures." Deciding long-term surveillance with esophagoscopy is advocated. which procedure to use and whether to bypass or resect In this regard, two prudent questions arise: To what the injured esophagus is influenced by local practice and extent should the clinician try. to -preserve the damaged the morbidity and mortality from esophageal resection. esophagus? When should attempts at dilatation-be Clearly, the risks associated with resection must be less abandoned?"-94 than the risk of cancer in the retained but bypassed esophagus.&.8,",."2,102 Currently, there is a trend toward earlier esophageal bypass in a severely injured esophagus, with the addition of resection of the damaged esophagus.9~95~109~~~~ Complications such as abscess or cyst formation in the RESULTS bypassed but retained esophagus are rare, and carcinoma has not been reuorted.".":! Between 1957 and 2003,327 children with caustic injuries Esophageal perforation, as evidenced by pain, fever, and of the esophagus were treated at the University of Cape tachycardia, is a life-threatening iatrogenic complication Town teaching hospitals (Red Cross Water Memorial of esophageal dilatation (Fig. 68-4).",m With immediate Children's Hospital and Groote Schuur Hospital). The . recognition by endoscopy-or contrast swallow, many average age was 35 months, with a range of 9 to 144 months. patients with a perforated esophagus can be treated Forty-eight percent were younger than 2 years. In recent conservatively with systemic antibiotics and parenteral years (1990 to 2003) there has been a trend toward an n~trition.9"~()7.~2~ Established methods of management increasing number of caustic ingestions (832), but only with either thoracostomy drainage or primary repair with 305 patients (36%) required hospitalization, and of these, proximal and distal esophageal and gastric diversion are only 24 (8%) developed strictures. The mean age was reserved for patients with delayed recognition or exten3.1 years, with a slight male predominance (58%). Most al irrigation with or sive disruption. ~ r a n s e s o ~ h a g ewater children ingested household cleaners or disinfectants without chest drainage as a supplement to conservative (Table 68-3). measures has also been advocated.'j3If dilatation has failed Overall, 82 of the 327 (25%)patients developed fibrous or if the esophagus cannot be salvaged, esophageal bypass strictures of the esophagus. Caustic soda was the most or substitution is indicated. O~erationscurrentlv used are common corrosive agent (78 of 82 patients) and was taken colonic interposition, gastric tube esophagoplasty, jejuin the crystal form by 31 children. This form of caustic nal interposition, and gastric advancement (see Chapter soda was used extensively on orchards and sheep farms. Colonic patch procedures have also been 69).y'.X"~~lOOJ1l.ll~ Acid burns were responsible for only four strictures.

A

B

C

Left-sided tension pneumothorax secondary to perforation after dilatation of an upper esophageal caustic stricture. A, Treatment by thoracotomy drainage. B, Contrast study 10 days later shows that the leak has been contained. C, Healed esophagus 12 weeks after perforation. Esophageal replacement was not required in this case.

1088

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THORAX

Substance

No. of Patients

Acids (toilet bowl cleaner, soldering flux, antirust compounds, battery acid) Anionic surfactants and polyphosphates (household cleaning agents) Sodium hydroxide (drain and oven cleaners) Ammonium hydroxide (bleach, cleaning agents) 2% to 3.5% sodium hypochlorite (bleach) 3.2% phenols, 2% alkali (household cleaners and disinfectants) Permanganate crystals Dishwasher detergent granules* Unknown *Very corrosive because of granular form and alkalinity of binders.

One patient with an acid burn who had extensive esophageal injury developed a severe stricture of the stomach antrum and upper jejunum; another patient presented 8 months after ingesting soldering acid with a near-complete antral stricture. Early management did not include steroids or the routine use of antibiotics; antibiotics were administered only in cases of infection, usually of the respiratory tract. Recently, we have empirically used an antifungal agent (nystatin [Mycostatin]) prophylactically and an antacid coating agent (sucralfate) to protect the esophagus from fungal infection and gastroesophageal reflux. Most patients had endoscopy only as far as the first grade I1 lesion encountered. A nasogastric tube was inserted into the stomach for feeding purposes and to prevent total occlusion of the esophageal lumen. Strictures were initially treated by regular prograde dilatation. Bougienage commencing 10 to 14 days after injury was performed with the patient under general anesthesia. Antegrade dilatation was initially performed through a rigid esophagoscope using gum elastic bougies; for the last 2 decades, however, this has been done using a fiber-optic endoscope with balloon dilators, the Eder-Puestow wire-guided dilator system, or string-guided dilatation with a transesophageal string and gastrostomy. Successful dilatation was usually accompanied by a steady lengthening of the interval between successive treatments and was confirmed by contrast-swallow radiography. Over the past decade, we have been using the string-guided system through the mouth because we found that the gastrostomy aperture is often too small for the largerdiameter bougies. The Eder-Puestow system is useful on occasion, but for the most part, it is too rigid and does not allow sufficient "feel" for safe dilatation. The esophageal balloon dilator was ineffective for established fibrotic strictures. Patients with an ulcerated esophagus requiring repeated dilatations were given prophylactic antibiotics with each dilatation as a precautioil against dissemination of bacteria, after a brain abscess occurred in one of our patients.' Two patients received a local injection of the steroid 1% triamcinolone-one into a very scarred supraglottic area, and the other into a fairly localized esophageal stricture-but neither patient had

sustained effects. An esophageal stent was used for 6 weeks in one patient with an extensive grade I11 injury, but within weeks of removal, complete obliteration of the lumen recurred. Of the 82 patients with strictures, 38 (46%) responded to repeated dilatations, whereas the other 44 required operative management. Ten of the 44 had severe oiopharyngeal burns in addition to the scarred esophagus, and 6 of these patients required tracheostomy. The 82 patients had an average of 18 dilatations (range, 1 to 38). The 38 who responded to dilatation had an average of 17 dilatations over a period of 15 months (range, 0.5 to 20 months); the 44 children with strictures who required esophageal replacement were dilated an average of 12 times-(range, 1 to 31) over a 13month period (range, 0.5 to 87 months). The outcome was poor when presentation was delayed for more than 1 month, with 8 of 10 such patients requiring esophageal bypass. Length of stricture greater than 5 cm was another adverse factor; 1'7 of 18 patients with this finding did not respond to dilatation. The most significant complication was esophageal perforation, which occurred in 11 patients (Table 68-4). Perforation occurred after an average of six dilatations. Two perforations occurred during the first dilatation, and others occurred after as manv as 14 dilatations, indicating that perforation can occur at any stage. With early recognition, perforation was associated with minimal morbidity, and some patients could be treated conservatively with intravenous antibiotics alone. If extension of the inflammatory process or perforation into the mediastinum or pleura occurred, these areas were drained. One patient developed a tracheoesophageal fistula and had esophagectomy of an extensively scarred esophagus, followed by retrosternal left colonic interposition; no complications such as cyst or abscess formation have occurred in the retained esophagus. Seven patients developed gastroesophageal reflux, six of whom underwent antireflux surgery. Four subsequently responded to dilatations, whereas the other three required esophageal replacement. Since 1969, we have performed an isoperistaltic retrosternal left transverse and left descending colon interposition based on the ascending branches of the left colonic vessels in 35 cases and local resection with end-to-end anastomosis in 1 case. Details of the operative procedure have been reported." Colonic interposition has proved to be a successful conduit for all nutritional needs, with satisfactory long-term results (Fig. 68-5; Table 68-5).

Complication Perforation Tracheoesophageal fistula Gastroesophageal reflux Pneumonia Cerebral abscess Hemorrhage Tracheostomy

No. of Patients 11

1 7 8 1 1 6

CHAPTER

68

Caustic Strictures of t h e Esoptlagus

1089

Some practical aspects of the operation are worthy of mention and should be emphasized, because most complications can be prevented. The feeding vessels of the conduit must be carefully selected and preserved with some adjacent mesentery. Usually, two of the ascending branches of the left colic artery can be retained. The colonic segment required to reach the upper esophagus and pharynx should be measured on the mesenteric border while the pedicle is being pulled taut. As this is being done, the bowel contracts circumferentially and shrinks in length after decompression and irrigation. Care must be taken to avoid entering the pleura when tunneling digitally in a substernal direction, because a tear into the pleural cavity sucks the colon into the adjacent thorax and may result in tortuosity of the graft. Redundancy of the lower end of the conduit should be avoided by resecting any distal redundancy before cologastric anastomosis is performed. The upper anastomosis is performed as a primary procedure in a meticulous manner with an inverted U-shaped inlay of colon into the anterolateral proximal esophagus or pharynx, thereby extending the length of the anastomosis and reducing the incidence of stricture. Pyloroplasty should be done as an adjunct to ensure adequate gastric emptying, thus preventing gastrocolonic reflux or reflux into the retained distal esophagus. Tight closure of the abdominal sheath in the epigastrium should be av0ided.303:~At the end of the procedure it is useful to hitch the stomach to the anterior abdominal wall with sutures or by placing a gastrostomy to avoid a posteriorly directed "bow" of the inferior aspect of the graft.

REFERENCES

Young man 21 years after substernal left colonic esophageal replacement for caustic injury, with accompanying esophagogram. He recently developed fatal squamous carcinoma of the cricopharynx nearly 30 years after caustic ingestion.

No. of Patients Early Death

Leaks (upper anastomosis) Recurrent laryngeal nerve palsy Late Stricture (upper anastomosis) Significant gastrocolonic reflux Intestinal obstruction (adhesions) Peptic ulceration (distal cologastric)

2 ( 1 small bowel volvulus; 1cardiac tamponade of PVC central line) 2 1

4 (2 revisions) 1 1 1

1. Adams JS, Brick HG: Pediatric caustic ingestion. Ann Otol Rhinolaryngol 1982;91:656. 2. Aghaji MAC, Chuklwu OC: Oesophageal replacement in pediatric patients. J R Coll Surg Edinb 1992;37:101. 3. Allen RE, et al: Corrosive injuries of the stomach. Arch Surg 1970;100:409. 4. Amoury RA, et al: Tracheoesophageal fistula after lye ingestion. J Pediatr Surg 1975;10:273. 5. Anderson KD, Rouse TM, Randolph JG: A controlled trial of corticosteroids in children with corrosive injury of the esophagus. N Engl J Med 1990;323:637. 6. Anderson KD, et al: Long-term follow-up of children with colon and gastric tube interposition for esophageal atresia. Surgery 1992;111:131. 7. Angel C, Wrenn E, Lobe T: Brain abscess: An unusual complication of multiple esophageal dilatations. Pediatr Surg Int 1991;6:42. 8. Appelqvist P, Salmo M: Lye corrosion carcinoma of the esophagus: A review of 63 cases. Cancer 1980;43:2655. 9. Ashcraft KW: Chemical esophageal injuries. In Ashcraft KW, Holder TM (eds): Pediatric Surgery, 2nd ed. Philadelphia, WB Saunders, 1993. 10. Ashcraft KW, Padula RT: The effect of dilute corrosives on the esophagus. Pediatrics 1974;53:226. 11. Bahnassy AF, Bassiouny IE: Esophagocoloplasty for caustic stricture of the esophagus: Changing concepts. Pediatr Surg Int 1993;8:103. 12. Benirschke T: Time bomb of lye ingestion? Am J Dis Child 1981;135:17.

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13. Berenson GA, et al: Intralesional steroids in the treatment of refractory esophageal strictures. J Pediatr Gastroenterol Nutr 1994;18:250. 14. Berkovits RN, et al: Caustic injury of the esophagus: Sixteen years' experience, an introduction of a new model oesophageal stent. J Laryngol Otol 1996;110:1041. 15. Bigelow NH: Carcinoma of the esophagus developing at the site of lye stricture. Cancer 1953;6:1159. 16. Bosher LJ Jr, Burford TH, Ackerman L: The pathology of experimentally produced lye burns and strictures of the esophagus. J Thorac Surg 1951;21:483. 17. Broor SL, et al: Long term results of endoscopic dilatation for corrosive oesophageal strictures. Gut 1993;34:1498. 18. Burford TH, Webb WR, Ackerman L: Caustic burns of the esophagus and their surgical management: A clinicoexperimental correlation. Ann Surg 1953;138:453. 19. ~ i n i n g t o JD: n Clinitest bums of the-esophagus. Ann Thorac Surg 1975;20:400. 20. Burrington JD, Raffensberger JG: Surgical management of tracheoesophageal fistula complicating caustic ingestion. Surgery 1978;84:329. 21. Butler C, et al: Morphologic aspects of experimental esophageal lye strictures. 11. Effect of steroid hormones, bouginage and induced lathyrism on acute lye burns. Surgery 1977;81:431. 22. Cadranel S, et al: Treatment of esophageal caustic injuries: Experience with high-dose dexamethasone. Pediatr Surg Int 1993;8:97. 23. Capella M, et al: Persistence of corrosive esophageal stricture due to gastroesophageal reflux in children. Pediatr Surg Int 1992;7:180. 24. Cardona JC, DalyJF: Management of corrosive esophagitis: Analysis of treatment, methods and results. N Y StateJ Med 1964;4:2307. 25. Chodak GW, Paesaro E Jr: Acid ingestion, need for gastric resection. JAMA 1978;239:225. 26. Christensen HBT: Epidemiology and prevention of caustic ingestion. Acta Pediatr 1994;83:212. 27. Coln D, Chang JHT: Experience with esophageal stenting for caustic burns in children. J Pediatr Surg 1986;21:588. 28. Cox JGC, et al: Balloon or bougie for dilatation of benign esophageal stricture. Dig Dis Sci 1994;39:776. 29. Crain EF, Gershel JC, Mezey AP: Caustic ingestions: Symptoms as prediction of esophageal injury. Am J Dis Child 1984;138:863. 30. Curtis JA, et al: Endocrine complications of topical and intralesional corticosteroid therapy. Arch Dis Child 1982; 57:204. 31. Cywes S: Challenges and dilemmas for a pediatric surgeon. J Pediatr Surg 1994;29:957. 32. Cywes S, et al: Corrosive strictures of the esophagus in children. Pediatr Surg Int 1993;8:8. 33. Dantas RO, Mamede RC: Esophageal motility in patients with esophageal caustic injury. 6J ~astroe-nterol1996; 91:1157. 34. Davis WM, Madden JW, Peacock EE Jr: A new approach to control of esophageal stenosis. Ann Surg 1972;176:469. 35. Demitbilek S, et al: Effects of estradiol and progesterone on the synthesis of collagen in corrosive esophageal burns in rats. J Pediatr Surg 1994;29:1425. 36. De Peppo F, et al: Conservative treatment of corrosive esophageal strictures: A comparative study of endoscopic dilatationsand esophageal stenting. Pediatr Surg Int 1993;8:2. 37. DiConstanzoJ, et al: New therapeutic approach to corrosive burns of the upper gastrointestinal tract. Gut 1980;21:370. 38. Estrera A, et al: Corrosive burns of esophagus and stomach: A recommendation for an aggressive surgical approach. Ann Thorac Surg 1986;41:276.

39. Fell SC, et al: The effect of intraluminal splinting in the prevention of caustic stricture of the esophagus. J Thorac Cardiovasc Surg 1966;52:675. 40. Ferguson MK, et al: Early evaluation and therapy for caustic esophageal injury. Am J Surg 1989;157:116. 41. Fyfe AH, Auldist AW: Corrosive ingestion in children. Z Kinderchir 1984;39:229. 42. Gandhi RE', Cooper A, Barlow BA: Successful management of esophageal strictures without resection or replacement. J Pediatr Surg 1989;24:745. 43. Gaudreault P, et al: Predictability of esophageal injury from signs and symptoms: A study of caustic ingestion in 378 children. Pediatrics 1983;71:767. 44. Gehanno P, Guedon C: Inhibition of experimental esophageal lye strictures by penicillarnine. Arch Otolaryngol1981;107:145. 45. Genc A, Mutaf 0 : Esophageal motility changes in acute and late periods of caustic esophageal burns and their relation to prognosis in children. J Pediatr Surg 1998;37:1526. 46. Gerzic Z, et al: Post corrosive stricture and carcinoma of the esophagus. In SiewertJR, Holsher AH (eds): Diseases of the Esophagus. New York, Springer Verlag, 1988. 47. Guelrud M, Ardeha M: Motor function abnormalities in acute caustic esophagitis. J Clin Gastroenterol 1980;2:247. 48. Gundogdu HZ, et al: Colonic replacement for the treatment of caustic esophageal strictures in children. J Pediatr Surg 1992;27:771. 49. Gupta S: Total obliteration of esophagus and hypopharynx due to corrosives.J Thorac Cardiovasc Surg 1970;60:264. 50. Gupta SK, Croffie JM, Fitzgerald JF: Is esophagogastroduodenoscopy necessary in all caustic ingestions? J Pediatr Gastroenterol Nutr 2001;32:50. 51. Hall RJ, LillyJR: Treatment of acid burns of the stomach in children by pedicle pyloroplasty. Surg Gynecol Obstet 1988; 167:153. 52. Haller JA Jr, Bachman K: The comparative effect of current therapy on experimental burns of the esophagus. Pediatrics 1964;34:236. 53. HallerJA Jr, et al: Pathophysiology and management of acute corrosive burns of the esophagus: Results and treatment of 285 children. J Pediatr Surg 1971;6:578. 54. Hawkins DB, Demerer MJ, Barnett TE: Caustic ingestion: Controversies in management. A review of 214 cases. Laryngoscope 1980;90:98. 55. Hill JL, et al: Clinical technique and success of the esophageal stent to prevent corrosive strictures. J Pediatr Surg 1976;11:443. 56. Holder TM, Ashcraft KW, Leape L: The treatment of patients with esophageal strictures by local steroid injections.J Pediatr Surg 1969;4:646. 57. Holinger PH: Management of esophageal lesions caused by chemical burns. Ann Otol Rhinolaryngol 1968;77:819. 58. Hopkins RA, Postlethwaite RW: Caustic burns and carcinoma of the esophagus. Ann Surg 1981;194:146. 59. Imre J, Kopp M: Arguments against long term conservative treatment of esophageal strictures due to corrosive burns. Thorax 1972;27:594. 60. Jackson C: Esophageal stenosis following swallowing of caustic alkalis. JAMA 1971;77:22. 61. Jelenko C: Chemicals that "burn." J Trauma 1974;14:65. 62. Jena GP, Lazarus C: A case report: Acid corrosive gastritis. S Afr Med J 1985;67:473. 63. Johnsen A, Jensen LI, Mauritzen K: Balloondilatation of esophageal strictures in children. Pediatr Radio1 1986;16:388. 64. Johnson EE: A study of corrosive esophagitis. Laryngoscope 1963;73:1651. 65. Kim 1-0, et al: Perforation complicating balloon dilatation of esophageal strictures in infants and children. Radiology 1993;189:741.

CHAPTER

66. Kirsch MM, Ritter F: Caustic ingestion and subsequent damage to the oropharyngeal and digestive passages. Ann Thorac Surg 1976;21:74. 67. Kirsch MM, et al: Treatment of caustic injuries of the esophagus. Ann Surg 1978;188:675. 68. Kirsch MM, et al: Intralesional steroid injections for peptic oesophageal strictures. Gastrointest Endosc 1991;37:180. 69. Kiviranta UK: Corrosion carcinoma of the esophagus. Acta Otolaryngol 1952;42:88. 70. Krey H: Treatment of corrosive lesions of the esophagus. Acta Otolaryngol 1952;102(Suppl):l. 71. Kuhn JR, Tunell WP: The role of initial cine-esophagography in caustic esophageal injury. Am J Surg 1983;146:804. 72. Landau G, Saunders W: The effect of chlorine bleach on the esophagus. Laryngol Rhinol Otol 1978;92:499. 73. Lansing PB, Ferrante WA, Ochsner JL: Carcinoma of the esophagus at the site of lye stricture. Am J Surg 1969;118:108. 74. Larimeau T, et al: Accidental caustic injury in children: Is endoscopy always mandatory? J Pediatr Gastroenterol Nutr 2001;33:81. 75. Leape LL, et al: Hazard to health-liquid lye. N Engl J Med 1971;284:578. 76. Litovitz R, Schmitz BF: Ingestion of cylindrical and button batteries: An analysis of 2382 cases. Pediatrics 1992;89:747. 77. Mansson I: Diagnosis of acute corrosive lesions of the esophagus. J Laryngol Otol 1978;92:499. 78. Marshall F: Caustic burns of the esophagus: Ten-year results of aggressive care. South Med J 1979;72:1236. 79. McCabe RE, Scott JR, Knox WC: Fistulation between the esophagus, aorta and trachea as a complication of acute corrosive esophagitis: Report of a case. Ann Surg 1969;35:450. 80. Mendelsohn HJ, Maloney WH: The treatment of benign strictures of the esophagus with cortisone injection. Ann Rhinol Laryngol 1970;79:85. 81. Middlekamp JN, et al: The management and problems of caustic burns in children. J Thorac Cardiovasc Surg 1969; 57:341. 82. Millar AJW, et al: Negotiating the "difficult" oesophageal stricture. Pediatr Surg Int 1993;8:445. 83. Millar AJW, et al: Detection of caustic oesophageal injury with technetium 99m-labelled sucralfate.J Pediatr Surg 2001; 36:262. 84. Mills LJ, Estrera SA, Platt MR: Avoidance of esophageal stricture following severe caustic burns by use of an intraluminal stent. Ann Thorac Surg 1979;28:60. 85. Moody FG, Garrett JM: Esophageal achalasia following lye ingestion. Ann Surg 1969;17:775. 86. Mutaf 0 : Esophagoplasty for caustic esophageal burns in children. Pediatr Surg Int 1992;7:106. 87. Mutaf 0 , et al: Management of tracheoesophageal fistula as a complication of esophageal dilatationsin caustic esophageal burns. J Pediatr Surg 1995;30:823. 88. Mutaf 0 , et al: Gastroesophagealreflux: A determinant in the outcome of caustic esophageal burns. J Pediatr Surg 1996; 31:1494. 89. Naef AP, Savary M, Ozzello L: Columnar lined lower esophagus: An acquired lesion with malignant predisposition: Report of 140 cases of Barrett's esophagus with 12 adenocarcinomas. J Thorac Cardiovasc Surg 1975;70:826. 90. Oakes DD, Sherck JP, Mark JBD: Lye ingestion: Clinical patterns and therapeutic implications. J Thorac Cardiovasc Surg 1982;83:194. 91. Orringer MB, Orringer JS, Arbor A: Esophagectomy without thoracotomy: A dangerous operation? J Thorac Cardiovasc Surg 1983;85:72. 92. Othersen BH Jr, Parker EP, Smith CD: The surgical management of esophageal stricture in children. Ann Surg 1988; 207:590.

68

Caustic Strictures of the Esophagus

1091

93. Panieri E, et al: Iatrogenic esophageal perforation in children: Patterns of injury, presentation, management and outcome. J Pediatr Surg 1996;31:890. 94. Panieri E, et al: Oesophageal replacement in the management of corrosive strictures: When is surgery indicated? Pediatr Surg Int 1998;13:336. 95. Pintus C, et al: Caustic ingestion in childhood: Current treatment possibilities and their complications. Pediatr Surg Int 1993;8:109. 96. Rappert P, et al: Diagnosis and therapeutic management of oesophageal and gastric caustic burns in childhood. Eur J Pediatr Surg 1993;3:202. 97. Ray JF, et al: The natural history of liquid lye ingestion. Arch Surg 1974;109:436. 98. Ritter F, Newman MH, Newman DE: A clinical and experimental study of corrosive burns of the stomach. Ann Otol Rhinol Laryngol 1968;77:830. 99. Rivosecchi M: Lye strictures (part 1) [editorial]. Pediatr Surg Int 1993;8:1. 100. Rode H, et al: Colonic oesophageal replacement in children-functional results. Z Kinderchir 1986;41:201. 101. Rode H, et al: Reflux strictures of the esophagus in children. J Pediatr Surg 1992;27:462. 102. Rodgers BM, Ryckman FC, Talbert JL: Blunt transmediastinal esophagectomy with simultaneous substernal colon interposition for esophageal strictures in children.J Pediatr Surg 1981;16:184. 103. Rothstein FC: Caustic injuries to the esophagus in children. Pediatr Clin North Am 1986;33:665. 104. Saeed ZA, Graham DY: Treatment of benign esophageal stricture: Where do we go from here? Dig Dis Sci 1994; 39:2099. 105. Sato Y, et al: Balloon dilatation of esophageal stenosis in children. AJR Am J Roentgen01 1988;150:639. 106. Sellars SL, Spence RAJ: Chemical burns of the oesophagus. J Laryngol Otol 1987;lOl:1211. 107. Shaffer HA, Valenzuela G, Mittal RK: Esophageal perforation: A reassessment of the criteria for choosing medical or surgical therapy. Arch Intern Med 1992;152:757. 108. Shemesh E, Czerniak A: Comparison between Savary-Gilliard and balloon dilatation of benign esophageal stricture. World J Surg 1990;14:518. 109. Spain DM, Molomut N, Haber A: The effect of cortisone on the formation of granulation tissue in mice. Am J Path01 1957;26:710. 110. Spechler SJ, et al: Barrett's epithelium complicating lye ingestion with sparing of the distal esophagus. Gastroenterology 1981;81:580. 111. Spitz L: Gastric transposition via the mediastinal route for infants with long-gap esophageal atresia. Pediatr Surg 1984;19:149. 112. Spitz L, Lakhoo K: Caustic ingestion. Arch Dis Child 1993;68:157. 113. Syrnbas PN, Vlasis SE, Hatcher CR Jr: Esophagitis secondary to ingestion of caustic material. Ann Thorac Surg 1983;36:73. 114. Tanyel FC, Buyukpamukcu NB, Hicsonmez A: An improved stringing method for retrograde dilatations of caustic esophageal strictures. Pediatr Surg Int 1987;2:57. 115. Thomas AN, Dedo HH: Pharyngogastrostomy for treatment of severe stricture of the pharynx and esophagus. J Thorac Cardiovasc Surg 1977;73:817. 116. Thomas AN, et al: Pharyngoesophageal caustic stricture. Am J Surg 1976;132:195. 117. Thompson DF, et al: Evaluation of regional and nonregional poison centers. N Engl J Med 1983;308:191. 118. Ti TK: Esophageal carcinoma associated with corrosive injury-prevention and treatment by esophageal resection. Br J Surg 1983;70:223.

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119. Tucker JA, et al: Tucker retrograde esophageal dilatation 19241974: A historical review. Ann Otol Rhinol Laryngol 1974;83(Suppl 16):1. 120. Ulman I, Mutaf 0 : A critique of systemic steroids in the management of esophageal burns in children. Eur J Pediatr Surg 1998;8:71. 121. Van der Zee DC, et al: Management of pediatric esophageal perforation. J Thorac Cardiovasc Surg 1988;95:692. 122. Walton WW: An evaluation of the poison prevention packaging act. Pediatrics 1982;69:363. 123. Wasserman RL, Ginshurg CM: Caustic substance injuries. J Pediatr 1985;107:169. 124. Webb WA: Esophageal dilatation: Personal experience with current instruments and techniques. Am J Gastroenterol 1988;83:471.

125. Wijburg FA, Heymans HAS, Urbanus NAM: Caustic esophageal lesions in childhood: Prevention of stricture formation. J Pediatr Surg 1989;24:171. 126. Yarrington CT Jr: The experimental causticity of sodium hypochloride in the esophagus. Ann Otol Rhinol 1970; 179:895. 127. Zarger SA, et al: Ingestion of strong corrosive alkalis: Spectrum of injury to upper gastrointestinal tract and natural history. Gastroenterology 1989;97:276. 128. Zarger SA, et al: The role of fibreoptic endoscopy in the management of corrosive ingestion and modifikd endoscopic classification of burns. Gastrointest Endosc 1991; 37:165.

Esophageal Replacement Lewis Spitz

The need to replace the esophagus is becoming increasingly I-are, mainly because of improved methods of retaining the native esophagus in infants born with l o n g gap esophageal atresia. In addition, general awareness of the damage that can occtu- as a consequence of intractable gastroesophageal reflux has resulted in more aggressive approaches in antireflux surgery, and with the introduction of childproof containers, fewer lye and caustic injuries to the esophagus occur. Nevertheless, there continue to be instances in which substitution of the esophagus is required, and it is therefore important for the pediatric surgeon to be aware of the various options available for replacement.

now possible to perform a primary interposition procedure, or if circumstances do not permit, a cervical esophagostomy is performed with a later replacement procedure. Although it is obvious that the patient's own esophagus is the best esophagus, persisting with futile attempts to retain the native esophagus in the presence of major complications (such as empyema, intractable stricture, and repeated recurrent fistulas) is occasionally detrimental to the wellbeing of the infant. In such situations, it is clearly in the patient's best interest and safety to abandon the esophagus and perform a replacement procedure at a later stage.

Peptic Strictures INDICATIONS FOR ESOPHAGEAL REPLACEMENT Esophageal Atresia Infants with long-gap esophageal atresia constitute the maill group that requires esophageal replacement because of failure to achieve end-to-end anastomosis. Numerous maneuvers have been adopted to ~ \ ~ e r c o mthe e long gap and achieve a primary anastomosis to allow retention of the infant's native esophagus. A list of these techniques is presented in Table 69-1. For isolated esophageal atresia, it is important to exclude an upper pouch tracheoesophageal fistula. When only a small nubbin of distal esophagus is present above the hiatus or there is no intrathoracic esophag~sat all, a replacement is clearly going to be required, and it is best to perform a cervical esophagostomy at an early stage and allow the infant to go home pending a later replacement procedure. The infant is now free of the danger of aspiration, and appropriate bonding with the fanlily can take place at home. If an anastomosis cannot be achieved even under extreme tension, current opinion favors an attempt at delayed primary repair. The infant is fed by gastrostomy while suction is applied to the upper esophageal pouch for a period of 6 to 12 weekx During this time, the gap between the two ends o f the esophagus gradually diminishes. If primary anastonlosis is i~npossibleat this stage, f ~ ~ r t h edelay r is t~~lprodt~ctive and esophageal stibstitution is required. It is

Antireflux surgery is usually performed for pathologic gastroesophageal reflux before intractable strictures develop. However, in children with severely scarred and

During the Initial Procedure Anastomosis under tension40.69.112 Tension-relieving p r o c e d ~ r e s 2 ~ , ~ 0 ~ ~ ~ ~ ~ ~ Flap techniq~e25.~~ Suture fistula48,100.103.104 Delayed Primary Anastomosis With bougienage: proximal,51,70 proximal and dista1,43 magnetic47 Without bougienageE9 Esophageal-lengthening techniques (e.g., flap,22.36 spiral m y ~ t o m y ,gastric l ~ ~ divisionlo1) Transmediastinal "Thread" With and without olive^"^^^^^ Kato techniques7 Esophageal Replacement Colonic i n t e r p o s i t i ~ n ~ ~ , ~ ~ ~ . ~ ~ ~ Gastric tube e s ~ p h a g o p l a s t y ~ , ~ ~ Jejunal interpositiong3 Gastric t r a n s p ~ s i t i o n ~ ~ . ~ ~ ~

I

1094

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VI

THORAX

inflamed strictures of the esophagus, most of these strictures resolve with effective antireflw surgery followed by regular postoperative esophageal dilatation. A small percentage requires limited "sleeve" resection of the strictured area, but some fail to respond and require esophageal replacement.

Caustic Strictures Though uncommon in developed countries as a result of legislation mandating childproof containers for caustic substances, many children in developing countries continue to sustain caustic esophageal injuries. Most cases are mild and respond to repeated dilatation. Full-thickness injury to more than a very short segment of the esophagus invariably results in an intractable stricture that fails to respond to dilatation and usually requires substitution. Continuing with dilatation at regular intervals for longer than 6 to 12 months is unproductive. The need to resect the damaged esophagus continues to be disputed. The risk for malignant conditions and the ease with which esophagectomy can be performed in children favor resection and substitution rather than bypass procedures. Caustic strictures are discussed extensively in Chapter 68.

Miscellaneous Indications

TYPES OF ESOPHAGEAL REPLACEMENT Although the colon continues to be the most frequently used organ for esophageal substitution in children, dissatisfaction by some surgeons has led to the use of alternatives. The methods most commonly used are shown in Figure 69-1. The advantages and disadvantages of the various substitution procedures are outlined in Table 69-2. Several artificial prostheses have been used as substitutes for the esophagus; however, all of them have functioned for only very short periods.loo

ROUTE FOR POSITIONING THE ESOPHAGEAL SUBSTITUTE The posterior mediastinurn is the shortest distance between the cervical region and the abdomen for esophageal r e p l a ~ e m e n t .Colonic ~~ interpositions were originally placed subcutaneously on the anterior chest wall, but the cosmetic appearance of this method is unacceptable and it

Right Colon

The need for replacement because of bleeding esophageal Left varices is virtually obsolete as a result of the success of alternative techniques, particularly sclerotherapy and portosystemic shunts. Tumors of the esophagus may require resection of extensive length of the esophagus. Examples of such tumors in children are diffuse leiomyReversed gastric tube oma and inflammatory pseudotumor. The esophagus may be extensively damaged by prolonged impaction of foreign bodies, such as aluminum ring pull-tabs, which are radiolucent and may escape detection on conventional radiography. Other unusual indications for esophageal R... replacement include intractable achalasia, diffuse candidiasis in children with immune deficiency, ~ c l e r o d e r m a , ~ ~ Jejunum - Interposition and epidermolysis bullo~a.~R

CHARACTERISTICS OF AN IDEAL ESOPHAGEAL SUBSTITUTION 1. The substitute must function as an efficient conduit from mouth to stomach to satisfy the nutritional needs of the child. 2. Gastric acid reflux into the conduit must be minimal; if reflux does occur, the substitute should be resistant to gastric acid. 3. The substitute should not impair respiratory or cardiac function. 4. The operative technique should be technically unchallenging and adaptable to small children. 5. The conduit should not produce any external deformity. 6. The conduit must grow-with the child and continue to function into adult life.13

Free graft

Stomach

Methods of esophageal replacement.

CHAPTER

Method

Advantages

Disadvantages

Colon

Adequate length Reflux seldom occurs

Precarious blood supply Graft necrosis High incidence of leaks and strictures Multiple anastomoses Redundancy over the long term Slow transit of food

Gastric tube

Adequate length Good blood supply

Very long suture line High incidence of leaks and strictures Reflux leading to Barrett's syndrome

Size of conduit appropriate Rapid transit

Esophageal Replacement

1095

is thriving and weighs at least 5 kg. In the interim, it is important to stimulate the swallowing. reflex by offering. sham oral feedings during regular gastrostom; feedingsy Infants who achieve good sham feeding will undoubtedly rapidly accept oral nutrition when the esophageal substitute has been successfully connected. In all cases, adequate mechanical preparation of the intestine is essential because the organ that has been selected for esophageal replacement may be unsuitable and an alternative technique may be required. Excellent comprehensive reviews of the history of esophageal replacement have been documented by May and Samson in 196974and by Postlethwait in 1983.87

COLONIC INTERPOSITION

Jejunum

Appropriate size

Very precarious blood supply Retention of peristaltic activity Length can be a problem Three anastomoses

Colonic interposition continues to be the most widely used procedure for esophageal replacement in children. In adults with carcinoma of the esophagus, the currently preferred technique is gastric transposition, with colonic interposition being reserved as a secondary procedure.

Free jejunal graft

Appropriate size Good peristaltic activity

Specialized technique for microvascular anastomosis Prolonged operating time Precarious blood supply High failure rate

History

Stomach

Adequate length easily attained Excellent blood supply Single anastomosis Ease of procedure

Bulk of stomach in thorax Reflux common early on Poor gastric emptying Affects pulmonary function? Affects growth?

has been abandoned. The advantages and disadvantages of the other routes are outlined in Table 69-3.

TIMING Although esophageal replacement is possible in newborns, the procedure should generally be delayed until the infant

1

69

In 1911, Kelling58used a segment of transverse colon to bypass the esophagus. Because the mesentery was too short for the planned jejunal interposition, he based the colon on the left colic artery. However, the patient died before an attempt could be made to join the cervical esophagostomy to the upper end of the colon. In 1911, V~llietl2~ preserved the mesenteric pedicle to the right end of the colon transplant in a cadaver. In 1914, Von Hacker carried out the first successful colonic interposition in an adult.lZ4The first successful colonic bypass in a child was reported by Lundblad in 1921.68The patient underwent the procedure for an esophageal stricture at 3 years of age and lived until he was 37 years old, at which time he died accidentally. Ochsner and Owens79 reviewed the literature in 1934 and could find only 20 reported cases of colonic esophagoplasty. In 1951, Rudler and Monod-BrocagVescribed the retrosternal ileocolonic graft. In 1955, Dale and ShermanZ0described two infants with esophageal atresia who underwent

Route

Advantages

Disadvantages

Retrosternal

Ease of procedure Useful when the transpleural and mediastinal routes are inflamed or surgery has previously been performed

Longest route from neck to abdomen Angulation of the graft unavoidable Problems with access if cardiac surgery is required

Transpleural

Convenience and ease of the procedure

Displacement of the lung Requires thoracotomy

Posterior mediastinal

Most direct route Organ contained in the mediastinum Little or no lung compression Thoracotomy not always required

Mediastinum may be unavailable because of previous surgery, fibrosis, or inflammation

1

1096

PART

VI

THOK.\X

reconstruction of the esophagus with a right colonic retrogasti-ic anterior ~nediastinali~lterpositioilat 2 years of age. Four years later, Battersby and Moore") reported five cases of right colon replacemeilt for conge~litalatresia of the esophagus. The three children who u~lderwent substernal placement of the colon survi\red. They recommended delaying the procedure until the intint was at least 9 months of age. Major advances in use of the colon for esophageal replacement were documented by Shernlarl and Waterston ill 1957,1(Niby Waterston in 1961 and 1964,l?Qnd by Belsey in 1965.12 Waterston and Belsey were strong proponents of the transpleural route and use of the left colon supplied by the left colic vessels. In 1967, Othersen and ClatworthyH3 stated that the colon was the best organ for esophageal replacement in children and recommended delaying the operation until the child was 18 to 24 months old so that gravity in the erect position would assist in food passage through the colonic interposition. Freeman and Cass,'" in 1982, advocated placing the transposed colon in the route of the native esophagus in the posterior mediastinum and reported an impressively low rate of complications.

Surgical Technique Colonic interposition entails use of either the right colon based on the ileocolic vessels placed in the retrosternal position or the left colon based on the left colic vessels positioned in a retrohilar position in the left pleural cavity or in the posterior mediastinum (Fig. 69-2).

Right Colon Retrosternal Technique The abdomen is opened through either a midline upper abdominal incision or a transverse upper abdominal muscle-cutting incision that transects both rectus abdominis mt~scles.The entire colo11 must be mobililed and exposed to provide detailed and accurate assessrrlent of its blood supply. In a study of 600 specimens, Sonrleland et al.L()X reported that only 24% of specinlens showed the typical textbook picture of three vessels to the right side of the colon arising from the superior mesenteric artery. The middle colic artery was absent in 3.6% of cases. The marginal artery was occasionally absent. 111 individual children, the anatomy of the vascular supply determines the section of colon most appropriate for the interposition procedure. The blood supply for the right colonic interposition is based on the middle colic artery. However, if a segment of terminal ileum is to be used for the interposition,llVhe ileocolic vascular supply to the graft must be preserved if possible. The length of intestine to be used is carefully estimated, and bulldog clamps are placed across all vessels that require division. The clamps are left in position for at least 10 minutes to ensure that the blood supply is adequate, that the marginal vessels continue to pulsate, and that the color of the section of colon selected for the interposition remains normal. The blood supply can be further evaluated by removing the appendix and observing the flow of blood in the appendicular artery. If the blood supply seems to be satisfactory, the vessels that require division are carefully and securely ligated and divided. It is important to preclude hematoma formation

in the mesentery. The ileum is divided between the clamps, and the distal stump is closed in preparation for relocation into the neck. The transverse colon is then divided to the left of the middle colic artery, and intestinal continuity is restored by an end-to-end ileotransverse colostorny. A transverse cervical incision that encircles the previously constructed ceivical esophagostomy is made. The incision should extend to the midline of the neck appl-oximately 1 c ~ nabove the ~nanubriumsterni. The upper border and posterior surface of the manubrium are exposed by dividing the cenical f.ascia and the origin ofthe stel-nomastoid muscle. It rriay be necessary to enlarge the openii~ginto the retrostcrnal space by removing the upper part of the ~nanubrium,sternoclavicular joint, or both. 'The I-etrosternal tunnel is developed from above through a cervical incision in a plane directly posterior to the sternum and anterior to the thymus and pericardiurn, and the anterior attachinents of the diaphragm are divided fi-om below. The tunnel must be wide enough to accomnlodate at least two to three fingers. The stornach is then ~nobilizedto allow the colon and its vascular pedicle to pass behind the stomach, over the anterior surfice of the liver, and through the retrostel-nal tunnel into the neck. It is vital to ensure that there are no kinks or twists in the graft that may impair the blood supply. The distal end of the colonic interposition is anastornosed to the anterior wall of the stomach close to the lesser curvature. An antireflux submucosal gastric tunnel has been devised as a method of preventing reflux of gastric acid into the colon graft."' The proximal end of the graft, which will comprise the ascending colon or the terminal ileum, is anastomosed in end-toend fashion to the dis~alend of the cervical esophagus. During preparation of the esophagus for anastomosis, it is imperative to preserve the blood supply and to meticulously mobilize the full thickness of the esophagus. The length of the colonic interposition must be.just suf'ficier~tto bridge the gap between the esophagus and the stomach. Excess intestine should be resected before anastomosis while the blood supply to the remaining graft is preserved. Redundancy is a problem that increases with tirne and can lead to stasis. Pyloroplasty is generally recommended to prevent this complication.

Left Colon Transpleural Technique The left colon transpleural technique was originally described by Waterston.wtl In this method the left transverse colon based on the ascending branch of the left colic artely is placed isopelistaltically in the retrohilar position. In the original description, the entire procedure was performed through a left thoracic incision with access to the abdomen provided by detaching the diaphragm peripherally from the chest wall. An alternative approach is to use separate abdominal and thoracic incisions or a thoracoab dominal incision.l? The left colon graft is based on the ascending branch of the left colic artery. Intestinal continuity is restored by an end-ttrend colocolic anastomosis. The colon graft is passed in a retrogastric and retropancreatic direction and then through a separate lateral incision in the posterior diaphragm into the left pleural cavity. The colon is passed behind the hilum of the left lung and into

the neck by tu~inelingthrough Sihson's fijsc.i;i in a posterior tiil-ection to the s~ibclavianvcsscls and I;itel-;~lto the carotid sheath. The PI-oximalend oi'thc colonic interposition is istorno tor nosed in cnd-to-rid f'nshion to the c.c~.\ic.al esophagus, and the distal end is anastornosed cithcl. to the distal sturnp of esophagus (in rases of' csol)h;igc~;~l ;~t~.csi;~) or prefera1)ly to the l)ostc~.iorw;ill of' tlic. stom;lcli. Qloroplasty is again i.cc.oll~lncndcd.F~.cc.m;~n ;ind (hss"' ~nodifiedthe proccd~ll.c.1,y ~)l;~cing the c.olon in the postcriol- ~nediastin~um in tlic. site of'the nornial csol)ha
Results With nloderrl ancstl~c.tic. tc~c.lr~licl~ics ;trld posti )pc~.alivc management, the mort;iIity fi.0111 colo~iic intc~.l)osition alone should be ncgligil,lc.~'VO~;ifi liccrosis sho111tl;~lsoI,c very rare, partic~llarlyif' mctic~llous;~ttclitio~i is paid t o ensuring that the grafi has ;In adcq~~;ttc 1)lood s~il)l)lyand that the vessels do 11ot kink as (lie gixfi is 1);lsscd t)cllir~dthe in g~.;td~i;~l i~ltarcstomach. Venous obstruction may i-cs~~lt tion of the colonic inteiposition wcc'ks 01. ~llontllsafter surgery. The most cornnlon con~plications;i~.c.;mastornotic leakage, particularly leakage involving the c.sol)li;~gocolo~~ic anastomosis in the neck, arid stricture fi)r~n;itioil.I .e;iks are C I I ~ of attributed to a pool- blood supply to the ~)t-oxilll;tl the colon or to damage to or impairnicnt of' thc blood supply to the esophageal wall. Most leaks 1r.so1vc spontaneously within a few weeks, but some progress to st1.ictur.e formation. Strictures at the cervical anastomosis generally resolve with dilatations, b ~resection ~ t of the st~ictni-cdarea and revision of the anastomosis are occasionally ncccssaly. The incidence of complications subsequent to colonic interposition in various large series in the literature is shown in Table 69-4. Gastric reflux into the colonic interposition may occur and occasionally results in peptic ulceration of the colon. This may progress to hemorrhage 01; on rare occasion, perforation with resultant empyenla. Late deaths from perforation and empyema have been reported. Complications after bypass procedures have also been described in the retained e~ophagus."~,"Shamberger et al.l0"eported eight patients in whom chronic inflammation developed in the esophageal remnant, including three cases of Barrett's syndrome. Others have documented mucocele and empyema developing in the retained esophag~s.~~ Peristalsis in the colonic segment is usually absent, and food is conducted through the colon by gravi~y:~:'Jj~."The intrathoracic colon may become increasingly redundant with timeF4and this redundancy may result in delayed e m p tying and stasis, which increases the risk for regurgitation and aspiration. It may be necessary to resect the redundant portion of colon, but in so doing, care must be taken to avoid damage to the blood supply to the remaining colon. The nutritional state of children after colonic interposition seems to be ~atisfactory.~? Children who originally had esophageal atresia tend to be in the lower percentiles for height and weight, whereas those who underwent esophageal replacement for caustic stricture fall into a normal growth curve."7-34.:+8." Nearly half the patients with colonic interposition have depleted stores of iron.93

1098

PART

VI

THORAX

Year

Author

1967 1967

Gross and Firestone38 Othersen and Clatworthya3 Azar et al.9 Soave107 Martin72 Rodgers et al.95 German and Water~ton~~ Freeman and Cass29 Campbell et al.15 Hendren and Hendren48 Rode et a1.94 West et a1.1Z7 Ahmed and Spitz2 Mitchell et al.76 Carneiro and Doigls Raffensperger et al.90 Khan et a1.60 Erdogan et al.27 Hamza et

1971 1972 1972 1978 1976 1982 1982 1985 1986 1986 1986 1989 1993 1995 1998 2000 2003

No. of Patients

Deaths

47 11

4 0

60 32 21 13 32 33 23 32 35 25 112 79 11 59 25 18 475

GASTRIC TUBE ESOPHAGOPLASTY History In 1905, Beck and Carrel" constructed tubes of the greater curvature of the stomach in dogs and cadavers; the tubes were brought antethoracically into the neck. In 1912, J i a n ~ successfully ~ ~ used this tube intrathoracically in two patients with strictures. In 1948, Mes7j showed that a tube of the greater curvature of the stomach could reach the neck. Later, researchers Gavriliu in Hunga@l-33 and Heimlich44245 in the United States popularized this method of esophageal replacement. More recent advocates for gastric tube esophagoplasty include Burrington and Stephens,'4 Cohen,lSEin et al.,24and Anderson et aL57

Surgical Technique The abdomen is opened through a transverse supraumbilical incision, and the gastrocolic omentum is divided at a safe distance from the gastroepiploic arcade (Figs. 69-3 and 69-4).Vhe right gastroepiploic artery is divided at the point of origin of the gastric tube; the site of division must be chosen carefully to avoid narrowing the pyloric outlet. The optimum location is usually approximately 2 cm proximal to the pylorus, where a vertical incision is made through the anterior and posterior walls of the stomach. An 18 to 24 French chest tube is placed in the stomach along the greater curvature to act as a guide to ensure the construction of an appropriately sized gastric tube, and a GIA stapler is applied 1.5 to 2.0 cm from the greater curvature and oriented so that both the anterior and posterior gastric walls are encompassed. The staple line is placed, and the stomach is cut parallel to the greater curvature. Three to four applications of the stapler

Leaks (%) -

------ Strictures (%)

6 (13) 4 (36)

7 (15) 3 (27)

5 5 2 0 1

1 5 (25) 28 (87) 4 (19) 5 (38) 7 (21)

1 8 (30)

2 1 1

2 (6) 8 (34) 2 (6)

2 (6) 4 (17) 0

8 (23) 1 0 (40) 5 4 (48) 23 (29) 5 (45) 11(19) 1 0 (40) 11(61) 47 (10)

5 (14) 11(44) 34 (30) 1 7 (22) 2 (18) 1 3 (22) 7 (28) 3 (17) 25 (5)

4 0 15 9 2 2 0 4 5

-

6 (28) 3 (23) 7 (21)

are usually required. The short gastric vessels are divided, and the spleen is protected during construction of the tube. Splenectomy is neuer necessary. The staple lines on the gastric tube and the native stomach are reinfbrced simultaneously with interrupted Lembert sutures of 4 0 nonabsorbable material. If the left gastroepiploic artery has been previously ligated and is unavailable to supply the antiperistaltic tube, an isoperistaltic tube based on the right gastroepiploic artery can be constructed. The route to the neck is selected at this point, and either a retrosternal tunnel is created or a left thoracotomy is performed in the sixth intercostal space. The neck incision is placed in the suprasternal notch for a substernal tube and in the left anterior triangle for the transthoracic route. Finger dissection from cervical and thoracic approaches facilitates selection of the safest place to incise Sibson's fascia. This position may be anterior or posterior to the subclavian vessels, depending on which space is larger. An incision is made in the diaphragm in a medial and anterior direction to the aortic hiatus, and the gastric tube is drawn into the chest and passed in a proximal direction into the neck. The orientation of the pedicle is maintained to prevent twisting or kinking of vessels. Anastomosis with the cervical esophagus is done with a single layer of nonabsorbable suture. A few sutures placed between tube and diaphragm anchor the tube in the chest. The gastrostomy is re-established in the remnant of the stomach. The chest and neck are drained, and the abdomen is closed without drainage. If the left gastroepiploic artery was damaged during a previous operation, the right gastroepiploic artery can be used to support the vascular pedicle, and the tube would be constructed in the reverse (isoperistaltic) direction. In this instance, after creation of the gastric tube, the stomach is rotated in a posterior direction so that the tube can be brought to the neck.

CHAPTER

69

Esophageal Replacement

1099

Left .gastroepiploic artery

Reverse gastric tube construction. A, The tube is vascularized by the left gastroepiploic artery. The right gastroepiploic artery is divided where shown, and the arcade is carefully preserved. B through E, Stepbystep division of the stomach with the GIA stapler. A chest tube along the greater curvature is used as a guide to ensure uniform size of the gastric tube. Oversewing of the staple line on the tube and stomach is also shown.

1100

PART

VI

THORAX

before bedtime. The gastric tube supports nutrition well. Children with lye strictures fall into normal growth curves, whereas those with esophageal atresia tend to fall in lower percentiles for weight and height but grow satisfactorily and maintain good n ~ t r i t i o n . ~ The mortality associated with gastric tube esophagoplasty is low, but leaks and strictures are common. Perforation of the gastric tube occurs occasionally.")x Peristalsis is generally absent, and the tube empties by gravity (Table 69-5).

JEIUNAL INTERPOSITION History

I

In 1906, Rouxq7 used the ieiunum in an antethoracic ., direction to bypass a caustic stricture in a 12-year-oldchild. Follow-up of this patient was published by Pirot-~ouxand Hase in 1950.X5The patient did well until 1940, when a large fistula developed subsequent to trauma, and in 1941, an epithelioma was found in the cutaneous portion of the esophagus; this disorder was successfully treated with radiation therapy. The patient died of unrelated causes at 53 years of age. In 1913, Lexer" combined the Roux isolated jejunal loop with a cutaneous skin tube when the jejunum was not long enough to reach the neck. Approximately 20 years later, Ochsner and Owens7!' reviewed the literature of antethoracic esophageal replacement and found that of 240 patients, 56% had tubes constructed of jejunum. In 1946, Reinhoffw performed the first intrathoracic jejunal replacement of the esophagus. He recommended the shorter irltrathoracic route and stated that the jejunum was long enough to reach the neck. LongmireMiin 1951 reported a jejunal interposition for caustic stricture in which the inadequate blood supply to the upper end of the jejunum was supplemented by an anastomosis between the internal mammary artery and the mesenteric artery of thejejunum. The advantages of the jejunum as an esophageal substitute are that peristaltic activity is preserved arid its caliber is similar to that of a normal esophagus (see Table 69-2). 0

A

-

.a

Reverse gastric tube. A, The spleen has been

preserved; staple closure of the tube and stomach has been reinforced with interrupted sutures. B, The tube is placed over the chest and reaches the cervical esophagostomy, to which the clamp is pointing. The intrathoracic course is even shorter.

Results The gastric tube tends to retain its shape without the redundancy and dilatation that is apt to occur in colon grafts. Reflux is almost always present and may cause Barrett's changes in the proxin~alesophageal stump.fi3 Peptic ulceration has been reported as a long-term com,~21 plication associated with gastric t u b e ~ . ~ 2 ~Nocturnal coughing is a common problem that can be alleviated by elevating the head of the bed and avoiding fluids shortly

Year

Author

1968 1973 1978 1985 1987 1998

Burrlngton and Stephens14 Ern et a1.Z4 Anderson and Randolph6 Goon et al.35 Eln et a1.Z5 Em23

Surgical Technique Two methods of jejunal replacement of the esophagus are use#8,9? (1) jejunal interposition-trar~section of the jejunum distal to the ligament of Treitz, ill which the proximal end of the loop is brought up ttlro~lghthe

No. of Patients 8 15 15 46 36 11

Deaths -- --1

1 3

-

-

Leaks --- - (%) -3 7 5 35 24 9

(37) (47) (33) (76) (67) (81)

--

Strictures (%) -- - -

9 (60) 5 (33) 27 (59) 1 5 (42) 8 (72)

CHAPTER

Year

Author

1958 1982 1988 1993

Jezioro and Kus54 Ring et a1.g3 Saeki et al.99 Cusick et al.19

No. of Patients 14 16 19 6

thorax into the neck to join the esophagus, the distal end is anastomosed to the stomach, and intestinal continuity is restored by a jejunojejunal anastomosis, and (2) free jejunal interposition-interposition of an isolated jejunal segment, in which case microvascular anastomosis of the jejunal pedicle is performed. The results of jejunal interposition in a small number of series reported are shown in Table 69-6.

Deaths 2 0 2 2

69

Esophageal Replacement

1101

Leaks (%)

Strictures (%)

3 (21) 4 (25) 3 (15) l(17)

1(7) 2 (12) 2 (10) 2 (33)

sited on the anterior surface of the body of the stomach well away from the greater curvature. The stomach is exposed through an upper midline abdominal incision. Alternatively, a left oblique musclecutting incision that may extend into a left thoracotomy may be used, particularly if resection of a fibrotic esophagus or previous colonic interposition is required. The gastrostomy is carefully mobilized, and the defect in the stomach is closed in two layers with interrupted 4 0 polyglycolic acid suture. Adhesions between the stomach and the left lobe of GASTRIC TRANSPOSITION the liver are lysed while care is taken to preclude damage to the major blood vessels. The greater curvature of the History stomach is mobilized by ligating and dividing the vessels in the gastrocolic omentum and the short gastric vessels. In 1922, Kummell reported mobilization of the esophagus These vessels should be ligated well away from the stomin two patients by bluntly freeing the esophagus with fingers introduced from cervical and abdominal w0unds.6~.~" ach wall to preserve the vascular arcades of the right The stomach was then transplanted into the esophageal gastroepiploic vessels. Meticulous care must be taken to bed and the esophagus was anastomosed to the stomach. avoid damaging the spleen. The lesser curvature of the stomach is freed by dividing the lesser omentum from Although both patients died, this was the first attempt at the pylorus to the diaphragmatic hiatus. The right gastric gastric transposition by means of the mediastinal route. In 1938,Adams and Phemisterl successfully resected a carartery is carefully identified and preserved, whereas the cinoma in the lower thoracic esophagus of a 53-year-old left gastric vessels are ligated and divided close to the patient and restored continuity by esophagogastrostomy. stomach (Fig. 69-5A). The lower portion of the esophagus is exposed by In 1944, Garlock's successful re-establishment of esophadividing the phrenoesophageal membrane, and the margogastric continuity after resection of the esophagus for gins of the esophageal hiatus in the diaphragm are carcinoma of the middle third in a 58-year-old man was defined. The inevitably short blind-ending lower rep~rted.:~u At follow-up, the only complication was reguresophageal stump in patients with isolated esophageal gitation in the recumbent position, and this problem was controlled by sleeping on two pillows. In 1945, Sweetii6 atresia is dissected out of the posterior mediastinum by a combination of blunt and sharp dissection through the recorded 12 esophageal resections with esophagogastric diaphragmatic hiatus. The vagal nerves are usually arlastomosis above the arch of the aorta, and in 1948,"' divided during this part of the procedure. The body and he described the successful application of his technique fundus of the stomach are now free of all attachments after resection of a carcinoma of the upper thoracic esophand can be delivered into the wound. The esophagus is agus with anastomosis of the stomach to the cervical transected at the gastroesophageal junction, and the esophagus. Soon thereafter, successful pharyngogastrosdefect is closed in two layers with 4-0 polyglycolic acid tomy was described. Replacement of the esophagus by suture. A Heineke-Mickulicz pyloroplasty is usually pergastric transposition is currently the procedure of choice formed, although whether it is necessary continues to be in adnlts with carcinoma, but its use in children has been controversial.17 The second part of the duodenum is limited." Atwell and Harrison-reported six children kocherized to obtain maximum mobility of the pylorus. who nnderwent gastric transposition; two died, but good The highest part of the fundus of the stomach is identilong-term results were achieved in the other four patients. fied, and stay sutures of different material are inserted to the left and the right of the area selected for the anastomosis. These sutures help avoid torsion of the stomach as Surgical Technique it is drawn through the posterior mediastinum into the Transhiatal gastric transposition without thoracotomy is neck (Fig. 69-5B). It is conthe procedure of choice (Fig. 69-5).X2,XX3101),111,i14 Attention is now turned to the neck, where a previously constructed cervical esophagostomy is mobilized through a traindicated in the presence of extensive scarring from 3 to k m transverse incision. Care must be taken to not previous siirgery or mediastinal inflammation. lo To preserve the vascular arcades of the gastroepiploic damage the muscular coat of the esophagus. The recurrent vessels, the initial feeding gastrostorny should ideally be laryngeal nerve that courses upward on the posterolateral

A, Technique of gastric tube esophagoplasty. The stomach is mobilized along the greater and lesser curvatures, with preservation of the right gastric epiploic and right gastric vessels. The short gastric vessels are carefully divided, with care taken to avoid trauma to the spleen. The left gastric vessels have been ligated and divided; the duodenum (to which the Kocher technique has been applied) and the site of pyloroplasty are indicated. The short stump of esophagus in a case of isolated atresia is shown being mobilized from within the esophageal hiatus of the diaphragm. The gastrostomy site has been sutured. B, Pyloroplasty has been completed, the distal esophageal stump has been resected, and the two sutures on the fundus of the stomach indicate the highest point of the stomach at the proposed site for the esophagogastric anastomosis. C, Fashioning of the posterior mediastinal tunnel by blunt dissection from above by means of a cervical incision to mobilize the esophagostomy or expose the esophagus in the case of caustic injury and from below by means of the esophageal hiatus in the diaphragm. The dissection is done strictly in the midline in the prevertebral plane. D,The final position of the stomach in the posterior mediastinum with the esophagogastric anastomosis in the lower part of the neck and the pyloroplasty situated immediately within the peritoneal cavity below the esophageal hiatus. A jejunostomy tube has been placed for postoperative enteral feeding.

CHAPTER

surface of the trachea is identified and preserved. A plane of dissection between the membranous posterior surface of the trachea and the prevertebral fascia is established, and a tunnel is created into the superior mediastinum by blunt dissection immediately in the midline. A similar tunnel is fashioned from below in the line of the normal esophageal hiatus in the tissues posterior to the heart and anterior to the prevertebral fascia.37When continuity of the superior and inferior posterior mediastinal tunnels has been established, the space to be occupied by the stomach is developed into a tunnel the width of two to three fingers (Fig. 69-5C). If thoracotomy was required for resection of a fibrotic esophagus (e.g., in cases of caustic or reflux esophagitis) or a nonfunctioning previous interposition or when blunt dissection would be hazardous because of fibrosis from previous surgery or infection, the transthoracic part of the procedure is carried out under direct vision and the remainder of the operation is done in the same manner as described for the mediastinal procedure. A long, blunt hemostat is passed into the posterior mediastinal tunnel from the cervical incision, and the two stay sutures on the fundus of the stomach are grasped. Gentle withdrawal of the hemostat pulls the stomach up through the esophageal hiatus and the posterior mediastinal tunnel into the cervical incision. The orientation of the fundus is checked by realigning the stay sutures in their correction position. The end of the esophagus is anastornosed to the highest part of the stomach with a single layer of interrupted 4-0 polyglycolic acid suture. A large-caliber (12-gauge) nasogastric tube is inserted into the stomach through the esophagogastric anastomosis. The tube remains in place to allow free drainage and is aspirated at regular intervals to prevent acute gastric dilatation in the early postoperative period. A soft rubber drain is placed at the site of the anastomosis, and the wound is closed in layers. The surgeon then returns to the abdomen, where the margins of the diaphragmatic hiatus are sutured to the antrum of the stomach with a few interrupted sutures so that the pylorus lies immediately below the diaphragm in the midline. A fine-bore feeding jejunostomy has been found to be of considerable value in providing enteral nutrition in the first few weeks after gastric transposition before full oral nutrition is established (Fig. 69-5D).

Postoperative Management Careful monitoring of vital functions is essential in the early postoperative period. Extensive dissection of the

Year

Author

1980 1987 1991 1995 2002 2004

Atwell and Harrison* Valente et al.lz2 Marujo et a1.73 Spitzlll Hirsch149 Spitz et al.113

No. of Patients 6 21 21 83 41 173

69

Esophageal Replacement

1103

soft tissues in a posterior direction to the trachea has been performed, and the resulting edema may cause respiratory compromise. Elective nasotracheal intubation with or without assisted ventilation for a few days may simplify the postoperative course and reduce the incidence of respiratory problems. Jejunal feedings are instituted on the second or third day after surgery. The safest technique for delivery of nutrition by this method is a slow, continuous infusion rather than a bolus technique, which can provoke a "dumping" effect. A contrast swallow is performed 7 days after surgery, and if no leak is identified at the anastomosis, careful oral feeding may begin. The cervical drain is removed when integrity of the anastomosis has been demonstrated. Since 1981, 173 gastric transpositions have been performed at Great Ormond Street Hospital, London.113 The most common indication for esophageal replacement was esophageal atresia in 127 patients, 70 of whom had failed primary repair and 43 had isolated atresia without a fistula. Twenty-three children had intractable caustic strictures. More than 80% of patients were referred from abroad or from other centers within the United Kingdom. The method of replacement was via the posterior mediastinum without thoracotomy in 90 patients (52%).In the remainder a thoracotomy was necessary because of dense mediastinal scamng secondary to the origmal injury (caustic, perforation) or as a result of previous failed attempts at esophageal reconstruction. All patients are currently routinely paralyzed and mechanically ventilated for at least 48 to 72 hours postoperatively. There have been nine deaths (5.2%),eight of whom had had complex courses before the transposition. Anastomotic leakage at the esophagogastric connection occurred in 12% of cases, all except one of which closed spontaneously. Strictures developed in 19.6% of patients, all but three of which responded to endoscopic dilatation.84 In these three cases, stricture resection plus reanastomosis was successfully carried out through a cervical approach. Strictures were more common after caustic injury (38%).Swallowing prob lems postoperatively were encountered in 30% of cases. Establishing oral feeding can be extremely difficult, particularly in infants with esophageal atresia who have not been properly sham-fed. The jejunal feeding tube greatly simplifies postoperative nutrition and avoids the need for parenteral nutrition. Vomiting, which may be bilious in nature as a consequence of pyloroplasty, is common in the early postoperative period, especially when the child is recumbent. A follow-up of 17 patients who underwent gastric transposition more than 5 years previously has shown

Deaths (%)

Leaks (%)

2 (33) 1 (4.7) 1 (4.7) 6 (7.2) 0 9 (5.2)

4 (19) 4 (17) 10 (12) 15 (36) 21 (12)

-

Strictures (%) -

3 (14) 3 (14) 10 (12) 20 (49) 34 (19.6)

1104

PART

VI

'I'IIoR,~

14. Burrington JD, Stephens CA: Esophageal replacement with a gastric tube in infants and children. J Pediatr Surg 1968;3:24. 15. Campbell JR, Webher RR, Harrison MW, Campbell TJ: Esophageal replacernent in infants and children by colon interposition. Am J Surg 1982;144:29. 16. Carneiro PM, Doig <:M: Colon interposition for wide gap oesophageal atresia. East Afr Med J 1993;70:682. 17. Cheung I<(:, Siu KC;, Wong.1: Is pyloroplasty necessary in esophageal replacernent hy stomach? A prospective randornised, controlled t~-ial.Surgery 1987;102:19. 18. (:ohen D: Oesophageal reconstruction using a gastric tube: A prelin~inaryreport. Aust 1'rdiatrJ 1970;6:22. 19. (:nsick EL, Hatchelor AAG, Spicer KI): Development of a techniqne ti)r jqjnnal interposition in long-gap esophageal atresi;i. J Pediatr S11t.g 1993;28:990. 20. 1)alc WA, Slicrtnian (11): 1.atc reconstruction of congenital rsol>hagral atrcsia I)y int~.;l~liol.acic colon transplantation. j 7'hol.a~Surg 1!155;29:344. 21. 1);tvenltort M, Rianclii A: 1':;1rIyc.xl)t,rience with oesophageal 11a11 csophagoplasty fi)r r.c.l)ail. of esophageal atresia. I'cdiat~.Silrg lnt 1990;5:332. 22. l)avcl~por-tM, Hosie (;P, Taskel- I<(:, et al: The long-term et'fcc.ts o f gastric transposition i l l chiltlren: A physiological st~tdy..] I'rdiatr S11r.g 1996;31:588. 23. Ein Sli: (:astric tubes in children with caustic esophageal injiu-):J l'ediatr S1u.g 1998;33:IJ(i3. 24. Ein SI1, Slnandling H, Sitnltson ,IS, Stcvcns (:A: A further look at the gi~stl-ic.tube as all c~sol)lii~gcal replacement in REFERENCES infants and chilt1rcw.J Pediatr. Surg 1!)73;8:859. 25. Ein SIi, Shandling R, Stcphcns (:A: 'livctity-one year expeI. A(Ia11isWF.,l'l~ctiiist(~t~ I)[{: ( ~ ~ r c i ~ iof'tlie o n ~ ;lower ~ tlioracic rience with thr pediatric gastric tnl)c. ,j I'cdiatr Surg 1987; 22:77. c s o p l i a g ~ ~Rcl)ot,t s 0 1 ' ;I s~~c.c.cssfr~l resection and esopha26. I'.r;lklis ,?j, Roscllo I:], ISallantinc 'IVN: ( : i ~ . ( . t l l ; ~ l(~sopliagoniy. gog;~stt"osioniy. ,] 1'lio1.;1cSl11.g 1!138;7:(i2 1 . otoniy of' rlplwt. po~tcllin prirnar~t.el);til. of long scgmnit 2. :2htncd A, Sl)it7 I.: '1'11e orltc.onlr of colonic. t.el)laccrncnt of' the c s o l ) i ~ ; ~in g ~(.liil(l~.cl~. ~s 1'1.o~Pctliatt. Surg 198(i;lI Is~. ~ I I ~ ~ I 1986. ~ - \ ' ~ I . I ;28. % ~Fokc.t.,]l<, , King M'S, Varco RI,: Tccl~nicl~lt. of:jc:jl~n;rlinterpo4. Andelson 1<1).Nol)lrtt 11. Rclsry R: I,ongtc~-m fi)llow-111)of sition fi,~.c,sophagt,al ~-cpl;~cc~~r~c~nt. 'I'Iiot.;i(. (k11~1iovasc S1u.g 1!182;83:928. cIiildr(~nwit11 (.OIOII :III(Ig;istric t1111c itit(~t.positionfor 29. Frccman N\f, (:ass D7'. (:olort intcrpositio~~: A 111odi1it.ation cso~~liageal atrcsi;~.Sttt.gcl.y lCI92;l 1 I :I31 . of' the \4'atcrston tecliniq~lrnsing the t~orrt~;tl c*sophagral 5. Anderson Kl). Karndol~)li.I(;: The gastr.ic t1111e for roltte. J l'ediatl. Surg 1982;17:17. csopliagc~alreplacc.rnc.tit in infants and childt.t~n. 'I'horac 30. (krlockJl4: licc~stahlishmcntof'esol)hagogitst~.ic.c.o~~titlrlity (:;~rdio\~asc Surg 1973;(i(i::Y33. fi)llo~\iiigresection of' csol~liagusf01.c;~~-cit~orrl;~ 01 rnitltlle (i. A~ltlcrson Kl), R;indolpli ](;: (;astric tllhc interltositio~i: . . third. Ru-g (;yiiecol Obstct 1944;78:23. A satis1kctol.y altrrn;%tive to the colon for csopl~agral 31. (;avrili~i 1): Etat ac.tl~al d r ~troc~cde de ~-c.col~str.r~c.tion t-cl>laccn~cnt in cliil(l~~cn. Ann Tiiorac Sun-g 1978;25:521. ctc I'ocxsophagc piit. tul)c' gastl-iqlte. Ann (:11i1. l!)(i5;1!):219. 7. An(Ict.so~~ KI). Ratidolpl~~jC;, 1,illt~y~jR: Peptic 111ce1.in chil32. (;;ivriliu D: As1,cc.t~oleso~)liagcalslll.gc~.y.(:III.I. 1'1.oI)l SIII-g dren \vitll gast1.i~tuhc interposition. J Pcdiatr S11t.g 1975; 1975;12:I. 10:701. tli~.cc.t;lc . t ~ 1rl;lte33. (hvt-ili~~ I), (;corgc'scnc' I .: Ksoll~gopl;~stic 8. At\vcll,jI), Harrisoln (;SM: 0l)sct-\rations1111 the, rt)lt. ofcsophrii~lgastric. Rev Stiintclor Medic;rle (I%uc.rl~.est) 1!)51;3:33. agoSastroston1y in infhncy ;ind childhood with partic~~lar 34. (;errnan,j(:, L4';itcrston I)]: (:olon intc.t.ltositiotl fi)t. ~.c.l)laccto the long-tc'rm rcsnlts and operativr niortalit): rrfc~rt~ncc j l'ediatr S1u.g 19XO:l5::30:3. mcnt of the esophag~~s in clrildt.cn. .] 1'cdi;rtr S11i.g 1!)7(i: 9. 'Arar H, (:lirispin /lR, blatcrston Dj: Esophageal rrplace11:227. nicnt with triansvc~rsc(.01011in infants and childl~n.JPcdiatr 35. <:cton HK, (:ohen DH, Middle-ton AW: C;;istr.ic tul)t. Snrg 1971;(i:3. ocsophagoplast!-;1 long-term assessment. Z Kintlc.~.c.liir. 1985;40:21. 10. Battersby JS, Moort. TC: Esophageal t-eplacrment and 36. Go~ighMH: Esopliagral atresia-nsc of'an antrrior flap in b?pass with the ascrnding and right half of transverse colon the difficult anastomosis. .j Pcdiati. Surg 1980;15:310. for the treatnient 01' congenital atresia of thc esophagus. 37. C;~-ossRH, Asha FP, (h1zc.r (;M, 0rringc.1-MR: (;astric. intc'1.Surg Gynecol Obstrt 1959;109:207. 11. Beck C, Oarre1 A: 1)elnonstration of specimens illustrating position following transhiatal rsoplnagc~cto~ny: (:'I' c\raluation. a method of fi)rnlation of a prethoracic esophagus. Illinois Radiology 1985;155:177. 38. (;ross RE, Firestone N: (:olonic ~.cconsti.~~ctiot~ of' the Med J 1905;7:463. 12. Belsey R: Recoristructiot~of the esophagus with left colon. esophagus in inf:ants and cliil(lt.cn. Sitt.gcry l9(i7;(il:955. J Thorac Cardiovasc Surg 1965;49:33. 39. Guzzetta PC, Randolph J<;: Antirc~flnxc~ologastricanastonnosis 13. Belsey R: Reconstrnction of the oesophagus. Ann R Coll following colonic interposition for csophag~alrrplaccmcnt. Surg Engl 1985;(55:3tiO. j Pediatl- Sun-g 1986;21:1137.

that the iutratlioi.;~c.icstotn;~chfiuictions as a coriduit as opposed to a l.csci~oil.tiw 1)oth liquids a n d solids." Rapid cnlptying (>5O%) of' 1)otll liquids a n d solids occurred within 5 minutes of'ingcstioil in 82% of'patients. Dumping a n early fcat~u-e,but these s y ~ n p t o n i ~ i l ioccasionall\, ~e s,mptolns ~.csolvcwithin ;I frxw weeks in most cases. O f 17 cliildl.en, 13 1vei.e \vitliiii no1.1nal percentiles fol- height lal for weight. Idow a n d 1 1 wrrc within ~ ~ o t ~ npel-centiles iron stores is :I f i ' i t t l i l . ~ i l l a11 types of' esophageal replaced ;dl patients who h ; ~ d m e n t a n d was d o c . ~ n n t ~ n t t in undergone gastric ~t.;~nsl)osition. All but o n e child l i i ~ d rcstl-ictcd pulrnon;tl.\. iilnc.tion. wit11 a mean total lung of (33% ; I I K ~ . ; I I ~ C ; I I Iti)i.cwi vital capacih of' 64% c:~p;~city o l ' ~ x l ) c c t c dwltics. I t is unc.ct.tain at prcscnt whether these ~ . c ~ d r ~ c\;~lilcs rti a r c a cx)llscxqllcncrof' ihc. pl-i~nalyconditi011or. ;I dil.cct rcs11lt of'g;~st~.ic. tt;?nsposition." outcome was 111 90% of' oiu. t);~ticnts,the long-ternl < .j~tclgedto I)c good to c'uc.cllcnt in terms ofa1)sencc of'swallo~vingdiffici~ltics; ~ n dother g;~sti.ointestinaI sympiolns 'There has been n o dctet-ios11c.h ;IS dlmll>ingor. di:u.~.lie;~. 1.atio11in filnction o f ' t l ~ ct ~ ~ ; ~ n s p o stomach sed over time. 7 T l ~ eolitcomc of' g;lstl.ic 11-;~nspositionin children is shown in Table 69-7. 3

CHAPTER

Hagberg - S, Rubenson A, Sillen U, Werkmaster K: Management of long-gap esophagus: Experience with endto-end anastomosis under maximal tension. Prog Pediatr Surg 1986;19:88-92. Hamza AF, Abdelhay S, Sherif H, et al: Caustic esophageal strictures in children: 30 years' experience. J Pediatr Surg 2003;38:828. H a ~ j uE, Isolauri J: Nutritional state after colon interposition for benign oesophageal disease. EurJ Clin Nutr 1988;42:351. Hays DM, Woolley M, Synder WH: Esophageal atresia and tracheoesophageal fistula: Management of the uncommon types. J Pediatr Surg 1966;1:240. Heimlich HJ: Peptic esophagitis with stricture treated by reconstruction of the esophagus with a reversed gastric tube. Surg Gynecol Obstet 1962;114:673. Heimlich HJ: Elective replacement of esophagus. Br J Surg 1966;53:913. Heiss K, Wesson D, Bohn D, et al: Respiratory failure due to retained esophagus: A complication of esophageal replacement. J Pediatr Surg 1991;26:1359. Hendren WH, Hale JR: Electromagnetic bougienage to lengthen esophageal segments in congenital esophageal atresia. N Engl J Med 1975;293:428. Hendren WH, Hendren WG: Colon interposition for esophagus in children. J Pediatr Surg 1985;20:829. Hirschl RB:Gamic transposition for esophageal replacement in children: Experience with 41 consecutive cases with special emphasis on esophageal atresia. Ann Surg 2002;236:531. Hoffman DG, Moazam F: Transcervical myotomy for widegap esophageal atresia. J Pediatr Surg 1984;19:680. Howard R, Myers NA: Esophageal atresia: A technique for elongating the upper pouch. Surgery 1965;58:725. Isolauri J: Colonic interposition for benign esophageal disease. Long-term clinical and endoscopic results. Am J Surg 1988;155:498. Isolauri J, Reinikainen P, Markkula H: Functional evaluation of interposed colon in esophagus. Manometric and 24-hour pH observations. Acta Chir Scand 1987;44:84. Jezioro Z, Kus H: Experiences with the retrosternal esophageal replacement employing jejunum or ileum. J Pediatr Surg 1958;44:275. Jianu A: Gastrostomie und Oesophagoplastik. Dtxh Z Chir 1912;11:8. Kamath MV, Ellison RG, Rubin JW, et al: Esophageal mucocele: A complication of blind loop esophagus. Ann Thorac Sr~lg1987;43:263. Kato T, Hollmann <,; Hopper F, et al: Ein neues Instrument zr~rFaden-legung ohne Thorakotomie in ausgewahlten Fallen von oesophagusatresie. Z Kinderchir 1980;29:20. Kelling G: Oesophagoplastik mit Hilfe des Quercolon. Zentralbl Ghir 1911;38:1209. Kelly JP, Shackelford GD, Roper CL: Esophageal replacement with colon in children: Functional results and long~ermgrowth. Ann Thorac Surg 1983;36:634. Khan AR, Stiff G, Mohammed AR, et al: Esophageal replacement with colon in children. Pediatr Surg Int 1998; 13:79. Kurnrnell HI: Ueber intrathorakale Oesophagus Plastik. Beitr Klin Chir 1922;126:264. 1,exer E: Oesophagoplastik. Zentrabl Chir 1914;40:1970. Lintla111 H, 1.01thimo I, Virkola K: Colon interposition or gastric tube? Follow-up study of colon-esophagus and gastric tube-esophagus patients. J Pediatr Surg 1983;18:58. I.indahl H. Rintala R. Sariola H. Louhimo I: Lonr-term n endoscopic and flow cytometric follow-up of colon interposition. J Pediatr Surg 1992;27:859. lividitis A: Esophageal atresia. A method of over-bridging large segment gaps. Z Kinderchir 1973;13:278.

69

Esophageal Replacement

1105

66. Longmire WP: Antethoracic jejunal transplantation for congenital esophageal atresia with hypoplasia of the lower esophagus. Surg Gynecol Obstet 1951;93:310. 67. Louhimo I, Pasila M, Visa Koepi JK: Late gastrointestinal complications in patients with colonic replacement of the oesophagus. J Pediatr Surg 1969;4:663. 68. Lundblad 0 : Uber antethorakale Osophagoplastik. Acta Chir Scand 1921;53:535. 69. MacKinlay GA, Burtles R: Oesophageal atresia: Paralysis and ventilation in management of the wide gap. Pediatr Surg Int 1987;2:10. 70. Mahour GH, Woolley MM, Gwinn JL: Elongation of the upper pouch and delayed anatomic reconstruction in esophageal atresia. J Pediatr Surg 1974;9:373. 71. Mansour KA, Malone CE: Surgery for scleroderma of the esophagus: A 12-year experience. Ann Thorac Surg 1988; 46:513. 72. Martin LW: The use of colon for esophageal replacement in children. Aust N Z J Surg 1972;42:160. 73. Marujo WC, Tannuri U, MaksoudJG: Total gastric transposition: An alternative to esophageal replacement in children. J Pediatr Surg 1991;26:676. 74. May IA, Samson PC: Esophageal reconstruction and replacements. Ann Thorac Surg 1969;7:249. 75. Mes GM: New method of esophagoplasty. J Int Coll Surg 1948;11:270. 76. Mitchell IM, Goh DW, Roberts KD, Abrahms CD: Colon interposition in children. Br J Surg 1989;76:681. 77. Ngan SY, WongJ: Lengths of different routes for esophageal replacement. J Thorac Cardiovasc Surg 1986;91:790. 78. Ochsner A, De Bakey M: Surgical aspects of cancer of the esophagus. A review of the literature. J Thorac Surg 1940; 10:401. 79. Ochsner A, Owens N: Antethoracic esophagoplasty for impermeable stricture of the esophagus. Ann Surg 1934; 100:1055. 80. Okmian Z, Booss D, Ekelund I: An endoscopic technique for Rehbein's silver olive method. Z Kinderchir 1975; 16:212. 81. Orringer MB, Kirsh MM, Sloan H: New trends in esophageal replacement for benign disease. Ann Thorac Surg 1977; 23:409. 82. Orringer MB, Sloan H: Esophagectomy without thoracotomy. J Thorac Cardiovasc Surg 1978;76:643. 83. Othersen HB Jr, Clatworthy HW Jr: Functional evaluation of esophageal replacement in children. J Thorac Cardiovasc Surg 1967;53:55. 84. Pierie JP, de Graaf PW, Poen H, et al: Incidence and management of benign anastomotic stricture after cervical oesophagogastrostomy. Br J Surg 1993;80:471. 85. Pirot-Roux L, Hase 0 : Epicrise de la premiere operatian de l'oesophagoplastie prethoracique faite par le Dr. Cesar Roux en 1906. Rev Med Suisse Romande 1950;90:19. 86. Postlethwait RW: Technique for isoperistaltic gastric tube for esophageal bypass. Ann Surg 1979;189:673. 87. Postlethwait RW: Colonic interposition for esophageal substitution. Surg Gynecol Obstet 1983;156:377. 88. Postlethwait RW: Surgery of the Esophagus, 2nd ed. Norwalk, CT, Appleton-Century-Crofts, 1995. 89. Puri P, Blake N, O'Donnell B, Guiney EJ: Delayed primary anastomosis following spontaneous growth of esophageal segments in esophageal atresia. J Pediatr Surg 1981;6:180. 90. Raffensperger JG, Luck SR, Reynolds M, Schwariz D: Intestinal bypass of the esophagus. J Pediatr Surg 1996; 31:38. 91. Rehbein F, Schweder N: Reconstruction of the esophagus without colon transplantation in cases of atresia. J Pediatr Surg 1971;6:746.

1106

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THORAX

92. Rienhoff WF: Intrathoracic esophagojejunostomy for lesions of the upper third of the esophagus. South Med J 1946;39:928. 93. Ring WS, Varco RL, L'Heureux PR, FokerJE: Esophageal replacement with jejunum in children: An 18 to 33 year follow-up.J Thorac Cardiovasc Surg 1982;83:918. 94. Rode H, Cywes S, Millar AJ, Davies MR: Colonic oesophageal replacement in children-functional results. Z Kinderchir 1986;41:201. 95. Rodgers BM, Talbert JL, Moazarn F, Felman AH: Fullctional and metabolic evaluation of colon replacement of the esophagus in children. J Pediatr Surg 1978; 13:35. 96. Rossello PI, Lebron H: The technique of myotomy in esophage~l reconstruction: An experimental study. J Pediatr Surg 1980;15:430. 97. Roux C: L'esophago-jejuno-gastrome: Nouvelle operation pour retrecessement infranchissable d e l'esophage. Semin Med 1907;27:37. 98. Rudler JC, Monod-Broca P: Uncas d'esophagoplastie palliative retro-sternale avec I'ileocolon droit. Mem Acad Chir (Paris) 1951;77:747. 99. Saeki M, Tsuchida Y, Ogata T, et al: Long-term results of jejunal replacement of the esophagus. J Pediatr Surg 1988;23:483. 100. Salo JA, Heikkila L, Nemlander A, et al: Barrett's oesophagus and perforation of gastric tube ulceration into the pericardium: A late complication after reconstruction of oesophageal atresia. Ann Chir Gynaecol 1995;84:92. 101. ~ c h a r l k: i Esophageal reconstruction in very long atresias by elongation of the lesser curvature. Pediatr Surg Int 1992;7:101. 102. Schier F, Schier C, Hoppner D, Willital GH: [Esophageal replacement with resorbable vicryl tubes-an animal t z resorbierbaren experiment study.] ~ s o ~ h a g u s e r s amit VicrylSchlauchen-Eine tierexperimentelle Untersuchung. Z Kinderchir 1987;42:224. 103. Schullinger JN, Vinocur CD, Santulli T: The suture-fistula technique in the repair of selected cases of esophageal atresia. J Pediatr Surg 1982;17:234. 104. Shafer AD, David TE: Suture fistula as a means of connecting upper and lower segments in oesophageal atresia. J Pediatr Surg 1974;9:669. 105. '~hambergerRC, Eraklis AJ, Kosakewich HP, Hendren WH: Fate of the distal esophageal remnant following esophageal replacement. J Pediatr Surg 1988;23:1210. 106. Sherman CD, Waterston DW: Oesophageal reconstruction in children using intrathoracic colon. Arch Dis Child 1957;32:11. 107. Soave F: Intrathoracic transposition of the transverse colon in complicated oesophageal atresia. Proc Pediatr Surg 1972; 4:91. 108. Sonneland J, Anson BJ, Beaton LE: Surgical anatomy of the arterial supply to the colon from the superior mesenteric artery based upon a study of 600 specimens. Surg Gynecol Obstet 1958;106:385.

109. Spitz L: Gastric transposition via the mediastinal route for infants with long-gap esophageal atresia. J Pediatr Surg 1984;19:149. 110. Spitz L: Gastric transposition for esophageal substitution in children. J Pediatr Surg 1992;27:252. 111. Spitz L: Gastric replacement of the esophagus. In Spitz L, Coran AG (eds): Pediatric Surgery, 5th ed. London, Chapman & Hall, 1995. 112. Spitz L, Kiely E, Brereton RJ, Drake D: Management of esophageal atresia. World J Surg 1993;17:296. 113. Spitz L, Kiely E, Pierro A: Gastric transposition in childrena 21-year experience. J Pediatr Surg 2004;39:276. 114. Spitz L, Kiely E, Sparnon T: Gastric transposition for esophageal replacement in children. Ann Surg 1987;206:69. 115. Stone MM, Fonkalsrud EW, Mahour GH, et al: Esophageal replacement with colon interposition in children. Ann Surg 1986;203:346-351. 116. Sweet RH: Transthoracic gastrectomy and esophagectomy for carcinoma of the stomach and esophagus. Clinics 1945;3:1288. 117. Sweet RH: A method of restoring continuity of the alimentary canal in cases of congenital atresia of the esophagus and with tracheo-esophageal fistula not treated by immediate primary anastomosis. Ann Surg 1948;127:757. 118. Touloukian RJ, Schonholz SM, Gryboski J D , et al: Perioperative considerations in esophageal replacement for epidermolysis bullosa: Report of two cases successfully treated by colon interposition. Am J Gastroenterol 1988; 83:857. 119. Touloukian RJ, Tellides G. Retrosternal ileocolic esophageal replacement in children revisited. Antireflux role of the ileocecal valve. J Thorac Cardiovasc Surg 1994;107:1067. 120. Tsujinaka T, Ogawa M, Kido Y, et al: A giant tracheogastric tube fistula caused by a penetrated peptic ulcer after esophageal replacement. Am J Gastroenterol 1988;83:862. 121. Uchida Y, Tomonari K, Murakami S, et al: Occurrence of peptic ulcer in the gastric tube used for esophageal replacement in adults. Jpn J Surg 1987;17:190. 122. Valente A, Brereton RJ, Mackersie A: Esophageal replacement with whole stomach in infants and children. J Pediatr Surg 1987;22:913. 123. Vizas D, Ein SH, SimpsonJS: The value of circular myotomy for esophageal atresia.J Pediatr Surg 1978;13:357. 124. Von Hacker V: [On esophagoplasty in general and on the repair of the esophagus by antethoracic construction of a skin-colon tube in particular.] Uber Oesophagoplastic in allgemeinen unter uber den ersatz der Speuserohre durch antethorackle Hauntdickdarmschlauchbildung im besonderen. Arch Klin Chir 1914;105:973. 125. Vulliet H: De l'esophagoplastie et des diverses modifications. Semin Med 1911;31:529. 126. Waterson D: Colonic replacement of esophagus (intrathoracic). Surg Clin North Am 1964;44:1441. 127. West KW, Vane DW, GrosfeldJL: Esophageal replacement in children: Experience with thirty-one cases. Surgery 1986; 100:751.

Disorders of Esophageal Function Juan A. Tovar

The esophagus has no significant secretory or absorptive function and acts only as a conduit interposed between the pharynx and stomach. Its main function is therefore propulsive, and disorders of this function induce several pathologic conditions that in general mirror their adult counterparts, but with specific pediatric features. However, some of these disorders are related to malformations and become clinically evident during infancy and childhood. Most are incompletely understood, mainly because of our limited knowledge of the mechanisms of regulation of gastrointestinal motility, but also because of the inadequacy of the diagnostic tools available to apply in children as a result of problems with size or cooperation. In the present chapter these motor disorders of the esophagus are addressed.

HISTORY Gastroesophageal reflux (GER) or chalasia has been recognized by pediatricians and pediatric surgeons for many years, and its history is addressed elsewhere in this book (Chapter 71). Conversely, the existence of other disorders of esophageal function in children has only recently been acknowledged. With the exception of achalasia"J3hnd "esophageal diverticulum," which probably correspond to cricopharyngeal acha1asiaj133 they were not even mentioned in the first modern pediThe nature of the atric surgery textbook~.",~~"l34~164 functional disturbances involved in their pathogenesis and their sometimes elusive symptoms have recently been elucidated, but only after the necessary diagnostic tools were developed and conveniently miniaturized. Since these conditions were investigated, new clinical manifestations in which dysmotility plays a role have been identified and examined.

EMBRYOLOGY The esophagus is derived from the foregut or cranial part of the endodermal tube that runs longitudinally along the embryonal body within the coelomic space. Cranially, it starts at the lower end of the pharynx, and

caudally, it is in continuity with the stomach, which is an expansion of the primitive foregut.% The endodermal lining of the foregut is surrounded by muscle fibers that originate from the mesoderm and progressively arrange themselves in two layers: an external layer in which the fibers are longitudinal and an internal layer in which they adopt a circular pattern. On approximately day 26 of gestation an outgrowth appears on the ventral side of the upper part of the foregut, and this anlage progressively undergoes more branching until it has the configuration of the definitive tracheobronchial tree.g* Interaction between the endoderm and the mesenchyme and the influence of various genes, transcription factors, and growth factors contribute to shaping of the lung with its multiple types of ~ e l l s . ~ ~ , ~ The endodermal lining undergoes changes leading to differentiation into either esophageal or tracheobronchial epithelia.189 This period of tracheoesophageal separation is crucial for normal organogenesis, and several malformations or dysfunctions of the esophagus have their origin at this point. On completion of these phases, the esophagus in its final configuration has two muscular layers, a submucosa and a nonkeratinized mucosa. Some esophageal glands derived from the endoderm are formed in the submucosal layer of the organ, but their alkaline secretion is minimal in comparison to that noted in other parts of the gastrointestinal tract.ln2 On weeks 8 to 12 of embryonal life, the neuroblasts that originate in the cranial neural crest colonize the primitive foregut in a craniocaudal direction and settle in the intermuscular and submucosal layers, where they establish fibrillar connections that allow for neural control of esophageal function by the parasympathetic and sympathetic systems.121 Nonadrenergic-noncholinergic, or nitrergic, innervation is present in the myenteric plexus in week 12 and in the submucosal plexus in week 14. It is fully developed by week 22'j8 or 23.19 Both the vagus nerves and the sympathetic paravertebral chains are of neural crest origin, and their development is synchronous with that of the intramural innervation. When the coelom is divided into the pleural and peritoneal spaces, the diaphragm establishes a functional relationship with the distal part of the esophagus that is crucial for its physiology: the stomach and a portion of

1108

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TIIOKAX

the esophagus are located below the diaphragm, whereas most of the organ remains intrathoracic. The muscle fibers of the diaphragm are contributed to by the truncal mesoderm, and a part of its myoblasts are probably of central tendon and other conneccervical origin.'s"he tive tissue structures derive from the post-hepatic mesenchymal plate that contributes to closure of the remaining pleuroperitoneal canals.88

ANATOMY The upper end of the esophagus is in direct continuity with the pharynx. Its muscle fibers fuse with those of the cricopharyngeal muscle, the lower portion of the inferior pharyngeal constrictor, and it acts as an upper esophageal sphincter (UES). The esophageal body is located in the posterior mediastinum in close contact with the spine posteriorly, with the trachea and heart anteriorly and both pleural spaces on the sides. The vagal trunks run on the surface of the esophagus, where they give off numerous branches. Esophageal length is less than 10 cm in the newborn and reaches 35 to 40 cm in adults. The lower end of the esophagus traverses the hiatus to become intra-abdominal before entering into the stomach. On this end there are no anatomically distinct sphincteric fibers, but at the level of the gastroesophageal junction the circular layer adopts a horizontal U shape on the right side of the esophagus (clasp fibers). On the left side the fibers arrange themselves into a U-shaped structure that overrides the gastric incisura and extends downward onto the anterior and posterior surfaces of the stomach (sling fibers) .98 The diaphragmatic sling that forms the hiatus from the right crus overlaps the distal end of the esophagus and the sphincter. Its striated fibers are closely attached to the esophagus and separate the thoracic space, lined by pleura, from the abdominal cavity, lined by peritoneum. The ensemble of these structures constitutes a zone of high pressure in which the lower esophageal sphincter (LES) and the crural sling are the main functional structures. In contrast to other segments of the gastrointestinal tract, the esophagus is devoid of a serosal layer, although it is in part in close contact laterally with the right and left mediastinal pleurae in the thorax and anteriorly with the peritoneum in its short intra-abdominal portion. The muscle layers are quite similar to those of the intestine except for the nature of the muscle fibers, which are striated in the upper third and smooth for the remainder of the organ. The intermuscular and submucosal plexuses contain ganglion cells and an extensive network of fibers that connect neurons among themselves and with the parasympathetic vagus, the sympathetic trunks, and the celiac plexus. The cholinergic and adrenergic mediators exert positive and negative motor effects, respectively, on the organ. Relaxation is mediated by nitrergic nerve endings that have their neurons in the intramural p l e x u s e ~The . ~ ~c-kit-positive interstitial cells of Cajal are distributed among the muscle fibers and have a pacemaker role.8"141JQJ79 The extent to which these cells are regulated by neural control has not been clarified.lg4

PHYSIOLOGY The function of the esophagus is primarily transportation of the alimentary (food) bolus from the pharynx to the stomach. ~econd&ily,this organ is respons~blefor the clearance of fluid that refluxes from the stomach. To avoid aspiration of digestive juices into the larynx and insufflation of the esophagus by air during inspiration, the UES maintains a permanent tone that relaxes only during deglutition when the glottis is closed and respiration ceases.77The unfavorable pressure conditions imposed on the esophagus by its intrathoracic location require that the distal end normally be closed to prevent reflux. This function is ensured by the LES, which mainThe balance tains its tone except during deg1utiti0n.l~~ between cholinergic and nitrergic mediators regulates closure of the sphincter and its relaxation.171 The intrathoracic location of most of the esophagus . . . together with the intra-abdominal location of the stomach allows maintenance of a permanent abdorninothoracic pressure gradient. As a consequence, the intermittent negative inspiratory thoracic pressure coupled with the permanently positive abdominal pressure tends to push the gastric contents back into the esophagus.lWThe normal resting tone of the LES opposes this gradient, assisted by the contribution of the rhvthmic contractions of the diaphragmatic crural sling, which aids in closure of the lumen during inspiration. At this point the unfavorable gradient is more powerful and the sling displaces the cardia downward, thereby accentuating the angle of His and lengthening the intra-abdominal segment of the esophagus.110 The synergistic play of' these smooth and striated muscular structures has been studied extensively and 8 ~ bears ~ ~ some resemblance to the in a n i m a l ~ " ' J ~ ~ mechanism of anorectal continence, in which the normal resting tone is provided by the internal sphincter and the intermittentlv reauired additional closure is achieved bv voluntary contraction of the striated muscle conlplex and the external sphincter. Deglutition is possible only if the UES and LES relax. Such relaxation occurs whenever the pharyngeal muscles mount a propulsive wave, and the relaxation lasts until the peristalsis of the esophageal body triggered by pharyngeal contractions reaches the lower end of the organ. To effect these propulsive waves, the muscles of the esophagus contract in a coordinated craniocaudal irlarlner along the entire length of the organ to push the esophageal contents in& the stomach. These are- 'j!nirnnryn waves. Normal muscle layers and neural control are necessary for achieving this complex f~inction,and motor disorders of the esophagus are probably the result of' . abnormalities in these two entities. Reflux is the retrograde passage of' gastric contents into the esophagus, which to a certain extent is normal because the-na&ral tone of the I.ES fails several tirnes every day, particularly during meals, and allows the iunwavering gastroesophageal pressure gradient to push gastric juice backward. This sphincter may be persistently insufficient in some patients, particularly in the neurologically impaired,j6 but it is presently acknowleclged that most episodes of reflux in adults and children are due to ,

I

CHAPTER

nondeglutitory extemporaneous relaxation of the s p h i n ~ t e r . " ' - ~ " During ~ ~ ~ , ~ ~these ~ relaxations, the esophageal lumen is filled with a refluxate that contains acidic gastric juice and eventually other digestive material. The mucosa is not prepared for this chemical insult, and it must clear the fluid promptly to avoid perinanent damage. To achieve this objective the esophagus initiates peristaltic contractions that may be independent of heglutition; they may arise at diffeient levels of the organ and are progressive and therefore able to propel the refluxed material back into the stomach. These are "secondary" waves.15" This motor action rids the esophagus of the bulk of the refluxed fluid, but the acid that adheres to the mucosa is completely cleared only after several deglutitions allow the buffering action of saliva (which is alkaline) and, to an unktlowrl extent, the alkaline secretion of esophageal glands to lleutralize the acid.hkti7A normal esophagus may also produce a limited number of simultaneous nonpropulsive motor waves that close the lumen of the esophagus along its entire length. These are known as "tertiary" waves and, when they occur too frequently, may contribute to some of the motor disturbances of the esophagus.7,8,@.l 16.175

MnHODS USED FOR EVALUATING ESOPHAGEAL FUNCTION

70

Disorders o f Esophageal Function

1109

pharynx UES

UES

upper esophagus

middle esophagus

lower esophagus

LES

Schematic drawing of pscss~trerecorded rnanometric.ally within the lunle~lof the esophagus during deglutition. Contraction of the pharyngeal co~lstrictossis accompanied hy relaxatioll of the cricopharyllgeal rrl~~sclr or upper esophageal sphincter (UES). Progressive peristaltic waves arc generated in ihe body of the esophagus. Thc lower esophageal sphinciri- (LES) rernains relaxed during the entire process allti closes suhstq~~crltly with a post-relaxation peak.

For Inany years the barium meal has been the main tool for investigating the esophagus. It shows not only anatomic anomalies of the organ but also abnormal contractility and relaxation of the UES and LES. However, significant radiation exposure is unavoidable if prolonged assessment is required, and such exposure has progressively limited its use. However, this method remains necessary for some of the conditions mentioned in this chapter. probes with lateral holes perfused at constant rates, the Scintigraphy with liquid or solid radionuclide-tagged pressure at any point of the esophageal luirlen can be meals has helped clarify the normal mechanisms of recorded through pressure transducers coililected in a esophageal clearance and is useful for assessing esophageal " T to the perfusion system. Assemblies of several probes transit and esophageal and gastric emptylng. However, it is with spaced holes cat1 explore the progression of pressure of relatively limited use in children.*',14"l"H.177 waves along the organ (Fig. 70-I).* Solid-state sensors can replace the perfused probes, but fragility and high price Endoscopy with suitable fiberscopes allows direct inspection of the esophageal lumen and mucosa. Some limit their use. contl-actility disorders may be detected by this proceMailorrletry is also helpful for assessing sphi~lcteric dure, but its nlaill usefulness resides in the information function. Use of a single perfused probe or assetnblies of several of them with radially arranged orifices and passage obtained by inspection and biopsy of the mucosa. Some functional disorders are related to esophagitis, and this of the recorditlg orifices through the gastroesophageal coilditio~lcall be adequately detected by endoscopy and junction at constant speed allows recording of the pressure profile of both the UES and LES.7,1-',H:3,10-I,Itl(i biopsy. For the Extended pH studies are pri~narilyinteilded to quantiLES the profile shows the gastric pressure followed by a "plateau" correspondit1g to the overlapping LES prestate the extent of acid exposure ofthe esophagus, but there are clear correlations between lrlotor f~~rlction and the sure and the crural sling contractio~~s.~" Furthestnore, clearailre capacity of the organ; therefore, the infornlatioll it allows detection of the point at which the esophagus gained by pH probes tnay be crucial for understatlditlg becomes intrathoracic because there is art "inversion some of' the inotor d i s t t ~ r b a n c e ~ kt'. ~ ~ ~ : ~ ~ ~ ~ ~ ~point" : ~ ~ ~when ~ the positive-pressure inspiratory deflectiotls become negative (Fig. 70-2). Stationary sphincter Manollletry is the lllai~ltool for exa~niilillgthe motor fuilciion of the esophagus. This procedul-e is based on the principle of Pascal, which states that the pressure exerted on any point of a liquid is tratlsinitted in all directious with si~nilar strength. Using tip-occluded

1110

PART

VI

TIIOMX

extended recordings of pressure or pH to be reduced to electrical signals that can be analyzed and measured in computers with the assistance of specifically designed software. It is likely that these diagnostic tools will be further miniaturized and adapted to use in children in the near future, thereby enlarging the scope of manometric studies.

DISORDERS OF THE UPPER ESOPHAGUS

Pull-through manometric recording of the lower esophageal sphincter (LES) in a normal child (ufifiertracing) with simultaneous recording of abdominal pressure (lower tracing). Intragastric pressure is first recorded with positive inspiratory deflections. A "plateau"corresponds to the high-pressure zone of the LES. When the probe enters the thoracic esophagus, intraluminal inspiratory deflections become negative (respiratory inversion point [rip]). From then on the pressure baseline is lower and the inspirations are recorded by negative waves. Withdrawal speed is 1 mm/sec. The time between vertical marks is 2 seconds.

manometry with one of the orifices at the sphincteric level allows detection and assessment of the extent of relaxation. However, because it is understood that reflux is possible with normal sphincteric pressure, more attention has been paid to the relaxations seen with continuous sphincteric Eecording probes with constantly perfused sleeves These located at the appropriate leve1.32~8"84,111~178 recording probes, coupled with the availability of very finely extruded Silastic probes, have permitted the study of gastroesophageal physiology in small babies and premature infants over relatively long periods.l22J23 Manometry requires bulky, expensive, and delicate equipment and some cooperation on the part of the patient, which may be difficult to obtain in children. In addition, sedation might change the registered pre~sures.~~,~~2 The recently introduced 24hour ambulatorv manometry coupled with pH-metry has generated important information on several esophageal disorders in both adultsl..5.&203"0.76612.5.51.5()3161 and children. However, the size of the solid-state sensor probes and the bulk of the equipment have limited these tests to older children for the present.29~"-174~18" These techniques have allowed

The cricopharyngeus occasionally fails to maintain its normal tonus or to relax during deglutition. This leads to difficulty swallowing and consequent choking, which may be life threatening during early infancy. Permanent cn'copharyngealrelaxation is sometimes seen in neurologically impaired patients who undergo repeated episodes of aspiration.lj9 Delayed or incomplete relaxation may be observed in children with the Chiari syndrome,l27J29 in those with 22q11.2 deletion,48or after diazepam medication.99 Absence of relaxation (cn'copharyngeal achalasia) occurs rarely as a primary phenomenon and is usually secondary to neuromuscular disorders.l",1~9In all these conditions the primary symptoms are choking during feeding and respiratory distress during early infancy, which often prompt urgent diagnostic workup. A barium meal or cineradiography depict simultaneous opacification of the respiratory and digestive tracts in cases of permanent relaxation and a dilated pharynx with permanent upper esophageal closure and occasional passage of contrast into the trachea in cases of delayed or absent relaxation.89J35 Manometry is useful for the diagnosis of cricopharyngeal disorders because it shows the incompleteness or absence of relaxation of the muscle during deglutition.22,129,1~9 However, it is particularly difficult to perform in infants because the use of perfused catheters in the upper part of the esophagus is unpleasant for the baby, who chokes, coughs, and does not cooperate. Recordings with sphincteric sleeves depict the lack of relaxation better and are associated with less risk for fluid aspiration.37 Gastrostomy may be necessary for feeding babies with permanent cricopharyngeal relaxation and also for Achalasia of the muscle those with UES achala~ia.MJ2~ , ~ ~extramucosal ,~~ can be treated by balloon d i l a t a t i ~ n but myotomy is more effective."J17 If reflux is present, concurrent fundoplication should be considered because insufficiency of both the upper and lower esophageal closure mechanisms may be devastating.113 Some nonspecific histologic changes in the muscle obtained during myotomy have been reported in cricopharyngeal achalasia.93

DISORDERS OF THE ESOPHAGEAL BODY Primary Motor Disorders Abnormal motility of the body of the esophagus is a frequent cause of symptoms in adults, in whom dij'jfuse esophageal spasm,10~40~144,1fl,181 nutcracker esophagus,21~82or other abnormal motor patterns impairing propulsion of

CHAPTER

the food bolus are occasionally diagnosed after investigation for dysphagia, non-cardiac-related chest pain, or suspected reflux. Simultaneous, nonpropulsive contractions or an excessive proportion of long-duration waves alternating with normal ones are found in the first of these conditions, whereas extremely powerful, highamplitude waves that can be peristaltic or retrograde are demonstrated in the second abnormality.Q5,160>161 Nutcracker esophagus has been noted to evolve into achalasia.* Manometry is the main diagnostic tool, and its accuracy has improved considerably since 24hour ambulatory recordings have become available because the disturbances may not be permanent and appear only occasionally at some point in the circadian cycle. Because of the difficulties of performing this procedure in children, primary motor disorders of the esophageal body were practically unheard of until recently, although apnea, bradycardia,s7 and bizarre posturing1" had been considered symptoms and signs of motor disturbances. However, the introduction of better manometric techniques has produced growing evidence of their existence in children. Food impaction in the absence of stenosis has been found in association with manometric patterns similar to those seen in adults with nutcracker esophagus (Fig. 70-3), but this disorder might not be primary because most patients have reflux as well and respond to treatment of esophagitis.26.YO.lJ8-185 Pharmacologic treatment of primary motor disorders with prokinetic agents or calcium channel blockersl7.61 is seldom indicated in children with these conditions.65 Sildenafil, a drug that helps induce nitric oxide-related relaxation of the esophageal body and LES, has been introduced for the treatment of motor disorders in

70

Disorders of Esophageal Function

a d ~ l t s , 9 * , l ~ ~ , ~it~ Q has u t rarely been used in children. Balloon dilatation or extended myotomy, procedures occasionally performed in adults, have not been used in children.

Secondary Motor Disorders

Abnormal esophageal motility has been demonstrated in several svndromes and chromosomal disorders. Abnormal peristalsis sometimes associated with reflux has been observed in children with Down's syndrome,16"195 Cornelia de Lunge ~ y n d r o r n e , ~ ~ ~ ~ ~ * ~ ~ ~ ) ~ ~ ~ ~ s c l e r o d e polymyositis-dermaGositis,'"' and lupus,w which are wellknown causes of esophageal dysmotility in adults that rarely start during childhood. Babies breast-fed by mothers also have esophageal motor with silicone implants9"ay disturbances similar to those of scleroderma. More relevant for pediatric surgeons are the motor disturbances of the esophagus experienced by survivors of neonatal operations for esophageal atresia with tracheoesophageal f i s t ~ l a . In ~ ~this~ malformation " ~ ~ ~ ~ ~the~ ~ ~ ~ structure of the muscle layersiwand the extrinsic38,1" and intrinsic'8J31 innervations are abnormal and impair the peristaltic pump, probably for life. This is particularly harmful in this condition because the function of the LES is also abnormal. Both these failures make GER a nearly constant aspect of the disease from birth, independent of the type of repair.lflJMIn addition, esophageal shortening ,~~ abnormal hiatus,I97 secondary to the a n a s t o m ~ s i san and perhaps operative denervation may influence dysmotility. Many studies have demonstrated that LES function is abnormal in survivors of operations for esophageal atresia.*"I" Some authors have shown that is permanently damaged even many years after clinical he relevance of these disthe a n a s t o m o s i s . ~ 7 0 J ~ ~ orders is probably greater than was previously thought. Patients who undergo surgery for esophageal atresia have swallowing problems that are perceived by them as minor but are nearly always present when specifically searched f0r.~"I73 These esophagi cannot prevent reflux, and because of the structural basis of these dvsfunctions. there is not much benefit from prokinetic medications. Furthermore, spontaneous improvement of the reflux with age, which is a part of the natural history of reflux in children without esophageal atresia, cannot be expected in patients operated on for esophageal atresia. GER should be treated in patients with esophageal atresia when it is symptomatic or when it causes esophagitis. Dysmotility, constant problem with this malformation, does not preclude complete fundoplication, which should be loose. Gravity is probably the main esophageal emptying force before.or after the plication, and there should be no problem if the wrap is loose enough. However, the incidence of long-term failure of the plication is high in this group of patients because all the causes of GER and dysmotility remain active despite the new valve:56,153 Other relevant conditions involving esophageal motor disorders are chronic intestinal pseudo-obstruction, a heterogeneous group of gastrointestinal dysfunctions with a myogenic or neural basis that are characterized by distal

a

Nocturnal ambulatory manometric recording of intraluminal lower esophageal pH (1) and upper (4), middle ( 5 ) , and lower (6) esophageal pressure in a 10-year-old boy with recurrent episodes of nonobstructive food impaction. The tracing demonstrates a nutcracker esophagus pattern of long duration, apparently peristaltic waves that are extremely powerful, particularly at the lower end of the esophageal body (more than 200 mm Hg or three to four times above normal). This occurs during sleep and without reflux as seen in the pH tracing.

1111

1112

PART

VI

'~II~U,AX

csophagcal dysmotility with s i m t ~ l t a n e o ~shot-t-lasting, ~s, low-amplit~tdewaves.1x,u'!',1'5 Howe\~el; the dysmotility is widcspl.cad and the esophageal part is not the most ilnl~ortant.l'atients wi tll Hi~:sch.sj)r~rngI~ r1i.s~n.s~ have silnl~ltancons and donble-peaked esophageal wave^,^^' and c1iiId1.cn with c.ong~nitnlr.~iltr(zl/t?poz~~?ztilntion syndlnm~ (Ondino? c.lr?:so);':'or (;oI(IP~~/~~).:s .S~)I(~?.I)?IZPI I* also havc also csol)hageal dysnlotility. Sr~i.vivorsof' neonatal operations for tnng~nitnltlinph~qqmntir.k~vtlinhave radiologic and clinic;11 evidence of' ;~l)iiorii~aI esophageal niotol- filnction10'.162.11'." that may 1)c rel;\teti t o innervation ano~nalies. Esopliagcal dysfilnction involving decl.eased sphincteric pl.css~~l-c oi- al,norrn;~l distal esophageal contl-actility has been dcsc.1-ihcd in childl-en with r.htnilir. t.up7nlfizibtr~,1:'2 Noor7(1iz:s s ? T ~ ~ ~ atid . o ~I'i~1.v P , IIZoOin ~ ~ .s?~ldrnnz~.'? The same anoinalies havtl I ~ c c nohscl.ved in adults with r~linr.di.sP~.sP." 13111 to 0111. knowledge, this issue has not heen in c1iild1-en. c~xan~incd (:11ild1.cn with ~1)77r).$17!~ i n j ~ 7 e \of' the esoptiag~lshave ililp;~il.cdl)c~.istilltic;~cti\ityboth in the acute postit!jtlly pc~.ioti"";lnd when sc.;i~.s; I I .e~tahlished.~:' ~ These manornetric findings Ii;tvc been confil.mcd hy radion~lclidcst1tdies.2' The coiit~-ih~~tion of' tlys~uotilityto the cli~iicalcourse and 1)1'ognosisof'tliis condition is still nnclcai; although secondat? esopliagitis may ; t g g l a ~ ~thc t c condition. 111 the last fkw years we have t~.catcda growing number of' patient5 with ~o.sinrtl,hilir. p.sc$ha
Tyl)ic.;~I"111ultil)lr ring" p~ttel-11 of'thc esophagus on til~eropticendoscopy in a11 I I-\c;~~.-old girl will1 dysphagia serondal-) to cosinophilir csophagitis. O n 1)iopsv thc murosa was heavily infiltl-atcdwith cosinophils. p H Icvcls were nol-anal, and thc patient did we11 aftel. a ro111-sc of'tl.eatlilc.ilt with s~eroids.

that d o occur respond to conservative treatment.11s9q Oral corticosteroids," fluticasone,lh7 o r eosinophil stabi. l ~ usually ~ helpful in the li7e1-s such as m o n t e l u k a ~ t ~are management of this c ~ n d i t i o n . ~ "

Disorders of the Distal Esophagus 137mo~:vgn-cl.stro~,soj)hng~nl r@ux involves both failure of' the gastl.ocsophageal barrier and abnormal esophageal ~notility.The etiolo
The sllcccss of' 111-okinctic ~~.c';~ttiicnt used extensively in the last 2 dcc;lctcs illllst~-atcst l i r s relevance of' the dysriiotility in (;ER disc:rsc. T'hcsr drr~gsact by reinfi)rcirig the failing spliinc~te~; 1,y Iiastening g~sii-icemptying, and by improving ],el-isti~lsis. 'The 1nol-e ch;~~.ac.tel-istic. rnoto1. cliso~.dcrof' the lower end of' the cso11h;lgus is rrr/1c1lrr,sic1, in w1lic.h the LES is iij~pe~~tonic and docs not ~.cl;~x d ~ ~ l . dcglutition. i~~g In addition, dilation of' the csopli;~grls ;111(1 l)~.ilnaly hjyo11e1-istaltisrnc.t.e;~tc~ a l,~~o~x~lsivc filn(.~io~l tll;~tis totally incffcctive. This c.ondition is ~.cliitivt~ly I.;I~.(. in young children, and altlio~lghsome cases have art c>;~t.lyonset, most are diagnosed in late childhood or c;~~.ly ;~dolcsc.cnce. Only a fi.w studies it,c.l~~de more tha11 ;I 1i;itited ntlrnber ()f cases,l".':'.'"*".l'~."li.l""an~ I;li.g(.s( Illrllti(.entcr set-ies in~olvcsonly 1 75 p;~tierlts.1 l X The ctiolo
CHAPTER

70

1)isordet-s of' E s o p h a g t d Function

1113

by adrenocortical insufficiency and alacrima, in addition to esophageal motor dysfunction. This association is called ALADIN syndrome (alacrima, achalasia, adrenal insufficiency, and neurologic disorder) .70 Achalasia is more frequent in boys, and it is occasionally associated with Down's syndrome.1"" Achalasia patients complain of progressive dysphagia and regurgitation of food retained in the esophagus; these findings should not be confused with vomiting. Some have retrosternal pain, which may become distressing. Patients lose weight and often have foul breath and respiratory symptoms such as nocturnal cough or repeated pneumonia because of frequent microa~piration.~2~~~ Patients with Allgrove's syndrome also have symptoms of adrenocortical insufficiency, such as progressive pigmentation and asthenia and eventually absence of tears (alacrima), but these symptoms and other manifestations of neurologic disease7()may appear later after the full clinical picture of achalasia has developed. The barium meal is often diagnostic: the esophagus is large (megaesophagus) and contains stagnant fluid above the barium column. There is marked aperistalsis, and the esophagogastric junction is filiform, with a classic "bird's b e a k shape.") The contrast material progresses into the stomach after a considerable time, and most of it is retained in the esophagus for hours (Fig. 70-5). Fiber-optic erldoscopy rules out the presence of a stricture; the esophagoscope can usually be advanced into the stomach with relative ease. Esophagitis may be seen after aspiration of the retained fluid, but it is generally secondary to fermentation of the stagnant fluid. pH studies

are not useful at this stage and can be ~nisleadincr <, " because this fluid is often acidic and the probe reading may suggest GER, which is in fact impossible. Kadioniiclide scintigraphy may depict the lack of' progression of the esophageal content and allows more prolonged ohservation with less radiation exposure, but it is less informative than the barium meal in regard to evaluating the shape of the distal end of the esophagus.'7sfifi Manometry is the most useful diagnostic tool for achalasia: the sphincter is hypertonic- and does not relax or relaxes incompletely during deglutitiorl. Esophageal peristalsis is absent, and rare pressure is present, particularly during meals. Such pressure is recorded sinlultaneously at all points in the lumen, which is in fact a common chamber (Fig. 70-6).1h,7H Twenty-hiir-hour ambulatory recordings performed with probes equipped with multiple solid-state sensors show that the aperistalsis is constant during the entire circadian cycle, including meals, a time when motor waves are normallv more activ;:17" Pharmacologic treatment, particularly calcium channel blockers such as nifedipine, may alleviate the spasm in some cases,l()%ut they cannot be relied on as a long-term

Bariuni meal in a 9-year-old patient with achalasia. The esophagus is enlarged arid contained stagnant fluid before the contrast was administered. Eniptyirig is very slow and the cardia has a typical "carrot" or "bird's b e a k pattern (left). Some feeble esophageal contractions are seen (right),but peristalsis is impossible because the esophageal walls remain widely separated.

Ambulatory esophageal tnariornetry in an 8-year-old boy with achalasia. In the upper tracing, the pressure at the upper (4), middle (5), and lower (6) levels of the esophagus is identical and no waves are seen. In the lower tracing, correspondirig to a meal, some waves are generated, but they are simultaneous and nonpropulsive (time between vertical marks, 5 seconds).

1114

PART

VI

THORAX

treatment i n children." Forceful balloon dilation of t h e distal e n d of t h e esophagus is often successful in adults with achalasia, b u t such treatment is seldom permanently effective in children.16.4"180 Local injection of botulinum toxin has also b e e n attempted i n children, b u t its success has b e e n limited as ~e11.7~,72,7"*7,1*6 Extramucosal Heller myotomy remains t h e treatment of choice in children, a n d it can b e performed through either t h e thorax o r t h e abdomen.1"78,*0,118.'74.'80 T h e latter a p p r o a c h probably allows a m o r e c o m p l e t e rnyotomy i n t h e gastric side a n d a n easier complementary fundoplication. I n fact, if sought after, reflux is rather constant after a Heller myotomy, a n d some form of fundoplication is probably reasonable to consider in children,-whose longlife expectancy after t h e operation supports t h e use of this procedure to prevent t h e compliA N i ~ ~ eantireflux n cations of GER.72,7~78,~.i,~40,174,1*0 procedure may b e inappropriate because of t h e often large diameter of t h e thickened esophagus; a posterior Toupet o r anterior Thal-Dor hemifundoplication is preferred.78J40,174 All these procedures can b e performed laparoscopically, a n d thisapproach is presentiy t h e gold standard.51."'.107,140 Postoperatively, patients a r e relieved of their symptoms immediately a n d they can feed properly a n d regain weight. However, t h e esophagus remains dilated for m o n t h s o r even years, a n d its function only rarely returns to normal. Most patients maintain rare a n d ineffective peristalsis despite the decrease in sphincteric pressure 174~1~0 provided by the myotomy (Fig. 7 0 - 7 ) . ~ 0 0 ~ 1 0 1 ~ 1 ~ ~ ~Some have low-level symptoms such as dysphagia a n d often require a few swallows of water during feeding, b u t esophagomyotomy allows a good quality of life. Esophageal replacement has been reported in s o m e rare cases o f achalasia i n which all o t h e r treatments have failed.llgJ56

I

s

S

S

P

r

s

s

Ambulatory esophageal manometry during a meal a 24year-old woman 12 years after a Heller myotomy for achalasia. She was asymptomatic, but esophageal motility remained very poor. The motor waves at the upper (4). middle (5),and lower (6) levels of the esophagus showed peristaltic organization but were very weak (less than 25 mm Hg, roughly half normal). The time between vertical marks is 5 seconds. in

This suggests that t h e myotomy relieves t h e obstruction b u t does n o t c u r e t h e condition. Long-term follow-up is essential.

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147. Shah N, Rodriguez M, Louis DS, et al: Feeding difficulties and foregut dysmotility in Noonan's syndrome. Arch Dis Child 1999;81:28. 148. Shokeir MH: The Goldenhar syndrome: A natural history. Birth Defects Orig Artic Ser 1977;13:67. 149. Siafakas CG, Ryan CK, Brown MR, Miller TL: Multiple esophageal rings: An association with eosinophilic esophagitis: Case report and review of the literature. Am J Gastroenterol 2000;95:1572. 150. Singh S, Stein HJ, DeMeester TR, Hinder RA: Nonobstructive dysphagia in gastroesophageal reflux disease: A study with combined ambulatory pH and motility monitoring. Am J Gastroenterol 1992;87:562. 151. Sinharay R: Eosinophilic oesophagitis: Treatment using montelukast. Gut 2003;52:1228. 152. Sivarao DV, Mashimo HL, Thatte HS, Goyal RK: Lower esophageal sphincter is achalasic in nNOS(-/-) and hypotensive in W/W(v) mutant mice. Gastroenterology 2001;121:34. 153. Snyder CL, Ramachandran V, Kennedy AP, et al: Efficacy of partial wrap fundoplication for gastroesophageal reflux after repair of esophageal atresia. J Pediatr Surg 1997; 32:1089. 154. Sondheimer JM: Gastroesophageal reflux: Update on pathogenesis and diagnosis. Pediatr Clin North Am 1988; 35:103. 155. Sondheimer JM: Clearance of spontaneous gastroesophageal reflux in awake and sleeping infants. Gastroenterology 1989;97:821. 156. Spitz L: Gastric transposition for esophageal substitution in children. J Pediatr Surg 1992;27:252. 157. Staiano A, Corazziari E, Andreotti MR, Clouse RE: Esophageal motility in children with Hirschsprung's disease. Am J Dis Child 1991;145:310. 158. Staiano A, Cucchiara S, Del Giudice E, et al: Disorders of oesophageal motility in children with psychomotor retardation and gastro-oesophageal reflux. Eur J Pediatr 1991;150:638. 159. Staiano A, Cucchiara S, De Vizia B, et al: Disorders of upper esophageal sphincter motility in children. J Pediatr Gastroenterol Nutr 1987;6:892. 160. Stein HJ, DeMeester TR: Indications, technique, and clinical use of ambulatory 24-hour esophageal motility monitoring in a surgical practice. Ann Surg 1993;217:128. 161. Stein HJ, DeMeester TR, Eypasch EP, Klingman RR: Ambulatory 24hour esophageal manometry in the evaluation of esophageal motor disorders and noncardiac chest pain. Surgery 1991;110:753. 162. Stolar CJ, Berdon WE, Dillon PW, et al: Esophageal dilatation and reflux in neonates supported by ECMO after diaphragmatic hernia repair. A J R - A J~ ~ o e n t ~ e n 1988; ol 151:135. 163. Stolar CJ, Levy JP, Dillon PW, et al: Anatomic and functional abnormalities of the esophagus in infants surviving congenital diaphragmatic hernia. Am J Surg 1990; 159:204. 164. Swenson 0 : Pediatric Surgery, vol 1, 3rd ed. London, Butterworths, 1969. 165. Takahashi T: Pathophysiological significance of neuronal nitric oxide synthase in the gastrointestinal tract. J Gastroenterol 2003;38:421. 166. Takano K, Iwafuchi M, Uchiyama M, et al: Evaluation of lower esophageal sphincter function in infants and children following esophageal surgery. J Pediatr Surg 1988; 23:410. 167. Teitelbaum JE, Fox VL, Twarog FJ, et al: Eosinophilic esophagitis in children: Immunopathological

response to fluticasone propionate. Gastroenterology 2002; 122:1216. 168. Thomas EJ, Kumar R, Dasan JB, et al: Radionuclide scintigraphy in the evaluation of gastro-oesophageal reflux in post-operative oesophageal atresia and tracheooesophageal fistula patients. Nucl Med Commun 2003;24:317. 169. Thompson LD, McElhinney DB, Jue KL, Hodge D: Gastroesophageal reflux after repair of atrioventricular septa1 defect in infants with trisomy 21: A comparison of medical and surgical therapy. J Pediatr Surg 1999;34:1359. 170. Tomaselli V, Volpi ML, Dell'Agnola CA, et al: Long-term evaluation of esophageal function in patients treated at birth for esophageal atresia. Pediatr Surg Int 2003;19:40. 171. Tomita R, Tanjoh K, Fujisaki S, Fukuzawa M: Physiological studies on nitric oxide in the lower eso~hapealswhincter of patients with reflux esophagitis. Hepatogastroenterology 2003;50:110. 172. Tovar JA, Arana J, Tapia I: Effects of sedation on motor function of the refluxing esophagus. Pediatr Surg Int 1990;5:418. 173. Tovar JA, Diez Pardo.TA, Murcia.1, et al: Ambulatory 2 4 hour manometric and pH metric-evidence of impairment of clearance capacity in patients with esophageal atresia. J Pediatr Surg 1995;30:1224. 174. Tovar JA, Prieto G, Molina M, Arana J: Esophageal function in achalasia: Preoperative and postoperative manometric studies. J Pediatr Surg 1998;33:834. 175. Triadafilopoulos G, Castillo T: Nonpropulsive esophageal contractions and gastroesophageal reflux. Am J Gastroenterol 1991;86:153. 176. Tuck IS, Bisset RA, Doig CM: Achalasia of the cardia in childhood and the syndrome of achalasia alacrima and ACTH insensitivity. Clin Radio1 1991;44:260. 177. Vandenplas Y, Derde MP, Piepsz A: Evaluation of reflux episodes during simultaneous esophageal pH monitoring and gastroesophageal reflux scintigraphy in children. J Pediatr Gastroenterol Nutr 1992;14:256. 178. Vandenplas Y, Hassall E: Mechanisms of gastroesophageal reflux and gastroesophageal reflux disease. J Pediatr Gastroenterol Nutr 2002;35:119. 179. Vandenvinden JM: Role of interstitial cells of Cajal and their relationship with the enteric nervous system. Eur J Morphol 1999;37:250. 180. Vane DW, Cosby K, West K, Grosfeld JL: Late results following esophagomyotomy in children with achalasia. J Pediatr Surg 1988;23:515. 181. Vantrappen G, Janssens J, Hellemans J, Coremans G: Achalasia, diffuse esophageal spasm, and related motility disorders. Gastroenterology 1979;76:450. 182. Vicente Y. da Rocha C. Perez-Mies B. et al: Effect of reflux and esophagitis on esophageal volume and acid clearance in piglets. J Pediatr Gastroenterol Nutr 2004;38:328. 183. Vicente Y, Da Rocha C, Yu J, et al: Architecture and function of the gastroesophageal barrier in the piglet. Dig Dis Sci 2001;46:1899. 184. Vicente Y, Da Rocha C, Yu J, et al: Individual inactivation of the sphincteric component of the gastroesophageal barrier causes reflux esophagitis in piglets. J Pediatr Surg 2002;37:40. 185. Vicente Y, Hernandez-Peredo G, Molina M, et al: Acute food bolus impaction without stricture in children with gastroes~~hageal reflux. J Pediatr Surg 2001; 36: 1397. 186. Walton JM, Tougas G: Botulinum toxin use in pediatric esophageal achalasia: A case report. J Pediatr Surg 1997; 32:916. L

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187. Wang WL, Tovar JA, Eizaguirre I, Aldazabal P: Airway obstruction and gastroesophageal reflux-an experimental study on the pathogenesis of this association. J Pediatr Surg 1993;28:995. 188. Warburton D, Schwarz M, Tefft D, et al: The molecular basis of lung morphogenesis. Mech Dev 2000;92:55. 189. Warburton D, Zhao J, Berberich MA, Bernfield M: Molecular embryology of the lung: Then, now, and in the future. Am J Physiol 1999;276:L697. 190. Watanabe Y, Ando H, Seo T, et al: Attenuated nitrergic inhibitorv neurotransmission to interstitial cells of Caial in the lower esophageal sphincter with esophageal achalasia in children. Pediatr Int 2002;44:145. 191. Weber P, Ganser G, Frosch M, et al: Twenty-four hour intraesophageal pH monitoring in children and adolescents with scleroderma and mixed connective tissue disease. J Rheumatol 2000;27:2692. 192. Weston S, Thumshirn M, Wiste J, Camilleri M: Clinical and upper gastrointestinal motility features in systemic sclerosis and related disorders. Am J Gastroenterol 1998;93:1085. J

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193. Wyllie E, Wyllie R, Rothner AD, Morris HH: Diffuse esophageal spasm: A cause of paroxysmal posturing and irritability in infants and mentally retarded children. J Pediatr 1989;115:261. 194. Yuksel B, Braun R, Topaloglu AK, et al: Three children with triple A syndrome due to a mutation (R478X) in the AAAS gene. Horm Res 2004;61:3. 195. Zarate N, Mearin F, Hidalgo A, Malagelada JR: Prospective evaluation of esophageal motor dysfunction in Down's syndrome. Am J Gastroenterol 2001;96:1718. 196. Zhang X, Tack J,Janssens J, Sifrim DA: Effect of sildenafil, a phosphodiesterase-5 inhibitor, on oesophageal peristalsis and lower oesophageal sphincter function in cats. Neurogastroenterol Motil 2001;13:325. 197. Zhou B, Hutson JM, Myers NA: Investigation of the intraabdominal oesophagus and hiatus in fetal rats with oesophageal atresia and tracheo-oesophageal fistula. Pediatr Surg Int 2001;17:97. 198. Zuccarello B, Nicotina PA, Centorrino A, et al: Immunohistochemical study on muscle actinin content of atresic esophageal upper pouch. J Pediatr Surg 1988;2:75.

Gastroesophageal Reflux Disease Keith E. Georgeson and Gonca Topuzlu Tekant

HISTORY

incomplete understanding of the underlying disease and evaluation of the effectiveness of treatment strategies. All of the surgical techniques just described have been performed in children. Nissen fundoplicaiion has emerged as the most frequently used procedure for refluxing children,80,83,"7,130 but there are many advocates of a partial-wrap fundoplication. Ashcraft popularized a modification of the Thal operation."I0 Boix-Ochoa performed a similar operation, which he described as an attempt to restore the anatomic and physiologic mechanisms that normally prevent GER.27229 In 1991, Dallemagne reported his initial experience with laparoscopic fundoplication in a d ~ l t s . 6Two ~ years later, Georgesonw and Lobe147independently reported laparoscopic fundoplication results in children. Today, minimally invasive techniques have become the standard for surgical correction of GERD in children."

Symptoms of gastroesophageal reflux (GER) have been recognized for hundreds of years. Shakespeare described the infant "mewling and puking in the nurse's arms" as part of the first stage of human life. Anatomic dissections performed during the Renaissance provided a way to study the consequences of esophageal injury and stricture in patients who had GER. One of the first recorded descriptions of childhood gastroesophageal reflux disease (GERD) was in 1828 in Paris, where children with repeated vomiting were found to have esophageal ulcerations at aut0psy.2~In 1836, Bright described partial herniation of the stomach into the chest and associated this anatomic abnormalitv with GER.37 In 1935. Winkelstein mentioned the term peptic esophagitis.?6l Allison defined the underlying causes of reflux esopha tis and presented an operative method of repair of hia hernia in 1943.6 He also defined the anatomic wroble as being a malfunctioning gastroesophageal vilve and\ INTRODUCTION described heartburn as the primary symptom of GER.5 One of the first detailed publications about pediatric Vomiting and regurgitation are common occurrences in GER was by Neuhauser and Berenberg, who coined the childhood. Seventy percent of 4-month-old infants regurterm "chalasia" to describe physiologic GER in infants.167 gitate daily, and only 25% of their parents consider it a In the 1960s, Carre emphasized the self-limited nature of problem.l65,246 The challenge for physicians is to differenthe disease in infants and suggested postural treatment tiate the symptoms that are physiologic and will resolve to control the ~ y m p t o r n s . ~ 2 , ~ ~ spontaneously from those that need medical or surgical Allison described and advocated hiatal hernia repair intervention. The spectrum of clinical signs in pathologic for the control of GER. Subsequently, Belsey and Nissen GER is variable, and recognition of these symptoms, folindependently described fundoplication procedures lowed by diagnostic evaluation and therapy, is important that effectively controlled reflux in most patients.20J68 to prevent the serious sequelae of this pathologic process. Rossetti modified the Nissen repair to include only the anterior wall of the stomach in the wrap.202 Lucius Hill emphasized the importance of keeping the gastroEMBRYOLOGYAND ANATOMY esophageal junction below the diaphragm.lO3 Thal and Toupet popularized partial-wrap fundoplications to preThe precise embryologic mechanisms that predispose infants and children to GER are unknown. Many explavent the symptoms associated with a tight complete ~q~~.231,237 nations of the embryology of reflux have been The development of improved diagnostic studies proposed.98~~34~160~2~4,262,268 One of the more interesting evolved about the same time as the surgical techniques concepts was offered by Mansfield, who believed that GER - p ~ in Homo sapiens stems from alterations in embryogenesis were being devised. Barium esophago~raphy,66,205 monitoring,llg endoscopy,244 scintigraphy,22 and manometry" were developed and refined over the last few *See references 86, 87, 89, 146, 156, 163, 182, 203, 216, 225, 228, 255 decades. These investigations have provided a better, yet

CHAPTER

to support the extrauterine consequences of adopting the upright position and bipedal locomotion.154Adopting the upright posture leads to changes in structure and positional relationships of many intracavitary organs and svstems. Rotation of the stomach, which alters the inferior &lationship of the antrum to the fundus and causes the dorsal aspect of the stomach to move to the left and the ventral aspect to move to the right, may be a critical aspect in-the etiology of reflux. ~ h e s echanges cause abnormalities in the intrinsic pinch valve mechanism and the gravitational pull on the stomach. The heart's vertical places more stress on the human diaphragm. Mansfield believes that these changes are significant and may be the underlying reason why humans are so prone to the develo~mentof GERD and related disorders. A high-pressure zone in the lower portion of the esophagus also plays an important role in the prevention of GER.fl4;"7 A critical length of intra-abdominal esophagus is necessary to prevent GERD.z6' Anatomic defects that affect the high-pressure zone of the gastroesophageal junction and interfere with rapid clearing of physiologic GER, such as esophageal atresia, diaphragmatic hernia, and motility disorders, are all associated with significant reflux pathology.*

DEFINITION GERD is defined as the pathologic consequences of the involuntary passage of gastric contents into the e~ophagus.")".'~"n adults, GERD is primarily concerned with peptic esophagitis and its complications, including heartburn, esophageal stricture, and the formation of Barrett's esophagus. In children, pathologic reflux ;is

e The extent of esophageal damage depends on the balance between the attack of reflux and the defense of the esophageal mucosa. In the assault of the esophagus, the acidity and volume of refluxing fluid and the duration of esophageal contact are counterbalanced by the clearance and resistance of the esophageal mucosa.

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considerably more c o m p l e x . 1 ~ ~ ~ 6 ~ 1 7 9Pathologic ~~0y~~4b~~49 GER is most commonly seen in children with neurologic dysfunction. Neurologically impaired children with GER often have associated swallowing disorders, failure to thrive, primary aspiration, spasticity, increased intraabdominal pressure, and central mechanisms for inducing gagging, choking, and retching. Additionally, they often have associated delayed gastric emptying, dysmotility of the esophagus and upper gastrointestinal tract, and a hiatal hernia and usually remain primarily in a supine position. Neurologically normal infants and children have refluxassociated reactive airways disease, aspiration, aspiration pneumonia, laryngeal symptoms, and apnea. Sometimes this apnea is prolonged and life threatening.177.'"~09~24~,2~6 Children also have digestive symptoms, including frequent regurgitation with failure to thrive, irritability, food rejection, heartburn, hematemesis, melena, dysphagia, and the epithelial changes associated with Barrett's esopha911S.96,100,101,183,209,210

PATHOPHYSIOLOGY GERD occurs when refluxed contents produce clinical symptoms or result in histopathologic alterations. The pathogenesis of GERD is multifactorial and complex. The primary anatomic and physiologic factors that become dysfunctional and are associated with GER are discussed in the following sections (Fig. 71-1).w,249 Secretion of Saliva: Saliva is responsible for the lubrication of food and enhanced esophageal transport. It contributes to the neutralization of refluxed contents with its alkaline content and stimulates primary peristalsis of the esophagus. The secretion of saliva and frequency of swallowing are decreased during sleep. Salivary flow can be increased by gum chewing, which has been offered

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as a nonpharmacologic treatment for some patients with GERD.125,249 Esophageal Peristalsis: Esophageal contractions are classified as primary, secondary, and tertiary. Swallowing initiates primary waves. Secondary peristalsis is induced by reflux of material into the esophageal lumen and contributes to esophageal clearance.l25J42 Tertiary contractions are simultaneous, nonpropagated waves that occur spontaneously and are unrelated to swallowing or reflux. Swallowing induces contraction waves that begin at the pharynx and advance through the striated and smooth During daytime reflux muscle to the ~ardia.~8,7"~2l episodes, swallowing frequency increases and is an effective mechanism for acid clearance.

Pars thoracalis Intraabdo. ,so,h~

0.65

0.75

1.2

1.35

1.55

2

0.27

0.5

0.8

1.25

1.4

1.48

, Mean values of the lower esophageal sphincter in neonates and infants.

Esophageal Clearance: Esophageal clearance is influenced by three primary factors: peristaltic waves, gravity, the bolus has passed through the region. Dodds et al. and saliva.1°2,*22Delayed clearance of acid in the esophafirst described the phenomenon of transient lower Swallowed saliva gus is a primary cause of e~ophagitis.~~JO5 esophageal sphincter relaxations (TLESRs), which are is responsible for neutralization of the refluxed material, responses mediated via vagal reflexes71TLESRs are initiand patients with GERD often have decreased salivary ated by stimulation of mechanoreceptors in the gastric function. The efficacy of positional treatment may be parfundus, or stretching of the gastric fundus.107 LES pressure tially related to Different types of decreases postprandially. Gastric contractions, gastric afferent neurons have been identified in the esophageal alkalinization, and proteins increase LES pressure. Gastrin, ~all.l","22~4"C unmyelinated fibers are responsible for motilin, and substance P also increak LES pressure, deep, burning pain, and A delta fibers are responsible for whereas cholecystokinin, glucagon vasoactive intestinal peptide, nitric oxide, dopamine, secretin, estrogen, nicosharp pain. Repeated noxious stimuli or one very strong tine, alcohol, mint, and chocolate all decrease LES stimulus can sensitize both types of fibers to respond to non-noxious stimuli. Visceral hyperalgesia may result in a p r e s s ~ r e . 2In ~ ~children, most reflux episodes occur in relation to TLESRs, and they are the predominant mechdisordered motility causing more reflux.120.181 Thus, in some patients, GERD may initially be caused by an abnoranism of GER in healthy term infants, as well as those mal stimulus, which in turn induces an abnormal motility with chronic lung d i ~ e a s e . ~ ~ O Large , l ~ l meals leading to problem. The sensation of pain is transported to the brain i increased secretory volume induce more TLESRs. Thus, via the neurotransmitters calcitonin gene-related peptide the efficacy of proton pump inhibitors (PPIs) and histaand substance P.8,266Substance P causes smooth muscle mine H2 receptor antagonists (H2RAs) may be related to contractions and vasodilatation and stimulates increased ecreased secretory gastric volume, independent of its pH. The antireflux effects of surgery may be related to mucosal permeability. It is released when there is tissue achievement of incomplete LES relaxation and a reducdamage. With esophagitis, the more substance P released, the greater the noxious effect of the reflux material, which tion in the number of TLESRs.128,129 leads to a vicious cycle. Substance P also causes release of Intra-abdominal Esophagus: The length of the intrahistamine from mast cells in the alveoli, thus contributing abdominal portion of the esophagus is an important part to bronchospasm. It has been speculated that substance P released in the esophagus may sometimes contribute to of the antireflux barrier. The intra-abdominal esophageal the initiation of reactive airways disease.190~224 diameter is approximately a fifth the diameter of the stomach. According to the law of Laplace, GER in response Lower Esophageal Sphincter: The concept of a defecto elevation of intra-abdominal pressure is prevented if tive lower esophageal sphincter (LES) as the prominent there is adequate length of the intra-abdominal part of the cause of pathologic GER was first demonstrated in 1971.53 esophagus with a significantly smaller luminal diameter The LES is a functional barrier 3 to 5 cm long in adults than that of the stomach. If the intra-abdominal segment of that manometrv has defined as an area of elevated distal the esophagus is short, less than 2.0 cm, or if the overall esophageal resting pressure; it serves as the barrier sphincter length is less than 2.0 cm, gastroesophageal reflux is much more likely to O C C U ~ During . " ~ ~the ~ first ~ ~ year ~ of against abnormal regurgitation of gastric contents into life, the length of the intra-abdominal portion of the the esophagus. Adult studies have demonstrated that mean LES pressure lower than 6 mm Hg and overall esophagus is physiologically short, which contributes to the sphincter length less than 2 cm are likely to be associated increased incidence of regurgitation in this population.30 with pathologic GER.l"Z69 Studies by Boix-Ochoa and ~ a n a i shave demonstrated that the l e k"t h of the LES is Angle of His: The angle of His is formed by the esophaonly 0.5 to 1.0 cm in neonates and increases with age as gus and the greater curvature of the stomach and is The antireflux effect of seen in Figure 71-2-30 normally an acute angle.11,28,144,189 The LES relaxes 2 seconds after the initiation of this angle becomes obvious when the child attempts to a swallow and remains open for 10 to 12 seconds until vomit and the gastric contents strike the fundus, which

'

rl

CHAPTER

closes the gastroesophageal junction. In cases in which the angle is obtuse, the stomach is converted into a funnel that directs its contents back into the esophagus with a sudden increase in abdominal pressure.I8 There is also a collection of convoluted folds of the esophageal mucosa at the gastroesophageal junction. With changes in intragastric pressure or with negative pressure in the thoracic esophagus, these mucosal folds squeeze together and act as a weak antireflux ~ a l v e . l ~ * , l ~ ~

71

Gastroesophageai Reflux Disease

1123

acid pH, whereas deconjugated bile salts and trypsin are harmful at a neutral pH.19334 With the development of intraluminal impedance and bilirubin-detecting technologies, studies have demonstrated bile salts in the refluxate of adults with GERD. Mixed refluxate may be more harmful to the esophageal mucosa than pure acid is.'40,241

Pinchcock Action: The esophageal hiatus at the diaphragm is formed by the sling shape of the right crus of the diaphragm. During deep inspiration, this sling pulls the esophagus toward the right and downward, which narrows the lumen of the distal end of the esophagUs.7,333,"8106.1 13,153,194,254 The action of the diaphragm can be observed during awake endoscopy.176

Intra-abdominal Pressure: The role of increased intraabdominal pressure in children has not been well . ~adults, ~ 17% investigated, and reports are c ~ n f l i c t i n gIn of GER episodes were related to increases in abdominal pre~sure.~? Obesity, ascites, and peritoneal dialysis have been shown to cause GER by increasing intra-abdominal pressure.17J6~J64Abdominal wall defects in children have also been related to an increased incidence of GER, apparently caused by the associated increased intra-abdominal pressure after closure of the defe~t.IgJ3~

Gastric Volume and Emptying: In children with significant GERD, gastric electrical abnormalities and delayed gastric empiyng have often been do~umented.~~,201 Two important physiologic reflexes are involved in the gastric response to food intake. In adaptive relaxation, the fundus of the stomach dilates in response to food entering the stomach. In receptive relaxation, the gastric fundus dilates when food passes down the esophagus. Nitric oxide is involved in both pathways and causes relaxation of the . ? 2 9 with neurocircular muscle of the f u n d u ~ . ~ ~ ~Children logic abnormalities often have abnormal gastric motility or delayed gastric emptying, or both.2,40J41J78,1Y"

Gastroesophageal Reflux Causing Gastroesophageal Reflux: GER is an important factor contributing to GER by initiating a positive feedback cycle. Contact of the refluxed acid with the esophageal mucosa increases regional blood flow and increases the secretion of prostaglandin EQ. Prostaglandin locally affects esophageal permeability, which increases the susceptibility of the mucosa to inflammation. Inflammation causes impairment in motility and decreases the resting pressure of the LES. It also leads to pylorospasm, which creates more reflux and esophagitis.249 The presence of trypsin, pepsin, and bile may potentiate damage to the esophageal mucosa.

Gastric Acid: The majority of reflux patients have normal Respiratory Factors: Respiratory problems cause deeper inspiratory efforts and more negative intrathoacid secretion, but some groups of pediatric patients with GERD have been shown to have gastric- hypersecre- ; racic pressure, which initiates GER.127 tion."J" Acid combined with pepsin can cause injury to ! ~ ~most ~ cases, the volume \ Medications and Hormones: Medications and hormones the esophageal m u c o ~ a . ' 8 0 .In secreted may be more important than the pH. Thus, PPIs k h as antihistamines,xanthines, theophyllines, chocolate, caffeine, calcium channel blockers, gastrin, dopamine, decrease gastric secretion volume and are potent in the glucagons, and prostaglandins are associated with an treatment of esophagitis despite nocturnal breakthrough increased incidence of GER.l"J92,22"23() of acid secreti~n."".~,go>Y" -

-

Helicobacter pylori Infection: In the past 3 decades, mortality rates related to gastric cancer, gastric ulcer, and duodenal ulcer have declined, whereas those of esophageal adenocarcinoma and GERD have risen.133Some studies suggest that H. pylori colonization may be protective against severe esophagitis and Barrett's esophagus.52,265 These epidemiologic data have led some to suggest that H. pylorishould not be eradicated in patients with GERD. However, H. pylori is a risk factor for the development of peptic ulcer and gastric cancer, which has caused many physicians to be uncomfortable with that recommendation. This issue remains under inve~tigation.g2,~~~J51 Pepsin, Ttypsin, and Bile Salts: Pepsin and trypsin are prote~lyticenzymes that have a traumatic effect on the esophageal mucosa. Pepsin causes its most significant damage at a pH of 2 to 3, whereas trypsin is most damaging at a pH between 5 and 8.Zo0243Bile salts increase the permeability of the esophageal mucosa to acid and are noxious to the esophageal mucosa in the presence of acid. Conjugated bile salts are injurious to the esophagus at an

Underlying Congenital Problems: Children with esophageal atresia are prone to pathologic GER.2"70,137,145,219,??3 In these cases, esophageal peristalsis is impaired and the LES is incompetent. The incidence of reflux in these children declines as the children grow, but complications of GERD mandate antireflux surgery in 10% to 30% of children after esophageal atresia repair.24,138,215 One of the common manifestations of GERD in children with esophageal atresia is recurrent esophageal anastornotic stenosis. Appropriate prophylactic medical treatment of reflux in these children may lead to diminished stricture formation. Children with congenital diaphragmatic hernia often have functional anatomic abnormalities of the esophagus leading to GER. The incidence of pathologic GER is reported to be greater than 20% in surviving infants. About 15%of children with congenital diaphragmatic hernia require an antireflux procedure.78,"5J24 Congenital abdominal wall defects such as gastroschisis and omphalocele are also associated with an increased incidence of GER, possibly because of increased intra-abdominal pressure.1gJ36

1124

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Neurologically Impaired Children: Neurologically impaired children are prone to the development of GER. The underlying cause is thought to be related to a foregut motility problem. Impaired esophageal motility and delayed gastric emptying are important factors contributing to reflux in these children.49922'

DIAGNOSIS There are few objective studies that compare the value of the various diagnostic techniques used for the diagnosis of GER in children. Tests for GER are individually useful in documenting different aspects of GER and are valuable only when used in the appropriate clinical context.

relation to the severity of the esophagitis.174 They also noted that some patients with esophagitis had pathologic duodenal-gastroesophageal reflux, but not pathologic reflux by pH probe analysis. Multiple intraluminal electrical impedance technologies with the capacity to detect all types of reflux (acid, nonacid, liquid, and air) have been developed over the last 2 decades. This technique is useful for investigating Belaji ~ . 2 ~et al. reported that 59% of nonacid r e f l u ~ . * 2 ~ . ' ~ GER events were not conventional acid reflux and were not detected by the pH probe studies.lVn infants, nonacid GER has been documented in association with respiratory symptoms such as apnea. Such findings have led investigators to hypothesize that apneic episodes in infants may be caused by a protective respiratory reflex. Further investirration will be recluired to determine the importance of impedance and other new technologies in identifying pathologic GERD in infants and children.l88,260 u

History and Physical Examination: The history and physical examination are the most important components of the evaluation of an infant or child with possible GERD. Documentation of the growth rate and identification of the primary symptoms, such as failure to thrive, primary aspiration, recurrent coughing, reactive airways disease, stridor, apnea, recurrent pneumonia, irritability, heartburn, abdominal pain, and dysphagia, are helpful in guiding the remainder of the patient's workup.209,2j0 Upper Gastrointestinal Contrast Series: An upper gastrointestinal contrast series is neither specific nor sensitive It does, however, provide a for the diagnosis of GER.1s47J87 detailed road map of the patient's anatomy to-rule out other causes of vomiting. Problems such as pyloric stenosis, malrotation, partial duodenal outlet obstruction, hiatal hernia, and esophageal stricture are readily seen. Esophageal pH Monitoring: Esophageal pH monitoring measures the duration and frequency of acid reflux episodes. It is most useful if used in conjunction with regular daily activities such as eating and sleeping. The presence of symptoms should be noted in parallel with the pH probe record. A reflux episode is defined as an esophageal pH of less than 4 for a period of 15 to 30 seconds. The percentage of total time that the esophageal pH is less than 4 is then converted into a reflux index, which reflects the cumulative exposure of the esophagus to acid.gVt should be remembered that acid reflux is more common in the first year of life and that adult indices are not applicable to these patients. In children, the upper limit of normal is a pH below 4 less than 5.5% of the time. In infants younger than 1 year, the normal value increases to 12%.31,7.5.20Y,2",248,266 Endoscopic and histopathologic confirmation of esophagitis shows a strong correlation with abnormal pH monitoring. Ninety-five percent of adults with biopsydocumented esophagitis will have an abnormal pH probe reading.2"1"z2'3 However, esophagitis is not the only significant symptom seen in children with pathologic GER.N,131,13pH probe monitoring does not detect nonacid reflux episodes. In some studies, the presence of duodenal contents in the esophagus has been confirmed by monitoring for the presence of bilirubin in the gastroesophageal refl~xate.~",84,1"~19"24' Ore1 and Markovic reported a study of 65 children with symptoms of GERD and noted that duodenal GER increased in

Endoscopy: Endoscopy and biopsy are useful for determining the presence and degree of esophagitis and the presence of other problems such as strictures, webs, or infections. There is a poor correlation between endoscopic appearance and histopathology, so esophageal biopsy is recommended at the time of endos~opy.2~J~~,207 The presence of intraepithelial eosinophils or neutrophils and increased morphometric measures of basal cell layer thickness and papillary height are valid indicators of reflux esophagitis.2"46,20Y Nuclear Scintigraphy: In nuclear scintigraphy, technetium-labeled formula or food is orally ingested, and patients are scanned for evidence of GER or aspiration. This technology can demonstrate nonacid reflux and can provide information relative to gastric emptying.l69,18j,218,232Lack of standardized techniques and the short duration of the study limit the value of this test.218 Esophageal Manometry: Esophageal manometry studies evaluate the activity of the lower and upper esophageal sphincters and monitor the organized contractile activity of the esophagus. The technique is not used for the diagnosis of GER, but helps the clinician better understand the g yis. useful in the differential underlying p a t h ~ ~ h ~ s i o l oIt diagnosis of primary and secondary esophageal motility alterations but is used infrequently to diagnose GER in the pediatric population.Y1."0."4 Other new technologies, including fiber-optic endoscopic evaluation of swallowing with sensory testing, are also being assessed for their value in the workup of GERD in children.143,233

EVALUATION OF PEDIATRIC PATIENTS WITH SUSPECTED GASTROESOPHAGEAL REFLUX DISEASE GERD in infants and children is multifaceted and complex. The appropriate steps in the evaluation of a child suspected of having GER are controversial. The workup must include a careful history and physical examination. An upper gastrointestinal study to look for anatomic abnormalities, a 24hour pH probe monitoring study, or an impedance study and, in some cases, endoscopy with

CHAPTER

biopsy of the distal esophageal mucosa are performed as a part of the workup. Please refer to Box 71-1 for the recommendations formulated by the Society of Pediatric Gastroenterology and Nutrition.209

Conservative Therapy Infants and children who have symptoms of GER can benefit from changes in lifestyle. Smaller and frequent feeding is encouraged in babies instead of larger feedings at infrequent intervals. Thickened feedings may be helpful

71

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in those with poor weight gain, and there is evidence to support a 1- to 2-week trial of hypoallergenic formula in Positioning formula-fed babies with vomiting.g7~209~2"~246.'4Y therapy is a widely adopted, but controversial part of antireflux therapy. Although esophageal pH monitoring has demonstrated that infants have significantly less GER in the prone position than in the supine position, prone positioning has been associated with a higher rate of sudden infant death syndrome (SIDS).7"161J84 In infants from birth to 12 months old with GERD, the risk for SIDS outweighs the benefits of prone sleeping. Therefore, the American Academy of Pediatrics recommends nonprone positioning during sleep.lz6Prone positioning is acceptable in an awake baby in the postprandial period. For older children,

Box 71-1 Evaluation o f Children for Gastroesolphageal Reflux Disease 1. Recurrent vomiting. Pediatric patients with recurrent vomiting should be evaluated with a detailed history and physical examination, with special attention paid to identify warning signals. These warning signals may be bilious or forceful vomiting, failure to thrive, gastrointestinal (GI) bleeding, fever, hepatosplenomegaly, signs of raised intracranial pressure, seizures, abdominal distention, diarrhea, constipation, feeding or respiratory problems, irritability, or genetic disorders. If none of these signs are present and the infant has a normal growth pattern, no diagnostic workup is necessary. Because vomiting in this group of patients will resolve by 12 months of age, conservative treatment, including supine positioning of the infant, a short trial of hypoallergenic formula, or thickening of feedings, may be recommended. If symptoms do not improve by 18 to 24 months of age, further evaluation with upper GI contrast studies should be considered. If an infant with recurring vomiting has additional symptoms, such as failure to thrive or irritability, or if the child is older than 2 years, an upper GI series, 24hour pH monitoring, and in selected cases, upper endoscopy with biopsy to rule out the presence of esophagitis may be performed. If the infant has failure to thrive despite adequate calorie intake, tests to include a complete blood count, electrolytes, bicarbonate, urea nitrogen, creatinine, alanine aminotransferase, ammonia, glucose, urine analysis, and urine ketones and reducing substances and a review of newborn screening tests must be performed. 2. Heartburn or chest pain. These patients are older children and adolescents, and initially, a change in lifestyle, avoidance of precipitating factors, and a 2- to 4week trial of histamine H p receptor antagonists (H2RAs) or proton pump inhibitors (PPIs) is recommended. If the symptoms do not resolve, an upper GI series to rule out esophageal motor disorders, such as achalasia, and upper endoscopy with biopsy to determine the presence and severity of esophagitis should be considered. 3. Esophagitis. This diagnosis can be confirmed with upper endoscopy and biopsy, and the initial treatment consists of lifestyle changes and H2RA or PPI therapy. In patients who do not respond to therapy, an incorrect diagnosis such as eosinophilic esopha&is or inadequate treatment should be considered. Esophageal pH monitoring is useful for determining the efficacy of the treatment being used. .

-

&

4. Dysphagia or odynophapa. An upper GI study is recommended in children with difficult or painful swallowing and upper GI endoscopy with biopsy in those with suspected esophagitis. 5. Apnea or apparent life-threatening event (AI,TE). ALTE can be identified as an episode of apnea or change in color and muscle tone in an infant requiring intervention. The first event genereally occurs around the first 2 months of life and rarely after the age of 8 months. These babies carry a high risk for sudden death and have a prevalence of vomiting of 60% to 70% and abnormal esophageal pH monitoring of 40% to 80%. Despite reports that demonstrate gastroesophageal reflux (GER) as a potential cause of aprlea, investigations in unselected patients with ALTE have not demonstrated a relationship between esophageal acidification and apnea or bradycardia. If an infant's esophageal pH monitoring demonstrates gross emesis or oral regurgitation at the time of ALTE, this group of patients may benefit from antireflux therapy. In severe cases not responding to medical management, surgery may be considered. Caution is advised when diagnosing and treating GER as an underlying cause of ALTE. c e children with asthma and 6. Asthma. ~ h e ~ r e v a l e n of abnormal esophageal pH monitoring ranges between 25% and 75%. It is suggested that esophageal acid exposure in asthmatic patients may cause airway irritability and variable airway obstruction. Thus, esophageal pH monitoring plus atrial of vigorous medic4 therapy for GER is recommended for children with asthma who may have the following problems: GER disease, radiologic evidence of recurrent pneumonia, nocturnal asthma occurring more than once a week, need for a high or continuous dose of corticosteroids, and inability-to wean from medical therapy. 7. Recurrent pneumonia. Clinical studies have demonstrated that GER can cause recurrent pneumonia and lead to pulmonary fibrosis. Flexible bronchoscopy with pulmonary iavage fluid demonstrating a large percentageof lipid-laden macrophages and nuclear scintigraphy can be used to detect aspiration, but both test results lack specificity. Neurologically impaired children may have abnormal swallowing leading to aspiration. In such cases, videofluoroscopic swallowing studies or fiber-optic endoscopic swallowing evaluation may be helpful in making the diagnosis. -

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1126

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recommended conservative treatment includes weight loss if the patient is overweight and avoidance of large meals, caffeine, chocolate, and spicy

The goals of antireflux medical treatment are to control symptoms, prevent complications, and facilitate the healing of esophagitis. Acid suppressants and prokinetic agents are the two major pharmacotherapies that can be used to prevent the symptoms and damage caused by GER. Antacids neutralize gastric acid, whereas antisecretory agents, H2RAs and PPIs, reduce the secretion of gastric acid.

gastric emptying. Cisapride is a mixed serotonergic agent that reduces esophageal acid exposure. Studies have shown that cisapride improves symptom scores, esophagitis, and pulmonary function in patients with GER.6oZl7,247However, it has also been noted to potentially cause serious cardiac arrhythmias and has been withdrawn from the market in Meta-analysis and randomized conmany co~ntries.1~,6"7~ trolled trials have demonstrated no clinically important benefits of cisapride in children.13," Metoclopramide, an antidopaminergic agent, is reported to give equivocal results in some studies.149.'09 Its adverse effects. such as dyskinesia, may be irreversible. In conclusion, thk present evidence is not suff~cientto support the use of prokinetic therapy for GER, although it is widely used.

Histamine H2 Receptor An tagonists

Erythromycin

H2RAs decrease acid secretion by inhibiting the H2 receptor at the parietal cell of the stomach. Ranitidine at an oral dose of 5.0 mg/kg has been shown to control gastric pH for 9 to 10 hours in infants.152 Different randomized controlled trials in adults have demonstrated that cimetidine, ranitidine, and famotidine are effective in controlling symptoms and treating esophagitis.4832sG

Reports have suggested that erythromycin has prokinetic effects on the gastrointestinal tract at doses lower than antimicrobial levels, but no randomized controlled trials have been performed.62

Proton Pump Inhibitors

Endoluminal therapy for GERD in adults as an alternative to other surgical therapies has been a new development. Two techniques are currently under active investigation. Internal gastroplication involves the placement of sutures just below the esophageal-gastric junction by way of an endoscope.l"~Z04 The other endoluminal technique uses radiofrequency energy delivered to the distal LES tissues and gastric cardia. This technique, known as the Stretta procedure, decreases LES compliance and increases LES muscle mass, thereby limiting the TLESRs responsible for GERD.238It has shown positive clinical results in openlabel prospective clinical trials.77,'38 Islam and associates have reported the use of radiofrequency to treat recurrent GEKD in six children. The short-term follow-up results appear to be promising.l1'

Medical Therapy

PPIs bond and deactivate Hf,K+-ATPase, or proton pumps, by crossing parietal cell membranes and accumulating in secretory canaliculi.26Vhese drugs are most effective if they are administered half an hour before a meal.2I1 Some studies have demonstrated that omeprazole may be very effective in the treatment of esophagitis that has been refractory to different treatment regimens, , ~ ~drug , ~ most often reported is including H ~ R A S . ~The omeprazole at dosages of 0.5 to 3.3 mg/kg daily.57 There are potential concerns regarding prolonged use of PPIs in children and associated hypergastrinemia. Pathologists have described parietal cell hypertrophy and polyps in fundus biopsy samples from patients receiving long-term PPI treatment." Additionally, because gastrin is a trophic hormone, patients maintained on long-term PPI therapy may have the potential for the development of colon cancer if they are genetically susceptible to do so.36

Antacids and Surface Agents Antacids neutralize gastric acid and are preferred for the short-term relief of GER symptoms such as heartburn and esophagitis. Studies have shown that treatment with aluminum-containing antacids increases plasma aluminum levels in infants.'" Because other safe alternatives are available, chronic use is not recommended. Sucralfate is a surface agent that adheres to damaged mucosal lesions on the esophagus. However, there are not enough data to determine the safety and efficacy of sucralfate in children.Z0"

Prokinetic Agents In recent studies, TLESRs are considered the most important component of GER. Prokinetic agents increase LES pressure, enhance esophageal peristalsis, and accelerate

Endoscopic Treatment

Indications for Surgical Treatment Surgical management is indicated in children under the following circumstancesll7.lfl220g9223.249:

1. Failure of medical therapy. In children who have continuing symptoms such as persistent pulmonary symptoms, life-threatening events, vomiting with failure to thrive, unremitting heartburn, or an inability to wean from medical treatment despite optimal medical therapy, surgery should be considered. 2. Presence of an associated anatomic defect such as a hiatal hernia, malrotation, or diaphragmatic hernia. 3. Esophageal stricture secondary to GERD. 4. Post-esophageal atresia repair status with a recurrent stricture that does not respond to conservative medical treatment. 5. Neurologically impaired children who have diiiculty feeding and have serious reflux as an associated symptom.

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71

Gastroesophageal Keflux Disease

1127

Surgical Techniques The aim of surgical treatment in GER is to prevent episodes of reflux while avoiding complications such as dysphagia and an inability to burp and vomit. Many operative techniques have been described for children. The main techniques currently used for children include the complete-wrap Nissen fundoplication, the modified complete-wrap Nissen-Rossetti fundoplication, and partialwrap procedures, including the Thal-Ashcraft fundoplication, the Toupet fundoplication, and the Boix-Ochoa f~ndoplication."2,8',2~6,223,2~0 All these techniques attempt to achieve a physiologic high-pressure zone at the distal end of the esophagus that will prevent reflux. Over the last decade, all of these procedures have been performed via a laparoscopic approach. Long-term results after laparoscopic fundoplication seem to be similar to those after the open procedure, but the laparoscopic procedures are less invasive and appear to have fewer complications.158 a Nissen fundoplication. There are advocates for each of the techniques just mentioned. The authors prefer a floppy Nissen fundoplication under all circumstances when corto complete the wrap. Some surgeons also place four to recting GER. Other surgeons advocate for a complete-wrap fundoplication in neurologically impaired six sutures to attach the esophagus to the crura circumchildren and a partial-wrap fundoplication in neurologiferentially above the wrap to prevent herniation of the wrap or other intra-abdominal contents into the chest cally normal children with GER." Still other authors prefer a partial-wrap fundoplication in all patients." No (Fig. 71-3). The wrap is performed over an appropriately high-quality randomized studies have been conducted to sized bougie within the esophagus to prevent the credetermine which operation is best under what circumation of a tight wrap. Additionally, the fundoplication stances. The senior author has retrospectively reviewed the should be loose enough to allow a blunt-tipped clamp to results after partial-wrap Toupet fundoplication in neuropass between the fundal wrap and the esophagus conlogically normal patients and complete-wrap Nissen taining the b o ~ g i e . ~ ~ fundoplication in a similar population and found the recurrence rate to be almost twice as high with the partialThal-Ashcraf? Fundoplication wrap procedure."l This finding is consistent with results In this technique, at least 2.0 cm of the distal intrareported by Jobe and others, who also found a much abdominal portion of the esophagus is mobilized higher recurrence rate in adult patients after a partialer, pediatric surgery wrap p r ~ c e d u r e . ~ ~ W o w e vmany circumferentially. The crural defect is closed posteriorly groups have advocated the efficacy of partial-wrap procewith a figure-of-eight suture that also passes through the dures in children with acceptable recurrence rates.~z~44~54posterior esophageal wall. Anteriorly, the fundus is folded over the anterior surface of the intra-abdominal part of the esophagus and held in place with running or Open Operative Techniques interrupted nonabsorbable suture. The fundus is attached to the crura and to the esophagus to achieve a Nissen Fundoplication 270-degree anterior fundoplication. Some surgeons The operation is best performed through an upper midprefer interrupted sutures for this suture line, but most line or left subcostal incision. The left lobe of the liver is surgeons use a running suture. The anterior 270-degree mobilized, folded on itself, and retracted to the patient's surface of the intra-abdominal portion of the esophagus right. Three or more upper short gastric vessels are is wrapped by the fundus (Fig. 71-4) ."I6 divided to mobilize the fundus of the stomach. The anterior peritoneum over the gastroesophageal junction is Toupet Fundoplication incised transversely. The distal end of the esophagus is In the Toupet technique, the esophagus is dissected in mobilized circumferentially. Dissection is continued up the same manner as for a Nissen fundoplication. The into the thorax when needed to achieve at least a 3.0-cm length of the intra-abdominal portion of the esophagus. crura are approximated posteriorly to snug the hiatus. The vagus nerves are mobilized with the esophagus. A The fundus is mobilized either with or without division Penrose drain is often looped around the esophagus and of the short gastric vessels. The fundus is then pulled vagi to help mobilize the distal esophageal segment. The through the retroesophageal space and secured to the diaphragmatic crura are repaired posteriorly with nonleft and right crura with interrupted sutures. The most absorbable suture. The fundus is then fitted around the cephalad sutures of the wrap incorporate all three strucesophagus for 360 degrees. Usually, three to four intertures: fundus, crus, and esophagus. The wrap is anchored posteriorly to the crura with two or three sutures. rupted sutures are placed in the fundus and esophagus

1128

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a

.

-

Thal-Ashcraft fundoplication.

The fundus is sewn to the right and left lateral borders of the esophagus to create a 270-degree posterior wrap, with the anterior quadrant of the esophagus left free of the wrap (Fig. 71-5).258

Boix-Ochoa Technique In this technique, a 2.0- to 3.0-cm length of the intraabdominal portion of the esophagus is restored. The cmral defect is repaired and the cmra are sutured to the esophagus at the anterior and two lateral points. To restore the angle of His, a suture is passed through the fundus and the right rim of the hiatus. Multiple sutures are placed between the fundus and the anterior esophageal wall. The fundus is then tacked to the diaphragm with sutures that open the fundus like an umbrella (Fig. 71-6).sl

-

Boix-Ochoa fundoplication.

Laparoscopic Nissen Fundoplication Although all the aforementioned open techniques have been performed laparoscopically, the most commonly performed laparoscopic technique is the Nissen fundoplication. The laparoscopic approach has the technical advantages of enhanced visualization and magnification and is associated with less postoperative pain. For these reasons, laparoscopic fundoplication has become the treatment of choice in children with pathologic GER over the last decade. Safe and effective laparoscopic procedures in the treatment of GER in infants and children require advanced laparoscopic skills, as well as sophisticated electronic equipment and specialized laparoscopic instruments.

Positioning and Trocar Placement The patient is placed at the end of the operating table with the lower extremities taped in a cross-legged position or, in the case of older children (>30 kg), with the legs supported in stirrups. Proper padding must be used to prevent pressures sores or peripheral neuropathy. The bladder is emptied with a Credi maneuver in infants. Catheterization is not usually necessary in older children. After the anesthesiologist has secured the airway, an appropriately sized dilator is placed. Because dysphagia is a common early postoperative problem unless carefully avoided, the authors prefer large dilators to fully distend the esophagus and avoid the formation of a tight wrap. The patient is placed in a reverse Trendelenburg position with the left side raised slightly. This position uses gravity to pull the small bowel loops and the transverse colon away from the upper part of the abdomen and establish better exposure of the gastroesophageal junction. The operating surgeon is positioned at the end of the table. An open technique is used to insert the first trocar. The authors prefer an expandable 5-mm trocar through the deepest aspect of the umbilicus. This expandable trocar helps keep air from leaking through the trocar site during the operative procedure. A 30-degree, 4 or 5-mm scope is then passed through the trocar after the pneumoperitoneum has been developed. The other four

CHAPTER

71

Gastroesophageal Reflux Disease

1129

-- -

, -

Laparoscopic Nissen fundoplication: a plane is

developed between the right crus and the esophagus.

.

-

Trocar placement for laparoscopic Nissen

fundoplication.

trocars are placed under laparoscopic surveillance as indicated in Figure 71-7. The trocars should be secured to the abdominal wall to avoid slippage in or out during insertion or withdrawal of instruments during the procedure. Three-millimeter and 4 m m trocars are used for most children up into adolescence. A segmented, multiarticulated retractor is used to hold the left lobe of the liver away from the esophageal hiatus. Fundoplication is begun by dividing the gastrohepatic ligament. A hook cautery or scissors can be used for this purpose. Dissection is continued up to the right crus. The small vessels and the hepatic branches of the vagus nerve in the gastrohepatic ligament are divided. If the left hepatic artery is encountered in the gastrohepatic ligament, it should be preserved. A plane between the right crus and the esophagus is identified and enlarged (Fig. 71-8). The dissection is continued over the top of the esophagus while taking care to not injure the anterior vagus nerve, which is usually adherent to the esophageal muscle. A hook cautery is used to divide the short gastric vessels (Fig. 71-9). The dissection is continued proximally along the fundus to the esophagus. The left side of the esophagus is freed from the crura. This circumesophageal dissection is continued until the entire esophagus has been freed from the crura. The window behind the esophagus is enlarged. The intra-abdominal portion of the esophagus should be freed until a tension-free, 3.0-cm length of esophagus is developed. The crura are approximated posteriorly with interrupted nonabsorbable sutures. The most cephalad of the sutures should also pass through the posterior wall of the esophagus while avoiding injury to the posterior vagus. Three to five more

sutures are then applied between the esophagus and the crura to prevent potential herniation of the wrap into the chest (Fig. 71-10). Additionally, it should be noted that the longer the intra-abdominal esophagus, the less likely the patient will suffer from migration of the fundoplication wrap into the chest. The fundus is wrapped around the esophagus after pulling it through the retroesophageal window (Fig. 71-11). The wrap is secured in position with interrupted nonabsorbable sutures (Fig. 71-12). The length of the wrap should be around 2.0 cm in children and 1.5 cm in infants. Longer wraps are associated with dysphagia and an inability to burp and vomit. The abdomen is inspected for bleeding and visceral injury. The instruments and trocars are removed

.

-

Laparoscopic Nissen fundoplication: the short gastric

vessels are divided with a hook cautery.

1130

PART

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1.aparoscopic Nissen fundoplication: the hiatus is

a

-

Laparoscopic Nissen fundoplication: the

closed posteriorly and the esophagus is attached to the crura with four to six sutures.

"floppy" fundoplication is secured to the esophaaus . . for a distance of 1.5 to 2.0 cm.

and the wounds closed according to the preference of the operating surgeon.

emptying showed marked improvement of their gastric emptying with fundoplication alone." Johnson et al. s u b sequently reported a small group of children with foregut autonomic dysfunction who did not show improvement of their gastric emptying after pyloroplasty alone.l18 Pyloroplasty or antroplasty to improve gastric emptying in children with gastrointestinal autonomic dysfunction remains controversial. It is likely that the fundoplication improves gastric emptying more than pyloroplasty does.

Pyloroplasty or Antroplasty The prevalence of foregut autonomic dysfunction is high in children with GER.49,227Approximately 50% of children with GER have delayed gastric emptying. Postfundoplication complications attributed to delayed gastric emptying include early satiety, gas bloating, and recurrent GER. Pediatric surgeons have often used pyloroplasty or a derivative pyloric operation with the intent to improve gastric emptymg after fundoplication, and multiple studies have shown improved gastric emptying after In 199'7, Brown et fundoplication and pyloric s~rgery.l~~,2~2 al. reported a study in which children with delayed gastric

.

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Laparoscopic Nissen fundoplication: the fundus is

pulled through the retroesophageal window and evaluated for appropriate symmetry with the "shoeshine" maneuver.

Gastrostomy Gastrostomy is often performed in children with swallowing disorders, food refusal, chronic failure to thrive, and aspiration with swallowing. Obviously, patients with a short-term need for enteral feeding are benefited by nasogastric or nasoenteric tubes. However, patients with a long-term need for enteric feeding are best served by a gastrostomy or jejunostomy. Currently, there are multiple surgical options for enteral feeding devices, including open gastrostomy, percutaneous endoscopic gastrostomy, a gastrojejunostomytube through the gastrostomy, laparoscopic gastrostomy, lesser curvature gastrostomy, simple jejunostomy, and Roux-en-Yjejunostomy. It is controversial whether patients who need gastrostomy placement should undergo a workup for GER. Some authors believe that no workup is needed."".Their view is that either most patients with a gastrostomy will not vomit or the vomiting will resolve after gastrostomy feedings are initiated. This view is not shared by many pediatric surgeons who believe that a workup for GER should be performed before gastrostomy placement.flJ73 If significant reflux is identified, an antireflux procedure should be performed along with the gastrostomy. A third view is that patients with GER who need enteric feedings should have either a gastrojejunostomy or a jejunostomy tube placed. The disadvantage of this third view is that the patients must then be fed by drip methods, which is a much less attractive option for parents who are struggling

CHAPTER

to care for their child. Gastrojejunal tubes are frequently dislodged. Many patients live a long distance away from a medical facility for children, so dislodgement of the tube is a difficult logistic issue for them to cope with. Feeding into the stomach without an antireflux procedure also risks massive aspiration. In our experience, parental fatigue seems to be much greater as parents try to cope with the persistent vomiting and poor weight gain of their vomiting child. For these reasons, the authors prefer to mle out gross reflux before performing a gastrostomy. Patients with significant documented reflux or a predilection for postgastrostomy reflux, such as those with a large hiatal hernia or spasticity associated with increased intra-abdominal pressure, are treated by simultaneous gastrostomy and fundoplication. Richards et al. reported that two thirds of patients who gag and retch postoperatively can be identified preoperatively by a careful history. They characterized these patients as vomiters and not refluxers and advocated the avoidance of fundoplication in such patients.lg7On the other hand, Owings reviewed 138 neurologically impaired patients undergoing fundoplication. She found that 33% of these neurologically impaired patients were cured of their gagging and retching by fundoplication. Thirty-five percent did not retch either preoperatively or postoperatively. Twenty percent of the patients retched both preoperatively and postoperatively, and these symptoms developed postoperatively in 12% (Owings E, personal communication). Because two thirds of neurologically impaired patients do not have significant retching postoperatively, the authors do not withhold fundoplication from these patients. When a patient needs chronic enteral feeding, several gastrostomy options are most frequently used. Open gastrostomy can be performed with a variety of techniques. The classic technique is a Stamm gastrostomy, which is usually performed by way of a small 4cm midline incision located equidistant between the xiphoid and umbilicus.l2 The anterior wall of the stomach is identified and two purse-string sutures are placed. A tube is passed through the left upper quadrant in an appropriate position. A balloon or mushroom catheter is inserted into the stomach inside the purse-string sutures (Fig. 71-13). The purse-string sutures are tied snugly. The gastrostomy is tacked in two to four quadrants to the abdominal wall with absorbable sutures (Fig. 71-14). The gastrostomy tube is secured to the skin with a suture. The percutaneous endoscopic gastrostomy (PEG) technique was first described by Michael Gauderer, a pediatric surgeon. Excellent descriptions of the PEG PEG is technique are available in the literat~re.~~,~53'" a minimally invasive technique that usually requires a general anesthetic in the pediatric population. Its disadvantages include an inability to choose the precise position on the stomach wall to site the gastrostomy and the fact that it is a blind technique that can lead to penetration of the colon or liver. Another common method for placement of a gastrostomy tube or button is laparoscopic gastrostomy. It is a minimally invasive technique that requires a general anesthetic. However, it is versatile and can easily be performed with other laparoscopic techniques. It allows precise placement of the gastrostomy

71

Gastroesophageal Reflux Disease

1131

.

Stamm gastrostorny: one or two purse-string sutures are placed in the anterior wall of the stomach and tied snugly around the gastrostomy tube.

device at the chosen site on the stomach wall. Placement of a primary button is relatively easy with this technique. Two methods are commonly used to place a gastrostomy laparos~opically.2~~ The first method is the port site method in which a medial left upper quadrant port site is enlarged. The intra-abdominal stomach is grasped at the site of the intended gastrostomy site and pulled up through the abdominal wall. Two stabilizing sutures are then passed through the fascia, through the wall of the stomach, and back out through the fascia on the opposite side.

a

-

Stamm gastrostomy: the stomach is secured to

the abdominal wall around the gastrostomy site with three or four sutures.

1132

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.

Laparoscopic U-stitch gastrostomy: the stomach is grasped and held near the abdominal wall while two U-stitches are placed for countertraction of the anterior stomach wall. •

This stitch is repeated on the lower side of the gastrostomy wound. The stomach is pulled out through the enlarged port site and a purse-string suture applied. A hole is made in the stomach wall inside the purse-string suture. The button or catheter is inserted through the hole and the stomach is allowed to return to the abdominal cavity. The purse-string suture is tied snugly. The two stabilizing sutures are also tied snugly. The gastrostomy tube or button can be fixed externally with a suture, depending on the surgeon's preference. This port site technique is simple but has some drawbacks. The port site, which is enlarged, can break down and allow evisceration of the stomach wall through the skin site, particularly in thinwalled infants. The most common problem with this technique is that it is difficult to completely return the stomach wall back into the peritoneal cavity. The gastrostomy tract is lined with gastric mucosa, which has a greater tendency to leak and also creates a troublesome, nonclosing gastrocutaneous fistula when the gastrostomy tube or button is removed."" The other commonly used laparoscopic gastrostomy technique is the U-stitch technique. In this technique, a U-stitch is passed through the abdominal wall adjacent and medial to a left upper quadrant port site, through the stomach wall, and back out through the abdominal wall. A second U-stitch is passed parallel to the first about 1 cm apart (Fig. 71-15). A needle is passed through the trocar site and directly into the stomach, which has been inflated with air through a Levine tube placed by the anesthetist. The needle is passed into the inflated stomach through the port site inside the two U-stitches. A guidewire is passed through this needle into the stomach (Fig. 71-16). The tract is dilated over the guidewire up to

-

Laparoscopic U-stitch gastrostomy: a needle and

guidewire are passed through the port site into the inflated stomach. Dilators are passed over the guidewire up to a size 20 French.

a size 20 French. A 14French balloon button is passed over the guidewire into the stomach, with an &French dilator used to stiffen the stem of the button as it is passed into the stomach. The U-stitches are tied over the wings of the gastrostomy button or over bolsters if a gastrostomy tube is being placed (Fig. 71-17)."3 The primary disadvantage of this technique is that the stomach

a

-

Laparoscopic Ustitch gastrostomy: the U-stitches

are loosely tied over the wings of the gastrostomy button and removed on the second postoperative day.

CHAPTER

is not directly secured to the abdominal wall. However, after placing over 1000 gastrostomy buttons in this manner, lack of site fixation does not seem to be a major problem, very much like a PEG tube does not usually lead to local leakage of gastric contents into the peritoneal cavity.2j5

Complications of Antireflux Procedures Complications may be classified according to occurrence during surgery, early after surgery, or late. Complications during surgery include bleeding from the short gastric vessels, the spleen, or an aberrant left hepatic artery. In adult laparoscopic series, it has been reported that perforation of the esophagus or stomach occurs in about 1% of ~ ~have seen only one gastric perprimary p r o ~ e d u r e s . 2We foration and no esophageal perforations during primary fundoplication in over 1000 laparoscopic fundoplication procedures. Pneumothorax may occur with either open or laparoscopic techniques. The pneumothorax usually develops during dissection of the mediastinal esophagus in an effort to gain more esophageal length. The pneumothorax can be relieved by placing a small intravenous catheter in the ipsilateral chest and removing it at the end of the operation after the abdomen has been closed. Conversion rates from laparoscopic to open surgery should be less than 3% for primary operations. Many fundoplication patients experience early dysphagia when the wrap becomes edematous several days after completion of the surgical procedure. This dysphagia can be avoided by keeping the wrap loose and floppy, dividing the upper short gastric vessels, and placing the patient on a soft diet for 2 to 3 weeks postoperatively.10Y A tight hiatus can likewise cause dysphagia and must be carefully avoided. It is also important to not make the wrap too long. In the authors' experience, a wrap 3.0 cm in length is more likely to elicit dysphagia than a floppy 2.0-cm wrap. Patients with severe esophageal dysmotility can report dysphagia even with a loose wrap. Prokinetic agents may be helpful in treating this group of patients. Recurrent reflux is a common complication after fundoplication in children.82 It is often related to postoperative retching and gaggng (Ngerncham M, personal communication). It is important to recognize that postfundoplication retching is most often initiated by central nervous system abnormalities and is not primarily a gastrointestinal symptom. The most common cause of postoperative gagging is overfeeding of the patient. Zealous parents are thrilled to have a reliable mechanism to feed their semistarved child and often overfeed them. A careful history of the timing of the retching is essential in determining its underlying cause. Gagging and retching can be ameliorated by drip feedings, emptying the stomach of air before initiating feedings, treating constipation, and as previously mentioned, avoiding overfeeding of the patient. However, postfundoplication gagging and retching remain a major problem, especially in neurologically impaired children. Other postfundoplication complications include gasbloating syndrome and an inability to vomit. Most patients with a floppy Nissen fundoplication can burp and vomit within 6 months of the operative procedure (Owings E, personal communication). True gas-bloating syndrome is

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uncommon in these patients. It is usually seen in neurologically impaired patients who are aerophagic. More commonly, patients who seem bloated are constipated and have a distended, air-filled colon rather than air in their stomach. These gas-bloating symptoms can be ameliorated by treating their constipation with fiber and appropriate laxative admini~tration.~" Dumping syndrome can also follow the formation of an antireflux wrap. The fundoplication streamlines the stomach and decreases the size and reservoir function of the stomach. The addition of a pyloroplasty is associated with an even higher incidence of dumping. Patients with sweating and diarrhea after feeding should be managed by restriction of food intake, reduction in carbohydrate intake, and drip feedings.'" Small bowel obstruction is another complication that is relatively rare after laparoscopic fundoplication, but not uncommon in patients after open fundoplication. A rate of 2.6% has been reported after open surgery.82

Outcome and Results The success rates of open and laparoscopic antireflux procedures are excellent. In a multicenter review of more than 7000 children over a 20-year period, good to excellent results were achieved in 95% of neurologically normal children and 84.6% of neurologically impaired children with the use of open surgical techniques.82z1jg Similar success rates can be achieved with laparoscopic fundoplication. Chung and Georgeson reported their success with both laparoscopic Nissen and Toupet fundoplication. They showed that of patients undergoing laparoscopic Nissen fundoplication, 3.5% had recurrent symptoms at 2 years versus 6.1% of those undergoing Toupet fundoplication." The most common cause of fundoplication failure after laparoscopic repair is slippage of the wrap into the chest (Ngerncham M, personal communication). For this reason, great effort should be made to prevent slippage of the fundoplication wrap into the chest. A recent report assessing laparoscopic Thal antireflux procedures showed a silent reflux rate of 25% in symptom-free children.108 As mentioned earlier, partial-wrap fundoplications appear to be associated with a higher recurrence of GER than complete-wrap fundoplications. A common problem is knowing what to do with a child who has failed multiple fundoplications. Medical management of the reflux should be used to control the recurrent symptoms whenever possible. Radiofrequency ablation is another possibility, as suggested by Islam et al.112 If redo surgery is necessary, Roux-en-Y esophagojejunostomy has been reported to be effective, but this technique is associated with a high rate of serious complications.~%other possibility is to redo the fundoplication with a Collis-Nissen technique108 or hiatopIa~ty,~O thereby lengthening the intra-abdominal portion of the esophagus. No reliable resolution to the problem of recurrent reflux after fundoplication in children has been reported thus far. The authors prefer performing a redo Nissen fundoplication after the first recurrence, followed by a laparoscopic Collis-Nissen procedure for a second recurrence of reflux symptoms.

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SUMMARY GER is a common disorder in children a n d often requires surgical correction. GER in infants a n d children is more complex than adult GER. Failure of medical management a n d a n inability to wean from antireflux medications are the most common indications for the surgical treatment of reflux. A complete-wrap fundoplication appears to have better outcomes t h a n partial-wrap fundoplication, although this contention is controversial. Postoperative retching a n d recurrent GER are the most common a n d vexing complications of antireflux surgery.

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174. Ore1 R, Markovic S: Bile in the esophagus: A factor in the pathogenesis of reflux esophagitis in children. J Pediatr Gastroenterol Nutr 2003;36:266. 175. Orenstein SR: Effects on behavior state of prone versus seated positioning for infants with gastroesophageal reflux. Pediatrics 1990;85:765. 176. Orenstein SR: Gastroesophageal reflux. Curr Probl Pediatr 1991;21:193. 177. Orenstein SR: An overview of reflux-associated disorders in infants: Apnea, laryngospasm, and aspiration. Am J Med 2001;lll (Suppl):60S. 178. Orenstein SR, Di Lorenzo C: Postfundoplication complications in children. Curr Treat Options Gastroenterol2001; 4:441. 179. Orenstein SR, Izadnia F, Khan S: Gastroesophageal reflux disease in children. Gastroenterol Clin North Am 1999; 28:947. 180. Orlando RC: Pathogenesis of gastroesophageal reflux disease. Gastroenterol Clin North Am 2002;31(Suppl):S35. 181. Orlando RC: Pathogenesis of gastroesophageal reflux disease. Am J Med Sci 2003;326:274. 182. Ostlie D, Holcomb GW: Laparoscopic fundoplication and gastrostomy. Semin Pediatr Surg 2002;11:196. 183. Othersen HB Jr, Ocampo RJ, Parker EF, et al: Barrett's esophagus in children: Diagnosis and management. Ann Surg 1993;217:676. 184. Oyen N, Markestad T, Skaerven R, et al: Combined effects of sleeping position and prenatal risk factors in sudden infant death syndrome: The Nordic Epidemiological SIDS Study. Pediatrics 1997;100:613. 185. Ozcan Z, Ozcan C, Erinc R, et al: Scintigraphy in the detection of gastro-oesophageal reflux in children with caustic oesophageal burns. A comparative study with radiography and 24h pH monitoring. Pediatr Radiol 2001; 31:737. 186. Page M, Jeffery H: The role of gastro-esophageal reflux in the aetiology of SIDS. Early Hum Dev 2000;59:127. 187. Pan JJ, Levine MS, Refern RO, et al: Gastroesophageal reflux: Comparison of barium studies with 2 4 h pH monitoring. Eur J Radiol 2003;47:149. 188. Pandolfino JE, Richter JE, Ours T, et al: Ambulatory esophageal pH monitoring using a wireless system. Am J Gastroenterol 2003;98:740. 189. Paterson WG: The normal antireflux mechanism. Chest Surg Clin North Am 2001;11:473. 190. Patterson PE, Harding SM: Gastroesophageal reflux disorders and asthma. Curr Opin Pulm Med 1999;5:63. 191. Patwari AK, Bajaj P, Kashyp R, et al: Diagnostic modalities for gastroesophageal reflux. Indian J Pediatr 2002;69:133. 192. Pehl C, Pfeiffer A, Wend1 B, et al: The effect of decaffeination of coffee on gastro-oesophageal reflux in patients with reflux disease. Aliment Pharmacol Ther 1997;11:483. 193. Penagini R: Bile reflux and oesophagitis. Eur J Gastroenterol Hepatol 2001;13:1. 194. Pettersson GB, Bombeck CT, Nyhus LM: The lower esophageal sphincter: Mechanisms of opening and closure. Surgery 1980;88:307. 195. Ponsky JL: Percutaneous endoscopic gastrostomy: Techniques of removal and replacement. Gastrointest Endosc Clin North Am 1992;2:215. 196. Ravelli AM, Milla PJ: Vomiting and gastroesophageal motor activity in children with disorders of the central nervous system. J Pediatr Gastroenterol Nutr 1998; 26:56. 197. Richards CA, Milla PJ, Andrews PL, et al: Retching and vomiting in neurologically impaired children after fundoplication: Predictive preoperative factors. J Pediatr Surg 2001;36:1401.

198. Richter J: Do we know the cause of reflux disease? Eur J Gastroenterol Hepatol 1999;11(Suppl):S3. 199. Richter JE: Importance of bile reflux in Barrett's esophagus. Dig Dis Sci 2001;18:208. 200. Richter JE: Duodenogastric reflux-induced (alkaline) esophagitis. Curr Treat Options Gastroenterol 2004;7:53. 201. Riezzo G, Chiloiro M, Guerra V: Comparison of gastric electrical activity and gastric emptying in healthy and dyspeptic children. Dig Dis Sci 2000;45:517. 202. Rossetti M, Hell K: Fundoplication for the treatment of gastroesophageal reflux in hiatal hernia. World J Surg 1977;1:439. 203. Rothenberg SS: Laparoscopic Nissen procedure in children. Semin Laparosc Surg 2002;9:146. 204. Rothstein RI, Filipi CJ: Endoscopic suturing for gastroesophageal reflux disease: Clinical outcome with the Bard Endocinch. Gastrointest Endosc Clin North Am 2003; 13:89. 205. Rowen SJ, Gyepes MT: 'The trumpeting elephant' sign of gastroesophageal reflux. Radiology 1978;167:188. 206. Roy-Choudhung S, Ashcraft KW: Thal fundoplication for pediatric gastroesophageal reflux disease. Semin Pediatr Surg 1998;7:115. 207. Ruchelli E, Wenner W, Voytek T, et al: Severity of esophageal eosinophilia predicts response to conventional gastroesophageal reflux therapy. Pediatr Dev Path01 1999;2:15. 208. Rudolph CD: Supraesophageal complications of gastroesophageal reflux in children: Challenges in diagnosis and treatment. Am J Med 2003; 115(Suppl):150s. 209. Rudolph CD, Mazur LJ, Liptak GS, et al: Guidelines for evaluation and treatment of gastroesophageal reflux in infants and children. Recommendations of the North American Society for Pediatric Gastroenterology and Nutrition. J Pediatr Gatroenterol Nutr 2001;32(Suppl):Sl. 210. Sacher P, Stauffer UG: The Herbst triad: Report of two cases. J Pediatr Surg 1990;25:1238. 211. Sachs G: Improving on PPI-based therapy of GERD. Eur J Gastroenterol Hepatol 2001;13(Suppl):S35. 212. Sampson LK, Georgeson KE, Royal SA: Laparoscopic gastric antroplasty in children with delayed gastric emptying and gastroesophageal reflux. J Pediatr Surg 1998; 33:282. 213. Sampson LK, Georgeson KE, Winters DC: Laparoscopic gastrostomy as an adjunctive procedure to laparoscopic fundoplication in children. Surg Endosc 1996;10:1106. 214. Sanudo JR, Domenech-Mateu JM: The laryngeal primordium and epithelial lamina: A new interpretation. J Anat 1990;171:207. 215. Schalamon J, Lindahl H, Saarikoski H, et al: Endoscopic follow-up in esophageal atresia-for how long is it necessary?J Pediatr Surg 2003;38:702. 216. Schier F: Indications for laparoscopic antireflux procedures in children. Semin Laparosc Surg 2002;9:139. 217. Scott RB, Ferreira C, Smith L, et al: Cisapride in pediatric gastroesophageal reflux.J Pediatr Gastroenterol Nutr 1997; 25:499. 218. Seibert J,Byrne WJ, Euler AR, et al: Gastroesophageal reflux-the acid test: Scintigraphy or the pH probe. AJR Am J Roentgen01 2001;140:1087. 219. Somppi E, Tammela 0 , Ruuska T, et al: Outcome of patients operated on for esophageal atresia: 30 years' experience. J Pediatr Surg 1998;33:1341. 220. Sondheimer J: Expanding the definition of GE reflux. J Pediatr Gastroenterol Nutr 2002;34:511. 221. Sondheimer JM: Continuous monitoring of distal esophageal pH: A diagnostic test for gastroesophageal reflux in infants. J Pediatr 1980;96:804.

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of animal and human studies. Gastroenterology 1995; 108:1897. 244. Vandenplas Y Reflux esophagitis in infants and children: A report from the working group on gastro-esophageal reflux disease of the European Society of Paediatric Gastroenterology and Nutrition. J Pediatr Gastroenterol Nurs 1994;18:413. 245. Vandenplas Y Invited review: Asthma and gastroesophageal reflux. J Pediatr Gastroenterol Nutr 1997; 24239. 246. Vandenplas Y Diagnosis and treatment of gastroesophageal reflux disease in infants and children. Can J Gastroenterol 2000;14:26D. 247. Vandenplas Y, de Roy C, Sacre L: Cisapride decreases prolonged episodes of reflux in infants.J Pediatr Gastroenterol Nutr 1991;12:44. 248. Vandenplas Y, Goyvaerts H, Helven R, et al: Gastroesophageal reflux, as measured by 24hour pH monitoring, in 509 healthy infants screened for risk of sudden infant death syndrome. Pediatrics 1991;88:834. 249. Vandenplas Y, Hassall E: Mechanisms of gastroesophageal reflux and gastroesophageal reflux disease. J Pediatr Gastroenterol Nutr 2002;35:119. 250. Vandenplas Y, Hegar B: Diagnosis and treatment of gastro-oesophageal reflux disease in infants and children. J Gastroenterol Hepatol 2000;15:593. 251. Vandenplas Y, Sacre-Smits L: Seventeen-hour continuous esophageal pH monitoring in the newborn: Evaluation of the influence of position in asymptomatic and symptomatic babies. J Pediatr Gastroenterol Nutr 1985;4:356. 252. van der Zee DC, Arendo NJ, Bax NM: The value of 24hour pH study in evaluating the results of laparoscopic antireflux surgery in children. Surg Endosc 1999;13:918. 253. van der Zee DC, Bax KN, Ure BM, et al: Long-term results after laparoscopic Thal procedure in children. Semin Laparosc Surg 2002;9:168. 254. Vantrappen G, Texter EC Jr, Barborka CJ, et al: The closing mechanism at the gastroesophageal junction. Am J Med 1960;28:564. 255. Wadre GM, Lobe TE: Gastroesophageal reflux disease in neurologically impaired children: The role of the gastrostomy tube. Semin Laparosc Surg 2002;9:180. 256. Waring JP, Lacayo L, Hunter J, et al: Chronic cough and hoarseness in patients with severe gastroesophageal reflux disease: Diagnosis and therapy. Dig Dis Sci 1995;40:1093. 257. Watson DI, de Beaux AC: Complications of laparoscopic antireflux surgery. Surg Endosc 2001;15:344. 258. Weber TR:. Toupet fundoplication for gastroesophageal reflux disease. Semin Pediatr Surg 1998;7:121. 259. Wenzl TG, Moroder C, Trachterna M, et al: Esophageal pH monitoring and impedance measurement: A comparison of two diagnostic tests for gastroesophageal reflux. J Pediatr Gastroenterol Nutr 2002;34:519. 260. Wenzl TG, Schenke S, Peschgens T, et al: Association of apnea and nonacid gastroesophageal reflux in infants: Investigations with the intraluminal impedance technique. Pediatr Pulmonol 2001;31:144. 261. Winkelstein A: Peptic esophagitis: A new clinical entity. JAMA 1935;104:906. 262. Winter HS: Disorders of the Oesophagus. Philadelphia, WB Saunders, 1984. 263. Wolfe MM, Sachs G: Acid suppression: Optimizing therapy for gastroduodenal ulcer healing, gastroesophageal reflux disease, and stress-related erosive syndrome. Gastroenterology 2000;118(Suppl):S9. 264. Woodard-Knight L, Fudge A, TeubnerJ, et al: Aluminium absorption and antacid therapy in infancy.J Pediatr Child Health 1992;28:257.

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265. Wu JC, Chan F B Ching JY, et al: Effect of Helicobacterpylori eradication on treatment of gastro-oesophageal reflux disease: A double blind, placebo controlled, rindomised trial. Gut 2004;53:174. 266. Yoshida Y, Tanaka Y, Hirano M, et al: Sensory innervation of the pharynx and larynx. Am J Med 2000;108(Suppl):51S. 267. Zaninotto G, DeMeester TR, Schwizer W, et al: The lower esophageal sphincter in health and disease. Am J Surg 1988;155:104.

268. Zaw-Tun HA: The tracheo-esophageal septum: Fact or fantasy? Origin and development of the respiratory primordium -and esophagus.- Acta Anat ( ~ a s e i )1982; 114:l. 269. Zwischenberger JB, Alpard SK, Orringer MB: Esophagus. In Townsend CM (ed): Sabiston Textbook of Surgery, 16th ed. Philadelphia, WB Saunders, 2001.

Note: Page numbers followed by the letter f refer to figures and those followed by t refer to tables. Page numbers followed by the letter b indicate boxed material.

AaDo, (alveolar-arterial oxygen difference) in congenital diaphragmatic hernia, 938, 942-943 in respiratory failure, 135 Aarskog's syndrome, 1149 ABCDE sequence, for life support, 267-272, 268f, 270f-271f with burn patient, 385 Abdominal cocoon, 1365 Abdominal compartment syndrome hepatic hemangiomas with, 2102, 2106 in trauma patient, 302-303, 303f infantile hepatic hemangioendothelioma with, 495, 496 Abdominal packing, 301-302 Abdominal pain in intussusception, 13'24, 1325 in peptic ulcer disease, 1228-1229 multidetector computed tomography in, 35,35f Abdominal pressure. See Intra-abdominal pressure. Abdominal trauma, 295-313 appendicitis secondary to, 1502 compartment syndrome in, 302-303,303f diagnostic modalities in, 295-297, 296f gastrointestinal, 310, 3 11-312 in birth injury, 405, 405f in child abuse, 404 laparoscopic repair of, 297, 299, 300f, 313 role of pediatric surgeon in, 295, 313 seat-belt injuries in, 31 1, 31 1f intestinal stricture secondary to, 1365 to kidney, 317 to colon, 310-31 1 to diaphragm. See Diaphragm, trauma to. to kidney. See Kidney, trauma to. to liver. See Liver, trauma to. to pancreas. See Pancreas, trauma to. to small intestine, 310, 311, 311f to duodenum, 303-304, 304t, 305f-307f, 306307, 3061, 307t to spleen. See Spleen, trauma to. to stomach, 297, 310 to vasculature, 378 Abdominal wall defects of, 1157-1 167. See also Bladder exstrophy; Ectopia cordis; Gastroschisis; Omphalocele; Umbilical hernia. antenatal considerations in, 1161 associated conditions with, 1162, 1162t cryptorchidism as, 1162, 1167, 1195 clinical features of, 1161-1 163 complications of, 1166, 1167 congenital syndromes with, 1160-1 161 embryological basis of, 1158-1 160, 1159f

Abdominal wall (Continued) genetics of, 1160, 1161 historical perspective on, 1157 in prune-belly syndrome, 1158, 1781, 1781f-1783f, 1786 intestinal malrotation with, 1346 obstetric delivery with, 1161 outcome of, 1 1 6 6 1167 spectrum of, 1157-1158,1158f-1159f, 1158t treatment of, 1163-1 166, 1164f, 1166f umbilicoplasty in, 1153, 1154f, 1163, 1166 desmoid tumor of, in Gardner's syndrome, 1422 embryology of, 1158-1 159, 1159f hernia of, rectus block for repair of, 245,245f soft tissue sarcoma of, 550 as rhabdomyosarcoma, 534 transplantation of, after intestinal graft, 749 trauma to, by seat belt, 311, 311f, 346 Abdominoplasty for prune-belly syndrome, 1781, 1782f-1783f patch, 303, 303f ABI (ankle-brachial index), 377-378 Ablative instruments, 40-42 Abortion. See also Fetus, selective reduction of; Termination of pregnancy. spontaneous, 2061 Abscess (es) appendiceal, 1502, 1503 breast, 887, 888, 890 Brodie's, 2033, 2034f, 2035, 2037f cervical lymphadenitis with, 845, 845f crypt, in Hirschsprung's disease, 1529, 1529f epidural, 2009, 2010,2010f spinal, 2013 first branchial anomaly with, 867 hepatic, 1642-1644,1643f, 1645-1646,1646f intra-abdominal, in appendicitis, 1509 intracranial, 2008-2013, 2010f secondary to sinusitis, 819, 2009 lung, 1015-1017, 1017f mastoid, subperiosteal, 815 mediastinal, 1028 otitis media with, 815, 816 perianal, 1597-1598,1598f in Crohn's disease, 1458 perinephric, 324 periorbital subperiosteal, 819 periphlebitic, 2132 peritonsillar, 823, 2132 pharyngeal space, 2132 presacral, 1396 psoas, 2040 renal, 1745 retropharyngeal/parapharyngeal, 823, 823f mediastinitis secondary to, 1027 torticollis secondary to, 877 salivary gland, 837, 839 spinal epidural, 2013 Volume 1, pages 1-1140; Volume 2, pages 1141-21

Abscess(es) (Continued) splenic, 1694 in leukemia patient, 1644 subperiosteal, 2034f intracranial, 2010, 2010f periorbital, 819 thyroid, pyriform sinus tract with, 869f urachal, 1149 vitelline duct remnant with, 1148 Abuse. See Child abuse; Sexual abuse. Acardiac twinning, 82t, 85, 2080 Accelerated hyperfractionated radiation therapy, 429 Accidental injury. See Emergency management; Trauma. ACE (angiotensin-converting enzyme), 629 ACE (angiotensin-converting enzyme) inhibitors for heart failure, in neonate, 148, 150t nephrotoxicity of, 2120 Acetabular index, 2020, 2020f Acetaminophen, 237-238,238t for fever, in brain injury, 273 toxicity of, liver transplantation for, 733 Acetate, in parenteral nutrition, 206, 2061, 207 Acetic acid solution, for infected wounds, 352 Acetylcholinesterase, amniotic fluid, abdominal wall defects and, 1161 Acetylcholinesterase inhibitor, for Ogilvie's syndrome, 1496 Acetylcholinesterase staining, of rectal biopsy in Hirschsprung's disease, 1518, 1518f, 1526, 1527 in intestinal neuronal dysplasia, 1562, 1563f N-Acetylcysteine for inhalation injury, 395 for meconium ileus, 1296 for milk curd syndrome, 1365 Acetylhydrolase, necrotizing enterocolitis and, 104 Achordoma, 2102 Acid burns, 395-396 Acid ingestion. See Esophagus, caustic injury to. Acid-base balance. See also pH. carbon dioxide equilibrium and, 95, 121 in fetus, 95-96,96t in neonate, 95, 96, 96t parenteral nutrition and, 207, 208 pulmonary circulation and, 120 Acidosis. See alro Lactic acidosis; Metabolic acidosis; pH; Respiratory acidosis. in fetus, 96, 96t in malignant hyperthermia, 231, 232, 232t in neonate, 96, 96t postoperative, 99 in trauma patient, with severe bleeding, 300-301,902 oxyhemoglobin dissociation curve in, 121 pulmonary vasoconstriction caused by, 120

Acinic cell carcinoma, salivary gland, 840, 840f ACLS (Advanced Cardiac Life Support), 69 Acoustic neuroma, in neurofibromatosis type 2,679 Acquired immunodeficiency syndrome (AIDS). See also Human immunodeficiency virus (HIV) infection. blood transfusion and, 189 respiratory infections in, 1008, 1009 Acquired tolerance, 685-693, 685f-693f Acrosyndactyly, 2074, 2074f, 2075 ACTH (adrenocorticotropic hormone), 629, 633-634, 634f, 635, 637 Actinomycin (dactinomycin), 423t, 428-429 Actinomycosis cervicofacial, 848 in persistent thyroglossal duct, 870 osteomyelitis in, 2044 Activated partial thromboplastin time (APTT), 183,184t, 185, 186 Activated protein C resistance. See Protein C. Actuators, microelectromechanical, 57, 58 Acute phase proteins in sepsis, 171 interleukin-6 and, 165 sulfur amino acids in, 104 Acute respiratory distress syndrome (ARDS). See also Respiratory failure. anti-LPS monoclonal antibody and, 172 continuous venovenous hemofiltration for, 779 extracorporeal life support for, 141t lung transplant for survivor of, 769 mechanical ventilation for, 125, 127 pharmacologic adjuncts for, 127 Acute tubular necrosis after renal transplantation, 707, 710 burn-related, 384 Acyclovir after intestinal transplant, 750 for herpes simplex viral esophagitis, 1386 for post-transplant lymphoproliferative disease, 762 Addison's disease, 636637 Adenitis, cervical, 832. See also Cervical lymphadenopathy. Adenoid (pharyngeal tonsil) anatomy of, 822 EBV-related hypertrophy of, 828 middle ear effusion and, 815 sleep-disordered breathing and, 823-825, 824f Adenoid cystic carcinoma, pulmonary, 641 Adenoidectomy, 815, 824-825 Adenoma adrenal, 635 aldosterone-secreting, 636 bronchial, 641, 642f hepatocellular, 495, 498 islet cell, 1683 nipple, 888, 891 parathyroid, 858, 858f pituitary, 633, 634, 635 salivary gland, 826, 839, 839f Adenomatous polyps, 1414, 1417. See also Familial adenomatous polyposis. Adenopathy. See Lymphadenopathy. Adenosine, for supraventricular tachycardia, 151, 152t Adenoviruses as gene therapy vectors, 16, 17, 17t, 18 bronchiolitis caused by, 1004 ADH (antidiuretic hormone), in neonate, 93-94,94t

Adhesins, 158 Adhesion molecules in biliary atresia, 1611 in Hirschsprung's disease, 1525-1526 in inflammation, 159-160, 160f, 161, 165, 166 in neonate, 167 in SIRS, 168, 169, 169f in tumor invasion, 418 Adhesions abdominal. See also Intestinal obstruction, adhesions with. perihepatitis as cause of, 1645 prevention of, 1360 labial, 1903, 1942 Adipose tissue brown, 98,99, 100 inflammation of, in obesity, 1244 measurement of, 195 Adolescent patients. See also Bariatric surgery in adolescents. consent by, 258 renal transplant recipients, 711 Adrenal gland(s), 628-638 anatomy of, 628 birth injury to, 405 cortical insufficiency of, 63&637 in Allgrove's syndrome, 1113 embryology of, 628-629 fetal, 628, 630, 637 hemorrhage of infection-related, 637 neonatal, 630, 637 hyperaldosteronism and, 636 hyperplasia of ACTH oversecretion with, 635 congenital, 637, 1913, 1914t. See also Pseudohermaphroditism, female. hyperaldosteronism in, 636 nodular, 634f, 635 hypoplasia of, congenital, 637 imaging of, 629-630 incidental mass of, 637 neoplasms of cortical, 633-636, 634f, 636f medullary. See Neuroblastoma; Pheochromocytoma. physiology of, 629 Adrenal rests, 628-629 in enteric duplication cyst, 964 inguinal, 1189 Adrenalectomy, 637-638, 638f for adrenocortical tumors, 635 aldosterone-secreting, 636 for incidental mass, 637 for nodular hyperplasia, 635 laparoscopic, 637, 638 Adrenaline. See Epinephrine (adrenaline). a-Adrenergic blockers for hypertension, 2120 preoperative, for pheochromocytoma excision, 632 R-Adrenergic blockers. See Beta blockers. Adrenocorticotropic hormone (ACTH), 629, 633-634, 634f. 635,637 Adrenogenital syndrome, 637, 1913, 1914t. See also Pseudohermaphroditism, female. Adriamycin (doxorubicin), 424t, 426, 428-429 as terato-gen, esophageal atresia and, 1054, 1070 Advanced Cardiac Life Support (ACLS), 6 9 Advanced Trauma Life Support (ATLS),266 for thoracic trauma, 276-277 mannequin simulators for, 69 musculoskeletal injuries and, 339, 341 Volume 1, pages 1-1140; Volume 2, pages 1141-21

AESOP (Automatic Endoscopic System for Optimal Positioning), 49, 49t, 50 for cholecystectomy, 1639, 1640, 1640f Afibrinogenemia, congenital, 185 AFP. See Alpha fetoprotein (AFP). Afterload, 146, 147 Afterload-reducing agents, for heart failure, in neonate, 148, 150t, 151 Aganglionosis colonic. See Hirschspmng's disease. short-bowel syndrome secondary to, 1369, 1369f, 1540 small intestine, 1531, 1539-1540, 1542f-1543f vs. meconium ileus, 1293 AIDS (acquired immunodeficiency syndrome). See also Human immunodeficiency virus (HIV) infection. blood transfusion and, 189 respiratory infections in, 1008, 1009 Air embolus, pulmonary laceration with, 282 Air-leak syndrome extracorporeal life support for, 140t high-frequency ventilation and, 126 Airway. See also Aspiration, pulmonary; Larynx; Trachea. functional anatomy of, 983-984 inflammatory disease of, 830-831 inhalation injury to, 394-395 by ammonia fumes, 1084 trauma to, 275, 275t, 276, 277, 278, 282-283, 283f, 291 Airway management. See also Endotracheal intubation. in burn patient, 385 in trauma patient, 267, 268f, 272 in upper airway obstruction, 827-829 Airway obstruction. See also Respiratory distress. anesthesia-related, laryngospasm in, 223, 229,233 caustic ingestion with, 1084 clinical presentation of, 983 deep neck space infection with, 823 evaluation of, 983 facial deformities with, 806, 812 fetal, 82t, 85 foreign body. See Foreign body, airway. inhalation injury with, 395 ammonia fumes in, 1084 laryngeal anomalies with, 829-830, 829f-830f laryngoscopy with, 973 laryngotracheobronchitis with, 830 lymphatic malformation with, 2099, 2138, 2139 macroglossia with, 825 management of, 827-829 neonatal airway anatomy and, 983-984 sleep-related, 823-825, 824f obesity and, 1246, 1252 stenosis with. See Laryngotracheal stenosis; Subglottic stenosis; Tracheal stenosis. supraglottitis with, 830-831 third branchial cleft anomalies with, 868 tracheotomy for. See Tracheotomy (tracheostomy). tuberculosis with, 1003 tumors with, 644. See also Subglottic hemangioma. hemangioma as, 2103 in Hodgkin's disease, 576, 576f laryngeal, 831, 831f, 989-990, 989f teratoma as, 563, 564, 564f vascular compression with, 997-998, 1070. See also Trachea, compression of. vocal cord immobility with, 988-989

Airway pressure release ventilation, 123, 125 Airway resistance, 119-120 ALADIN syndrome, 1113 Alagille's syndrome, 732, 1613-1614 Albumin in fluid replacement, 226 for burn patient, 387, 388t in meconium, 1290-1291, 1292 intra-alveolar, for congenital diaphragmatic hernia, 945 serum calcium and, 209 nutritional status and, 195 serum-ascites gradient of, 1409 Alcohol. See Ethanol, injection of; Fetal alcohol syndrome. Aldosterone, 628, 629. See also Mineralocorticoids. excess of, 636 myocardial fibrosis caused by, 148 neonatal acid-base balance and, 96 Aldosteronoma, 636 Alemtuzamab (Campath) before transplantation, 693 for intestinal transplantation, 749 Alkali ingestion. See Esophagus, caustic injury to. Alkaline phosphatase placental, germ cell tumors and, 556 serum, osteogenic sarcoma and, 654 Alkalosis. See also Metabolic alkalosis. controlled, for brain injury, 273 hypertonic saline causing, 389 in fetus and neonate, 96t oxyhemoglobin dissociation curve in, 121 pulmonary vasodilation caused by, 120 Alkylating agents, 422, 42% Allantois, 1143, 1144f, 1145 cloaca and, 1566 Allen's test for radial artery catheter placement, 123 in hand trauma, 348 Allergic colitis, 1386 Allergy airway obstruction in, 828 fungal sinusitis in, 819 milk protein, 1386 Allgrove's syndrome, 1112-1 113 Alloderm, 390 Aloe vera, for first-degree burns, 385 Alosetron, for intestinal pseudo-obstruction, 1366 Alpha fetoprotein (AFP), 77 abdominal wall defects and, 1161 conditions with elevation of, 77, 555-556 germ cell tumors and, 555-556 ovarian, 595, 609 pineal, 673, 678 teratoma as cervicofacial, 564, 565 mediastinal, 565, 962 ovarian, 566 sacrococcygeal, 560,562 testicnlar, 567 testicular, 622, 623, 626 yolk sac tumor as, 567, 609, 622, 623,626 liver tumors and benign, 495-496,498, 499 malignant, 502, 503, 505, 510, 511 normal levels of, by age, 495, 495t, 555, 555f, 595t Sertoli-Leydig cell tumors and, 606 Aluminurn toxicity, 209 Alveolar dead space, 120. See also Dead space, pulmonary.

Alveolar proteinosis, extracorporeal life support for, 142 Alveolar rhabdomyosarcoma, genetics of, 415-416,417t, 419 Alveolar soft part sarcoma, 547 Alveolar-arterial oxygen difference (AaDo*) in congenital diaphragmatic hernia, 938, 942-943 in respiratory failure, 135 Amebiasis. See Entamoeba histolytica infection. Amelia, 2051f Amenorrhea, congenital anomalies with, 1568 vaginal agenesis as, 19361937 American Board of Surgery, 5 American Pediatric Surgical Association, 5 American Society of Anesthesiologists (ASA) fasting guidelines, 224, 224t monitoring standards, 234 patient status classification, 221-222 Amiloride, for adrenocortical hyperplasia, 636 Amino acids conditionally essential, 196, 196t, 204 essential, 196, 196t in enteral formulas, 1372 in neonatal diet, 101, 104, 108, 196 in breast milk, 202 in parenteral formulas, 204, 208 in parenteral formulas, 204, 208 for short-bowel syndrome, 212 hypercalciuria and, 209 Aminocaproic acid, during extracorporeal life support, 139 Aminophylline, necrotizing enterocolitis and, 1429 5-Aminosalicylic acid (ASA) compounds for Crohn's disease, 1455 for ulcerative colitis, 1465-1466 Amiodarone, for supraventricular tachycardia, 151, 152t, 153 Amniocentesis, 78 for diagnosis of cystic fibrosis, 1292, 1293 Arnnioreduction, for twin-twin transfusion syndrome, 82t, 85 Amniotic bands, 2075 fetoscopic intervention for, 78 Amniotic fluid. See also Oligohydramnios; Polyhydramnios. abdominal wall defects and, 1161 alpha fetoprotein in, 77 fetal fluid balance and, 92, 93f lung development and, 934,936 therapeutics delivered via, 81-82, 82t Amphotericin B for Aspergillus infection, 775, 1006 renal insufficiency secondary to, 779 Amputation, 2050-2059 congenital limb deficiency and, 2050-2054, 2051f-2055f, 2054t for purpura fulminans, 2058 for trauma, 345, 379, 2055, 2056t for tumors, 205G2058, 2056t, 2057f bone, 658,659,659f, 660,662,665, 666667 soft tissue sarcomas, 548 for vascular disease, 2058 overview of, in children, 2050 phantom phenomenon secondary to, 2058-2059 stump overgrowth secondary to, 2050, 2058 traumatic, 345, 2054-2055 replantation for, 352, 2055-2056 Anabolic steroids for chronic anemia, hepatocellular adenoma caused by, 498 for Fanconi's anemia, 179

Anal continence, 1591, 1592. Seealso Incontinence, fecal. Anal fissure, 1385, 1596-1597 constipation and, 1549, 1592, 1596, 1597 in Crohn's disease, 1458, 1465, 1597 sexual abuse as cause of, 1599 Analgesia. See Pain management. Analgesic Ladder, 236, 237f Anaphylaxis latex-induced, 232 thiopental-induced, 233 Anaplastic large cell lymphoma, 580, 582, 584 Anastomosis, virtual reality simulator for, 69 Anatomic dead space, 120 Anderson-Hynes pyeloplasty, 1734f Androblastoma, 606 Androgen insensitivity, 1914t, 19161917, 1919-1920 inguinal canal in, 1174, 1188-1 189 Androgens. See also Intersex abnormalities; Testosterone. adrenal synthesis of, 629, 1916f, 1916t breast hypoplasia and, 887 cryptorchidism and, 1197, 1198 epididymal development and, 1195 for aplastic anemia, hepatocellular adenoma associated with, 495 from ovarian tumors, 594, 595t, 604, 606, 607, 612 testicular descent and, 1193-1 194, 1194f Anemia, 178-182, 179f. See alsoAplastic anemia; Hemolytic anemias; Iron-deficiency anemia. birth injury as cause of, 405 indwelling arterial lines and, 123 postoperative apnea associated with, 223 Anencephaly, 1987,1990 Anesthesia complications of, 231-232, 232t gastrointestinal motility and, 1361 during extracorporeal life support, 138-139 epidural, 247-249, 247f, 248t fluid management with, 225-226 for diaphragmatic hernia repair, 942 for fetal surgery, 79 for fracture reduction, of hand, 352 for inguinal hernia repair, 244, 1175-1 176 in neonate hypothermia associated with, 99 physiology of, 221, 222f, 222t, 228 infiltration, 243, 244 inhalation, 227-229, 227t, 228f dose versus age, =1,222f, 228 laryngospasm associated with, 223, 229 malignant hyperthermia associated with, 231-232, 2321 intramuscular induction for, ketamine in, 239 intravenous agents in, 221, 222f, 232-233, 233f ketamine as, 238t, 239 local anesthetics for, 243, 243t metabolism of children and, 21 1, =1, 222f, 222t, 228 monitoring of, 233-235, 234f mortality associated with, 222-223 neuraxial, 243, 247-249,247f, 248t neuromuscular blocking agents with, 229-231,2301 monitoring of, 235 patient preparation programs for, 223 pediatric anesthesiologists for, 221, 222-223 physical status classification for, 221-222 physiology of, 221, 222f, 222t, 228 premedication for, 221, 224-225 preoperative evaluation for, 223

Volume 1, pages 1-1 140; Volume 2, pages 1141-2146.

Anesthesia (Continued) preoperative fluid restrictions for, 223-224, 224t. 225 regional, 243-249, 245f-247f intravenous, 244 risk of, 221-223 topical, 243, 244, 244t Aneuploidy. SPPPloidy, of cancer cells. Aneurysm (s) congenital, 21 11, 21 12f in connective tissue disorders, 2114, 2114f mycotic, 2115-2116, 2116f traumatic, 21 1 4 2 115. See also Pseudoaneurysm. intracranial, 366 venous, 2 126,2129 Aneurysmal bone cyst, 652f, 654,655f, 659 Angioblastoma of Nagakawa. See Tufted angioma. Angiofibrorna, juvenile nasopharyngeal, 821 Angiogenesis biology of, 418 corticosteroid inhibition of, 2104 in cancer, 419 in neuroblastoma, 473, 474, 475, 486 inhibition of, 422, 426427 by fenretinide, 484 in engineered tissi~es,22, 25 in hemangioma, 2095, 2104 in pathologic processes, 418-419 Angiography. SPPalso Compnted tomographic angiography; Magnetic resonance angiography (MRA). in portal hypertension, 1657 of liver tumors benign, 496, 497, 498 malignant, 504 of pulmonary embolism, 2132 of renal artery stenosis, 21 19, 21 19f, 2120 of trauma, 377 aortic, 278, 287, 290 catheter-related, 380 fracture-related, 342 renal, 319, 322, 324 upper extremity, 379 of vascular anomalies, 2103 arteriovenous malformation as, 21 13 Angioma, 546, 2094 tufted, 2094, 2098 Angiomyolipoma, renal, 1709 Angioplasty for central venous obstruction, 2124 for renal artery stenosis, 2120 for subclavian-axillaryvein thrombosis, 2131 Angiosarconla breast, 892 hepatic, 505 secondary to radiation, 497 Angiotensin, 629 Angiotensin receptor blockers, for heart failure, in neonate, 150t Angiotensin-converting enzyme (ACE), 629 Angiotensin-converting enzyme (ACE) inhibitors for heart failure, in neonate, 148, 150t nephrotoxicity of, 2120 Angle of His, 1122-1 123 Aniridia, 420-421, 446, 447, 451 Ankle fracture of, physeal, 342 tumor resection in, 666 Ankle-brachial index (ABI), 377-378 Ankyloglossia, 825, 825f Annular pancreas, 1260, 1261, 1261t, 1262, 1262f, 1263-1264, 1266, 1671 pancreatitis associated with, 1674, 1675, 1675f

Anoplasty, for perineal fistula, 1569, 1571 Anorectal achalasia, 1531 Anorectal atresia, Hirschsprung's disease with, 1528 Anorectal malformations, 15661588. See also Anus, imperforate. as imperforate anus without fistula, 1566, 1569, 1569f, 1571, 1571f-1572f, 1577-1578 associated anomalies with, 1567-1568, 1567f hypospadias as, 1567, 1894 spinal, 1810 classification of, 1566, 1566t clinical findings in, 1569, 1569f-1572f, 1571 colostography of, 1573-1574, 1573f-1574f, 1586 colostomy for, 1484, 1484f, 1485, 1485t, 1488, 1573 closure of, 1584 complications of, 1573, 1586 decision making for, 1569-1571, 1569f, 157lf, 1586 permanent, 1587 embryological basis of, 15661567 historical perspective on, 1566 incidence of, 1566 initial management of, 1569-1574, 1569f, 1571f, 1573f-1574f outcomes with, 1585-1588, 1586t, 15871, 1588t pathophysiology of, 1568-1569 reconstruction for, 1574-1585 as reoperation, 1588 basic principles of, 1574 complications of, 1585-1588 rectal prolapse as, 1586, 1596 female, 1578-1584, 1579f-1581f, 1583f-1585f, 1947-1949, 1948f in cloacal exstrophy, 1865-1866 limited anorectoplasty in, 1573 male, 1574-1578, 1575f-1578f postoperative care for, 1584-1585, 1584t teratoma with, 557, 559, 560, 564 Anorectal manometry, 15161517, 1517f, 1531 after pull-through, for Hirschsprung's disease, 1542, 1546 in constipation, 1593, 1594 in fecal soiling without constipation, 1595 in intestinal neuronal dysplasia, 1562, 1594 Anorectal myectomy, 1531, 1543-1544, 1544f-1545f Anorectal venous malformation, 2107 Anorectoplasty, posterior sagittal basic principles of, 1574 complications of, 1585-1588 in females, 1578-1582, 1579f-1581f, 1948-1949, 1948f in males, 1574-1578, 1575f-1578f limited, 1573 postoperative care with, 1584-1585, 1584t Anoxic brain damage, cerebral palsy and, 405 Antacids for gastroesophageal reflux, 1126 for peptic ulcer disease, 1229, 1230 prophylactic, stress ulcers and, 1231 Antegrade enema, 1483f, 1485 for incontinence, 1834, 1834f in cloacal exstrophy, 1866 Antegrade pyelography, of megaureter, 1772 Anthracycline, 423t-424t Antibiotic lock technique, 209-210 Antibiotic prophylaxis in heart transplantation, 761 in lung transplantation, 771, 775 to prevent necrotizing enterocolitis, 1445

Volume 1, pages 1-1140; Volume 2, pages 1141-2146

Antibiotic therapy for appendicitis, 1506, 1509 for burns intravenous, 394 topical, 383, 389-390, 389t, 396 for catheter-related infection, with parenteral nutrition, 209-2 10 for fracture, open, 344 for gastritis and peptic ulcer, 1230, 1230t for intracranial infection, 2012 for lung infection. SeeLung(s), infections of. for lymphadenitis, acute, 845 for musculoskeletal infection, 2044, 2045t for necrotizing cnterocolitis, 1438, 1439 for osteomyelitis, acute, 2037-2039, 2038t for otitis media, 815, 816 for peritonsillar cellulitis, 823 for pharyngotonsillitis, 8= for retropharyngeal/parapharyngeal infection, 823 for sepsis, 172, 173 for septic arthritis, 2040, 2041 t for urinary tract infection, 1745-1747, 1747t in Crohn's disease, 1456 in cystic fibrosis, 1011 in short-bowel syndrome, 1373-1374 Antibiotics, antitumor, 422, 423t-424t Antibodies. Set also Immunoglobulin (s); Monoclonal antibodies. for immunosuppression, with transplant heart, 761, 761f islet cell, 724, 726 liver, 738t, 739 lung, 770-771, 771t pancreas, 720 renal, 707,708-709 radiolabeled, to detect metastases, 47 Antibody-dependent cell-mediated cytotoxicity, 163 Anticardiolipin antibody, 187, 2121-2122, 2130 Anti-CD3 antibodies. See OKT3 (muromonabCD3). Anticholinergic agents for bladder dysfunction, 1824 in dysfunctional elimination syndrome, 1812 in nocturnal enuresis, 1815 in overactive bladder syndrome, 1814 neuropathic, 1809, 1810, 1810f, 1811 with posterior urethral valves, 1812 preoperative, 224, 231 with ketamine, 239 Anticholinesterase agents, with neuromuscular blockade, 231 Anticonvulsants, for head injury patients, 273, 366367 Antidiuretic hormone (ADH), in neonate, 93-94,94t Antigen matching, 695 Antihistamines for anaphylaxis, 232, 233 for transfusion reactions, 189, 190 Antilymphocyte antibodies, in transplantation. SPPalso OKT3 (muromonab-CD3); Thymoglobulin. heart, 76lf intestinal, 750 liver, 738t renal, 707, 708, 710, 712 Antimetabolites, 422, 423t Antimicrobials, topical, for bums, 383, 389-390, 389t, 396 Antioxidants for burns, 384 for systemic inflammatory response syndrome, 173 vitamins as, 198

Antiphospholipid antibodies, 2121-2122 venous thrombosis and, 187,2130 Antiplasmin, 186 Antisialagogues, preoperative, 224 Antithrombin 111, 184t, 186-187 deficiency of, 187,2130,2131 Antithymocyte globulin (ATG), 707. See also Thymoglobulin. in heart transplantation, 761, 761f in intestinal transplantation, 749 in lung transplantation, 770, 771, 771t, 774 a,-Antitrypsin as inhibitor of fibrinolysis, 186 deficiency of, 1606 in stool, protein malabsorption and, 213 Antivenin, 353 Antral atresia, 1232, 12321, 1233f Antrectomy, for stress ulcers, 1231, 1232 Antrochoanal polyp, 818 Antroplasty, gastric emptying and, 1130 ~ Anorectal entries. Anus. S P al,so abscess adjacent to, 1597-1598, 1598f in Crohn's disease, 1458 anatomy of, 1590-1591, 1590f Crohn's disease in region of, 1454, 1457, 1458, 1459, 1460, 1598 dilation program for postoperative, 1584, 15841, 1586 with fissure, 1597 embryology of, 1566-1567 fissure of. .Yep Anal fissure. fistula in, 1597, 1598, 1598f. See also Anorectal malformations. imperforate. See also Anorectal malformations. bladder exstrophy with, 1842, 1843f in prune-belly syndrome, 1783, 1786 urinary tract abnormalities with, 1822, 1823f 1824 with sacral agenesis, 1822 without fistula, 1566, 1569, 1569f, 1571, 1571f-1572f, 1577-1578 internal sphincter achalasia of, 1594 n~alpositioned constipation secondary to, 1593 measurement of, 1593 rhabdomyosarcoma of, 535 sexual abuse and, 1599 sphincter mechanism of, 1568, 1590-1592 trauma to, 312, 404, 1599 Anxiety, patient pain management and, 236,274 preoperative, 22 1, 223, 224 with burns, 394 Aorta. Ser also Great vessels, anomalies of. acute obstruction of, catheter-related, 380 adrenal rests along, 628, 631 arteritis of, 21 17 coarctation of, 1961-1964, 196'Lf-1963f subisthmic, 2120 traumatic, 277-278, 287 with ventricular septa1 defect, 153 midaortic syndrome of, 21 18, 21 19, 2120, 2121 robotic anastomosis of, ovine, 55, 56t trauma to, 276,277-278, 279,287-288, 287t, 288f-289f, 290, 31 1, 378 epidemiology of, 275, 275t, 276 seat belt causing, 346 Aortic aneurysm abdominal, congenital, 21 11 mycotic, 21 15, 2116, 2116f Aortic arch(es), 861, 862f anomalies of, 1980, 1980f-1981f, 1982 airway obstruction by, 997,998 Aortic graft, vs. engineered tissue, 21

Aortic valve congenital stenosis of, 86 endocarditis of, 21 15-21 16 Aortograph, of trauma, 278,287, 290 Aortopexy, for tracheomalacia, 998, 1070 APC (adenomatous polyposis coli) gene, 421, 519, 1420, 1421 Apert's syndrome, 22, 797-798, 797f, 799f, 800, 2074, 2074f Aphthous stomatitis, in ulcerative colitis, 1465 Aphthous ulcer, in Crohn's disease, 1453, 1454 Aplasia cutis congenita, 2063 Aplastic anemia, 179 amegakaryocytic thrombocytopenia with, 182 androgen therapy for, hepatocellular adenoma associated with, 495 in copper deficiency, 199 Apnea. See also Respiratory distress. during sleep, 823-825, 824f obesity and, 1246, 1252 gastroesophageal reflux with, 1124, 1125b mida~olamsedation and, 224 of prematurity, xanthines for, 1429 postoperative, 223 reflex, 997-998 tracheomalacia with spells of, 1070 Apnea index, 823 Apoptosis, 414 cytotoxic T lymphocytes and, 163 Hirschsprung's disease and, 1526 in tumors, 419, 426 neuroblastoma as, 475, 486, 487 Wilms' tumor as, 459 necrotizing enterocolitis and, 1433 radiation damage and, 43 Appendectomy, 1505-1509, 1507f-1508f complications of, 1509 adhesive bowel obstruction as, 1358, 1509 for spontaneous bacterial peritonitis, 1477 in Ladd procedure, 1352, 1354 in reduction of intussusception, 1333, 1336 laparoscopic, 1506, 1508, 1508f normal appendix found at, 1504, 1505, 1506, 1508 ulcerative colitis and, 1466 Appendicitis, 1501-1509 chronic, 1502 complications of, 1509 diagnosis of, 1503-1505 multidetector computed tomography in, 35,35f differential diagnosis of, 1505, 1505t vs. Meckel's diverticulum, 1309, 1505 epidemiology of, 1501-1502 gangrenous, 1502 historical perspective on, 1501 in cystic fibrosis, 1299, 1502 in Hirschsprung's disease, 1502, 1530 misdiagnosis of, 1502, 1503, 1504, 1509 outcomes of, 1509 pathophysiology of, 1502-1503 perforated, 1502, 1503, 1506, 1508-1509 hepatic abscess in, 1642-1643 in Hirschsprung's disease, 1530 preoperative pain management in, 236 presentation of, 1502-1503 recurrent, 1502, 1509 simple, 1502 spectrum of, 1502 spontaneous resolution of, 1502, 1503, 1506 treatment of, 1505-1509, 1507f-1508f. See also Appendectomy. unusual locations of, 1501 Appendicostomy, 14801, 1483, 1484, 1485 after anorectal malformation repair, 1587 urinary diversion concomitant with, 1796 Volume 1, pages 1-1140; Volume 2, pages 1141-21

Appendicovesicostomy, 1795, 1797, 1797f, 1798, 1832, 1833f robot-assisted, 53, 54t, 55 Appendix anatomical variations of, 1348, 1501 anatomy of, 1501 carcinoid tumors of, 518, 518f, 1502, 1505 embryology of, 1501 function of, 1501 histology of, in Hirschsprung's disease, 1530, 1531 in inguinal hernia, 1188 umbilical fistula to, 1146, 1149 Appendix testis. Sre Hydatid of Morgagni. Apple-peel intestinal atresia, 1276, 1276f, 1282, 1283 Aprotinin, for postoperative bleeding, after lung transplant, 772 Apt test, 1385 APTT (activated partial thromboplastin time), 183, 184t, 185, 186 APUD (amine precursor uptake and decarboxylation) tumors carcinoid. See Carcinoid tumors. neuroblastoma as, 470 Aqueductal stenosis, 82t, 85, 1995f, 2001 Arachidonic acid, 197, 197f Arbaprostil, peptic ulcers and, 1230 ARDS. See Acute respiratory distress syndrome (ARDS). Arginine, 196 necrotizing enterocolitis and, 1431 Argon beam coagulator, 41 Arrhenoblastoma, 606 Arrhythmias, cardiac extracorporeal life support for, 142 in congenital heart disease, with pulmonary hypertension, 766 in malignant hyperthermia, 231, 2321 in trauma patient, 272 myocardial contusion and, 285, 286 inhalation anesthetics and, 228, 228f, 229 neonatal, 151, 152t, 153 uncontrollable, transplantation for, 756 Arterial catheter, 123. See also Umbilical arteries, catheterization of. complications of, 380, 2058, 21 16 intraoperative, 235 Arterial disorders, classification of, 21 11, 21 12t. See also specijc. disordms. Arterial embolism, 21 15-21 17, 21 15t Arterial grafts, tissue-engineered, 24 Arterial occlusion. See also Ischemia. amputation secondary to, 2058 clinical manifestations of, 21 16 syndromes associated with, 21 17-2122, 2118f-2119f, 2118t Arterial switch operation, 1975, 1976f myocardial infarction secondary to, 38 Arterial thrombosis, 21 15-21 17, 2115t. See also Thrombosis. Arteriography. See Angiography. Arteriovenous fistula arteriovenous malformation with, 2100, 2101,2113 in Parkes-Weber syndrome, 2129 iatrogenic, 380 portal hypertension caused by, 1654 post-traumatic penile, 331 renal, 319, 324 Arteriovenous malformation (AVM), 2112-2114, 2113f classification of, 21 12 clinical features of, 2100, 2100f, 21 12-21 13 familial, 2096

Arteriovenous malformation (Continued) hepatic, 495, 497, 2102, 2112 histopathology of, 2095 in hereditary hemorrhagic telangiectasia, 2101 intracranial, 21 11, 21 13 radiosurgery for, 45, 46 management of, 2107,2113-2114 oral and pharyngeal, 826 spinal cord, 21 11 staging of, 2100 vs. hemangiopericytoma, 546 Arteritis aneurysms in, 21 15 etiologies of, 21 17 fibromuscular hyperplasia as, 2118, 2119 in Kawasaki disease, 848, 2117 stroke secondary to, 21 17 Takayasu's, 21 17, 2120 Arthralgia in Crohn's disease, 1454 in ulcerative colitis, 1464 Arthritis gonococcal, 2040,2044 in Crohn's disease, 1454 Lyme, 2044 septic, 2033,2034f, 2039-2041,2040t, 2041t Arthrodesis, after tumor resection, 666 Arthrography, 342 Arthrogryposis multiplex congenita, 1194, 2074-2075 Arthroscopy, 342 Artificial erection, 1887, 1891 Artificial sphincter, urinary, 1831, 1831f Arytenoid lateralization, 989 Arytenoidectomy, partial, 989 Arytenoidopexy, 989 ASA. See American Society of Anesthesiologists (ASA); 5-Aminosalicylic acid (ASA) compounds. Ascariasis, 1365 Ascites, 1407-141 1. See also Intraperitoneal fluid. after portoenterostomy, 1612 anatomy and pathophysiology of, 1407-1408 biliary, 1409-1410, 1409t, 1615 causes of, 1407t chylous, 1409t, 1410-1411, 2107,2140 clinical features of, 1408 diagnosis of, 1408-1409, 1408f, 1409t vs. omental cyst, 1402 hepatocellular, 1407t, 1408f, 1409, 1409t laparoscopic evaluation of, 440 necrotizing enterocolitis with, 1437, 1439, 1440 portal hypertension with, 1656, 1658 after shunt operation, 1663 primary peritonitis with, 1475, 1476 urinary, 1409t, 1411 prenatal, 1817 Asia, pediatric surgery in, 9-10 ~ A p a r a g i n a s e424t , Aspergillus infection in cancer patient, 1006, 1006f in HIV-infected patient, 1010 in transplant patient bone marrow, 781 liver, 740t lung, 775 Asphyxia at birth, gastrointestinal perforation secondary to, 1235 traumatic, 276, 291, 291f Asphyxiating thoracic dystrophy, 915-917,917f

Aspiration, pulmonary. See also Pneumonia, aspiration. anesthesia-related, preoperative fasting and, 224, 224t, 225 enteral feeding and, 203 esophageal atresia with, 1015, 1057, 1058 extracorporeal life support for, 141t gastroesophageal reflux and, 1125b laryngotracheoesophageal cleft and, 995 lung transplant for fibrosis secondary to, 767 tracheoesophageal fistula with, 1016 Aspirin anemia associated with, 180 bleeding time and, 183 for arteritis, 2117 gastroschisis and, 1160 peptic ulcers associated with, 1228 platelet function and, 183, 190 Reye's syndrome and, 238 Asplenia, 1693 Assist mode, in mechanical ventilation, 124 Asthma anesthesia-related laryngospasm and, 223 bronchiectasis in, 1013 extracorporeal life support for, 142 gastroesophageal reflux and, 1125b mechanical ventilation for, 127 misdiagnosis of, in airway obstruction, 983 obesity-related, 1246 recurrent pneumonia associated with, 1011 Astrocytoma, 671, 671t, 673 anaplastic, 678 cerebellar, 674, 674f cervicomedullary, 676 hypothalamic/chiasmatic, 676677,676s low-grade supratentorial, 677, 677f malignant supratentorial, 678 pineal region, 678 Ataxia brain tumor with, 672 cerebellar, neuroblastoma with, 469 Ataxia telangiectasia, alpha fetoprotein in, 555 Atelectasis esophageal atresia with, 1056 liquid ventilation and, 126 mechanical ventilation and, 123, 125, 126, 127, 128 mechanism of, 119 post-traumatic bronchial injury and, 283 postoperative, 291 pulmonary tumors with, 644 adenoma as, 641 rhabdomyosarcoma as, 644f ATG. See Antithymocyte globulin (ATG). ATGAM (equine antithymocyte globulin), 707 Athetoid cerebral palsy, nutritional support in, 214, 214t Atlantoaxial subluxation, torticollis secondary to, 368, 875t, 877, 877f ATLS. See Advanced Trauma Life Support (ATLS). Atracurium, 230t Atrial flutter after lung transplantation, 773 in neonate, 153 Atrial natriuretic peptide, postnatal surge in, 93 Atrial septal defect, 1964-1966, 1964f-1966f traumatic, 285, 286 Atrial septostomy during extracorporeal life support, 138 for primary pulmonary hypertension, 766 Atrioventricular nodal reentry, 151 Atrioventricular node, fetal, immune destruction of, 151 Volume 1, pages 1-1 140; Volume 2, pages 1141-21

Atrioventricular septal defect, 153, 1968-1971, 1969f-1971f Atropine for bradycardia, in propofol anesthesia, 233 for trauma patient, during intubation, 267 to prevent sialorrhea, with ketamine, 239 ~ t y ~ i cteratoid/rhahdoid al tumors, 671, 678, 679 Audiometry, 814 Auditory canal, external, 813, 814 embryology of, 865f first branchial anomaly and, 814, 862, 867-868,867f-868f laceration of, 817 Aural atresia, 814 Auricle (pinna) anatomy of, 813 displacement of, in mastoiditis, 815, 816f embryology of, 814 fabrication of, 791 preauricular cysts and, 871 trauma to, 816 Autonomic nerve tumor, gastrointestinal (GANT) , 516 Avalvulia, 2127 Avascular necrosis, femoral head fracture-related, 345 hip dysplasia and, 2021, 2022, 2023 Avastin. See Bevacirumab (Avastin). AVM. See Arteriovenous malformation (AVM). AWU mnemonic, for neurologic evaluation, 272 Axilla, lymphatic malformation in, 2099, 2099f Axillary vein, thrombosis of, 2131-2132 Azathioprine, 686,687-689, 687f, 689f, 708 for Crohn's disease, 1455 for ulcerative colitis, 1466 in heart transplantation, 760,76Ot, 761,761f in lung transplantation, 770, 771, 771t

B lymphocytes, 163, 165, 166. See also Lymphocytes. development of, 581, 581f Hodgkin's disease and, 575 in neonates, 167-168 Bacille Calmette-GuCrin, HIV infection and, 1009 Bacitracin, for burns, SNt, 390, 396 Backboard, pediatric, 346, 346f, 356 Backwash ileitis, 1463, 1471 Bacteria intestinal. See Intestine, bacteria in. toxins of, 158-159. See also Lipopolysaccharide (LPS, endotoxin). in necrotizing enterocolitis, 1436 virulence of, 158-159 in neonatal sepsis, 170 Bactroban (mupirocin), 3891 Bag-mask ventilation, of trauma patient, 267 Ballard score, 89, 90f Bands, in sepsis, 168, 171 Bannayan-Riley-Ruvalcaba syndrome, 2102 Barbiturates. See also Thiopental. highdose, in brain injury, 364 Bardet-Biedl syndrome, 1936 Bariatric surgery in adolescents. See also Obesity. compliance following, 12461248, 1247t, 1253 complications of, 1248, 1250, 1251, 1252 ethical considerations in, 260-261 outcomes of, 1242-1243, 1252-1253,1253t patient selection for, 213, 1250-1252, 1251f, 1251t

INDEX Bariatric surgery in adolescents (Continued) procedures for, 1248, 1248t, 1249f, 1250 regionalization of, 1242, 1252, 1253 robotic systems and, 52 surgeon training for, 1248 team approach to, 1243,1247, 1251,1253 Barium contrast. See also Barium enema; Esophagography; Upper gastrointestinal contrast series. contraindicated, in necrotizing enterocolitis, 1437 Barium enema. See also Enema, contrast. in appendicitis, 1504 in constipation, 1593-1594 in Hirschspmng's disease, 1515, 1516f, 1549 in intestinal neuronal dysplasia, 1562 in intussusception, 1326-1327, 1327f, 1328-1329,1329f-1330f perforation secondary to, 1328, 1329, 1334, 1334f in neonatal intestinal obstruction, 1271-1272, 1273f-1275f, 1274 with meconium ileus, 1292 Barlow maneuver, 2019, 2020,2021 Barotrauma, 123, 124, 128 after inhalation injury, 395 high-frequency ventilation and, 126 in bronchopulmonary dysplasia patient, 123 in extracorporeal support patient, 138 inverse ratio ventilation and, 125 pneumoperitoneum secondary to, 1437 ventilator settings and, 127, 128 Barrett's esophagus adenocarcinoma and, 517 after caustic injury, 108G1087 after esophageal atresia repair, 517, 1069 bile reflux and, 1039 congenital diaphragmatic hernia and, 944 in remnant, after colonic interposition, 1097 Basal cell carcinoma, sebaceous nevus progressing to, 2064 Basal cell nevus syndrome, ovarian fibromas in, 593, 605 Basal metabolic rate, 98. See also Resting energy expenditure (REE). Basiliximab (Simulect), 707, 738t, 770-771,771 t Bastionelli maneuver, 1178 Battle's sign, 366, 817 Bcl-2 protein fanlily in Hirschsprung's disease, 1526 in neuroblastoma, 475, 486 in Wilms' tumor, 459 Bear claw deformity, in Crohn's disease, 1454, 1454f Becker's nevus, of breast, 886 Beck's triad, 286 Beckwith-Wiedemann syndrome abdominal wall defects in, 1151, 1160, 1167 adrenocortical carcinoma in, 633 genetics of, 447 hepatoblastoma in, 449, 502 hyperinsulinemia in, 1680, 1681, 1682t nephrogenic rests in, 451 neuroblastoma in, 467 rhabdomyosarcoma in, 525 Wilms' tumor in, 446,447, 449, 461 Bell-clapper testis, 1205, 1207 Benchekroun procedure, 1833 Benzodiazepines for burn patient, 394, 394t for intubation, in trauma patient, 267 ketamine with, 239 opioids with, 240 preoperative, 224 Bernard-Soulier syndrome, 183, 190

Beta blockers for burn patient, 392-393, 393f for hypertension, 2120 for hyperthyroid symptoms, 853 for portal hypertension, 1658 in neonate for heart failure, 148, 150t for supraventricular tachycardia, 151, 1521, 153 preoperative, for pheochromocytoma excision, 632 Beta cell adenoma, 1683, 1685 Beta cell carcinoma, 1685 Betaprost, for pulmonary vascular disease, 766 Bevacizumab (Avastin), 426 Bianchi intestinal lengthening procedure, 1377-1378, 1377f with resection of duplication, 1395 Bicarbonate for acidosis, 96 for burn patient, 389, 396 for uric acid calculi, 1751 in local anesthetic, 244 in short-bowel syndrome, 213 parenteral nutrition and, 207 Bidirectional Glenn anastomosis, 1977 Bier block, 244 Bifid renal system, 1758, 1761. See also Duplex collecting system. Bifid sternum, 914915,914t, 915f-916f Bile. See also Cholestasis. in short-bowel syndrome, 1370, 1373 Bile acid binder, for short-bowel syndrome, 213 Bile acids, serum, 1606 Bile duct(s) adenocarcinoma in, 1420 common anomalies of pancreatic part of, 1672 perforation of, 1409-1410, 16141615 injury to, 303, 304f endoscopic treatment of, 301, 303, 304f paucity of, 1613-1614 Bile reflux, into esophagus, 1039, 1123, 1124 Bile salts, for liver dysfunction, in short-bowel syndrome, 1373 Bilhaut-Cloquet procedure, 2075 Biliary ascites, 1409-1410, 1409t, 1615 Biliary atresia, 1603-1613 associated anomalies with, 1604 classification of, 1603-1604, 1604f clinical presentation of, 1605 complications of, 1611-1613 liver abscess as, 1643 diagnosis of, 1605-1607, 1606t differential diagnosis of, 1603, 1605 etiology of, 1604 historical perspective on, 1603 incidence of, 1603 intrahepatic, 1613 nutritional complications of, 1611 nutritional support in, 212, 212t, 1611 jejunal feeding for, 1481-1482 vitamin E in, 198 outcomes with, 1610-1611 pathology of, 1604-1605, 1605f portosystemic shunt in, 1659 treatment of, 1603, 1607-1610, 1608f-1609f, 1609t liver transplantation in, 732, 732f, 739, 1608, 1609, 1610, 1612, 1613 Biliary carcinoma in choledochal cyst, 1622, 1630-1631 molecular biology of, 1631 Biliary dyskinesia, 1635, 1636, 1642 in cystic fibrosis, 1299 Volume 1, pages 1-1140; Volume 2, pages 1141-2146.

vii

Biliary hypoplasia, 1605, 1608f, 1613-1614 Biliary tumors, rhabdomyosarcoma as, 535 Biliopancreatic diversion, 1248, 1248t, 1250 Bilirubin, serum, in parenteral nutrition patient, 209 Billroth I procedure, for spontaneous gastric perforation, 1236 Billroth I1 procedure, for stress ulcers, 1231 Biobrane dressing, 390, 390f, 396 Bioluminescent imaging, 38-40 Biopsy, 437-442 bone, 655-656,655f intestinal, in graft-versus-host disease, 780 laparoscopic, 439-440 liver. See Liver, biopsy of. lung. See Lung, biopsy of. needle, 438-439,439f, 439t laparoscopically directed, 440 of fetal tissues, 78 open incisional, 442 of soft tissue sarcoma, 548 overview of, 437 robot-assisted, .53, 54t salivary gland, 837 specimen handling for, 437-438 stereotactic, of brain tumors, 673 thoracoscopic, 439, 440-442, 441f, 977-980 Bioreactors, 21-22, 23, 27 Birth injuries, 404-405, 405f diaphragmatic eventration in, 937, 946 retinal hemorrhage in, 402 to nose, 820 Birth weight, 89, 90, 9lf. See also Gestational age; Low-birth-weight infant. growth rate and, 194 obesity risk and, 1245 Bishop-Koop procedure, 1297-1298, 1297f, 1299, 1300 Bismuth, for Helicobacterpylori infection, 1386 Bisphosphonates, for malignant bone tumors, 657 Bite injuries, 352-353 BK virus infection, after renal transplant, 712 Bladder anatomical relationships of, 327 calculi in, 1748, 1750, 1752, 1753 urinary diversion and, 1800, 1801 capacity of age and, 320, 1824 measurement of, 1824 diverticulum(a) of, 1820, 1821f posterior urethral valves and, 1811, 1811f vs. ureterocele, 1763-1764, 1764f inguinal hernia sac with, 1188 pressure in, 1817-1818. See also Urodynamic evaluation. prune-belly syndrome and, 1783, 1783f-1784f, 1784 trauma to, 327-329, 328f at bladder neck, 331 diagnostic evaluation of, 319-320 grading of, 320, 321t iatrogenic, 327, 3'28 pelvic fracture with, 318, 320, 327, 328, 328f tumors of exstrophy and, 1858 neuroblastoma as, primary, 468 rhabdomyosarcoma as, 532,533, 1949 ureterocele and, 1763-1764, 1764f valve, 1818, 1818f

viii

INDEX

Bladder augmentation or replacement, 1795-1797, 1796f, 1798-1799, 1799f, 1824-1828. See also Urinary diversion (s). after bladder exstrophy repair, 1858 artificial sphincter with, 1831, 1831f autoaugmentation for, 1827, 1829f, 1835 before renal transplantation, 1835 choice of donor site in, 1825 complications of, 1799-1801, 1835-1837 continent channel for use with, 1797-1798, 1797f-1798f, 1832-1833, 1832f-1833f. See also Mitrofanoff procedure. fecal incontinence and, 1833-1834, 1834f for cloacal exstrophy, 1863 for dysfunctional elimination syndrome, 1812 for neuropathic bladder, 1809, 1810f gastric segment for, 1797, 1827, 1827f complications of, 183G1837 ileocecal, 1797, 1799, 1799f, 1825-1826,1837 indications for, 1818-1819, 1822, 1824 large bowel for, 1797, 18261827 philosophy of, 1824 physiologic considerations in, 1824-1825, 1825f small bowel for, 17961797, 1825, 1826f 1827f ureter for, 1825, 1827-1828, 1828f, 1835 with posterior urethral valves, 1812 Bladder base reconstruction, for ureterocele, 1767 Bladder dysfunction, 1805-1815, 1817-1818, 1818f. See also Bladder outlet obstruction; Urodynamic evaluation. assessment of, 1805-1807, 1805t, 1806f-1808f in dysfunctional elimination syndrome, 1812-1813, 1812f-1814f in nocturnal enuresis, 18141815 in overactive bladder syndrome, 1813-1814 neuropathic. See Neuropathic bladder. renal disease contributing to, 1818 renal transplantation and, 700, 701, 705-706 Bladder exstrophy, 1841-1 859 anatomic variants of, 1842, 1843f-1844f, 1846 clinical presentation of, 1842-1845, 1844f cloacal exstrophy and, 1158, 1158t. 1160, 116'2 covered, 1846 cryptorchidism associated with, 1195 diagnostic studies in, 1847 duplicate, 1843f, 1846 embryogenesis of, 1841-1842, 1842f genital defects in, 1845, 1845f-1846f historical perspective on, 1841 incidence of, 1841 prenatal diagnosis of, 18461847 rectal prolapse associated with, 1596, 1845 treatment of, 1847-1859 approaches in, 1847, 1847f bladder neck reconstruction in, 1852-1853, 1853f complications of, 1858 epispadias repair in, 1851-1852, 1851f-1852f Kelly repair in, 1853-1855, 1854f-1855f single-stage, 1855-1857, 1856f-1857f staged recoristruction in, 1847-1851, 1847f-1850f summary of, 1858-1859 urinary diversion in, 1847, 1857 umbilicus and, 1149, 1153

Bladder neck reconstruction, 1828-1832, 1830f-1831f in bladder exstrophy, 1852-1853, 1853f, 1858 in cloacal exstrophy, 1863 Bladder neck-rectal fistula, 1570f anorectoplasty for, 1577, 1577f-1578f Bladder outlet obstruction, 1818. See also Bladder dysfunction; Urethra, obstruction of; Urethral valves. causes of, 1811 diverticula and, 1820, 1821f in prune-belly syndrome, 1783, 1784 megaureter caused by, 1772 Bladder outlet resistance, 1817 artificial sphincter for, 1831, 1831f procedures for correction of, 1828-1832, 1830f-1831f Blalock-Taussig shunt, modified, 1972, 1977 Blastoma, pulmonary, 641-642, 643f, 6431 Bleeding. See Coagulation; Hemorrhage. Bleeding time, 183, 184t Bleomycin, for lymphangioma, 2139 Blepharoptosis, congenital, 2070-2071, 2070f Block vertebra, 2026f, 2027 Blocksom vesicostomy, 1792, 1792f Blood gases, arterial extracorporeal life support and, 135, 138 in burn patient, 386 in congenital diaphragmatic hernia, 938, 939-940,942-943,945 in malignant hyperthermia, 232 in trauma patient, 269 with thoracic injury, 277 measurement of arterial catheter for, 123 intraoperative, 235 microelectromechanical analyzer for, 58 vs. transcutaneous gas tensions, 122 neonatal acid-base imbalance and, 96 pulmonary circulation and, 120 weaning from ventilator and, 128 Blood pressure. See also Hypertension. as afterload, 146, 147 children's maintenance of, in hypovolemia, 319 hypocalcemia and, with fresh frozen plasma transfusion, 227 measurement of arterial catheter for, 123 microelectromechanical sensors for, 58 Blood transfusion. See Transfusion therapy. Blood volume. See also Hypovolemia. burns and, 384, 385,388,389 estimation of lost volume, 226 hematocrit and, 226, 226t maintenance of, central catheter and, 236 normal, 187,226 Blood-brain barrier post-traumatic edema and, 356 tumors causing breakdown of, 672 Blood-spinal cord barrier, post-traumatic edema and, 356 Blood-testis barrier, 1185, 1207 Blue rubber bleb nevus syndrome, 2102-2103, 2107 Boari flap, 327 Bochdalek hernia. See Diaphragmatic hernia, congenital (CDH). Body composition, measurement of, 195 in obese patients, 1252 Body mass index (BMI), 213, 1244-1245, 1244f, 1246, 1251f, 1252 definition of, 1243 Boerhaave's syndrome, 1047 Boix-Ochoa fundoplication, 1127, 1128, 1128f

Volume 1, pages 1-1140; Volume 2, pages 1141-2146

BOLD (blood oxygen level-dependent) imaging, 37 Bone biopsy of, 653,655-656, 655f hyperostosis of, in melorheostosis, 21 14 immature, 337-339, 338f-341f infection of. See also Osteomyelitis. tuberculous, 2042, 2044 lymphangiectasia of, 2140 maturation of, nutritional status and, 195 mineral density of bariatric surgery and, 1250, 1252 measurement of, 195 parenteral nutrition and, 207, 209 tissue-engineered, 22-23, 23f trauma to. See Fracture (s); Musculoskeletal trauma. Bone cement, 661 Bone cyst(s), 650, 650t aneurysmal, 652f, 654, 655f, 659 fracture secondary to, 651, 651f, 658 locations of, in relation to physis, 652f, 654 treatment of, 658 unicameral. See Unicameral bone cyst. Bone disease Gorham-Stout syndrome as, 2099 metabolic, in parenteral nutrition patients, 209 Bone graft after resection, of benign tumor, 661 distraction osteogenesis prior to, 22 for cleft anomaly, 806, 809 Bone marrow, lymphocyte origin in, 581 Bone marrow failure, 178-180, 179f amegakaryocytic thrombocytopenia in, 182 Bone marrow transplantation, 431-432, 779-782. See also Stem cell transplantation. complications of, 780-782, 780f lymphoproliferative disease as, 584-585 pulmonary infection as, 100G1008 veno-occlusive disease as, 431-432, 780-781, 1654 cytomegalovirus-safe blood products and, 188 for acquired aplastic anemia, 179 for Diamond-Blackfan anemia, 180 for Fanconi's anemia, 179 for neuroblastoma, 479-480, 481, 483-484, 485,486 immunological principles of, 685, 687, 688f, 689, 690f-691f, 691,692 in utero, 83t, 86 lung transplant subsequent to, 768 overview of, 779 types of, 779 vascular access for harvest in, 779 Bone metastasizing renal tumor of childhood, 450 Bone scan of osteomyelitis, 2035, 2042 of rib fractures, in child abuse, 278 of tumors, for staging, 655 Bone transport, 663,664f Bone tumors, 649-667 age of child and, 650t, 653,664-665 benign, 649,650,650t fracture through, 650, 651, 651f giant cell, 652, 653 irradiation contraindicated for, 656 locations of, 651, 652f metastases from, 652 radiography of; 654 reconstruction after resection of, 661 site of, 652 staging of, 659

Bone tumors (Continued) treatment of, 658, 659 biopsy of, 653,655-656,655f chemotherapy for, 656657,661 in metastatic disease, 666667 clinical presentation of, 653-654 commonly occurring, 649, 650t. See also specific tumors. cryotherapy for, 657-658, 660f diagnosis of, 649, 653-654 fracture associated with, 650-651, 651f at joint, 652 in telangiectatic osteogenic sarcoma, 652 through osteogenic sarcoma, 656 genetics of, 653, 653f growth and, 663, 663f, 665 incidence of, 649,650t local recurrence of, malignant, 661 locations of, in relation to physis, 651, 652f magnetic resonance imaging of, 654 malignant histologic types of, 6501, 652-653 metastasis(es) from management with, 6 6 6 6 6 7 staging and, 654-655 to lung, 645-646,645t, 666 with benign tumors, 652 minimally invasive treatment of, 658 multiplicity of, 651-652 radiation therapy for, 656, 657, 657f, 659 reconstruction after resection of, 657-658, 661-664, 662f-665f metastases and, 666667 site and, 665-666 resection of, 657-658 adjuvants in, 659 biopsy and, 655-656 compartments for, 654, 658-659,659f of benign lesions, 659, 660f of malignant lesions, 659-661, 660f-661f role of pediatric surgeon for, 649 sites of, 652 reconstruction and, 665-666 size of, 650-65 1 staging of, 654-655 Bone's criteria, 170 BOOP (bronchiolitis obliterans organizing pneumonia), 781 Bosentan, for pulmonary vascular disease, 766 Botulinum toxin for anal sphincter hypertonicity, 1530, 1543f for esophageal achalasia, 1114 Bovie. .Yep Electrocautery. Bowel. See Colon; Duodenum; Intestine; Small intestine. Bowel vaginoplasty, 1937,1939-1941,1940f BPI (bactericidal permeability-increasing) protein, 172, 173 Brachial plexus, birth injury to, 404-405 Brachydactyly, 2075 Brachytherapy, 430 for bone tumors, 659 Bracka buccal graft hypospadias repair, 18861887, 1889f-189Of, 1891, 1893, 1894, 1895 Bradykinin antagonists, for burns, 384 Brain. S ~al.~o P Central nervous system; Cerebral entries. arteriovenous malformation in, 2111,2113 infections of, suppurative, 2008-2013, 2010f-2011f positron emission tomography of, 38 stereotactic radiosurgery of, 43,44-47, 45f-46f

Brain injury, traumatic, 357-367 basic concepts for management of, 356 birth-related, 405 coagulopathy in, 273-274, 363 complications of, early, 365-367 contusion as, 356, 357-358, 358f, 365 delayed deterioration in, 365 early management of, 269,272-273,356 in "minor" injury, 365 in severe injury, 363-365, 364f-365f, 364t surgical, 364-365 epidemiology of, 357 evidence-based recommendations for, 355 in child abuse, 357, 361-362, 363,401-402, 401t, 402f outcomes with, 367 seizures secondary to, 366 in traumatic asphyxia, 291, 291f initial assessment in, 362-363, 362f outcomes after, 367 penetrating gunshot, 361 low-velocity, 358, 359f surgery for, 364 vascular injury in, 366 prevention of, 357 primary vs. secondary, 272-273,355-356 transport in, 356-357 types of, 357-362,358f-361f Brain tumors, 671-679. See also Pineal gland, tumors in region of. age at presentation with, 671, 671t clinical features of, 671-672 genetics of, 679 histologic classification of, 671 imaging of, 672-673 in Turcot's syndrome, 1422 incidence of, 671 location of, relative to tentorium, 671, 671t metastatic, 679 radiosurgery for, 45, 4 6 4 7 radiotherapy for, 46, 673 specific iypes of, 674-679, 674f-678f germinoma, 556,563,678 neuroblastoma metastatic, 469 primary, 468 teratoma, 557, 558, 563, 671t, 678 surgical intervention for, 673-674 torticollis secondary to, 877 Brainstem contusion of, 359 herniation of, in child abuse, 401 tumors of glioma as, 673, 675f, 676, 679 surgery for, 674 Branchial anomalies coexisting thyroglossal duct cyst with, 870 embryogenesis of, 861-865,862f, 863t, 864f-865f epidemiology of, 865-866 first, 814,861,862, 865, 867-868,867f-868f as parotid masses, 837-838 vs. preauricular cyst, 871 piriform sinus, 861, 863, 868-869, 869f second, 826, 861,862-863,865-867,866f thymic cyst as, 865, 872 vs. cervicofacial teratoma, 564 Branchial arch syndrome, first and second, 788-789 Branchio-oculofacial syndrome, 866 Breast (s), 885-892. See also Gynecomastia. absence of, congenital, 886, 2066 in Poland's syndrome, 886, 907, 908f, 912, 2071 rolume 1, pages 1-1140; Volume 2, pages 1141-2146.

Breast(s) (Continued) accessory, 886, 886f asymmetry of, 8 8 6 8 8 7 congenital anomalies of, 886-887, 886f-887f, 2064, 2066, 2067f-2069f, 2068-2070 development of normal, 885,885t, 888, 2064 premature, 885 ovarian tumors with, 594, 604 discharge from, 888, 888f. 890, 891 enlargement of, 887,887t, 888 fibrocystic changes in, 891 hypoplasia of, 8 8 6 8 8 7 in Poland's syndrome, 907, 912 iatrogenic injury to, neonatal, 886, 886f infections of, 887, 888, 890 masses in, 888-892, 889f, 889t, 891t pain in, 891 trauma to, 891 tuberous, 2066,2068f Breast cancer. See also Phyllodes tumor. genetics of, 593-594,892 in children, 891-892 in Klinefelter's syndrome, 2068 juvenile papillomatosis and, 891 maternal, rhabdomyosarcoma associated with, 525 Breast-feeding, 202. See also Milk, human. biliary atresia and, 212 breast reduction surgery and, 887 childhood obesity and, 1245 intestinal flora and, 1433, 1445 inverted nipples and, 886 milk allergy and, 1386 silicone implants and, 1111 Breath hydrogen test in chronic intestinal pseudo-obstruction, 1549 in necrotizing enterocolitis, 1435 Brodie's abscess, 2033, 2034f, 2035, 2037f Bronchial adenoma, 641, 642f Bronchial arteries, embolization of, 1014, 1015f Bronchiectasis, 1012-1014, 1013f in atypical mycobacterial infection, 1004 in tuberculosis, 1003, 1013 lymphedema associated with, 2141 Bronchioalveolar carcinoma, 641, 642t Bronchiolitis, 1004-1005, 1004f Bronchiolitis obliterans biopsy of, 1024f lung transplant for, 768 secondary to lung transplant, 768, 773-774, 774f, 775, 776 Bronchiolitis obliterans organizing pneumonia (BOOP),781 Bronchioloalveolar carcinoma, 957 Bronchogenic carcinoma, 641, 642 Bronchogenic cyst, 641, 642t, 955, 963-964, 963f-964f. See also Bronchopulmonary foregut malformation. lung abscess associated with, 1015 thoracoscopic excision of, 977 Bronchography, of distal bronchial injury, 283 Bronchopleural fistula, thoracoscopy and, 980 Bronchopulmonary dysplasia, 128, 135 barotrauma in patient with, 958 lung transplantation and, 769 vitamin A for, 198 vitamin E for, 198 Bronchopulmonary foregut malformation. See also Bronchogenic cyst. computed tomography of, 35 Bronchopulmonary sequestration, 955, 956, 957-958,958f

Bronchoscopy, 974-977 after lung transplant, for biopsy, 771 for foreign body removal, 974, 975-976, 975f, 977, 1012, 1014, 1015 history of, 971 in bronchiectasis, 1014 in chronic lung infection, 1014 in inhalation injury, 395 in thoracic trauma, 278, 283, 291 indications for, 974 instrumentation for, 974975,974f-975f, 975t in esophagoscopy, 1044 of lung abscess, 1016, 1017 of tumors, 644 virtual reality simulator for, 69 Bronchus(i) inflammation of, in laryngotracheobronchitis, 830 mainsten) atresia of, 958 stricture of, post-traumatic, 283 trauma to, 276, 277, 282-283, 283f epidemiology of, 275, 275t Brooke formula, 388t Broviac-type catheter, 203, 209 Brown adipose tissue, 98, 99, 100 Brown-Skquard syndrome, 368 Buccal graft hypospadias repair, 18861887, 188%-1890f, 1891, 1894, 1895 Buccal mucosal vaginoplasty, 1939 Bucket-handle fractures, 403 Budd-Chiari syndrome, 1654, 1656, 1660 Budesonide, for Crohn's disease, 1455 Bupivacaine, 243, 243t caudal, 248 epidural infusion of, 248t Rurkholdm'a c~pacia,766, 1011 Burkitt's lymphoma, 580-581 clinical presentation of, 583-584, 584f growth rate of, 583 histology of, 582, 582f intestinal involvement of, 1364 treatment of, 585-586, 588 Burn centers, 389,389t Burns, 383-397 analgesia for, 394, 394t antibiotics for, intravenous, 394 antimicrobials for, topical, 383, 389-390, 389t, 396 causes of, 383 chemical, 385, 395-396. .Yep also Esophagus, caustic ir?ju~yto. child abuse as cause of; 383, 383f, 403 complement activation by, 164 degree of, 385, 385f depth of, 384, 385-386, 385f. dressings for, 389, 390, 390f electrical, 383, 385, 396 amputation secondary to, 2058 epidemiology of, 383 escharotomy for, 385, 386, 386f excision and grafting for, 385, 389, 390-391, 391f, 39'2, 394 extracorpo1-eal life support for, 142 first aid for, 385, 386 first-degree, 385, 385f, 389 flnid resuscitation for, 385, 386-389, 388t with chemical burn, 395 with inhalation injury, 395 historical perspective on, 383 hypermetabolic response in, 391-393, 392f-393f infectious complications of, 385, 390, 394 inhalation injrny in, 386, 394-395 major, definition of, 389t ~nannequinsimulation of, 69-70

Burns (Continued) nutrition for, 393, 393t outpatient, 396 pathophysiology of, 384-385, 384f rehabilitation with, 39G397 scar formation secondary to, 397 sedatives and anxiolytics for, 394, 394t size of, 386, 387f-388f, 387t stress ulcers secondary to, 1226, 1231 transfer to burn center for, 389, 38% Busulfan, 42% Butterfly vertebra, 2027f N-Butyl-cyanoacrylate, as scleroagent, 2129

CA-125, ovarian tumors and, 602, 606 Caffeine fibrocystic breasts and, 891 gastroesophageal reflux and, 1126 Cajal, interstitial cells of Hirschsprung's disease and, 1527 mesenchymopathies of, 1547, 1548 Calcineurin inhibitors. See Cyclosporine; Tacrolimus. Calcitonin gene-related peptide, testicular descent and, 1174, 1194, 1194f Calcium. See also Hypercalcemia; Hypocalcemia. deficiency of, after massive enterectomy, 1372 heart muscle and, 147 in p a r e n t e d nutrition, 206t, 207, 208, 209 serum, in neonate, 95 supplementation with gastrointestinal polyps and, 1422 hyperosmolar, bowel mucosa and, 1429 Calcium channel blockers contraindicated in neonate, 147, 153 for esophageal achalasia, 1113-1 114 for Raynaud's syndrome, 2121 Caliceal diverticulum, 1713 infected, horseshoe kidney with, 1719 Caloric requirements, 195, 1951, 196, 225 in burn patient, 393, 393t neonatal, 96, 97-99, 98f Calorimetry, 195, 196, 210, 212 Camey enterocystoplasty, 1825, 1826f Campath. See Alemtuzamab (Campath). Camptodactyly, 2074 Camptothecins, 422, 424t, 429 Canadian pediatric surgery, 5, 6 Cancer. See also Angiogenesis; Chemotherapy, cancer; Oncogenes; Radiation therapy; Tumor suppressor genes; speczjir organ or tumor type. after renal transplantation, 712-713 chromosomal abnormalities in, 415-416, 416f, 417t, 418, 420-421 diagnostic methods for, 419, 420t clinical trials in, 426, 432 epidemiology of, 41 1-412, 41% genetic screening and, 421 hereditary disorders associated with, 420-42 1,446 histopathologic stages of, 418 history of pediatric oncology, 411, 412 hypercalcemia in, 857 immunotherapy for, 427 for nenroblastoma, 427, 485 invasive stage of, 418,419 lung infections in patient with, 1005-1008, 1006f-1007f metastasis of, 418, 419

Volume 1, pages 1-1 140; Volume 2, pages 1141-2146.

Cancer (Continued) molecular biology of, 412-419, 413f, 415t, 416f, 417t molecular diagnostics in, 419-420, 420t, 437-438 open biopsy and, 442 normal cell physiology and, 412-414, 413f ploidy in, 415, 438 risk-stratified treatment for, 425, 437, 442 stem cell transplantation for, 431-432. See also Bone marrow transplantation. in utero, 83t, 86 stereotactic radiosurgery for, 43, 44-47, 45f-46f extracranial, 43, 46, 47 in children, 4 6 4 7 targeted therapy for, 425-426 transfusion in patient with, 188 of platelets, 190 Candida infection catheter-related, 210 in immunocompromised patient, 1006, 1007 as hepatic or splenic abscess, 1644 colonic obstruction caused by, 1495 in necrotizing enterocolitis, 1436 of burns, 389, 390 parastomal, 1488 transplantation and liver, 740t lung, 771, 775 Cantrell. .Yep Pentalogy of Cantrell. Cantwell-Ransley epispadias repair, 1851-1852, 1851f, 1858 Capillary hemangioma, 2094, 2096 Capillary leak syndrome, 168, 17'2 Capillary malformation (port-wine stain), 2063, 2095, 2096, 2098, 2098f lumbosacral, 2102 management of, 2106 vs. hemangioma, 2097 with pyogenic granuloma, 2097 Capillary refill time, 348 Capillary-arteriovenous malformation, 2101 Capillary-lymphatic-venolismalformation. See Klippel-Trenaunay syndrome. Capillary-venous malformation, 2101 Capnography, 234235, 234f Capnometry, 122 Carbohydrate. See al.~oGlucose (dextrose). malabsorption of, 203, 213 metabolism of, in neonate, 100-102, 101t, 104 postoperative, 107, 107f, 108 nutritional requirements for, 195, 196-197 Carbon dioxide acid-base regulation and, 95, 121 arterial cerebral blood flow and, 139 congenital diaphragmatic hernia and, 938,939-940,942,943,945 extracorporeal support and, 138, 139 in trauma patient, 269 measurement of, 122, 123 mechanical ventilation and, 127, 128 caprlography of, 234-235, 234f end-tidal in trauma patient, 267, 277 malignant hyperthermia and, 231, 232 measurement of, 122,234235,234f extracorporeal removal of, 126 Carbonic anhydrase, 95 in erythrocytes, 121 in proximal tubules, 96 mafenide acetate as inhibitor of, 389

Carboplatin, 423t Carboxyhemoglobin, 122 Carcinoembryonic antigen (CEA), in colorectal carcinoma, 521 Carcinoid syndrome, pulmonary tumor with, 641 Carcinoid tumors gastrointestinal, 518, 518f in appendix, 518, 518f, 1502, 1505 in Meckel's diverticulum, 1311 pulmonary, 518,641 renal, in horseshoe kidney, 1718-1719 Cardiac. See also Heart. Cardiac arrest anesthesia-related, 222, 223, 227, 229 extracorporeal life support and, 135, 138, 141t, 142 in child abuse, with brain injury, 401 traumatic, 266, 277, 285 Cardiac arrhythmias. See Arrhythmias, cardiac. Cardiac catheteri~ation,21 16 Cardiac defects. Sef Heart disease, congenital. Cardiac failure. See Congestive heart failure. Cardiac output, 146-147, 147f measurement of, 123 mixed venous oxygen saturation and, 122,123 Cardiac surgery. See also Heart disease, congenital. extracorporeal life support following, 141, 141t mediastinitis secondary to, 1028 Cardiac tamponade, 277, 278, 285, 286,287f amebic abscess as cause of, 1646 chylous, 1027 during extracorporeal life support, 140 penetrating injury with, 291 vs. tension pneuniothorax, 280 Cardiogenic shock extracorporeal life support and, 135, 142 inotropic agents for, 150t, 151 Cardiomyopathy congestive, in neonate, 148, 151 extracorporeal life support for, 141t transplantation for, 754, 755, 755f, 756, 760, 762, 763 Cardiopulmonary bypass. See also Extracorporeal life support (ECLS). for aorta repair, with traumatic rupture, 290 Cardiovascular disorders. See also Heart disease, congenital. multidetector computed tomography of, 35 neonatal arrhythmias as, 151, 152t, 153 congenital heart disease as, 153 congestive heart failure as, 148, 150t, 151 renal trans~lantas risk factor for. 713 ~ardiovasculsrphysiology, neonatal, 146-147, 147f Cardioversion, 151 Carney's triad, 515-516 Carnitine, in parenteral nutrition solution, 208 Caroli's disease, 1623, 1626, 16'29, 1630 liver transplantation for, 732 Carotid artery injury to, 378, 380 during birth, 405 pseudoaneurysm of, after craniopharyngioma surgery, 677 Carpenter's syndrome, 798 Cartilage articular, 337, 338f injury to, 341, 342 repair of, 22 tissue-engineered, 22, 23, 23f

Cartilaginous tumors. See also specific tumors. commonly occurring, 650t MRI of, 654 sites of, 652 in relation to physis, 651, 652f size of, 650 wide resection of, 650, 651f CAS (computer-assisted surgery), 42 Caspases, 414, 426 in neuroblastoma, 475, 486 Caspofungin, 1007 Casting of fracture, 339f, 342, 344 Castleman's disease, 848 Catecholamines adrenal synthesis of, 628, 629 halothane interactions with, 228 in burn patients, 391-392 in neonate in perinatal period, 101, 102, 103 in postoperative period, 101, 106, 107, 107f, 108 inflammation and, 166 neuroblastoma as source of, 468, 469, 470 pheochromocytoma and, 631, 632,635 Catheterizable channels, continent, 1797-1 798, 1797f-1798f, 1832-1833, 1832f-1833f. See also Mitrofanoff procedure. Catheterization. See also Arterial catheter; Urinary catheterization; Vascular access; Venous catheter. virtual reality simulator for, 69 Cat-scratch disease, 832, 847, 847f, 1644-1645 Cauda equina syndrome, neuroblastoma with, 469 Caudal block, 247-248, 247f after sevoflurane anesthesia, 229 vs. penile block, 246, 1893 Cauliflower ear, 816 Cavernous hemangioma, 2094,2096,2099 Cavernous lymphangioma, 2138 Cavitation ultrasound aspirator, 41 CD3. See OKT3 (muromonab-CD3). CD20. See Rituximab (anti-CD20 monoclonal antibody). CD34+-selected peripheral blood stem cells, in neuroblastoma, 484 CD44, in neuroblastoma, 474, 486 CDH. See Diaphragmatic hernia, congenital (CDH). CEA (carcinoembryonic antigen), in colorectal carcinoma, 521 Cecostomy, 1483,1485 continent, 1834, 1834f Cecum, volvulus of, 1350, 1356, 1363, 1364, 1498 Celecoxib, in cancer chemotherapy, 426 Celiac disease, esophageal dysmotility in, 1112 Cell cycle, 412-413, 413f cancer chemotherapy and, 422,425 malignant transformation and, 413,417,418 radiation damage and, 43, 44 CellCept. See Mycophenolate mofetil (CellCept). Cellulitis lymphatic malformation with, 2106, 2107, 2138 lymphedema with, 2142 orbital, 818-819 peritonsillar, 822-823 retropharyngeal/parapharyngeal, 823 Cellulose, for adhesion prevention, 1360 Cement, bone, 661 Central core disease, malignant hyperthermia in, 231

Volume 1, pages 1-1140; Volume 2, pages 1141-21

Central hypoventilation syndrome (Ondine's curse) esophageal dysmotility in, 1112 genetic mutation in, 1523 Hirschsprung's disease with, 1528 neuroblastoma associated with, 467 Central nervous system. See also Brain; Spinal cord. cysts in, with gastrointestinal mucosa, 1393 germinoma of, 556,567 infections of, suppurative, 2008-2013, 2010f-2011f sarcoma of, 546 teratoma of, 557 Central pontine myelinolysis, 389 Central venous catheter, 194, 203, 204. See alto Venous catheter. caval thrombosis secondary to, 2130 deep venous thrombosis secondary to, 2131 in bone marrow transplantation, 779 in emergency trauma management, 270 infection associated with, 209-210, 2132 intraoperative, 235 technical complications of, 210 CEP-751, antitumor activity of, 426 Cephalohematoma, subgaleal, in birth injury, 405 Cerebellar ataxia, neuroblastoma with, 469 Cerebellum herniation of, brain tumor with, 672, 674f tumors of astrocytoma as, 674, 674f surgery for, 674 Cerebral contusion, 356, 357-358, 358f, 365 Cerebral edema, post-traumatic, 356, 357, 36Of, 362, 365 Cerebral palsy cryptorchidism in, 1196, 1198-1 199 difficult delivery and, 405 neuropathic bladder in, 1810-181 1 nutritional support in, 214, 214t Cerebral perfusion pressure, in trauma patient, 272, 273, 356, 363 Cerebrocostomandibular syndrome, 917-918 Cerebrospinal fluid (CSF). See also Hydrocephalus; Intracranial pressure (ICP) . head trauma and drainage of, 364, 364t leak of, 358,363,366 ear trauma with, 817 neonatal sepsis and, 171, 173 physiology of, 1996 rhinorrhea of, nasal encephalocele with, 820 tumor markers in with germinoma, 556,678 with pineal tumors, 673, 678 Cerebrovascular injuries, 366 Cerumen, 813, 814 Cervical lymphadenopathy, 844-848, 845f-847s anatomy of, 844,844f-845f atypical mycobacteria in, 1003, 1004 general approach to, 832, 844 in lymphoma, 827,833,848 in pharyngotonsillitis, 822, 823 in thyroid carcinoma, 848, 851, 854, 855, 856,857 Cervical spine. See a130 Spine. hemivertebrae in, torticollis secondary to, 877 lymphangiectasia of bone in, 2140 pseudosubluxation of, 346,369 trauma to, 267, 346, 346f 356, 368, 369-370 as birth injury, 405

xii

INDEX

Cervical vascular injuries, 378 Cervicofacial teratoma, 563-565, 563f-564f Cervicomedullary astrocytoma, 676 Cervix, adenocarcinoma of, 1951-1952 Cesarean delivery. Set a1.w EXIT (ex utero intrapartum treatment). abdominal wall defects and, 1161, 1165 after hysterotomy, for fetal surgery, 79, 80 defects managed by, 78t, 81 for teratoma cervicofacial, 564 sacrococcygeal, 560 CFTR (cystic fibrosis transmembrane conductance regulator), 12, 12f Chagas' disease, megaesophagus in, 1112 Chamberlain procedure, 577, 586f, 587 CHAOS (congenital high airway obstruction syndrome), 868 CHARGE association, 1055 Chkdiak-Higashi syndrome, ovarian tumors in, 593, 606 Chemical burns, 385,395-396 Chemoemboli~ation,of liver tumors, 511, 733 Chemosis, 819 Chemotaxins, 160, 161, 165 Chemotherapy, cancer. See also sperzfic cancer: adjuvant, 421 common agents for, 422, 423t-424t complications of hemorrhagic cystitis as, 781-782 lung infections as, 1005-1008, 1006f-1007f thyroid carcinoma as, 855 veno-occlusive disease as, 1654 principles of, 421-422, 425 radiation therapy with, 428-429 risk stratification for, 425, 437 stem cell transplantation following, 431, 779 targeted, 425-426 Chest. See also Mediastinum. evaluation of, with multidetector computed tomography, 35 rhabdomyosarcoma of, 534-535 Chest injury. Set Thoracic trauma. Chest pain, in esophageal disorders, 1125b Chest radiography in airway obstruction, 828 of burn patient, 386 of trauma, 278, 280, 280f-284f, 281, 282, 286f-288f, 292 penetrating, 291 to aorta, 287-288, 287t, 288f to diaphragm, 284, 284f, 285t, 312-313 Chest tube after core needle biopsy, 439 for chylothorax, 1027 for pneumothorax in neonate, 1021-1 023, 1022f in older child, 1023, 1023t in trauma patient, 280, 280f-281f, 281, 282 spontaneous, 1021 in trauma patient, 269, 270f, 279, 292 placement of, 269, 270f with airway injury, 283, 283f with hemothorax, 281, 282 with pleural effusion, 282 with pneumothorax, 280, 280f-281f, 281, 282 removal of, topical anesthesia for, 244 Chest wall congenital deformities of, 894-918 depression in. Set Pectus excavatum. diaphragmatic hernia with, 944 in diffuse skeletal disorders, 915-918, 917f918f in Poland's syndrome. See Poland's syndrome.

Chest wall (Continued) multidetector computed tomography of, 35 protrusion in. See Pectus carinatum. sternal, 912-915, 913f-916f, 914t soft tissue sarcoma of, 550 as rhabdomyosarcoma, 534535 trauma to, 269, 275, 279 Chiari malformation prenatal treatment and, 84 vocal cord immobility caused by, 988 Chiari I1 malformation, 1992-1993, 2066f Child abuse, 400-404, 402f-403f. See also Sexual abuse. burns in, 383,383f, 403 chylothorax in, 1025 chylous ascites in, 1410 emergency management in, 265 epidemiology of, 400 fractures in, 347,40lt, 402-403 rib, 278, 279, 403, 404 head injury in, 357, 361-362, 363, 401-402,401t outcomes with, 367,402 seizures secondary to, 366 legal aspects of, 400 ophthalmologic evaluation in, 363 pancreatitis in, acute, 1673 presentation of, 400-401,401t primary peritonitis secondary to, 1475 rectal injury in, 312 vaginal injury in, 312 Child-Pugh score, 1658, 1664, 1664f Children's Oncology Group (COG), 432,445 Chimeric proteins. See Fusion genes and proteins. Chlamydia pneumoniae, 1002-1003 Chlamydza trachomatis, perihepatitis caused by, 1645 Chloral hydrate, for burn patientq, 394t Chloride in fluid therapy, 225 in parenteral nutrition, 206, 206t, 207, 208 Choanal atresia, 819, 819f Choking, in esophageal motor disorders, 1110 Cholangiocarcinoma, 505 Cholangiography in biliary atresia, 1607 in biliary hypoplasia, 1607, 1608f in inspissated bile syndrome, 1614, 1614f of choledochal cyst, 1625-1626, 1625f with pancreas divisum, 1677, 1677f of choledocholithiasis, 1638-1639, 1638t, 1639f, 1642 Cholangitis after portoenterostomy, 1609, 1611-1612, 1613 cholelithiasis with, 1637 sclerosing in ulcerative colitis, 1464, 1464f liver transplantation for, 732 Cholecystectomy, 1637-1642, 1638f-1641f, 1638t, 1642t for biliary dyskinesia, 1636, 1642 for gallbladder polyps, 1636-1637 for hydrops of gallbladder, 1636 in hemolytic anemias, 181, 182, 1635-1636, 1641 in short-bowel syndrome, prophylactic, 1371 robot-assisted, 53, 54t, 1639, 1640f simulation software for laparoscopy in, 68 Cholecystitis acalculous, 1635, 1636, 1637 calculous, 1637. See also Cholelithiasis. Cholecystokinin, for liver dysfunction, in short-bowel syndrome, 1373 iolume 1, pages 1-1140; Volume 2, pages 1141-21

Cholecystolithotomy, 1637 Choledochal cyst, 1620-1631 anatomic classification of, 1620, 1621f carcinoma arising in, 1622, 1630-1631 clinical presentation of, 1624-1625, 1625f diagnosis of, 1625-1626 etiology of, 1622-1623, 1623f historical perspective on, 1620 intrahepatic, 1620, 1629 liver abscess secondary to, 1643 liver transplantation and, 7% pancreatitis and, 1624, 1625, 1631, 1672-1673, 1677, 1677f pathology of, 1620-1622 prenatal diagnosis of, 1623-1624, l623f surgical management of, 1626-1629, 1627f-1628f outcomes of, 1629-1631 timing of, 1624 Choledochocele, 1620, 1621, 1621f etiology of, 1623 surgical treatment of, 1628-1 629 Choledocholithiasis, 1638-1639, 1638f; 1638t, 164'2 pancreatitis associated with, 1672, 1674, 1675 Cholelithiasis, 1635-1636, 1637 after ileal resection, 1371, 1635, 1636 complications of, 1637 in bone marrow transplant patients, 780, 1642 in cystic fibrosis, 1299, 1635 in hemolytic anemias, 181, 182, 1635-1636, 1637, 1641, 1642, 1673, 1693, 1698 nonsurgical treatment of, 1637 pancreatitis and, 1637, 1642, 1672, 1673 parenteral nutrition and, 209, 1635, 1636, 1637, 1673 surgical treatment of, 1637-1642, 1638f-1641f, 1638t, 1642t Cholestasis in chronic graft-versus-host disease, 782 in necrotizing enterocolitis, 1443 liver transplantation for, 732-733, 732f parenteral nutrition and, 196, 204, 206, 209, 1373 stoma for bile drainage in, 1482 surgical lesions with, in intbncy, 1603, 1613-1615, 1614f. Set ~ L Y OBiliary atresia; Choledochal cyst. Cholesteatoma, of middle ear, 816 Cholestyramine for diarrhea, in short-bowel syndrome, 1373 for short-bowel syndrome, 213 Choline magnesium tl-isalicylate, 238, 238t Cholylsarcosine, 1373 Chondroblastoma, 652, 652f, 654, 659, 665 Chondrocytes, in tissue engineering, 22, 23f Chondrogladiolar deformity, 904, 905,905f Chondroma periosteal, 659 pulmonary, 515-516 Chondromanubrial deformity, 904, 005, 906f, 907 Chondromyxoid fibroma, 652f Chondrosarcoma, 652,653 cryotherapy for, 660f glucose intolerance with, 654 in hereditary multiple exostoses, 651 in Maffucci syndrome, 2129 resection of, 651f Chordae tendineae, injury to, 286, 286f.

I

! ! I I

I I

!

Chordee epispadias with, 1858 hypospadias with, 1870, 1879, 1880, 1887, 1890f curvature repair in, 1887-1888, 1891, 1891f-1892f, 1895 preservation of urethral plate and, 1884, 1885f, 1886 sex assignment surgery and, 1927, 1929f penile torsion with, 1907 urethral duplication with, 1904 Chorioangiopagus, 85 Choriocarcinoma, 555, 556 extragonadal, 568 hepatic, 505 pineal region, 678 ovarian, 594t, 595, 595t, 607, 609 testicular, 622 Chorionic villus sampling, 78 Choristoma, 826 Choroid plexus tumors, 671, 678-679 sarcomas, 546 Chromaffin cells, 628, 629 Chromium, 198t, 199,206 Chromosomal abnormalities fetal karyotyping and, 78 in cancer, 415-416,416f, 417t, 418, 420-421 diagnostic methods for, 419, 420t Chronic granulomatous disease, liver abscesses in, 1643, 1643f Chyle, composition of, 1026, 2141 Chylothorax, 1024-1027, 1025f, 2140-2141. See also Thoracic duct. thoracoscopic treatment of, 977, 980 traumatic, 290, 10241025, 1026, 1027 in birth injury, 405, 1026 Chylous ascites, 1409t, 1410-141 1, 2107, 2140 Chyluria, 2140 CIC (clean intermittent catheterization), 1824. Set also Continent catheterizable channels; Urinary diversion (s). in dysfunctional elimination syndrome, 1812 with neuropathic bladder, 1808, 1809, 1810, 1810f, 1811 with posterior urethral valves, 1812 Cidofovir, for laryngeal papilloma, 990 Cimetidine for gastroesophageal reflux, 1126 for peptic ulcer disease, 1229, 1230 unilateral thelarche caused by, 888 Circumcision, 1905-1906 complications of, 331, 1905, 1906, 1906f in chronic graft-versus-host disease, 782 penile block for, 246-247, 247f topical anesthesia for, 244 urinary tract infection and, 1741, 1905 Cirrhosis biliary atresia with, 1605, 1610, 1611 biliary hypoplasia with, 1614 choledochal cyst with, 1622 hepatocellular carcinoma and, 502, 503 in cystic fibrosis, 766 liver transplantation for, 732-733 portal hypertension with, 1652, 1656, 1657, 1658, 1661, 1665 primary peritonitis with, 1475, 1476 transjugular portosystemic shunt in, 1387 with esophageal varices, 1387 Cisapride for adhesion prevention, 1360 for chronic intestinal pseudo-obstruction, 1549 for gastroesophageal reflux, 1126 for postoperative ileus, 1361 Cisatracurium, 230t Cisplatin, 423t, 428

Cisterna chyli, 1025, 1025f, 1026 embryology of, 2137, 2138f Citrate toxicity, 188, 227, 273 Citrulline, dependency on parenteral nutrition and, 1371 Clam cystoplasty, 1824, 1825, 1826f Clavicular fracture in birth injury, 404 in child abuse, 403 Clear cell sarcoma of kidney, 450, 454, 454t, 455,460, 461 Cleft anomalies, 788-792, 788f-792f. See also Craniofacial anomalies. adenotonsillar hypertrophy in, 824 classification of, 788, 788f middle ear effusions associated with, 815 of lip and palate, 803-812, 2062 associated anomalies with, 811-812 embryology of, 803 ethnic differences in, 803 etiology of, 805 genetic counseling about, 806, 806t orthodontic appliances for, 806 prenatal repair of, 83t, 86 submucous, 812 surgical correction of, 805-809,807f-810f revisions of, 809-811,811f teratoma with, 557 variations in, 803, 804f unusual, 803,805,805f Cleft hand, 2073 Clefts, branchial, 861, 862f, 863t. See also Branchial anomalies. Clinical Risk Index for Babies (CRIB), 91 Clinical trials, 259 for cancer, 426,432 Clinodactyly, 2074 Cloaca embryology of, 1566-1567 persistent, 1566, 1566t, 1571, 1571f-1572f, 1945, 1947, 1947f cutaneous vesicostomy with, 1791-1792 in prune-belly syndrome, 1786 postoperative care with, 1584, 1585 reconstruction for, 1578, 1579f-1581f, 1580-1582, 1583, 1584, 1947-1949, 1948f urologic problems secondary to, 1585, 1588, 1588t Cloacal exstrophy, 1149, 1158, 1158t, 1160, 1162, 1842, 1843f, 1859-1865, 1860f-1863f, 1862t continent urinary reservoir for, 1798 sex assignment surgery in, 261 Clonal exhaustion-deletion, 691-693, 6935 696 Clonidine caudal, 248 epidural infusion of, 248, 248t with sevoflurane anesthesia, 229 Closing capacity, 118f, 119, 128 Closing membrane, 861, 863 Clostridium difJicilecolitis, 1387 in bone marrow transplant patient, 780 Clostridium species, necrotizing enterocolitis and, 1433,1436 Clotting factors. See Coagulation factors. Cloverleaf skull, 798, 798f Clubfoot, 2024-2025, 2024f Clubhand, 2073 CMV. See Cytomegalovirus (CMV) infection. Coagulation, tests of, 183, 184t, 185 Coagulation cascade, 184f Coagulation disorders, 183, 185-187, 185t thrombosis in, 2130 trauma patient with, 274

Coagulation factors, 184f deficiencies of, 183,185-186, 185t blood loss with, 226 in head trauma, 274 natural anticoagulants and, 186-187 synthesis of, 186 tests of, 183, 184t, 185 Coagulopathy. See also Thrombocytopenia. in systemic inflammatory response syndrome, 172 in trauma patient, 273-274 brain injury and, 273-274, 363 with severe bleeding, 300-301, 302 mesenteric venous thrombosis in, 2130 neuroblastoma with, 469, 481, 482 renal vein thrombosis in, 1754 Cocaine necrotizing enterocolitis and, 1429-1430 tetracaine with, 244, 244t Coccidioides infection, 1010 osteomyelitis in, 2044, 2045f Cochlea anatomy of, 813 dysplasia of, 814 temporal bone fracture and, 817 Cochlear implant, 814-815 Cockett's syndrome, 2127 Cocoon, abdominal, 1365 Codeine, 240, 240t for diarrhea, 1373 Codman's triangle, 654 COG (Children's Oncology Group), 432, 445 Cohen cross-trigonal ureteral reimplantation, 1748f Cold, common, 818 Colectomy for Crohn's colitis, 1457-1458, 1459 for familial adenomatous polyposis, 1421-1422 for ulcerative colitis, 1464, 1466, 1467, 1468, 1469 history of, 1462-1463 Colitis. See also Enterocolitis; Necrotizing enterocolitis, neonatal; Ulcerative colitis. allergic, 1386 amebic, liver abscess secondary to, 1645 Crohn's. 1457-1458. 1459 ileoanal pouch in, 1457, 1458, 1471 eosinophilic, 1599 indeterminate, 1457, 1466-1467 infectious bloody diarrhea in, 1387 Clostridium difficik in, 780, 1387 pseudomembranous, in Hirschsprung's disease, 1529 Collagen. See also Connective tissue disorders. in burn dressing, 390 Collis-Nissen fundoplication, 1069, 1133 Coloanal venous malformation, 2107 Colon atresia and congenital stenosis of, 1275, 1493-1 495, 1494f vs. Hirschsprung's disease, 1519 with Hirschsprung's disease, 1493, 1495, 1528 duplications of, 1391, 1395-1397, 1396f-1397f malrotatjon of. See nLso Intestinal rotation and fixation. in prune-belly syndrome, 1786 nutrient absorption by, 137'2

Volume 1, pages 1-1140; Volume 2, pages 1141-2 146.

xiv

INDEX

Colon (Continued) obstruction of, 1363-1366, 1493-1498, 1494f-1495f, 1497f-1499f. See also Hirschsprung's disease; Intestinal obstruction; Intussusception; Meconium ileus. in reverse rotation, 1348, 1349f, 1356 polyps of. See Polyp(s), gastrointestinal. segmental dilatation of, congenital, 1498 stricture(s) of, 1364, 1495-1496, 1495f in cystic fibrosis, 1300 postoperative, in Hirschsprung's disease, 1546 stromal tumors of, 515 tissue-engineered, 25, 25f, 26 transit time in, studies of, 1594 trauma to, 310-31 1 varices of, 1655 vascular malformations in, 1598 volvulus of, 1363-1364, 1498, 1499f Colon conduit, 1793-1794 Colon interposition esophageal, 1095-1097, 1096f, 1098t for caustic strictures, 1088-1089, 1089f, 1089t for short-bowel syndrome, 1376, 1376f Colonic manometry, 1595 Colonic neobladder, 1827 Colorectal carcinoma, 518-522, 519t, 52Of-521f, 1364, 1496 colonic obstruction by, 1364, 1496 familial adenomatous polyposis and, 421, 519, 1419-1420, 1421 hereditary nonpolyposis, 520 in Crohn's disease, 519-520, 1459-1460 in ulcerative colitis, 519, 1459-1460, 1464, 1464f in urinary diversion, 520, 1837 juvenile polyposis and, 1417 Colostogram, of anorectal malformation, 1573-1574, 1573f-1574f, 1586 Colostomy. See also Enterostoma(s). choices for, 1482f, 1484f, 1485, 1485t complications of, 1489-1490, 1489f, 1489t parastomal hernia as, 1363, 1489 for anorectal malformations. See Anorectal malformations, colostomy for. for refractory constipation, 1595 in chronic intestinal pseudo-obstruction, 1549 in Crohn's disease, 1458 in Hirschsprung's disease, 1485, 1488, 1489f leveling, 1530, 1533 indications for, 1483-1484, 1483f stoma care in, 1488 takedown of, 1488-1489 technical aspects of, 1488 Coma, 272. See also Consciousness. emergency management with, 272 in diffuse axonal injury, 359 Combretastatin, 426 Common cold, 818 Commotio cordis, 276, 285 Compartment syndrome abdominal hepatic hemangiomas with, 2102, 2106 in trauma patient, 302-303, 303f infantile hepatic hemangioendothelioma with, 495, 496 in burned extremities, 386 in musculoskeletal trauma, 344-345, 349 in vascular trauma, 379, 381 Complement system, 164-165, 164f in neonate, 168, 170 macrophage activation and, 161 phagocytosis and, 160, 163

Computed tomographic angiography of cerebral trauma, penetrating, 358,366 of renal trauma, 319 of vascular trauma, 377, 378f aortic, 288, 290 iatrogenic, 380 Computed tomographic cystography, of bladder trauma, 320 Computed tomography (CT), 3 4 3 6 as virtual reality data source, 63, 64f, 67-68 for needle biopsy, 438, 439 for thoracoscopic biopsy, 441, 441f in image-guided radiation therapy, 429, 430 in image-guided surgery, 42 in PET/CT scanning, 38, 39f multidetector, 35, 35f of appendicitis, 1504 of fetus, 77 of salivary glands, 836 of trauma abdominal, 295-296, 296f, 297, 311-312 to bladder, 319, 320 to duodenum, 304,305t, 306,306t to kidney, 319, 320, 323, 324, 325 to pancreas, 308, 308f, 308t, 309, 3091, 310 to ureter, 320, 326 brain for initial assessment, 362-363, 362f, 365, 366, 367 in child abuse. 402 type of injury And, 357, 358, 358f-361f, 359, 361 musculoskeletal, 342 spinal, 368, 369 thoracic, 278, 281, 283 to aorta, 288, 289f, 290 to diaphragm, 284-285 to pericardium, 287 of tumors bone, for staging, 655 brain, 672 three-dimensional, 34, 35-36, 36f for preoperative planning, 67-68,68f Computer-assisted surgery ( C A ), 42 Concussion, cerebral, 357, 359, 365, 367 Condyloma acuminata, 1599 Conformal radiation therapy, 429 Congenital adrenal hyperplasia, 637, 1913, 1914t. See also Pseudohermaphroditism, female. Congenital heart disease. See Heart disease, congenital. Congestive heart failure after heart transplant, 762 anthracycline therapy and, in Wilms' tumor patients, 461 arteriovenous malformation with, 2100, 2107,2112,2113 in Parkes-Weber syndrome, 2129 benign liver tumors with, 495, 496, 497 bronchopulmonary sequestration with, 957 causes of, 150t extracorporeal life support for, 134135, 140, 141, 141t, 142 in neonate, 148, 150t, 151, 153 in pulmonary vascular disease, 766 medications for, 150t renal artery stenosis with, 2118, 2120 transplantation for, 756 traumatic, 278 tumor-related with cardiac teratoma, 565 with hemangioma, 2097, 2102, 2105f, 2106 Volume 1, pages 1-1 140; Volume 2, pages 1141-21

Conjoined twins, 2079-2091 anesthetic management for, 2085 classification of, 2080, 2081f, 2081t clinical experience with, 2090-2091 embryogenesis of, 2080 ethical issues regarding, 2083-2084 heteropagus (parasitic), 2079, 2080, 2091 hindgut duplications in, 1396 historical perspective on, 2079 incidence of, 2079 obstetric management of, 2080-2082 organ system reconstruction in abdominal wall, 2089 central nervous system, 2086 gastrointestinal system, 2086-2087 genitourinary system, 2087, 2088f, 2089 heart, 2087 liver and pancreaticobiliary system, 2086 skeletal system, 2089 skin, 2083, 2084f, 2085 prenatal diagnosis of, 2080, 2081f preoperative diagnostic studies of, 2082-2083,2082t, 2083f preoperative planning for, 2085 survival of, prior to separation, 2079-2080 timing for separation of, 2084-2085 Connective tissue. See Soft tissue(s). Connective tissue disorders. See also Ehlers-Danlos syndrome; Marfan's syndrome. arterial disease in, 21 14, 21 14f inguinal hernia in, 1188 maternal, neonatal heart block and, 151 Consciousness. See also Coma. traumatic brain injury and, 359, 362, 363 Consent, 258, 259 for sex assignment surgery, 261-262 Constipation, 1592-1595 acute, 1592 anorectal malformations and, after repair, 1569, 1586, 1586t, 1587 chronic, 1592-1595, 1593t sphincter hypertrophy in, 1813 definition of, 1592 diet and, 1592, 1594 functional, 1592, 1593t idiopathic, 1549-1550, 1549t, 1550f, 1550t, 1594-1595 vs. appendicitis, 1505 vs. Hirschsprung's disease, 1516f, 1519, 1549-1550, 1550t in Hirschsprung's disease at presentation, 1593, 1594 postoperative, 1541-1542, 1543f, 1545, 1546 ultrashort, 1531 in intestinal neuronal dysplasia, 1561, 1562, 1563 voiding dysfunction secondary to, 1813, 1813f, 1814 Continence. See also Incontinence. fecal, 1591, 1592 Continent catheterizable channels, 1797-1798, 1797f-1798f, 1832-1833, 1832f-1833f. See also Mitrofanoff procedure. Continent stomas, 1488 appendicostomy as, 1587 Continent urinary reservoirs, 1791, 1795, 1798-1799,1799f, 1826 Continuous positive airway pressure (CPAP), 125 Contractility, cardiac, 146, 147 inotropic agents and, 148, 150t, 151

Contrast studies. See also Barium contrast; Enema; Esophagography; Upper gastrointestinal contrast series. BOLD functional MRI, 37 in necrotizing enterocolitis, 1437-1438 ultrasound, 33-34, 34f Copper, 198t, 199,206 Cor pulmonale, laryngomalacia with, 986 Cord blood, endogenous opioids in, 105 Core needle biopsy, 438-439,439f, 439t laparoscopically directed, 440 thoracoscopically directed, 980 Cornelia de Lange syndrome, 1111,1498 Corner fractures, 403 Coronary artery aneurysms, 21 15 Coronary artery disease, in graft, 754, 762,763 Corpus callosotomy, 2007 Corpus luteum cysts, 601 Corticosteroid therapy antenatal, congenital diaphragmatic hernia and, 939 calcium losses caused by, 207 cancer chemotherapy with, 424t for Addison's disease, 637 for airway obstruction, 828, 830 for anaphylaxis in latex sensitivity, 232 thiopental-induced, 233 for arteritis, 21 17 for biliary atresia, postoperative, 1609-1610, 1609t for bone cyst, unicameral, 658 for bronchiolitis obliterans organizing pneumonia, 781 for congenital adrenal hyperplasia, 1920-1921 for congenital diaphragmatic hernia, 939, 945 for Crohn's disease, 1455, 1458 for Diamond-Blackfan anemia, 180 for esophageal injury, caustic, 1083, 1085, 1086, 1088 for hemangioendothelioma, hepatic, 496 for hemangioma, 2104, 2104f subglottic, 994, 995 vaginal, 1951 for idiopathic (immune) thrombocytopenic purpura, 183,1693 for intussusception, 1323, 1327-1328 for pulmonary fibrosis, 767-768 for transfusion reactions, 189, 190 for ulcerative colitis, 1464, 1466, 1467 in acute respiratory distress syndrome, 127 in brain injury, 363 in brain surgery, 674 in septic shock, 173 in spinal cord injury, 370 in transplantation, 686, 687-688, 687f, 708 diabetes secondary to, 724 heart, 760, 760t, 761 intestinal, 749, 750 liver, 737, 738t, 739 lung, 769,771, 771t pancreas, 721 renal, 495, 708, 710 maternal fetal hydrops and, 83 fetal lungs and, 117 necrotizing enterocolitis and, 1444 neonatal, hyperglycemia and, 102 peptic ulcer disease caused by, 1226, 1228, 1229 Pneumocystis pneumonia and, 1007, 1008

Corticotropin-releasing hormone (CRH), 629, 633,635,637 Cortisol, 628, 629. See also Glucocorticoids. elevation of in burn patients, 391-392, 393 in Cushing's syndrome, 633-635, 634f postoperative, 106, 107 Cotton-Myer subglottic stenosis grading system, 991,99lf, 993 Cough, 827,828,829,830,831 chylothorax caused by, 1025 Counseling. See Genetic counseling; Prenatal counseling. Cowper's duct cyst, 1819, 1820f, 1903 CPAP (continuous positive airway pressure), 125 Cranial defects, tissue-engineered repair of, 22,23 Cranial neuropathy brainstem glioma presenting as, 676 branchial anomaly with, 866 traumatic, 363 after basilar skull fracture, 366 Cranial suspensory ligament, 1193,1194f Craniectomy strip, 795-796 therapeutic decompressive, 365 Craniofacial anomalies. See also Cleft anomalies. distraction osteogenesis for, 2063 middle ear effusions associated with, 815 reconstruction for, 787-800 computer-assisted planning for, 67-68, 68f for clefts, 788-792, 788f-792f for craniosynostosis nonsyndromic, 793-796, 793f-795f syndromic, 793,796800,796f-800f history of, 787 principles of, 787-788, 788f sleep apnea in, 824, 825 vs. positional deformations, 794 Craniopharyngioma, 677, 677f Craniosynostosis nonsyndromic, 793-796, 793f-795f syndromic, 793, 796800, 796f-800f Creactive protein, 171 Cremasteric contraction reflex, 1196 testicular torsion and, 1205 CRH (corticotropin-releasing hormone), 629, 633,635,637 CRIB (Clinical Risk Index for Babies), 91 Cricoid cartilage, 984 Cricoid split anterior, 992, 992t posterior, 989 Cricopharyngeal disorders, 1110 Cricopharyngeus, birth injury to, 405 Cricothyrotomy, 828 in trauma patient, 267 Cricotracheal resection, 992, 992f-993f, 993-994 Crohn's colitis, 1457-1458, 1459 Crohn's disease, 1453-1460 anal fissure in, 1458, 1465, 1597 appendicitis in, 1505 clinical features of, 1454, 1454t bloody diarrhea as, 1387 colon carcinoma in, 519-520, 1459-1460 diagnosis of, 1454-1455, 1455f epidemiology of, 1453 etiology of, 1453 Meckel's diverticulum in, 1305 medical treatment of, 1455-1456 pancreatitis in, 1672 pathology of, 1454, 1454f Volume 1, pages 1-1140; Volume 2, pages 1141-21

Crohn's disease (Continued) perianal, 1454,1457,1458, 1459, 1460 fistula in, 1598 surgical treatment of, 1456-1458, 1456t, 1457f outcomes of, 1458-1459, 1458f-1459f, 1459t vs. indeterminate colitis, 1457, 1466-1467 Crossed renal ectopia, 1717, 1719-1720, 1720f Crossmatching for transplantation, 695-696 intestinal, 747 renal, 702 Cross-trigonal ureteral reimplantation, 1748f for megaureter, 1775 Croup, 828, 830-831 Crouzon's syndrome, 22, 796-797, 796f Crush injuries, of skull, 361, 361f Cryoablation, of liver tumors, 51 1 Cryoprecipitate for head trauma patient, with coagulopathy, 274 for von Willebrand's disease, 183 Cryotherapy, 41-42 for bone tumors, 657-658,659, 660f Cryptococcus infection, 1010 Cryptorchidism, 1193-1205 acquired, 1196, 1197, 1200, 1203, 1205 associated abnormalities with, 1194-1 195 abdominal wall defects as, 1162, 1167, 1195 imperforate anus as, 1567 inguinal hernia as, 1198, 1199, 1200, 1204, 1205 myelodysplasia as, 1806 prune-belly syndrome as, 1195, 1781, 1785 scrota1 ectopia as, 1907-1908 testicular-epididymal fusion as, 1163 classification of position in, 1195-1 196, 1195f complications of, 1197-1 199, 1197f diagnosis of, 1199 embryology of, 1174, 1194 iatrogenic, 1184 in cystic fibrosis, 1300 incidence of, 1196-1 197 splenogonadal fusion presenting as, 1189 torsion in patient with, 1198, 1205 trauma to inguinal testis in, 1198-1 199 treatment of, 1200, 1201f-1202f, 1203 complications of, 1203-1204, 1204t fertility after, 1204, 1204t hormonal, 1200 laparoscopic, 1203 tumors associated with, 622, 1198, 1205 germinoma as, 567 CSF. See Cerebrospinal fluid (CSF). CT. See Computed tomography (CT). Curling's ulcer, 1226 Currant jelly stool, intussusception with, 1314f, 1317,1317f, 1324, 1386 Currarino's triad, 560, 560f, 1396, 1528, 1567 Cushing's disease, 634, 634f, 635 Cushing's syndrome, 633-635,634f Cushing's ulcer, 1226, 1227, 1231 CyberKnife, 46, 46f, 47, 49, 49t Cyclin-dependent kinases, 413, 425 Cyclins, 413 Cyclooxygenase, necrotizing enterocolitis and, 1432 Cyclophosphamide, 422, 423t, 425,428 Cyclosporine for Crohn's disease, 1456 for ulcerative colitis, 1466 in transplantation heart, 754, 760, 760t, 761f liver, 689, 689f, 737, 738t, 739 lung, 770, 771, 771t, 775

xvi

INDEX

Cyclosporine (Continued) pancreatic, 721 renal, 707-708 mechanism of action, 707-708, 738t side effects of, 708, 737, 738t, 739 renal insufficiency as, 779 Cylindroma, pulmonary, 641 Cystadenocarcinoma, pancreatic, 1684 Cystadenoma ovarian, 593, 1418 pancreatic, 1683, 1684 Cyst(s) and cystic lesions bile duct. See Choledochal cyst. bone. See Bone cyst(s). central nervous system, gastrointestinal mucosa in, 1393 Cowper's duct, 1819, 1820f, 1903 dermoid oral, 826 ovarian, 61 1f duplication. See Duplication(s), alimentary tract. epidermoid. See Epidermoid cyst(s). Gartner's duct, 1902-1903, 1950-1951 hepatic, nonparasitic, 499 laryngeal, 830 leptomeningeal, enlarging, 366 lymphatic, 2101. Y . ep also Cystic hygroma. mediastinal, 955, 959-966, 960t, 961f-966f, 1393 mesenteric. See Mesenteric and omental cysts. neck. See Neck, cysts and sinuses of. oral, 826 ovarian. See Ovarian cysts. pancreatic. See Pancreas, cysts associated with. paraurethral, female, 1902-1903, 1950-1951, 1951f pericardial, 963, 1393 pharyngeal, 826 preauricular, 871 pulmonary. See Lung(s), cystic lesions of. renal. See Kidney (s), cystic disease of. retroareolar, 890-891 salivary gland, %6, 826f, 838, 838f sebaceous, in Gardner's syndrome, 1422 splenic, 1692-1693, 1697, 1698 thymic, 865, 872, 955,960t, 961,962f umbilical, 1146, 1147f, 1148, 1307f umbilical cord, 1307f, 1310 urachal, 1148-1149, 1148f Cysteine, in parenteral solution, 207, 208 Cystic adenomatoid malformation, congenital, 641, 642t, 955, 956, 957 lung abscess associated with, 1015 pneumatocele associated with, 1016f prenatal treatment of, a t , 83 Cystic fibrosis appendicitis in, 1299, 1502 bronchiectasis in, 1013, 1013f, 1014 cholelithiasis in, 1299, 1635 clinical presentation of, 1010 colonic fibrosis in, long-segment, 1498 colonic obstruction in, 1498, 1498f cryptorchidism in, 1300 diagnosis of, 1010, 1292, 1293 etiology of, 1010 genetics of, 12, 12f, 1289-1290 hemoptysis in, 1014, 1015f hydrocele in, 1300 hypersplenism in, 1697 inguinal hernia in, 1188, 1300 intussusception in, 1320 jejunoileal atresia in, 1274, 1282 jejunostomy in, 1481, 1483f lung infections in, 1003, 1010-1011

Cystic fibrosis (Continued) lung transplant for, 765-766, 773, 775, 1011 meconium ileus in. See Meconium ileus. meconium plug syndrome in, 1294 nasal polyps in, 818 pancreatitis in, 1673 pediatric surgeon's involvement in, 1011 pneumothorax in, 1021 portal hypertension in, 766 portosystemic shunt for, 1659, 1660f primary peritonitis in, 1476 rectal prolapse in, 1299, 1595-1596 vas deferens abnormalities in, 1188 vitamin E in, 198 Cystic hygroma, 826, 1400, 2138, 2139, 2139f, 2140. See also Lymphatic malformations. mediastinal, 966, 2139, 2139f terminology for, 2098, 2138 vs. cervicofacial teratoma, 564 Cystic nephroma, 1712-1713,1712f Cystitis, hemorrhagic, after bone marrow transplantation, 781-782 Cystography of bladder injury, 319-320 of megaureter, 1772 Cystolitholapaxy, 1752, 1753 Cystoplasty. See Bladder augmentation or replacement. Cystosarcoma phyllodes, of breast, 890, 892 Cystoscopy before gender assignment surgery, 1921-1922, 1922f fetal, 78 Cystourethrography. Seevoiding cystourethrography. Cytarabine, 423t Cytogenetics. See Chromosomal abnormalities. Cytokines. See also Interleukin entries. in Crohn's disease, 1453 in host defense, 159, 160, 161, 163, 165-166 in necrotizing enterocolitis, 1430-1432, 14301, 1433, 1434 in neonatal sepsis, 170-171 in stress response, 105-106 in systemic inflammatory response syndrome, 168-169, 169f, 170, 172, 173 recombinant, in cancer therapy, 427 Cytomegalovirus (CMV) infection esophageal, 1386 in cancer patient, 1007 in HIV-infected patient, 1009-1010 in transfused lymphocytes, 188, 189 sialadenitis caused by, 837 transplantation and heart, 757, 761, 762 intestinal, 747, 750, 751 liver, 739, 740t lung, 775 renal, 712 Cytotoxic crossmatching, 747 Cytotrophoblasts, 568, 609

da Vinci Surgical System, 49-53, 49t, 51f, 52t clinical applications of, 53, 54t, 55 conclusions on, 55, 57 experimental applications of, 55, 56t to neck lesions, 867 for splenectomy, 1696 Dacarbazine, 423t Volume 1, pages 1-1 140; Volume 2, pages 1141-214

Daclizumab (Zenapax),707 in transplantation intestinal, 749 islet cell, 724 liver, 738t lung, 770-771, 771t renal, 707, 708 Dactinomycin. SeeActinomycin (dactinomycin). DAI (diffuse axonal injury), 273, 357, 358, 359, 360f, 361 in shaken baby syndrome, 401 Dakin solution, 389t, 390 Dal-Pont osteotomy of mandible, simulation of, 68 Damage-control strategy for abdominal trauma, 301-302, 301t for thoracic trauma, 279 Dantrolene, for malignant hyperthermia, 231, 232, 232t Data Knife, 57, 57f DataGlove, 66, 66f Daunomycin, 423t DDAW (desmopressin). See also Vasopressin. for nocturnal enuresis, 1814, 1815 for syndrome of inappropriate ADH secretion, 94 D-dimer assay, 184t in disseminated intravascular coagulation, 186 de Quervain's thyroiditis, 852 Dead space, pulmonary, 118t, 120 capnographic tracing and, 234f high-frequency ventilation and, 125 weaning from ventilator and, 128 Decerebrate posturing, 272, 359 Decompressive craniectomy, therapeutic, 365 Decorticate posturing, 272 Decortication, for empyema, 1018 Deep venous thrombosis (DVT) complications of, 2132-2133, 2133t in iliac compression syndrome, 2127 in ventilated patient, 128-129 lower extremity, 2131, 2132 mesenteric venous thrombosis and, 2130 upper extremity, 2131-2132 Defecation. See also Constipation; Feces; Incontinence, fecal. functional disorders of, 1549-1550, 1549t, 1550f, 1550t, 1592, 1593t, 1595 in newborn, 1515, 1519, 1592 normal frequency of, 1549, 1592 physiology of, 1568-1569, 1591-1592 Defensins, 161, 167 Deflux. See Dextranomer-hyaluronic acid copolymer (Deflux). Demyelinating syndromes, 1523 Dendritic cells, immunotherapy and, for neuroblastoma, 485 Denys-Drash syndrome, 421, 446, 447, 461 Depsipeptide, 426 Dermal sinus tract, 1994 Dermal substitutes, synthetic, 390 Dermoid cyst cervical, 865, 870-871 mediastinal, 962 nasopharyngeal, 826 oral, 826 Dermoid sinus nasal, 819-820, 820f suprapubic, 1149 Dermoid tumor, ovarian, 611f Desflurane, 222t, 227t, 229 Desmoid tumor, abdominal, in Gardner's syndrome, 1422 Desmoid-type fibromatosis, 542

Desmoplastic infantile ganglioglioma, 671 Desmoplastic small round cell tumor, 544t, 547 ovarian involvement by, 615 Desmopressin (DDAW). See also Vasopressin. for nocturnal enuresis, 1814, 1815 for syndrome of inappropriate ADH secretion, 94 Detrusorrhaphy, extravesical, 1749f Detrusor-sphincter dyssynergy, 1807, 1808f, 1809, 1817,1818 in myelodysplasia, 1821-1822, 1822f Developmental disabilities, nutritional support in, 214,214t Dexamethasone. See also Corticosteroid therapy. for meningitis, 173 maternal, necrotizing enterocolitis and, 1444 Dexamethasone suppression test, 634f, 635 Dextran as plasma substitute, 188 for adhesion prevention, 1360 Dextranomer-hyaluronic acid copolymer (Deflux), 1748,1766,1767,1776 Dextrose. See Glucose (dextrose). Diabetes mellitus. See also Insulin; Islet cell transplantation; Pancreas, transplantation of. Haemophilus vaccine and, 1002 in cystic fibrosis, lung transplantation and, 766,775 in neonate, 10'2 management of, complications and, 717 maternal arterial thrombosis and, 21 15 childhood obesity and, 1245 neonatal hypoglycemia and, 102 polysplenia syndrome and, 1604 sacral agenesis and, 1810, 1822, 2029 small left colon syndrome and, 1496, 1497f, 1498 post-transplant, 708, 724, 775 type 2 bariatric surgery and, 1252 in children, 1246 inflammation and, 1244 type 1, arterial occlusion in, 2121 Dialysis, renal acquired renal cystic disease and, 1713 parenteral amino acids and, 204 peritoneal. See Peritoneal dialysis. transplantation and, 700, 701, 710, 713 vascular access for, 700, 701-702 in bone marrow transplant patient, 779 Diamond anastomosis, duodenal, 1264, 1265, 1265f Diamond-Blackfan anemia, 179, 180 Diapedesis, 159, 160, 168 Diaphragm embryology of, 933, 1107-1108 erosion of, by amebic abscess, 1646 eventration of, 935,937, 946 in children's breathing, 276 trauma to, 269 abdominal injury with, 312-313 epidemiology of, 275, 275t, 292 laparoscopic repair of, 297, 313 thoracic injury with, 276, 278, 284-285, 284f, 285t Diaphragmatic hernia. See also Pulmonary hypoplasia. congenital (CDH), 83-84,931-945 associated anomalies with, 932-933 bronchopulmonary sequestration as, 958 hypoplastic left heart syndrome as, 153

Diaphragmatic hernia (Continued) malrotation as, 1346 pectus anomalies as, 894, 944 scoliosis as, 944 diagnosis of postnatal, 93&937 prenatal, 936, 936f, 937, 938-939 differential diagnosis of, 937 embryology of, 933-934,935 epidemiology of, 932 esophageal dysmotility associated with, 1112 gastroesophageal reflux and, 142,944, 944f, 1123 genetics of, 932 historical perspective on, 931-932,932f molecular biology of, 934 outcomes with, 943-944,944f pathology of, 934936, 934f-935f prognostic factors in, 937-938 pulmonary hypertension and, 123,935 treatment of, 938-945 ECLS in, 135, 139, 140, 140t, 142 ECMO in, 83, 127, 767,932f, 938, 939, 940,942-944,945,945f fetal, 259, 939, 944-945 for recurrent defects, 942 future, 944945,945f liquid ventilation in, 126-127, 945, 945f lung transplant in, 767, 945 postoperative, 942 preoperative, 939-940 surgical, 940-942,941f ventilator in, 938, 939-940, 942, 943 gastric volvulus associated with, 1234, 1234t, 1235 of Morgagni, 937,945-946 robot-assisted repair of, 53, 54t thoracoscopic closure of, 977 Diaphyseal aclasis, 651 Diaphyseal fractures, 342 Diaphysis, 337, 338f tumors in relation to, 652f, 654 Diarrhea after bone marrow transplantation, 780 bloody, 1387 in short-bowel syndrome, 1372, 1373 tumor-associated, with neuroblastic tumors, 469,486 Diastematomyelia, 1994, 2027, 2102 Diatrizoate enema for meconium ileus, 1275, 1289, 1292, 1295-1296 for milk curd syndrome, 1365 Diazepam, for burn patients, 394, 394t Diazoxide, for persistent hyperinsulinemic hypoglycemia in infancy, 1681, 1683 Diencephalic syndrome, 676 Diffuse axonal injury (DAI), 273, 357, 358, 359,36Of, 361 in shaken baby syndrome, 401 Diffuse brain injury, 357, 358-359, 361 early management of, 364, 365 initial CT findings in, 359, 360f, 361, 362, 362f, 364f subdural hematoma with, 359, 364, 364f Diffuse intrinsic pontine glioma, 676 Diffuse large cell lymphomas, 580, 582, 583, 583f Diffusion capacity, 118t, 120 DiGeorge syndrome, heart defects in, 153 Digital ischemia syndrome, 381 Digoxin, for heart failure in neonate, 148, 150t, 151 with supraventricular tachycardia, 151 Diphallia, 1907, 1907f Volume 1, pages 1-1140; Volume 2, pages 1141-2146

Diphenoxylate, 1373, 1466 2,3-Diphosphoglycerate, 121 Disabled children gastroesophageal reflux in, 214, 1121, 1126, 1127, 1131 nutritional support for, 214, 214t Disappearing bone disease, 2099 Discitis, 2042 Dismembered pyeloplasty, 1734-1 736, 1734f Disseminated intravascular coagulation causes of, 186 diagnosis of, 186 in head injury, 273-274 in liver failure, 186 in neonatal sepsis, streptococcal, 170 purpura fulminans secondary to, 2058 treatment of, 186 Distal intestinal obstruction syndrome, 1291, 1299 after lung transplant, 773 Distraction osteogenesis during chemotherapy, 663 of facial bones, 2063 prior to bone grafting, 22 Diuretic renography, 1729, 1729f, 1733, 1737 with megaureter, 1771-1772 Diuretics calcium losses caused by, 207, 209 for ascites, 1409 for heart failure, in neonate, 148, 150t for hypertension, 2120 Diverticulosis, small-bowel, multiple atresias with, 1276 Diving reflex, 1235, 1433 DNA cancer chemotherapy and, 422,423t-424t cell cycle and, 412-413, 413f DNA content (ploidy), 415, 438 DNA damage by ionizing radiation, 43-44 by nitric oxide, 161-162 DNA index, 415 DNA microarrays, 40, 419, 420, 425 DNA repair genes, mutations of, 421 DNET (dysembryoplastic neuroepithelial tumor), 671, 677-678, 678f Dobutamine, for heart failure, 150t, 151 Docetaxel, 4241 Donnai-Barrow syndrome, 1160-1 161 Donut sign, of intussusception, 1326, 1326f Dopamine adrenal synthesis of, 629 for brain injury, 273 for heart failure, 150t, 151 neonatal acid-base balance and, 96 Doppler ultrasound imaging, 32, 34 for needle biopsy, 438 of amniotic flow, 936 of arterial occlusion, 21 16 of arteriovenous fistula, penile, 331 of burned extremity, 386 of hand circulation, 348 of hepatic artery, after Kasai procedure, 1611 of intestinal malrotation, 1350, 1351f of renal allograft, 70&707 of salivary glands, 836, 836f of tumors, hepatic, 504 of vascular injury, 377 Dor fundoplication, robot-assisted, 53, 54t Dorsal lumbotomy approach, 1735, 1736, 1736f Double aortic arch, airway obstruction by, 997,998 Double bubble sign, of duodenal obstruction in atresia or stenosis, 1262, 1262f in volvulus, 1350, 1351f

xviii

INDEX

Double minutes, 417 Double wall sign, of pneumoperitoneum, 1437 Down syndrome (trisomy 21) adenotonsillar hypertrophy in, 824 anorectal malformations in, 1566, 1571 duodenal atresia in, 1260, 1261t, 1269 esophageal dysmotility in, 1111, 1113 heart defects in, 153 Hirschsprung's disease in, 1528, 1529, 1545 leukemia in, 420 macroglossia in, 825 middle ear effusion in, 815 nutritional support in, 214, 214t Doxorubicin. See Adriamycin (doxorubicin) . Dressings for burns, 389, 390, 390f outpatient, 396 for soft tissue wounds, 352 Drooping flower sign, 1764, 1765f, 1949, 1950f Drop mets, 673, 675 Dropped lung, 283 Drotrecogin alfa, for sepsis, 173 Drug delivery systems, microelectromechanical, 58 Dual energy x-ray absorptiometry, 195 Duchenne's muscular dystrophy, malignant hyperthermia in, 231 Ductus arteriosus closure of, 148,935, 1959 fetal, 148, 149f afterload and, 147 indomethacin and, 79 indomethacin and, 79,238 maintaining patency of, 153, 756, 943 patent, 1959-1961, 1960f-1961f afterload and, 147 arterial catheterization with, 123, 235-236 congenital diaphragmatic hernia with, 148 historical perspective on, 4 in Down syndrome, 153 pulmonary hypertension with, 123 robot-assisted ligation of, 54t, 55 thoracoscopic occlusion of, 977 Ductus venosus, 148 Duhamel operation, 1532f, 1536, 1538, 1539, 1539f-154Of, 1542 complications of, 1546-1547 redo of, 1545f Duodenal atresia and stenosis, 1260-1267, 1261f-1265f, 1261t imperforate anus with, 1567 jejunal feeding in, 1481 iejunoileal atresias with, 1270, 1276 malrotation with, 1262, 1263, 1346 pyloric web with, 1233 Duodenal duplication, 1391, 1392f, 1393-1394, 1394f Duodenal intubation, for diagnosing biliary atresia, 1607 Duodenal switch, biliopancreatic diversion with, 1248, 1248t, 1250 Duodenal ulcer. See Peptic ulcer disease. Duodenostomy, cyst, 1626, 1627f, 1629 Duodenum adenocarcinoma of, 1421 biopsy of, in thrombocytopenic patients, 780 obstruction of. See abo Duodenal atresia and stenosis. by congenital bands. See Ladd's bands. by preduodenal portal vein, 2126 polyps in, 1420, 1421, 1422 trauma to, 303-304, 304t, 305f-307f, 306-307, 306t, 307t

Duplex collecting system. See also Ureteral duplication. definition of, 1758 Gartner's duct cyst with, 1950 megaureter associated with, 1771 partial nephroureterectomy with, 1767 terminology for, 1758 ureteropelvic obstruction with, 1761, 1761f, 1762, 1767 urinary tract infection with, 1743, 1744f vesicoureteral reflux with, 1760, 1761, 1762, 1762f-1763f, 1763, 1765-1 766, 1766, 1767, 1768 Duplex exstrophy, 1842, 1843f Duplication(s), alimentary tract, 1389-1397 appendiceal, 1501 associated anomalies with, 1389, 1390 clinical manifestations of, 1390-1391 definition of, 1389 diagnosis of, 1391-1392,1391f-1392f vs. mesenteric cyst, 1400, 1402 duodenal, 1391, 1392f, 1393-1394,1394f esophageal associations of, 964-965, 965f-966f, 1392, 1393, 1393f etiology of, 1389-1390 foregut. See also Bronchogenic cyst. abdominal, 1393-1394, 1394f thoracic and thoracoabdominal, 955, 959, 960,963-966,963f-966f, 1393, 1393f thoracoscopic biopsy of, 977 gastric, 1391, 1393-1394, 1678 gastric mucosa in, heterotopic, 1308, 1387, 1389, 1390, 1391, 1392, 1393, 1394, 1395, 1396 hemorrhage associated with, 1386, 1387 hindgut, 1391, 1392, 1395-1397, 1396f-1397f, 1498 intestinal obstruction with, 1366, 1391, 1395 intussusception with, 1319, 1321, 1366, 1391, 1392, 1395 locations of, 1389, 1389t pancreatic involvement by, 1391, 1392f, 1394, 1678 pyloric, 1234 pyloroduodenal cyst as, 1232 small intestine, 1390, 1391, 1391f-1392f, 1392,13941395, 1395f Duplication (s), genitourinary. See also Duplex collecting system; Ureteral duplication. colorectal duplications with, 1396 in bladder exstrophy, 1843f, 1846 of horseshoe kidney, 1717 penile, 1904, 1907, 1907f urethral, 1819,1820f-1821f, 1904-1905, 1904f uterine, 1943-1944,1943f-1944f vaginal, 1943-1944, 1943f-1944f Dura mater closure of, after brain tumor surgery, 674 sarcomas of, 546 DuraGen, 674 DVT. See Deep venous thrombosis (DVT) . Dyschezia, infant, 1549, 1549t Dyschondroplasia, in Maffucci syndrome, 2129 Dysembryoplastic neuroepithelial tumor (DNET), 671, 677-678,678f Dysfibrinogenemias, 185 Dysfunctional elimination syndrome, 1812-1813, 1812f-1814f Dysgerminoma, 554,567. See also Germinoma. biologic markers associated with, 556, 594t, 595 gonadoblastoma coexisting with, 613 in mixed germ cell tumors, 568

Volume 1, pages 1-1140; Volume 2, pages 1141-2146.

Dysmotility, gastrointestinal. See Enteric nervous system; Esophageal dysmotility; Gastric emptying; Intestinal dysmotility; Intestinal pseudo-obstruction. Dysphagia. See also Swallowing. after esophageal atresia repair, 1070-1071, 1111 evaluation of, 1125b esophagoscopy in, 1040 in esophageal achalasia, 1113, 1114 Dystocia sternomastoid tumor and, 875 teratoma causing cervicofacial, 564 sacrococcygeal, 559:560

Ear, 813-817 anatomy of, 813 branchial anomalies associated with, 867-868,867f vs. preauricular cyst, 871 cholesteatoma in, 816 congenital anomalies of, 814 embryology of, 814, 863, 863t, 864f examination of, 814-81 5 infection of, 815-816, 816f tissue-engineered, 22 trauma to, 81G817, 817f tumors of, 817 Ear tags, 789, 789f, 814 Ebstein's anomaly of tricuspid valve, 151 EBV. See Epstein-Barr virus (EBV) infection. ECF (extracellular fluid) in fetus and neonate, 91-92,93, 94,95 third-space loss and, 226 Echinococcal infection liver abscesses in, 1646, 1646f pulmonary, 1005, 1005f Echocardiography antenatal, omphalocele and, 1161 in chest trauma, 278, 285, 286, 290, 291 in pectus excavatum, 898 Eclampsia, sacrococcygeal teratoma and, 85 ECLS. See Extracorporeal life support (ECLS) ECMO. See Extracorporeal membrane oxygenation (ECMO). Ectopia cordis, 912-914, 1157-1158, 1158f, 1158t, 1162 embryogenesis of, 1160 outcome of, 912,913,914,1167 prenatal diagnosis of, 1161 treatment of, 912-914,913f-914f, 1165 Edema cerebral, post-traumatic, 356, 357, 360f, 362, 365 lower extremity. See also Lymphedema. causes of, 2141 pulmonary. See Pulmonary edema. EDNRB. See Endothelin-B receptor (EDNRB). Edrophonium, with neuromuscular blockade, 230 Effort thrombosis, 2131-2132 EGF. See Epidermal growth factor (EGF). Ehlers-Danlos syndrome arterial degeneration in, 21 14, 21 14f inguinal hernia in, 1188 Eisenmenger's syndrome, 766, 770 Ekehorn's rectosacropexy, 1596 ELA-Max, 244,244t

Elbow injury to fracture in, 342f posterior fat pad sign in, 341, 341f ultrasonography of, 342 reconstruction of, after tumor resection, 665 Electrical burns, 383, 385, 396 amputation secondary to, 2058 Electrocardiogram, in trauma patient, 272 with thoracic injury, 278, 285, 286 Electrocautery, 40-41 Electroencephalography (EEG) in seizure evaluation, 2003, 2004, 2005 intracranial, 2005 Electrogastrography, 1548 Electrolytes. See also Fluid management or resuscitation. in burn patient, 388-389 in fluid therapy, 225 intraoperative, 226 in neonate, 91-96, 93f, 94t, 96t in parenteral nutrition patient disturbances, 208-209 requirements, 206-207, 206t Electrosurgery, 40-41 Elephantiasis, 2099 ELSO (Extracorporeal Life Support Organization), 134, 136, 137, 140-141, 140t, 141t Embolism arterial, 2115-2117, 2115t pulmonary, 2132-2133 in ventilated patient, 129 septic, jugular thrombophlebitis with, 2132 venous. Y . ep Thromboembolism, venous. Embolization bronchial artery, 1014, 1015f in abdominal trauma for hepatic hemorrhage, 301, 301f for renal injury, 319, 324 for splenic injury, 297 for splenic pseudoaneurysm, 299, 299f of aneurysm, congenital, 21 11 of liver tumors, benign, 496, 497 hemangioma as, 2106 of nasopharyngeal angiofibroma, 821 of vascular anomalies, 2103 arteriovenous malformation as, 2107, 2113,2114 Embolosclerotherapy, of arteriovenous fistula, in Parkes-Weber syndrome, 2129 Embryology alimentary tract duplications and, 1389-1390 bladder exstrophy and, 1841-1842, 1842f choledochal cyst and, 1622-1623 cloaca1 exstrophy and, 1862 colonic atresia and, 1493-1494 duodenal atresia or stenosis and, 1260 gastroesophageal reflux and, 1120-1121 germ cell tumors and, 554 Hirschsprung's disease and, 1523-1526, 1524f-1525f inguinal hernia and, 1173-1 174 Meckel's diverticulum and, 1304 mesenteric-omental cysts and, 1399-1400 of abdominal wall, 1158-1 159, 1159f of adrenal glands, 628-629 of anus and rectum, 1566-1567 of appendix, 1501 of biliary system, 1604 of breast, 885, 2064 of central nervous system, 1987, 1988-1990, 1988f-1989f of cleft lip and palate, 803 of cloaca, 1842, 1842f

Embryology (Continued) of diaphragm, 933, 1107-1 108 of ear, 814 of enteric nervous system, 1523-1525, 15245 1560 of esophagus, 1107-1 108 of female genital tract, 1935-1936 of foregut, 1053-1054,1071,1107 of hand, 2071 of intestinal rotation and fixation, 1342-1346, 1343f-1347f of kidney, 1705, 1715, 1716f, 17241725 of lungs, 1 1 4 116, 115f, 933-934 congenital diaphragmatic hernia and, 934,935 of lymphatic system, 2137, 2138f of male genitalia, 1871-1874, 1872f-1874f of mediastinal masses, 955 of neck, 861-865,862f, 863t, 864f-865f of nose, 818 of pancreas, 1671-1672 of parathyroid glands, 850 of portal vein, 1651-1652 of salivary glands, 835 of skin, muscle, connective tissue, and tendons, 2061-2062 of spleen, 1691 of testicular descent, 1174,1193-1 194, 1194f of thoracic duct, 1025 of thyroid glands, 850 of twinning, 2080 of umbilicus and related structures, 1143, 1144f, 1145, 1145t, 1304 of ureter and ureteral anomalies, 1758-1 761, 1759f-1760f of venous system, central, 2124, 2125f sexual differentiation in, 1911-1913, 1912f ureteropelvic junction obstruction and, 17241725 Embryonal brain tumors, 671, 671t Embryonal carcinoma, 555 biologic markers associated with, 556, 594t, 595 extragonadal, 567 in sacrococcygeal teratoma, 559 pineal region, 678 in mixed germ cell tumors, 568 ovarian, 5941,607,609 Embryonal sarcoma, undifferentiated, hepatic, 505 Emergency management, 265-274. See also Trauma. ABCDE in, 266-272,268f, 270f-271f coagulopathy and, 273-274 for burns, 385, 386 pain management in, 274 peaks of mortality and, 265-266 prehospital, 266 primary survey in, 266-272, 268f, 270f-271f resuscitation phase in, 267, 272-273, 277 secondary survey in, 267 signs of successful resuscitation in, 269 EMLA (eutectic mixture of local anesthetics), 244, 244t Emphysema acquired lobar, in viral bronchiolitis, 1004, 1004f congenital lobar, 955,958-959,959f pulmonary interstitial, barotrauma-related, 128 Empyema, 1017-1018, 1019f-1020f pleural debridement for, 977, 978,980 Volume 1, pages 1-1 140; Volume 2, pages 1141-2

Encephalocele capillary malformation overlying, 2098 nasal, 820 nasopharyngeal, 826 Encephalopathy, portal hypertension with, 1655, 1656, 1658,1659,1661, 1664, 1665, 2126 Enchondroma, location of, in relation to physis, 652f Enchondromatosis, 651-652. See also Maffucci syndrome; Ollier's disease. ovarian tumors associated with, 593, 606 Encopresis, 1549, 1549t, 1592, 1595 vs. ultrashort Hirschsprung's disease, 1531 End ureterostomy, 1792, 1793f End-diastolic volume. See Preload. Endocarditis, bacterial, embolic complications of, 2115-2116, 2116f Endocatch 11,1695, 1695f, 1696 Endodermal sinus tumor. SeeYolk sac (endodermal sinus) tumor. Endometriosis, 601-602 magnetic resonance imaging of, 597 sarcomas arisitlg from, 614-61 5 Endophthalmitis, pyogenic liver abscess with, 1644 Endopyelotomy, 1719, 1736, 1737 Endoscopic retrograde cholangiopancreatography (ERCP) in ascariasis, 1365 in choledocholithiasis, 1638, 1638f, 1642 in infants, 1607 in pancreatitis, 1674, 1675, 1677f of biliary duct injury, 303, 304f of ductal anomalies, 1625 of pancreas divisum, 1676 of pancreatic injury, 308, 309, 309f, 310 of pancreatic pseudocyst, 1678 Endoscopy. See also Bronchoscopy; Esophagoscopy; Laparoscopy; Laryngoscopy; Thoracoscopy. colonoscopy, 1465 fetal, 78, 79-80, 79t, 81f, 83, 84, 85 for biopsy, 439-442, 441f for gastrostomy tube placement, 199, 1042-1043 for urethral alignment, after injury, 330 history of, 971 microelectromechanical devices and, 57 robotic systems and, 48, 49, 50, 53 training simulations for, 61, 68-69, 69f, 70 virtual, with 3-D CT, 35-36, 36f Endothelial cells cytokines secreted by, 165 in angiogenesis, 418, 419 cancer chemotherapy and, 422,426 in systemic inflammatory response syndrome, 168, 169f, 172, 173 in tissue engineering, 22, 23, 24, 27, 27f neutt-ophils and, 159-160, 167 Endothelin-3. 1521. 1522-1523. 1523t. 1525 Endothelin-1, in hepatopulmonary syndrome, 1656 Endothelin converting enzyme-1, 1521, 1523, 1523t Endothelin-B receptor (EDNRB) Hirschsprung's disease and, 1521, 1522-1523, 15231, 1526 intestinal neuronal dysplasia and, 1560 Endotoxin. See Lipopolysaccharide (LPS, endotoxin). Endotracheal intubation. See also Extubation. complications of, 128, 129 esophageal, 1047, 1048. 1049 gastric perforation as, 1235, 1236

Endotracheal intubation (Continued) long-term, 983,984,990-991,996 for upper airway obstruction, 828 in burn patient, 385 in inhalation injury, 395 in trauma patient, 266, 267, 268f, 269, 272 with brain injury, 356, 364 with spinal injury, 356, 370 with thoracic injury, 277 Endotracheal tube, 127 removal of, 128 selection of, 267, 828 End-stage liver disease (ESLD) in biliary atresia, 1611, 1612, 1613 transplantation for, 731, 732-733, 734 with intestinal transplant, 745 End-stage renal disease (ESRD), transplantation for, 699, 700, 701, 702, 710, 711, 713 Enema an tegrade for bowel management, 1483f, 1485 for cloaca1 exstrophy, 1866 for incontinence, 1834, 1834f contrast. See (also Barium enema; Diatrizoate enema. in distal intestinal obstruction, 1494 in Hirschspmng's disease, 1515-1516, 1516f vs. idiopathic constipation, 1549 with total colonic aganglionosis, 1531, 1531f in meconium plug syndrome, 1496, 1497f for bowel management after anorectal malformation repair, 1587 antegrade, 1483f, 1485 in intestinal neuronal dysplasia, 1562, 1563 for constipation, 1550, 1550f, 1594 acute, 1592 Energy metabolism, 195-196, 195t in cerebral palsy, 214 in neonate, 96-99, Y8f postoperative, 105, 105f, 107, 108, 212 protein metabolism and, 104, 108 with biliary atresia, 212 obesity and, 1243, 1245 postoperative, 195-196, 210-21 1 in critically ill patient, 212 in neonate, 105, 105f, 107, 108 Enflurane, 228,228f gastric emptying and, 1361 Enprostil, peptic ulcers and, 1230 Entamoeba histolytica infection in graft-versus-host disease, 780 liver abscess in, 1645-1646 Enteral nutrition, 199, 200t, 201t, 202-203 See also Formula(s);Gastrostomy. for biliary atresia, 212 for burn patient, 386, 393 for Crohn's disease, 1456 for failure to thrive, 213-214 for short-bowel syndrome, 203, 212-213 for surgical patient, 21 1 nasogastric, 199, 203 Enteric nervous system aganglionosis and, 1527-1528, 1527f anal sphincter and, 1591 disorders of, 1547, 1548 embryology of, 1523-1525, 1524f, 1560 ganglion cell density of, 1561 hyperganglionosis and. See Intestinal neuronal dysplasia. physiology of, 1527, 1527f postnatal development of, 1561 Enteritis, infectious, after intestinal transplant, 750

Enterocolitis, 780. See also Hirschsprung's disease, enterocolitis of; Necrotizing enterocolitis, neonatal. in graft-versus-host disease, 780 methicillin-resistant S. aureus in, 1495 Enterocystoplasty. See Bladder augmentation or replacement. Enteroenterostomy, robotic, porcine, 55, 56t Enterostoma(s), 1479-1490. See also Appendicostomy; Colostomy; Gastrostomy; Ileostomy; Jejunostomy. care of, 1488 choices for, 14841485, 1484f, 1485t closure of, 1488-1 489 complications of, 1489-1490, 1489f, 1489t parastomal hernia as, 1363, 1489 continent, 1488 historical perspective on, 1479 in chronic intestinal pseudo-obstruction, 1549 in Crohn's disease, 1457, 1458, 1459 in Hirschsprung's disease, total colonic, 1531 in necrotizing enterocolitis, 1440, 1441-1442, 1482,1483f in ulcerative colitis, 1467, 1468, 1470f, 1471, 1482-1483 indications for, 1480-1484, 1483f-1484f quality of life and, 1479-1480 sites for, 1486, 1486f-1487f, 1488 umbilical, 1153, 1484f, 1486 technical aspects of, 1485-1486, 1486f-1487f, 1488 types of, 1480, 1480f-1482f, 1480t, 1481t Enuresis. See also Incontinence, urinary. airway obstruction and, 824 nocturnal, 18141815 Envenomation injuries, 352-353 Eosinophilic esophagitis, 1112, 1112f, 1125b Eosinophilic granuloma, temporal bone involvement of, 817 Eosinophilic proctocolitis, 1599 Ependymoma, 671, 671t, 675-676,675f in Turcot's syndrome, 1422 Epidermal growth factor (EGF), in gastrointestinal tract, 1430, 1430t Epidermal growth factor receptor (EGFR), 414,419, 425 in germ cell tumors, testicular, 556 Epidermoid carcinoma, salivary gland, 827 Epidermoid cyst(s) cervical, 869 hepatic, 499 in Gardner's syndrome, 1422 testicular, 622, 623 Epidermolysis bullosa, pyloric atresia associated with, 1233 Epididymis rupture of, 331 undescended testis and fusion with, 1199 separation from, 1195 Epididymitis, 1205-1 206, 1206t ectopic ureter with, 1763 Epidural abscess, 2009, 2010, 2010f spinal, 2013 Epidural anesthesia, 247-249, 247f, 248t postoperative ileus and, 1361 Epidural catheter, 248-249, 248t Epidural hematoma, 273, 358, 359, 364365, 365f Epiglottitis, 830 Epilepsy surgery, 2002-2008, 2003f. See also Seizures.

Volume 1, pages 1-1140; IJolume 2, pages 1141-21

Epinephrine (adrenaline) adrenal synthesis of, 628, 629 arrhythmias associated with, inhalation anesthetics and, 228, 228f, 229 for anaphylaxis latex-induced, 232 thiopental-induced, 233 for bronchospasm, in inhalation injury, 395 postoperative levels of, 106, 107, 107f racemic, in airway obstruction, 828, 830 Epiphysiodesis contralateral to tumor resection, 663 with vascular malformations, 2108 Epiphysis, 337, 338f fracture of in birth injury, 404 in child abuse, 403 injury to, ultrasonography of, 342 tumors in, 652f, 654 Epipodophyllotoxins, 422, 424t Epispadias, 1842, 1843f repair of, 1851-1852, 1851f-1852f complications of, 1858 Epistaxis, 820-821 Epithelioid sarcoma, 549f-550f Epstein-Barr virus (EBV) infection Hodgkin's disease and, 575 in HW-infected patient, 837 lymphoid interstitial pneumonitis and, 1008, 1009f leiomyosarcoma and, 543 mononucleosis in, 822, 837, 848 neuroblastoma therapy and, 484 transplantation and heart, 757 intestinal, 750-751 liver, 739, 740t lymphoproliferative disorder and, 585, 712, 739, 740t, 750-751, 774 Epulis, 825-826, 825f ERBBP proto-oncogene, 417,425 Erb's palsy, 404-405 diaphragmatic eventration in, 946 ERCP. See Endoscopic retrograde cholangiopancreatography (ERCP). Erectile dysfunction postoperative ileoanal pouch procedure and, 1470 in Hirschsprung's disease, 1546 post-traumatic, 330, 331 Erection artificial, 1887, 1891 prevented by penile block, 1893 Ergotamine, maternal use of, intestinal atresia and, 1269 Erythema nodosum, in ulcerative colitis, 1464, 1464f Erythroblastopenia of childhood, transient, 179-180 Erythrocytes (RBCs) 2,3-diphosphoglycerate in, 121 enzymes in carbonic anhydrase, 121 deficiencies of, 182 glutathione peroxidase, 199 transketolase, in thiamine deficiency, 198 mean corpuscular volume of, 178, 179f transfusion of, 187-189, 190 during extracorporeal life support, 138 for anemia, 180 hematocrit and, 187, 188, 226, 2'26t in sickle cell disease, 181 in B-thalassemia, 182 in traumatic emergency, 271

Erythromycin for gastroesophageal reflux, 1126 for intestinal pseudo-obstruction, 1366, 1549 postoperative ileus and, 1361 Erythropoietin, 1430-1431, 1430t Eschar, 384, 385, 386, 389 excision of, 385, 389, 390-391 microorganisms in, 394 Escharotomy, 385, 386, 386f Exherichia coli human milk and, 202 in neonatal sepsis, 170, 172 ESLD. See End-stage liver disease (ESLD). Esmolol, in neonate, for supraventricular tachycardia, 151, 152t, 153 Esophageal achalasia, 1112-1 114, 1113f-1114f, 1125b. Seealso Esophageal dysmotility. gastric adenocarcinoma with, 518 Esophageal atresia. See also Tracheoesophageal fistula. aspiration associated with, 1015, 1057, 1058 associated anomalies with, 1054-1056, 1055t anorectal, 1569 classification of, 1052-1053, 1053f, 1053t, 1056, 1056t clinical presentation of, 10561057 complications after repair of, 1067-1071, 1068f, 1070f anastomotic stricture as, 1041-1042, 1041f, 1045, 1068, 1068f, 1069 after circular myotomy, 1064 suture material and, 1061 Barrett's esophagus as, 517, 1069 motor disturbances as, 1111 diagnosis of, 1056-1058,1057f-1058f vs. pyloric atresia, 1232 epidemiology of, 1054 gastroesophageal reflux in after repair, 1068, 1069, 1070, 1071, 1111, 1123 preoperative, 1058, 1111, 1123 historical background of, 1051-1053, 1052f operative repair of by replacement. See Esophageal replacement. esophagoscopy of anastomosis in, 1041-1042, 1041f-1042f thoracoscopic, 977, 1061, 1062f with distal fistula, 1059-1061, 1059f-1060f, 1062f with long gap, 1061, 1063-1065, 1063f-1064f, 1093, 1093t with upper-pouch fistula, 10661067 without fistula, 1065-1066 outcomes with, 1067 pathogenesis of, 1053-1054 preoperative treatment of, 1058, 1058f Esophageal dysmotility, 1107-1 114 after caustic injury, 1086 after esophageal atresia repair, 1070-1071 anatomical basis of, 1107-1 108 aspiration secondary to, 1015 evaluation of, 1038-1039, 1109-1 110, 1109f-1110f, 1125b overview of, 1107 physiological basis of, 1108-1 109 specific disorders of, 1110-1 114, 111If-1 114f Esophageal manometry, 1038-1039 after atresia repair, 1069 in motility disorders, 1109-1 110, 1109f-Illof, 1111, l l l l f achalasia as, 1113, 1113f-1114f gastroesophageal reflux and, 1124

Esophageal overdrive pacing, 153 Esophageal replacement, 1093-1 104 colonic inteiposition for, 1095-1097, 1096f, 1098t for caustic strictures, 1088-1089, 1089f, 1089t, 1097 for esophageal atresia, 1065 for achalasia, 1114 for atresia, 1065, 1093, 1093t gastric transposition for, 1065, 1101, 1102f, 1103-1104, 1103t gastric tube for, 1065, 1098, 1099f-1100f, 1100, llOOt ideal substitute for, 1094 indications for, 1093-1094 jejunal interposition for, 1065, 1100-1 101, IlOlt routes for positioning of, 1094-1095, 1095t summary of methods for, 1094,1094f, 1095t timing of, 1095 Esophageal stricture after transection, for varices, 1663 anastomotic, 1041-1042,1041f, 1045, 1061, 1064, 1068, 1068f, 1069 caustic, 1082, 1083, 1085, 1085f-1086f complications of, 1085-1087, 1087f, 1088t esophageal replacement for, 1088-1089, 1089f, 1089t, 1094, 1097, 1103 outcomes of, 1087-1089, 1089f, 1089t congenital, 1071-1072, 1072f gastroesophageal reflux and, 1123, 1126 peptic, 1093-1094 Esophageal transection, for varices, 1662-1663 Esophageal varices. SeeVarices. Esophagitis after esophageal replacement, 5 17 bleeding in, 1386 diagnosis of, 1124-1 125, 1125b dysmotility with, 1112, 1113 eosinophilic, 1112, 1112f, 1125b esophagoscopy in, 1039-1040, 1041 reflux. See also Gastroesophageal reflux disease (GERD). bile reflux in, 1039, 1123, 1124 biopsy in, 1124 esophagoscopy in, 1039-1040 factors affecting, 1122, 1123 medical therapy for, 1123, 1126 pH monitoring in, 1039, 1069, 1124 Esophagoesophagostomy, 1059-1061, 1060f, 1062f robotic, porcine, 55, 56t Esophagography, 1038-1039, 1041 of atresia, 1057, 1057f-1058f of caustic injury, 1084, 1085f of congenital stenosis, 1071, 1072f of esophageal achalasia, 1113, 1113f of perforation, 1048, 1049 of tracheoesophageal fistula, 1057, 1058f Esophagojejunostomy, Roux-en-Y, after failed fundoplication, 1133 Esophagoscopy, 1038, 1039-1045, 1040f-1042f in eosinophilic esophagitis, 1112, 1112f in gastroesophageal reflux, 1039-1040, 1040f, 1124, 1125b in motility disorders, 1109, 1113 of caustic injury, 1084, 1084t, 1086, 1088 Esophagus acid clearance from, 1122 anatomy of, 1108 autonomic innervation of, 1107, 1108 biopsy of, 1038, 1039, 1124, 1125b caustic injury to, 1082-1089 carcinoma secondary to, 517, 1086 Volume 1, pages 1-1140; Volume 2, pages 1141-21

Esophagus (Continued) clinical presentation of, 1083-1084 diagnosis of, 1040-1041, 1084t dysmotility secondary to, 1112 epidemiology of, 1082 esophageal replacement for, 1088-1089, 1089f, 1089t, 1094, 1097, 1103 management of, 1082, 1084-1086 outcomes of, 1086-1089, 1088t, 1089f, 1089t pathophysiology of, 1083 perforation in, 1047, 1083, 1084, 1087, 1087f, 1088 substances involved in, 1082-1083, 1083t, 1088t compression of, by vascular anomalies, 1978, 1979 congenital anomalies of. See also Esophageal atresia; Tracheoesophageal fistula. endoscopy of, 1041 laryngotracheoesophageal cleft as, 995-996, 1072-1074, 1073f-1074f true congenital stenosis as, 1071-1072, 1072f dilatation of, 1041-1042, 1045 for anastomotic stricture, 1068, 1071-1072 for caustic stricture, 1068, 1082, 1085-1086, 1087, 1087f, 1088 duplications associated with, 964-965, 965f-966f, 1392, 1393, 1393f embryology of, 1107-1108 evaluation of, 1038-1039. See alto Esophagoscopy. foreign body in, 1043, 1044, 1045 after atresia repair, 1068, 1069 congenital stenosis with, 1071 esophageal replacement for injury caused by, 1094 perforation by, 1047, 1050 motility of, 1108-1 109, 1122 methods for evaluation of, 1038-1039, 1109-1110, 1109f-1110f motor disorders of. See Esophageal dysmotility. obstruction of, by teratoma, 563, 564 perforation of, 1041, 1045, 1047-1050, 1048f-1049f caustic, 1047, 1083, 1084, 1087, 1087f, 1088 pseudodiverticulum of, 1048, 1050, 1064 rupture of, spontaneous, 1047, 1048-1049 stenosis of, congenital, 1071-1072, 1072f tissue-engineered, 25, 25f, 26 trauma to, 277,279,283-284,291, 1041, 1047-1050 epidemiology of, 275, 275t, 276 iatrogenic, 1041, 1045, 1047-1050, 1049f in birth injury, 405 mediastinitis secondary to, 1027, 1028 tumors of, 515, 517, 1069 after caustic injury, 517, 1086 esophageal replacement after resection of, 1094 ESRD (end-stage renal disease), transplantation for, 699, 700, 701, 702, 710, 711, 713 Estrogen exposure esophageal atresia and, 1054 hepatocellular adenoma secondary to, 498 Estrogen secretion by adrenocortical tumors, 635 by ovarian lesions, 594, 595t, 600, 604, 606, 609 ESWL (extracorporeal shock wave lithotripsy), 1748, 1751, 1752

xxii

INDEX

Ethanol, injection of in complex vascular malformation, 2129 in liver tumors, 51 1 in lymphatic malformation, 2107 Ethics, 257-262 decision making in, 258 of bariatric surgery, 260-261 of gene therapy, 18 of innovation and research, 258-260 of living donor lung transplantation, 776 of renal transplantation, 695 of separating conjoined twins, 2083-2084 of sex assignment surgery, 261-262 of stem cell use, in tissue engineering, 28 of treating congenital anomalies, 1260 principles of, in pediatric surgery, 257-258 Ethylenediaminetetraacetic acid, hypocalcemia associated with, 273 Etoposide, 424t. 428 Euglobulin lysis time, 184t Europe, pediatric surgery in, 7 Eustachian tube, 813, 815 branchial anomaly associated with, 868 cholesteatoma and, 816 embryology of, 863 Eustachian valve, 148 persistent, 2 124 Everolimus, 708 Ewing's family tumors, 652-653. See also Ewing's sarcoma; Primitive neuroectodermal tumors (PNETs). Ewing's sarcoma, 652-653 biopsy of, 655 chemotherapy for, 6 5 6 6 5 7 epidemiology of, 654, 664 genetics of, 415, 416, 417t, 419 lactate dehydrogenase and, 654 locations of, in relation to physis, 652f, 654 pulmonary metastases from, 645 radiation therapy for, 657 resection and reconstruction for, 662f, 664f staging of, 654, 655 EXIT (ex utero intrapartum treatment), 781, 82t, 85 for cenicofacial teratoma, 564 for cystic lung lesions, 956 Exomphalos. See Omphalocele; Umbilical hernia. Exostoses, multiple hereditary, 651 Expiratory reserve volume, 118, 118f Exposure, of trauma patient, 272 Exstrophy complex, 1842, 1843f urethral duplication in, 1904 Extracellular fluid (ECF) in fetus and neonate, 91-92, 93, 94, 95 third-space loss and, 226 Extracellular matrix bacterial adherence to, 158 in tissue engineering, 21, 22 of cardiac valves, 23 invasive cancer and, 418 Extracorporeal carbon dioxide removal, 126 Extracorporeal life support (ECLS), 126, 134-142. See also Extracorporeal membrane oxygenation (ECMO). circuit for, 136137, 136f, 137t, 142 complications of, 139-140 configurations for, 135-136, 136f contraindications to, relative, 135 cost of, 142 discontinuation of, 139 for primary pulmonary hypertension, 127 future of, 142 historical background of, 134 indications for, 134-135

Extracorporeal life support (ECLS) (Continued) operative procedures during, 138-139 patient management in, 137-139, 138f purpose of, 134 results of, 134, 140-142, 140t, 141t Extracorporeal Life Support Organization (ELSO), 134, 136,137, 140-141, 140t, 141t Extracorporeal membrane oxygenation (ECMO), 134. See also Extracorporeal life support (ECLS). after bone marrow transplantation, 779 contraindications to, intracranial hemorrhage as, 135 during resection of sacrococcygeal teratoma, 562 ex utero intrapartum initiation of, 85 for heart transplant candidate, 756, 757 in congenital diaphragmatic hernia, 83, 127, 767,9325 938,939,940, 942-944,945,945f in congestive heart failure, 151 liquid ventilation with, 127, 945, 945f lung transplant for patient on, 768 vascular complications of, 380 vs. high-frequency ventilation, 126, 141 Extracorporeal shock wave lithotripsy (ESWL), 1748, 1751, 1752 Extremity(ies). See also Amputation; Ischemia; Limb deficiency, congenital; Limb length inequality. tumors of, 20562058,2056t, 2057f. See also Bone tumors. nonrhabdomyosarcomatous sarcomas, 548-550,549f-550f rhabdomyosarcoma, 535-536, 549 vascular trauma to, 348, 351, 378-380, 379t venous thrombosis in, 2131-2132. See also Deep venous thrombosis (DVT). Extubation failure of, anterior cricoid split for, 992,992t laryngotracheal reconstruction and, 993 Eye (s). See also Visual abnormalities. endophthalmitis of, pyogenic liver abscess with, 1644 trauma to, 272 uveitis of, in ulcerative colitis, 1465 Eyelid, congenital drooping of, 2070-2071, 2070f

Facial anomalies. See Cleft anomalies; Craniofacial anomalies. Facial hypoplasia, torticollis as cause of, 878, 878f, 879 Facial nerve anatomy of, 813,814 parotid gland and, 835, 836, 837 surgical exposure and, 867-868,868f first branchial anomalies and, 862, 867-868, 868f neuroma of, 817 paralysis of during parotid surgery, 867 otitis media with, 815-816 temporal bone fracture with, 817, 817f Factor V Leiden mutations, 187, 2130 Factor VII, recombinant for biopsy-related hemorrhage, 442 for massive hemorrhage, 301 for variceal bleeding, 1658 Volume 1, pages 1-1140; Volume 2, pages 1141-21

Failure to thrive nutritional support for, 213-214 sodium depletion causing, 213 Falciform ligament, nonfixation of, 1362-1363, 1363f Fallopian tube in inguinal hernia, 1178-1 179, 1179f, 1186, 1187 in hermaphrodite, 1189 salpingitis of, acute, with perihepatitis, 1645 salpingo-oophorectomy of, robot-assisted, 54t Familial adenomatous polyposis, 421, 519, 1419-1422, 1420f hepatoblastoma in, 421, 502 Familial Mediterranean fever, 1477 Familial polyposis ileoanal pouch procedure in, 1421, 1472 ileostomy in, 1483, 148G1485, 1486 Famotidine for gastroesophageal reflux, 1126 for peptic ulcer disease, 1230 Fanconi's anemia, 179, 182 Farnesyl transferase inhibitors, 425 Fascia iliaca block, 246, 246f Fascial sling, for bladder outlet, 1831, 1831f Fasciotomy for snakebite, 353 in lower extremity trauma, 379 in upper extremity trauma, 351 of burned extremity, 386 in electrical burn, 396 FAST (focused abdominal sonography for trauma), 296297. 296f echocardiography in conjunction with, 286 gastrointestinal trauma and, 311, 312 renal trauma and, 319 Fasting euglycemia during, 225 preoperative, 223-224, 224t, 225 fluid deficit caused by, 225 Fat (s) body composition of, 195 in chyle, 1026 in enteral formulas, 200t, 201t, 202 for short-bowel syndrome, 212-213 intestinal adaptation and, 1370 in parenteral formulas, 204-206, 208 peroxidation of, 108 malabsorption of, 213 metabolism of carnitine and, 208 in neonate, 100, 101, 102-104, 103f postoperative, 106, 107-108 nutritional requirement for, 195, 197, 197f Fatty acids deficiencies of, in biliary atresia, 212 omega-3, for Crohn's disease, 1456 requirements for, 197, 197f Fawn tail, 2102 Fc receptors, 163, 164 FDG (fluorodeoxyglucose). See Positron emission tomography (PET). Fear. See Anxiety, patient. Fecal pigment, spectroscopy of, 1607 Fecalith, in appendicitis, 1502, 1504 Fecaloma, 1593, 1594 Feces. See also Defecation; Incontinence, fecal. formation of, 1568 in failure to thrive, 213 in short-bowel syndrome, 213 unabsorbed carbohydrates in, 203 Feet. See Foot (feet).

Female genital tract. See also Cloaca; Ovary(ies); Uterus; Vagina. embryology of, 1935-1936 Feminizing tumors, adrenocortical, 635 Femoral artery, iatrogenic injury to, 378f, 380 Femoral cutaneous nerve, lateral, fascia iliaca block and, 246, 246f Femoral deficiency, 2050-2051,2052f-2053f Femoral head, avascular necrosis of fracture-related, 345 hip dysplasia and, 2021, 2022, 2023 Femoral hernia, 1175, 1185, 1188 Femoral neck, fracture of, 345,345f Femoral nerve, fascia iliaca block and, 246, 246f Femoral shortening osteotomy, 2022, 2022f Femur. See (~1.50Femoral head; Femoral neck. fracture (s) of fixation of, 343f growth disturbances secondary to, 339, 341f in birth injury, 404 in child abuse, 403 reconstruction of, after tumor resection, 666,667 Fenretinide (4HPR), for neuroblastoma, 484 Fentanyl, 240, 241, 241t, 242 caudal, 248 during extracorporeal life support, 138-139 epidural infusion of, 248, 24% in neonate, operative stress and, 106, 211 in patient-controlled analgesia, 243, 243t inhalation anesthetics with, 229 transdermal, 242 Ferric gluconate, 207 Ferritin, serum, in neuroblastoma, 470,487 Ferrous sulfate, peptic ulcers associated with, 1228 Fetal alcohol syndrome neuroblastoma in, 467 rhabdomyosarcoma in, 525 Fetal hydantoin syndrome, 467 Fetal interventions. See also Prenatal diagnosis; Shunt, thoracoamniotic; Stem cells. fetoscopic, 78, 79-80, 79t, 81f, 83, 84, 85 tracheal occlusion as, 259 for congenital diaphragmatic hernia, 259, 939 for cystic mediastinal lesion, 960, 965 for enteric cyst, thoracic, 1393 for gastroschisis, 1161 for lung mass, 956, 956f for myelomeningocele, 83t, 84-85, 1991-1992, 1992f, 2062 for posterior urethral valves, 82t, 83, 1899-1900 for teratoma mediastinal, 565 sacrococcygeal, 82t, 85, 559 historical perspectives on, 6, 78, 79t management of mother and fetus in, 78-79 medical, 81-82, 82t open technique of, 78, 80f percutaneous, 78, 80,83,85,86 problems amenable to, 33, 78, 78t, 82-86, 82t-83t risks of, 79-80 robotic, in animal models, 48, 55, 56t Fetus. See also Embryology; Prenatal diagnosis. acid-base balance in, 95-96, 96t alpha fetoprotein in, 77, 555 biochemical screening and, 77 cardiovascular physiology of, 146, 147-148, 149f, 935 cell sampling from, 77, 78, 86 fluid balance in, 91-92, 93f

Fetus ( Continued) healing without scarring in, 86-87 hepatic tumors in hemangioendothelioma as, 496 mesenchymal hamartoma as, 497 imaging of with computed tomography, 77 with MRI, 37, 77 with ultrasound, 32-33, 77, 78 lung development in, 114117, 115f-116f medical treatment of, 81-82,82t. See also Fetal interventions. metabolism in, 97, 100, 101 neuroblastoma in, 467 renal function in, 93 selective reduction of, 82t, 85 small intestinal development in, 1370 stem cell transplantation in, 82, 83t, 86, 87 tissue engineering for, 28, 78 water content of, 91,98 Fetus in fetu, 558, 2080 intrahepatic, 499 retroperitoneal, 558, 558f Fiber, dietary constipation and, 1592, 1594 gastrointestinal polyps and, 1422 Fibrin casts, in inhalation injury, 395 Fibrin degradation products, 184t, 186 Fibrin sealant for adhesion prevention, 1360 for airway injury, 283, 283f for biopsy-related hemorrhage, 442 for lymph leak, 1411 for lymphangioma, 2139 in perianal Crohn's disease, 1458 Fibrinogen, 186 congenital deficiency or defect of, 185 Fibrinolysis, 186 Fibrinolytic therapy. See Thrombolytic (fibrinolytic) therapy. Fibroadenoma, of breast, 889-890,889f Fibroblast growth factor, basic (bFGF) hemangioma and, 2095,2104 Wilms' tumor and, 448, 460 Fibroblasts cytokines secreted by, 165 on synthetic dressing, 390 Fibroma (s) chondromyxoid, 652f in Gardner's syndrome, 1422 non-ossifying, 652, 652f, 654 ovarian, 593, 605-606 Fibromatosis(es), 542 Fibromuscular hyperplasia, 21 17-21 18, 21 19, 2119f, 2120-2121 Fibronectin aganglionosis and, 1525 bacterial adherence to, 158, 168 Fibroproliferative lung disease, pre-ECLS mechanical ventilation and, 135 Fibrosarcoma breast, 892 in Gardner's syndrome, 1422 infantile, 542, 543, 544t, 546 vs. lymphatic malformation, 2099 ovarian, 593, 615 pulmonary, 546 tracheal, 546 Fibrous dysplasia, 654 in Gardner's syndrome, 1422 resection of, 659 Fibrous hamartoma of infancy, 542 Fibular deficiency, 2051, 2053f, 2054, 2054t femoral deficiency with, 2050-2051 Fimbriae, 158 Iolume 1, pages 1-1 140; Volume 2, pages 1141-2

Fine-needle aspiration biopsy, 438 in lymphadenitis, 845, 846, 847 needle tract tumor recurrence and, 439 of thyroid nodule, 8 5 4 8 5 5 salivary gland, 837 Finger, tissue-engineered, 23, 23f, 82 Finite element models, in simulation, 61, 64 First and second branchial arch syndrome, 788-789. See also Branchial anomalies. FISH (fluorescence in situ hybridization), 419, 425,437,438 Fish oil, for Crohn's disease, 1456 Fistula(s) anal, 1597, 1598, 1598f anorectal anomalies with. See Anorectal malformations. arteriovenous. See Arteriovenous fistula. in Crohn's disease, 1454, 1456, 1457, 1458 neck. See Neck, cysts and sinuses of. omphaloileal, 1304, 1307f, 1310-131 1, 1311f superior rresical, 1842, 1843f, 1846 thoracic duct, 1026, 1027 urethrocutaneous, 1890f, 1894, 1894f Fitz-Hugh-Curtis syndrome, 1645 Five Ps in compartment syndrome, 344 in ischemia, 348 FK-506. See Tacrolimus. Flail chest, 269, 277, 279 in cerebrocostomandibular syndrome, 918 Flap procedures, for ureteropelvic junction obstruction, 1734, 1734f-1735f, 1735 Flap tissue transfer, 2063 Flap valve, 1797, 1797f, 1832, 1832f. See also Mitrofanoff procedure. Flatfoot deformity, 2024 Flavopiridol, 425 Fletcher factor, deficiency of, 185-186 Flexor digitorum, test of, 350, 351f Florida pouch, 1826 Flow cytometry, 415, 437 Fluid balance in fetus, 91-92, 93f in neonate, 91-96,94t, 96t preoperative fasting and, 225 third-space loss and, 226 Fluid management or resuscitation for burn patient, 385,386389, 388t with chemical burn, 395 with inhalation injury, 395 for critically ill infants, 225 for pheochromocytoma patient, 632 for premature infants, =5 for renal transplant patient, 704, 705, 706 for sepsis or SIRS, 17'2 for trauma, 271-272 to brain, 356, 363, 364, 364t, 365 in gastrointestinal hemorrhage, 1384 in hypertrophic pyloric stenosis, 1218 in short-bowel syndrome, 1372, 1373 intraoperative, 225-226 maintenance, 196, 225 parenteral nutrition and, 206 preoperative restriction in, 223-224, 224t, 225 Fluorescence in situ hybridization (FISH), 419, 425,437,438 Fluorodeoxyglucose (FDG). See Positron emission tomography (PET). &Fluorodopamine, 630 5-Fluorouracil, 423t, 428 Focal brain injury, 357-358,358f-359f, 366

xxiv

INDEX

Focal nodular hyperplasia (FNH), 495, 498-499, 499f Focal segmental glomerular sclerosis (FSGS), 699, 700, 701, 710, 711 Foley Y-V-plasty, 1734f, 1735 Folic acid, 1250 neuroblastoma and, 487 supplementation of after bariatric surgery, 1250 during pregnancy, 805, 1808,1988,1990 Follicular cysts, ovarian, 600-601, 600f, 602 Fontan procedure, 1975, 1977-1978, 1978f Foot (feet) ablation of, 2051, 2054 bone tumor in, 666 congenital anomalies of, 2023-2025, 2023f-2024f puncture of, with osteomyelitis, 2042, 2043f Football sign, of pneumoperitoneum, 1437 Foramen cecum, 850,865,866f Foramen ovale, 120, 148, 149f closure of, 148, 935 patent in congenital diaphragmatic hernia, 148 in neonate referred for cardiac transplant, 756 Forearm, reconstruction of, after tumor resection, 665 Foregut cyst duplication. See Duplication(s), alimentary tract, foregut. in floor of mouth, 826 Foreign body airway abscess secondary to, 1015 bronchiectasis secondary to, 1013, 1014 bronchoscopic removal of, 974,975-976, 975f, 977, 1012, 1014, 1015 pneumonia caused by, 1011, 1012 esophageal. See Esophagus, foreign body in. in appendix, 1502 in Meckel's diverticulum, 1311 intestinal obstruction caused by, 1364 nasal, 821 soft tissue injury caused by, 351, 352 Foreskin phimosis of, 1905 preservation of, in hypospadias repair, 1884, 1885f Formula(s) enteral, 200t, 201t, 202-203 for burn patients, 393 hyperosmolar, 1428-1429 hypoallergenic, 1125, 1372 intestinal flora and, 1433 necrotizing enterocolitis and, 202, 1428-1429,1432, 1433,1434, 1435, 1439, 1444, 1445 parenteral, 204-206 low-fat, 1410 Fourth ventricle area postrema of, 672 trapping of, 2001-2002 tumors in, 674, 675, 675f Fowler-Stephens orchidopexy, 1203 in prune-belly syndrome, 1785 Fractionated radiosurgery, 4 4 4 5 , 46 Fractionated radiotherapy, 44, 4 6 4 7 , 429 Fracture (s). See also Musculoskeletal trauma. birth injury with, 404 child abuse with, 347, 401t, 402-403 rib fractures in, 278, 279 deformities secondary to, 339, 341f, 342 evaluation of, 339, 341-342, 341f physical findings in, 349

Fracture(s) (Continued) femoral neck, 345, 345f growth disturbances secondary to, 339, 342, 344 hand, 349-350,351-352 healing of, 338-339, 340f-341f, 342 lymphangiectasia as cause of, 2140 management of definitive, 342, 342f-343f, 344 immediate, 342 mechanics of, 337 nasal, 820 open, 344 of hand, 349-350 pelvic, urinary tract injuries with, 318, 327, 328, 328f, 329, 330-331 periosteum and, 337, 338, 339f, 342, 345 physeal, 337-338, 339, 339f imaging of, 341f, 342 management of, 342,343f, 344 premature closure caused by, 345 rib. See Rib(s), fracture of. skull, brain injury with, 357, 358, 358f-359f, 363,364 spinal, 345-346, 346f temporal bone, 816817, 817f tumor-related, 650-651, 651f atjoint, 652 telangiectatic osteogenic sarcoma with, 652 through osteogenic sarcoma, 656 types of, 337, 338f unicameral bone cyst with, 651, 651f, 658 vascular trauma with, 342, 344, 345 in extremities, 378-380, 379t Frank-Starling relation, 147, 147f FRC. See Functional residual capacity (FRC). Free flaps, 352 Free radicals. See Oxygen free radicals. Fresh frozen plasma citrate in, hypocalcemia caused by, 227 during extracorporeal life support, 138 for disseminated intravascular coagulation, 186 for head trauma patient, with coagulopathy, 274 for massive blood loss, 226 for neonatal sepsis, 173 Fryns' syndrome, 1161 FSGS (focal segmental glomerular sclerosis), 699, 700, 701, 710, 711 Functional residual capacity (FRC) , 118, 118f, 119 in congenital diaphragmatic hernia, 938 low, in children, 276 mechanical ventilation and, 125, 128 Fundoplication, 1127-1 130, 1127f-1130f after esophageal repair for achalasia, 1114 for atresia, 1065, 1069, 1111 for congenital stenosis, 1072 complications of, 1133 gastrostomy with, 199, 1131 laparoscopic, 1127, 1128-1 130, 1129f-113Of, 1133 outcomes of, 1133 pyloroplasty and, 1130, 1133 robot-assisted, 53, 54t Fungal infection catheter-related, 210 hepatic, 1644 in necrotizing enterocolitis, 1435-1436, 1438 in transplant patient bone marrow, 781 heart, 761

Fungal infection (Continued) liver, 737, 739, 740t lung, 775 mediastinal, 1028 of burns, 389, 390, 394 pulmonary bronchiectasis and, 1013 in cancer patient, 1006-1007, 1006f in HIV-infected patient, 1010 sinusitis as, 819 Ft~rlowpalate repair, 809, 810f Furosemide. See also Diuretic renography. for heart failure, in neonate, 148, 150t Fusion genes and proteins, 415, 416, 419,427 fine-needle aspiration biopsy and, 438

Gabexate mesylate, 1673 Galactorrhea, 888, 888f juvenile hypothyroidism with, 601 Galactosemia, soy formulas in, 200t, 202 Galeazzi's sign, 2019 Gallbladder. See also Cholecystectomy; Cholecystitis; Cholelithiasis. absent, 1237 hydrops of, 1636, 21 15 polyps of, 1636-1637 Gallium 67 scan, in non-Hodgkin's lymphoma, 585 Gallstones. See Cholelithiasis. Gamma cell tumor, 1685 Gamma globulin for neonatal sepsis, 173 prophylactic, for low-birth-weight infants, 173 Gamma Knife, 45, 45f Ganciclovir after heart transplant, 762 after intestinal transplant, 750, 751 after lung transplant, 775 for cytomegalovirus esophagitis, 1386 Gangliocytoma, 671 Ganglioglioma, 671, 677, 677f Ganglion cell tumors, of brain, 671 Ganglion cells in neuroblastoma, 472, 473 intestinal. See also Aganglionosis; Hirschsprung's disease; Intestinal neuronal dysplasia. staining of, 1562, 1562f-1563f stem cells for, 1526 Ganglioneuroblastoma diarrhea associated with, 469, 486 horseshoe kidney with, 1719 neuroblastoma maturing to, 473 pathology and histology of, 472, 472t, 473,473f Ganglioneuroma diarrhea associated with, 469,486 neuroblastoma maturing to, 468,473,483,487 pathology and histology of, 472, 472t, 473,473f Gangrene. See also Ischemic necrosis, gastrointestinal. extremity amputation secondary to, 2058 arterial thrombosis and, 21 15, 21 16 intestinal adhesive obstruction with, 1359, 1360 appendicitis with, 1502 intussusception with, 1314f, 1317, 1333 necrotizing enterocolitis with, 1439, 1440 umbilical, 1146 vasospasm causing, 380, 381, 2121

Volume 1, pages 1-1140; Volume 2, pages 1141-2146.

GANT (gastrointestinal autonomic nerve tumor), 516 GAP (glans approximation procedure), 1880, 1882, 1883f Gardner's syndrome, 519, 1420, 1422 Gartner's duct cyst, 1902-1903, 1950-1951 Gas exchange, pulmonary, 120-121, 121f Gastrectomy, partial for spontaneous perforation, 1236 for stress ulcers, 1231-1232 Gastric. See also Stomach. Gastric acid. See also pH, esophageal monitoring of. gastroesophageal reflux and, 1123,1126 hypersecretion of, after massive enterectomy, 1372, 1373 in preterm infant, 1226, 1428, 1433 ulcers and, 1225, 1225t, 12261228, 1229, 1230, 1231 Gastric band, laparoscopic adjustable, 260, 1242-1243, 1248, 1248t, 1250 Gastric cancer. See Stomach, tumors of. Gastric dilatation, in spinal injury, 369 Gastric duplication, 1391, 1393-1394, 1678 Gastric emptying gastroesophageal reflux and, 1123, 1124 inhalant anesthetics and, 1361 prokinetic agents and, 1126 pyloroplasty and, 1130, 1133 Gastric emptying study before enteral feeding, 199 with suspected gastroesophageal reflux, 1124 Gastric mucosa, ectopic, 1307-1308, 1308f, 138G1387 in duplications, 1308, 1387,1389,1390, 1391, 1392, 1393, 1394, 1395,1396, 1678 Gastric outlet obstruction. See also Pyloric stenosis, hypertrophic. by foreign body, 1364 congenital, 1232-1234, 1232f-1233f, 1232t duplication presenting as, 1391, 1394 in peptic ulcer disease, 1230 Gastric perforation, spontaneous, in newborn, 1235-1236, 1236f Gastric transposition, for esophageal replacement, 1065, 1101, 1102f, 1103-1104, 1103t Gastric tube. See also Nasogastric tube. esophageal injury caused by, 405 in trauma patient, 272 Gastric tube esophagoplasty, 1065, 1098, 1099f-llOOf, 1100, ll00t Gastric ulcer. See Peptic ulcer disease. Gastric varices, 1654, 1657, 1659, 1662, 1663-1664. See also Varices. Gastrin, maternal, neonatal ulcers and, 1230 Gastrinoma, 1231, 1685 Gastritis bleeding in, 1385, 1386 causes of, 1225t, 1386 clinical presentation of, 12281 epidemiology of, 1226 Helzcobacter pylon' in, 1227, 1229 stress, in neonate, 1385 Gastrocystoplasty, 1797, 1827, 1827f before renal transplantation, 1835 complications of, 18361837 Gastroduodenoscopy with duodenal obstruction, 1263 with gastroesophageal reflux, 1039-1040,1040f Gastroduodenostomy, for gastric perforation, 1236 Gastroenteritis, acute, vs. appendicitis, 1505 Gastroesophageal junction, esophagoscopy of, 1038

Gastroesophageal reflux, normal physiologic, 1108-1109, 1124 Gastroesophageal reflux disease (GERD), 1120-1 134. See also Esophagitis; Fundoplication. after lung transplant, 772-773 bleeding in, 1386 clinical features of, 1121 congenital diaphragmatic hernia with, 142, 944,944f, 1123 congenital esophageal stenosis and, 1071, 1072 definition of, 1121 diagnosis of, 1120,1124-1125, 1125b esophagoscopy in, 1039-1040,1040f, 1124 manometry in, 1039, 1069, 1124 embryological basis of, 1120-1 121 enteral feeding and, 199, 203, 1130-1131 esophageal atresia and after repair, 1068, 1069, 1070, 1071, 1111 before repair, 1058, 1111 esophageal cancer secondary to, 517 esophageal dysmotility in, 1112 esophageal injury and caustic, 1086, 1088 peptic, 1093-1094 gastroschisis with, 1123, 1162 gastrostomy and, 199, 1130-1 131 historical perspective on, 1120 in disabled children, 214, 1121, 1126, 1127, 1131 laryngeal stenosis with, 991 laryngomalacia with, 829, 986 laryngotracheoesophageal cleft with, 995 microgastria with, 1237-1238 omphalocele with, 1162 pathophysiology of, 1121-1124, 1121f-1122f primary, 1112 respiratory complications of, 1124, 1125b aspiration as, 1015 esophageal pH monitoring and, 1039 robotic surgery for, 53 spasmodic croup in, 830 summary of, 1134 treatment of, 1125-1133 conservative, 1125-1 126 endoluminal, 1126 medical, 1126 surgical, 1126-1 133, 1127f-1132f Gastrografin. See Diatrizoate enema. Gastroileal pouch, 1799 Gastrointestinal autonomic nerve tumor (GANT), 516 Gastrointestinal hemorrhage. See Hemorrhage, gastrointestinal. Gastrointestinal motility. See Enteric nervous system; Esophageal dysmotility; Gastric emptying; Intestinal dysmotility; Intestinal pseudoobstruction. Gastrointestinal stromal tumors (GISTS), 515-517,5171 Gastrointestinal tumors, 515-522 carcinoid, 518, 518f clinical presentation of, 515 colorectal adenocarcinoma, 518-522, 5191, 520f-521f in familial adenomatous polyposis, 421 esophageal, 517 gastric, 515, 517-518 incidence of, 515 stromal, 515-517, 517t Gastrojejunal tube, 1484 dume 1, pages 1-1140; Volume 2, pages 1141-2

Gastrojejnnostomy for stress ulcers, 1231 intnssusception around tube in, 1322 Gastropexy, for congenital esophageal stenosis, 1072 Gastroplasty, vertical banded, 1248, 12481 Gastroplication, endoscopic, 1126 Gastroschisis, 1157, 1158, 1158f, 1158t, 1160, 1160f associated conditions with, 1162, 1162t cryptorchidism as, 1195 intestinal atresia as, 1270, 1271, 1277, 1281, 1282,1283 clinical features of, 1162 complications of, 1166, 1167 short-bowel syndrome as, 1369, 1369f gastroesophageal reflux associated with, 1123,1162 genetics of, 1161 incidence of, 1I62 obstetric delivery with, 1161 outcome of, 1 1 6 6 1167 prenatal diagnosis of, 1161 prenatal treatment of, 831, 86 rotational abnormality in, 1346 treatment of, 1165, 1164f, 1165-1 166,1166f enterostomy in, 1484f, 1486 umbilicoplasty after repair of, 1153, 1154f Gastroscope, flexible video, for esophagoscopy, 1043-1 044 Gastrostomy, 199 endoscopic, 199, 1042-1043 gastric perforation in placement of, 1236 gastroesophageal reflux and, 199, 1130-1131 in cricopharyngeal disorders, 1110 in esophageal atresia, 1061, 1065 in short-bowel syndrome, 1372 intnssnsception around tube in, 1322 robot-assisted, 53 techniques of, 1131-1133,1131f-1132f, 1480t Gaucher's disease, 1693, 1697 GD2 ganglioside, in neuroblastoma, 427, 474, 485 GDNF (glial cell line-derived neurotrophic factor), 1521-1522, 1522f, 1523t, 1524,1525, 1705 Gefitinib (Iressa), 425 Gemcitabine, 428 Gene amplification, 417, 419, 420t, 426 Gene chips, 40 Gene expression radiolabeled probes of, 38 RNA microarrays and, 419-420 Gene therapy, 15-18, 16f, 17t anticancer, 427 for hepatocellular carcinoma, 510 with angiogenesis inhibitors, 475 fetal, 82 for cystic fibrosis, 1011 for Hirschsprung's disease, 1526 liver shortage and, 740 Genetic counseling, 1 4 1 5 about cleft lip and palate, 806, 806t about Hirschsprung's disease, 1523 Genetic testing cancer and, 421 guidelines for, 594 prenatal, 1 4 1 5 , 78 Genetics. See also Cancer, molecular biology of. molecular, 11-15, 12f, 13t of inflammatory response, 166, 169 of obesity, 1243 Genioplasty, osseous, 789, 790f, 800

xxvi

INDEX

Genitalia ambiguous. See also Intersex abnormalities; Sex assignment. hypospadias with, 1870, 1894, 1919 burns to, 403 lymphedema of, 2144 trauma to, 312, 331, 404 Genitourinary anomalies. See also Bladder exstrophy; Cloaca1 exstrophy; Duplication (s), genitourinary; Intersex abnormalities; Urethra, anomalies of. anorectal malformations with, 1567 imperforate anus as, 1822, 1823f, 1824 hindgut duplications associated with, 1396 rhabdomyosarcoma with, 524 sacrococcygeal teratoma with, 557, 559 urinary tract infection and, 1742 Wilms' tumor with, 446 Genitourinary trauma, 312, 317-331 anatomic considerations in, 317-318, 327 clinical features of, 318 diagnostic evaluation of, 318-320 epidemiology of, 317 grading of, 320, 321, 321f, 321t, 323, 325, 329,330 iatrogenic, 317, 326, 327, 328, 329, 331 in child abuse, 312, 401t, 404 mechanisms of injury in, 317 to bladder, 318,319-320,321t, 327-329,328f to bladder neck, 331 to external genitalia, 312, 331, 404 to kidney. See Kidney, trauma to. to ureter, 320, 321t, 326327 to urethra, 312, 318, 320, 321t, 329-331, 329f, 1901-1902 Genitourinary tumors. See also specific organ or tumor type.

rhabdomyosarcoma as, 532-534 Genomic imprinting, 446, 447 GERD. See Gastroesophageal reflux disease (GERD). Germ cell tumors biologic markers of, 555-556 cytogenetics of, 556557, 596 embryology of, 554 extragonadal. See also Teratoma. choriocarcinoma as, 568 cytogenetics of, 557 embryonal carcinoma as, 567 future perspectives on, 569 germinoma as, 563,567-568 gonadoblastoma as, 568 mediastinal, 557, 565, 567, 568, 959, 960t, 961,96lf, 962-963 mixed, 567,568-569 pineal. Seepineal gland, tumors in region of. polyembryoma as, 568 prognosis of, 554 staging of, 555, 555t treatment for, overview of, 569 yolk sac tumor as, 559, 561, 562, 567 histologic types of, 55+555 ovarian. See Ovarian tumors, germ cell. overview of, 554 risk stratification of, 569 sites of, 554 testicular. See Testicular tumors. Germ cells, cryptorchidism and, 1198 Germinoma, 567 extragonadal, 567-568 intracranial, 556, 563, 678 ovarian, 567, 607, 608f. See also Dysgerminoma. testicular, 567. See also Seminoma.

Gershoni-Baruch syndrome, 1160 Gestational age, 89,90, 90f-9lf. See also Birth weight. necrotizing enterocolitis and, 1428 neonatal mortality and, 90, 92f total body water and, 92 GFR (glomerular filtration rate) in fetus, 93 in neonate, 93, 94 Giant cell rich osteogenic sarcoma, 652 Giant cell tumor, of bone, 652,653,654,659 Giantcell arteritis, 21 17 Gingivostomatitis, herpetic, 822 GISTS (gastrointestinal stromal tumors), 515-517,517t Glans approximation procedure (GAP), 1880, 1882, 1883f Glansplasty, meatal advancement (MAGPI), 1880-1882, 1881f-1882f Glanzmann's thrombasthenia, 183, 190 Glasgow Coma Scale, in traumatic brain injury, 362, 367 Glaucoma, in Sturge-Weber syndrome, 2098 Gleevec. See ST1571 (Gleevec). Glenn anastomosis, bidirectional, 1977 Glial cell line-derived neurotrophic factor (GDNF), 1521-1522, 1522f, 1523t, 1524,1525,1705 Glioblastoma, 678 in Turcot's syndrome, 1422 Glioma, 671 brainstem, 673, 675f, 676 gefitinib for, 425 nasal, 820 Gliomatosis peritonei, ovarian teratoma with, 610,611 Glomangiomatosis, 2100 Glomerular filtration rate (GFR) in fetus, 93 in neonate, 93, 94 Glomus tympanicum tumor, 817 Glomuvenous malformations, familial, 2100 Glossoptosis, 803, 812, 825 glossopexy for, 1070 Glottis, laryngoscopic evaluation of, 973,983 Glucagon in burn patients, 391-392 in perinatal period, 100, 101, 103 in reduction of intussusception, 1330 postoperative stress and, 107 small left colon syndrome and, 1498 Glucagon-like peptide-2, for short-bowel syndrome, 1374 Glucocorticoids. See also Corticosteroid therapy; Cortisol. adrenal synthesis of, 628, 629 inflammation and, 166 insufficiency of, 636637 Gluconeogenesis, 197 cortisol and, 629 in neonate, 100, 101, 102, 103 postoperative, 106, 107 Glucose (dextrose) in fluid therapy, 225 for burn patient, 387, 388t in parenteral formulas, 204, 206, 208,210 intraoperative administration of, 225 nutritional requirement for, 196197 Glucose intolerance, obesity and, 1246 Glucose metabolism in neonate, 100-102, lOlt postoperative, 106, 107, 107f, 108 postoperative, 106, 107, 107f )lume 1, pages 1-1140; Volume 2, pages 1141-2146.

Glucose polymer, in enteral formulas, 202 Glutamine for short-bowel syndrome, 1374 in parenteral feeding, of neonates, 104, 196 y-Glutamyl transpeptidase, 1606 Glutathione peroxidase, 199 Glyceryl trinitrate, for anal fissures, 1597 Glycogen, storage of, 97 in neonate, 197 in perinatal period, 100-101 Glycogen storage disease, type I focal nodular hyperplasia in, 495 hepatocellular adenoma in, 495, 498 Glycogenolysis, 197 in neonate, 100-101 postoperative, 107 Glycopyrrolate, to prevent sialorrhea, with ketamine, 239 Glypican-3, in Wilms' tumor, 448 Goiter, 850, 851-853, 852t Goldenhar's syndrome, esophageal dysmotility in, 1112 Goldie-Coldman model, 422, 657 Goldstein test, 1181 Gonadal dysgenesis, 1912f, 1915t, 1917 diagnosis of, 1918t, 1919t, 1920 gonadoblastoma in, 568, 1920 ovarian, 612-613 testicular, 624 mixed, 1912f, 1915t, 1917, 1921, 1922, 1930 diagnosis of, 1918t, 1920 gonadectomy in, 624, 1920 Gonadoblastoma, 1920 extragonadal, 568 ovarian, 568,595t, 612-613 robot-assisted oophorectomy for, 53 testicular, 624 Gonadotropins. See also Human chorionic gonadotropin (hCG). cryptorchidism and, 1197 ovarian tumors and, 595t, 607 Gonococcal infection as arthritis, 2040, 2044 as perihepatitis, 1645 as peritonitis, 1477 GorhamStout syndrome, 2099 Graft-versus-host-disease bone marrow transplantation with, 431, 432, 779, 780, 782 chronic, 782 cytomegalovirus infection associated with, 1007 immunological basis of, 685, 689, 692 lymphoproliferative disease associated with, 584 transfusion-related, 188, 189, 190, 782 Granulocyte colony-stimulating factor for bone marrow transplant patient, 781 with typhlitis, 780 for hypersplenism, 1664 with chemotherapy, for lymphoma, 588 Granulocytic sarcoma, ovarian, 615 Granuloma(s) eosinophilic, temporal bone involvement of, 817 in chronic granulomatous disease, liver abscesses with, 1643, 1643f in Crohn's disease, 1454, 1455 pulmonary plasma cell, 640-641 vs. metastasis, 441, 441f pyogenic, vs. hemangioma, 2097 suprastomal, with tracheotomy, 986 umbilical, 1143, 1146

Granulosa-theca cell tumors, 593, 594, 595t, 604-605,605f in Peutzjeghers syndrome, 1418 Graves' disease, 851, 852-854 Great vessels, anomalies of. See also Aorta; Ductus arteriosus. pulmonary slings, 1978-1980, 1978t, 1982-1983, 1983f, 1984 airway obstruction by, 997,998 transposition of great arteries, 151, 1973-1975, 1974f, 1976f-1977f vascular rings, 1978-1984, 19781, 1979f-1983f robot-assisted division of, 54t, 55 Greater saphenous vein cutdown of, in trauma patient, 269-270, 271f duplication of, varicosity and, 2130 Growth malnutrition and, 195 normal, 194 of premature infant, 90, 91f, 97, 194 Growth factor receptors, 413f, 414,415 Growth factors hypertrophic pyloric stenosis and, 1216 lung development and, 117 congenital diaphragmatic hernia and, 945 malignant transformation and, 414, 415 necrotizing enterocolitis and, 1430-1431, 1430t signal transduction and, 413, 413f Wilms' tumor and, 459-460 Growth failure, in Crohn's disease, 1454, 1456 Growth hormone for burn patients, 391, 392, 392f, 393 for renal transplant patients, 713 for short-bowel syndrome, 1374 Growth plate. See Physis. Growth retardation in ulcerative colitis, 1464, 1465, 1466 intrauterine (IUGR), 89-90 hypoglycemia and, lOlt Gunshot wounds, to brain, 361 Gustilo classification, of open fractures, 344 Gynecomastia, 892,892f, 2066,2068-2070, 2069f adrenocortical tumors with, 635 Sertoli cell tumor with, 622, 624

HAART (highly active antiretroviral therapy), 1008, 1009 Haemophilus injluenzae infection, 1002 type B (HIB), 1002 acute lymphadenitis in, 845 osteomyelitis in, 2033-2034, 2037, 2038, 2038t septic arthritis in, 2040, 2041t supraglottitis in, 830-831 Haemophilus parainjluenzae peritonitis, 1477 Hageman factor, deficiency of, 185-186 Hairy nevus, giant, 2063-2064,2065f Halothane, 222, 222t, 227, 227t, 228, 228f, 229 gastric emptymg and, 1361 Hamartoma(s) breast, 886,891 fibrous, of infancy, 542 gastric polyps as, 1421 hepatic in tuberous sclerosis, 495, 498 mesenchymal, 495,496,497-498,497f-498f malignant tr-ansformation of, 505 vs. nonparasitic cyst, 499

Hamartoma(s) (Continued) in tuberous sclerosis, 1709 intestinal polyps as, 1364, 1414, 1415 in Peutzjeghers syndrome, 1417, 1418, 1418f lipofibromatous, of median nerve, 2075 lymphangioma as, 2137 pancreatic, 1684 pulmonary, 641 splenic, 1697 umbilical, 1149 Hand(s) bone tumor in, 665 congenital anomalies of, 2071, 2073-2075, 2073t, 2074f in Poland's syndrome, 907,908f, 2071, 2074 embryology of, 2071 ischemic necrosis of, radial artery catheter causing, 123 trauma to, 348-352,349f-351f Hand-foot syndromes, 181 Hand-foot-and-mouth disease, 822 Handicapped children. See Disabled children. Haptic feedback, 48,60-61, 6667,66f, 68 Harlequin eye sign, in coronal synostosis, 794 Harmonic scalpel, 41 for liver resection, 507, 508 for splenectomy, 1694, 1695-1696, 1695f partial, 1697 for splenic cyst excision, 1692-1693 Harmonic ultrasound imaging, 34, 34f Harrison's grooves, 904 Hartmann's pouch, for Crohn's disease, 1457-1458, 1459 Hashimoto's thyroiditis, 852 hCG. See Human chorionic gonadotropin (hCG). Head and neck masses. See also Neck. fine-needle aspiration biopsy of, 438 rhabdomyosarcoma as, 531-532 teratoma as, 563-565, 563f-564f Head circumference, normal, 195 Head trauma. See also Brain injury, traumatic; Skull fracture. early complications of, 365-367 epidemiology of, 357 outcomes with, 367 resuscitation in, 269 temporal bone fracture in, 81G817, 817f Hearing loss, 814-815,816, 817 Heart. See also Cardiac entries; Pericardial entries; Valves, cardiac. bacterial endocarditis of, 21 15-21 16, 21 16f ectopic. See Ectopia cordis. imaging of, ultrasound, contrast-enhanced, 33-34, 34f trauma to, 279, 285-287, 286f-287f epidemiology of, 275, 275t, 276, 292 initial resuscitation with, 277 penetrating, 291 presentation of, 276,277, 278 tumors of rhabdomyosarcoma as, 535 teratoma as, 557,558,565-566 Heart block, in neonate, 151 Heart disease, congenital. See also Great vessels, anomalies of; Valvular disorders, cardiac. associated anomalies with asplenia as, 1693 chest wall deformities as, 895, 904905 diaphragmatic hernia as, 932,933 esophageal atresia as, 1055 imperforate anus as, 1567 olume 1, pages 1-1 140; Volume 2, pages 1141-21

Heart disease (Contznued) atrial septal defect, 1 9 6 4 1966, 1964f-1966f atrioventricular septal defect, 153, 1968-1971, 1969f-1971f congestive heart failure in, 148, 150t, 151 heart block in, 151 hypoplastic left heart syndrome, 1975, 1977-1978, 1977f-197% in utero tolerance of, 148 neonatal management of, 153 neuroblastoma in situ in, 467 prenatal correction of, 82t, 85-86 tetralogy of Fallot, 153, 1971-1973, 1972f-1974f transplantation for heart, 754-755, 755f, 762,763 lung, 766767 ventricular septal defect, 153, 19661968, 1967f-1968f in tetralogy of Fallot, 1971, 197'2, 1972f-1973f omphalocele with, 1163 with transposition of great arteries, 1975 Heart failure. See Congestive heart failure; Right-sided heart failure. Heart rate, 146 in trauma patient, 267 Heart transplantation, 754-763 ABO-incompatihle, 757 combined with lung transplant, 767 complications of, 761-762, 761t mediastinitis as, 1028 contraindications to, 756 donor evaluation for, 757 extracorporeal life support as bridge to, 141, 756, 757 for hypoplastic left heart syndrome, 153, 754-755, 756, 757, 758, 759f, 762 for teratoma, resectable, 566 history of, 685, 686t, 688-689, 754, 754f immu~osuppressionfor, 754, 760-761,76Ot, 761f indications for, 754755, 755f operative techniques in, 757-760, 758f-759f organ allocation for, 757 organ procurement for, 757 postoperative management in, 760 preoperative evaluation for, 755-756, 756t preoperative management in, 75G757 results of, 762-763, 762f ventricular assist device as bridge to, 151, 756, 757 Heartburn. See Gastroesophageal reflux disease (GERD). Height, normal growth and, 195 Heineke-Mikulicz strictureplasty, 1457, 1457f Helicobacter pylori infection diagnosis of, 1229 gastroesophageaI reflux disease and, I123 in heterotopic mucosa, in Meckel's diverticulum, 1307 peptic ulcer disease and, 1226, 1227, 1227t, 1228, 1229, 1386 primary gastritis and, 1386 Heliox, 828 Helium dilution test, 118 Heller myotomy, 1114 robot-assisted, 53, 54t Hemagglutinin, 158 Hemangioendothelioma infantile hepatic, 495, 496497, 496f, 2112 transplantation for, 733 kaposiform, 2094, 2097-2098, 2097f, 2105 salivary gland, 839

xxviii

INDEX

Hemangioma (Continued) associated anomalies with, 2096, 2102 arteriovenous malformation as, 21 13 breast, 888-889, 889f cavernous, 2094,2096, 2099 clinical features of, 209S2097, 2096f-2097f congenital noninvoluting, 2097 rapidly involuting, 2097, 2097f, 2102, 2106 cutaneous hepatic hemangioendothelioma with, 495,496 subglottic hemangioma with, 830, 994 differential diagnosis of, 2097, 2102 gastrointestinal bleeding caused by, 1387 obstruction caused by, 1364 head and neck, 826,2096f, 2104 bifid sternum with, 914 hepatic, 497, 2102, 2105f, 2106 focal nodular hyperplasia with, 498 in Maffucci's syndrome granulosa cell tumors with, 593 of hand, 652 management of, 2103-2106,2104f-2106f with corticosteroids, 2104, 2104f for subglottic lesion, 994, 995 for vaginal lesion, 1951 with interferon-a, 21042105 for mediastinal lesion, 966 for subglottic and tracheal lesions, 994, 995 for vaginal lesion, 1951 mediastinal, 966 ovarian, 614 pathogenesis of, 2095 radiologic characteristics of, 2103 salivary gland, 835, 836, 836f, 838-839 splenic, 1697 subglottic, 828,830,830f, 99&995,994f, 2103 tracheal, 994995 ulceration of, 2103 vaginal, 1951 visceral, 2102 Hemangiopericytoma, 542, 546 Hematemesis in child, 1387 in infant, 1386 in newborn, 13841385 varices as cause of, 16541655, 1657 Hematocele, 331 Hematochezia, 1386 anal fissure with, 1596, 1597 eosinophilic proctocolitis with, 1599 rectal ulcer with, 1599 Hematocrit, blood products and, 187, 188, 226, 226t Hematoma bladder, 328, 329 duodenal, 3 0 4 , 3 0 4 ~305f, 306,306t secondary to biopsy, 780 gastrointestinal, 310 hepatic abscess secondary to, 1643 in birth trauma, 405, 405f iatrogenic, femoral catheterization and, 380 in birth injury, 404, 405, 405f in vascular injury, 377 intracranial, 266, 272, 273, 357, 358, 359, 359f in birth injury, 405 in child abuse, 401 in "minor" injury, 365 surgery for, 364365, 365f nasal, septal, 820

Hematoma (Continued) penile, 331 secondary to nerve block, 246, 247 perinephric, 322 pulmonary, 281 renal, 323 retroperitoneal, 322, 323 scrotal, 331 upper extremity, 379 Hematoma block, for fracture reduction, of hand, 352 Hematopoietic growth factors, recombinant, for anemia, 179 Hematopoietic stem cell transplantation. See Stem cell transplantation. Hematuria evaluation of, multidetector computed tomography in, 35 in hemorrhagic cystitis, 781-782 urinary tract trauma with, 318-319, 320 renal, 319,320-321,323, 324 ureteral, 326 urethral, 329 Hematuria-dysuria syndrome, 1797, 1800, 1836 Hemi-Fontan procedure, 1977, 1977f, 1978 Hemihypertrophy adrenocortical tumors with, 633 hepatoblastoma with, 502 vascular malformations with, 2101, 2101f, 2107-2108, 2112, 2114 Wilms' tumor with, 446, 449 Hemi-Kock pouch, 1833 Hemimelia, 2051f Heminephroureterectomy, robot-assisted, 53, 54t Hemisacrum, 1567, 1572 Hemiscrotectomy, orchiectomy with, for germ cell tumor, 623 Hemivagina(s), 1568, 1571, 1582, 1583, 1583f, 1585f Hemivertebra(e), 2027,2027f-2029f anorectal malformations with, 1567, 1569 in spondylothoracic dysplasia, 917, 918f neurenteric cyst with, 965 torticollis secondary to, 877 Hemoglobin fetal in Diamond-Blackfan anemia, 179 oxygen saturation and, 122 oxyhemoglobin dissociation curve and, I21 nitric oxide and, 161, 162 oxyhemoglobin dissociation curve and, 121, 121f Hemoglobin concentration, mixed venous oxygen saturation and, 122, 123 Hemoglobin saturation, 118t monitoring of, 121-123 Hemoglobinopathies. See Hemolytic anemias. Hemolymphangioma, 2138 Hemolysis during extracorporeal life support, 140 in transfusion reactions, 189 Hemolytic anemias, 181-182. See also Sickle cell disease; Spherocytosis, hereditary; Thalassemia(s). cholecystectomy in, 1635-1636, 1641 cholelithiasis in, 181, 182, 1635-1636, 1637, 1641,1642,1673,1693, 1698 splenectomy in. See Splenectomy, in hemolytic anemias. Hemolytic-uremic syndrome colonic stricture in, 1495 renal graft loss in, 71 1

Volume 1, pages 1-1 140; Volume 2, pages 1141-2146

Hernoperitoneum adrenal hemorrhage with, in neonate, 637 FAST sonography of, 297 Hemophilia, 185 gene therapy for, 18 trauma patient with, 274 Hemopneumothorax, 269,272 epidemiology of, 275t Hemoptysis, 1014, 1015f Hemorrhage. See also Hematoma; Vascular trauma. adrenal infection-related, 637 neonatal, 630, 637 after open biopsy, 442 anemia secondary to, 180-181 estimation of blood loss in, 226 extracorporeal life support with extracranial, 140 intracranial, 135, 136, 137, 139 gastrointestinal, 1383-1387 common causes of, 13841387, 1385t diagnostic algorithms for, 1383f-1384f esophagoscopy in, 1041 in blue rubber bleb nevus syndrome, 2103,2107 in necrotizing enterocolitis, 1435, 1439 in peptic ulcer disease, 1229, 1230, 1231 initial management of, 1383-1384 juvenile polyps with, 1387, 1415, 1416 lymphoid polyps with, 1419 Meckel's diverticulum with, 130S1309, 1308f-1309f portal hypertension with, 1654-1655, 1657, 1658. See also Varices. rectal. See Rectal bleeding. stress ulcers with, 1231 submucosal, 1364 vascular malformations with, 1598 hepatic during resection, 508 in birth injury, 405 in coagulation disorders, 183, 185-186, 185t in trauma patient, 272, 377 abdominal injury and, 299,300-302, 300f-301f, 301t brain injury and, 358-359, 358f-361f, 361, 365, 366 hand injury and, 348 renal injury and, 324 thoracic injury and, 280f, 281-282,291 intracranial. See also Intraventricular hemorrhage. brain tumor with, 672, 673, 679 in birth injury, 405 in child abuse, 401 intraperitoneal, ruptured hepatocellular adenoma with, 498 intraventricular as birth injury, 405 in premature infants, vitamin E and, 198 traumatic, 359, 360f, 361, 362 massive, recombinant factor VII for, 301 platelet transfusion for, 190 portal hypertension with, 1654-1656, 1657 pulmonary, 1014, 1015f after lung transplant, 772 in pulmonary vascular disease, 766 retinal, in child abuse, 361 Hemorrhagic cystitis, after bone marrow transplantation, 781-782 Hemorrhagic disease of the newborn, 1384 Hemorrhagic shock, nitric oxide synthase and, 169

INDEX Hemorrhoids, 1598-1599, 1599f in ulcerative colitis, 1465 Hemosiderosis, transfusional, 180 Hemostatic instruments, 40-41 Hemothorax, 269, 276, 277, 278, 280f, 281 epidemiology of, 275, 275t, 276 traumatic, 282 Henderson-Hasselbalch equation, 95, 118t, 121 HenochSchonlein purpura intussusception in, 1320, 1327-1328 renal graft loss in, 711 subrnucosal hemorrhage in, 1364 Heparin antithrombin I11 and, 187 during extracorporeal life support, 138, 139, 140 for disseminated intravascular coagulation, 186 for inhalation injury, 395 for pulmonary embolism, 2132 for venous thrombosis, 187 renal vein, 1754, 1754t in parenteral nutrition solution, 207 prophylactic for liver transplant patient, 737 for spinal injury patient, 370 Hepatic veno-occlusive disease, 431-432, 780-781,1654 Hepaticojejunostomy, robotic, porcine, 55, 56t Hepatitis bacterial, 1644 cirrhosis secondary to, 733 Hepatitis B hepatocellular carcinoma and, 503 transfusion-acquired, 189 Hepatitis C, transfusion-acquired, 189 Hepatobiliary scintigraphy. See Radionuclide studies, hepatobiliary. Hepatoblastoma, 502-511, 502t, 505f, 505t, 509f, 511t. See also Liver, tumors of. biopsy of, hemorrhage secondary to, 442 etiology of, 502 glypican9 in, 448 in Beckwith-Wiedemann syndrome, 449,502 in familial adenomatous polyposis, 421,502 laparoscopic visualization of, 440 transplantation for, 733 vs. hemangioendothelioma, 496 Hepatocellular adenoma, 495, 498 Hepatocellular ascites, 1407t, 1408f, 1409, 1409t Hepatocellular carcinoma, 502-51 1, 502t, 505t, 51 1t. See also Liver, tumors of. arising in hepatocellular adenoma, 498 transplantation for, 733 vs. focal nodular hyperplasia, 498 Hepatocytes injury to, portal hypertension caused by, 1652-1653,1653t necrosis of, in posthepatic portal hypertension, 1653-1654 tissue engineering with, 26-27 Hepatopulmonary syndrome, 1656 Herceptin. See Trastuzumab (Herceptin). Hermaphroditism, 1915t, 1917 diagnosis of, 1918t, 1920 inguinal contents of, 1188-1 189 management of, 1921, 1922, 1926, 1930

Hernia. See Abdominal wall, hernia of; Diaphragmatic hernia; Femoral hernia; Inguinal hernia; Internal hernia; Intestinal obstruction, hernias with; Parastomal hernia; Umbilical cord hernia; Umbilical hernia. Herniography, 1175, 1187 Herpangina, 822 Herpes simplex virus (HSV) as gene therapy vector, 17, 17t esophagitis caused by, 1386 gingivostomatitis caused by, 822 liver transplantation and, 740t Heterotaxia, intestinal malrotation in, 1346, 1348, 1350, 1354f High-frequency oscillatory ventilation (HFOV), 125,126,141 Highfrequency ventilation (HFV), 125-126 Hilar twist, for lung trauma, 277, 279 Hilgenreiner's line, 2020, 2020f Hill gastropexy, for congenital esophageal stenosis, 1072 Hinman syndrome, 1812-1813, 1812f Hip, developmental dysplasia of, 2018-2023, 2019f-2023f, 2020t Hirschspmng's disease, 1514-1547 acquired, 1530 animal models of, 1520,1526 appendicitis in, 1502, 1530 associated anomalies with, 1528 colonic atresia as, 1493, 1495, 1528 imperforate anus as, 1567 in Waardenburg's syndrome, 1522 neuronal dysplasia as, 1560, 1561 clinical presentation of, 1515 constipation in, 1593, 1594 diagnosis of, 1515-1519, 1516f-1518f differential diagnosis of, 1519, 1519t vs. idiopathic constipation, 1516f, 1519, 1549-1550, 1550t vs. intestinal neuronal dysplasia, 1562 vs. meconium ileus, 1293-1294, 1295f embryogenesis of, 1523-1526, 1524f-1525f enterocolitis of, 1515, 1516, 1516f, 1528-1530, 1529f-1530f colostomy in, 1533 in Down syndrome patients, 1528 recurrent, 1541-1542, 1543f, 1544, 1545, 1546 esophageal dysmotility in, 1112 genetic counseling and, 1523 genetics and molecular biology of, 13, 13t, 14, 1519-1523, 1519f-1522f, 1523t historical perspectives on, 4, 5, 1514, 1532, 1532f ileoanal pouch for, 1469 in adolescents and adults, 1515, 1530-1531 in premature infants, 1532 in small intestine, 1531, 1539-1540, 1542f-1543f incidence of, 1514 neuroblastoma associated with, 467 outcomes with, 1545-1547 pathology of, 1526-1527, 1526t in appendix, 1530, 1531 pathophysiology of, 1527-1528, 1527f postoperative stooling problems in, 1541-1542, 1543f, 1544 intestinal neuronal dysplasia with, 1561 quality of life in, 1547 rectal biopsy in, 1517-1519, 1517f-1518f, 1532-1533, 1533f after pull-through, 1542, 1543f segmental, 1530 Volume 1, pages 1-1 140; Volume 2, pages 1141-21

xxix

Hirschsprung's disease (Continued) small intestine, 1531, 1539-1540, 1542f-1543f stem cell research for, 1526 surgical techniques in, 1532-1544 anorectal myectomy, 1531, 1543-1544, 1544f-1545f colostomy, 1485, 1488, 1489f leveling, 1530, 1533 complications of, 1529, 1530, 1545-1547 Duhamel operation, 1532f, 1536, 1538, 1539, 1539f-154Of, 1542 complications of, 1546-1547 redo of, 1545f endorectal pull-through, 1534, 1535f-1537f, 1536 historically common, 1532, 1532f in extended small intestinal disease, 1539-1540, 1542f-1543f in right-sided disease, 1538, 1542f in total colonic disease, 1538-1539 rectal biopsy, 1517-1519, 1532-1533, 1533f redo pull-through, 1544, 1545f workup for, 1543f Swenson procedure, 1532, 1532f, 1538, 1540, 1541f complications of, 1546 redo of, 1545f total colonic, 1531-1532, 1531f genetics of, 1519-1520, 1519f intestinal transplant for, 1540 outcome with, 154G1547 pathology of, 1526t in appendix, 1530, 1531 surgical techniques in, 1538-1539 ultrashort, 1528, 1531, 1543-1544, 1544f-1545f Histamine, tissue injury and, 106 Histamine H2 receptor antagonists for gastroesophageal reflux, 1122, 1125b, 1126 for peptic ulcer disease, 1229, 1230 in parenteral nutrition solution, 207 in short-bowel syndrome, 1372, 1373 in Zollinger-Ellison syndrome, 1231 prophylactic, stress ulcers and, 1231 Histidine-tryptophan-ketoglutarate solution, 735 Histiocytic necrotizing lymphadenitis, 848 Histiocytosis X. See Langerhans cell histiocytosis. Histone deacetylase inhibitors, 426 Histoplasmosis bronchiectasis and, 1013 in HIV-infected patient, 1010 mediastinitis in, 1028 History of pediatric surgery, 3-10, 3f-5f, 8b, 9f-10f HIV. See Human immunodeficiency virus ( H N ) infection. HLA (human leukocyte antigen) bone marrow transplantation and, 685, 779 in cystic fibrosis, 12 organ transplantation and, 691,695,696 heart, 757 intestinal, 747 lung, 774, 776 pancreatic, 723 renal, 702, 703 Hodgkin's disease, 57.5-580. See also Lymphoma. clinical presentation of, 575-576, 576f cervical lymphadenopathy in, 833, 848 diagnosis of, 576, 576f, 577 vs. thyroglossal duct cyst, 870

Hodgkin's disease (Continued) epidemiology of, 575 histologic subtpes of, 576, 576f historical perspective on, 575 in mediastinum, 576, 576f, 577, 960t outcome with, 580 prognostic factors in, 580 splenectomy in, 577-578,579-580, 1697 staging of, 576-577, 577t complications of, 579 treatment of, 577-578,578t complications of, 575, 578-580 for recurrent disease, 580 for refractory disease, 580 osteogenic sarcoma secondary to, 653 Holt-Oram syndrome, 2073 Homeobox genes hypospadias and, 1876 intestinal neuronal dysplasia and, 1560 Homocysteine, thrombosis and, 187, 2130 Homovanillic acid, urinary, neuroblastoma and, 468,470,483, 487 Hormone-sensitive lipase, in neonate, 102, 103 Horner's syndrome brachial plexus injury with, 405 first rib fracture with, 279 neuroblastoma with, 468, 479 spinal cord injury with, 368 Horseshoe kidney, 171G1719, 1718f-1719f Wilms' tumor with, 457,458f Hox. See Homeobox genes. 4HPR (fenretinide), for neuroblastoma, 484 H-probe, 58 HPV. See Human papillomavirus (HPV). HSV. See Herpes simplex virus (HSV). Human chorionic gonadotropin (hCG), cryptorchidism and, 1197, 1200 0-Human chorionic gonadotropin (PhCG) , from germ cell tumors, 555, 556, 595 choriocarcinoma as, 568,609,622 pineal, 673, 678 polyembryoma as, 568, 609 precocious pseudopuberty and, 594 seminoma as, 622 teratoma as intracranial, 563 mediastinal, 565, 962 ovarian, 566 sacrococcygeal, 560 testicular, 567 Human immunodeficiency virus (HIV) infection. See also Acquired immunodeficiency syndrome (AIDS). acute, 832 blood transfusion and, 189 Candida in, colonic obstruction caused by, 1495 Epstein-Barr virus infection in, 837 ieiomyosarcoma in, 543 lung infections in, 1008-1010, 1009f lymphadenopathy in, 848 salivary gland cysts in, 838 Human leukocyte antigen. See HLA (human leukocyte antigen). Human papillomavirus (HPV), papillomas caused by laryngeal, 831, 989-990, 989f perianal, 1599 pharyngeal, 826 Humerus, fracture of in birth injury, 404 in child abuse, 403 vascular injury in, 342

Hunter-Hurler syndrome, inguinal hernia in, 1188 Hiirthle cell carcinoma, 854 Hyaline membrane disease extracorporeal life support for, 140t high-frequency ventilation for, 126 Hyaluronan, Wilms' tumor and, 448,459-460 Hyaluronic acid, serum, in biliary atresia, 1611 Hyaluronic acid membrane, abdominal adhesions and, 1360 Hydatid disease hepatic, 1646, 1646f pulmonary, 1005,1005f Hydatid of Morgagni, 1205, 1206 Hydranencephaly, 1997,1997f Hydrocele abdominoscrotal, 1189 acute, 1189 testicular torsion with, 1206 after hernia repair, 1184, 1187 congenital, 1189 embryogenesis of, 1173,1173f, 1174 herniography of, 1175 in cystic fibrosis, 1300 traumatic, 331 tumor with, 622 teratoma as, 567 ventriculoperitoneal shunt and, 1187 vs. inguinal hernia, 1173f, 1189 Hydrocephalus, 1995-2002. See also Intracranial pressure (ICP). brain tumor with, 672,673,674 cerebellar astrocytoma as, 674, 674f craniopharyngioma as, 677, 677f medulloblastoma as, 675 of choroid plexus, 678 of pineal region, 678 tectal glioma as, 676 teratoma as, 563 clinical features of, 1997 etiology of, 1995f, 199G1997, 1997f management of, 1998-2002 myelomeningocele with, 84, 1993 outcome and prognosis with, 2002 pathophysiology of, 1995-1996 radiologic features of, 1997-1998 vocal cord immobility caused by, 988 Hydrochlorothiazide, for hypertension, 2120 Hydrocodone, 240,240t Hydrocolpos, malformations with, 1568, 1571, 1572, 1579f, 1582 cutaneous vesicostomy and, 1791-1792 imperforate hymen as, 1902, 1941, 1950 vaginal agenesis as, 1936, 1937 Hydrofluoric acid burns, 396 Hydrogen, bacterial production of in chronic intestinal pseudo-obstruction, 1549 in necrotizing enterocolitis, 1435, 1436 Hydrogen peroxide in phagolysosome, 160 reperfusion injury and, 158 Hydrometrocolpos imperforate hymen with, 1902, 1941 in McKusick-Kaufman syndrome, 1936 Hydromorphone, 241, 241t, 242 caudal, 248 epidural infusion of, 248, 248t in patient-controlled analgesia, 243, 243t Hydronephrosis. See also Hydroureteronephrosis; Ureteropelvic junction (UPJ) obstruction. definition of, 1723 diagnostic evaluation of, 1727-1732, 1728f-1732f, 1743, 1743f, 1745 olume 1, pages 1-1140; Volume 2, pages 1141-2146.

Hydronephrosis (Continued) differential diagnosis of, 1727, 1727t management of, 1733. See also Pyeloplasty. megaureter with, 1771, 1772 multicystic dysplastic kidney and, 1710-1711,17lOf, 1725, 1727 persistent cloaca with, 1791 prenatal diagnosis of, 1723, 1725, 1726f grading of, 1725, 1725t prenatal counseling and, 1725-1726 renal development and, 1725-1726 spontaneous resolution of, 1733 urethral obstruction causing, 82t, 83 ureteral anomalies with, 1763, 1764f-1765f urinary tract infection and, 1743 Hydrops fetalis chylothorax with, 1026 cystic lung mass with, 955-956, 956f, 957, 958 cystic mediastinal lesion with, 960, 965 heart block causing, 151 teratoma causing mediastinal, 565 sacrococcygeal, 559, 560 thoracic duplications with, 1391 treatment of, 82t, 83, 83t, 85 Hydrops of gallbladder, 1636,2115 Hydroureteronephrosis. See also Hydronephrosis. in bladder exstrophy, 1842 in male fetus, with posterior urethral valves, 1819 in prune-belly syndrome, 1781, 1784 in spinal dysraphism, 1808 Hydroxyapatite-coated implants, 59 Hydroxyl radical, 160, 162, 167 5-Hydroxytryptamine, tissue injury and, 106 Hymen, imperforate, 1902, 1941, 1941f, 1942, 1950, 1951f Hyoid bone abscess above, 867 anatomy of, 827 dermoid cyst adjacent to, 871 thyroglossal duct cyst and, 864, 865f, 869, 870 Hypaque. See Diatrizoate enema. Hyperacute rejection, 695-696 renal, 702 Hyperaldosteronism, 636 Hyperammonemia after urinary tract reconstruction, 1836 parenteral amino acids and, 204 portal hypertension with, 1655 Hyperbaric oxygen, for necrotizing fasciitis, 1146 Hyperbilirubinemia. See alsoJaundice. during extracorporeal life support, 140 in acute liver failure, 733 intravenous fat emulsions and, 206 neonatal, 1606 self-limited, 1603 Hypercalcemia differential diagnosis of, 857, 857t familial hypocalciuric, 857 in hyperparathyroidism, 857, 858, 858f in hypervitaminosis D, 198 in neonate, 95 Hypercapnia, permissive, 128 in congenital diaphragmatic hernia, 940 Hypercarbia extracorporeal life support and, 139 in respiratory failure, 127 Hypercoagulable state. See Coagulopathy. Hyperfractionated radiation therapy, 429

Hyperglycemia in central nervous system injury, 356, 363 in parenteral nutrition patients, 208, 209 intraoperative, 225 neonatal, 102, 197 postoperative, 106, 107, 107f in critically ill patient, 211-212 Hyperinsulinism, 102, 1679-1683, 1679t, 1681f, 1682t, 1683f Hyperkalemia aldosterone production and, 629 in malignant hyperthermia, 231, 232,232t in neonate, 95 in parenteral nutrition patients, 209 succinylcholine causing, 267 Hyperlipidemia, familial, 2130 Hypermagnesernia, in parenteral nutrition patients, 209 Hypermetabolic response, in burn patient, 391-393, 392f-393f Hypernatremia in burn patient, 389 in neonate, 94, 94t Hyperoxaluria after massive enterectomy, 1372 renal graft loss in, 71 1 Hyperparathyroidism, 857, 858, 858f Hyperphosphatemia, in parenteral nutrition patients, 209 Hypersplenism after portoenterostomy, 1612 partial splenectomy for, 1697 portal hypertension with, 1653, 1655, 1661-1662,1663, 1664-1665 Hypertelorism, 792, 792f, 800 in Crouzon's syndrome, 797 Hypertension. See also Blood pressure. controlled, for brain injury, 273 hyperaldosteronism with, 636 in renal transplant patient, 706, 713 incidence of, in children, 2118 intracranial, decompressive laparotomy for, 303 malignant, 21 18, 2120 neuroblastoma with, 468 pheochromoc~omawith, 630,631,631f, 632 portal. See Portal hypertension. pulmonary. See Pulmonary hypertension. renovascular. See Renovascular hypertension. sleep apnea and, 1246 ureteral abnormalities and, 1762 Hyperthermia after traumatic brain injury, 273, 356 for germ cell tumors, 569 malignant, 231-232,232t oxyhemoglobin dissociation curve in, 121 Hyperthyroidism, 852-854, 853t Hypertonic saline resuscitation, for burninduced shock, 389 Hypertriglyceridemia, in parenteral nutrition patients, 208, 210 Hyperventilation, controlled, for brain injury, 269, 272, 273, 363, 364, 364t Hyperviscosity syndrome, 21 15 Hypervolemia, serum sodium and, in neonate, 94, 94t Hypocalcemia in citrate toxicity, 188, 227, 273 in malnourished patient, albumin and, 209 in neonate, 95 Hypocarbia, for head trauma patient, 269, 272, 273 Hypoganglionosis, 1594. See also Aganglionosis Hypoglossal nerve, branchial anomalies and, 862.866

Hypoglycemia. See also Hyperinsulinism. differential diagnosis of, 1680-1681, 1681f in neonate, 101-102, lOlt during fluid therapy, 225 in Addison's disease, 637 in burn patient, prevention of, 387 in neonate, 100,101-102, 101t, 103, 197 on parenteral formula, 204 with sepsis, 170 in parenteral nutrition patients, 204, 208 Hypogonadism, gynecomastia with, 892 Hypokalemia in hyperaldosteronism, 636 in neonate, 94 in refeeding syndrome, 208 neuroblastic tumors with, 469 Hypomagnesemia in neonate, 95 in refeeding syndrome, 208 Hyponatremia fluid therapy and, 226 in burn patient, 388-389 in brain-injured patient, 364, 365 in burn patient, 388-389,390, 393 in neonate, 94, 94t renin and, 629 Hypoparathyroidism, secondary to thyroid surgery,856 Hypopharynx, 822 Hypophosphatemia in premature infants, 207 in refeeding syndrome, 208 Hypoplastic anemia, congenital, 179, 180 Hypoplastic left heart syndrome, 1975, 1977-1978, 1977f-1978f transplantation for, 153, 754, 756, 757, 758, 759f, 762 Hypopnea, 823-824 Hypospadias, 1870-1895 ambiguous genitalia with, 1870, 1894, 1919, 1921 anatomy of, 1877-1880, 1877f-1879f associated anomalies with, 1875 anorectal, 1567, 1894 fistula as, 1894, 1905 penile torsion as, 1907 scrotal, 1907-1908 chordee in, 1870, 1879, 1880, 1887, 1890f presenration of urethral plate and, 1884, 1885f, 1886 repair of, 1887-1888, 1891, 1891f-1892f classification of, 1870-1871, 1870f-1871f embryogenesis of, 1872,1916 etiology of, 1875-1877 historical perspective on, 1871 incidence of, 1870, 1874-1875 repair of, 1880-1895 age for, 1893 algorithm for, 1880f anesthesia for, 246247, 247f, 1893 anterior, 1880-1884, 1881f-1885f complications of, 1890f, 1893-1894, 1894f for curvature, 1887-1888, 1891, 1891f-1892f, 1895 in sex assignment surgery, 1927-1928, 1929f-1930f phases of, 1880 posterior, 1884-1887, 1885f-1890f results of, 18941895 summary of, 1895 technical considerations in, 1892-1893 two-stage, 18861887, 1889f with multiple failures, 1890f, 1891-1892 Volume 1, pages 1-1 140; Volume 2, pages 1141-2

Hypotension during anesthesia inhalation agents and, 227, 229 intravenous agents and, 233 escharotomy-related, 386 extracorporeal life support and, 135, 142 in sepsis or SIRS, 170, 172 in trauma patient, 377 pericardial tamponade and, 286 shock with, 319, 378 with abdominal injury, 378 with brain injury, 355 with spinal injury, 355, 368, 370 Hypothalamic-pituitary-adrenal axis, 629 Hypothalamus, glioma of astrocytoma as, 676-677,676f genetics of, 679 Hypothermia coagulopathy in, 301 extracorporeal life support for, 142 in neonate during surgery, 99 with sepsis, 170 in trauma patient, 272, 273 with severe bleeding, 300-301, 302 oxyhemoglobin dissociation curve in, 121 Hypothyroidism, 851 alpha fetoprotein in, 555 breast hypoplasia in, 887 galactorrhea in, 888 hepatic hemangiomas with, 2102, 2106 in Hashimoto's thyroiditis, 852 infantile hepatic hemangioendothelioma with, 496 ovarian cysts in, 601 premature thelarche in, 885 weaning from ventilator and, 128 Hypoventilation. See Central hypoventilation syndrome (Ondine's curse). Hypovolemia. See also Blood volume. children's maintenance of blood pressure in, 319 in burn patient, 388 in trauma patient, 271 plasma substitutes and, 188 serum sodium and, in neonate, 94,94t Hypovolemic shock, 180 vs. neurogenic shock, 368 Hypoxemia in respiratory failure, 127 inverse ratio ventilation for, 125 pulmonary vasoconstriction caused by, 120 Hypoxia children's predisposition to, 276 extracorporeal life support and, 139, 140 in central nervous system injury, 355, 357 in neonate gastrointestinal perforation secondary to, 1235 necrotizing enterocolitis and, 1433 tissue, in systemic inflammatory response syndrome, 169-170, 172

Ibuprofen, 238,238t ICAM-1 (intercellular adhesion molecule-I) , 159, 173 in biliary atresia, 1611 in Hirschsprung's disease, 1526 ICF (intracellular fluid) in fetus and neonate, 91-92,93 third-space loss and, 226 ICP. See Intracranial pressure (ICP).

xxxii

INDEX

Idiopathic (immune) thrombocytopenic purpura, 182-183 accessory spleens and, 1692 splenectomy in, 183, 1693, 1696, 1698 Ifosfamide, 423t, 428 Ig. See Immunoglobulin(s). IGF. See Insulin-like growth factor entries. IGF binding protein 1, in hyperinsulinism, 1680 IL. See Interleukin entries. Ileal atresia. SeeJejunoileal atresia and stenosis. Ileal channel, continent catheterizable, 1798, 1798f Ileal conduit, incontinent, 1793-1794, 1793f Ileal interposition, for ureteral injury, 327 Ileoanal pouch procedure, 14661469, 1468f-1471f complications of, 1470-1471 Crohn's colitis and, 1457, 1458, 1471 history of, 1462-1463 in familial polyposis, 1421, 1472 outcomes of, 1469-1470 stapled anastomosis in, 1472 stoma site for, 1487f Ileocecal cystoplasty, 1797 Ileocecal reservoir, 1799, 1799f Ileocecal valve, in short-bowel syndrome, 1371f, 1372, 1373, 1375 Ileocystoplasty, 1796-1797, 1825, 1826f Ileorectal anastomosis in Crohn's disease, 1457, 1457f, 1458, 1459 in ulcerative colitis, 1467 Ileostomy. See also Enterostoma(s). choices for, 1482f-1483f, 1484-1485 complications of, 1489-1490, 1489t in chronic intestinal pseudoubstruction, 1549 in Crohn's disease, 1457, 1459 in necrotizing enterocolitis, 1482, 1483f, 1484, 1486 in ulcerative colitis, 1467, 1482-1483, 1484-1485 after pouch removal, 1471 stoma site in, 1486, 1487f technique of, 1468, 1470f indications for, 1482-1483 sites for, 1486, 1486f stoma care in, 1488 technical aspects of, 1486, 1486f-1487f Ileovesicostomy, 17941795,1832-1833 Ileum duplications of, 1390, 1391, 1391f-1392f, 1392, 1394-1395, 1395f, 1397 Hirschsprung's disease in, 1531, 1540, 1542f-1543f lymphoid hyperplasia of, 1418, 1419f mesenteric cyst of, 1366, 1402 resection of, consequences of, 1371-1372, 1373, 1837 Ileus. See also Meconium ileus. functional, microcolon in, 1519 postoperative, 1360-1 361 enteral feedings and, 199, 202, 1361 renal trauma with, 324 Iliac vein(s), compression of, 2127, 2128f, 2141 Ilioinguinal-iliohypogastricblock, 245-246, 245f Iloprost, for pulmonary vascular disease, 766 Image. See also Three-dimensional images. modes of manipulation and, 31-32, YLt, 40 Image-guided biopsy, 438,439-442 Image-guided radiation therapy, 429-430 Image-guided radiosurgery, 43, 44-47, 45f-46f Image-guided surgery, 42-43

Imatinib for gastrointestinal stromal tumors, 516 neuroblastoma and, 475 Imipramine, for nocturnal enuresis, 1815 Immune response cortisol and, 629 Hirschsprung's disease and, 1526, 1528 in gastric and duodenal epithelium, 1227 postoperative stress and, 106 preterm gastrointestinal tract and, 1432, 1434 Immunoblastic lymphoma, 583 Immunocompromised patient. See also Human immunodeficiency virus (HIV) infection; Immunosuppression; Severe combined immune deficiency (SCID). atypical mycobacterial infection in, 846, 1003 fungal sinusitis in, 819 Hodgkin's disease in, 576 lung infections in, 1001 in cancer, 1005-1008, 1006f-1007f in cystic fibrosis, 1010-1011 in HIV infection, 1008-1010, 1009f thoracoscopic biopsy in, 977 transfusion in, 188, 189 Immunoglobulin (s), 163-164. See also Antibodies. in human milk, 104, 168, 202 in neonate, 167-168,170 opsonization by, 160, 160f, 163, 164 oral administration of, necrotizing enterocolitis and, 1444 Immunoglobulin A, 157, 157f, 163, 164 in Hirschsprung's disease, 1528 in neonate, 168, 170, 1444 Immunoglobulin A nephropathy, renal graft loss in, 71 1 Immunoglobulin E, 163, 164, 166 Immunoglobulin G, 163, 164, 166 bacterial defense against, 159 fetal heart block caused by, 151 for immune thrombocytopenic purpura, 1693 in neonate, 167-168, 170, 1444 Immunoglobulin M, 163-164 in neonate, 167, 168, 170 lymphomas with expression of, 581, 581f, 582-583 Immunoglobulin superfamily, adhesion molecules of, 159 Immunosuppression. See also Immunocompromised patient. for Crohn's disease, 1455-1456 for transplantation bone marrow, 779 heart, 754, 760-761, 760t, 761f intestinal, 742-743, 749 islet cell, 724-725, 726, 727 liver, 737, 738t, 739, 740-741 lung, 770-771, 771t, 774 pancreas, 720-721,722-723 principles of, 685,686-689, 687f, 690-693, 690f, 693f, 695,696 renal, 707-709,711, 712-713 for ulcerative colitis, 1466 lymphoproliferative disease secondary to, 584-585, 712, 739, 750-751, 774 Immunotherapy, cancer, 427 for neuroblastoma, 427, 485 Impedance measurement of body composition, 195 of gastroesophageal reflux, 1124 Impedance pneumography, 122 Imprinting, genomic, 446, 447

olume 1, pages 1-1 140; Volume 2, pages 1141-2146

IMV (intermittent mandatory ventilation), 123, 124, 128 In situ hybridization, 419, 420t Incontinence child abuse and, 404 fecal. See also Defecation; Soiling, fecal. anal manometry and, 1542 anorectal malformations and, 1569, 1586-1588, 1587t antegrade enema for, 1834, 1834f functional, 1549, 1549t, 1592, 1595 in Hirschsprung's disease, after surgery, 1545-1546, 1547 sacral defects with, 1567, 1573 urinary tract reconstruction and, 1833 urinary. See also Bladder dysfunction; Enuresis. bladder outlet resistance and, 1817, 1828-1832, 1830f-1831f dysfunctional elimination syndrome with, 1813 ectopic ureter with, in female, 1762, 1763, 1767-1768,1903 endoscopic injection for, 1747-1748, 1749f-1750f in Hirschsprung's disease, after surgery, 1546 neuropathic bladder with, 1809, 1810, 1811 posterior urethral valves with, 1812 spinal cord tethering with, 1810 urethral injury with, 330, 331 Indiana pouch, 1799, 1799f, 1826, 1833 Indomethacin ductus arteriosus and fetal, 79 for medical closure, 238, 1429 gastrointestinal perforation and, 1235, 1237,1429 necrotizing enterocolitis and, 1429 Infant. See Neonate(s); Premature infant. Infantile hepatic hemangioendothelioma, 495, 496-497,496f transplantation for, 733 Infection. See also Abscess(es) ; Sepsis. barriers to, 157-158, 157f burns and, 385, 390 fungal. See Fungal infection. host defense against, 159-168 humoral factors in, 163-166, 164f lymphocytes in, 162-163 monocytes-macrophages in, 161-1 62 neonatal, 166168 neutrophils in, 159-161, 160f hyperglycemia in, in neonate, 102 in necrotizing enterocolitis, 1435-1436 in parenteral nutrition patient, 209-210, 211 in transplant patient bone marrow, 780, 781 heart, 761, 762, 763 intestinal, 750-751 liver, 739, 740t lung, 771, 774-775 renal, 71 1-712 intraspinal, 2013 of bone. See Osteomyelitis. of brain, 2008-2013, 2010f-201 If of breast, 887, 888, 890 of fracture, open, 344 of liver, 1642-1646, 1642t, 1643f, 1646f of lung. See Lung(s), infections of. of mediastinum, 1027-1 028 from descending neck infection, 823, 1027

Infection (Continued) of middle ear and mastoid, 815-816, 816f of umbilicus, 1146, 1149, 1150 of upper respiratory tract. See also Sore throat. piriform sinus and, 868 Infection control, necrotizing enterocolitis and, 1444 Inferior petrosal sinus sampling, 634f, 635 Inferior vena cava. SerVena cava. Infertility feniale appendicitis and, 1509 bladder exstrophy and, 1858 v~ginalagenesis and, 1937 vaginal septum and, 1943 mal,: bladder exstrophy and, 1858 cryptorchidism and, 1198, 1199 after orchidopexy, 1203, 1204, 1204t in prune-belly syndrome, 1785 cystic fibrosis with, 1300 Fiodgkin's disease therapy and, 579 nguinal hernia repair and, 1185-1 186, 1187 ~esticulartorsion and, 1207 testicular tumors and, 626 varicocele and, 1207, 1208, 1209 Infiltration anesthesia, 243, 244 Inflammation. See also Infection; SIRS (systemic inflammatory response syndrome). bacterial lipid A and, 159 cortisol and, 629 cytokines and, 106, 159, 160, 161, 165-166 in necrotizing enterocolitis, 1430, 1430t, 1431-1432, 1433, 1434 genetic differences in, 166, 169 in burn patient, 384-385, 392 in inhalation injury, 395 in neonate, 167 postoperative, 105 macrophages in, 161-162 neutrophils in, 159-161, 160f obesity-induced, 1243-1244 summary of, 168 Inflammatory adhesions, 1361 Inflammatory bowel disease. See also Crohn's disease; Ulcerative colitis. bloody diarrhea in, 1387 colorectal carcinoma associated with, 519-520 I multidetector computed tomography in, 35 Inflammatory myofibroblastic tumor. See Inflammatory pseudotumor. Inflammatory polyps, gastrointestinal, 1364, 1387, 1414-1416, 1415f Inflammatory pseudotumor gastrointestinal, 1364-1 365 hepatic, 499 pulmonary, 640-641 Inflicted injuries. See Child abuse. Infliximab for Crohn's disease, 1456, 1458 for ulcerative colitis, 1466 Influenza, 1004 Information-guided therapy, 42-43 Informed consent, 258,259 for sex assignment surgery, 261-262 Inguinal hernia, 1172-1 189 bladder exstrophy with, 1844 clinical features of, 1174 contralateral exploration with, 1180-1 182 cryptorchidism with, 1198, 1199, 1200, 1204,1205

Inguinal hernia (Continued) direct, 1185, 1188 embryogenesis of, 1173-1 174 epidemiology of, 1173 examination for, 1174-1 175, 1175f factors contributing to, 1174, 11741 herniography of, 1175,1187 in connective tissue disorders, 1188 in cystic fibrosis patient, 1188, 1300 in intersex patient, 1188-1 189 in premature infant, 1173, 1176, 1185, 1186,1187 incarcerated, 1174, 1182-1 184, 1182f-1183f in premature infants, 1187 mortality associated with, 1186 ovary in, 1184, 1186 testicular atrophy secondary to, 1186 indirect, 1173, 1174 mortality associated with, 1186 peritoneal dialysis and, 1187 recurrent, 1184-1185, 1187, 1188 repair of, 1175-1 182 adrenal rests found in, 1189 anesthesia for, 244, 245-246, 245f, 1175-1176 complications of, 1 1 8 4 1186 historical development of, 1172-1 173 laparoscopic, 1179-1 180, 1180f complications of, 118G1187 open technique of in females, 1178-1179, 1179f in males, 117G1178, 1177f-1178f pain control following, 1176 same-day, 1176 timing of, 1176 sliding, 1187-1 188 fallopian tube in, 1178-1 179, 1179f, 1187 ultrasonography of, 1175, 1176f, 1181 with strangulation, 1182 ventriculoperitoneal shunt and, 1185, 1187 vs. hydrocele, 1173f, 1189 Inhalation injury, 386, 394395 by ammonia fumes, 1084 Inhibin, granulosa-theca cell tumors and, 604 Injury. See Emergency management; Trauma. Innominate artery compression of, 996, 996f erosion of, by tracheotomy tube, 986 tracheal compression by, 996,996f, 997, 998, 1979, 1982, 1982f Innovation. See Technological innovation. Inotropic agents, for heart failure, in neonate, 148, 150t, 151 Inotropy. See Contractility, cardiac. Inspiratory capacity, 118, 118f Inspiratory reserve volume, 118, 118f Inspissated bile syndrome, 1614, 1614f Insulin. See also Diabetes mellitus; Hyperinsulinism; Islet cell transplantation; Pancreas, transplantation of. chromium and, 199 cortisol and, 629 for burn patient, 391, 392, 393 in perinatal period, 100, 101, 102, 103 in postoperative period, 106, 107 micropumps for, 58 parenteral nutrition and, 207, 208 Insulin resistance, 1244, 1245, 1246 Insulin-like growth factor-1 (IGF-1) in biliary atresia, 1611 in burn patient, 391, 392 in tumor growth, 419, 426 receptor for, 414

Insulin-like growth factor-2 (IGF-2) Beckwith-Wiedemann syndrome and, 525 hepatoblastoma and, 502 rhabdomyosarcoma and, 525 Wilms' tumor and, 447 Insulin-like growth factor 3, testicular descent and, 1193, 1194f, 1912 Insulinoma, 1683, 1685 Integra, 390 Integrin receptors, 158, 160 Integrins, 159, 161, 166, 167, 173 invasive cancer and, 418 Intensity-modulated radiation therapy, 429430 Intensive care unit neuromuscular syndrome, 231 Interceed. See Cellulose. Intercellular adhesion molecule-1 (ICAM-l), 159,173 in biliary atresia, 1611 in Hirschsprung's disease, 1526 Intercostal nerve block, for rib fractures, 279 Interferon-a as angiogenesis inhibitor, 426 for hemangoendothelioma, hepatic, 496-497 for hemangioma, 21042105 mediastinal, 966 subglottic and tracheal, 994, 995 vaginal. 1951 for Gtestinal lymphangiectasia, 2140 for laryngeal papilloma, 990 ~nterferon-7,1 a , - l 6 1 , 163, 166 in neonate, 167, 168 in systemic inflammatory response syndrome, 169 tumor cells and, 426 Interleukin-1 (IL-1) corticosteroids and, 1455 in neonate, 167 in sepsis, 170-171 postoperative, 106 inflammation and, 159, 161, 165, 166, 1430t in systemic inflammatory response syndrome, 168-169, 170, 172 Interleukin-2 (IL-2), 166 for neuroblastoma, 427, 485 gastrointestinal, 1430t in neonate, 167 Interleukin-2 (IL-2) receptor antagonists. See also Cyclosporine. in transplantation heart, 761, 761f intestinal, 749 islet cell, 726 liver, 738t lung, 770-771,771t renal, 707, 709 Interleukin-4 (IL-4), gastrointestinal, 1430t, 1431 Interleukin3 (IL-5), in ulcerative colitis, 1463 Interleukin-6 (IL-6) in neonate in sepsis, 170-171 postoperative, 106 inflammation and, 165 in systemic inflammatory response syndrome, 168, 170, 171, 172 Interleukin-8 (11,-8) in inhalation injury, 395 in necrotizing enterocolitis, 1431 inflammation and, 160, 165 in systemic inflammatory response syndrome, 168, 169, 170 Interleukin-10 (IL-lo), necrotizing enterocolitis and, 1430t, 1431

Volume 1, pages 1-1140; Volume 2, pages 1141-2146.

xxxiv

INDEX

Interleukin-1 1 (IL-1l ) , necrotizing enterocolitis and, 1430t, 1431 Interleukin-12 (IL-12), 166 in cancer chemotherapy, 426 for neuroblastoma, 485 in necrotizing enterocolitis, 1432 Intermittent mandatory ventilation (IMV), 123, 124, 128 Internal hernia, 1348-1349, 1349f, 1350, 1354, 1356, 1361-1363, 1362f-1363f Intersex abnormalities, 1911-1932. See also Sex assignment. carcinoma in situ in germ cells of, 1198 classification of, 1913, 1914t-1915t, 1916-1917 diagnosis of, 1917-1920, 1918t, 1919t embryological basis of, 1911-1913, 1912f ethics of surgery for, 261-262 gonadoblastoma in, 624, 1920 inguinal hernia in, 1188-1 189 medical management of, 1920-1921 surgical reconstruction in, 1921-1931 for female assignment, 1922-1926, 1923f-1928f for male assignment, 192G1931, 1929f-1932f preparation for, 1921-1922, 1922f Intestinal adaptation, 743-744, 1369-1370, 1372, 1373, 1374 isolated liver graft for, 745 Intestinal atresia and stenosis abdominal wall defects with, 1162, 1164, 1166, 1167 classification of, 1275-1276, 1276f colonic, 1275, 1493-1495, 1494f duodenal, 1260-1267,1261f-1265f, 1261t jejunoileal atresias with, 1270, 1276 pyloric web with, 1233 duplication associated with, 1395 etiological theories of, 1390 Hirschsprung's disease with, 1528 intussusception associated with, 1270, 1272, 1274f, 1316 jejunoileal. SerJejunoileal atresia and stenosis. rectal, 1578 short-bowel syndrome secondary to, 1369, 1369f Intestinal dysmotility, 1547-1549, 1547f. See also Constipation; Enteric nervous system; Hirschsprung's disease; Ileus; Intestinal neuronal dysplasia; Intestinal pseudo-obstruction. after resection, 1370 colonic obstruction in, 1496 in pseudo-obstruction, 1366, 1547 multivisceral graft for, 745 opioids and, 1360-1361 rectosigmoid, in anorectal malformations, 1569 Intestinal exstrophy, 1862-1863, 1863f, 1864, 18641, 1865-1866, 1865f Intestinal failure, 743, 744, 745 Intestinal infarction. See also Ischemic necrosis, gastrointestinal. in inguinal hernia, 1184, 1186 mesenteric or omental cyst with, 1401 Intestinal lengthening procedures, 1377-1379, 1377f-1379f with resection of duplication, 1395 Intestinal neuronal dysplasia, 1496, 1547, 1560-1563, 1562f-1563f after pull-through, for Hirschsprung's disease, 1542, 1544 anorectal manometry in, 1562, 1594

Intestinal obstruction. See also Colon, obstruction of; Enema; Internal hernia; Intestinal atresia and stenosis; Intestinal dysmotility; Intestinal rotation and fixation; Intussusception; Meconium ileus; Volvulus. adhesions with in familial Mediterranean fever, 1477 inflammatory, 1361 postoperative, 1358-1360, 1359f-1360f after appendectomy, 1358, 1509 causes of, 1358 miscellaneous, 1364-1366, 1498 congenital bands with. SeeLadd's bands. Crohn's disease with, 1456-1457 duplications with, 1366, 1391, 1395 gastrointestinal tumors with, 515 colorectal carcinoma as, 521, 521f hernias with, 1361-1363 inguinal, 1174, 1182 internal, 1348-1349, 1349f, 1350, 1354, 1356,1361-1363,1362f-1363f Meckel's diverticulum and, 1306, 1308f, 1309, 1310-1311,1310f mesenteric or omental cyst with, 1401, 1401f, 1402 postoperative adhesive, 1358-1 360, 1359f-1360f after lung transplant, 773 intussusception with, 1321-1322, 1321f, 1356, 1361 vs. ileus, 1360 vitelline duct remnants and, 1148, 1309, 1310f Intestinal perforation in appendicitis, 1502, 1503, 1506, 1508-1509 in colonic atresia, 1494 in Crohn's disease, 1456, 1457 in Hirschsprung's disease, 1515, 1529 in neonate, 1236-1237 meconium ileus with, 1291, 1296, 1298, 1298f necrotizing enterocolitis with, 1437, 1439, 1440 in small left colon syndrome, 1498 intussusception with, 1317-1318, 1328, 1329,1330,1334, 1335-1336 Meckel's diverticulum with, 1309, 1311f radiographic diagnosis of, 1359 seat-belt trauma with, 1365 Intestinal pseudo-obstruction, 1366, 1366t chronic, 1111-1 112, 1356, 1496, 1523, 1547-1549 vs. segmental volvulus, 1498 Intestinal rotation and fixation, 1342-1356 disorders of. See also Volvulus. asplenia with, 1693 asymptomatic, 1348 classification of, 1346-1347, 1346f-1347f clinical manifestations of, 1347-1350, 1347f, 1349f, 1385 duodenal atresia with, 1262, 1263, 1346 historical perspective on, 4, 5, 1341 in prune-belly syndrome, 1786 jejunoileal atresia and, 1270, 1272, 1274, 1283, 1346 mesocolic hernia as, 1348-1349, 1349f, 1350,1356,1361, 1362f radiologic diagnosis of, 1350, 1350f-1354f, 1385-1386 reversed, 1346, 1348, 1349f, 1356 terminology for, 1346 treatment of, 1352-1354, 1355f, 1356 laparoscopic, 1354

Volume 1, pages 1-1140; Volume 2, pages 1141-2146

Intestinal rotation and fixation (Continued) normal, 1342-1346, 1343f-1347f fixation in, 1346, 1346f radiographic appearance of, 1350, 1350f Intestinal stricture (s) in Crohn's disease, 1457, 1459 in necrotizing enterocolitis, 1442-1443 post-traumatic, 1365 Intestinal transplantation, 742-752 complications of, 749-751, 750f donor selection for, 745, 747, 747f future prospects for, 752 graft options in, 745, 746f history of, 693, 742-743, 742t, 743t immunosuppression for, 742-743, 749 in chronic intestinal pseudo-obstruction, 1549 in Hirschsprung's disease, 1540 in short-bowel syndrome, 1373, 1379 after failed lengthening procedure, 1378 in jejunoileal atresia, 1283 indications for, 743t, 744 operative procedures in, 747-749,747f-748f outcomes of, 751-752, 751f postoperative management in, 749 recipient selection for, 743-745, 743t, 745t rejection in, 749-750, 750f Intestinal valves, construction of, 1375, 1375f Intestine. See also Colon; Small intestine. bacteria in as probiotics, 1444-1445 necrotizing enterocolitis and, 1433, 1434, 1444-1445 overgrowth of diagnosis of, 1549 in short-bowel syndrome, 1373-1374 barriers to infection in, 157, 157f, 158 herniated through diaphragm, 284-285, 284f tissue-engineered, 22, 24-26, 25f trauma to, 310-311, 311f diagnostic modalities in, 296, 297, 31 1-312 laparoscopic repair of, 297 vascular malformations in, 1598 Intestinocystoplasty, 1791 Intra-abdominal pressure cryptorchidism and, 1195 gastroesophageal reflux and, 1123 hydrocele and, 1187 inguinal hernia and, 1186, 1187 measurement of, 302-303 Intracellular fluid (ICF) in fetus and neonate, 91-92, 93 third-space loss and, 226 Intracranial pressure (ICP). See also Cerebrospinal fluid (CSF); Hydrocephalus. brain tumor and, 672 teratoma as, 563 craniosynostosis and, 795, 798 in trauma patient, 269, 272, 273, 356 management of, 363, 364, 364t, 365 monitoring of, 363, 364, 365 refractory elevation of, 364, 364t decompressive laparotomy for, 303 outcomes with, 367 with diffuse injury, 357 with gunshot wound, 361 with intracerebral hematoma, 358 monitoring of in shunt patient, 2001 in trauma patient, 363, 364, 365 Intraosseous vascular access in burn patient, 386 in trauma patient, 269,270-271

Intraperitoneal fluid. See also Ascites. FAST ultrasonography for detection of, 319 intestinal trauma and, 312 Intrauterine growth retardation (IUGR), 89-90 hypoglycemia and, 101t Intravascular oxygenation, 126 Intravenous pyelography ( I W ) in trauma patient, 319, 323, 326 of ureteral duplication, 1761, 1762f Intravenous urography ( N U ) in ureteropelvic junction obstruction, 1727 with ureteral anomalies, 1763, 1763f, 1764, 1765f Intraventricular hemorrhage as birth injury, 405 in premature infants, vitamin E and, 198 traumatic, 359, 360f, 361, 362 Introitus, masses of, 1949-1951, 1949f-1951f Intubation. S P Endotracheal ~ intubation; Endotracheal tube. Intussusception, 1313-1337 classification of, 1318-1323,1318f, 1320-1322f currantjelly stool in, 1314f, 1317, 1317f, 1324,1386 diagnosis of clinical, 1316f, 1323-13'25 radiologic, 1325-1327, 1325f-1327f, 1364 duplication as cause of, 1319, 1321, 1366, 1391, 1392, 1395 epidemiology of, 1316-1317 future expectations for, 1337 historical perspective on, 1313-1314 in cystic fibrosis, 1299 in diffuse juvenile polyposis infancy, 1416 intentional, for short-bowel syndrome, 1375, 1375f intrauterine, intestinal atresia with, 1270, 1272, 1274f, 1316 Meckel's diverticulum with, 1309, 1311, 1319, 1335 outcomes of, 13361337 overview of, 1314-1315, 1314f-1315f, 1386 pathogenesis of, 1315t, 1318-1323,1318f, 1320f-1322f, 1364, 1366 pathologic anatomy of, 1314f, 1317-1318 postoperative, 1321-1322, 1321f, 1361 after 1,add procedure, 1356 recurrent, 1318f, 1320, 1322-1323, 1323f, 1332, 1336 research update on, 1315t, 1316t, 1337 spontaneous reduction of, 1319 treatment of, 1327-1335 medical, 1323, 1327-1328, 1330 operative, 1328f, 133'2-1335, 1333f-1334f complications of, 1336 laparoscopic, 1335 overview of, 1327 radiologic, 1327f, 1328-1332, 1329f-1332f complications of, 1335-1336 delayed repeat enema in, 1327f, 1331, 1336 with pathologic lead point, 1321, 1321f, 1335 Invasins, 158 Inverse ratio ventilation, 125 Iodomethyl-1-19-norcholesterol (NP-59), 630, 635 Iowa (Kimura) intestinal lengthening procedure, 1378-1 379, 1378f Iressa. See Gefitinib (Iressa). Irinotecan, 424t, 429 Iron deficiency, esophageal replacement and, 1104 Iron dextran, in parenteral nutrition solution, 207, 208t

Iron overload, from transfusion, in Pthalassemia, 495 Irondeficiency anemia, 180-181 gastrointestinal tumors with, 516 in parenteral nutrition patients, 207 postoperative apnea and, 223 Ischemia. See also Arterial occlusion. amputation secondary to, 2058 bowel, mesenteric venous thrombosis with, 2130 five Ps in, 348 in arterial occlusion, 2116-2117 in central nervous system injury, 356, 357 in upper extremity trauma, 348, 351, 379-380 in vascular injury, 377, 378-380,379t iatrogenic, 380, 381 Ischemia-reperfusion injury. See Reperfusion injury. Ischemic necrosis, gastrointestinal. See also Gangrene; Intestinal infarction; Necrotizing enterocolitis, neonatal. adhesive obstruction with, 1359 gastric perforation in, 1235-1237 intussusception with, 1318, 1326, 13341335,1336 malrotation with, 1354, 1356 mesenteric venous thrombosis with, 2130 thrombotic, in infant, 2115 Islet cell adenoma, 1683, 1685 Islet cell carcinoma, 1685 Islet cell transplantation, 717, 723-727, 724f-725f Isochromosome, definition of, 596 Isodisomy, uniparental, 447 Isoflurane, 222f, 222t, 227t, 228, 228f, 229 Isosulfan blue, lymph node drainage and, with soft tissue sarcomas, 549, 549f Isotretinoin. See 13-cisRetinoic acid. IUGR (intrauterine growth retardation), 89-90 hypoglycemia and, lOlt I W (intravenous pyelography) in trauma patient, 319, 323, 326 of ureteral duplication, 1761, 1762f N U (intravenous urography) in ureteropelvic junction obstruction, 1727 with ureteral anomalies, 1763, 1763f, 1764, 1765f

Jaffe-Campanacci syndrome, 652, 654 Jarcho-Levin syndrome, 917, 918f Jaundice. See also Hyperbilirubinemia. diagnostic evaluation in, 1605-1607, 1606t in cholelithiasis, 1636, 1637, 1642 in chronic graft-versus-host disease, 782 in hypertrophic pyloric stenosis, 1216, 1218 in jejunoileal atresia, 1271, 1271t in parenteral nutrition patient, 209 liver transplantation and, 732, 733, 739 neonatal, self-limited, 1603 portal hypertension with, 1656 surgical lesions with, in infancy, 1603, 1613-1615, 1614f. See also Biliary atresia; Choledochal cyst. Jejunal interposition, for esophageal replacement, 1065, 1100-1101,1101t Jejunectomy, consequences of, 1371, 1371f, 1372 Jejunoileal atresia and stenosis, 1269-1284 classification of, 1275-1276, 1276f clinical presentation of, 1271, 1271t colonic atresia with, 1493

Jejunoileal atresia and stenosis (Continued) diagnosis of, 1271-1272, 1272f-1274f differential diagnosis of, 1272, 1274-1 275, 1275f vs. meconium ileus, 1293 etiology of, 1270 Hirschsprung's disease with, 1528 historical understanding of, 1269, 1270 incidence of, 1269 jejunal feeding in, 1481 malrotation with, 1270, 1272, 1274, 1283, 1346 meconium ileus associated with, 1271, 1271t, 1274-1275, 1275f, 1282, 1293, 1294f morbidity and mortality in, 1282-1284,1283t treatment of, 1276-1281, 1278f-1281f postoperative care in, 1282 Jejunostomy. See also Enterostoma(s). choices for, 1480f-1481f, 1480t, 1484 choledochal cyst excision with, 16261631, 1627f-1628f gastroesophageal reflnx and, 1130-1 131 in chronic intestinal pseudo-obstruction, 1549 in necrotizing enterocolitis, 1441 indications for, 1480-1482, 1483f nutrition and, 199, 202, 203 technical aspects of, 1485-1486 Jejunum, Hirschsprung's disease in, 1531, 1540 Jeune's disease, acquired, 901 Jeune's syndrome, 915-917,917f Joint (s) bone tumor and reconstruction ofjoint, 662, 662f-665f retention ofjoint, 660, 661f cartilaginous lesions about, 652, 652f Crohn's disease and, 1454 infection in, 2033,2034f, 2039-2041, 2040t, 2041t gonococcal, 2040, 2044 in Lyme disease, 2044 tuberculous, 2042, 2044 trauma to, 34'2, 344 ligament injury in, 350 ulcerative colitis and, 1464 Jugular vein injury to, 378, 380 internal aneurysm of, 2129 thrombophlebitis of, 2132 thrombosis of, infected, 823 Juvenile nasopharyngeal angiofibroma, 821 Juvenile papillomatosis, of breast, 891 Juvenile polyps bleeding with, 1387, 1415, 1416 classification of, 1414 in polyposis syndromes, 1414, 14161417, 1417f colon carcinoma in, 519 intestinal obstruction caused by, 1364 isolated, 1414-1416, 1415f

Volume 1, pages 1-1140; Volume 2, pages 1141-2146.

Kaposiform hemangioendothelioma, 2094, 2097-2098,2097f, 2105 salivary gland, 839 Karyotyping. See also Chromosomal abnormalities. fetal, 78 of tumors, 419, 420t Kasabach-Merritt syndrome, 495, 496, 826 kaposiform hemangioendothelioma with, 2097-2098,2097f, 2105

xxxvi

INDEX

Kasai procedure. See Portoenterostomy. Kawasaki disease, 848, 21 15, 21 17 hydrops of gallbladder in, 1636,2115 Kelly technique, for bladder exstrophy, 1853-1855, 1854f-1855f Keratinocytes, cultured, for burn patient, 391 Ketamine, 238t, 239 caudal, 248 for burn patients, 394, 394t Ketoconazole, in burn patients, 393 Ketone bodies, in neonate, 97, 100, 102, 103-104, 103f surgery and, 107-108 Ketorolac, 238-239,238t with sevoflurane anesthesia, 229 17-Ketosteroids, 595t, 624 Ketotic hypoglycemia, 1680-1681, 1681f Kidney (s). See also Renal entries. bladder dysfunction and, 1817-1818, 1818f, 1819 in myelodysplasia, 1821, 1821f congenital anomalies of, 1705-1706, 1715-1720, 1717f-1720f. Seealso Duplication(s), genitourinary; Renal dysplasia. anorectal malformations with, 1567 duplications as, 1743, 1744f, 1758 extrarenal pelvis as, 1728, 1728f in prune-belly syndrome, 1781, 1783, 1783f, 1786, 1789 trauma in setting of, 318 crossed ectopia of, 1717, 1719-1720, 1720f cystic disease of, 17061713 acquired, 1713 benign multilocular, 1712-1713, 1712f caliceal diverticulum as, 1713 classification of, 1706, 1706t in tuberous sclerosis, 1709 in von Hippel-Iindau disease, 1709-1710 multicystic dysplastic kidney as, 1705, 1706, 1710-1711, 1710f-1711f, 1725, 1727, 1762 polycystic. See Polycystic kidney disease. simple cyst as, 1713, 1713f ectopic, 1715-1716, 1717f-1718f with ureterocele, 1762, 1763 embryology of, l705,1715,1716f, 172G1725 horseshoe, 17161719, 1718f-1719f Wilms' tumor with, 457, 458f pelvic, 1715, 1717f-1718f thoracic, 1715-1716, 1717f trauma to, 320-326 algorithm for management of, 322f anatomic considerations in, 317-318 clinical features of, 318 complications of, 324 diagnostic evaluation in, 318-319, 320 epidemiology of, 317 grading of, 320,321,321f; 321t, 323,325 mechanisms of, 317 penetrating, 323 vascular, 322, 323-324, 325f tumor lysis syndrome and, 588 tumors of. See also Wilms' tumor. clear cell sarcoma as, 450, 454, 4 5 4 ~ 455, 460,461 in horseshoe kidney, 1718-1719 rhabdoid, 450, 451f, 460 synovial sarcoma, primary, 546 Kidney stones. See Urolithiasis. Kikuchi's disease, 848 Kimura (Iowa) intestinal lengthening procedure, 1378-1379, 1378f Kimura patch procedure, 1540, 1542f, 1547 King-Denborough syndrome, malignant hyperthermia in, 231

Kininogen, high-molecular-weight, 186 kit gene and kit protein germ cell tumors and, 554, 556 in cerebrospinal fluid, 556 in gastrointestinal stromal tumors, 516, 517t Kleeblattschadel malformation, 798, 798f Klinefelter's syndrome germ cell tumors in, 420 mediastinal teratoma as, 565 gynecomastia in, 892, 2068 Klippel-Feil syndrome, 2027, 2064, 2071 Klippel-Trenaunay syndrome, 2098,2101, 2101f, 2114, 2128-2129, 2129f Klumpke's palsy, 405 Knee congenital dislocation of, 2025-2026, 2026f reconstruction of, after tumor resection, 662f-6635 666 Kock pouch, 1467,1799,1800, 1824, 1825, 1827f, 1833 Kropp procedure, 1829,1830f, 1831 Krukenberg procedure, 2073 Kumar clamp technique, 1639, 1639f Kyphosis, congenital, 2026f, 2027, 2028-2029, 2029f

L Labia, lymphedema of, 2144 Labial adhesions (fusion), 1903, 1942 kaboratory studies in child abuse, 401t of ascitic fluid, 1408-1409, 1409t of burn patient, 386 of parenteral nutrition patient, 210, 21 1t of trauma patient, 272 Laceration Of canal, external, 817 pericardial, thoracoscopy of, 287 pulmonary, air embolus and, 282 repair of, topical anesthesia for, 244 soft tissue, 352 Lactase deficiency, 197, 202 Lactate, postoperative levels of, 106 Lactate dehydrogenase (LDH) ~ w ifamily ~ ~tumor ' ~ and, 654 germ cell tumors and, 556, 565, 568, 595, 607 in pleural fluid, with empyema, 1018, 1019f neuroblastoma and, 470, 487 non-Hodgkin's lymphoma and, 589 Lactated Ringer's solution for resuscitation of burn patient, 386, 387, 388t, 389 of trauma patient, 271 intraoperative, 225-226 Lactic acidosis in short.bowel syndrome, 1372, 1378 in thiamine deficiency, 206 Lactose, 197, 202 Lactose intolerance, after bowel resection, 1282 Ladd procedure, 1352, 1353-1354, 1355f, 1356 adhesive obstruction secondary to, 1359f Ladd's bands, 1261, 1262, 1348, 134gf, 1362, 1362f division of, 1352, 1353-1354, 1355f radiographic appearance and, 1350, 1353f Laminin, aganglionosis and, 1525 Langerhans cell histiocytosis, 833 diagnostic features of, 544t radiation therapy for, 657 Langerhans cells, 2062 Lansoprazole, for peptic ulcer disease, 1229 Lap Band. See Gastric band, laparoscopic adjustable.

Volume 1, pages 1-1140; Volume 2, pages 1141-2146.

Laparoscopy. See also Endoscopy; Minimal access surgery; Robotic surgery; specific procedure. diagnostic, 439-440 in abdominal trauma, 297 for diaphragmatic injury, 297, 313 for splenic pseudocyst, 299, 300f of ovarian lesions, 599-600, 599f, 601, 602, 613 operative stress and, 107 postoperative ileus and, 1361 simulation of, 60, 61, 68-69, 69f Lap-belt injuries. See Seat-belt injuries. Large cell lymphomas, 582, 583,583f, 584 Laryngeal atresia, 987 Laryngeal cleft, 995-996, 995f Laryngeal mask airway, 973,976 Laryngeal nerve recurrent, risk to in lung transplantation, 772 in piriform sinus surgery, 869, 869f in total thyroidectomy, 856 superior branchial arches and, 862, 863 risk to, in piriform sinus surgery, 869, 869f Laryngeal webs, 987-988, Y87f, 989,990 Laryngocele, 830 Laryngoesophageal cleft, 972,973 Laryngomalacia, 829, 829f, 984,986987, 987f laryngoscopy of, 973,973f Laryngoscopy, 971-973,972f-973f in airway obstruction, 983 Laryngospasm inhalation anesthesia and, 223, 229 thiopental induction and, 233 Laryngotracheal stenosis, 990-994, 991t, 992f-993f, 992t. See also Subglottic stenosis; Tracheal stenosis. Laryngotracheobronchitis, 828, 830 Laryngotracheoesophageal cleft, 995-996, 1072-1074, 1073f-1074f Laryngotracheoplasty, posterior graft, 989 Larynx. See also Airway; Vocal cords. anatomy of, 267,827,983-984 congenital anomalies of, 829-830, 829f-830f functions of, 827, 983 inflammatory disease of, 830-831 neoplasms of, 831,83lf, 989,989f trauma to during intubation, 129 vocal cord paralysis secondary to, 988 Laser ablation for vocal cord immobility, 989 in subglottic stenosis, 991-992 of capillary malformation, 2106 of esophageal lesions, 1043 of subglottic hemangioma, 994-995, 2105 Lasers, surgical, 41 Lasix renography. See Diuretic renography. Latex sensitivity, 232 bladder augmentation and, 1796 Laxative therapy, 1550, 1550f, 1592, 1594 for anal fissure, 1597 for intestinal neuronal dysplasia, 1562 LBP ( l i ~ o ~ o l ~ s a c c h a rbinding ide protein), 168, 169f, 172 LDH. See Lactate dehydrogenase (LDH). Leadbetter-Politano ureteral reimplantation, 1748f LeFort procedures, 798-799,800,800f after cleft repair, 811 Leg length. See Limb length inequality. Leiomyoma, ovarian, 614, 615

Leiomyosarcoma breast, 892 gastric, 515 intestinal, 1364 ovarian, 615 soft tissue, 543 Lemierre's syndrome, 823 Length, body, 194, 195 Leptomeninges cyst of, enlarging, 366 sarcomas of, 546 vascular anomaly of, 2098 LET (linear energy transfer), 43, 44 Leucovorin, 422 Leukemia acute lymphoblastic, torticollis in, 877 acute myelogenous, ovarian granulocytic sarcoma in, 615 arterial thrombosis in, 2115 fungal abscesses in, 1644 gene therapy as cause of, 15, 18 ovarian involvement by, 615 Poland's syndrome with, 907 testicular involvement by, 625 Leukocyte adhesion deficiency, 160, 161 delayed cord separation in, 1146 Leukocyte chimerism, 685-686, 687, 689, 690f, 691, 692f, 695 Leukocyte count in appendicitis, 1504 in neonatal sepsis, 171 Leukocyte scan in appendicitis, 1504 in musculoskeletal infection, 2035 Leukocyte-reduced blood products, 188, 189. 190 Leukocytes, in postoperative stress response, 106 Leukodystrophy, central dysmyelinating, 1523 Levobupivacaine, 243, 243t epidural infusion of, 248t Leydig cell tumor ovarian, 606-607 testicular, 622, 623t, 624 Leydig cells chemotherapy resistance of, 626 in cryptorchidism, 1197, 1198 LHR (lung-to-head ratio), 77, 83, 84,937 Lich-Gregoir procedure, modification of, 1749f Lidocaine epidural infusion of, 248t for fracture reduction, of hand, 352 for local anesthesia, 243, 243t in topical anesthetics, 244, 244t Life support. See ABCDE sequence; Advanced Trauma Life Support (ATLS); Extracorporeal life support (ECLS) Li-Fraumeni syndrome, 418, 421 nonrhabdomyosarcomatous soft tissue sarcomas in, 543 osteogenic sarcoma in, 653, 653f, 654 rhabdomyosarcoma in, 524525 I.igament(s), trauma to, 351 in hand, 350 Ligament of Treitj. in atypical malrotation, 1350, 1352f normal intestinal fixation and, 1346, 1346f, 1350, 1352f LigaSure vessel sealing device, 1696 Light index, 1020 Limb deficiency, congenital, 2050-2054, 2051f-2055f, 2054t. See also Foot (feet) ; Hand (s). phantom pain in, 2058

Limb hypertrophy. See Hemihypertrophy. Limb ischemia. See Ischemia. Limb length inequality after fracture, 339 after osteomyelitis, 2039 after septic arthritis, 2041 hip dysplasia with, 2019 iatrogenic vascular injury with, 380 multiple enchondromatoses with, 651,654 multiple hereditary exostoses with, 654 vascular malformations with, 2101, 2101f, 2107-2108, 2112, 2114, 2128, 2129f Linear accelerator for radiosurgery, 45-46,46f, 47 for radiotherapy, 44 Lingual thyroid, 826, 850, 864, 870, 871f Linoleic acid, 197 in biliary atresia, 212 Lip. See also Cleft anomalies. fistulas (pits) in, 805, 811-812 herpetic gingivostomatitis of, 822 pleomorphic adenoma of, 816 Lipid. See Fat(s). Lipid A, 158-159, 168. See also Lipopolysaccharide (LPS, endotoxin). sepsis therapies derived from, 172, 173 Lipid cell tumor. See Steroid cell tumor. Lipid emulsion, intravenous, 204-206 hypertriglyceridemia and, 208 iron dextran and, 207 Lipofibroma, of breast, 891 Lipoma(s) in Gardner's syndrome, 1422 intraspinal, 1594, 1806f, 1809f, 1810, 1822, 1993-1994,2027,2102 Lipopolysaccharide (LPS, endotoxin), 158-159, 161, 164, 165 absorption of, in preterm intestine, 1433 burns and, 384 in systemic inflammatory response syndrome, 168, 169f, 172, 173 necrotizing enterocolitis and, 1432, 1433, 1435 Lipopolysaccharide-binding protein (LBP), 168,169f, 172 Lipoprotein (a), thrombosis and, 187 Lipoprotein lipase heparin as cofactor of, 207 in neonate, 102, 103, 103f in systemic inflammatory response syndrome, 170 Lipoprotein X, 1606 Liposarcoma, 547 of breast, 892 Liquid ventilation, 126127,945, 945f Listeria monocytogenes, in neonatal sepsis, 170, 172 Lithotripsy, extracorporeal shock wave (ESWL), 1748,1751, 1752 Little's area, 818, 820 Liver anatomy of, segmental, 507-508,507f-508f, 734,734f arteriovenous malformation in, 495, 497, 2102 biopsy of, 440 biliary atresia and, 1606 biliary hypoplasia and, 1613, 1614 in portal hypertension, 1657 of tumors, 504 hemorrhage secondary to, 442 cyst of, nonparasitic, 499 fibrosis of, 1652-1653,1656, 1657, 1659 in polycystic kidney disease, 1707, 1709 Volume 1, pages 1-1140; Volume 2, pages 1141-21

Liver (C;ontinued) hematoma of abscess secondary to, 1643 in birth trauma, 405, 405f herniation of, fetal, 83, 84 infections of, 1642-1646,1642t, 1643f, 1646f of burn patient, fat deposition in, 392, 393 regeneration of, after resection, 26, 509 resections of ex vivo, 508 hemostasis in, 508 regeneration following, 26, 509 segmental anatomy and, 507-508, 507f-508f technique of, 507-509 tissueungineered, 22, 26-27 trauma to abscess secondary to, 1643 biliary duct injury in, 303, 304f cysts secondary to, 499 complications of, 299, 299f-300f imaging of, 295, 296f laparoscopic repair of, 297 nonoperative treatment of, 295, 297-298, 297t, 298t, 299,300 operative intervention for, 298, 300-302, 300f-301f, 301t tumors of, 502-51 1. See also Hepatoblastoma; Hepatocellular carcinoma. ablative therapies for, 51 1 adjuvant therapy for, 509-510,510f algorithm for diagnosis and treatment of, 503f benign, 495-499, 496f-499f hemangioma as, 497, 498, 2102, 2105f, 2106 incidence of, 505t biopsy of, 504 hemorrhage secondary to, 442 carcinoid, 518 clinical presentation of, 503 differential diagnosis of, 504-505 abscess in, 1644 epidemiology of, 502-503,502t, 505t follow-up of, 51 1 genetics and molecular biology of, 502 histology of, 505, 505f imaging of, 504, 504f laboratory studies with, 503 prognosis of, 51 1 radiation therapy for, 510 staging of, 505-506, 505t, 506f surgery for, 506-509 teratoma as, 496, 499, 505, 557 transplantation for, 509, 509f, 733, 739-740 Liver disease. See alto Cholestasis. clotting factor deficiencies in, 186 hepatocellular carcinoma and, 502 in short-bowel syndrome, 1373 metabolic, transplantation for, 733 obesity-related, 1246 portal hypertension caused by, 1652-1653, 1653t primary peritonitis in, 1475, 1476 trauma patient with, 274 Liver failure acute, transplantation for, 732, 733, 734 disseminated intravascular coagulation in, 186 extracorporeal support in, 26-27 in parenteral nutrition patient, 209, 744, 745 parenteral amino acids and, 204 Liver function tests, in biliary atresia, 1606, 1611

xxxviii INDEX Liver transplantation, 731-741 anatomical basis of, 734, 734f cell replacement as, 26 combined with intestinal transplant, 742, 744, 745,746f-747f, 748-749, 750 in Hirschsprung's disease, 1540 combined with lung transplant, 766 complications of acute pancreatitis as, 1673 infectious, 737, 739, 740t, 1643 portal hypertension as, 1653, 1654, 1654f technical, 737 donor operation for, 734735, 735f extracorporeal support prior to, 2 6 2 7 history of, 685, 686, 686f, 686t, 688-689, 6885 693,731 immunosuppression for, 737, 738t, 739, 740-741 indications for, 732-733, 732f absent portal vein as, 2126 a,-antitrypsin deficiency as, 1606 biliary atresia as, 732, 732f, 739, 1608, 1609, 1610, 1612, 1613 biliary hypoplasia as, 1614 hepatopulmonary syndrome as, 1656 total parenteral nutrition and, 1373 tumors as, 509,509f, 733, 739-740 veno-occlusive disease as, 781 organ allocation for, 731, 733-734, 740 organ preservation for, 694, 694f, 695, 734-735 outcome of, 739-741 postoperative care in, 737 rejection in, 739 renal transplantation with, for oxalosis, 71 1 transplantation operation in, 735-736, 736f Lizard bites, 353 Lobectomy, pulmonary fetal, 82t, 83 for abscess, 1017 for bronchiectasis, 1014 thoracoscopic, 977 Local anesthetics, 243, 24% for epidural infusion, 248, 248t for fracture reduction, of hand, 352 for wound repair, in soft tissue injury, 352 topical formulations of, 244, 244t Long QT syndrome, ventricular tachycardia in, 153 Loop diuretics, calcium losses caused by, 207 Loop ureterostomy, 1792, 1793f Loopography, 1573-1574, 1573f-1574f Loperamide, 1373, 1466 Lorazepam, for burn patients, 394, 394t Lordosis, congenital, 2026f, 2027 Loss of hetero~ygosity(LOH), in Wilms' tumor, 446,447,448, 459 Low-birth-weight infant, 89, 90, 9lf. See also Premature infant. growth rate in, 194 hepatoblastoma in, 502 necrotizing enterocolitis in, 1427, 1428, 1429 neonatal hyperglycemia in, 102 neonatal infection in, 170, 173 obesity risk in, 1245 parenteral nutrition for, 204, 206 respiratory quotient of, 97 LPS. See Lipopolysaccharide (LPS, endotoxin). Luciferase, 38, 39 Lumbar spine. See also Spine. trauma to, 346, 368 in seat belt injury, 311, 346f, 368

Lung(s). See also Pulmonary entries; Respiratory entries. abscess of, 1015-1017, 1017f biopsy of after lung transplant, 771 core needle, 439 in bone marrow transplant patient, 781 in HIV-infected patient, 1008, 1010 open, 1023-1024, 1024f thoracoscopic, 440-442,44lf, 977-980 cystic lesions of, 955-959, 956f, 958f-959f. See also Bronchogenic cyst; Cystic adenomatoid malformation, congenital. malignancy in, 641, 642, 642t, 643t, 644, 957 vs. pneumatocele, 1015 development of, 114-1 17,115f-116f, 933-934 congenital diaphragmatic hernia and, 934,935 hemorrhage in, 1014, 1015f after lung transplant, 772 in pulmonary vascular disease, 766 infections of. See also Pneumonia. barriers to, 157 bronchiectasis secondary to, 1012-1014, 1013f echinococcal, 1005, 1005f epidemiology of, 1001 in immunocompromised patient, 1001 with cancer, 1005-1008, 1006f-1007f with cystic fibrosis, 1010-1011 with HIV infection, 1008-1010, 1009f open biopsy of, 1023-1024, 1024f viral bronchiolitis as, 1004-1005, 1004f inhalation injury to, 394-395 lymphangiectasia in, 2140 physiology of, 117-121, 118f-119f, 118t, 121f trauma to, 269, 272, 276, 277, 279, 281-283, 282f-283f computed tomography of, 278 epidemiology of, 275, 275t tumors of, 640-646 benign, 640-641,64Ot, 644 malignant, 640, 640t, 641-642, 642f-644f, 644 carcinoid, 518, 641 cystic malformations with, 641, 642, 642t, 643t, 644,957 fibrosarcoma as, 518 rhabdomyosarcoma as, 535,536, 642, 643t, 644f metastatic, 640, 644-646, 645t from benign bone lesions, 652 from osteosarcoma, 645-646,645t, 666 from rhabdomyosarcoma, 526, 536, 645 from thyroid carcinoma, 855,856857 from Wilms' tumor, 448-449, 455, 645 thoracoscopy of, 440,441f thoracoscopy of, 440-442 volumes of, 118, 118f Lung transplantation, 765-776 complications of, 771-775, 773f-774f contraindications to, 768-769, 769t extracorporeal life support following, 142 for congenital diaphragmatic hernia, 767, 945 for cystic fibrosis, 765-766, 773, 775, 1011 future considerations in, 776 history of, 685, 686t, 693, 765 immunosuppression for, 770-771,771 t, 774 indications for, 765-768, 765t living donor, 770, 776 lung growth and function after, 775-776

Volume 1, pages 1-1140; Volume 2, pages 1141-2146.

Lung transplantation (Continued) operative technique in, 770 organ procurement for, 769-770 post-transplant surveillance with, 771 retransplantation for failure of, 768, 774 survival after, 775, 775f Lung-to-head ratio (LHR), 77, 83, 84, 937 Lupus anticoagulant, 187, 2130 Lupus erythematosus antiphospholipid antibodies in, 2121 esophageal dysmotility in, 1111 maternal, neonatal heart block and, 151 Luteinized thecoma, 595t, 605 Luteinizing hormone after orchiectomy or oophorectomy, 556 cryptorchidism and, 1197 Luteinizing hormone-releasing hormone, for cryptorchidism, 1200 Luteoma, stromal, 606 Lyme arthritis, 2044 Lymph, abdominal, 1407 Lymph node metastases, detection of isosulfan blue in, 549, 549f nanoparticles for, 59 radiolabeled antibodies for, 47 Lymph nodes, cervical, anatomy of, 844, 844f-845f Lymphadenectomy, iliac and retroperitoneal, robot-assisted, 53 Lymphadenitis cervical. See Cervical lymphadenopathy. mesenteric, 1505 Lymphadenopathy cervical. See Cervical lymphadenopathy. in cat-scratch disease, 16441645 mediastinal, 1027, 1028 Lymphangiectasia, 2137, 2140, 2141 Lymphangiography contrast, of lymphatic malformation, 2107 radionuclide in chylothorax, 1027 in chylous ascites, 2140 of lymphatic obstruction, 2140 of lymphedema, 2141,2142 Lymphangioma, 2137-2140,2138f-2139f. See also Lymphatic malformations. breast, 888-889 chylothorax associated with, 1025, 1025f, 1027 chylous ascites associated with, 1410 classification of, 2138 OK432 treatment for, 1404,2107, 2139 pathogenesis of, 2137 terminology for, 2098 vs. mesenteric-omental cyst, 1399 Lymphangiosarcoma, 2137,2142 Lymphangitis, 2138, 2141, 2142 Lymphatic hypoplasia, 2101 Lymphatic malformations, 2098-2099, 2099f. See also Cystic hygroma; Lymphangioma. chylothorax secondary to, 1027, 2140-2141 chylous ascites associated with, 1410, 2107, 2140 head and neck, 826 histopathology of, 2095 in complex-combined malformation, 2101, 2101f intestinal obstruction by, 1365-1366 lymphangiectasia as, 2137, 2140, 2141 lymphedema caused by, 2141 management of, 21062107 with OK-432, 1404, 2107 mediastinal, 2099, 2099f, 2107

Lymphatic malformations (Continued) mesenteric or omental cyst as, 1366 pathophysiology of, 2137 radiologic characteristics of, 2103 salivary gland, 835, 838, 839 vs. hemangioma, 2097 Lymphatic obstruction chylous ascites associated with, 1410 intestinal, 2140 lymphatic malformations secondary to, 2137 lymphedema caused by, 2141 pulmonary, 2140 Lymphatic system anatomical organization of, 2137 embryology of, 2137,2138f interstitial fluid and, 2137 Lymphedema, 2099,2137,2140,2141-2144, 2141f, 2143f-2144f upper extremity, 2141,2144 Lymphoblastic lymphoma, 580, 581-582, 583, 583f clinical presentation of, 584, 584f treatment of, 587,588t Lymphocele, after renal transplantation, 707 Lymphocytes, 161, 162-163, 165. See also B lymphocytes; T lymphocytes. development of, 581,581f-582f immunosuppressive agents and, 707, 708 in chyle, 1026, 1027 in Crohn's disease, 1453, 1455, 1456 in human milk, 202 in ulcerative colitis, 1463, 1466 transfused in immunodeficient patient, 189 in late let concentrate. 190 ~ym~h'ocytic interstitial pnkumonitis, 1008, 1009f Lymphocytic thyroiditis, chronic, 852 Lymphoid hyperplasia intestinal polyps as, 1414, 1418-1419, 1419f intussusception caused by, 1319, 1327-1328 Lymphoid polyps, 1418-1419, 1419f Lymphoma. See also Hodgkin's disease; NonHodgkin's lymphoma. in oral cavity and pharynx, 827 intestinal obstruction in, 1364 intussusception with, 1320, 1321 mediastinal lesions in, 959, 960t, 961 thoracoscopic biopsy of, 977 Lymphoproliferative disease, immunosuppression and in neuroblastoma, 484 post-transplant, 584-585, 712, 739, 750-751, 762,774 Lymphosarcoma, ileal, 1335 Lynch syndrome, 520 Lysosomes, 158, 160, 161

MAC (minimum alveolar concentration), 222f, 222t, 228 MACE procedure, 1595 Macroglossia, 825 lymphatic malformation with, 2099 Macrophages, 161-162, 163, 164, 165, 166 bacterial evasion of, 159 in burn patient, 384 in obesity, 1244 in systemic inflammatory response syndrome, 168, 169, 169f, 172 neonatal, 167 Macrostomia, 789, 789f

Mafenide acetate (Sulfamylon), 383, 389-390, 389t Maffucci syndrome, 652, 2128, 2129 ovarian tumors in, 593, 615 Magnesium failure to thrive and, 214 serum, in neonate, 95 short-bowel syndrome and, 1372 Magnetic resonance angiography (MRA) in portal hypertension, 1657 of conjoined twins, 2082, 2083, 2085 of hepatic tumors, 504, 504f of trauma, 377 catheter-related, 380 cerebral, 358, 366 Magnetic resonance cholangiopancreatography in biliary atresia, 1607 in pancreatitis, 1674, 1675, 1676f of ductal anomalies, 1625,1626 of pancreas divisum, 1676, 1676f of pancreatic trauma, 309 Magnetic resonance imaging (MRI), 36-37 as virtual reality data source, 63, 64f, 67-68 fetal, 37, 77 of cervicofacial teratoma, 564 of congenital diaphragmatic hernia, 936 of conjoined twins, 2080 of cystic lung lesion, 957 of esophageal atresia, 1056 of intestinal atresia, 1271 of sacrococcygeal teratoma, 559,560f functional, 37 brain tumors and, 673,677 in image-guided radiation therapy, 429, 430 in image-guided surgery, 42 intraoperative, for brain tumor resection, 673 molecular imaging with, 40 of pelvic lesions, 597 of salivary glands, 836 of trauma cerebral, 358, 359, 361, 363 musculoskeletal, 342 spinal, 346, 346f, 369 thoracic, 278, 285 of tumors brain, 672-673 hepatic, 504, 504f ultrafast, 3 6 3 7 Magnetic resonance spectroscopy, 547 Magnetic resonance urography (MRU), 1730, 1731f Magnetic resonance venography (MRV), 2126,2127,2128f MAGPI (meatal advancement glansplasty) , 1880-1882, 1881f-1882f Maintenance fluid requirement (MFR), =5 Mainz pouch, 1826 Major histocompatibility complex (MHC), 161, 163, 165, 166, 167 Malabsorption in cystic fibrosis, 1299 in short-bowel syndrome, 1371-1372, 1373 lymphangiectasia with, 2140 secondary to necrotizing enterocolitis, 1443 secondary to urinary tract reconstruction, 1837 Malussaiafurfur infection, catheter-related, 210 Malignant fibrous histiocytoma, 541, 542, 543 of breast, 892 of lung, 641 Malignant hyperthermia, 231-232,232t Malignant melanoma of soft parts, 547 Mallory-Weiss tear, 1041

Volume 1, pages 1-1140; Volume 2, pages 1141-2146.

Malnutrition assessment of, 194-195 failure to thrive in, 213-214 in burn patients, 393 in surgical patients, 21 1 Malone procedure, 1587 Malrotation. See also Intestinal rotation and fixation; Volvulus. asymptomatic, 1348 atypical, 1346, 1350, 1352f, 1354, 1356 definition of, 1346 Mammary duct ectasia, 888 Mandatory minute ventilation, 123, 125 Mandible hypoplasia of, 789, 789f distraction osteogenesis for, 2063 in Pierre Robin sequence, 803, 812 osteotomy of, simulation of, 68, 68f overgrowth of, lymphatic malformation with, 2099 Mandibulofacial dysostosis, 789, 79Of-79lf, 791 Manganese, 198t, 199, 206 Mangled Extremity Severity Score (MESS), 345, 379,379t, 2055, 2056t Mannitol for brain injury, 273, 364 for electrical burns, 396 Mannose receptors, 158 Mannose-binding lectin, in cystic fibrosis, 12 Manomeq. See Anorectal manometry; Colonic manometry; Esophageal manometry. Mapleson D system, 234f Marfan's syndrome arterial degeneration in, 21 14 with traumatic aortic dissection, 287 bronchiectasis in, 1013 inguinal hernia in, 1188 pectus excavatum in, 894, 899 Marijuana gynecomastia caused by, 892 macromastia caused by, 887 Masculinization. SeeVirilization. Mask airway, laryngeal, 973, 976 Mask ventilation, of trauma patient, 267, 269 Mastitis, neonatal, 887 Mastoid, 813 cholesteatoma extending to, 816 temporal bone fracture and, 816,817 Mastoidectomy, 815 Mastoiditis acute, 815-816,816f intracranial abscess secondary to, 2009,2010 Mathieu procedure, 1880, 1882-1883, I884f, 1893,1894 Matrix metalloproteinases, 418 angiogenesis and, 2095, 2104 Mayer-Rokitansky-Kiister-Hauser syndrome, 19361937 May-Thurner syndrome, 2127 McBurney's point, 1501, 1502, 1503, 1506 McCune-Albright syndrome, 593 McGoon index, modified, 998 McIndoe procedure, 1937-1938, 1938f McKusick-Kaufman syndrome, 1936 MCP-1 (monocyte chemotactic protein l ) , 160, 161, 165 MDCT (multidetector computed tomography), 35,35f Measles virus, Crohn's disease and, 1453 Mechanical ventilation, 123-1 29 breath phases in, 123-124 classification of ventilators for, 124 complications of, 123, 125, 126, 128-129

Mechanical ventilation (Continued) airway obstruction as, 983, 990 diaphragmatic eventration as, 946 control mode in, 124 extreme alternatives to, 126127. See also Extracorporeal life support (ECLS). goals of, 123 historical perspective on, 123 in brain injury, 363, 364t in congenital diaphragmatic hernia, 938, 939-940,942,943 in emergency management, 267,269 in neonate, neurodevelopmental impairment and, 140 in sepsis or SIRS, 172 in spinal cord injury, 370 investigational adjuncts to, 127 management of respiratory failure with, 127-129 modes of, 124-126 neuromuscular blocking agents for, 229 prior to extracorporeal life support, 135 pulmonary compliance and, 119, 119f, 124, 125, 127, 128 tidal volume and, 120, 124, 125, 126, 128 initial setting for, 127 time constants and, 120, 127 tracheotomy for, 984 weaning from, 124, 125, 127, 128 opioids and, 242 with extracorporeal life support, 138 Meckel's diverticulum, 1145t, 1147f, 1148, 1304-1311 anatomic variants of, 1307f anomalies associated with, 1305 anomalies related to, 1304, 1307f clinical manifestations of, 13061311 hemorrhage as, 13861387 intnssusception as, 1309, 1319, 1321, 1335 ectopic gastric mucosa in, 1386 embryogenesis of, 1304, 1305f-1306f incidence of, 1304 incidentally discovered, 1304, 1305-1306 inflammatory pseudotumor of, 1365 technetium 99m scan of, 1308, 1308f, 1386 vs. appendicitis, 1309, 1505 vs. ileal duplication, 1392 Meckel's scan. See Radionuclide studies, of gastric mucosa. Meconium . albumin concentration in, 1290-1291, 1292 passage of normal, 1592 with anorectal malformation, 1569, 1571 Meconium aspiration syndrome extracorporeal life support for, 140, 140t mechanical ventilation for, 127 Meconium cyst, 1291, 1296, 1298, 1298f Meconium ileus, 1289-1 300 adolescent patient with, 1498, 1498f clinical presentation of, 1291, 129lf complicated, 1275f. 1291, 1298, 1298f complications of, 1299-1300 diagnostic evaluation of, 1291-1293, 1291f-1293f differential diagnosis of, 1293-1 294, 1294f-1295f genetics of, 1289-1290 historical perspective on, 1289 jejunoileal atresia with, 1271, 1271t, 12741275, 1275f, 1282,1293, 1294f management of nonoperative, 12941296 operative, 12961298, 1296f-1297f postoperative, 1298-1 299

Meconium ileus (Continued) necrotizing enterocolitis in, after hyperosmolar enema, 1429 pathogenesis of, 1290-1291 results of treatment for, 1300, 1300f short-bowel syndrome secondary to, 1369 without cystic fibrosis, 1294, 1299 Meconium ileus equivalent, 1291, 1299, 1300 Meconium peritonitis, 1291, 1296, 1298 jejunoileal atresia with, 1271, 12735 1274, 1282,1283 Meconium plug syndrome, 1294, 1295f, 1299, 1369, 1496, 1497f with Hirschsprung's disease, 1519 Meconium staining, gastroschisis and, 1160 Median nerve lipofibromatous hamartoma of, 2075 macrodactyly and, 2075 test of, 348-349,349f Median sternotomy, mediastinal infection secondary to, 1028 Mediastinal tumors cystic, 959-961, 960t, 961f, 962-963 germ cell, 557, 565, 567, 568, 959, 960t, 961,96lf, 962-963 lymphoma as, 581,583,584,584f, 586587, 586f, 588,959,960t, 961 in Hodgkin's disease, 576, 576f, 577,960t thoracoscopic biopsy of, 977 Mediastinitis, 1027-1028 from descending neck infection, 823, 1027 Mediastinotomy. See Chamberlain procedure. Mediastinnm anatomic subdivisions of, 959 branchial anomaly in, 869 chyle in. See Chylothorax. cystic lesions of, 955,959-966,96Ot, 961f-966f lymphatic malformation as, 2099, 2099f, 2107 enteric duplications in, 1393 thoracic trauma and, 269, 276, 278, 280 with aortic rupture, 288 thoracoscopic biopsy in, 441, 977, 980 thoracoscopic inspection of, 440 Mediterranean fever, familial, 1477 Medium-chain triglycerides, 202, 212-213 for chylous ascites, 1410 Medulla oblongata. See also Brainstem. tumor of, vomiting associated with, 672 Medulloblastoma, 674-675, 6755 679 in Turcot's syndrome, 1422 Medulloepithelioma, 671 Megacolon, toxic, 1463, 1464, 1464f, 1466 Megacystis-microcolon-intestinal hypoperistalsis syndrome, 1496, 1548-1549 Megaesophagus, 1112, 1113 microgastria with, 1237 Megalourethra, 1905, 1905f Megaureter, 1771-1780 assessment of, 1771-1772 in prune-belly syndrome, 1771, 1780, 1783, 1783f-1785f, 1787f-1788f, 1789 presentations of, 1771 repair of complications of, 1778-1 780, 1779f-1780f endoscopic injection in, 1776, 1777f imbrication in, 1775-1776, 1776f indications for, 1772-1 773 lower, 1773, 1774f-1777f, 1775-1776 peristalsis and, 1778, 1779f robot-assisted, 54t, 55 upper, 1773, 1776, 1778, 1778f summary of, 1780 types of, 1771, 1772f ~ l u m e1, pages 1-1 140; Volume 2, pages 1141-21

Melanocytic nevi, congenital, 2063-2064,2065f Melanoma, malignant nevus degenerating to, 2063, 2064 of soft parts, 547 Melanotic neuroectodermal tumors in infancy, 671 Melanotic spots, in Peutzjeghers syndrome, 1417, 1418 Melorheostosis, 21 14 Melphalan, 423t Membranoproliferative glomerulonephritis, renal graft loss in, 711 Membranous croup, 831 MEN. See Multiple endocrine neoplasia entries. Menarche, early, obesity and, 1245 Meninges. See Dura mater; Leptomeninges. Meningioma, 679 pineal region, 678 Meningitis cerebrospinal fluid leak and with otorrhea, 816 with rhinorrhea, 820 nasal encephalocele associated with, 820 neurenteric cyst and, 966 otitis media progressing to, 816 sepsis secondary to, in neonate, 170, 171, 173 skull fracture associated with basilar, 366 temporal bone, 817 Meningocele, 1808, 1821, 1987 anterior thoracic, 966 Meniscus, tissue-engineered, 22 Menstrual disorders congenital anomalies with, 1568 liver dysfunction with, 1613 Meperidine, 241, 241t for burn patients, 394t patient-controlled analgesia and, 243, 243t Mercaptopurine, 423t for Crohn's disease, 1455 for ulcerative colitis, 1466 Mesalamine for Crohn's disease, 1455 for pouchitis, 1471 for ulcerative colitis, 1465, 1466 Mesenchymal hamartoma, 495, 496,497-498, 497f-498f malignant transformation of, 505 vs. nonparasitic cyst, 499 Mesenchymoma, pulmonary, 642 Mesenchymopathies, intestinal, 1547, 1548 Mesenteric adenitis, 1505 Mesenteric and omental cysts, 1399-1405 as lymphatic malformations, 1365-1366 chylous ascites associated with, 1410 classification of, 1399, 1404, 1404f clinical presentation of, 1400-1402, 1401f-1402f, 1401t, 1402t definition of, 1399 diagnosis of, 1402, 1403f differential diagnosis of, 1400, 1400t vs. cystic lymphangioma, 1399 vs. duplication cyst, 1400, 1402 epidemiology of, 1399, I399 t etiology of, 1399-1400 locations of, 1400, 1400t malrotation associated with, 13461347 outcomes with, 1404 pathologic features of, 1400, 1401t summary of, 14041405 treatment of, 1403-1404, 14041 Mesenteric artery, superior, trauma to, 378 Mesenteric ischemia burn-related, 384 short-bowel syndrome secondary to, 1369

INDEX Mesenteric vein, superior, thrombosis of, 2130 Mesenteric vein-to-left portal vein bypass (Rex shunt), 1662,1662f, 1663, 1665 Mesentery gastrointestinal stromal tumors in, 515 of small intestine, desmoid tumor of, 1422 postoperative defects in, 1363 Mesoblastic nephroma, congenital, 450 Mesocaval shunt, 1660, 1663 Mesocolic (paraduodenal) hernia, 1348-1349, 1349f, 1350, 1356, 1361, 1362f MESS (Mangled Extremity Severity Score), 345, 379, 379t, 2055, 2056t Metabolic acidosis. See also Acidosis. after urinary tract reconstruction, 1800-1801, 1836 congenital diaphragmatic hernia with, 939 in cardiac failure, extracorporeal life support and, 135 in fetus and neonate, 96, 96t in malignant hyperthermia, 231, 232, 232t in necrotizing enterocolitis, 1435, 1440 in neonatal sepsis, 170 in parenteral nutrition patients, 207, 208, 209 mafenide acetate as cause of, 389 Metabolic alkalosis. See also Alkalosis. gastrocystoplasty as cause of, 1836 hypertrophic pyloric stenosis with, 1217 in fetus and neonate, 96t in hyperaldosteronism, 636 parenteral nutrition and, 207 Metabolic rate. See Resting energy expenditure (REE). Metabolic syndrome, 1246 Metabolism. See also Energy metabolism; Nutritional requirements. in burn patient, 391-393, 392f-393f in neonate of energy, 9699,98f biliary atresia and, 212 postoperative, 105, 105f, 107, 108, 212 protein and, 104, 108 of nutrients, 100-104, 101t, 103f postoperative, 106, 107-108, 107f, 21 1 stress and, 104-108, 105f, 107f Metaiodobenzylguanidine (MIBG), 630, 632 Metalloproteinases, 418 angiogenesis and, 2095, 2104 Metanephrine, urinary, pheochromocytoma and, 631,635 Metaphyseal fractures, 342, 347 in child abuse, 403 Metaphysis, 337, 338f tumors in relation to, 652f, 654 Metastasis, molecular biology of, 418, 419 Metatarsus adductus, 2023-2024, 2023f Methadone, 241, 241t, 242 patient-controlled analgesia and, 243, 243t Methemoglobin, 122 nitric oxide and, 162 Methemoglobinemia, prilocaine-induced, 243,244 Methicillin-resistant Staphylococcus aureus colonic strictures and, 1495 in osteomyelitis, 2037, 2038 in septic arthritis, 2040 Methimazole, 853 Methohexital, dose versus age, 222f Methotrexate, 422, 423t for Crohn's disease, 1455-1456 Methylene blue in thoracoscopic lung biopsy, 441 oxygen saturation and, 122

Methylprednisolone. See also Corticosteroid therapy. for transplant rejection heart, 761 kidney, 708 liver, 739 lung, 771 in spinal cord injury, 370 Metoclopramide for gastroesophageal reflux, 1126 postoperative ileus and, 1361 Metronidazole, for Crohn's disease, 1456, 1458 Metronomic dosing, of cancer chemotherapy, 422 MFR (maintenance fluid requirement), 225 MHC (major histocompatibility complex), 161, 163, 165, 166, 167 MIBG (metaiodobenzylguanidine), 630, 632 Microarray analysis, 40, 419-420, 425, 437 Microchimerism. See Leukocyte chimerism. Microcolon in functional ileus, 1519 in jejunoileal atresia, 1272, 1293, 1293f, 1294 in meconium ileus, 1275f, 1291,1292, 1293f in meconium peritonitis, 1273f in megacystis-microcolon-intestinal hypoperistalsis syndrome, 1496, 1548-1549 Microelectromechanical devices, 57-58, 57f as vascular networks, for tissue engineering, 27, 27f Microgastria, congenital, 1237-1238 Micrognathia, in cerebrocostomandibular syndrome, 917 Microlithiasis, testicular tumor with, 622, 623 Micropumps, for drug delivery, 58 Microsatellite instability, in colorectal carcinoma, 521 Microsomia, craniofacial, 788-789, 789f-790f Microtubules, inhibitors of, 422, 424t Microwave energy, for tissue ablation, 41 Midaortic syndrome, 21 18, 21 19, 2120, 2121 Midazolam for burn patients, 394, 394t in trauma patient, for intubation, 267 preoperative, 224, 229 propofol with, 233 Mikulicz resection, 1297, 1297f, 1298, 1299, 1300 Milk. See also Breast-feeding. cow's allergy to, 1386 constipation and, 1592, 1594 Crohn's disease and, 1453 for burn patient, 393 iron deficiency and, 180 vitamin Kin, 186 human, 202 epidermal growth factor in, 1430 erythropoietin in, 1430 fat content of, 100, 102, 212 immunoglobulins in, 104, 168, 202 in short-bowel syndrome, 1372 necrotizing enterocolitis and, 104, 1430, 1432, 1433, 1434, 1444 PAF acetylhydrolase in, 1445 preoperative feeding of, 224, 224t protective factors in, 1444 proteins in, 104 vitamin K deficiency and, 186 Milk curd syndrome, 1365 Milk line, 885, 886, 2066 Millard rotation-advancement cleft lip repair, 806807, 807f-808f Milrinone, for heart failure, 150t, 151 Volume 1, pages 1-1140; Volume 2, pages 1141-21

xli

Milroy's familial lymphedema, 2141 Mineralocorticoid receptors, blockade of, for heart failure, 148 Mineralocorticoids. See also Aldosterone; Corticosteroid therapy. adrenal synthesis of, 628, 629 insufficiency of, 636-637 Minerals. See Trace elements. Minimal access surgery. See also Laparoscopy; Robotic surgery. computerized image guidance for, 42,43 for biopsy, 437, 439442, 441f instruments for, 48, 48f robotic systems and, 47, 48, 51, 52,52t, 55,57 Minimum alveolar concentration (MAC), 222f, 222t, 228 Minoxidil, for hypertension, 2120 Minute ventilation, 120, 127 mechanical ventilation and, 123, 124, 125, 128 Mirror hand, 2075 Mirror syndrome, sacrococcygeal teratoma and, 85, 559 Misoprostol, peptic ulcers and, 1230 Mitomycin C, 428 for caustic esophageal injury, 1083 for laryngeal webs, 988 Mitosis, cell cycle and, 413, 413f Mitotane, for adrenocortical tumors, 635-636 Mitotic karyorrhexis index (MKI), of neuroblastoma, 472, 472t, 473f Mitral valve endocarditis of, 21 15-21 16,2116f trauma to, 285, 286f Mitral valve prolapse, pectus excavatum with, 898,922 Mitrofanoff procedure, 1794, 1795, 1797-1798, 1797f-17985 1832-1833, 1833f imperforate anus and, 1822, 1824 robot-assisted, 53, 54t with gastrocystoplasty, 1827 with sigmoid cystoplasty, 1826 with Young-Dees-Leadbetter bladder neck reconstruction, 1829 Mivacurium, 23Ot Mixed germ cell tumor, 555 extragonadal, 567, 568-569 ovarian, 607, 613 Mixed gonadal dysgenesis, 1912f, 1915t, 1917 diagnosis of, 1918t, 1920 Mixed tumor. See Pleomorphic adenoma. Mixed venous oxygen saturation, 118t, 122-123 in extracorporeal life support, 138 in malignant hyperthermia, 231 mechanical ventilation and, 127, 128 Mobius' syndrome, 789,907,2071 Molecular diagnostic methods, 419420, 420t Molecular genetics, 11-15, 12f, 13t. See also Cancer, molecular biology of. Molecular imaging, 38-40 Molybdenum, 199 Monfort abdominoplasty, for prune-belly syndrome, 1782f-1783f Monoclonal antibodies for burns, in animal models, 384 for immunosuppression, with transplant heart, 761, 761f islet cell, 724, 726 liver, 738t, 739 lung, 770-771,771t pancreas, 720 renal, 707, 709 for systemic inflammatory response syndrome, 172

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Monoclollal antibodies (Continued) in cancer treatment, 425,426, 427 OK432, for lymphangioma, 1404,2107,2139 to tumor necrosis factor, for Crohn's disease, 1456 Monocyte chemotactic protein 1 (MCP-1), 160,161, 165 Monocytes, 159, 160, 161, 164, 165, 166 in neonate, 167, 170 Mononucleosis, infectious, 822, 837, 848 Montgomery, areolar glands of, 888, 890 Montgomery's tubercles, 890 Monti-Yang ileal channel, 1798, 1798f Morgagni diaphragmatic hernia of, 937, 945-946 robot-assisted repair of, 53, 54t hydatid of, 1205, 1206 Morphine, 2 4 1 , 2 4 1 ~242 caudal, 248 epidural infusion of, 248, 248t, 249 for burn patients, 394t in neoriates, 106, 240 in patient-controlled analgesia, 243, 243t Morrison's pouch, ultrasonography of, in trauma patient, 296, 296f Motility, gastrointestinal. See Enteric nervous system; Esophageal dysmotility; Gastric emptying; Intestinal dysmotility; Intestinal pseudoobstruction. Mowat-Wilson syndrome, 1523 Moyamoya disease, 21 17 MRA. See Magnetic resonance angiography (MU). MRI. See Magnetic resonance imaging (MRI). MRU (magnetic resonance urography), 1730, 1731f MRV (magnetic resonance venography), 2126,2127,2128f Mucin(s) in cystic fibrosis, 12, 1529 in Hirschsprung's disease, 1528, 1529 Mucocele, oral, 826 Mucociliary transport system, 813, 818 Mucocutaneous lymph node syndrome, 848 Mucoepidermoid carcinoma pulmonary, 641,642f salivary gland, 827, 840 Mucormycosis, in bone marrow transplant patient, 781 Mucosal immunity, 164. See also Immunoglobulin A. Mullerian agenesis, 1912f Mullerian anomalies, anorectal malformations with, 1568 Mullerian inhibiting substance, 1912-1913, 1916 cryptorchidism and, 1197, 1198 granulosa-theca cell tumors and, 604 testicular descent and, 1193, 1194, 1194f Mullerian remnant prostatic utricle as, 1904 robot-assisted excision of, 54t, 55 Multicystic dysplastic kidney, 1705, 1706, 1710-1711, 171Of-1711f, 1725, 1727 with ureterocele, 1762 Multidetector computed tomography (MDCT), 35,35f Multidrug resistance (MDR)-associated protein gene, in neuroblastoma, 474,487 Multiorgan system failure activated macrophages in, 162 extracorporeal life support for, 141 trauma-related, 266

Multiple endocrine neoplasia type 1 (MEN 1) gastrin-secreting tumor in, 1231, 1685 insulin-secreting tumor in, 1683 parathyroid hyperplasia in, 858 Multiple endocrine neoplasia type 2 (MEN 2) chronic intestinal pseudoobstruction in, 1548 medullary thyroid carcinoma in, 855, 857 parathyroid hyperplasia in, 858 pheochromocytoma in, 632 RETgene mutations in, 1520f, 1521, 1523 Multiple subpial transection, 2007 Multivisceral graft, 745, 746f-747f, 747-748, 751f Multivitamins, parenteral, 206 Mumps orchitis, 1205-1206 Mupirocin (Bactroban), 389t Murmur, heart myocardial rupture and, 286 pectus excavatum with, 895 Muromonab. See OKT3 (muromonabCD3). Muscle (s) cell culture of, 22 congenital anomalies of, 2070-2071,2070f, 2072f disuse atrophy of, 231 malignant hyperthermia and, 231-232 Muscle flaps, 352 Muscle relaxants, 229-231, 230t adverse effects of, 230-232,23Ot, 232t for laryngospasm, anesthesia-related, 223 in trauma patient, for intubation, 267 monitoring of effects of, 235 Musculoaponeurotic fibromatosis, 542 Musculoskeletal trauma, 337-347. See also Fracture(s). evaluation of, 339,341-342, 341f high-priority child abuse as, 347,401t compartment syndrome as, 344-345, 349 femoral neck fracture as, 345,345f joint penetration as, 344 mangled extremities as, 345, 379, 379t open fractures as, 344 spine trauma as, 345-346, 346f immediate treatment of, 342 in children vs. adults, 337-339, 338f-341f myc gene (s) c-myc gene in B-cell lymphomas, 581 in germ cell tumors, 557 endodermal sinus, 596 N-myc gene in germ cell tumors, 557 in neuroblastoma, 472, 474, 474t, 475, 476t, 480, 481, 482, 483 bone marrow transplantation and, 484 prognosis and, 486,487 MYCNproto-oncogene, 417,419, 425,426 Mycobacterial infection atypical, 832 adenitis as, 845-846 pulmonary, 1003-1004 in HN-infected patient, 1009 Crohn's disease and, 1453 tuberculous. See Tuberculosis. Mycophenolate mofetil (CellCept) in transplantation heart, 760t, 761, 761f intestinal, 749 liver, 738t, 739 lung, 771, 771t pancreas, 721, 722, 722f renal, 708, 709 mechanism of action, 708, 738t side effects of, 708, 738t slume 1, pages 1-1 140; Volume 2, pages 1141-21

Mycoplasma pneumoniae, 1002-1003, 1013 Mycotic aneurysm, 21 15-21 16, 21 16f Myectomy anorectal, 1531, 1543-1544, 1544f-1545f internal sphincter for constipation, 1594 for intestinal neuronal dysplasia, 1563 small bowel, in Hirschsprung's disease, 1540, 1543f Myelinolysis, central pontine, 389 Myelodysplasia. See also Myelomeningocele. neuropathic bladder and, 1807-1810, 1809f-181Of, 1817, 1821-1822, 1821f-1822f occult, 1805, 1806f, 1822, 1993-1994, 2102 cutaneous lesions in, 1993 Myelomeningocele, 1987, 1987f, 1990-1992. See also Myelodysplasia; Neural tube defects; Spina bifida. cloaca1 exstrophy with, 1867 cryptorchidism associated with, 1195 fetal surgery for, 83t, 84-85, 1991-1992, 1992f, 2062 hydrocephalus associated with, 84, 1993 intrauterine repair of, in animal model, 55, 56t lumbosacral, vs. sacrococcygeal teratoma, 559 neurologic deterioration in, 1995 neuropathic bladder and, 1807f, 1808-1809, 181Of, 1821 nutritional support with, 214, 214t urinary diversion in, 1794 Myenteric plexus. See also Enteric nervous system. disorders of, 1547, 1548 Myocardial contusion, 285-286 Myocardial rupture, 286 Myocarditis, extracorporeal life support for, 141t Myofibromatosis, 542 Myofibrosarcoma, 544t Myoglobinemia, in malignant hyperthermia, 231 Myoglobinuria, electrical burns with, 396 Myopathies, visceral, 1547, 1547f, 1548-1549 Myringotomy, 815, 816 Myxoma, ovarian, 614

NADPH-diaphorase staining, Hirschsprung's disease and, 1527 Naloxone, 239, 240t Nanotechnology, 57, 58-59, 59f Nasal. See also Nose. Nasal airways, 828 Nasogastric feeding, 199, 203 Nasogastric tube. See aho Gastric tube. esophageal injury caused by, 1047-1048, 1049, 1049f in burn patient, 386 in esophageal stricture management, 1085, 1086, 1088 in trauma patient, 272 with skull injury, 363 with spinal injury, 369 with thoracic injury, 277 Nasojejunal feeding, 199, 1484 Nasopharyngeal angiofibroma, juvenile, 821 Nasopharyngoscope, fiber-optic, 972 Nasopharyngoscopy, in airway obstruction, 983 Nasopharynx, 822 benign masses of, 826 branchial anomaly associated with, 868 lymphoma of, 827

Nasotracheal intubation, 127, 129 in trauma patient, 267, 276 Natural killer (NK) cells, 162, 163, 165, 166, 168 NCAM (neural cell adhesion molecule), 1525-1526 Neck. See also Cervical entries; Head and neck masses. clinical evaluation of, 831-832 cysts and sinuses of, 826, 830, 861-872. See also Branchial anomalies; Cystic hygroma. dermoid, 865,870-871 embryogenesis of, 861-865,862f, 863t, 864f-865f enteric, 964 incidence of, 865 malignancy in, 861, 866,870 preauricular, 871 thymic, 865,872,961,962f thyroglossal duct, 826, 861, 865, 865f, 869-870,871f inflammatory and infectious masses of, 832-833 in branchial anomalies, 866, 867 retropharyngeal/parapharyngeal, 823,823f malignant neoplasms in, 833 stereotactic radiosurgery of, 46 thymic tissue in, ectopic, 961 trauma to, vocal cord immobility in, 988 vascular injuries in, 378 webs in, congenital, 2064 Necrosis. See Ischemic necrosis, gastrointestinal. Necrotizing enterocolitis, neonatal, 1427-1 445 breast milk and, 104, 1430, 1432, 1433, 1434,1444 classification of at laparotomy, 1440-1441 for staging, 1438, 1438t clinical features of, 1434-1435 complications of, 1442-1443 colonic stricture as, 1495, 1495f intraoperative liver hemorrhage as, 1440 short-bowel syndrome as, 1369, 1369f, 1441,1443 cytokines and growth factors in, 1430-1432, 1430t, 1433,1434 epidemic clusters of, 1436 formula feeding and, 202, 1428-1429, 1432, 1433, 1434,1435, 1439, 1444,1445 gastric perforation in, 1235, 1237 historical perspective on, 1427 hyperglycemia in, 102 imaging in, 1436-1438, 1436f incidence of, 1427 ketorolac contraindicated in, 239 laboratory findings in, 1435 management of, 1438-1442 ileostomy in, 1482, 1483f, 1484, 1486 microbiology of, 1435-1436 overview of, 1385 overwhelming sepsis in, 173 pathogenesis of, 1432-1434 pathology of, 1434, 1434f prevention of, 1443-1 445 protein turnover in, 108 rectal bleeding in, 1385, 1435 recurrent, 1443 risk factors for, 1427-1430 staging of, 1438, 1438t survival with, 1442, 1442t taurine supplementation in, 209 Necrotizing fasciitis in urethral injury, female, 331 umbilical, 1146

Necrotizing granuloma, PET-CT imaging of, 39f Needle biopsy, 437, 438-439, 439f, 439t. See also Core needle biopsy; Fineneedle aspiration biopsy. laparoscopically directed, 440 of lung abscess, 1016 Neoadjuvant chemotherapy, 421-422 Neomycin, for outpatient burns, 396 Neonatal isoimmune thrombocytopenia, 182 Neonate (s) acid-base balance in, 95,96, 96t anesthesia in hypothermia and, 99 physiology of, 221,222f, 222t, 228 cardiovascular management in of arrhythmias, 151, 152t, 153 of congenital heart disease, 153 of congestive heart failure, 148, 150t, 151, 153 cardiovascular physiology of, 146-147, 147f energy metabolism in, 9 6 9 9 , 98f postoperative, 105, 105f, 107, 108, 212 protein metabolism and, 104, 108 with biliary atresia, 212 extracorporeal life support in, 140-141, 140t, 142 fluid and electrolyte balance in, 91-96, 93f, 94t, 96t gestational age of, 89,90, 90f-9lf mortality and, 90, 92f necrotizing enterocolitis and, 1428 total body water and, 92 growth rate of, 194 infection in. See also Sepsis, in neonate. host defenses against, 166-168, 170 prevention of, 1444 mechanical ventilation in, high-frequency, 126,141 mortality of, 89, 90-91,91t, 92f nutrient metabolism in, 100-104, 101t, 103f surgery and, 106, 107-108, 107f, 21 1 nutrition for parenteral, 205f requirements, 195, 196, 197, 198 organ failure score for, 91, 92t pain in, 221,236 clonidine for, 248 hyperglycemia associated with, 102 opioids for, 240, 241, 242 epidural, 248, 249 half-life of, 221 operative stress and, 105, 106 polycythemia in, 2115 premature. See Premature infant. renal function in, 93-94, 96 size of, 89-90,9lf energy metabolism and, 98 nutrient metabolism and, 101, 102, 103 stress response in, 104108, 105f, 107f thermoregulation of, 99-100 trauma in rectal, 312 vaginal, 312 vitamin K deficiency in, 186 Neostigmine for Ogilvie's syndrome, 1496 with neuromuscular blockade, 231 Nephrectomy. See also Nephroureterectomy. fetal, pulmonary hypoplasia and, 117 for renal vein thrombosis, 2130 for renovascular hypertension, 2120, 2121 in end-stage renal disease, 1835 in kidney donor, 702 in kidney recipient, 700-701

Nephrectomy (Continued) of multicystic dysplastic kidney, 1711 robot-assisted, 54t, 55 Nephroblastoma. See Wilms' tumor. Nephroblastomatosis. See Nephrogenic rests (nephroblastomatosis) . Nephrogenic rests (nephroblastomatosis) , 446,447, 448,450-451,451f bilateral Wilms' tumor with, 457 in multicystic dysplastic kidney, 1711 Nephrolithiasis. See Urolithiasis. Nephroma congenital mesoblastic, 450 cystic, 1712-1713, 1712f Nephrostolithotomy, percutaneous, 1751-1753 Nephrostomy, percutaneous after pyeloplasty, 1737 for megaureter, 1773 for transplant complications, 707 for urolithiasis, 1751 with urethral valves, 1793 Nephrotic syndrome primary peritonitis in, 1475, 1476 transplantation in patient with, 700-701 Nephroureterectomy, partial, 1767, 1768 Nerve blocks, 243, 244247, 245f-247f digital, for fracture reduction, 352 Nerve graft(s), in upper extremity trauma, 35 1 Nerve stimulator, 235 Nerves, peripheral, trauma to, 377 in hand injury, 348-349,349f-350f, 351 Neuhauser's sign, of meconium ileus, 1274 Neural cell adhesion molecule (NCAM), 1525-1526 Neural crest cell development, 1523-1524, 1524f, 1525, 1560 Neural tube defects, 1987-1995. See also Myelomeningocele. associated anomalies with, 1992-1993 capillary malformation as, 2098 congenital diaphragmatic hernia as, 932 cryptorchidism as, 1195 classification of, 1987-1988 closed, 1805,1806f, 1822,1987,1993-1994 diagnosis of, 1991 embryological basis of, 1987, 1988-1990, 1988f-1989f epidemiology of, 1988, 1990 etiology of, 1990 folic acid and, 1808, 1988, 1990 outcome and prognosis of, 1995 pathology of, 1990-1991 treatment of, 1991-1992, 1992f Neuraxial block, 243, 244, 247-249, 2472 248t Neurenteric cyst, 963, 965-966, 1393, 1994 Neuroblast, 467, 472 Neuroblastoma, 467-488 anatomic sites of, 467-468,468f, 628 brain as, 671 mediastinurn as, 959 neck as, 833,848 urachal remnants as, 1149 angiogenesis in, 419 bilateral, 483 chemotherapy for, 483-484 targeted, 426 clinical presentation of, 468-469, 469f congenital, 467 cystic, 482-483, 482f diagnosis of, 470-471, 470f-471f antenatal, 467 vs. adrenal hemorrhage, 630

Volume 1, pages 1-1140; Volume 2, pages 1141-2146.

xliv

INDEX

Neuroblastoma (Continued) differential diagnosis of, 470, 544t epidemiology, 467 etiological factors in, 467 future directions for, 487-488 genetics and molecular biology of, 415, 417, 418, 419, 425,467,474475,474t immunotherapy for, 427,485 in infancy, 480-481, 480f of stage IV-S, 469, 471, 471t, 472, 474, 481-482, 481f, 482t vs. hemangioendothelioma, 496 mass screening for, 468 metastatic to bone, 664 multifocal, 483 nutrition and, 486487 operative management of, 475-480,477f-479f palliative radiotherapy in, 484485 parasympathetic, 470 pathology and histology of, 472-473, 472t, 4735 486 prognosis of, 467,485-487 radiation therapy for, 484-485 accelerated hyperfractionation in, 429 risk-based management of, 425, 437, 475, 476t spontaneous regression of, 467, 468, 482, 483,486,487 staging of, 471-472, 471t summary of, 487 Neuroblastoma in situ, adrenal, 467 Neurocristopathies, 1520, 1520t, 1521, 1522, 1523,1528 Neuroendocrine tumors. See Carcinoid tumors. Neuroenteric cyst. See Neurenteric cyst. Neurofibromatosis neck tumors in, 833 renal artery stenosis in, 21 18, 21 18f Neurofibromatosis type 1 (NF1) macrodactyly in, 2075 tumor susceptibilities in, 421 bone tumors, 654 glioma, 679 neuroblastoma, 467 nonrhabdomyosarcomatous sarcomas, 543,546 pheochromocytoma, 632 rhabdomyosarcoma, 524 suorasellar astrocvtoma as. 676 ~eurokbromatosis&e 2 (NFZ),meningioma in, 679 Neurofibrosarcoma, 543, 546547 Neurogenic bladder. See Neuropathic bladder. Neurogenic sarcoma, 5 4 6 5 4 7 Neurogenic shock, 368 Neurologic evaluation, in traumatic emergency, 272 Neuroma, facial nerve, 817 Neuromuscular blocking agents, 229-231, 230t adverse effects of, 230-232, 230t, 232t in trauma patient, for intubation, 267 monitoring of effects of, 235 Neuromuscular function, monitoring of, 235 Neuromuscular syndrome, intensive care, 231 Neuronal dysplasia. See Intestinal neuronal dysplasia. Neuron-specific enolase, in neuroblastoma, 470,487 Neuropathic bladder, 1807-1811, 1808f-1810f, 1820-1822, 1821f-1822f assessment of, 1805-1807, 1806f-1808f, 1821, 1821f, 1822 renal prognosis with, 1817

Neuropathy (ies) compression, amniotic bands and, 2075 peripheral demyelinating, 1523 visceral, 1547, 1548 Neurosarcoma, 54G547 Neurosurgery planning for, functional MRI in, 37 spatial tolerance in, 42 Neurotrophins in hypertrophic pyloric stenosis, 1216 in neuroblastoma, 426, 474, 486 Neurturin, 1521, 1522, 1523t, 1525 Neurulation, 1987, 1988-1990, 1988f-1989f Neutropenia chemotherapy-induced, 1005-1006 in bone marrow transplant patient, 780, 781 in necrotizing enterocolitis, 1435 Neutropenic enteropathy, after bone marrow transplantation, 780, 780f Neutrophils, 159-161, 160f, 164, 165, 166 abdominal packing and, 302 abnormal, delayed umbilical cord separation and, 1145 in burn patient, 384385 with inhalation injury, 395 in neonate, 167, 170 sepsis and, 171 in systemic inflammatory response syndrome, 168, 169f, 172 Nevus(i). See also Basal cell nevus syndrome; Blue rubber bleb nevus syndrome. Becker's, of breast, 886 congenital, 2063-2064, 2065f Nevus flammeus neonatorum, 2098 Nevus sebaceus of Jadassohn, 2064 NF. See Neurofibromatosis. NF-KB. See Nuclear factor-kappa B (NF-KB). Nicotine, for ulcerative colitis, 1466 Nipple adenoma of, 888,891 congenital anomalies of, 886, 887f, 2066 in Poland's syndrome, 907,908f development of, 885 discharge from, 888, 8885 890, 891 inverted, 886 Nipple valve, 1832, 1832f Nissen fundoplication, 1127, 1127f after esophageal repair for atresia, 1065, 1069 for congenital stenosis, 1072 complications of, 1133 laparoscopic, 1128-1 130, 1129f-1130f outcomes of, 1133 robot-assisted, 53, 54t Nitric oxide arginine and, 196, 1431 arterial injury and, 380 for heart transplant recipient, 760 for reperfusion injury, after lung transplantation, 773 from macrophages and monocytes, 161-162, 167 in gastrointestinal tract, 1430t, 1431-1432 aganglionosis and, 1525, 1527-1528, 1527f enteric nervous system and, 1527, 1527f in hepatopulmonary syndrome, 1656 in necrotizing enterocolitis, 1430t, 1431-1432, 1433 in neonatal sepsis, 171 in respiratory management neonatal, 127, 135, 141 of ARDS, 127 of congenital diaphragmatic hernia, 940 ~ l u m e1, pages 1-1 140; Volume 2, pages 1141-2146.

Nitric oxide (Continued) in systemic inflammatory response syndrome, 169, 169f, 171 reactions of, 161-162, 162t uterine contractions and, 86 Nitric oxide synthase aganglionosis and, 1528 esophageal achalasia and, 1112 hypertrophic pyloric stenosis and, 1216 in cystic fibrosis, 12 in gastrointestinal inflammation, 1431-1432, 1433 in hypertrophic pyloric stenosis, 14 interferon-y and, 166 isoforms of, 161, 1431 penile development and, 1878, 1878f systemic inflammatory response syndrome and, 169 Nitrofen model, 934, 945 Nitrogen mustard, 423t Nitrogen washout test, 118 Nitroglycerin, as tocolytic agent, 79 ~itroprusside,for makgnait hypertension, 2120 Nitrous oxide, 227, 227t, 228 Nizatidine, for peptic ulcer disease, 1230 NK (natural killer) cells, 162, 163, 165, 166, 168 nm23, in neuroblastoma, 474 Nocturnal enuresis, 18141815 Nodular hyperplasia, focal (FNH), 495, 498-499,499f Non-Hodgkin's lymphoma, 580-589. See aL~o Lymphoma. classification of, 580,581,582-583,582f-583f clinical presentation of, 583-585, 584f cervical lymphadenopathy in, 82G827, 833,848 complications of, 588 cytogenetics of, 581-582 diagnosis of, 585 epidemiology of, 580-581 histopathology of, 582-583, 582f-583f in breast, 892 in mediastinum, 581, 583, 584, 584f, 586-587,586f, 588,959,960t, 961 lymphocyte development and, 581,581f-582f molecular biology of, 581-582 oral, 826827 post-transplanr, 584585, 712, 739 prognostic factors in, 588-589 staging of, 585, 585t, 587, 588 summary of, 589 testicular involvement by, 625 treatment of, 585-588, 586f, 588t osteogenic sarcoma secondary to, 653 vs. seminoma, 556 vs. soft tissue sarcomas, 544t Non-ossifying fibroma, 652, 652f, 654 Nonpolyposis colorectal cancer, hereditary, 520 Nonshivering thermogenesis, in neonate, 99 Nonsteroidal anti-inflammatory drugs (NSAIDs), 238-239,238t. See also Aspirin. colonic stenosis caused by, 1495-1496 for first-degree burns, 385 for inflammatory pseudotumor gastrointestinal, 1365 pulmonary, 641 for osteoid osteoma, 654, 658 peptic ulcers caused by, 1226, 1228, 1229 postoperative ileus and, 1361 preemptive analgesia with, 237 Nonvalidated procedures, 259-260 Noonan's syndrome, 1112,2141

Norepinephrine (noradrenaline) adrenal imaging and, 630, 63'2 adrenal synthesis of, 628, 6'29 postoperative levels of, 107, 107f Norwood procedure, 1977, 1977f Nose, 817-82 1. Srr cclso Nasal entrir~. anatomy of, 817-818 airway and, 984 congenital ~nalforrnationsof, 819-820, 8 19f-820f embryology of, 818 examination of', 818 Sol-eign body in, 821 inflammatory conditions of, 818-819 acute pharyngitis with, 822 sleep apnea and, 825 trauma to, 820-821 tumors of, 1 NP-59 (iodomethyl-I-19-norcholesterol), 630, 635 NSAIDs. Srr Aspirin; Nonsteroidal antiinflammatory drugs (NSAIDs). Nucleal- factor-kappa B (NF-KB),106 apoptosis and, 414 in systemic inflammatory response syndrome, 169, 173 necrotizing enterocolitis and, 1432 Nuclear medicine. Srr Radionuclide studies. Numhy Stuff; 244, 244t Nuss procedure, for pectus excavatum, 921-929, %Sf-%Sf, 928t Nutcracker esophagus, 1110-1 111, 111If Nutritional requirements, 195-199, 195t, 196t, 197s. Srr ccko Caloric requirements; Metabolism. aftel- bal-iatric surgery, 1250, 1252 for iron, 180 Nutritional status, assessment of, 194-196 Nutritional support enteral. Srr Ente~.alnutrition. for biliary atl-esia, 212, 212t vitamin E in, 198 for burn patient, 393, 39% fix chylothorax, 290 for disabled children, 214, 214t for failure to thrive, 213-214 for obese patients, 213 for ostoinate, 1488 fo~.shot-t-bowelsyndrome. Srt Short-bowel syndrome. fix surgic;ll patients, 210-212 historical perspective on, 194 in Crohn's disease, 1456 in ulcerative colitis, 1466 parenteral. Srr Total parenteral nutrition (TPN). Nystagn~us,neuroblastoma with, 469, 486 Nystatin for burns, 389, 389t, 390 for heart transplant patient, 761 for lung transplant patient, 775

a

Obesity. Sw rcko Bariatric surgery in adolescents. algorithm for rrlanagement of, in adolescent, 1250, 1251f definition of; 1244, 1244f epidemiology of, 1242, 1244-1 245 hcalth consequences of, 1245-1246, 1245t in disabled child, 214 maternal, fetal developn~entand, 1252 overview of, 213 science of, 1243-1 244

Obturator nerve, fascia iliaca block and, 246 0ctl.eotide for chylothorax, 1026-1027 for diarrhea, in short-bowel syndrome, 1373 for intestinal pseudo-obstruction, 1366 for pancreatic pseudocyst, 1678 for persistent hyperinsuline~nic hypoglycemia in infancy, 1681 for postoperative ileus, 1361 for variceal herr~orrhage,1658 esophageal, 1387 after portoenterostomy, 1612 P Dysphagia. Odynophagia. S ~nL\o evaluation of, 1125b OEIS (on~phalocele-exstrophy-imperforate anus-spinal defects) complex, 1160, 1161, 186'2 Ogilvie's syndron~e,1496 0 1 (oxygenation index), in congenital diaphragmatic hernia, 938, 942-943 OK43'2, for lymphangioma, 1404, 2107, 2139 OKT3 (muromonab-CD3), 707 in heart transplantation, 761, 761f in islet cell transplantation, 726 in liver transplantation, 7381, 739 in lung transplantation, 770, 771t in renal transplantation, 709 Oligodendroglioma, 671 Oligogenic disorders, 12, 12f, 13 Oligohydramnios multicystic dysplastic kidney with, 1710 polycystic kidney disease with, 1709 renal agenesis with, 1706 treatment of, 83 Ollier's disease, 651 ovarian tumors in, 593, 606 Omental cyst. See Mesenteric and omental cysts. Omentum, gastrointestinal stromal tumors in, 515 Omeprazole for gastroesophageal reflux, 1126 for peptic ulcer disease, 1229 Omphalitis, 1146 bacterial hepatitis associated with, 1644 Omphalocele, 1157-1158, 1157f, 1158t. See nl.~oUmbilical hernia. associated conditions with, 1160-1 161, 1162, 1162t cloaca1 exstrophy as, 1862, 1865 cryptorchidism as, 1195 ectopia cordis as, 913, 914, 1160 intestinal atresia as, 1270, 1277 intestinal rnalrotation as, 1346 clinical features of, 1161-1 162 complications of, 1166, 1167 embryogenesis of, 1159-1 160 giant, 1164 incidence of, 1162 obstetric delivery with, 1161 outcome of, 1166, 1167 prenatal diagnosis of, 1161 small, 1145, 1149, 1151 bladder exstrophy with, 1153 treatment of, 1163-1165 umbilicoplasty after repair of, 1153 vs. umbilical cord hernia, 1160 Omphaloileal fistula, 1304, 1307f, 1310-131 1, 1311f Omphalomesenteric duct. SerVitelline (omphalomesenteric) duct. Oncogenes, 413f, 414, 415t, 417,425-426. See also myc gene; KAS proto-oncogene; RET proto-oncogene; Trk entries. gene therapy and, 18 targeted therapy and, 425 Volume 1, pages 1-1 140; Volume 2, pages 1141-21

Ondine's cursr. Srr (:entral hypovel~tilatioi~ syntlromc (Ondine's curse). Onion skiiu~ing,radiographic, 654 Onlay island flap hvpospadias I-epair; 1884-1885, 1886s-1887f Oophorectoiny, rol,ot-assisted, 53, 54t Ophthalmologic evaluation in basilar skull fr;~cturc,J66 in child abuse, 363 Opioid reccptoi antagonisi, 239, 240t Opioids, 236, 239-242, 240t, 241 t, 24% Analgesic 1,addci-; I I I ~2:46, , 237f coi~tir~uous i i ~ f ~ ~of, s i242 o~~ ei~tloger~oirs, in rlcon;ctcs, 105 epiduial infusior~of, 248-249, 248t for burn patielits. 394, JY4t foi- diart-hea, 1373, 1466 in neonates. 240, 24 1 , 242 half-lif of', 22 l operative stress aitd, 105, 106 in patier~t-c-or~trollrti analgesia, 242-243, 24% for burn paiients, 394 rnitia~olar~~ with, 224 preemptive analgesia with, 2:37 propofbl with, 233 regional anesthesia and, 244, 248-2411 side effects of; 239, 241 inanagcment of, 239, 2401 on gastrointrsdt~almotility, 1360-1361 Opitl-(; syncirotne, 995 Opaite for- donor sites, 391 for second-degree burns, 390 Opso~nyocloi~~~s, neui-ohlastoma with, 469, 486 Opsoni~ation,159, 160, ItiOt; Itis, 164, 165 in neonate, 167, 168 Optic chiasin, astrocytoma of; 676677, 6766 679 Optic nerve compression of, tumor-related, 672 trauma to as birth injury, 405 basilar skull fracture with, 366 Oral cavity anatomy of, 821 benign lesions ot; 826, 831 caustic injury to, 1084, 1088 disorders of, %?5-82ti, 8251-826f herpetic git~givostoinatitisof, 822 malignant lesions ot; 826827 Oral contraceptives esophageal atresia and, 1051 fibrocystic breasts and, 891 gastroschisis and, 1160 hepatocellular adenoma and, 495 ovarian cancer and, 593, 594 Orbit cellulitis of; 818-819 rhabdoinyosarcon~aof, 531-532 Orchidectomy for testicular tumors alpha fetoprotein and, 6'22 technique of, U25 with teratoma, 567, 6'23 with yolk sac tumor, 623 of ischemic gonad, after torsion, 1207 Orchidopexy, 1200, 120lf-I202f, 1203 complications of, 1203-1 204, l204t for intermittent testicular pain, 1207 ilioinguinal-iliohypogastric block for, 245-246, 245f in prune-belly syndrome, 1781, 1785, 1786 laparoscopic, 1203 in prune-belly syndrome, 1785 testicular cancer and, 622, 1205

Orchitis, 1205-1206, 1205f, 12061 Organ failure score, for neonates, 9 1, Y2t Organ preservation, 694-695 Organ procurement, 693-694, 694f P Organ transplantation. S ~ Transplantation. Oropharynx anatomy of, 821, 822 caustic injury to, 1084, 1088 erythema of, in Kawasaki disease, 848 infections of, 822 malignant lesions of, 826427 Ortolani maneuver, 2019, 2021 Osler-Weber-Rendu disease. See Telangiectasia, hereditary hemorrhagic. Osmotherapy, for brain injury, 273, 363, 364 Ossicles, 813, 814 injury to by cholesteatoma, 816 in otitis media, 815 in temporal bone fracture, 817 reconstruction of, 815, 816 Ossification centers, 337, 338f, 341 Osteoarthritis, after cartilage repair, 22 Osteoblastoma, 652f Osteochondrodystrophy, Jeune's syndrome as, 915-917, 917f Osteochondroma diaphyseal aclasis secondary to, 651 location of, in relation to physis, 652f, 654 malignant degeneration of, 651 multiple, 651 resection of, 659 Osteogenic sarcoma (osteosarcoma), 652-653,652f-653f age of diagnosis, 650t, 664 chemotherapy for, 656-657 fine-needle aspiration biopsy of, 438 in breast, primary, 892 metastases from, 666-667 pulmonary, 645-646,645t, 666 radiation therapy for, 657 radiography of, 654 resectiorl of, 658, 661 reconstructior~following, 663f-665f secondary, in sarcoma survivors, 550 serum alkaline phosphatase and, 654 Osteoid osteoma, 652f, 654 treatment of, 658 Osteornalacia in parenteral nutrition patients, 209 in ulcerative colitis, 1465 Osteomas, in Gardner's syndrome, 1422 Osteomyelitis actinomycotic, 2044 acute hematogenous, 2033-2039, 2034f-2037f, 2038t chronic, 2039 chronic recurrent multifocal, 2041-2042 coccidioidomycotic, 2044, 2045f foot puncture with, 2042, 2043f sacroiliac, 2041 sternal, 1028 subacute, 2041 vertebral, 2042 Osteopetlia, in parenteral nutrition patients, 209 Osteoporosis, in ulcerative colitis, 1465, 1466 Osteosarcoma. SPYOsteogenic sarcoma (osteosarcoma). 0stling9sfolds, 17'23, 1724f, 1737 Ostomy. SPYEnterostoma(s). Otitis media acute suppurative, 815 cornplicatiorls of, 815-816, 816f chronic, 816 with effusion, 815

Otomandibular dysostosis, 788 Otorrhea cholesteatoma causing, 816 first branchial anomaly with, 861 of cerebrospinal fluid, trauma-related, 817 Ovarian cysts, 597, 597t after ileoanal pouch procedure, 1470 clinical presentation of, 594 diagnosis of, 595t,596597,596f-597f laparoscopy of, 599f syndromes associated with, 593 treatment of, 600-601, 600f, 602 Ovarian tumors, 593-615 Burkitt's lymphoma as, 584 classification of, 597, 598t, 602 clinical presentation of, 594 diagnosis of, 594-597,594t, 595t, 596f-597f epidemiology of, 593-594 epithelial-stromal, 593, 598t, 602-604, 603f genetics of, 593-594,595-596 germ cell, 554, 556, 557, 558, 566, 567, 568, 607-613,608f, 610f-612f chemotherapy for, 613-614 classification of, 598t, 607 diagnosis of, 594-596, 594t, 5951, 597f incidence of, 602,607 mixed, 607,613 robotic surgery for, 53 staging of, 598, 599, 613 surgical guidelines for, 613 in Peutz-Jeghers syndrome, 593, 606, 1418 incidence of, 593, 602 initial resection of, 597, 599 laparoscopy of, 599-600,599f, 601,602,613 non-neoplastic, 597, 597t. See nlso Ovarian cysts. clinical presentation of, 594 treatment of, 600-602,600f secondary (metastatic), 615, 615t sex cord-stromal, 593, 594, 595t, 598t, 604607,605f staging of, 597-599, 598t, 599t, 613 summary of, 615 unclassified benign, 614 malignant, 614-615 Ovary(ies) age-related changes in, 596 embryology of, 1912, 1912f inguinal hernia with incarceration of, 1184, 1186 radiation injury to, 579 splenic tissue fused to, 1189 Overactive bladder svndrome. 1813-1814 Overfeeding, parenteral, complications from, 210 Overweight, 1244-1245, 1244f. See also Obesity. Ovotestis, 1189 Oxalosis, renal graft loss in, 71 1 Oxandrolone, for burn patient, 392, 393 Oxidative phosphorylation, 97, 99-100 nitric oxide and, 161 Oxybutynin after hypospadias repair, 1893 for increased intravesical pressure, 1817-1818 for overactive bladder syndrome, 1814 Oxycodone, 240-241, 2401 Oxygen fractional inspired (Fio,) in emergency management, 269 mixed venous oxygen saturation and, 122,128 ventilator setting for, 127, 128 supplemental for burn patient, 385

Volume 1, pages 1-1140; Volume 2, pages 1141-214

Oxygen (Continued) for inhalation injury, 395 for trauma patient, 269 with thoracic in,jury, 277 Oxygen consumption, metabolic rate and, 195 P Reactive oxygen Oxygen free radicals. S ~ olso intermediates (ROIs). in ischemia-reperfusion injury, 386 mechanical ventilation and, 128 r~ecrotizingenterocolitis and, 14'29, 1433 parenteral nutrition and, 108, 21 1 Oxygen index (01), 135 Oxygen partial pressure (Po,) congenital diaphragmatic hernia and, 938, 939,942-943,945 extracorporeal life support and, 135 in trauma patient, 269 with brain injury, 273 measurement of, 123 intraoperative, 235 transcutaneous, 122 mechanical ventilation and, 127, 128 Oxygen saturation, 118t in congenital diaphragmatic hernia, 939,943 mixed venous, 118t, 122-123 in extracorporeal life support, 138 mechanical ventilation and, 127, 128 monitoring of, 121-123, 234, 235 in thoracic trauma, 277 Oxygen toxicity, 123, 127, 128 Oxygenation index (01), in congenital diaphragmatic hernia, 938, 942-943 Oxyhemoglobin dissociation curve, 121, 121f pulse oximetry and, 122

p53gene and p53 protein, 413,418,419, 421 brain tumors and, 679 Wilms' tumor and, 459 Pacemaker, cardiac, implanted, in neonate, 151 Paclitaxel, 424t Paco,. See Carbon dioxide, arterial. PAF. See Platelet-activating factor (PAF). Paget-von Schroetter syndrome, 2131 Pain. See nlso Abdominal pain. assessment of, 237 bone tumors with, 654, 658 hypersensitization to, 23WL37 in compartment syndrome, 344 in neonate, 221, 236 hypergiycemia associated with, 102 in spinal injury, 368, 369 perception of, in children, 236 undertreatment of, 236, 242 untreated, 236237 Pain management, 236243 Analgesic Ladder for, 236, 237f appropriate use of, 236, 249 for burns, 394, 394t in acute injury, 274 in neonate, 221, 236 opioids for, 105, 106, 221, 240, 241, 242, 248,249 nonopioid analgesics for, 236, 237-239, 237f. 238t nonpharmacologic techniques for, 236 opioid analgesics for. See Opioids. oierview of236 patient-controlled, 242-243, 2431 for burn patients, 394 244, 249 preemptive, 23-37, regional anesthesia for, 24.%244, 247, 248-249 withholding of, for diagnosis, 236

INDEX Palate. See also Cleft anomalies. anatomy of, 821 benign lesions of, 826 primary vs. secondary, 803 rhabdomyosarcoma of, 826 Palatine tonsils. See Tonsils. Palliative radiation therapy, 430 Pallister-Hall syndrome, 995 Palmaris longus tendon, congenital absence of, 2063 Pancreas anatomy of, surgical, 1672 congenital anomalies of, 1671-1672, 1671t. Ste also Annular pancreas; Pancreas divisum. pancreatitis and, 1673, 1674-1675 cystic neoplasms in, 1684 cysts associated with, 1677-1678 duplications as, 1391, 1392f, 1394, 1678 mesenteric, 1402, 1404 ectopic tissue of at umbilicus, 1149 in Meckel's diverticulum, 1304 embryology of, 1671-1672 hyperinsnlinism and, 102, 1679-1683, 1679t, 1681f, 1682t, 1683f islet cell transplantation and, 717, 723-727, 724f-725f neoplasms of, 1683-1686 pseudocysts of, 307-308, 309, 309f-310f, 309t, 310, 1678-1679, 1679f transplantation of; 717-723, 719f-722f history of, 685, 686t, 693, 717-718, 717f immunosuppression for, 720-721, 722-723 indications for, 720 intestinal transplant with, 745, 748 trauma to, 295, 299, 303, 307-310, 307f-310f, 308t, 30%. Set also Pseudocyst. pancreatitis caused by, 1673, 1674 with renal injury, 322 Pancreas divisum, 1672, 1673, 1674-1675, 16761677, 1676f Pancreatectomy for chronic pancreatitis, 1676 for pancreatic pseudocyst, 1678 for persistent hyperinsulinemic hypoglycemia in infancy, 1681, 1682t, 1683, 1683f Pancreatic enzyme replacement, complications of, 1498 Pancreatic insufficiency in cystic fibrosis, 1011 in Shwachman-Diamond syndrome, 1673 Pancreaticobiliary malunion, 167'2, 1673, 1674, 1675, 1677 Pancreaticoduodenectomy (Whipple procedure) for chronic pancreatitis, with islet autotransplantation, 724 for duodenal duplication, 1394 for duodenal trauma, 304,307 for pancreatic carcinoma, 1686 for pancrratic pseudocyst, 1678 Pancreaticojejunostorny, 1675f, 16761677 Pancreatitis acute, 1672-1674, 1673t pseudocyst in, 1678 choledochal cyst and, 1624, 1625, 1631, 1672-1673, 1677, 1677f choledochocele with, 1629 choledocholithiasis with, 1672, 1674, 1675 cholclithiasis with, 1637, 1642, 1672, 1673 chronic, 167'2, 1674-1677, 1675f-1677f, 1675t islet autotransplantation for, 72.3-724, 724f duplication as cause of, 1391, 1394, 1678 overview of, 167'2

Pancreatoblastoma, 1685, 1686 Pancreatogastrostomy, 1676 Pancuronium, 230t Panda eyes, neuroblastoma with, 469, 469f Pao2. See Oxygen partial pressure (Pog). Papillary cystadenoma lymphomatosum, 839 Papillary-cystic endothelial tumor of pancreas, 1684 Papilloma choroid plexus, 671, 678-679 laryngeal, 831,989,989f web secondary to treatment of, 988,989, 990 mammary, intraductal, 888 squamous laryngeal, 831 oral, 831 pharyngeal, 826 Papillomatosis juvenile, of breast, 891 recurrent respiratory, 831, 831f, 989-990, 989f Paracentesis, 1408, 1409, 1410 in necrotizing enterocolitis, 1439 in primary peritonitis, 1476 Paraduodenal (mesocolic) hernia, 1348-1349, 1349f, 1350, 1356, 1361, 1362f Paraganglioma, extra-adrenal, 515-516 with pulmonary hamartoma, 641 Paralysis. See also Paraplegia. in spinal cord injury, 368 muscle relaxants as cause of, 231 Paranasal sinuses. See Sinuses, paranasal. Paraplegia. See also Paralysis. neurenteric cyst and, 966 postoperative, after aortic repair, 290, 291 traumatic, ureteral injury associated with, 326 tumor-related, with neuroblastoma, 469, 477-478 Parasitic infections appendicitis in, 1502 ascariasis as, 1365 in Meckel's diverticulum, 1311 pulmonary, 1005, 1005f Paraspinal tumors, rhabdomyosarcoma as, 534 Parastomal hernia, 1363, 1489 Parathyroid glands adenoma of, 858, 858f embryology of, 850,863,864,864f-865f hypercalcemia and, 857, 857t, 858 injury to, in thyroidectomy, 856 physiology of, 857 Parathyroidectomy, 858 Paraumbilical block, 245, 245f Parenteral nutrition. SeeTotal parenteral nutrition (TPN). Parents, ethical issues and, 258 Parkes Weber syndrome, 2096, 2098, 2101, 2112,2128,2129 Parkland formula, 386, 388t Parotid gland(s). See also Salivary glands. anatomy of, 835 facial nerve and, 835, 836, 837, 867-868, 868f hypoplasia of, 789 surgery of, 840, 841f, 842 for branchial anomaly, 867-868, 868f Parovarian cysts, 601, 602 Parvovirus B19 infection, 1693 Passerini genitovaginoplasty, 1945 Patch abdominoplasty, 303, 303f Patella, congenital dislocation of, 2026 Patient-controlled analgesia, 242-243, 24% for burn patients, 394 Pavlik harness, 2021, 2021f

Volu m e 1, pages 1-1140; Volume 2, pages 1141-21

xlvii

Pc:~,.See Carbon dioxide. PCR (polymerase chain reaction), of tumors, 419, 420t, 425,437 PDGF. See Platelet-derived growth factor (PDGF). Peak inspiratory pressure (PIP), 124, 127, 128 P E W - 1 (platelet-endothelial cell adhesion molecule 1 ), 159-160, 173 Pectoral muscles, anomalies of. Set Poland's syndrome. Pectus carinatum, 904-907, 905f-906f pulmonary function and, 896 Pectus excavatum, 894-904 cardiovascular function in, 895, 897-898 cause of, 894, 894t clinical presentation of, 894-895, 895f conservative treatment of, 921-922,922f epidemiology of, 894 minimally invasive surgery for, 921-929, 922f-929f, 928t complications of, 928-929, 928t pulmonary function and, 897, 922,929 mitral valve prolapse in, 898, S'L'L open surgical repair of, 898-899, 900f-903f complications of, 899, 901, 904, 904f prune-belly syndrome with, 1786 pulmonary function in, 895, 89G897, 922,929 spontaneous resolution of; 894 Pediatric anesthesiologists, 221, 2'22-223 Pediatric surgery. See also Surgery. history of, 3-10, 3f-5f, 8b, 9f-10f PEEP. See Positive end-expiratory pressure (PEEP). PEG (percutaneous endoscopic gastrostomy), 199, 1131 PELD score, 1658, 1664, 1664f Pelvic inflammatory disease, with perihepatitis, 1645 Pelvic kidney, 1715,1717f-1718f Pelvic osteotomy, for hip dysplasia, 2023, 2023f Pelvis fracture of, urinary tract injuries with, 318, 327, 328, 328f, 329, 330-331 reconstruction of, after tumor resection, 662f, 665-666 tumors of, rhabdomyosarcoma as, 535 Penicillamine, macromastia caused by, 887 Penile block, 246247, 242; 1893 Penis. See alro Prepuce. anomalies of. See also Epispadias; Hypospadias. agenesis as, 261, 1907 bladder exstrophy with, 1845, 1845f-1846f repair of, 1851-1852, 1851f-1852f, 1853-1857, 1854f-1857f, 1858 cloaca1 exstrophy with, 1862, 1867 duplication as, 1904, 1907, 1907f torsion as, 1907 hematoma of, 331 secondary to nerve block, 246, 247 injury to, 331, 404 lymphedema of, 2144 meatal stenosis of, 19061907 normal anatomy of, 1877-1 878, 1877f-1878f Penn pouch, 1826 Penoscrotal transposition, 1907-1908 Pentalogy of Cantrell, 912, 945, 1157, 1158t, 1160, 116'2 treatment of, 1165 Pentamidine, aerosolized, 771, 1008 Pentoxifylline endotoxic shock and, 173 neonatal sepsis and, 171

Pcpiic ulcer disease, 1225-1 232 after massive entereciomy, 1372 bleeding in, 1386 classification of; 1225, 1225t clinical presentation of. 1228-1 229, 1228t diagnosis of, 1229 epidemiology, 1225-1226 etiologies of; 1225, 1225t historical iirlderstanding of, 1225 in ectopic gastric nlucosa, 1307, 1386, 1389, 1391, 1395, 1678 in Zol1inge1--Ellisonsyndrome, 1231, 1685 neonatal, bleeding or perforated, 1230 pathophysiol~~gy cot', 1226-1228, 12271 pel-fo~ationin, 12'29, 1230, 1231, 1236 stress ulcers in, 1225t, 1226, 1227-1228, 1229, 1231-1232 treatment of, 1229-1232, 1230t Percutaneous endoscopic gastrostomy (PEG), 199, 1131 Perfl11orocarboi1s as plasma substitutes, 188 for liquid ventilation, 126127, 945, 945f Pericardial cyst, !)(is. 1393 Pericardial effusion, 278, 287f, 291. Src also (2ardiac Gttnponade. chylous, 1027 lymphoblastic lymphoma with, 587 thoracoscopic treatment of; 977, 978 Pel-icardialtamponadc. Sw (krdiac tamponade. Pericardial window, subxiphoid, 291 Pericardioce~~tesis, of acuic iamponade, 277, 278, 286 chylous, 1027 Pericardiu~n,565 teratoma ot; 565, 962 trauma to, '278, 285, 28W287, 291 FAST sonography in, 296, 296f Perihcpatitis, 1645 Peritleal fistula. 1569. 15(i9f-l57"f, 1571, 1573 Perinephiic abscess, :Y24 Perintwm bul-11sto, 403 extra openings on, d11p1ic;ttionswith, 1396, 1397 rl~;tbdomyosarco~~a of, 535 trautna to, 312, 318, 929. 331 in clrild abuse, 404 Pel-iosieal chondi-oma, 659 Pcriosteum, 537 fracture healing and, 338 fi-acttu-cI-cduction and, 337, S39f; 342, 344 in mangled extremity, 34.5 radiogl-aphic signs ;und, 654 Peripheral demyelinating neuropathy, 1523 Peripher-a1 ncl-ve slleath tumor, malignant, 543, 544t, 546-547 tumor, 515 vs. gastrointestinal st~-omal Peristalsis esophageal. Srr Esophag~is,motility of: intestinal. Sro liitestinal tlysmotility. ureteral in prune-belly syndro~nr,1783-1784 1778, 1779f with meg;t~u-cte~; Peritoneal bands, congenital, 1498 Peritoural cavity. Srr ( r h o Asciies. diagnostic lapal-oscopy of, 439-440 Peritoneal.dialysis, 701, 702, 710 aftel- hrart ti-anspl;tntation, 762 gastroesoph;\geal reflux caused by, 1123 inguinal hernia and, 1187 peritonitis associated with, 1476-1477, 14771 Pcritone;tl drainage, for intestinal pel-fol-at ion, in neonate, 1237, 1440

Peritoneal lavage, diagnostic, 297 in necrotizing enterocolitis, 1439 Peritoneovenous shunt, 1409, 1411, 2140 Peritonitis amebic abscess with, 1646 appendicitis with, 1503 biliary, 1615 meconium, 1291, 1296, 1298 jejunoileal atresia with, 1271, 1273f, 1274, 1282, 1283 necrotizing enterocolitis with, 1435, 1436, 1437, 1440 primary, 1475-1477, 1475t, 1477t strangulated inguinal hernia with, 1174, 1182, 1183 v o l \ ~ ~ l with, u s 1347, 1356 Permissive hypercapnia, 128 PET. Srr Positron emission tomography (PET). Peut~~Jeghers syndrome, 1417-1418, 1418f carcinoma in, 519, 1418 intussusception in, 1321f ovarian tumors in, 593, 606, 1418 Peyer's patches, intussusception and, 1319, 1335, 1386 Pfannenstiel approach, to incarcerated inguinal hernia, 1184 Pfeiffer's syndrome, 798 P-glycoprotein in germ cell tumors, 596 in neuroblastoma, 474 pH, 95, 96, 120, 121. See a130 Acid-base balance; Acidosis. congenital diaphragmatic hernia and, 938, 940 esophageal monitoring of, 1039, 1069 in gastrocsophageal reflux, 1124, 1125b in ~notilitydisorders, 1109, 1110, I1 1If, 1113 mechanical ventilation and, 127, 128 PHACE syndrome, 2102 Phagocytosis. Sre r ~ D oMacrophages; Neutrophils. bacterial evasion of, 159 by macrophagcs, 161 by ncutrophils, 160, 160f; 168 helper T cells and, 163 in neonates, 167, 168 opsonization and, 159, 160, 160f, 163, 164, 165 in neonate, 168 Phagolysosomes, 158, 160-1 61, 160f, 162, 168 Phantorn phenomenon, 2058-2059 Pharyngeal space infection, thrombophlebitis secondary io, 2132' Pharyngeal tonsil. Sre Adenoid (pharyngeal tonsil). Pharyngitis, 822-823, 823f, 844. Srr nlro Sore throat. jugular thrombophlebitis and, 2132 torticollis secondary to, 877 Pharynx anatomy of, 822 benign masses of, 826 caustic injury to, 1084, 1088 cyst of, brarlchial cleft, 866 ernbryoloLqof; 863, 864f-865f malignant lesions of, 8 2 6 8 2 7 obstruction at level of, 828 sleep-disordered breathing and, 823-825, 824f Phenobarbital, for seizures, in head trauma paticnt, 273 Phenoxvbenzarnine, for malignant hype1 tension, 2120 'olume 1, pages 1-1140; Volume 2, pages 1141-2146

Phenytoin during pregnancy cleft anomalies associated with, 805 neuroblastoma associated with, 467 for seizures, trauma-related, 273, 366 Pheochromocytoma, 6'28, 630-633, 63lf, 631 t, 633f ectopic ACTH secretion and, 635 imaging of, 630 laparoscopic adrenalectomy and, 638 RETproto-oncogene in, 632, 1521 Phimosis, 1905 in chronic graft-versus-hosi disease, 782 Phlebitis, 2131, 2132 Phlebography. SPPVenography (phlebography). Phlebolith, in venous malformation, 2099, 2103 Phlegmasia, 21 31 Phlegmon. Srr (:ellulitis. Phocomelia, 2051f, 2073 Phosphodiesterase inhibitors, for systemic inflammatory response syndrome, 173 Phosphorus in failure to thrive, 214 in parenteral nutrition, 206, 2061, 207, 208-209 Photodynamic therapy, 41 PHOX2B (paired like homeobox 2B), 1521, 1523, 1523t Phrenic nerve, injury to diaphragmatic eventration caused by, 935,946 during birth, 405 in lung transplantation, 772 Phyllodes turnor, of breast, 890, 892 Physiologic dead space, 120 Physis ablation of, contralateral to tumor resection, 663 amputation and, 2050 anatomy of; 337, 338f fracture of, 937-338, 339, 339f imaging of, 3411; 342 rnanagrrnent of, 342, 343t; 344 premature closur-e caused by, 345 osteomyelitis and, 2033, 2039 premature closure of fracture-related, 345 radiation therapy causing, 657 tumors in relation to, 651, 652f, 654 management issues with, 660, 66Of, 665 Pierre Robin sequence, 803, 806, 812, 825 esophageal dysn~otilityassociated with, 11 12 Pigmented villonodular synovitis, MRI of',654 Pili, 158 Pineal gland, tumors in region of, 678 diagnosis of; 673 germ cell, 557, 678 choriocarcinoina as, 568 gerrninoma as, 567 teratoma as, 563 yolk sac tumor as, 567 resection of, 673-674 Pineoblastoma, 678 Pineocytoma, 678 Pinna. Srt. Auricle (pinna). PIP (peak inspiratory pressure), 124, 127, 128 Piriform sinus, 861, 863, 868-869, 869f PIRO system, 171-172 Pituitary adenoma, (:ushing's synclro~neand, 633,634, 635 Pituitary tumors, ilipple discl~argecaused by, 888

Placenta choriocarcinorna of, 609 chorionic gonadotropin produced by, 556 fetal circulation and, 148 i~nmunoglobulinC; transport across, 164, 167-1 68 therapeutics delivered via, 81, 821 transfusion to neonate fi-om, 92 Placental alkaline phosphatase (PLAP), germ cell t~imorsand, 556, 565, 568 pineal, 673, 678 Placentomegaly, sacr-ococcygeal teratoma and, 559, 560 Plagiocephaly, tol-ticollis as cause of, 878, 878s Plain radiography. Sr? Radiography. Plasma. Srr Fresh frozen plasma. Plas~nacell granuloma. Srr Inflammatory pseudot~unor. Plastna substitutes, 187, 188 Plasinacytoid lymphoma, 583 Plasrnaphercsis, tbr recurrent focal segmental glomerular sclerosis, 71 1 Plasmit~ogenactivator. Sup Tissue plasminogen activator (tPA). Platelet colunt, 183, 184t Platelet-activating factor (PAF), 160, 165, 166 in systemic inllarnrnatoty response syndrome, 168, 170-171, 173 necroiizing enterocolitis and, 1432, 1433, 1444, 1445 Platelet-derived growth factor (PDGF), 414, 425,426 ii-om ne~u-oblastorna,475 in cystic lung masses, 957 Platelet-endothelial cell adhesion rnolecule 1 (PECAM-I), 159-160, 173 Platelets. Srr nlro Thrombocytopenia. disorders of function of, 183, 190 ketorolac causing, 239 inflammation and, 166 transf~~sion of, 183, 189-190 dill-ii~g exiracor-pol-eal life support, 138, 139, 1 40 during surge~-y, 226-227 for dissen~inatedintravascular coagulation, 186 in trauma patient, 273 Pleo~norphicadcnoma, salivary gland, 826, 8311, 839f Plethysmograph): total-body, 118 P l c ~ ~ rdbbride~ncnt, al for ernpyema, 977, 978, 980 Ple111-aleffhsion. Srr also E~npyema; Hemothorax. chest tube insertion Sol; 1023, 1023t cliylotis, 1024, 1025, 1026, 10'27, 2141 decortication Sol; 1018 Iymphangiectasia with, 2140 pulmonary contusions with, 282 Pleural space. Srr alto Pncumothorax. thoracoscopy o f ; 440, 441 Pletirodesis fix pleural eff~ision 1027 chylo~~s, ~y 2140 in p t ~ l ~ n o n alynlphangiectasia, for pnrutnothorax, 980 spontaneous, 1021 l'le111-operitonealshunt, fat- chylothorax, 1027 Plexus block, 243, 244, 245-246, 245f I'loidy, of cancer cells, 415, 438 PLUG therapy. Srr TI-achealocclusion. PNETs. SPPPrimitive neul-oectodermal tumors ( PNETs).

Pneumatocele, 1014-1015, 1016f empyema with, 1018 post-traumatic, 282 Pneumatosis intestinalis, in necroti~ing enterocolitis, 1433, 1434, 1434f, 14361437, 1436f, 1438, 1439 Pneumococcal (Streptococru.~ pneumonzue) infection as meningitis, after basilar skull fracture, 366 as peritonitis, 1476, 1477 as pneumonia, 1001 postsplenectotny, 1697, 1698 Pnrumocyslis cnrinii pneumonia corticosteroid therapy and, 994, 1007 extracorporeal life support for, 141t in cancer patient, 1007-1008, 1007f in HIV-infected patient, 1008, 1010 in transplant patient heart, 761 liver, 740t lung, 771 Pneumocytes, 115, 116, 116f; 117, 933 oxygen toxicity to, 128 Pneurnography, impedance, 122 Pneumomediastinum esophageal perforation with, 1047, 1048, 1048f-1049f in barotrauma, 128 in birth injur): 405 Pneurnonectomy for bronchiectasis, 1014 lung transplant subsequent to, 769 Pneumonia. See also Lung(s), infections of. after inhalation injury, 395 aspiration. Sre also Aspiratiorl, pulmonary. abscess in, 1015-1016, 1017f recurrent, 1011, 1015 vs. pulmonary contclsion, 281 atypical, 1002-1003 bronchiolitis obliterans organi~ing (BOOP), 781 chronic or recurrent, 1011-1012, 1012f aspiration as cause of, 1011, 1015 classificatiorl of; 1011 community-acquired bacterial, 1001-1004, 100'Lf complications of, 1014-1020, 1015f-10176 1019f-1020s cytomegalovirus, in bone marrow transplant patient, 1007 extracorporeal life support for, 140t, 141, 141t in cystic fibrosis, 1300 in HIV-infected children, 1008 mimicking appendicitis, 1503, 1504 nosocomial, in ventilated patient, 128 Pne?tmoc:ystzs. See Pnrumoc~sliscarznii pneumonia. recurrent, gastroesophageal reflux as cause of, 1125b tuberculous, 1003 Pneurnonitis interstitial chronic, in cytomegalovirus infection, 1009-1 0 10 lymphocytic (LIP), 1008, 1009f tracheoesophageal fistula causing, 10.57, 1058, 1066 Pneunioperitoneum diagnostic, inguinal hernia and, 1181 during reduction of intussusception, 1330, 1334 in necrotizing enterocolitis, 1436, 1437, 1439 in newborn with colon perforation, 1494 with gastric perforation, 1236, 1236f

Pneumothorax causes of barotraurna as, 128 birth injuty as, 405 esophageal rupture or perforation as, 1047, 1048, 1049 intermittent mandatory ventilation as, 124 ruptured pneurnatocele as, 1014-1015 thoracoscopic biopsy as, 442 trauma as, 269, 276, 277, 278, 279-281, 280f-281t 282 epidemiology of, 275, 275t, 276 chest tube insertion for in neonate, 1021-1023, 1022f in older child, 1023, 1023t in sponlancous pneun~otlrorax,1021 in trauma patient, 280, 280f-281f, 281, 282 during extracorporeal life support, 140 high-frequency \'entilation for, 126 spontaneous, 10'20-1 021 tension, 280-281, 28 1 f , 283 esophageal ruptur-e with, 1047 spon tancous, 1020, 1021 thoracoscopic treatment of',977, 980 Po,. SPPOxygen pal-tial pressure (Po,). Poland's syndrome, 907-912, 2071, 207% arnastia in, 886, 907, 908f, 912, 2071 pectus carinatum in, 904, 910,912, 2072s ulnar deft-cts in, 2073 Polyalveo1a1-lobe, 958 Polyalveolosis, 958 Polycystic kidney disease autosomal dominant, 170(i-1707, 1707s autosomal rcccssive, 1707, 1707f-1708f, 1709 hepatic cysts in, 499 hepatic fibrosis in, I657 nephrcctomy in, 701 Polycystic ovary syndl-ome, vs. ~nrlliiplc fi)llicular cysts, 601 Polycythemia neonatal, 21 15 placental transfnsion causing, 92 Polydactyly, 2075 Polydimethylsiloxane, for vesicourcte~-al I-eflux, 1748 Polyembryotna, 555, 568 ovarian, 609 Polyethylene glycol 3350, 1550, 15501' Polygenic disorde~.~, 12, 12f, 13- 14 Polyhydramnios cystic lung mass and, 955, 956 diaphragmatic hernia and, 936, 937 duodenal atrcsia with, 1262 esophageal atresia and, 1056 jejimoileal atresia with, 1271, 1271t mcconium ileus with, 1291 microgastria with, 1237 pyloric atresia and, 1232 teratolna and cervicotacial, 564 mediastinal, 565 sacrococcygeal, 559, 560 Polymastia, 2066 Polymcrase chain reaction (I'(:R), of tumors, 41% 420t, 425, 437 Polymyositis-dernlato~nyositis, esophageal dysmotility in, 11 11 Polymyxin B, for outpatient burns, 396 Polyp(s) gallbladder, 1636-1637 gastrointestinal, 1414-1422 Srr nbso Fa~nilial adenomatous polyposis. bleeding with, 1387, 1414, 1415, 1416

Volume 1, pages 1-1 140; Volume 2, pages 1141-2146.

Polyp(s) (Continued) ileoanal pouch for, 1421, 1469,1470,1472 in Peutzjeghers syndrome, 519, 1321f, 1417-1418, 1418f intussusception with, 1319, 1320, 1320f, 1321f, 1335, 1364 juvenile, 519, 1364, 1387, 1414-1417, 1415f, 1417f lymphoid, 1418-1419, 1419f obstruction with, 1364 rectal, 1416, 1596 nasal and sinus, 818 sleep apnea and, 825 vs. encephalocele, 820 vs. glioma, 820 nasopharyngeal, 826 umbilical, 1147f, 1307f, 1310 ureteral, 1724 Polyposis syndromes, 421, 519. See also Familial adenomatous polyposis. Polysorbate 80, for meconium ileus, 1295, 1296 Polysplenia syndrome, 1604, 1606, 1693 congenital short pancreas in, 1672 Polysporin, for burns, 389t, 390, 396 Polytetrafluoroethylene. SeeTeflon injection. Polythelia, 2066 Pontine glioma, 673, 675f, 676 Popliteal artery, injury to, 378, 379 Popliteal vein, aneurysm of, 2129 Portacaval shunt, 1660, 1661 for portal vein aneurysm, 2126 Portal hypertension, 1651-1665. See czlso Varices. after liver transplantation, 1653, 1654, 1654f after portoenterostomy, 1612-1 613 causes of, 1652-1 654, 1652t, 1653f-1654f, l653t clinical presentation of, 1654-1656, 1655f collateral circulation in, 1652 definition of, 1652 diagnosis of, 16561657 embryological basis of, 1651-1652 hemorrhoids in, 1598-1599 historical perspective on, 1651 in congenital obstruction of inferior vena cava, 2124 in cystic fibrosis, 766, 1659, 1660f in polycystic kidney disease, 1709 liver transplant for patient with, 732, 733, 1658 portal vein aneurysm with, 2126 summary of, 1665 treatment of', 1657-1663, 1660f-1662f complications of, 1663 options for, 1663-1665, l664f Portal vein aneurysm of, 21 26 cavernous transformation of, 1653, l653f, 1657 congenital absence of, 2125, 2126 congenital anomalies of, 2124-2126 gas in, in necroti~ingenterocolitis, 1436, 1436f, 1437, 1438, 1439 inflammation of. See Pylephlebitis. preduodenal, 1261, 1262, 1266,2126 biliary atresia with, 1606 thrombosis of, 1653, 1655, 1657, 1659,2131 Rex shunt for, 166'2, 166'2f, 1663, 1665 secondary to aneurysm, 2126 splenorenal shunt for, 1661 Portoenterostomy, 1603, 1607-1609, 1609f complications of, 1611-1613 laparoscopic, 1608 liver transplantation and, 732, 1613 outcomes of, 1610-1611 robotic, porcine, 55, 56t

Portosystemic shunt(s), 1653, 1654, 1655 complications of, 1663 congenital, 2125, 2126 decision making for, 1663-1665, 1664f emergency, 1663 for portal vein aneurysm, 2126 hepatopulmonary syndrome and, 1656 surgical methods of, 1660-1662, 1661f transjugular intrahepatic (TIPS), 1387, 1409, 1654, 1657, 1659, 1660f Port-wine stain. See Capillary malformation (port-wine stain). Positive end-expiratory pressure (PEEP), 123, 124, 125, 127-128 in extracorporeal support patient, 138 thoracic duct flow and, 1026 Positron emission tomography (PET), 37-38, 39f, 40 in epilepsy, 2004 in PET/CT scanning, 38, 39f of bone tumors, 655 of pheochromocytoma, 630 of sarcomas, 547 Postconcussion syndromes, 367 Posterior fat pad sign, 341, 341f Posterior urethral valves. Sre Urethral valves, posterior. Post-thrombotic syndrome, 2133, 2133t after caval thrombosis, 2130 Post-transplant lymphoproliferative disorder (PTLD), 584-585, 712,739, 750-751, 762, 774 Post-traumatic intestinal stricture, 1365 Potassium. ,'Tee also Hyperkalemia; Hypokalemia. in failure to thrive, 214 in fluid therapy, 225 in parenteral nutrition, 2061, 207 in short-bowel syndrome, 213 serum, in neonate, 94-95 Potter facies, 1706, 1709, 1710 Potter's syndrome, 1411 Pott's puffy tumor, 2010, 2010f Pouch continent urinary, 1799, 1799f ileoanal. See Ileoanal pouch procedure. in familial adenomatous polyposis, 1421-1422 Pouch of Douglas, ultrasonography of, in trauma patient, 296, 296f Pouches, branchial, 861,862f, 863t. See also Branchial anomalies. Pouchitis of ileoanal pouch, 1470, 1471 in familial adenomatous polyposis patient, 1421-1422 of Kock pouch, 1467 Povidone-iodine for burns, 3891 on dressings, for infected wounds, 352 Prader-Willi syndrome, nutrition in, 214t Prealbumin binding protein, nutritional status and, 195 Preauricular cyst, 871 Prednisone. See also Corticosteroid therapy. in transplantation, 686, 687-688, 687f,-693f, 708 heart, 760, 761f lung, 770, 771, 775 Preemptive analgesia, 236-237, 244, 249 Pregnancy, after portoenterostomy, 1613 Prekallikrein, 185-186 Preload, 146-147, 147f, 148 Premature infant. See also Low-birth-weight infant. acid-base balance in, 96 Aume 1, pages 1-1 140; Volume 2, pages 1141-2146

Prcmature infant (Continurd) apnea in, postoperative, 223 bowel perforation in, spontaneous, 1237 cryptorchidism in, 1197 definition of, 89 energy metabolism in, 97-98 enterocolitis in. See Necrotizing enterocolitis, neonatal. extracorporeal life support in, 135, 139 fluid therapy for, 225 gastric acid in, 1226, 1428, 1433 gastrointestinal tract of, 1428, 1432-1433 growth rate of, 90, 91f, 97, 194 Hirschsprung's disease in, 1532 hyaline membrane disease in, highfrequency ventilation for, 126 infection in, host defenses for, 167-168, 170 inguinal hernia in, 1173, 1176, 1185, 1186, 1187 insulin response in, postoperative, 107 isoflurane anesthesia in, 228 lactase deficiency in, 197 mortality of, 89,90-91,91 t, 92f nutrient metabolism in, 100-101, 102, 103, 104 nutrition for enteral, 199, 200t, 20'2 parenteral, 203, 204, 206-207, 208, 209 protein requirement, 196 taurine supplementation, 204 vitamin E, 198 pain management in, 236 subgroups of, 89 total body water in, 92 Prenatal counseling, 77 in hydronephrosis, 17'25-17'26 Prenatal diagnosis. See ulso Fetal interventions; Magnetic resonance imaging (MRI), fetal. genetics in, 14-15, 78 management of defects found in, 33, 77, 78t,81-82, 82t of abdominal aortic aneurysm, 21 11 of abdominal wall defects, I161 of adrenal hemorrhage, 637 of anorectal malformations, 1572 of ascites, 1408, 1411 of bladder exstrophy, 18461847 of bladder outlet obstruction, 1811 of cervicofacial teratoma, 563, 563f of choledochal cyst, 1623-1624, l623f of congenital adrenal hyperplasia, 1921 of congenital diaphragmatic hernia, 936, 936f, 937,938-939 of congenital limb deficiency, 2050 of conjoined twins, 2080, 2081f of cystic lung lesions, 955-956, 956f, 957, 958,958f of duplications, alimentary tract, 1391, 1394, 1395 of ectopia cordis, 91 3, 1161 of esophageal atresia, 1056 of facial deformities, 805-806 of hydrocolpos, 1941 of hydronephrosis, 1723, 1725-17'26, 17251, 1726f with megaureter, 1772 with posterior urethral valves, 1819, 1899 with ureteral duplication, 1763 of imperforate hymen, 1941 of lymphangioma, 2157 of lymphatic malformations, 2099 of megaureter, 1772 of omental cyst, 1402, 1402f of ovarian lesions, 596, 596f; 600 of posterior urethral valves, 1819, 1899

Prenatal diagnosis (Continued) of sacrococcygeal teratoma, 559-560, 560, 560f of small bowel obstn~ction,1262, 1262f. 1271 in ~ n e c o n i u ~ileus, n 1291 of third branchial cleft anomaly, 868 of ureteropelvic junction obstruction, 1723, 1725 ultrasound imaging in, 32-33, 77, 78 Prenatal interventions. See Fetal interventions. Preoperative planning, virtual reality in, 67-68,68f Prepuce bacterial colonization of, 1742 embryology of, 1872, 1873f Pressure sensors, rnicroelectromechanical, 58 Pressur-e support ventilation (PSV), 123, 124-125 weaning from, 128 Pressure-cycled ventilators, 119f, 124, 127, 128 Preterm delivery, defects managed by, 77, 78t, 81 Preterm infant(s). See Premature infant. PRETEXT staging system, for liver tumors, 505-506, 506s Priapism in spinal cord injury, 368 post-traumatic, 331 Prilocaine, 243, 24% 244, 244t Primary survey, 267-272,268f, 270f-271f, 277 burns and, 385 n~usc~tloskeletai injuries and, 339 Primitive neuroectodermal tumors (PNETs) central, 671, 671t, 674-675, 675f, 678 peripheral as Ewing's family tumors, 653 diagnostic features of, 542, 544t Pringle maneuver, 507,511 Probiotic bacteria, for prevention of necrotizing enterocolitis, 1444-1445 of pouchitis, 1471 Procainatnide, for supraventricular tachycardia, 151, 152t, 153 Processus vaginalis, 1173-1 174, 1173f, 1193 Proctocolecto~ny for Crohn's disease, 1457, 1459 for ulcerative colitis, 1466, 1467 Proctocolitis, eosinophilic, 1599 Programmed cell death. See Apoptosis. Prokinetic agents, 1126 Prolactinoma, 888 Properdin pathway, 164f, 165 Propofol, 221, 222f, 233 Proportional assist ventilation, 123, 125 Propranolol for burn patient, 39'2-393, 393f for hypertension, 21 20 for hyperthyroid symptoms, 853 for supraventricular tachycardia, in neonate, 151, 152t, 153 Prostacyclin for puln~onaryvascular disease, 766 for vasospasm, 2121 Prostaglandin(s) angiogenesis and, 2104 peptic ulcers and, 1228,1230 synthesis of, 197, 197s Prostaglandin E, in acute respiratory distress syndrome, 127 Prostaglandin El for reperfiision injury, after lung transplantation, 773 for vasospasm, 2121 to maintain patent ductus, 756 synthesis of, 197, 197f to nlaintain patent ductus, 153

Prostaglandin E, macrophage function and, 166 synthesis of, 197, 197s Prostaglandin E3, synthesis of, 197, 197f Prostate, tumors of, rhabdomyosarcoma as, 532-533 Prostatic utricle, 1904 Prosthesis, extensible, 663-664, 663s Protein malabsorption of, 213 metabolism of in burn patient, 392-393, 393f in neonate, 100, 104 postoperative, 108 nutritional requirement for, 195, 1951, 196, 196t Protein C, 184t, 186, 187,2130,2131 in systemic inflammatory response syndrome, 172-173 recombinant, for septic complications, 173, 2133 Protein kinase C, in neutrophils, 160 Protein S, 184t, 186, 187, 2130, 2131 Protein-calorie malnutrition, in burn patients, 393 Protein-losing enteropathy in diffuse juvenile polyposis, 1416 lymphatic malformation with, 2099, 2140 Proteomics, 419, 425 Proteus syndrome, 2101-2102 Prothrombin, 185, 186187 Prothrombin time (PT), 183, 184t, 185, 186 Proton beam radiation therapy, 430 fbr neur.obIastoma, 484485 Proton pump inhibitors for gastroesophageal reflux, 1122, 1123, 1125b. 1126 for peptic ulcer disease, 1229, 1230, 1230t, 1386 in short-bowel syndrome, 1372, 1373 in Zollinger-Ellison syndrome, 1231 prophylactic, stress ulcers and, 1231 Proto-oncogenes. See Oncogenes. Proximal femoral focal deficiency, 2050-2051, 2052f-2053f Prune-belly syndrome, 1780-1789 abdominal wall in, 1158,1781, 1781f-1783f, 1786 associated anomalies with, 1786 megalourethra as, 1905 urethral atresia as, 190'2 bladder in, 1783, 1783f-1784f, 1784 cryptorchidism in, 1195, 1781, 1785, 1786 kidneys in, 1781, 1783, 1783f, 1786, 1789 management of, 1786, 1787f-1788f, 1789 abdominal wall, 1781, 1782s-1783f, 1786 megaureter in, 1771, 1780, 1783, 1783f-1785f, 1787s-1788f, 1789 overview of, 1780-1781 umbilicus in, 1153, 1784 urethra in, 1784, 1785f urinary ascites in, 1411 Pseudoaneurysm carotid, after craniopharyngioma surgery, 677 iatrogenic, 2115 catheter-related, 380 traumatic, 21 14-21 15 intracranial, 366 renal, 319, 324 splenic, 299, 299f Pseudocyst pancreatic, 307-308,309,309f-310f, 309t, 310, 1678-1679,1679f splenic, 299, 299f-300f, 1693 ~ l u m e1, pages 1-1 140; Volume 2, pages 1141-21

Pseudoephedrine, maternal use of, intestinal atresia and, 1269 Pseudoexstrophy, 1846 Pseudohermaphroditism female, 1913, 1914t diagnosis of, 1918-1919, l918t, 191% medical management of, 1920-1921 surgical reconstruction in, 1921-1926, 1922s-1928f male, 1913, 1914t, 1916-1917 diagnosis of, 1918t, 1919-1920, 19191 medical management of, 1920-1921, 1921 surgical reconstruction in, 1026-1931, 192961932' preparation Sol; 1921-1922, 1Y22f Pseudomembranous colitis, in Hirschsprung's disease, 1529 Ps'srudomonasinfection in cystic fibrosis, 1010-1011 of wound, dressing for, 352 Pseudo-obstruction. See Intestinal pseudo-obstruction. Pseudosubluxation, of cervical spine, 346, 369 Pseudotumor, inflammatory hepatic, 499 pulmonary, 640-641 Psoas abscess, 2040 Psoas hitch. 327 PSV (pressure support ventilation), 123, 124-125 weaning from, 128 PT (prothrombin time), 183, 184t, 185, 186 Pterygia, 2064 PTLD (post-transplant lymphoproliferative disorder), 584585, 712, 739, 750-751, 762, 774 Puberty delayed in Crohn's disease, 1454 in ulcerative colitis, 1464, 1465 obesity and, 1245, 1251 precocious adrenocortical tumors with, 635 hypothyroidism with, 601 ovarian lesions with, 594, 600, 601, 609 pineal region tumors with, 678 premature thelarche in, 885 suprasellar astrocytoma with, 676 teratoma with, 563, 565 testicular tumors with, 622, 624 pseudoprecocious, ovarian lesions with, 594, 600, 604, 605f, 607 Pubic diastasis, 1842, 1843, 1843f-1844f, 1846 repair of, 1850-1851, 1850f in cloaca1 exstrophy, 1868 urethral duplication with, 1904 Pull-through, endorectal for Hirschsprung's disease, 1534, 1535s-1537f, 1536 redo of, 1543f, 1544, 1545f for intestinal neuronal dysplasia, 1563 for vascular malformation, 1598 Pulmonary. Y . ep ( ~ k Lung(s); u Respiratory ent~es. Pulmonary agenesis, unilateral, 1055 Pulmonary artery(ies). See also Great vessels, anomalies of. congenital diaphragmatic hernia and, 935,936 development of, 117 fetal circulation and, 148 sling of, 1978-1980, 1978t, 1982-1983, 1983f, 1984 airway obstruction by, 997, 998 tissue-engineered reconstruction of, 24, 24f

lii

I~nt;.s

Pulmonary artery cathetel-, 125, 235 Puhnonary at-tery occlusion press~u-e,123 Pn1mon;try aspii.ation. Svr Aspiration, p11lmona1-y. P~~linon;t~-y aircsia, lung transplant for, 767 Pulmonary blasto~na,(541-642, 6436 643t, 957 Puln~ona~-y blood flow, 118t 1'11l111onarychondl-onla, 5 15-5 16 Pulmon;~~-y circ~~lation, 120 neonatal establish~ncntof, 148 Pctlrnon;~~-y compliance, 119-120, 1l9f in congenital diaphragmatic hernia, 938, 944, 945 mechanic;11 ventilation ;md, 119, 119f; 124, 125, 127, 128 Pul~nona~-y contusion, 269, 272, 278, 281-282. 282f epidr~niolokyof, 275, 2751, 276 Pu11non;it.ye d e ~ n a dnring extracorporeal life support, 138 in inh;tl;iiion injt~r):395 in tramna patient, 271-272 Pulmon;~ryc~nbolism,213'2-2133 in ventil;lted p ~ t i t n t 129 , Pulmonary fibrosis gastroesophageal I-etluxand, 1l25b lung transplant for, 767-768, 769 Pi~lmonaryfnnction tests, 118 in congenii;tl diaphragmatic hernia, X38, 944 Pulmonary gas exchange, 120-1 21, 121f Pi11mona1-yhypertension congenital diaphragmatic hernia and, 123, 93.5, 936,939,940, 941, 943,944 heart Failure with, in neonate, 151 heart transplantation and, 756, 757, 760 Imlg transplantaiior~for, 766-767 persistent, of newborn extracorporeal life support for, 140, 140t pharmacologic treat~nentof, 940 portal hypertension with, 1656 PI-imax-y for, 766-767 lung tra~~splantation nitric oxide for, 127 ventilator settings in, 127 and, 123 radial artery catheterizatio~~ upper airway obstr~~rtion with, 983 laryngomal;~ciaand, 986 veno-occlitsive disease with, 781 Pulmonary hypoplasia. Srr rclso Diaphragmatic hernia. animal models of', 117, 934, 935, 935f, 939,945 ectopia cordis wiih, 914 extracorporeal life support and, 135, 139, 140, 142 fetal intervention for, 82t, 83-84, 939 lyinphatic effusion as cause of, 1026 posterior urethral valves with, 1811 prune-belly syndrome with, 1781, 1786 renal agenesis with, 1706 Pulmonary lymphangiectasia, 2140 Prllmonary physiology, 117-121, 118f-119f, 1181, 12lf Pu11nonai.yslings, 1978-1980, 1978t, 1982-1983, 19836 1984 airway obstrr~ctionby, 997, 998 Pulmonary toilet, tlxcheotomy for, 984 P~~lmonary valve, stenosis of, 86 in tetralo&gyof Fallot, 1971 in U'illian~ssvndro~ne,21 17 tl-anspositior, of great arteries wiih, 1975

Pulse oximetry, 121-122 during anesthesia, 234 during epidural infusion, 249 during opioid infirsion, 242, 243 of b11m patient, 385 of traurna patient, 267 Pulsus paradoxus, 286 Pumps, n~icroelectromcchanical,58 Purpi~ra Henoch-Schiinlein in, 1320, 13'27-1328 intnss~~sception renal grafi loss in, 71 1 siibrnucosal hemorrhage in, 1364 idiopathic (immune) th~-o~nbocytopenic, 182-183 accessory spleens and, 1692 splenectomy in, 183, 1693, 1696, 1698 Purpura fulminans, 186, 187, 2058 Push-back palatal procedure, 809, 809f Putty sign, of meconi11m ileus, 1291 Pyelogenic cyst, 1713 Pyclography. Ser alto Urography. antegrade, of megarrreter, 1772 intravenous (IVP) of trauma, 319, 523, 326 of ureteral duplication, 1761, 1762f retrograde of trauma, 320, 326 of ureteropelvic junction obstruction, 1730-1731, 1731f, 1735, 1736 Pyelolithotomy, robot-assisted, 541, 55 Pyelonephritis abscess secondary to, 1745 after pyeloplasty, 1737 clinical presentation of, 1741 imaging of, 1743, 1744, 1745 Pyeloplasty, 1734-1 737, 1734f-1736f complications of, 1737 in duplex system, 1767 laparoscopic, 1736-1 737 outcome of, 1737 reflux resolved by, 1730 retrograde pyelography for, 1730-1731, 1731f, 1735, 1736 robot-assisted, 54t, 55, 1736, 1737 Pyelostomy, cutaneous, 1793 with posterior urethral valves, 1819 Pyeloureterostomy, in duplex system, 1767 Pylephlebitis, after appendectomy, 1509, 1643 Pyloric atresia, 1232-1233, 1232f-1233f, 12321 Pyloric duplication, 1234 Pyloric stenosis, hypertrophic, 1215-1222 clinical features of, 1216 diagnosis of, 1217-1218, 1217f differential diagnosis of, 12161217 duplication in, 1234, 1394 epidemiology of, 1215 etiology of, 14, 1215-1216 hemorrhagic emesis in, 1386 pathology of, 1215, 1215f peptic ulcers secondary to, 1230 treatment of, 1218-1221, 1219f-1220f, 1221t, 1222t complications of, 1221, 1222, 1222t outcome of, 1222 umbilical incision in, 1153 Pyloroduodenal duplication cyst, 1232 Pyloromyotomy, for hypertrophic pyloric stenosis, 1153, 1218-1222, 1 2 1 9 s1220f, 1221t, 1222t Pyloroplasty for peptic ulcer disease, 1230 for pyloric atresia, 1233 for stress ulcers, 1231 gastric emptying and, 1130, 1133

Volume 1, pages 1-1140; Volume 2, pages 1141-2146.

Pyocolpos, 1568 Pyodern~agangrenosu~n,in ulcerative colitis, 1464, 1464f Pyogenic granuloma, vs. hen~angioma,2097 Pyogenic liver abscess, 1643-1644 Pyopneurnothorax, ruptured pneumatocele as cause of, 1014-1015 Pyramid hypospatiias repair, 1882, 1883f Pyriform aperiiive stenosis, 819 Pyruvate kinase deficiency, 182

Qiuadriceps ~n~lscle, biopsy of; fascia iliaca block for, 246 Quinsy, 823

R115777, 425-426 ~ r ~ a469, 46% Raccoon eyes, n e ~ ~ r o b l a s t owith, Radial artely caiheteri~ationof, 123, 235 ligation of, in traurna patient, 351 Radial deficiencies, 2073 Radial head, fiacture of, as birth inji~ry,404 Radial nerve, test of', 349, 350f Radial nerve palsy, in birth injury, 404 Radiation sensitizers, 428 Radiation therapy, 44, 427-431. Srr ( L k O \pec.ifir cancer: adverse effects of, 430-431, 43 1t cerebral, 46, 675, 676-677 hypomastia as, 886 in Hodgkin's disease therapy, 579, 891-892 fractionated, 44, 46-47, 429 image-guided, 429-430 intraoperative, 430 for bone tumors, 657, 657f, 659 rnalignancics secondary to breast, 891-892 cerebral, 675 colorectal carcinoma as, 520, 520f malignant fibrous histiocytoma as, 543 osteogenic sarcoma as, 653, 657 thyroid, 855 radioiodine, for thyroid carcinoma, 856, 857 stem cell transplantation following, 431, 779 Radiobiology, 43-44 Radiofrcquency ablation, 41 of bone tumors, 658 of fetal tumors or anomalous twins, 78 of liver tumors, 51 1, 733 metastatic, desmoplastic, 547 of lower esophageal sphincter, 1126, 1133 Radiography chest. Sru Chest radiography. in abdominal trauma, 295 in head trauma, 363 in musculoskeletal trauma, 341, 341f, 342 to hand, 349, 351, 352 to joint, 344 to spine, 346, 346f, 368, 369 of bone tumors, 649, 654 Radioimmunoguided sul-gery, 47 Radionuclide studies. Svr c ~ k oPositron emission tomography (PET); Single-photon emission computed tomography (SPECT). gallium 67 scan, in non-Hodgkin's lymphoma, 585 hepatobiliary, 1606, 161 1

INI)EX Radionuclide studies ((,'o?~lin~trd) of bile leak, 1410, 1615 of c1iolcdoch;tl cyst, 1625 Icttkocyte scan in appendicitis, 1504 iir 1nusc11loskclct;\1 infection, 2035 lymphatic. Srr I.yt~lpl~angiography, ~ldionnclide. molccrilar, 38, 40 of adrrual glaitds. (230, 635 of hone. Src, Bone scair. of esoph;~gus iir caustic inju~): 1084 in ~notilitydisordel-s, 1109, 1112, 1113 with g;~sti-ocsol)I~ageal reflux, I124 of g;~lll~l;lddc~; 1637 of' gastric ~l~ucosa. hcterotopic, 1308, 1308f, I :38(;, 1:wi in entci-ic duplicatio~~, 1392, 1395 of p a ~ ~ t h y r o gl;urds, id 858 782 of splenic platelet scq~~estration, of thoracic duct fistula, 1027 of thyroid. Src.Tliyl-oid scan. of' urin;~ry$1-act afirr infection. 1744t, 1745 after trauma, 325 in ureteropcIvic,juirctiou obstl-uction, 17'28-1 750, 1729i11730f; 1767 with 111e9;111retet;1771-1772 with ~nulticystickitl~re):1710-171 1 with u1-cte~11 nnoinalics, I7(iI, 1763, 17(i4-17(i5, 1765f; 1766, 1767 Radiosul-gel-):stercotactic, 43, 44-47, 45f-46f exttxci-anial, 43, 46, 47 in children, 4G47 staged, 45 Radiothciapy. Sw Radiatioir therapy. Ranitidine for gasirocsophageal reflux, 1126 for- peptic t~lccrdisease, 1230 RANTES (I-cgulatedon activation, normal T exp1.esst.d anti secreted), 165 Rantila, 826, 826I; 8.18, 838f Kapamycirr. Sw Sirolimus (raparnycin). R4S proto-oncogeile, 41 7, 421, 425-426 glionlas and, 679 rhabdon1yosa1-comaand, 525 R;lstclli procedure, 1975, 1977f Raynar~d'ssyntiroine, 2121 RB. Srr Rt~tiiioblastonla. RR(:s. Srr Erythrocytcs (RB(:s). RDA (reco~r~rnended dietary allowance), for e n r r p , 195, I96 Reactive oxygen i~rtertnediates(ROIs). Set also Oxygen f r r ~ radicals. in nlacroplrages, 161-162 in neonatal ~nonocytcs,167 in ncutl-opliils, l(i0-161 in nitric oxide I-eactions, 161-162, 162t in systenlic i11flammatoryresponse syitdromc, 168, 169f, 173 n?croti/ing enterocolitis and, 1432 I-cprrf11sioi1ii!j~u-yand, 158 Rectal atrcsia and stetiosis, 1578 Rectal biopsy in gr-aft-versus-hostdisease, 780 in Hirschspn~rrg'sdisease, 1517-1519, 1517f-15181' after pull-through, 1542, 1543f fiill-thickness, 1517, 1518-1519, 1532-1533, 1533f suggested by constipation, 1593 in intestinal ner~rotlaldvsplasia, 1561-1562, 15 6 2 5156%'

Rcctal bleeding, 1385, 1386-1387 11emo1-rhoidswith, 1598 in necrotizing cntcrocolitis, 1435 int~~ssusccption with, 1324, 1325 polyps with, 1414, 1415, 1416 juvenile, 1364 lymphoid, 1419 tumors with, 515, 520 varices with, 1655 Rectal examination in appendicitis, 1503 in chronic co~istipation,1593 in Hirschsprung's discasc, 1515 Rectal mucosectorny. 1467, 1461) for vetlous malformation, 2107 Rectal prolapse, 1595-1 596, 15951' bladder exstrophy with, 1596. 1845 in cystic fibrosis, 1299, 1595-1596 of it~tussusccption,1324 polyps with, 1596 juvenile, 1416 postoperative, with anorectal ~nalformations,1586, 1596 solitary rectal ulcer with, 1599 Rcctoanal dyssynergy, 1594 Rectourethral fistula, 1566, 1569, 1570f anorectoplasiy for, 1574-1577, 1575f-1576f postoperative care with, 1584 Rectovestibula~-fistula, 1566, 157I, 1571f-1572f anorectoplasty f'or, 1578 s~ ~?~trir.\. Kcctum. .SPP( ~ 1 Anorectal anal junction with, 1590, 1590f, 1591 defecation and, 1591 duplications of', 1392f, 1395-1 397, 1396f-1397f embryology of, 15661567 malformations of, sacrucoccygeal teratorna with, 557, 559, 560 normal motility reflex of, 1527 polyps of'. .SPPPolyp(s), gastrointestinal. sexual abuse and, 1599 trauma to, 312, 404 pelvic fracture with, 318 ~ Colorectal carcinoma. tumors of. S Palso carcinoid, 518 stromal, 515 ulcer of, solitary 1599 vascular malformations in, 1598 Rectum-bladder neck fistula, 1570f anorectoplasty fol-, 1577, 1577f-157% Rectus block, 245, 245f Recurrent respiratory papillomatosis, 831, 831f, 989-990,989f Red blood cells. SecErythrocytes (RBCs). 5cc-Reductase deficiency, 1915t, 1917, 1920, 1921 KEE. .SPPResti~igenergy expenditure (REE). Reed-Sternberg cells, 575, 576, 576t 577 Refeeding syndrome, 208 Reflex apnea, 997-998 Reflex sympathetic dystrophy, 2121 Reflux esophageal. Srr Gastroesophageal reflux. intrarenal, 1817 ureteral. Seevesicoureteral reflux. Regional anesthesia, 243-249, 245f-247f intravenous, 244 Reifenstein's syndrome, 1894, 1914t Reinke crystals, 607, (i24 Renal. Set a1.w Kidney (s) . Renal abscess, 1745 Renal agenesis, 1705-1706 Gartner's duct cyst with, 1950 Renal aplasia, 1705, 1711

Volume 1, pages 1-1140; Volume 2, pages 1141-2146

liii

Rcnal ;rrtci.y aneurysm of t>1.;1ncIrvcssc~l,21 20 c o ~ ~ g c n i t ;21 ~ l11 . ~I-;UIIII;I to, 31 7, 322, 329-324, 3251' :~i-tc~.iog~.;~i>Iry in, 319 qrading of', :Y2O, :121 t Rcnal artery stc,nosis, 2 1 17-2 1 20, 21 181-21 191: .%Pnl,o Rc.~~ov;isc~~l;rr Irylxrtcnsion. Rrnal blood Ilow, in frtus, 0:1 Rtwal cc.11 c;~rcino~ila I>I-castanomalies with, 20(i(i in 1101-scshockitinc): 1718 Renal dysgcncsis. 1705-1 706 Rcn;\l dvspl;rsi;t, 1705, I 706. SOPcrl\o M~~liicystic tiyspl;~stickidne). fetal 11rct11r;tI O ~ S ~ I . I tioil I( ; I I I ~ Wt, , 83, 1817 (;artnc~-'sduct cyst witlr, 11KO in duplex systcnls. 17fi0. 17(iOf, 1 i(i2 in p~rnc-hcllysvndromc, 1781, 1783, 1783f. 17x6, 1789 ~x>stcrioi. 111.et1iral \,alvcs with, I81 7, 1000. 1901 Rcnal Failure. Sr(, rrl\o 1)ialysis. i.cnal. acquired rc>nalcystic- disc;rsc in, 17 13 esophageal dysnlotility in, 11 12 hypu-pal-atl~yroidistn ill, 858 in hlu-n 1);iticnt. 384, 389 in polycystic kidncy discasc, 1707 Rcnal fi~nction bul-ns and, 3x4 in fetus, 93 in neonate, 93-94, 9(i scintigraphic s t ~ ~ d iorf s, 1728-1 730. I729f-1 7301 UI-etcralohstrnction and. 1732 Renal Ilypodyspl;tsia, 170fi Renal hypoplasia, 1705, 1706 renal ar-tcry stcirosis with, 21 18 Renal insufficiency dul-ing extracorporeal life suppoi-t, 138, 140 in utcro, pulinonai.y hyl~oplasia caused by, 142 Renal scarring as indication for s~u-gel-y, 1747 with megaureter, 1772 irrcidence of, 1741, 174:3 scintigraphy of', 1745 ureteral anonlalies ;md, 1762, 1766 Rcnal scintigraphy, .S(v Kadionuclidc studies, of UI-inarytract. Renal transplailtation, 699-713 hladdcl- augmentation prioi- to, 1835 complicatioi~sof, 71 1-71 3 early, 707 data registries for, 699 delayed graft function in, 710 dialysis access and, 700, 701-702 donol- for, 702-70:3, 7021 early dysfunction in, 70fi-707 historical perspective oil, 685, 686-688, 686t, 687E 692, (i93 immunosuppression for, 707-709, 71 I, 712-713 nephrectomy in relation to, 700-701 noncompliance of patient in, 71 1 organ preservation fi~r,693-605, (i04f outcomes of', 709-713, 709f pancreas transplant with, 7 18, 719, 7lYf, 7'20, 7'21-723, 721f-722f postoperative care with, 706 recipieut diagnoses in, 699-700, 699t for, 700-701, 7OOt r e c i p i e ~ evaluation ~t recurrent primary disease arld, 71 1

I~V

INDEX

Renal transplantation ((~ontinurrl) rejection in acute, 71 0-71 1 chronic, 71 1 graft f'ailr~recaused by, 710 treatment of, 708-709 sul-gel-yfor ad~nissionfo~;703 anesthesia for, 703-704 fluid man;~gementin, 704, 705 monitoring in, 704 in, 704-706 operative techniq~~es timing of, 701, 710 tissue typing fiw; 695-696 urologic isst~esin, 700, 701, 705-706, 1834-1835 Renal vein congenital anomalies ot; 2124 throtnbosis of, 1753-1 754, 1754t, 2130 after transplant, 707 trauma to, 322, 323-324, 325f, 326 Rendu-Oslcr-Weher discase. Srr Telangiecta!iia, hereditary hetnorrhagic. Reuin, 629, 636 Rcnography, diuretic, 1729, 1729f, 1733, 1737 Renovascular hypertension, 21 17-2121, 2118f-2119f, 211th congenital aneul-ysnl with, 21 11 post-traumatic, 324 Wilms' t ~ ~ m with, o r 448 Reno\~ascularinj11i.y 322, 323-324, 325f Repel-fusion it!jur): 157-158 after lung transplantation, 773 expel-imental thel-apies for, 173 in burned tissues, 386 necrotizing enterocolitis and, 1434 Reporter transgene technology, 38-40 Research. Srr Technological innovation. Residual volume, 118, 118f Respiration ahhrc-tiations and symbols for, 118, 1181 form~tlasfix, 118, 118t monitoring of; 121-123 physiology of, 117-121, 118f-ll9f, 118t, 121f Respiratory acidosis. Srr alto Acidosis. in fetus and neonate, 96, 96t lipogenesis and, 107 in malignant hyperthermia, 231 parentera1 nutrition and, 207 weaning f~.omventilator and, 128 Respiratol-yalkalosis, in fetus and neonate, 9(it Respiratol-yburst, 160, 165 Respiratory distress. Srr rrl\o Airway obstruction; Apnea. cl~oanalatresia with, 819 chylothorax with, 1026, 1027 congenital diaphl-agmatic hernia with, 936937.939 congenital lobar emphysema with, 959 congenital neck anomalies and, 861, 868, 870, 872 lymphatigioma as, 2138 cystic tnediasiinal lesions with, 959 enteric cyst with, 1393 esophageal rupture with, 1047 gastric perforation with, 1296 pulmonary lymphangiectasia with, 2140 Respiratory distress syndrome esophageal atresia with, 1061 extl-acorporeal life support for, 140, 140t

Respiratory disturbance index, 824 Respiratory failure. See also Acute respiratory distress syndrome (ARDS). after inguinal hernia repair, 1186 anesthesia-related, 223 definition of, 127 in congenital diaphragmatic hernia, 942-943 in congenital thoracic syndromes, 915-917, 918 in spinal cord injury, 370 in systemic inflammatory response syndrome, 168, 170 in traumatic asphyxia, 291 rnanagement of extracorporeal life support for, 134135, 139, 140-141, 140t, 142 mechanical ventilation for, 123, 127-129 pharmacologic agents in, 127 trauma-related, 269 Respiratory papillomatosis, recurrent, 831, 831f, 989-990,989f Respiratory quotient, 1181, 121 in neonate, 97 parenteral overfeeding and, 210 Respiratory rate measurement of, 122 ventilator setting foi; 127, 128 Respiratory syncytial virus (RSV) infection, 1004-1005, 1004f cystic fibrosis and, 1011 epidemiology of; 1001 extracorporeal life support for, 141 in bone marrow transplant patient, 1007 Resting energy expenditure (REE), 195-196 in cerehral pals): 214 in neonate, 97, 98-99, 98f post ope^-ative, 105, 108 with biliary atresia, 212 Resuscitation of newborn, overzealous, gastric perforation and, 1235, 1236 of' tractma patient. .YCF Et~iergency rnanagement. Res~~scitation phase, 267, 27'2-273, 277 RETproto-oncogene, 13, 131 Hirschsprung's disease and, 13, 131, 1520-1522, 1520f-1522f, 1523, 15231, 1524, 1525 pheochromocytoma and, 632, 1521 thyroid carcinoma and, 4'21, 855, 857, 1521 Retinal detachment, in protein C deficiency, 187 Retinal hemorrhage, in child abuse, 361, 401, 402 Retinoblastoma, familial, 421 osteogenic sarcoma associated with, 653 Retinohlastoma (RR) protein, 413 Retinoblastoma (KB)tumor suppressor gene, 418, 421 molecular imaging study of, 39 osteogenic sarcoma associated with, 653 13-czs-Retinoicacid (isotretinoin) during pregnancy, 805 for laryngeal papilloma, 990 for neuroblastoma, 483-484, 485, 486 Retinoids, for neuroblastoma, 483-484, 485, 486 Retinol binding protein, nutritional status and, 195 Retinopathy in premature infants, vitamin E and, 198 renovascular hypertension with, 21 18, 2120 Retroareolar cyst, 890-891

Volume 1, pages 1-1140; Volume 2, pages 1141-2146

Retrograde pyelograplly of trauma, 320, 326 of ureteropelvic ,jnnction obstruction, 1730-1731, 17Jlf, 1735, 1736 Retrograde urethl-ograplry, of trauma, 320, 320, 330, 1902 Retroperitoneal cyst, 1399, 1400, 1404, 1404s Retroperitoneal liernatoma, 322, 323 Retroperitoneal lymph node dissection, with testicular tumors, 623-624, 625-626, V25f-626f Retroperitoneal tumors desmoid, in Gardner's syndrorne, 1422 fetus in fetu as, 558, 558f rhahdomyosarcoma as, 535 rectal cancer aficr radiation for, 520, 520f tcratoma as, 557, 558, 558f; 566 yolk sac tumor as, 567 Retropharyngcal abscess, 823, 823f mediastinitis secondary to, 1027 torticollis secondary to, 877 Reversed vein graft fol- iatrogenic injury, catheter-relatrd, 380 for lower extremity trantna, 379 for- upper extremity trauma, 351 Rex shunt, 16V2, 16fi2f, 1663, I(iti5 Reye's syndrome, 238 Rhabdoid tumor of kidney, 450, 45lf, 460 of liver, 505 Rhabdoid/atypical teratoiti tumor; of central nervous system, (571, 678, 679 Rhabdomyotna, intracardiac, ventric~ilar tachycardia and, 153 Rliabdo~nyosarco~i~a, 524-537 clinical presentation of, 526 clinical trials fot; 524, 531 diagnosis of; 527, 527t biopsy for, 527, 529 differential diagnosis of, 543, 544t epidemiology of, 524525,542 genetics and molecular biology o f ; 524-525 histology of, 524, 525-526, 526t historical perspective on, 524 management of by site, 531-536 chemotherapy in, 530-531 complications of, 536 for metastatic disease, 530, 531, 536537 radiotherapy in, 531 surgery in, 528-530 metastatic, 526 management of, 530, 531, 536-537, 549 to lung, 526, 536, 645 outcomes with, 537 sites of, 524, 526 bladder, 532, 533, 3949 breast, 892 extremities, 535-536, 549 head and neck, 826, 833 liver, 505 lung, 535,536,642, 643t, 644f, 957 management and, 531-536 ovary, 6 14 pancreas, 1683 retroperitoneurn, 535 rectal cancer after radiation for, 520, 520f risk groups and, 528t, 531 salivary gland, 840, 840f staging and, 527t temporal bone, 817 urachal remnants, 1149 vagina, 534, 1902, 1949 staging and clinical grouping of; 527-528, 5 2 3 , 528t

Rhinorrhea, 820, 821 Rhinosinusitis, 818 heterozygous cystic fibrosis mutations with, 12 Rib(s). Srr also Chest wall, congenital deformities of. aplasia of, in Poland's syndrome, 907-908, 907t, 90%-9llf, 910-912 defects of, in diffuse skeletal disorders, 915, 917-918,917f-918f fracture of computed tomography of, 278 epidemiology of, 275, 275t, 276 in child abuse, 278, 279, 403, 404 lung trauma caused by, 282 pulmonary contusion with, 269 treatment of, 279 Rickets, in parenteral nutrition patients, 209 Rieger's syndrome, 1149 Right ventricular hypertrophy, in tetralogy of Fallot, 1971-1973 Right-sided heart failure, in pulmonary vascular disease, 766 Ring block, 247 Rings, vascular, 1978-1984, 1978t, 1979f-1983f robot-assisted division of, 541, 55 Rituximab (anti-CD20 monoclonal antibody) for B-cell lymphornas, 588 for post-transplant lymphoproliferative disease, 585, 751, 774 RNA microarrays, 419-420 Robinow's syndrome, 1149 Robodoc, 49, 491 Robotic surgery, 47-57 advantages of, 47-48, 48f, 51-52,52t, 57 applications of clinical, 47-48, 53, 54t, 55 experimental, 55, 56t to neck lesions, 867 in cholecystectomy, 53, 541, 1639, 1640, 1640f in pyeloplasty, 54t, 55, 1736, 1737 in splenectomy, 53, 541, 1696 conclusions on, 55, 57 development of, 48-49 limitations of, 52-53, 57 systems for, 49-51, 49t, 50f-51f, 52t thoracoscopy in, 977 Rocuronium, 230t ROIs. Set Reactive oxygen intermediates (ROIs) . Ropivacaine, 243, 243t epidural infusion of, 248t Rotationplasty, 660, 661f, 66'2, 2051 Roux-en-Y cystojejunostomy, for pancreatic pseudocyst, 1678 Roux-en-Y esophagojejunostomy, after failed fimdoplications, 1133 Roux-en-Y gastric bypass, 260, 1242-1243, 1248, 1248t, 1249f, 1250, 1252 Roux-en-Y,jejunostorny feeding, 1480t, 1481f, 1484 with choledochal cyst excision, 16'26-1631, 1627f-l628f, 1677 Rovsing's sign, 1503 RSV. Srr Respiratory syncytial virus (RSV) infection. RT-PCR (reverse transcriptase-polymerase chain reaction), 419, 420t, 425, 437 Rule of twos, for Meckel's diverticulum, 1304 Rule of nines, For burn surface, 386, 387f Rule of tens, for cleft lip repair, 806 Runnels, 904

Saccular cyst, laryngeal, 830 Sacral agenesis, 2029 neuropathic bladder in, 1810, 1822 Sacral ratio, 1567, 1567f, 1573 Sacrococcygeal teratoma, 557, 557f-561f, 558-563 prenatal treatment of, 82t, 85, 559 Sacrococcygeal yolk sac tumor, 559, 561,562, 567,608 Sacroiliac osteomyelitis, 2041 Sacrum congenital defects of, 1567, 1567f, 1569. See also Currarino's triad. presacral teratoma with, 560, 560f, 561 enteric duplications associated with, 1396 rectal suspension to, for prolapse, 1596 Saethre-Chotzen syndrome, 798 Saliva epidermal growth factor in, 1430 gastroesophageal reflux and, 1121-1 122 Salivary glands, 835-842 anatomy and physiology of, 835 calculi in, 836, 836f, 837 cystic disease of, 837-838 ranula as, 826, 826f, 838, 838f diagnostic evaluation of, 835-837, 836f embryology of, 835 inflammatory disease of, 837, 838f, 842 minor, 835 benign lesions of, 826, 837, 838, 839 biopsy of, in Sjogren's syndrome, 837 malignant lesions of, 840 neoplasms of, 827,838-840,839f-840f, 842 pathology of, 835 surgical considerations for, 840-842, 841f Salpingitis, acute, with perihepatitis, 1645 Salpingo-oophorectomy, robot-assisted, 54t Salter-Harris classification, 338, 339f, 343f, 344,349 child abuse and, 403 Santulli enterostomy, 1297F, 1298 Saphenous vein autogenous graft of, for renal artery stenosis, 2121 cutdown of, in trauma patient, 269-270,271f duplication of, varicosity and, 2130 Sarcoma(s) bone, 652-653. See also speciJic sarcomas. breast, 892 fine-needle aspiration biopsy of, 438, 542,548 hepatic, 505, 5051 ovarian granulocytic, 615 primary, 614615 soft tissue. See Rhabdomyosarcoma; Soft tissue sarcoma. Sarcoma botryoides, 1949 Sarfeh shunt, 1661 SBP (spontaneous bacterial peritonitis), 1475-1477, 1475t, 1477t Scalp, congenital aplasia of, 2063 Scardino-Prince vertical flap, 1735, 1735f Scarring. See Renal scarring. Schatzki ring, in eosinophilic esophagitis, 1112 Schiller-Duval bodies, 567, 609, 623 Schwann cells, in neuroblastoma, 472, 473 Schwannoma malignant, 546-547 vs. gastrointestinal stromal tumor, 515 Sciatic vein, persistent, 2128, 2129 SCID. See Severe combined immune deficiency (SCID).

Scintigraphy. See Radionuclide studies. SCMORA (spinal cord injury without radiographic abnormality), 346, 368-369 Sclerosing stromal tumors, ovarian, 593, 606 Sclerotherapy of capillary malformation, 2129 of complex malformation, in Parkes-Weber syndrome, 2129 of esophageal varices, 1043, 1045, 1612, 1613, 1659 of lymphangioma, 2107 mediastinal, 966 of mesenteric or omental cyst, 1404 of varicocele, 1209 of venous malformation, 2107 Scoiiosis compensatory, with torticollis, 878, 880 congenital, 2026-2027, 2026f, 2028 diaphragmatic hernia with, 944 osteoid osteoma with, 654 pectus carinatunl with, 904 pectus excavatum with, 894, 896 thoracoscopic diskectomy for, 977 Score for Neonatal Acute Physiology (SNAP), 90,9l Scorpion stings, 353 Scrotum. See e~hoHydrocele; Testis(es); Varicocele. acute, 1205-1207, 1205f, 1206t anomalies of, 1907-1908 sex assignment surgery and, 1930-1931, 1932f chyle fistula to, 2140 fat necrosis in, 1206, 1206t idiopathic edema of, 1206, 12061 lymphedema of, 21 44 trauma to, 331, 404 tumors of, rhabdomyosarcoma as, 526,533 Seat-belt injuries to abdomen, 311, 311f intestinal stricture secondal-y to, 1365 to breast, 891 to kidney, 317 to spine, 346, 346f, 368 Seat-belt sign, 31 1, 31 If, 346 cervicothoracic, 378 Sebaceous cysts, in Gardner's syndrome, 1422 Sebaceous nevus, 2064 Second messengers, 413, 413f Secondary injury, to central nervous system, 273,355-356,367 Secondary survey, 267 in thoracic trauma, 277 musculoskeletal injuries found in, 339, 341 Sedation for burn patient, 394, 394t of trauma patient for intubation, 267 with brain injury, 363, 364 preoperative, 221, 224 Seizures. See aho Epilepsy surgery. brain tumor with, 671, 672, 677, 677f in Addison's disease, 637 in Sturge-Weber syndrome, 2098 postoperative, with heart transplant, 762 post-traumatic, 273, 356, 366-367 assessment with, 363 early, 366367 in child abuse, 361 with cerebral contusions, 358 Selectins, 159, 160, 161, 167 in inhalation injury, 39.5 in systemic inflammatory response syndrome, 168, 169f, 173

Volume 1, pages 1-1140; Volume 2, pages 1141-2146.

Ivi

INDEX

Seleilium, l98t, 199, 206 Self-assembly, of narlomaterials, 57, 59 Seminoma, 554, 567, 622. Srr rclso Germinoma. gonadoblastoma degenerating to, 624 Sensors, microelectromechanical, 57-58, 57f Sentinel lymph node mapping, with soft tissue sarcomas, 549, 549f as rhabdomyosarcoma, 530, .536, 549 Seprafilm. Srr Hyaluronic acid membrane. Sepsis. Srr abo SIRS (systemic inflammatory response syndrome). arterial thrombosis in, 21 15 bal-riers against, 157f blood replacement in, 226 cytoki~iesin, 165, 166, 169 definition of, 156, 168 diagnosis of; 170, 171-17" epiderniology of, 156 extracorporeal life support for, 140t, 141t in burn patients, 389, 393, 394 in cystic fibrosis patient, 1300 in intestinal transplant patient, 749, 750 in neonate, 166-167, 170-171, 173 catheter-related, 204, 209-210 wiih ~ ~ e c r o t i ~enterocolitis, ing 173, 1435, 1436, 1438 in parenteral nutrition patient, 208, 209-2 10, 744 in surgical patient, nutrition and, 211-212 pathophysiology of, 169-170 posisplenectomy, 1698, 1699 in Hodgkin's disease, 579-580 trauma-related, 266 abdominal packing and, :102 in urethral irijury, female, 331 treatment of, 172-1 73 recombinant protein (; in, 2133 Sepsis-Related Organ Failure Assessment (SOFA), 9 1 Septic arthritis, 2033, 2034f, 2039-2041, 20401, 2041t Septic shock corticosieroids in, 173 extracorporeal life support for, 141 lipid A in, 159, 172 monoclonal antibody therapy for, 172 purpura fulminans secondary to, 2058 Serial transverse enteroplasty (STEP), 744, 1379, 1379f Serotonin. Ser 5-Hydroxytryptamine. Sertoli cells, in cryptorchidism, 1197, 1198 Sertoli-Leydig cell tumor ovarian, 593, 594, 5951, 606 testicular, 622, 623t, 624 in Peutz-Jeghers syndrome, 1418 Severe combined immune deficiency (SCID) for stem cell trarlsplantaiio~~ extracorporcal life support following, 779 prenaial, 86 X-linked (XSCID), gene therapy for, 1.5, 18 Sevoflurane, 2221, 2271, 228, 229 Sex assignment. Srr cclso Iniersex abnormalities. bladder exstrophy and, 1845, 1847 cloacal exstrophy and, 1864, 1867 ethics of, 261-262 hypospadias and, 1870 in col!joiued twin, 2087 in male psrudoher~naphroditism,1919, 1920 in pe~lileageneais, 261, 1907 with a r ~ i ~ u l tubules, ar Sex cord tu~nol-s oval-ian, 593, 606 -s, 594, 595t, Sex cord-stromal t u ~ n o ~ ovariat~, 51)8t, (i04-607, 60%'

Sexual abuse. See also Child abuse. anorectal pathology secondary to, 1599 gonococcal arthritis secondary to, 2040 injuries caused by, 312 primary peritonitis secondary to, 1475 Sexual differentiation, 1911-1913, l912f Shah-Waardenhurg syndrome, 1522, 1523 Shaken baby syndrome, 401, 402f Shenton's line, 2020, 2020f Shivering, meperidine for, 241 Shock abdominal trauma with as birth injury, 405 renal injury in, 319 vascular injury in, 378 burn-induced, 389 hypovolemic, 180 neurogenic, 368 septic. See Septic shock. Short-bowel syndrome, 1369-1380 after resection for Crohn's disease, 1458-1 459 for intestinal atresia, 1283-1284 for malrotation, 1356 for meconiurn ileus, 1298-1299 for necroiizing enterocolitis, 1369, 1369f, 1441, 1443 bacterial overgrowth in, 1373-1374 causes of, 743, 743t, 1369, 1369f clinical course in, 137'2 in aganglionosis, 1369, 1369f, 1540 intestinal adaptation in, 743-744, 745, 1369-1370, 1372, 1373, 1374 nutritional deficiencies in, 1371-1372 nutritional support for, 198, 199, 137'2-1374 enteral, 203, 212-213, 137'2-1373, 1374 lengthening procedure and, 1378 parei~teral(TPN), 206, 212-213, 743, 743f, 1372-1373, 1374, 1375 complicationsof, 209, 744, 745, 1373, 1374 dependence on, 1370-1372, 1371f, 1374 ileocecal valve and, 1375 lengthening procedure and, 1378 with jejunoileal atresia, 1282, 1283 prevention of, 1374 prognostic factors in, 1370-1372, 1371f treatment of algorithm for, 1379f conclusions on, 1379 intestinal transplant for, 1283, 1373, 1378, 1379 pharmacologic, 1373, 1374 surgical (Bianchi procedure, STEP, tapering enteroplasty), 1374-1379, 1375f-1379f tissue-engineered, 24-26, 1379 Shoulder birth injuries of, 404-405 reconstructiorl of, after tumor resection, 653f, 663f, 665 Shriners-Galveston formula, 386, 388t Shunt Blalock-Taussig,modified, 1972, 1977 for hydrocephalus, 1998-2002 brain tumor and, 674, 676 in aqueductal stenosis, 82t, 85 inguinal hernia and, 1185, 1187 spontaneous bacterial peritonitis with, 1477 vocal cord imrnohility and, 988 left-to-right, anesthetic induction with, 228 mesenieric vein-to-left portal vein, 1662, 1662f, 1663 peritoneovenous, 1409, 1411, 2140 pleuroperitoneal, for chylothorax, 1027 portosystemic. See Portosystcmic shunt(s). right-to-left, 120, 121, 935

Volume 1, pages 1-1140; Volume 2, pages 1141-2146

Shunt (Continued) anesthetic induction with, 227-228 arterial sampling and, 235 in congenital diaphragmatic hernia, 939 thoracoamniotic for cystic adenornatoid malformation, 83 for hydrops, 956,965 with enteric duplication, 1391 vesicoamniotic, 82t, 83 with posterior urethral valves, 1899 Shunt fraction, 118t Shwachman-Diamond syndrome, 1673 SIADH (syndrome of inappropriate ADH secretion), 94, 941 Sialadenitis, 837 Sialography, 836, 836f; 838f Sickle cell disease, 181-182 acute chest syndrome in, 1011, 1012f, 1636 after splenectomy, 1697 cholelithiasis in, 1635-1636, 1637, 1642, 1673 extracorporeal life support for, 142 malaria resistance in, 166 osteornyelitis associated with, 2042 splenectomy in, 1693, 1697, 1698-1699 thrombosis and embolism in, 2 1 15 SIDS (sudden infant death syndrome) sleeping position and, 794, 1I25 thyroglossal duct cysi and, 870 Sigmoid cystoplasty, 1797, 1X2Ci-1827 Sigmoidostomy, 1483, 1483f; 1485 Signal transduction, 41 3-414, 41 3f maligllailt transformatioil and, 414, 415, 417 Sildenafil, for esophageal motility disorders, 1111 Silicone inlplants, breast-feeding and, 1111 Silk string sign, of inguinal hernia, 1 174 Silo, Silastic in abdominal traiirna patieni, 301-30'2, 303f in gastroschisis reduction, 1164f, 1166 in omphalocele reduction, 1163-1 164 Silver nitrate in burn care, 383, 389, 389t, 390 in stoma care, 1488 Silver sulfadia~ine(Silvadene), 383, 389, :189t, 390, 396 Simulation, surgical, 59-70 commercial systems for training, 68-70, 69f for preoperative planning, 67-68, 68f principles of, 59-62 virtual realiiy fol; 62-69, 64f-661, 70 Simulect. See Basiliximab (Simtilect). Single-photon emission cornpuied tomography (SPECT) , 40 in epilepsy, 2004 Sintered biomaterials, 59 Sinus. See e1.w Neck, cysts allti sinuses of. dermal, 1994 umbilical, 1146, 1147, 1147f; 1304, 1307f urachal, 1148, 1148f Sinuses, paranasal, 8 18, 82 1 Sinusitis, 818-819 acute phary~lgitiswiih, 822 illtracranial abscess seconda~yto, 2009, 2010 nasotracheal intubation causing, 129 Sirolimus (rapamyciil) as anticai~ceragerli, 425 in transplantation heart, 76lf intestinal, 749 islet cell, 724 liver, 738t, 739 lung, 771, 7711 pancreas, 72 1, 722, 7221 renal, 708, 709 mechanism of action, 708, 7381 side effects of, 7:18t, 739

SIRS (systemic inflammatory response syndrome), 156157. See also Sepsis. diagnosis of, 168, 171-1 72 in neonate, 170 pathogenesis of, 168-171, 169s physiologic and metabolic consequences of, 169-1 70 I-iskfactors in, 168 trauma-related, 266 treatment of; 172-173 Situs inversus. Srr Heterotaxia. Sjiigren's syndrome, diagnosis of, 837 Skin anatomy of, 384 congenital anomalies of, 2063-2064, 2065s classificatior~of, 2061, 2062-2063 enlbryology of, 2061-206'2 of, 384, 2061 fi~nciior~s inteiitional injury to, 383, 383f, 401t, 403, 403f ulcerative colitis and, 1464, 1464f Skin cancer. Ser r~lsoMelanonla, malignant. after renal tl-a~lsplantation,712-713 basal cell carcinoma, 2064 gynecomasiia and, 2069, 2070 Skin expanders. Srr Tissne expansion. Skin flaps, 352 Skin grafts, :152 aftel- bone tumor resection, 662 for burtls, :NO-391, 391f; 392, 394 Skull c..I 1,al~;ll ,. .' defect of, congenital, 2063 osteomas of, in Gardner's syndrome, 1422 Skull fracture basilal; 366 with, 357, 358, 358s-359f, 363 brain i~?jui-y co~rlplic;~tions in, 366 in child abnse, 401, 402 in crnsh injury, 361, %If', 366 sul-gery tix, 364 co~ltplicationsot; 3ti6 growing, :Mi trmpor;~lbone. 816817, 817s Sleep-disol-derectbreathing, 823-825, 824f obesity a d , 1246, 12% Slide t~~acheoplasty, 997, Y97f, 998 Smati inter;lcting pwtcin-1 (SIPl), 1521, 1523, 15231 Small, 11oncleavrd cell (undifferentiated) lymphomas, 581, 58 If-582f, 582-583 clinic;~lpl-csentaiio~~ of, 583-584, 584f tt-eatiuent of; 585-586, 587-588, 588t S~nallcell c;it-ci~~oma, of ovary, 603 S111allcell ohtt.ogcnic sat-coma, 652 Sm;ill intcsti~lc.S(,r c~L\o1)uodcnal rntrir.\; Ileal n1/1,ir3:I~~tcstinal watrir.~; Jejut~-wztrks. a d c ~ ~ o c a r c i ~ ~of; o iill l ~duplication, :~ 1395 burn-rt2l;tted damage to, 384, 393 of; 1:300, 1391, 1391f-1392f, duplic;~tio~ls 139% ,394-1:3!)5, 1395s Fiil-schsprung's disease in, 1.531, 1539-1510, 1.59'261543f length of, in i~liant,1370 l y ~ ~ ~ p h a ~ ~ g i cof, c ~2' i140, s i i ~2 14 1 lymphatic obstrttctioi1 in, "40 111ese11te1.y of; drsmoid tunlor of, 1422 polyps in ;ltlcllolu:llolls, 51'1, 1420 in Peut/rjcgt~csssyndronle, 1417-1418 ti.;rllm;l to, 310, :31 1, Sl I t tumors of c;~rcinoid,5 18 stso111,1l,515, 516 S ~ n i ~IeSt l l colon s y n d r o ~ ~1496, ~ e , 1497f, 1498 vs. ~ncconiuinilcus, 1294, 12!)5f with Hirschsprung's disease, 1519

Small round blue cell tumors. See ulso Ewing's sarcoma; Leukemia; Neuroblastoma; Non-Hodgkin's lymphoma; Primitive neuroectodermal tumors (PNETs); Rhabdomyosarcoma; Small cell osteogenic sarcoma. fine-needle aspiration biopsy of, 438 Smith-Lemli-Opitz syndrome, 1528 Smoke. See Inhalation injury. Smoking maternal abdominal wall defects and, 1160 cleft anomalies and, 805 ulcerative colitis and, 1466 Smooth muscle tumors. See alto Leiomyoma; Leiomyosarcoma. gastric, with pulmonary hamartoma, 641 vs. gastrointestinal stromal tumors, 515 Snakebites, 352-353 SNAP (Score for Neonatal Acute Physiology), 90, 91 Snodgrass tubularized incised plate urethroplasty, 1880, 1883, 1884s-1885s Soap-bubble sign of colonic atresia, 1275 of mecorlium ileus, 1274, 1292, 1292s-1293s Soave procedure, 1532f, 1534, 1540, 1545 SOCS (suppressors of cytokine signaling), 166 Sodium. See also Hypernatremia; Hyponatremia. in fluid therapy, 225, 226 in parenteral nutrition, 206-207, 206t in short-bowel syndrome, 213 serum, in neonate, 94, 941 Sodium bicarbonate, for acidosis, 96 Sodium cronloglycate, for enterocolitis, in Hirschsprung's disease, 1530 Sodium ferric gluconate, 207 Sodium hypochlorite. See Dakin solution. SOFA (Sepsis-Related Organ Failure Assessment), 91 Soft tissue(s) benign tumors of, 541, 541t, 542 diagnosis of, 542-543 congenital anomalies of. See also Breast(s); Hand (s). classificatiorl of, 2061, 2062-2063 embryologic basis of, 2061-2062 of muscles, tendons, and co~~nective tissue, 2070-2071, 2070f, 2072f infections of, in bone Inarrow trarlsplarlt patients, 781 traunla to, 348, 350-351, 352 as birth injury, 404 Soft tissue sarcoma, 541-550, 541t. See nlso .specz$(. &arcomas. diagnosis of, 542-543 differential diagnosis of, 543, 544t incidence of, 541-542 rlonrhabdo~nyosarcomatous,543, 544t, 545-547 biopsy for surgical planning with, 548 extremity, 548-550, 54%-550f grading of, 542, 542t lymph node involvement in, 548-549 new itrlagi~lgmodalities for, 547 trunk, 550 pulmonary metastases from, 645 relatively benign, 541, 542, 543 rhabdomyosarcomatous. See Rhabdomyosarcoma. Soiling, fecal, 1549, 1549t, 1592, 1593, 1594, 1595. See also Incontine~icc. Vohune 1, pages 1-1 140; Volume 2, pages 1141-21

Somatostatin for chylothorax, 10261027 for esophageal varices, 1387 for pancreatic injury, 309 in short-bowel syndrome, 1370, 1373 receptors for, of neuroblastic tumors, 469, 486 Somatostatin analogues. See Ocireotide. Somites, 2062 Sore throat. See ulso Pharyngitis. in upper airway obstruction, 827 infectious, 822 pharyngeal cyst with, 866 piriform sinus with, 868 SOX10 transcription factor, 1521, 1522-1523, 1522f, 1523t, 1525 Soy formulas, 200t, 202 Soy intolerance, 1386 Spasmodic croup, 830 Specimen handling, 437-438 SPECT (single-photon emission computed tomography), 40 in epilepsy, 2004 Spermatic cord, hydrocele of, 1189 Spherocytosis, hereditary, 178, 182 accessory spleen and, 1692 cholelithiasis in, 1636, 1637-1638, 1642, 1673 splenectomy in, 1637-1638, 164'2, 1693, 1696, 1697, 1698 Sphincteroplasty, for chronic pancreatitis, 1676, 1677 Sphincterotomy, anal, 1597 Spider bites, 353 Spina bifida, 1987, 1990, 2062. Sre also Myelomeningocele. latex sensitization in, 29'2 urinary catheterization in, epididymoorchitis associated with, 1206 Spinal block, 247 Spinal cord. Srr alro Central nervous system; Myelodysplasia. arteriovenous malformation in, 21 11 cervicomedullary astrocytoma and, 676 compression of; mediastinal mass with, 959 ependymoma of, 675 malformations of lipomatous, 1993-1994 occult, 1993-1994,2 102 sacrococcygeal teratoma with, 557, 559 split, 1994, 2027 tethered anorectal malformations with, 1567, 1569, 1573 bladder dynamics and, 1809, 1822 constipation with, 1594 occult, 1805, 1806f; 1810, 18'22, 1993-1994, 2102 with cloaca1 exstrophy, 1867 Spinal cord irljtrry, 355-356, 367-370. See also Paraplegia. in child abnse, 403 transport in, 346, :146f, 356357 without radiographic abnormality, 346, 868-369 Spinal dysraphisrn. Ser Myelodysplasia; Neural tube defects; Spina bifida. Spine. Ser nlso (:el-vical spine; Lumbar spine; Thoracic spine. anatomical features of,,juvenile, 368, 369 anomalies of, 20262029, 2026f-2029t Srr ril,so Hemivertehra(e). anorect;tl ~ilalti)rin;~tions with, 1567, 1569, 1573 constipation with, 1594 sacl-ococcygraltci-atornawith, 557, 559, 561 epidural abaccs in, 201 3

lviii

INDEX

Spine (Continued) liponla in, 1594, 1806f, 1809f, 1810, 1822, 1993-1994,2027,2102 metastases to, from brain tumor, 673, 675 neurenteric cyst in, 965-966, 1994 osteomyelitis of, 2042 rhabdoid/atypical teratoid tumor in, 678 trauma to, 345-346,346f, 367-368,369,370 in child abuse, 403 MRI in, 342 surgical therapy for, 370 thoracic, 278, 346 Spinning top deformity, in dysfunctional elimination syndrome, 1813, 1814f Spiral flap, 1735, 1735f Spirometry, 118 Spironolactone for adrenocortical hyperplasia, 636 for ascites, 1409 for heart failure, in neonate, 148, 1501 Spleen. See rrl.\o Hypersplenism. abscess of, 1694 fungal, 1694 in leukemia patient, 1644 accessory, 1692, 1696, 1699 anatonlic abnormalities of, 1692-1693, 1692f in polysplenia syndrome, 1604, 1606, 1693 with short pancreas, 1672 splenogonadal fi~sionas, 1189, 1693 anatomy of, 1691 cysts of, 1692-1693, 1697, 1698 embryology of, 1691 functions of, 1691-1692 pseudocyst of, 299, 299f-SOOf, 1693 trauma to imaging of, 295, 296, 296f in birth injury, 405 laparoscopic repair of, 297, 1696, 1697 nonoperative treatment of, 295,297-299, 297t, 298t, 300, 1691 complications of, 299, 299f-300f operative intervention for, 298-299, 300 wandering, 1692, 1692f, 1696, 1698 Splenecto~ny after bone marrow transplantation, 782 complications of, 1697 infection as, 159, 1691, 1692 sepsis as, 1698, 1699 in Hodgkin's disease, 579-580 in hernolytic anemias, 181, 182, 1693 hereditary spherocytosis, 1637-1638, 1642, 1693, 1696, 1697, 1698 partial, 1697-1698, 1698f sickle cell, 1637, 1641, 1642-1643 in Hodgkin's disease, 577-578, 579-580, 1697 in idiopathic thrombocytopenic purpura, 183, 1693, 1696, 1698 in portal hypertension, 1661-1662, 1663 indications for, 1693-1694 outcomes of, 1698-1699 overview of, 1691 partial, 1697-1698, 1698f for cyst excision, 1692-1693 technique of, 16941698, 1694f-1695f, 1698f conversion to open, 1696, 1698 open, 1694, 1697 robot-assisted, 53, 54t, 1696 Splenic artery, aneurysm of, cotlgenital, 21 11 Splenogonadal fi~sion,1189, 1693 Splenornegaly, portal hypertension with, 1655, 1655f, 1656 Splenore~lalshunt, 1660, 1661, 166lf, 1663, 1664, 1664f, 1665 in polycystic kidney disease, 1709

Splinting for burns, 396 of fracture, 342 of hand, 352 Split notochord theory, 1390 Split-thickness skin grafts, 352 Spondylothoracic dysplasia, 917, 918f Squamous cell carcinoma laryngeal, 989 salivary gland, 827 Squamous papilloma laryngeal, 831,989-990,989f oral, 831 pharyngeal, 826 Stamm gastrostomy, 1131, 1131f Stapedius muscle, 813 Staphylococcus aureus antibiotic-resistant in acute lymphadenitis, 845 in enterocolitis, 1495 in mastitis, 887 in osteomyelitis, 2037, 2038 in septic arthritis, 2040 hepatic abscess caused by, 1644 mycotic aneurysm caused by, 2115 pneumonia caused by, 1002 pneumatocele secondary to, 1014 ~ta~hylococcus epidermidis, in neonatal sepsis, 170,172 Steatohepatitis, obesity-related, 1246 Steatosis, parenteral nutrition and, 208, 209, 210 Steeple sign, of subglottic edema, 828, 830 Stellate cells, 1652-1653 Stellate ganglion, neuroblastoma involving, 468,479 Stem cell factor from neuroblastoma, 475 gastrointestinal stromal tumors and, 516 gonadal embryology and, 554 Stem cell transplantation, 431-432. See also Bone marrow transplantation. in utero, 83t, 86 Stem cells in fetal therapy, 82, 831, 86, 87 for Hirschsprung's disease, 1526 in islet cell therapy, 727 in tissue engineering, 28 neonatal neutrophil pool and, 167 Stents airway after lung transplant, 772 for tracheomalacia, 1070 biliary, 303, 304f drug-eluting, 59 endovascular for central venous obstruction, 2124 for iliac vein compression, 2127 for renal artery stenosis, 2120 for renal artery trauma, 324 for subclavian-axillaryvein thrombosis, 2131 esophageal, for caustic injury, 1085, 1088 pancreatic duct, 308, 309f ureteral. See Ureteral stent. urethral, after hypospadias repair, 1893 STEP (serial transverse enteroplasty), 744, 1379, 1379f Stereotactic radiosurgery, 43, 44-47, 4 5 s46f extracranial, 43, 46, 47 for pineal tumors, 673 in children, 46-47 Sternal turnover, for pectus excavatum, 899 Sternomastoid tumor, 875-876,878-880, 879f Sternotomy, median, mediastinal infection secondary to, 1028

Volume 1, pages 1-1140; Volume 2, pages 1141-2146

Sternum congenital defects of. See also Chest wall, congenital deformities of. cleft defect as, 914-915, 914t, 915f-916f ectopia cordis as, 912-914, 913f-914f fracture of, 279 osteomyelitis of, 1028 Steroid cell tumor, 606-607 Steroid hormones, biosynthesis of, 1916f, 1916t Steroid therapy. See Corticosteroid therapy. Stertor, 828 ST1571 (Gleevec), 425 Stoma. See Enterostoma(s);Gastrostomy; Urinary diversion(s). Stomach. See also Gastric entrie.7; Pyloric entries. congenitally small, 1237-1238 herniated, through diaphragm, 284-285 perforation of, spontaneous, in newborn, 125551236, 1236f polyps in, 1417, 1420, 1421 tissue-engineered, 25, 25f, 26 transplantation of, in multivisceral graft, 745,748 trauma to, 310 laparoscopic repair of, 297 tumors of adenocarcinoma, 517-518 carcinoid, 518 peptic ulcer disease and, 1231-1232 smooth muscle, with pulmonary hamartoma, 641 stromal, 515-516 teratoma as, 566 volvulus of, 1234-1235, 1234t, 1235f Stomatitis aphthous, in ulcerative colitis, 1465 herpetic, 822 Stool, 203, 213 Streak gonads, 1917, 1=O gonadoblastoma in, 613, 19'20 Streptococcus group A R-hemolytic, 822, perianal dermatitis with, 159'2 peritonitis caused by, 1477 group B, neonatal sepsis caused by, 170, 171, 172 Streptococcus pneumoniae. See Pneumococcal (Streptococrus pneumoniae) infection. Streptokinase. See a l ~ Thrombolytic o (fibrinolytic) therapy. for empyema, 1018 for renal vein thrombosis, 1754 Streptolysin, 159 Stress gastritis, in neonate, 1385 Stress response in burn patient, 384 in trauma patient, 274 to surgery, in neonate, 104-108, 105f, 107f Stress ulcers, 12'25t, 1226, 1227-1228, 1229, 1231-1232 Strictureplasty, for Crohn's disease, 1457, 1457f, 1459 Stridor, 828, 829, 830, 831 definition of, 971 laryngonlalacia with, 986 laryngoscopic evaluation of, 971 location of lesion and, 828, 983 second branchial cleft anonlaly with, 866 tracheomalacia with, 996 Strip craniectomy, 795-796 Stroke, arterial ischemic, 21 17

INI)EX Stroke vol~un~e. 14G147 Stro~nalI ~ ~ t r o m606 a, Stuart Hamilton cq~ration,123 Stump overgrowth, 20.50, 2058 Sturge-Webel-syndl-ome,2098 S ~ t b a c ~thyroiditis, ~te 852 S~tbarachnoidhemorrhage as birth initu.): 405 traumatic, 358, 360f, 361, 362 Subclavian artery ii!j~ity to, 279 stenosis of, 21 17, 21 19f S~tbclavianvein, titrombosis of, 2131-2132 Subd~u-alcmpyema, 2009, 2010, 201 lf, 2012 Subdul-al liematoma, 359, 364, 364f ): as birth i n j r ~ ~405 in shaken baby syndrome, 401 St~bglottichem;~ngio~tia, 828, 830, 830f, 904-995, 994f, 21 03 Subglottic space, 984 S~tbglotticsteitosis, 829, 829f, 830, 990-994, 99Of-993f, 991t, 992t posterior cricoid split and rib graft for, 989 secoiid;~~-y to s~ipraglottoplasty,987 tracheototny tot; 984, 991 with laryngeal web, 988 Subinandibular gland. SPPnl,\o Salivary glands. brattchial anomaly associated with, 868 surgei-yof', 841-842 Subperiostcal abscess, 2034f iniracl-anial, 201 0, 201 Of Succitiylcholinc, 230, 23Ot, 231 fol- intubation, in trauma patient, 267 for laryngospasm, anesthesia-related, 223 Sucralfate for gasti-oesophageal reflux, 1126 for peptic nlccr disease, 1230 Slidden incant death syndrome (SSDS) sleepiiig position and, 794, 1125 thyroglossal duct cyst and, 870 Sufentanil, as anesthesia, during extrarorporeal life support, 139 Sugiltra operation, 1663 Suicidc gene therapy, for liepatocellular carcinoma, 510 Sulfaniylon. SPPMafenide acetate (Sulfamylon). Sulfasala~ine for (:I-ohn's disease, 1455, 1456 for ulcerative colitis, 1465 Sr~lindac,gasti-ointestinal polyps and, 1422 S~t~ibui-n, 385 Suitburst appearance, I-adiographic, 654 Superior vena cava. Srrl'ena cava. S~tperiorvena cava syndrome grant~lomatousmediastinitis with, 1028 mediastinal ttunol- with in Hodgkin's disease, 576 in non-Hodgkin's lymphoma, 584 tel-atonia as, 565 Superior vesical fistula, 1842, 1843f, 1846 Supernumerary arteries, of lung, 117 Superoxide, 160, 162, 16'Lt, 167 ~-rccrotizingeiiterocolitis and, 14% reperf~rsioninjury and, 158 Superoxide dismutase, 160 Supraglottitis, 830 S~~praglottoplasty, 98G987, 987f Stiprapobic cystostomy with delayed ~irethroplasty,330 Supraventriculai-tachycardia, in neonate, 148, 151, 152t, 153 Surface area. SPPTotal body surface area (TBSA), of burn. Surface rendering, 63, 64f

Surfactant, pulmonary compositional changes in, 116 high-frequency ventilation and, 125 in acute respiratol-y distress syndrome, 127 in congenital diaphragmatic hernia, 940 lung transplant for abnormalities in, 768 type IS pneumocytes and, 116, 116f, 117,933 Surfactant protein B deficiency 768 Surgery pediatric, history of, 3-10, 3f-5f., Ub, 9f-10f stress response to, 104108, 105f, 107f, 210-211 Surgical assist devices, 49, 49t Sutures, for soft tissue injury 352 Swallowing. SPPalso Dysphagia. acid clearance by, I122 endoscopic evaluation of, 1124 Swan-Ganz catheter. S ~Pulmonary P artery cathete~: Sweat chloride test, 1292, 1293 Swensoii procedure, 1532, 153'Lf, 1538, 1540, 1541f complications of, 1546 redo of, 1545f Swimming pool peritonitis, 1475 Synchl-onized intermittent mandatory ventilation, 124 Syncytiotrophoblasts, 556, 568, 594, 595, 609 Syndactyly, 2073, 2074, 2074f in Poland's syndrome, 907, 2071, 2074 Syndrome of inappropriate ADH secretion (SIADH), 94, 94t Synovial fluid, 2040, 2040t Syno~ialsarcoma, 543, 544t, 545-546 Synovitis pigmented villonodular, MRI of, 654 toxic, 2039, 2040t Syringocele, Cowper's, 1903 Syringomyelia, 1992f Systemic inflammatory response syndrome. SPPSIRS (systemic inflammatory response syndrome).

T lymphocytes, 161, 163, 165, 166. SPPalso Lymphocytes. autoreactive, in islet cell transplantation, 726 burns and, 385 development of, 581, 582f imtnunotherapy and, for neuroblastoma, 485 in Hirschsprung's disease, 1528-1529 in neonate, 167, 170 in systemic inflammatory response syndrome, I69 in ulcerative colitis, 1463, 1466 Wiskott-Aldrich syndrome and, 182 T, toxicosis, 853 TAC (tetracaine, adrenaline, cocaine), 244, 244t Tachyarrhythmias, in neonates, 148, 151, 152t, 153 Tachycardia, as shock indicator, 319 Tacrolimus in transplantation, 693, 693f heart, 760, 761s intestinal, 742-743, 749 islet cell, 724 liver, 689, 689f, 737, 738t, 739 lung, 770, 771, 771t, 775 pancreatic, 721, 722, 722f renal, 707-708 mechanism of action, 707-708, 738t side effects of, 708, 737, 738t, 739 ~ l u m e1, pages 1-1 140; Volume 2, pages 1141-21

lix

Takayasu's arteritis, 21 17, 21 20 Talipes equinovarrls, 20242025, 2024f Tapering entcroplasty, 13713-1377, 1377f TAR (thrombocytopenia-absent radius) syndrome, 1936, 2073 Target sign, of int~rssusception.1YL6, 1326f Taurine, 196, 202, 204, 209 Taurolidine, for systemic inflammatory response syndrome, 173 Taxanes, 424t TBSA (total body surface area), of bum, 383, 384,386, 387, 3871, 388f outcornes and, 383, 397 therapies and, 389, 390, 391, 393, 394, 395 TBW (total body water), in fetus and neonate, 91, 92, 98 Technetium 991n. SPPRatiion~rclidestudies. Technological innovation, 31-32, 32t ethics of, 258-260 surgical fellowship in, 70 Tectal glioma, 676 Teeth, abnormal, in Gardner's syrtdrorne, 1422 Teflon injection, for vesicor~rctcralreflux, 1747, 1766, 1767 with megaureter, 1776, 1780 Tegadernt, for superficial scrond-degree hurns, 390 Telangiectasia, hereditary hcrnorrhagic, 2096, 2101 hepatic lesions in, 497 Telangiectatic osteogcnic sax-coma,652 Teleoperator robots, 49-53, 491, 50f-51f, 52t applications of; 53, 54t, 55, 56t conclusions on, 55, 57 Tclomerase, 414 in ncul-obl;~stoina,474, 483 Telomerasr inhibitors, 426 Telomeres, 4 14 Te~nozoloniidc,423t Temperature rnonito~.ing,234 Temporal bonc branchial anomaly with involveinetit of; 868 fracture of', 816-817, 817s tumors with involvement of', 817 Temporomandibularjoitit,disk o f , tissueengineered, 22 Tendon (s) congenital anomalies involving, 2070-2071, 2070f; 2072f flexion deformities as, 2074-2075 trauma to, 351 in hand, 350, 350f-351f Teniposide, 4241 Tension pneulnotliorax, 280-281, 2Xlf, 283 spontaneous, 1020, 1021 Tensor tympani muscle, 813 Teratoma, 554, 555, 557-567. .SPPa150 Fetus in fetu. anomalies coexisting with, 557, 559, 564, 566 cardiac, 557, 558, 565-566 cervicofacial, 557, 563-,565, 563f-564f cytogenetics of, 557 embryogenesis of', 2080 gastric, 566 grading of, 558 hepatic, 496, 499, 505, 557 histology and pathology of, 557-558, 558f in mixed germ cell tumors, 568 iiitracranial, 557, 558, 563 mediastinal, 557,565,959,961,961f; 962-963 nasopharyngeal, 826 neuroblastoma foci in, 468 ovarian, 557, 558, 566, 593, 594t, 607, 609-612, 610f-61% computed tomography of, 557f

.Ic~-;itoni;t . ((.~IJI/I~II/P//) n~o~~odcl-mnl. ti1 2 ~xognosisot; 558 ~.rtrol)c~.itontal, 557, 558. 5.5Xt; 5(i(i s;tc~-ococcygciil,557, 557f-5(i1 t; 558-,353 tI.c';11I11('I11 of. 821. 85 1~l~cll;lt;l1 sites 01, 5.57, 5571 557, 567, (i'22, 623, (i2:lt, (i'241 tcsticr~l;i~; ~tgi11;11, 5(i(i 583 Tc~.nli~l;~l d c o ~ y ~ ~ i ~ c l e 11 o ;~nsfk~.;isc, ti~lc Trrn1in;ttion of' 1)rcgllanc.v..Sr,r, nlso Frti~\, sclccti\c I-cductionof. d c f c t s n~;~r~;iged I)!; 77, 78t. 81 gci~ctic; ~ s s c s s ~ ~ 01'1issl1c i'~~t ii.o~n.1.5 wit11 ;~l)donlin;~l \\.;illdcfbcts, I l(i1 \\.it11 l)owi~s y ~ ~ d ~ o i12(iO ~ic. Tcssicl- cl;issific;~iio~~, 788. 78Xf. 80:l. 8051 Tcstici~l;~~. ft.~ni~li/;~tio~t, 19141, 191(i-l!417 Tcstict11;11tuinol-s, 622-(i"(i, (i2:lt. (i24f-(i2(5t: of. Sr~r,///soS ~ I - o t u ~tunio~.s n, 1)iologic ~ n ; i ~ . kof; c ~ 556. s (?22-(i'2:4 I)iol)s\ of. 442, (22. (723 ca1cific;itions in, (222, t?L:l crvpto~'cl~itiisni : ~ n d(922, , 1198. 1205 gc~.~ninoni;r ;is, 567 cytogwictics ot. 557 g y ~ i c c o ~ i ~ ;;111d, ~ s t i ;2O(i!)-2070 ~ S ~ I ~ ( ~ I ~ O I14 I I I8 (~, in I'c~i~t~~]c~glnc~~s orchidopcxy ;anti, (i22. 120.5 scininorn;i ;IS. ,554. ,565. (i22 tc~.:ito~i~:t ;is, 557, 567, (i'22, (723. (Y2:lt. (84f vs. splc~iogo~~;~d;il fi15io11.I 1 89 yolk s;ic tuinor as, 567, (i22. (i23,(i23t. V24f Tcstis(cs). SPP/rL\o Sc~.otii~ii. id^-cn;il tissuc ;~tt;ic-lictito, 1 1 8<) appendages of', 1205, 1206 ;it-tcl-ialsi~pplvto, 120X. 1208f 1 l<)(i.11!)7, 119!). 1200, 1204, asccndi~~g, 1205 atrol>hyof alic.1-01-chidopcxv,1 20 1 int~.;it~tc~~.inc, 1 I!) scconti;~~-v to 1icrni;i I cp;rii; 118.5, 118(i, 1187 scconda~-yto WI-icocclc,1207, 1208, 1209 descent of, 1174, 11<)3-1105, 1194f enll)~.yologyof, 191 1-191 3, I9l2f epididynnal fi~sionwith, ;il)norni;~l,1I!)!) ~xrinin acute, 1206 elironic, 1201) i~~tcr~iiittcnt, 1207 I l!)(i, 1 IW, I l!)8, 1 l<)!), 1200, ~~ct~~;ictilc, 1204. 1205 splenic tissue 1i1scdto, l 189 01; 1197, I lWf, 1200, 1207, tetiipei.;~ti~~-c 1208 torsion of, 1205-1 207. I205t; 1206t cryptol-chidis~nwith, 1 198, 1205 ti-allllla to, :$:$I wit11 ing11i11;11 c ~ ~ ~ > t o ~ ~ c lIi I<)X-l1!)9 idis~~i, undcsccndcd. Sr.r (:ryl,to~-cl~idisni. I I$)!) ~111isIii11g. venous drain;igc 01, 1208, 12081' Tc,stostr~.onr.SPP/rho Antii-oge~is. Ixain dcvclopmcnt and. (i24 deficiency ot; 1914t. Il)l(i, 1917, 11419, I921 , I , 1872. 1874 ktal genitalia ; ~ n d 187 1875, 1876 in Iiy~x)sp;~di;\s. fix bur11patient, 3'12 for pe~nilecnl;rrgcn~ent,hcfi)rc>hypospadias I-cp;iir, 1893, 192 I onrian tuniors and, 51).5t, (5O(i,607 tcstici~l;i~. drsccnt and, 1193, 11114, 1194E 1197

'I'etl-acainc, 244, 244t Tetralogy of' Pallot, 153, 1971-1973, 19i2f-1974f T(;F-R. Srr TI-ansfol-minggrowth factor.R (TGF-13). Thal fil~tdoplication,1069, 1133 I-obot-assisted, 53 Tlial-i\slicraft frundoplication, 1127, l l28f Tlialassemia(s), 182 ;icutc chest syndronte in, 10121' cl~olelithiasisin, 1636, 1673 il-on ovcl-load in, 495 sl>lcncctoniyin, I693 Thai-Do1 lie~nifundoplication,11 14 Tlialidomidc as angiogenesis inliibito~;426, 475 esophageal atresia and, 10.54 Thrcoma, 595t, 605, (506 Tl~clarclic nol-nial, 885, 885t, 888 ~ x c ~ n i a t i ~885 re. oval-ian trunors with, 594, 604 'l'lic~.apc~~tic index, 422 T1nc1-modilution,for cardiac output determination, 123 Thrl-1no1-cgl~lation. S ~nko P Hyperthel-mia; Hjptherrnia. ill neonate, 09-100 deficiency ot; 198, 206 Tlnia~riin~, T l ~ i c r s r lwire, i ~ 1596 Tliiopr~rtal,221, 222t, 232-233, 233f in traunta patient, fol- intubation, 267 Tliirti vrntl-iculosto~~~y, endoscopic, 2002 Third-space loss, 226 Tl~o~.acc~~tesis in cliylotlio~.ax,1027 in rmpyem;i, 1018, 1019f Thol.acic ticf01-mitics.SOPn1.w Chest wall, congenital drSo~-milies of. it1 tiifti~scskeletal disorders, 915-918, 917f-9181 Thot.;rcic ciltct. SPPn1.50 <:hyIothot.;rx. anatomy of, 1025, 1025f enibryology of; 2 1:37, 2198f 1ig;rtioit of, 1026, 1027, 2141 thoracoscopic. 980, 1027 physiology of, 1025-102(5, 1025f trauma to, 290 Tliol-acic kidney, 1715-1716, 17171' Tltoracic outlet syntll-onne first I-ib 1'1-actlrl-c\vith, 279 venous tlnro~nhosiswith, 2131-2332 .I'horacic spine. SPPolto Spine. scoliosis of, thoracoscopic treatnient of; 9; '7 spo~idylotlioracicdysplasia of, 917, 918f tr-awns to, 278, 346, 368 Thoracic tralcnla, 275-292 asphyxia in, 276, 291, 291f c1inic;il presentation of, 276, 277-278 coniplications of; 291 damage c o ~ ~ t rin, o l 279 tiiagtiosis and initial resi~scitationin, 268-269, 270f, 276278, 2771 epideniiolo&y of, 275-'Li'(5, 275t, 291-292 imaging of, 278 in birth injury, 4405 in child abuse, 404 operative approach in, 279 olitcomc of; 291-292 pe~teiratilig,291 epidemiology of; 275-276, 2751 initial ~.es~rscitation with, 277 plrul-al space itn. Srr Hen~othor-ax; Pneumothorax. prevention of, 276 Volun~e1, pages 1-1 140; Volume 2, pages 1141-

Thoracic tl-au~na((:on/in7rrd) summary of nranage~nentfix; 278-279, 292 to aorta. SPPAorta, traunia to. io chest wall, 269, 275, 279 to diaplirag~n.SPPl)iaphrag~n,traurna to. to esophagus. Srv Esophagus, traunia to. to heart. Src, Heiirt, tGttuna to; I'cl-icardiurn, tt'illlllla to. to lung, 269, 272, 276, 277, 279, 281-283, 2821'-2831' 01; 278 comprlicd to~riogr;~y)l~y cpideiniology of, 275, 2751 to tlior-;icic dr~ct,290 Tho~rcoscopy,977-980 cornplic;rtio~rs01; 980 Sor-aor-topcxy, 1070 for biopsy).,4.19, 440-442, 4411; 977-980 Sol-csophagcal atrcsia repait; 077, 1061, I Oti'Lf 1iistoi.y o f , 971 indications f i ~ ;977 instl.ii~ne~~t;ttio~~ fi)r, 977, !)781-!47!)f of benign p ~ l r n o r ~ a tilniot.s, ry fiw rcsc.ction, 644 video-;~ssistcd for clll~~~c~lll;l, 10 18, I Owi lacel-ation scc.11 in, 287 [>e~'ica~-dial Tllol-acosto~nytr~ljc..Srv (:hest tulle. Tl~ol-acotoniy chylotl~ol-axscc011t1;iryto, 1026 in 11-aiun;~ xit tic lit enic~-gc~icy for ;tir c~nljol~ts, 282 illdieations ti)r; 277, 277t fol- ;~i~.w;i\ i11j111.y 283 f o ~;to1 . tic i n j u ~y, "10 Sol-llcll1otllol~;lx,281 gut, 285 fol- hc~.l~i;itrd Sol-pencil-;iling i~!jury,291 f o ~pcricarcli;~l . t;in~po~~;~ 286, ( I c 291 , illcision in, 279 Thl-cc-di~nrn~io~ial i111;1ges co~nputcdtomogl-;~pl~ic, :34, :35-36, :$(if for prcopc~.;iti~(~ ~ I ~ I I I I ~ (i7-(i8, I I ~ , (i8f in ilnagca-gt~idcdI-adiatio~~ tllt.i.;~py,420 in ~.ol)otics ~ ~ r g e ~50, . y 51, , 521, 53, 57 (il , 68-70 in training sin~~~l;rtions, i l l virtt~al~.c,;ility, (92, (i:$-(i5, 641, (i(i fix rxcopc~-;iti\~ pl;lnnii~g,67-68, (i8f of conjoined t~vins.2083, 20831. 2085, 2089 ultl.;~sor~nd, 33, :I:H in 1bt;tl intcrvcntio~~, 77 T l ~ r o ~ n h itinnr, n 1841 Tl~r-ornbocytopc~~ia, 182-18:3. Sr~r,nlso Knsabac11-Mel-$-it1 syndt.on~e. aficl- pol-toc~itc~.ostot~~y, l 612 benign liver tilmol-s with, IO5, 406, 497 witli niassivc t t ' i ~ ~ ~ s f i t s279 io~~, dilutio~~al, witli, 780 di~odcnalIjiopsy ill l);rtic~~t in hone nial-r-o\\,i ~ - a n s l ~ l ~xitic~lt, ; i ~ ~ t 782 1435, 1439, in necroti~ingc~~terocolitis, 1440 ill neonatal sepsis, 171 neo~latalisoi~nmiinc,182 platelet tra~isfi~sio~l fiw; 1!)0 ThroniI)ocytopcni;~-ahsm~.;~cli~ts (TAK) syndrorrrc, I!4:l(i. 2073 Tlnrombocyto~~c~~ic purpr~ra,idiop;itIlic (in~trlunc),182-183 accessory sljlccns ;it~d,I (592 s p l c ~ ~ c c t oin, ~ ~ 183, i y I (iW, I ($
lxii

INDEX

Toxic synovitis, 2039, 20401 Toxins. SPPBacteria, toxins of. Toxoplasmosis, 848 tPA. SPPT i s s ~ ~ plasrninogen c activator ([PA). TPN. S ~ ~ T o tparenteral al nutrition (TPN). Trace elements, requirements for, 198-199 in pal-enteral ilutrition, 198-199, 198t, 206 Trachea. Srr nL\o Airway. anatomy of, in infancy, 984 aiiomalies of clefts as, 995-996 congenital diaphragmatic hernia with, 932 imperforate anus with, 1567 compression of, \rascular, 997-998, 1070 by innominate al-tei-y996, YYGf, 997, 998, 1979, 1982, 1982f hemangioma of', 994-995 percutaneous lieedle ventilation of, 828 I-?pail-of, extracorporeal life s ~ ~ p p o i - t following, 142 short, 276 tissue-engineered, 22 trauma to, 276, 277, 282-288 by endotracheal intubation, 129 epidemiology of, 275 tlllllors of fihrosarcoma, 518 papilloma, 831, 989, 990 Tracheal intuhation. SYPEndotracheal intubation. Tracheal occlusion, for fetal diaphragmatic hernia, 84, 85, 117, 259, 939, 944-945 Tracheal rings, 996. 996f, 998 TI-achcal sterlosis. SPPalso 1,alyngotracheal stenosis. congenital, 996-997, 996f-997s Traclieitis bacterial, 831 viral, 830 Tracheobronchial vasc~llarcompression, 997-998, 1070 Trachcobror~chor~~alacia, 829 Traclieocsophageal compression, by vascular anomalies, 1978, 1979-1980, 1982, 1983, 1984 Tracheocsophageal fistula. See nL50 Esophageal atresia. associated anomalies with, 1054-1 056, 10551 callstir etiology of, 1083, 1088 classificatior~ot; 1052-1053, 1053f, 1053t, 1056, 1056t complications after repair of', 1068, 1069-1 070, 1070f motor disorders as, 1111 diagnosis of, 1057-1058, 1058f epidemiology of, 1054 historical background of, 1051-1053 H-type (isolated) associated anomalies with, 1055 definition of, 1053f diagnosis of, 1057, 1058f, 1066 operative repail- of, 1066, 1067f laryngeal cleft with, 995 operative repair of H-type (isolated), 1066, 1067f with distal fistula, 1059-1061, 1059f-1060f, 1062f with upper-pouch fistula, 1066-1067 pathogenesis of, 1053-1054 preoperative treatment of, 1058 recurrent, 1068, 1069, 1070 thoracoscopic repair of, 977 tracheomalacia associated with. 996, 1070

Tracheomalacia, 984, 996, 996f after esophageal atresia repair, 1069-1070, 1070f clinical presentation of, 996, 1070 esophageal atresia with, 1056, 1066 laryngotracheal reconstruction with, 993 pathogenesis of, 1070 vascular compression as cause of', 998, 1070 Tracheotomy (tracheostomy) complications of; 985-986 laryngeal papilloma as, 989 emergent, 267, 828429,984 indications for, 984, 986 hemangioma, 994,995 iiifla~nmatorydisease, 830-831 laryngeal atresia or web, 987 laryngeal papilloma, 990 la~yngealstenosis, 991, 992-993 laryngomalacia, 986, 987 vocal cord immobility, 988,989 technioue of. 984-985.984f-985f Training, surgical. S PSimulation, ~ surgical Transaxillan. mini-thoracotomy, for spontaneous pneumothorax, 1021 Trauscription factors, 413, 413f malignant transformation and, 414, 415,416 TransCyte, 390 Transforming growth factor-p (TGF-P) hereditary hemorrhagic telangiectasia and, 2101 in cystic fibrosis, 12 macrophage function and, 166 receptor for, 414 Transfusion reactions, 188-189 in platelet transfusion, 190 ill sickle cell patient, 181 Transfusion therapy, 187-190. See also Erythrocytes (RBCs), transfusion of:, Platelets, transfirsion of. for anemia, 180 hepatocellular adenoma associated with, 498 iron overload caused by, 495 for bone marrow transplant patient, 782 for gastrointestirial bleeding, 1384 for surgical patient, 2W~-227,2261 for trauma patient, 271, 273 with brain injury, 364 with spleen or liver injury, 299, 300, 302 whole blood in, 187, 188, 226 Transient erythroblastopenia of childhood, 179-1 80 Transplacental medical treatment, 81,82t Transplantation. See also Tissue engineering; specific organ. future prospects for, 696 historical perspective on, 685-693, 685f-691f, 6861 lymphoproliferative disease secondary to, 584-585,712, 739,750-751, 762,774 multivisceral, 745, 746f-747f, 747-748, 751f organ preservation for, 694-695 organ procurement for, 693-694, 694f tissue typing for, 695-696, 69% Transposition of great arteries, 151, 1973-1975, 1974f, l976f-1977f Transtracheal ventilation, 828 Transureteroureterostomy, 327 Transverse tubularized island flap, 1885, 1888f TRAP (twin reversed arterial perfusion) syndrome, 82t, 85 Trastuzumab (Herceptin), 425

.

Volume 1, pages 1-1 140; Volume 2, pages 1141-21

Trauma. .S~P also Amputation; Child abuse; Emergency management; Laceration. abdominal. See Abdominal trauma. anal, 312, 404 aneurysm secondary to. SPPPsettdoaneurysm. birth injury as, 404-405, 405s retinal hemorrhage in, 402 bite-related, 352-353 breast, 89 1 complications of, 266 diaphragmatic. SPPDiaphragm, trauma to. ear, 816-817, 817f epidemiology of, 265, 266f, 274 extracorporeal lifr support for; 141t, 142 genital. Sre Gei~itourinatytrauma. hand, 348-352, 349f-351 f head. SPPBrain injul-y, trauinatic; Skull fi-acttire. historical perspective o n surgery for, 6 lymphatic, ascites secondary to, 14 10 rnusc~~loskeletal. SPPFractul.e(s); Musculoskeletal trauma. nasal, 820-821 operative, stress response to, 104-108, 105f. 107f perineal, 31 2, 31 8, 329, 331 in child abuse, 404 prevention of; 274 rectal, 312, 404 pelvic fracture with, 318 soft tiss~re,348, 350-351, 352 spinal. Sur Spinal cord iiljui-y;Spine, ti-auma to. thoracic. SPPThol-aric trau~na. tri~nodalmoi-tality and inorbidity in, 265-266 urinary ti-act. Srr (;enitourinary ti-autna. vascular. Srr Vascular trauma. Treacher <:ollins syndl-ome, 22, 789, 7 9 0 f 791f, 79 1, 2074 Treitz, ligament of in atypical tnalr-oration, 1350, 1352f normal intestinal fixation and, 1346, 1346f, 1350, 1352f Triamcinolonc, intralesional, for hemaiigioma, 2104 Tricuspid valve, Ebstein's anomaly of, 151 Triglycerides medium-chain, 202, 212-21 3 for chylous ascites, 1410 parenteral, i l l neonate, 108, 204 plasma carnitine and, 208 in ueonatC, parenteral glucose and, 107 Tripod fixation, for pcctus excavatum, 899 Trisorny 21. SPPDown syndrome (trisomy 21 ). Trk-A, in neurohlastoma, 425, 426, 474, 475, 482,483, 486, 487 Trk-B in neuroblasto~na,425, 426, 474, 486 in Wilms' turnor, 459 Trk-C, in neuroblastoma, 426, 474, 486 Trophoblastic tumor, 568 Troponin, cardiac, myocardial contusion and, 285 Trunk, soft tissue sarcoma of; 550 as rhabdomyosarcoma, 534-535 Trypsin, stool, meconium ileus and, 1292-1293 Tube feeding. Sre Enteral nutrition. Tuberculin skin test, 1003, 1009 Tuberculosis bone and joint, 2042, 2044 lymphadenitis in, 832-833, 846-847,846f mediastinitis in, 1028 pulmonary, 1003

Tuberculosis (Continued) bronchiectasis in, 1003, 1013 empyema in, 1018 in HN-infected patient, 1008-1009 Tuberous breast, 2066,2068f Tuberous sclerosis aneurysms in, 2114 liver hamartomas in, 495, 498 renal cysts in, 1709 Tubularized incised plate urethroplasty, 1880, 1883, 1884f-1885f Tubularized island flap, transverse, 1885, 1888f Tufted angioma, 2094, 2098 Tularemia, 848 Tumor. See Cancer; specijc organ or tumor type. Tumor lysis syndrome, in non-Hodgkin's lymphoma, 586,588 Tumor necrosis factor-a (TNF-a) apoptosis and, 414 genetic polynlorphisms of, 169 in cystic fibrosis, 12 in inflammation, 159, 161, 165, 166 in neonate, 167 in sepsis, 170-171 in systemic inflammatory response syndrome, 168-169, 170 therapies directed at, 17'2, 173 in trauma response, 106 monoclonal antibody to for Crohn's disease, 1456 for ulcerative colitis, 1466 necrotizing enterocolitis and, 1432, 1433, 1495 Tumor suppressor genes, 414,415t, 417-418, 425, 446. See also p j 3 gene and p53 protein. colorectal cancer and, 1421 Turcot's syndrome, 519, 1422 Turner's syndrome aneurysms in, 21 14 lymphedema in, 2141 neck webbing in, 2064 renal abnormalities in, 1717 vascular malformations in, gastrointestinal, 2103 Twin reversed arterial perfusion (TRAP) syndrome, 82t, 85 Twinning. See also Conjoined twins. abortive, 1390, 1396 embryogenesis of, 2080 incidence of, 2079 neuroblastoma in, 467 Twin-twin transfusion syndrome, 78, 82t, 85, 2080 Two-hit mechanism, 415, 446 Tympani muscle, tensor, 813 Tympanic membrane, 813, 814 branchial anomaly associated with, 867,868 embryology of, 863, 865f perforation of, 815, 816 temporal bone fracture and, 817 Tympanocentesis, 815 Tympanoplasty, 815 Tympanostomy tube placement, 815, 816 Typhlitis, after bone marrow transplantation, 780, 780f Tyrosine kinase inhibitors, 425, 426 Tyrosine kinases, 413. See also WI' proto-oncogene; Trk entries. in gastrointestinal stromal tumors, 516 in Wilrns' tumor, 459 Tyrosinernia alpha fetoprotein in, 555 hepatoccllular carcinoma and, 502

Ulcer. See also Peptic ulcer disease. cutaneous hemangioma with, 2103 in ulcerative colitis, 1464 venous, 2127, 2133, 2133t intestinal anastomotic in jejunoileal atresia, 1284 necrotizing enterocolitis and, 1443 aphthous, in Crohn's disease, 1453, 1454 Meckel's diverticulum with, 1306, 1307, 1309, 1309f rectal, solitary, 1599 Ulcerative colitis, 1462-1472 clinical manifestations of, 1463-1465, 1464f colorectal carcinoma in, 519, 1459-1460, 1464, 1464f diagnostic evaluation in, 1465, 1465f etiology of, 1463 medical management of, 1465-1466 outcomes in, 1469-1472 pathology of, 1463, 1463f summary of, 1472 surgical management of, 1466-1469, 1468f-1471f, 1482-1483, 14841485 after pouch removal, 1471 complications of, 1470-1471 historical development of, 1462-1463 outcomes of, 1469-1470 site of ileostomy in, 1486, 1487f stapled anastomosis in, 1472 vs. Crohn's disease, 1453, 1455, 1463 Ulnar artery, 348 Ulnar defects, 2073 Ulnar nerve, test of, 349, 349f Ultimobranchial body, 850,863,864f-865f Ultrasonography, 32-34. See also Doppler ultrasound imaging; Prenatal diagnosis. contrast-enhanced, 33-34, 34f for needle biopsy, 438, 440 harmonic, 34,34f intraoperative, for brain tumor resection, 673 intrathoracic, 441 of abdominal mass adrenal hemorrhage appearing as, 630,637 adrenal tumor as, 630 of appendicitis, 1504 of bladder after urinary tract infection, 1743, 1744f, 1744t in voiding dysfunction, 1806, 1807f of gallbladder, 1606 of inguinal hernia, 1175, 1176f, 1181 strangulated, 1182 of intussusception, 1326, 1326f, 13% of kidney after urinary tract infection, 1743, 1743f-1744f, 1744t in hydronephrosis, 1727-1728, 1728f, 1733, 1737 of liver lesions, malignant, 504 of salivary glands, 836, 836f of trauma abdominal. See FAST (focused abdominal sonography for trauma). in birth injury, 405, 405f musculoskeletal, 342 renal, 319, 325 scrotal, 331 thoracic, 278, 291 vascular, 377 three-dimensional, 33, 33f, 77 voiding urosonography, 1730 Volume 1, pages 1-1140; Volume 2, pages 1141-21

Ultrasound surgical technologies, 41 Umbilical arteries catheterization of, 123, 235, 1152 bladder rupture secondary to, 328 in congenital diaphragmatic hernia, 939 thrombosis or embolism secondary to, 2116 vascular injury secondary to, 378, 380 embryology of, 1144f, 1145t, 1159f remnants of, 1145t, 1150 infection of, 1146 single, 1149 Umbilical cord care of, 1145, 1146, 1149 cyst of, 1307f, 1310 embryology of, 1144f, 1145, 1306f giant, 1149 separation of, 1145-1 146 hernia and, 1151 keloid formation secondary to, 1149 Umbilical cord blood sampling of, 78 stem cells in, 431, 779 Umbilical cord hernia, 1151, 1158, 1158t, 1159f, 1160 clinical features of, 1163 reduction of, 1166, 1167 vs. omphalocele, 1160, 1161, 1163 Umbilical hernia, 1145, 1150-1 152, 1150f, 1152f. See also Omphalocele. bladder exstrophy with, 1844 distinguishing features of, 1158 large, reconstruction after repair of, 1153 rectus block for repair of, 245, 245f Umbilical polyp, 1147f, 1307f, 1310 Umbilical ring, 1145, 1149, 1150, 1151 Umbilical sinus, 1146, 1147, 1147f, 1304, 1307f Umbilical vein catheterization of, 1152 embryology of, 1144f, 1145t, 1159f in fetal circulation, 148 remnant of, 1145t, 1150 Umbilicoplasty, 1153, 1154f, 1163, 1166 Umbilicus, 1143-1 154 absent psychological effects of, 1167 reconstruction of, 1153 acquired conditions of, 1149-1 150, 1150t appearance of abnormal, in congenital syndromes, 1149 aesthetics of, 1143, 1153 normal variations in, 1146 at birth, 1145-1 146 congenital abnormalities of, 1143, 1146-1 149, 1147f-1148f, 1307f, 1310-1311, 1311f. Seeako Abdominal wall, defects of. drainage from of feces, 1146, 1147f of urine, 1148, 1149 embryology of, 1143, 1144f, 1145, 1145t granuloma of, 1143, 1 146, 1310 historical perspective on, 1143 infection of, 1146, 1149, 1150 lint in, 1150 piercing of, 1143, 1150 reconstruction of, 1153, 1154f, 1163, 1166 surgical uses of, 1152-1 153, 1484f, 1486. See cclso Umbilical arteries. Unconsciousness. See (;onsciousness. Uncoupling protein 1, 99 Undifferentiated lymphomas, 581, 581f-582f, 582-583 clinical presentation of, 583-584, 584f treatment of, 585-586,587-588,5881 Undiversion, urinary, 1791, 1818

lxiv

INDEX

Unicameral bone cyst fracture secondary to, 651, 651f, 658 locations of, in relation to physis, 652f, 654 treatment of, 658, 659, 665 Uniparental isodisomy, 447 United Kingdom, pediatric surgery in, 6 9 , 8b, 9f-10f Utliversity of Wisconsin (UW) solution, 695 in islet cell transplantation, 726 in liver tratlsplantatiott, 734-735 in lung transplantation, 770 UP]. Srr Ureteropelvic junction (UPJ). Upper airway resistance syndrome, 824 Upper gastrointestitlal contrast series. See also Esophagography. in adhesive bowel obstruction, 1359, 1360f in Crohn's disease, 1455, 1455f in duodenal atresia or stenosis, 1263, 1263f, 1266 in gasiroesophageal reflux, 1124, 1125b in hypertrophic pyloric stenosis, 1217-1218, 1217f in intestinal malrotation, 1350, 1352f, 1385-1 386 in intestinal stenosis, 127'2 in necrotizirtg enterocolitis, 1437 in postoperative intussusception, 1361 Urachus embryology of, 1145, 1145t patent, 1148, 1148f, 1149 in prune-belly syndrome, 1784 remnants of, 1145t, 1148-1149, 1148f resection of, robot-assisted, 53, 54t tumors arising from, 1149, 1149t Ureter(s). See also Megaureter. blind-ending, 1761 calculi in, 1752, 1753. See also Urolithiasis. ectopic, 1758, 1762, 1763, 1764f-1765f as megaureter, 1771 with Gartner's duct cyst, 1950 with incontinence, 1762, 1763, 1767-1768, 1903 peristalsis in in prune-belly syndrome, 1783-1784 with megaureter, 1778, 1779f prune-belly syndrome and, 1781, 1783-1784, 1783f reimplantation of, 1748f, 1766 for megaureter, 1773, 1774f-1775f, 1775, 1778-1 780, 1780f in bladder base reconstruction, 1767 in end-stage renal disease, 1835 in renal transplantation, 705-706, 707 robotic, in ani~nalmodel, 56t trauma to, 320, 326327 grading of, 320, S'Ll t iatrogenic, 326 Ureteral duplication, 1759-1760, 1761-1762, 1761f-1765f, 1763-1765. See also Duplex collecting system. entbryogenesis of, 1758-1 761, 1759f-1760s management of, 1765-1 768 summary of, 1768 terminology fo~;1758 Ureteral polyps, 1724 Ureteral stent after pyeloplast): 1736, 1737 in megaureter repair, 1775, 1778 in renal transplantation, 705, 707 in trauma repail; 322, 324, 326, 327 in urolithiasis treatment, 1751, 1753 Ureteral triplication, 1761 Ureteral valves, 1724 Ureterocalicosto~ny,1719

Ureterocele, 1743, 1744f, 1762-1765, 1763f-1765f embryogenesis of, 1761 management of, 1766-1 767 megaureter associated with, 1771 prolapse of, in girls, 1902, 1949, 1950f summary of, 1768 terminology for, 1758 vesicoureteral reflux and, 1762, 1766 Ureterocystoplasty, 1827-1828, 1828f Ureteroneocystostomy. See Ureter(s), reimplantation of. Ureteropelvic junction (UPJ) anomalies of, 1723-1 724, 1723f-17'24s injury to, 317, 318, 320, 326, 327 Ureteropelvic juuction (UPJ) obstruction, 17'23-1737. See also Hydronephrosis. clinical manifestations of, 1725, 17'261727 crossing vessels in, 1723, 1732-1733, 1734-1735 diagnosis of, 1727-1 733, 1728s-17Y2f prenatal, 1723, 17'25 differential diagnosis of, 1727, 1727t embryogenesis of, 17241725 etiology of, 1723-1 724, 1723f-1724s horseshoe kidney with, 1719 in duplex system, 1761, 1761f, 1762, 1767 in prune-belly syndrome, 1783 incidence of, 1723 management of, 1733-1737, 1734f-1736f multicystic dysplastic kidney with, 1710 natural history of, 1733 summary of, 1737 with urolithiasis, 1753 Ureteroscopy, for stone extraction, 1752, 1753 Ureterosigmoidostomy, colorecial carcinoma associated with, 520, 1837 Ureterostomy, cutaneous, 1792-1793, 1793s for megaureter, 1772-1773 in prune-belly syndrome, 1786, 1788f Ureteroureterostomy, 1766 Ureterovesical junction (UVJ) obstruction, 1724, 1727 Urethra anomalies of, 1819-1820, 1819f-1821f. Sre also Bladder exstrophy; Epispadias; Hypospadias; Rectourethral fistula; Urethral valves. atresia as, 1902 duplication as, 1819, laof-1821f, 1904-1905, 1904f in prune-belly syndrome, 1784, 1785f megalourethra as, 1905, 1905f closure of, surgical, 1831-1832 cysts in region of Cowper's duct, 1819, 1820f female, 1902-1903, 1950-1951, l951f diverticulum of after hypospadias repair, 1894 in girls, 1901 ectopic ureter ending in, 1762 megaureter as, 1771 fistula of after hypospadias repair, 1894, 1894f congenital, 1890f, 1905 mass in, in girls, 1902-1903, 1949, 1949f-1950f obstruction of, 1763. See alto Urethral valves. by ureterocele, 1763, 1766-1767 fetal, 82t, 83 lesions with, 1819-1820, 1819f-1821f' polyps of, 1903, 1903f prolapse of, in girls, 1902, 1949, 1949f replacement of. Srr Continent catheteri~ablechannels. )lume 1, pages 1-1140; Volume 2, pages 1141-21

Urethra ((,'ontinur(l) ster~osisof, in girls, 1902 stricture of, 1901-1902 after hypospadias repair, 1890f; 1894 trauma to, 312, 318, 320, 329-331, 329f, 1901-1902 grading of, 320, 321t, 329, 330 in females, 330-331 Urethral nlobilization, 1882 Urethral plate, preservation of', 1884, 1885, 1885f, 1886, 1895 Urethral valves anterior, male, 1819, I901 posterior, 1811-1812, IXllf, 1819, 1819s-182Of, 1899-1901, 1900f ascites caused by, 1408, 1411 cryptorchidism associated with, 1195 in prune-belly syndrome, 1784, 1785f megaureter associated with, 177 1, 1772 prenatal treatment of; 821, 83, 1899-1900 pyelostorny with, 1793 renal dysplasia with, 1817, 1900, I901 renal transplantation and, 706 ureterostorny with, 1792-1793 valve bladder- cauaetl by, 1818, 1818f vesicostomy with, 1791 voiding cystourcthrography of, 1744, 1745f, 1900f Urethrocutancous fistula, 1894, 1894f Urethrography, retrograde, of trauma, 320, 329, 330, 1902 Urethr-oplasty, iubularized incised plate, 1880, 1883, 1884s-1885f Urethroscopy. of urethral iraurna, in females, 331 Urinalysis after stone treatment, 1751, 1753 in uri~tarytract i n k ction, 1743 Urinary ascites, 14091, 1411 prenatal, 1817 Urinary catheteri~ation.Sre r~lto(:I(: (clean internmittent cathetel-ization). f61-urine culture, 1743 in trauma patient, 27'2 of reservoir. Srr Urinary diversion (s). Urinary diversion ( s ) , 1791-1 80 1. Srr r~ko Bladder attgtr~entationor replace~nent. continent, 1791, 1795-1799, 1796f-1799f for bladdel- cxstrophy, 1847, 1857 for megaureter, 1772-1773 for posterior 111-eihralvalves, 1819 in prune-belly syndrome, 1786, 1788t incontirlent, 1791-1795, 1792t-1793f indications Sol; 1791 irttestinal conduits for, 1484, 179:4-1794 complications associated with, 1799-1801 tumors associated with, 520, 1794, 1800 umbilical exit site o i , 1153 renal transplantation antl, 705-706 summary of, 180I u~ribilicalexit site fox; 1153 t, 1795, Urinary reservoirs, c o n t i ~ ~ e n1791, 1798-17119, 1799f Urinary sphincter, artifici;rl, 1831, 1831f Uri~larytract. Srr (L%\U (knitourinary rr~lrirs. Urinary tract infection, 1741-1748. Srr nl\o Pyelonephr-itib. clinical presentation o f , 1741, 1742-1743 diagnosis ot; 174:4, 17431 cpididyntitis second;cry t o , l'LO(i imaging aiier, 174%1745, 1743-1 7451; 1744t intravesical presstu-c.and, I8 17-1 8 18 megaureter with, 1771 pathogenesis of, 1741, 1742t

Urinal-y tract infection (Continu~d) postoperative, after pyeloplasty, 1737 prevalence of, 1741, 1742t recurrent, 1746-1747 risk factors for, 1741-1742, 1742t treatment of, 1745-1748, 1746f, 1747t ureteral duplication and, 1761, 1762, 1762f, 1763, 1768 ureteropelvic junction obstruction with, 1727 urinary diversion with, 1800 nrolithiasis and, 1750, 1751, 1751f, 1751t, 1752 vesicoureteral reflux and, 1742, 1743, 1744-1745, 1746, 1747, 1766 cutaneous vesicostomy and, 1791-179'2 voiding dysfi~nctionand, 1747, 1813, 1817 vs. appendicitis, 1505 Urinary tract obstruction. Se? oboBladder outlet obstruction; Hydronephrosis; Uxete.;upeluic junctiun (UPJ) obstruction; Urethra, obstruction of; Urethra1 valves. al'ter I-enal transplantation, 707 ascites in, 1409t, 1411 by stone, 1751, 1752 fetal surgery for, 78, 82t, 83 hydl-ocolpos with, 1568 infection and, 1743 inegaureter with, 1771, 1772, 1772f, 1780, 1780f priu~e-bellysyndrome with, 1786, 1787s ureteral duplication with, 1762 ureterocele with, 1763 Urinary tract reconstruction. Sur Bladder augn~entationor replacement; Urinary diversion (s). Urinary tract trauma. See Genitourinary trauma. Urine, osrnolality of, in neonate, 93, 94 Urine cultt~re,1743, 174% Urinoma after renal transplantation, 707 after renal iraurna, 322, 324 afier ureteral trauma, 327 Urodynamic evaluation, 1807, 1808f for surgical planning, 1818 with neuropathic bladder, 1808f, 1809, 1810, 1811, 1817, 1821, 182lf with posterior urethral valves, 1812 Urogenital advancement, total, 1945, 1946s Urogenital sinus anomalies, 19441945, l945f-1946f Urogrnital sinus inobili~ation,total, 1925-1926, 1928f Urography. Srr czho Pyelography. intravenous ( N U ) in i~reieropel~icjunction obstruction, 17'27 with ureteral anomalies, 1763, 1763f, 1764, 1765f magnetic resonance, 1730, 173lf Urokinase. Srr czL\o Thrombolytic (fihrinolytic) therapy. for etnpycnra, 1018 for- throntbosis 21 15, 21 16 ;~rteri;~l, cathete~~related, 381 rrnal vein, 1754 Urolithiasis, 1748, 1750-1753, 1751f, 1751t, 1752t ;ifier inassive enter-ectorny, 1372 horseshoe kitiney with, 1719 in i~lcerativr.colitis, 1465 nt~rliidctcctorcoinputed tornography of, 35 u~-eteropel\ic,jt~~~ction obstruction with, 1726 urinal-y diversions and, 1800, 1801 vita~nin<: excess causittg, 198

Urology, pediatric, robotic surgery in, 53, 54t, 55 Ursodeoxycholic acid, for liver dysfunction in biliary atresia, 16091, 1610 in short-bowel syndrome, 1373 Urticaria, in transfusion reactions, 188-189 Uterus malformations of anorectal malformations with, 1568 duplications, 1943-1944, 1943s-1944s rhahdomyosarcoma of, 534 Utricle, prostatic, 1904 Uveitis, in ulcerative colitis, 1464f, 1465 UVJ (ureterovesical junction) obstruction, 1724, 1727 Uvula rhabdomyosarcoma of, 826 squamous papilloma of, 826 UW solution. See University of Wisconsin (UW\ sulution.

Vaccines, antitumor, 427, 485 VACTERL association crossed renal ectopia in, 1720 esophageal atresia in, 1054, 1055, 10551 genetics of, 1054 laryngeal cleft in, 995 VACTERL-H association, 1055 Vagina agenesis of, 19361941, 1936f, 1938f, 1940s anorectal malformations and, 1568. Srr a130 Cloaca; Rectovestibular fistula. reconstructions for, 1582-1584, 1583s-1585f, 1947-1949, 1948f duplication of, 1943-1944, 1943s-1944f embryology of, 1935-1936 hindgut duplications associated with, 1391, 1396, 1397, 1397s introital masses of, 1949-1951, 1951f obstruction of, congenital, 1902, 1941-1943, 1941f-1942f trauma to, 312, 331, 404 tumors of adenocarcinoma, 1951-1952 hemangioma, 1951 rhabdon~yosarcoma,534, 1902, 1949 teratoma, 566 yolk sac tumor, 566, 567, 1949-1950 ureteral insertion into, 1764f, 1950 urogenital sinus anomalies and, 19441945, 194%-1946f Vaginal switch maneuver, 1582, 1583f Vaginitis, peritonitis associated with, 1475, 1477 Vaginoplasty bowel, 1937, 1939-1941, 1940s for urogenital sinus anomaly, 1944-1945, 1946s Vagotomy for peptic ulcer disease, 1230 for stress ulcers, 1231, 1232 \ragus nerve abnormalities of, esophageal atresia and, 1056 esophageal innervation by, 1108, 1122 injury to, vocal cord paralysis in, 988 reflex apnea and, 998 stimulation of, for epilepsy, 2008 Valve bladder, 1818, 1818f Valves, cardiac bacterial cndocarditis of, 21 15-21 16, 21 16f trauma to, 285, 286, 286f

Volume 1, pages 1-1 140; Volu~ne2, pages 1141-21

Valvl11a1-disorders, cardiac. SPPalso Pulmonary valve, stenosis of. Ebstein's anomaly of tricuspid valve, 151 mitral valve prolapse, pectus excavatum with, 898, 922 prenatal treatment o f , 821, 86 tissue-engineered valves fix, 23-24 with atrioventricular septa1 defect, 153 van der Woude's syndrome, 805, 812 Van Nes rotationplasty, 660, 661f, 2051 Vanillylmandelic acid, urinary neuroblastorna and, 468, 470, 471, 483, 487 pheochromocytoma and, 631,635 Vanishing bile duct syndrome, 739 Varicella-roster virus infection after renal transplant, 71 2 pneumonia in, 1007 Reye's syndrome and, 238 Varices, L387,1653, I653f, 1654-lti55,1657, 1658 after portoenterostotny, I6I 2 biliary atresia with, 1605, 1612, 1613 esophagoscopy of, 1041 polycystic kidney disease with, 1709 predicting blccding frolr~,1655, 16.57 treatment of', 1658-1 659 banding for, 1659, 1663 ligation for, 1043, 1659, 1663, 1665 nonshirnt operations tor, 1662-1653 portosyste~nicshunts fix, 1659, 1660, 1661, 1663-I665 sclerotherapy fix; 104:1, 1045, 1612, 1613, 1659 Varicocele, 1207-1210, 1207f-1209f; 12101 Varicose veins congenital a n o ~ ~ ~ a associated lies with, 2129-2 130 arteriovenous malformation as, 21 12, 2113 avalvulia as. 2 127 Kiippel-Trenaunay syntirorne as, 2 128. 2129 post-thrombotic, 21 30, 21 33, 2 133t Vas deferens abnorn~alitiesof cryptorchidisn~with, 1195 in cystic fibrosis, 1188 absent, in cystic fibrosis, 1300 injtuy to, in hernia repair, 1185-1 186, 1187 Vascular access. See r~ltoAI-tel-ialcatheter; Veno~rscatheter. cannulas for for extracorporeal support, 137, 137t M-number of, 137 fetal, 78 for parenterdl nutrition, 203, 204, 207 for- stem cell harvest, 779 in burn patient, 386 in emergency nlanagernent, 269-271, 271f Vascular anornalic.~.S1.r also Vi~scular rnaIfi)r~riations;Vascular- tumors. classification of', 2094-209.5, 2094t diagnosis of; 2095 Vascular cond~rits,tissue-engineerrd, 24, 24f Vascular endothelial growth factor (VtXF), 419,426 antibody against, tor liver- ttuuors, expel-irncntal, 510 familial lynlphctierna ;~ntl,2141 hemangioma and, 2095, 2 104 nc~iroblastr)rr~a ; u ~ d47.5 , testicula1-gci-1x1cell iuniors and, 556 M'ilms' tutnor and, 448, 458, 460

lxvi

INDEX

Vascular malfornlations. See also Arteriovenous malformation (AVM); Capillary malformation (port-wine stain); Lymphatic malformations; Venous malformations. classification of, 2094-2095, 2094t, 21262127 clinical features of, 2095, 2098-2102, 2098f-2101f complexcombined, 2095,2098,2101-2102, 2101f, 2128-2129,2129f management of, 2107-2108, 2129 diagnosis of, 2095 genetics of, 2095-2096 histopathology of, 2095 intestinal, 1598 management of, 21062108 oral and pharyngeal, 826 radiologic characteristics of, 2103 salival-y gland, 835, 838-839, 839f visceral, 2102-2103 Vascular rings, 1978-1984, 1978t, 1979f-1983f robot-assisted division of, 54t, 55 Vascular surgery, historical perspective on, 4, 5 Vascular trauma, 376381. See also Aorta, trauma to. as birth injury, 405 epidemiology of, 376377, 376t evaluation of, 377-378, 378f extremity, 348, 351, 378-380, 379t fracture-related, 342, 344, 345 in extremities, 378-380, 379t iatrogenic, 377, 378, 378f, 380-381, 21 16 in central nervous system injury, 356, 357,358 direct cerebrovascular, 366 in soft tissues, 351 overview of, 376 truncal, 378 Vascular tumors. Ser also Angiosarcoma; Hemangioendothelioma; Hemangioma; Lymphangiosarcoma. classification of, 2094, 2094t clinical features ot; 2095, 20962098, 2096f-2097f diagnosis of, 2095 hepatic, benign, 495, 496497, 496f pathogenesis of, 2095-2096 radiologic characteristics of, 2103 Vasculitis. Sep Arteritis. Vasoactive intestinal peptide (VIP) i i o n ~neuroblastic tumors, 469, 486 from VIPoma, 1685 Vasodilators, for heart t i l u r e , in neonate, 148, 150t Vasopressin. See (~150Desmopressin (DDAW). for bleeding stress ulcer, 1231 for esophageal varices, 1387 Vasospasin. 21 2 1 in arterial i~?ju~-y, 379, 380-381 in digital ischeinia syndl-oine, 381 VATER association, 153, 1055, 2028, 2073 laryngeal cleft in, 995 VATS. See Video-assisted thoracoscopic surgery (VATS). Veau-Wardill-Kilner palate repair, 809, 809f Vecchietti procedure, 1937, 1939 Vecuroniurn, 23Ot in trauma patient, for intubation, 267 VEGF. Ser \lasculat. endothelial growth factor (VEGF). Vein graft for iatrogenic injury, catheter-related, 380 for lower extre~rlitytraurna, 379 for. upper extremity trauma, 351

Vena cava. See also Superior vena cava syndrome. aneurysm of, 2126 congenital anomalies of, 2124 embryology of, 2124, 2125f thrombosis of, 1753, 1754, 2130 Wilms' tumor in, 2141 Vena caval filter, 2132-2133 Venography (phlebography). See also Magnetic resonance venography (MRV). in subclavian-axillary thrombosis, acute, 2131 of venous anomalies, 2103, 2127, 2129 transjugular hepatic, 1657 Veno-occlusive disease, hepatic, 431-432, 780-781, 1654 Venous aneurysm, 2126, 2129 Venous anomalies, congenital of central veins, 2124-2126, 2125f of peripheral veins. See also Varicose veins; Venous malformations. as aneurysms, 2129 in course and union, 2130 Venous catheter. See also Central venous catheter. digital ischemia caused by, 381 for parenteral nutrition, 194, 203, 204, 207 infection associated with, 209-210 technical complications of, 210 for renal dialysis, 701-702 in burn patient, 386 in emergency trauma management, 269-271, 271f septic thrombophlebitis secondary to, 2132 Venous insufficiency, chronic, 2127, 2130, 2131,2133,2133t Venous malformations, 21262127,2128f aplasia of deep veins as, 2127, 2129 avalvulia as, 2127 clinical features of, 2099-2100,21OOf, 2127 genetics of, 2096 histopathology of, 2095 in complex-combined malformation, 2101, 2lOlf, 2128-2129, 2129f management of, 2107 radiologic characteristics of, 2103, 2127 visceral, 2 102-2103 vs. hemangioma, 2097 Venous thrombosis, 2130-2132. See also Thrombosis. causes of, 187 complications of, 2132-2133, 2133t deep vein. See Deep venous thrombosis

(Dm). dialysis catheter and, 700, 701-702 heparin for, 187 in venous malformation, 2099-2100, 2107 renal, 1753-1754, 1754t, 2130 after transplantation, 707 Venous valves, absence of, 2127 Venoverlous hemofiltration, for acute respiratory distress syndrome, 779 Ventilation. See Emergency management; Mechanical ventilation. Ventilation-perfusion matching, 120-121 Ventilation-perfusion mismatching capnography in, 235 in thoracic trauma, 269 Ventilatory index (VI), in congenital diaphragmatic hernia, 938 Ventricles. Set Choroid plexus tumors; Fourth ventricle; Intraventricular hemorrhage.

Ventricular assist device, as bridge to transplantation, 151 Ventricular septa1 defect, 153, 19661968, 1967f-1968f in tetralogy of Fallot, 1971, 1972, 1972f 1973f omphalocele with, 1163 traumatic, 278, 279, 285, 286 with transposition of great arteries, 1975 Ventricular tachycardia, in neonate, 153 Ventriculoamniotic shunt, for aqueductal stenosis, 82t, 85 Ventriculoatrial shunt, 1998 Ventriculoperitoneal shunt, 1998-2001 inguinal hernia and, 1185, 1187 spontaneous bacterial peritonitis with, 1477 Ventriculostomy for brain injury, 273 third, endoscopic, 2002 Verapamil, contraindicated in neonate, 147, 153 Vertebrae. See Spine. Vertical banded gastroplasty, 1248, 124th Vesical fistula, superior, 1842, 1843f, 1846 Vesicoamniotic shunt, 82t, 83 with posterior urethral valves, 1899 Vesicostomy cutaneous, 1791-1792, 1792f umbilical exit site for, 1153 with posterior urethral valves, 1819 fetoscopic, 83 Vesicoureteral reflux anorectal malformations with, 1567 bladder dysfunction with, 1807, 1817-1818 in myelodysplasia, 1809, 1821f bladder exstrophy with, 1850 causes of, 1747, 1747f, 1747t diagnostic procedures for, 1730 grading of, 1742 horseshoe kidney with, 1718 hydronephrosis and, 1727, 1730, 1733 management of, 1747-174X,1748f-l750f, 1765-1 766 cutaneous vesicostomy in, 1791, 1792 endoscopic injection in, 1748, 1766, 1767, 1776, 1780 robot-assisted, 54t, 55, 561 megaureter with, 1771, 1772, 1772f, 1773, 1775, 1776, 1777f, 1780 multicystic dysplastic kidney with, 1710 posterior urethral valves with, 1811-1812, 1817, 1818, 1901 postoperative, with megaureter repair, 1778, 1780, 1780f prune-belly syndrome with, 1783, 1784, 1786 renal transplantation and, 1834-1835 spontaneous resolution of, 1742, 1765-1766 ureteral anomalies with, 1760, 1761, 1762, 1762f-1763f, 1763, 1765-1766, 1767, 1768 urinary tract infection and, 17%, 1743, 1744-1745, 1746, 1747 voiding cystourethrography of, 1730, 1744, 1745f VESPA (virtual environment for surgical planning and analysis), 68 VEST Endoscopic Surgery Trainer, 68, 69f Vestibular apparatus, 813 temporal bone fracture and, 817 Vestibular fistula, 1566, 1571, 1571f-157'Lf, 1578 anorectoplasty for, 1578 VI (ventilatory index), in congenital diaphragmatic hernia, 938 Video endoscopy, of esophagus, 1038, 1039, 1040, 1043-1044

Volume 1, pages 1-1 140; Volume 2, pages 1141-2146.

Video-assisted thol-acoscopic surgery (VATS) foi- cmpyema, 1018, 1120f for spontancons pneumothorax, 1021 fol-vascular rings, 1984 pcricardi;d laceration seen in, 287 Vinhlastine, 4241 Vinca alkaloids, 424t Vii~cent'scurtsy, 1818 Vincristine. 424t. 428 for hemangio~na.2105 VIP (vasoacti\reintestinal pcptide) fiwn neuroblastic tumors, 469, 486 firom VIPotna, 1685 VIPoina, I685 Viral vectors, for gene transfer, 15-18, 16f, 17t Virilization adrenocortical tu~norswith, 63.5, 636f ovarian tu~iiorswith, 594, 604, 606, 612-613 Vil-tual endoscopy, with 3-D CT, 35-36, 36f Virtual I-raliiy,50-ti0, (2-69, 62f, 64f-66f., 70 Virulence Factors, 158-159 neonatal sepsis and, 170 V i s c e ~ myopathies. ~l 1547, 1547f, 1548-1549 Visceral ncul-opatliies, 1547, 1548 Visihle Hutnan Project, 63, 64t; 70 Visual abnoi-n~alities.Srr rrlso Eye (s). brain tumoi.s with, 67'2, 676 cr;~niosynostosiswith, 705 tacial \;~scularanot11alit.s with capillary ~nalfi)rn~;ltion as, 2098 heinangio~naas. 2103, 2105-2106 pel-iorbi~tlabscess with, 819 Vital capacity 118, 118f Vitaniii~(s) nutritional I-equiretnents for; 198 pai.en teral m~tltivitamitlformulas, 206 supplementation of after bariatl-ic surgery, 1250, 1252 in cholestasis, 212, 212t Vitatilit1 A deficiency of, in congenital diaphragmatic 11~1-nia, 032 in parcntcral nlnltivita~nins.206 requirr~ncntfbi; 198 Vitamin B complex, 198 after bariatl-ic surgery, 1252 Vitamin BIZ,198 deficiency ot', after minary tract recotlstrt~ction,1800, 1837 malabsol-ption of; in short-bowel syndrome, 1372, 1373 Vitamin (:, 198 gastrointestinal polyps and, 1422 Vitamin D, 198 in parentcral nutrition patients, 209 parathyl-oid hortnone and, 857 Vitamin E, 198 fihrocystic breasts and, 891 in pa~-entcralfor~nulas,206 necroti~ingelitel-ocolitis and, 1429, 1433 Vitamin K deficiency of, 186, 198 in biliary atresia, 212, 2121 in newborn, 1384 in parenteral fornmnlas, 206 protein <: and, 187 protein S and, 187 Vitelline (on~phalotnesenteric)duct, 1143, 1144f, 1145, 1145t. 1304, 1305f-1306f patent, 1146, 1147f, 1148, 1304, 1309 remnants of, 1145t. 11461148, 1147f; 1149, 1304, ISOTf, 1310-1311, 13llf intestinal obstruction associated with, 1S09, 1310-1311, ISlOf, 1362

Vitronectin bacterial adherence to, 158 in tissue engineering, 22 Vocal cords cyst adjacent to, 830 endotracheal intubation and, 267 fibrosis of, postoperative, 988 fixation of, 988-989 laryngoscopy of, 973 papilloma of, 989, 990 paralysis of, 988-989 congenital, 829 secondary to lung transplant, 772 trauma to, laryngeal web secondary to, 988 Voiding cystourcthrography after urinary tract infection, 1743-1745, 17441, 1745f, 1746, 1747 before renal transplantation, 701 in bladder dysf~inction,1806-1807, 1807f in myelodysplasia, 1809 in dysfunctional elimination syndrome, 1813, 1814f in urctcropelvic junction obstruction, 1730, 1733 of posterior urethl-a1valves, 1744, 1745f, 1900f of ruptured bladder, 328f of ureteral duplication, 1761, 1762f of ~~reterocele, 1763, 1764f of \resiconreteral reflux, 1730, 1744, 1745f racial difference in, 1730 with multicystic dysplastic kidney, 1710 with urinal-) ascites, 1411 Voiding dysfunction. S ~ nL\o P Bladder dysfunction; Urethral valves. urinary tract infection and, 1747, 1813 Voiding urosonography, 1730 Volnme rendering, 63-64 Volume-assisted pressure support ventilation, 125 Volume-cycled ventilators, 124 Volutrauma, 125 Vol\iulus. ,St< also Intestinal rotation and fixation. cecal, 1350, 1356, 1363, 1364, 1498 colonic, 1363-1 364, 1498, 149% duplication as cause of, 1391, 1392, 1395 gastric, 123G1235, 1234t, 1235f intestinal atrcsia or stenosis and duodenal, 1261, 1262, 1263, 1346 ~cjunoileal,1270, 1271, 1274, 1277, 1278, 1278f, 1283 with meconium ileus, 1275f Meckel's diverticulum with, 1309 meconium ileus causing, 1369 tnesenteric cyst with, 1346-1347, 1366, 1401, 1402, 1404 midgut, 1347-1348, 1347f, 1385-1386 radiographic diagnosis of, 1350, 1351f, 1353f recurrent, 1356 reduction of, 1352, 1355f short-bowel syndrome secondary to, 1369, 136% miscellaneo~rslesions associated with, 1364, 1366 von Hippel-Lindau disease pheochromocytoma in, 632 renal cysts in, 1709-1710 von Langenbeck repair, 808 von Willebrand's disease, 183 trauma patient with, 274 Vulva, rhabdomyosarcoma of, 534 Vulvovaginitis, peritonitis associated with, 1475 Vulvovaginoplasty, Williams, 1937, 1938-1939 Volume 1, pages 1-1140; Volume 2, pages 1141-21

Waardenburg's syr~tiroinc-,1522, 1523 WAGR syndroine, 420-421, 446, 447, 461 M7aldeyer'sring, 822. SPPnlco Adenoid (phal-yngeal tonsil); Tonsils. lymphonla of', 82Ci827 M'andel-ing spleen, l(i92, I692f; 1696, 1698 Warfarin, 187 for- antiphospholipic1 antibody syndrome, 2122 fo1- lymphcderna, 2142 for pul~nonar-ycrnholistn, 21 32, 21 :33 Warthin's tumor, 831) M'arts, pcrianal, sexual abnse and, 1591) Water body contcnt of; 195, I96 in t t u s and neonate, 91, $12, 98 for, 196 nutritional I-rquire~net~t Webs, congenital, skin anti soft tissue, 2064 Weight. S(,r nko Ohcsity. fiil~u-eto thrive and, 21 3 normal growth and, 194 null-itional status and, 1<)4-195 Weight loss, 1<)4-1!).", in (:rohn's discxsc, 1454 WerdnigHoftin;uln di~case,997 M'harton'sjclly, 1145 M'harton's 111-ocedurc.1937, 19.311 Whipple proccdlu-e. Srr Panc.1-caticoduodent~cto~ny (Wliipplc pi-occd~trc). WI1itakc1-test, 1731-1 732, 17Xf Williams syrtdl-oine, 21 17, 2 1 18, 21 19f Williams \~ulvoragii~oplasty, 1037. 1038-1939 Wiltns' tumor, 445-462 ACTH-scc.1-eting,635 anomalies associated witl~,44(i hilatcl-al, 45(&457, 45(if, 460 che~notl~erapy fo~;453-455, 4.531, 4541 clinical presentation of, 448, 448f diagnosis of, 448-449, 449f differential tiiagnouis o f ; 450 epidemiology of', 445-146 future directions fi)r; 4V2 genetics and molecular biology of, 415t, 417, 418, 420-421, 446448, 459-460, 1705 historical pel-spective on, 445 horseshoe kidney with, 457, 45Xf intravascu1a1-extension ot; 448, 452, 453, 45.5-456, 456s lower cxtrcmity edetna and, 2141 late effects of therapy for; 46-462 metastases T~roiii,451-452 hepatic, biopsy of; 442 p53 mutations and, 459 pulmonar): 448-449, 455, 645 thoracoscopy of; 440, 441 f multicystic dysplastic kidney with, 1710, 1711 multilocular cyst with, I71 2t, 1713 open hiopsy of, 442, 452, 453 operative treatment of, 452-453, 452f partial nephrcctomy in, 453, 457, 458 outcomes with, 460-462 pathology of, 449-451, 450f-45 1 f prognostic iactors in, 458-460 radiotherapy for, 455 recurrent, 458 screening for, 449 specialized treaunent of, 452 staging of, 451-452, 453, 455

M'ilso~i'sdisc;isc, livc.1- t~.a~~spl;lntatiori in, 733 M'irid-l,lown I I ; I I I ~ , 2075 M'i~idsock dcli)~-miiy, d1iode11;11,1261, 1266 M'inkclm;inn ~.otatioriplasty(i(i0,66lf Wi~kort-i\lcl~.icli syndr-o~uc,182 Mi)ltf-P;~~.kinso~~-WIii~ sy~idrorne,151 M'o~undhc~;~ling, c o tisol ~ arid. 621) SIV c r l t o 1ncei.atioii; TIAII~LI. Mi)~~ntls. soft tiss~cc.,lii;rti;lgcnictlt o f ; 352

Yellow nail syndt-orne, 2141 Yerncnite deailhlind hypopig~nerltation syndl-oinc, 1.523 Yolk sac, 1143, 11441, 1145 Yolk sac (eridodermal sinus) tuinoi-, 555 alpha tetoprotein and, 595 as coniponciit of teratoma, 557, 558 sacrococcygeal, 559,561, 562 cytogenetics of, 596 extragonadal, 567 rncdiastinal, 962 pineal region, 678 vaginal, 566, 567, 1949-1950 it1 tnixctl germ cell turnol-s, 568 oval-ian, 567, 593, 594t, 607-609 icstic~rlal;567, 622, @3, 623t, 624f

X~~niliinc dcl-i\;~ii\.cs.~iccroti/ingentct.ocolitis anti, 1429 X ; ~ i i t l l o g ~ ~ ; i ~ i ~ i lpycloncphr-itis. o ~ i ~ ; ~ t o ~ ~ ~in kidney 171$1 I~o~.scshoc Xenon-133 sc;uniing, in i~illalationinjury, 395 X ~ I I ~ ~ I ~ ; I I I \ ~ ti$Ni )~;II~~;I~~~II,

Zcnapax. Srr Uaclii.u~nal,( Z c ~ ~ a l ~ a x ) . Zeus System, 49-50, 491, 50f, 51-53, 5% clinical applicaiioiis of, 53, 541, 55 'oncl~~sions on, 55, 57 cxpcriinental ;~pl,lir;~tions of, 55, !?(it Zinc, 198-190, 1981, 206 shol-t-l~owclsyndl-omc ;~tid,2 I ?I Zollingcr-Ellison syr~dromc..1231, 1685 Z-plasty cleft palatc rcl~ait;XOIJ, 8lOf' Zuckcr-kandl, organ o l e ~ r ~ t ) ~ - y oolf ;o ~ 628 y of. 468 ric~~rohlaston~a

Vol~ime1, pages 1-1 140; Volume 2, pages 1141-2146.

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