Diagnosis and Management: Soft Tissue Sarcoma

Diagnosis and Management of Soft Tissue Sarcoma

Diagnosis and Management of Soft Tissue Sarcoma

Murray F Brennan, MD Chairman, Department of Surgery Memorial Sloan–Kettering Cancer Center New York and

Jonathan J Lewis, MD, PhD Chief Medical Officer Antigenics, Inc. New York with contributions from James M Woodruff, MD Attending Pathologist Memorial Sloan–Kettering Cancer Center New York and Ephraim S Caspar, MD Attending Physician Chief, Medical Oncology Memorial Sloan–Kettering Cancer Center New York

Martin Dunitz

© 2002 Martin Dunitz Ltd, a member of the Taylor & Francis group First published in the United Kingdom in 2002 by Martin Dunitz Ltd, The Livery House, 7–9 Pratt Street, London NW1 0AE Tel.: +44 (0) 20 74822202 Fax.: +44 (0) 20 72670159 E-mail: [email protected] Website: http://www.dunitz.co.uk This edition published in the Taylor & Francis e-Library, 2003. All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, electronic, mechanical, photocopying, recording, or otherwise, without the prior permission of the publisher or in accordance with the provisions of the Copyright, Designs and Patents Act 1988 or under the terms of any licence permitting limited copying issued by the Copyright Licensing Agency, 90 Tottenham Court Road, London W1P 0LP. Although every effort has been made to ensure that all owners of copyright material have been acknowledged in this publication, we would be glad to acknowledge in subsequent reprints or editions any omissions brought to our attention. Although every effort has been made to ensure that drug doses and other information are presented accurately in this publication, the ultimate responsibility rests with the prescribing physician. Neither the publishers nor the authors can be held responsible for errors or for any consequences arising from the use of information contained herein. For detailed prescribing information or instructions on the use of any product or procedure discussed herein, please consult the prescribing information or instructional material issued by the manufacturer. A CIP record for this book is available from the British Library. ISBN 0-203-21417-X Master e-book ISBN

ISBN 0-203-27083-5 (Adobe eReader Format) ISBN 1 901865 14 2 (Print Edition) Distributed in the USA by Fulfilment Center Taylor & Francis 7625 Empire Drive Florence, KY 41042, USA Toll Free Tel.: +1 800 634 7064 E-mail: cserve@routledge_ny.com Distributed in Canada by Taylor & Francis 74 Rolark Drive Scarborough, Ontario M1R 4G2, Canada Toll Free Tel.: +1 877 226 2237 E-mail: [email protected] Distributed in the rest of the world by ITPS Limited Cheriton House North Way Andover, Hampshire SP10 5BE, UK Tel.: +44 (0) 1264 332424 E-mail: [email protected] Composition by

Tek-Art

Contents Introduction

vii

Acknowledgements

viii

91

8 Principles of management 141

1 Historical perspectives and evolution of treatment

1

2 Incidence, etiology

7

3 Pathologic classification with James M Woodruff

7 Clinical and pathologic correlates

21

9 Adjuvant management with Ephraim S Casper

153

10 Special sites

185

4 Clinical features, diagnosis and extent of disease evaluation 55

11 Special techniques

209

12 Treatment of recurrence

235

5 Staging

67

13 Future directions

245

6 Prognostic factors

77

Index

251

Introduction Once a rare and unfamiliar disease, of interest to a small group of clinicians and pathologists, soft tissue sarcoma has progressively ‘come of age’. In the USA, the incidence is still relatively low, 7000–8000 cases each year, about half of whom will go on to die of their disease. Sufficient experience has now been accumulated by the appropriate use of prospective databases, to define the important issues in management. Major advances have been made in defining prognostic factors for outcome, such that predictions can be made prior to treatment for

high-risk and low-risk groups. Appropriate low morbidity treatment can then be applied to the low-risk group, whereas high-risk subgroups can be identified for investigational treatment in efforts to minimize local recurrence, metastasis and death. This text draws heavily on the experience at Memorial Sloan-Kettering Cancer Center, based on a prospective database begun by the senior author in 1982 and maintained by the institution with extensive support from many colleagues.

Acknowledgements The authors would like to acknowledge the great contributions made over the years to Data Management, particular Ms Claudia Friedrich, Ms Nicole Miller and Ms Monica Cha. Without their diligence and attention to detail, all of the efforts would have been lost. For supporting, collating and integrating the material in this book, none of this would be possible without Ms Gwen Besson and Ms Victoria Frohnhoefer. Many colleagues have been involved in the management of these patients, particularly Dr John Healey in Orthopedic Oncology, Dr Ephraim Casper in Medical Oncology, Dr Louis Harrison and Dr Kaled Alektiar in Radiation Oncology, Dr David Panicek in Radiology,

Dr James Woodruff, Dr Steven Hajdu and Dr Christina Antonescue in Pathology, Dr Jeffrey Gaynor and Dr Denis Leung in Biostatistics, Dr Michael Burt and Dr Robert Downey in Thoracic Surgical Oncology, and numerous Surgical Fellows with whom the authors have had the privilege to work. Finally, none of the information described herein would have been possible without the quite extraordinary involvement of our patients. They, above all, have taught us more than we can possibly acknowledge. The publishers would like to thank the editors of the journals from which material has been acknowledged for permission to use data and illustrations.

1 Historical perspectives and evolution of treatment

Historical perspectives The term ‘sarcoma’ is derived from the Greek word ‘sarkoma’, meaning a fleshy excrescence. In his writings, Galen (AD 130–200) regarded these fleshy tumors as cancerous and cautioned against surgical intervention.1 With the advent of the light microscope in 1592, a few descriptions were recorded of soft tissue sarcoma, including that of a myxoid liposarcoma by Marcus Severinius (1580–1637)2 and a retroperitoneal liposarcoma by Morgagni (1682–1771).3 The use of thin sections and the achromatic lens, along with other refinements of the microscope, permitted further advances in the recognition of soft tissue sarcoma. In the eighteenth and nineteenth centuries, Bichat (1771–1801), Abernathy (1780–1848) and Laennec (1781–1826) were among those who made important contributions to the morphologic understanding of cancer. As best we know, the term ‘soft cancer’ was introduced by Wardrop (1782–1869), an Edinburgh surgeon who studied in Vienna, but the name in terms of the definition of soft cancer, as differentiated from carcinoma, has been attributed to Charles Bell (1774–1842), a neuroanatomist. Bell’s book, Surgical Observations, was published in 1816.4 Bichat postulated that anatomic structures consisted of parenchymal cells, which he called ‘filaments’, and stroma, which he called

‘fiber’ or ‘tissue’, thus beginning the science of histology. He saw that the stroma was common to many tumors, while the parenchymal cells were specific.5 Abernathy, a pupil of John Hunter, was a prominent surgeon of London who recognized the difference between true neoplasms and nonneoplastic swellings such as cysts, aneurysms, and abscesses. He suggested that tumors be classified by their anatomic structure and offered the first classification of sarcomas.6 Early descriptions to which names have been applied include those of Dupuytren, who in 1832 reported on bladder soft tissue lesions and plantar fibromatosis. Understanding of the nature of soft tissue sarcoma progressed in the nineteenth century through the studies of cellular pathologists, particularly those of Cruveilhier (1791–1874) and Johannes Muller (1801–1858), who described the cellular origin of various soft tumors. He seems to have coined the term ‘desmoid’ in 1838.4 Many of his ideas were reinforced by Rokitansky (1804–1878). Most importantly, Virchow (1821–1902) advanced the significant view that ‘annis cellula et cellulare’, which literally means ‘where a cell arises, there a cell previously existed’. Sarcomas he defined as ‘new formations of the connective tissue … distinguishable from the corresponding fully evolved tissue by their immaturity’, thereby laying the foundation for

2

Diagnosis and Management of Soft Tissue Sarcoma

the histogenetic classification. His further classification according to microscopic features, which separated sarcomas from carcinomas of epithelial origin, was published in 1863, and is similar to what is accepted today.7 His observations and concepts formed some of the most important milestones in the study of soft tissue sarcomas and paved the way for the development of our current understanding and treatment of these neoplasms. At that time sarcomas were considered essentially benign, and ‘local growths’ and ‘carcinoma’ were still reserved for lesions that had potential for metastasis. Samuel Gross (1805–1884) described distinctions between sarcoma and carcinoma in the fourth edition of his book, A System of Surgery, in 1866. When Mallory (1862–1941) introduced his method of staining tissues at the beginning of the twentieth century, the study of soft tissue sarcoma by histopathologic techniques began, and the description and histogenetic classification of sarcomas was advanced by others. At the Mayo Clinic in the 1920s, Broders suggested that the number of dividing cells in a tumor, mitotic index, might reflect its malignant potential, and gave an illustration of its application in fibrosarcomas.8 The histopathologic grading of sarcomas, vital to the study and treatment of these tumors, was thus begun. Stout (1885–1967), in a monograph published in 1932, also elucidated on the nature, morphology and treatment of sarcomas.9 His classification of soft tissue sarcoma included the histogenesis, grade of malignancy, including mitotic activity, and cellular as well as stromal organization. Except for minor modifications, this classification remains in use today. The first comprehensive treatise on soft tissue sarcomas10 was the product of his studies.11 Murray and Stout published their classic tissue culture studies of Schwann cells in

1942.12 With their later studies of synovial tissue and synovial sarcoma, they confirmed the mesenchymal origin of synovial sarcomas, even though these tumors may show epithelial characteristics.13 Classic contributions to the description and histogenetic classifications of sarcoma were made at the Memorial Hospital for Cancer and Allied Diseases, starting with Dr James Ewing (1866–1943) (Figure 1.1). James Ewing was the first Professor of Pathology at Cornell University Medical Center. Having graduated in 1891 with his MD degree, he assumed the position of Chief of Pathology at Memorial Hospital in 1899 at the age of 33. When he published the first edition of his monograph, Neoplastic Diseases, in 1919, his observations

Figure 1.1 Dr James Ewing.

Historical perspectives and evolution of treatment and concepts of tumors laid the foundation for the surgical pathology of neoplasms.14 He completed the book despite trigeminal neuralgia. In 1926 neurosurgery by Dr Harvey Cushing replaced the paroxysms of tic doloureux with a painful anesthesia which disabled him for the rest of his life. In a succession of editions, he gave a clear classification of soft tissue sarcoma and stated that ‘Sarcoma is a malignant tumor composed of cells of the connective tissue type … This definition is based on the morphology of the tumor cells and on their histogenesis.’ He listed benign and malignant counterparts of tumors arising from fibrous tissue, cartilage, bone, myxomatous tissue, fatty tissue, blood and lymphatic vessels, smooth and striated muscle, and vascular endothelium. He also recognized that the accepted scope of sarcomas has been subject to much revision, since there is often much difficulty in determining the origin of cellular tumors. One of his most important contributions was his description of Ewing’s sarcoma, first described in 1920.15 The suggestion that grade was of importance in the outcome of sarcomas was first emphasized in the fourth edition of Neoplastic Diseases, published in 1931.4 William Coley (Figure 1.2) in 1889 had treated the 17-year-old Elizabeth Dashiell at Memorial Hospital for Cancer and Allied Diseases for an extremity sarcoma. Despite his surgical efforts, this young friend of John D Rockefeller Jr died from her disease in June 1890. This had a significant effect on Coley and influenced him to study sarcoma. He continued to study the treatment and outcome of patients of his mentor, William Tillinghast Bull. In the lower east side of Manhattan, Coley found a patient with recurrent sarcoma. After the patient had multiple recurrences resected from his neck, he was then

3

Figure 1.2 Dr William Coley. surprisingly cured by a postoperative erysipelas infection. Based on this, Coley started using Coley’s toxins in 1892 and instituted the advent of immunotherapy in cancer. A great many contributions to pathologic evaluation have come from Memorial SloanKettering Cancer Center, from Ewing to Stout in 1942, who introduced the term ‘hemangiopericytoma’. Moreover, Stout’s classification of liposarcomas in 1944 was a first, as was his description, with Ackerman, of leiomyosarcoma of soft tissue in 1947. He published a comprehensive listing of tumors of soft tissue in an Armed Forces Institute of Pathology fasicle in 1953.10 In 1948, Stewart and Treves at Memorial Hospital (Figures 1.3 and 1.4) described

4

Diagnosis and Management of Soft Tissue Sarcoma

Figure 1.3 Dr Frederick Stewart.

Figure 1.4 Dr Norman Treves.

lymphangiosarcoma, a highly malignant tumor, in post-mastectomy patients with chronic lymphedema of the upper limb.16 Since their original description, lymphangiosarcoma has been found in non-edematous post-mastectomy upper limbs17 and in patients with limbs congenitally lymphadematous or edematous due to filariasis or trauma.18 Stewart, in 1952, reported the first case of alveolar soft part sarcoma. In the 1940s to1960s, the term ‘giant and spindle cell sarcoma’ was often used as a descriptive pathologic diagnosis for many soft tissue sarcomas. Myxoid and histiocytic cellular elements often combined with a varying amount of collagenous tissue in the stroma in these neoplasms. In 1967, Stout and Lattes described the morphology of these tumors and coined the term (malignant) fibrous histiocytoma, which they considered to be embryonal forms of fibroblastic neoplasms. Steven Hajdu, for long the recognized authority on soft tissue sarcoma at Memorial Hospital, collated much of the rich resources into his text Pathology of Soft Tissue Tumors in 1979, and a further version, from his 25 years of experience, in 1985.4 In the evolution of the classification of soft tissue sarcoma, leukemias, lymphomas, and myelomas, which were of mesenchymal origin, were separated from the broad classification of sarcomas in the 1940s, along with bone sarcomas. Malignant peripheral nerve tumors, derived from Schwann cells of neurocrest origin, were included with sarcomas. Often excluded in our present classification are lesions of presumed endothelial (Kaposi’s sarcoma) or mesothelial (mesothelioma) origin. Ewing’s words, ‘Future investigation will doubtless reveal many new and more precise facts regarding the etiology, conditions of incidence, histogenesis, and clinical course which will warrant the recognition of many

Historical perspectives and evolution of treatment sarcomas as specific pathological entities’, continue to hold true.14

Evolution of treatment of soft tissue sarcoma The progress that has been made in soft tissue sarcoma therapy has come about gradually, by early recognition of risk factors and, by trial and error, judiciously combining the available modalities of treatment, including surgery, radiation and chemotherapy. Such combined therapy has improved local tumor control, enabling surgeons to salvage many limbs that previously would have required amputation.19,20 There have been advances in the control as well as the prevention of pulmonary metastases, the most common cause of death from soft tissue sarcoma. Surgical resection of pulmonary metastases started in the middle of the twentieth century, and oncologists have vigorously treated metastatic soft tissue sarcoma with chemotherapeutic agents. Starting in the 1970s, accounts of successful resection of lung metastases from soft tissue sarcoma were recorded in the literature, with prolonged survival of 20–40% of the patients.21 Today, surgical resection of lung metastases in appropriately selected patients has become a treatment of recognized efficacy.22–24 A succession of studies has shown increasing tumor responses to chemotherapy as new drugs became available, including the alkylating agents, methotrexate, actinomycin D, the nitrosoureas, and doxorubicin (adriamycin). The introduction of chemotherapy in an adjuvant setting was a natural development of the 1970s, but was also met with considerable scepticism. Rosenberg et al, at the National Cancer Institute, showed in a prospective randomized trial, using doxorubicin, cyclophosphamide and methotrexate, that

5

patients who received such adjuvant therapy enjoyed a significantly higher local recurrencefree survival rate.25 It still remains unclear as to whether current chemotherapy impacts on disease-specific survival. Ifosfamide is the most active recent drug addition. As much is being learned about the molecular and genetic biology of these tumors, newer treatments will evolve. Several translational studies are currently being conducted which include immunotherapy, gene therapy and the use of small DNA molecules. It is likely that some of these will be included as standard therapies in the future.

References 1. Long ER. History of Pathology. Baltimore: Williams & Wilkins, 1928. 2. Mettler CC. History of Medicine. Philadelphia: Blakiston, 1947. 3. Morgagni JB. The Seats and Causes of Disease Investigated by Anatomy, letter 39, Vol. 2. London: Millen & Cadell, 1769. 4. Hajdu SI. Differential Diagnosis of Soft Tissue and Bone Tumors. Philadelphia: Lea & Febiger, 1986. 5. Bichat X. Anatomic General 1801, Vol. 3, translated by Hayrook. Boston: Richardson and Ford, 1822. 6. Abernathy J. Tumor classification. In: Surgical Observations. London: Longman & O’Rees, 1804. 7. Virchow R. Die Krankhaften, Vol. 3. Berlin: Geschwuelste, 1863:1–15. 8. Broders AC, Hargrave R, Meyerding HW. Pathologic features of soft tissue fibrosarcoma. Surg Gynecol Obstet 1939;69:267. 9. Stout AP. Human Cancer: Etiologic Factors, Precancerous Lesions, Growth, Spread, Symptoms, Diagnosis, Prognosis, Principles of Treatment. Philadelphia: Lea & Febiger, 1932. 10. Stout AP. Tumors of the soft tissues. In: Atlas of Tumor Pathology, section 2, fascicle 5.

6

11. 12.

13.

14. 15. 16.

17.

18.

19.

Diagnosis and Management of Soft Tissue Sarcoma Washington, DC: Armed Forces Institute of Pathology, 1953. Stout AP. Sarcomas of soft parts. J Missouri Med Assoc 1947;44:329. Murray MR, Stout AP. Demonstration and formation of reticulin by schwannian tumor cells in vitro. Am J Pathol 1942;18:585. Murray MR, Stout AP, Pogogeff IA. Synovial sarcoma and synovial tissue cultivated in vitro. Ann Surg 1949;31A:619. Ewing J. Neoplastic Diseases: A Treatise on Tumors. Philadelphia: WB Saunders, 1919. Ewing J. Further report on endothelial myeloma. Proc NY Pathol Soc 1924;24:93–101. Stewart FW, Treves N. Lymphangiosarcoma in postmastectomy lymphedema: a report of six cases of elephantiasis chirurgica. Cancer 1948;1:64–81. Woodward AM, Ivins JC, Soule EM. Lymphangiosarcoma arising in chronic lymphedematous extremities. Cancer 1972;30:562–72. Muller R, Hajdu SI, Brennan MF. Lymphangiosarcoma associated with chronic filarial lymphedema. Cancer 1987;59:179–83. Rosenberg SA, Kent H, Costa J et al. Prospective randomized evaluation of the role

20.

21.

22.

23.

24.

25.

of limb-sparing surgery, radiation therapy and adjuvant chemoimmunotherapy in the treatment of adult soft tissue sarcomas. Surgery 1978;84:62–9. Rosenberg SA, Tepper J, Glatstein E et al. The surgical treatment of soft tissue sarcoma of the extremities. Ann Surg 1982;196:305–15. McCormack PM, Martini A. The changing role of surgery for pulmonary metastases. Ann Thorac Surg 1979;28:139. Gadd MA, Casper ES, Woodruff J et al. Development and treatment of pulmonary metastases in adult patients with extremity soft tissue sarcoma. Ann Surg 1993;218:705. Verazin GT, Warneke JA, Driscoll DL et al. Resection of lung metastases from soft tissue sarcomas: a multivariate analysis. Arch Surg 1992;127:1407. Casson AG, Putnam JB, Natarajan G et al. Five-year survival after pulmonary metastectomy for adult soft tissue sarcoma. Cancer 1992;69:662. Rosenberg SA, Tepper J, Glatstein E et al. Prospective randomized evaluation of adjuvant chemotherapy in adults with soft tissue sarcoma of the extremities. Cancer 1983;52:424–34.

2 Incidence, etiology

Incidence, prevalence by site and type

Figures 2.3 and 2.4. Although sarcoma may develop in any anatomic site, approximately half occur in the extremities (Figure 2.5). Figures 2.6–2.8 depict the regional sites for lower extremity, upper extremity and gastrointestinal/visceral tumors. Approximately two-thirds of the tumors are high grade and one-third low grade (see Chapter 3) (Figure 2.9). Size distribution is shown in Figure 2.10: one-third of all patients have tumors greater than 10 cm. Size distribution in the extremities is shown in Figure 2.11. Only 13% are superficial (Figure 2.12) (see Chapter 3). The histopathologic subtype varies widely, but is dominated by liposarcoma, malignant fibrous histiocytoma (MFH) and leiomyosarcoma (Figure 2.13). Age distributions for these subtypes are illustrated in Chapter 4. There is clearly a variability in age for all histopathologic

In the USA, the incidence of soft tissue sarcoma is approximately 7000–8000 new cases per year. This incidence is comparable to that of tumors of the testis and of the tongue (Figure 2.1). These tumors account for approximately 1% of all adult malignancies and 15% of pediatric malignancies. The data presented here are derived from a prospective database of all patients over the age of 16 who had been admitted and treated in Memorial Sloan-Kettering Cancer Center (MSKCC) with a diagnosis of soft tissue sarcoma, from 1 July 1982 to 31 December 2000. The number of patients admitted each year is illustrated in Figure 2.2. The distribution by sex and site for patients is illustrated in

New cases Deaths

Number (in thousands) 8.1

7.4

6.9

6.9

4.7

4.6 1.7

1.4 0.3 Hodgkin’s disease

Testis

Soft tissue

Tongue

1.2 Small intestine

Figure 2.1 Incidence of soft tissue sarcoma in the USA, 2000. From Greenlee et al.1

8

Diagnosis and Management of Soft Tissue Sarcoma 400

Number of patients 352 337 337 344

350 300

281 242 242

250 206

211 209 214 219 188

200 150

204 205

190 184

205

126

100 50 0 1982

83

84

85

86

87

88

89

90

91

92

93

94

95

96

97

98

99

2000

Year

n=4496

Figure 2.2 The number of sarcoma patients admitted each year to MSKCC, 12/82–12/00.

Male 50%

2270

2226

Trunk 10%

Female 50% n=4496

Figure 2.3 Distribution by sex for total patients admitted, MSKCC, 7/82–12/00.

Retroperitoneal/ intraabdominal 15%

Upper extremity 13% Visceral 18%

Lower extremity 32% Other 12%

Figure 2.4 Distribution by site for total patients admitted, MSKCC, 7/82–12/00.

Incidence, etiology

9

Thigh 42% 844

352

Other lower 18%

Hip 1%

Groin 7%

252

94 119 128

204

Other upper 5% Forearm Lower leg 6% Upper arm 10% 6%

Shoulder/axilla/ scapula 13%

Thigh 60%

n =1993 Knee 8%

Figure 2.5 Extremity distribution of soft tissue sarcoma, MSKCC, 7/82–12/00. subtypes. Fibrosarcoma and synovial sarcoma are more commonly seen in patients less than 40 years of age, while MFH tends to be a tumor of the older age group. Age groups for liposarcoma and leiomyosarcoma are more uniformly distributed. Histopathology also varies by site (see Chapter 3). The majority of extremity lesions are liposarcoma and MFH, and the majority of visceral tumors are gastrointestinal stromal tumors (GIST), either leiomyosarcoma or GANT (gastrointestinal autonomic nerve tumors), or GIST–NOS (not otherwise specified). In the retroperitoneum, liposarcoma dominates, followed by leiomyosarcoma.

Etiology and predisposing factors Soft tissue sarcomas comprise a widely diverse group of neoplasms. They vary in site of origin, occurring in all parts of the body and,

Lower leg 15%

Ankle 2%

Foot 6% Toes 1% n =1400

Figure 2.6 Regional sites: lower extremity, MSKCC, 7/82–12/00. in the main, are thought to share a common mesodermal embryologic origin. However, even that shared commonality varies, and there may be exceptions. For example, tumors derived from nerve and nerve sheath are predominantly neuroectodermal in origin. It is of interest that the incidence of tumors arising

10

Diagnosis and Management of Soft Tissue Sarcoma

Liver 2%

Gastric 34%

Duodenum 7%

Shoulder 23%

Colon 4%

Scapula 5% Other 24%

Small bowel 20%

Axilla 14% Upper arm 22% Rectum 9% n=354

Elbow 7%

Forearm 20%

Figure 2.8 Regional sites for gastrointestinal/visceral tumors, MSKCC, 7/82–12/00.

Wrist 2% Hand 6% Fingers 1%

High 67% 2906 1410

n=593

Figure 2.7 Regional sites: upper extremity, MSKCC, 7/82–12/00.

Low 33% n=4316

Figure 2.9 Distribution of soft tissue sarcoma by grade (all available data), MSKCC, 7/82–12/00.

Incidence, etiology

>5 cm, <=10 cm

11

>10 cm 1290

Superficial 13%

1448

559

3885 1286 Deep 87% <=5 cm

n=4444

n=4024

Figure 2.10 Distribution of soft tissue sarcoma by size (all available data), MSKCC, 7/82–12/00.

Figure 2.12 Distribution of soft tissue sarcoma by depth (all available data), MSKCC, 7/82–12/00.

Liposarcoma 19%

<=5 cm

Other 21%

839 956

682

MFH 18%

149 146

810

619 >5 cm, <=10 cm

GIST 3% MPNT 3%

309

577

Synovial 7% 808

>10 cm n=1878

Figure 2.11 Distribution in the extremities by size, MSKCC, 7/82–12/00.

n=4496

Leiomyosarcoma 18%

479

Fibrosarcoma 11%

Figure 2.13 Distribution of soft tissue sarcoma by histopathologic subtype, MSKCC, 7/82–12/00. MPNT, malignant peripheral nerve tumor.

12

Diagnosis and Management of Soft Tissue Sarcoma

in mesodermal tissues is quite small, even though mesodermal tissues comprise 75% of the body mass. The salient factor in soft tissue sarcoma appears to be behavior, with characteristics relating to patient, tumor and treatment defining outcome, rather than histopathologic subtype. In the etiology of soft tissue sarcoma, predisposing genetic and physical factors have been identified, as well as physical and chemical environmental factors (Table 2.1). In a substantial proportion of sarcomas, alterations in the RB-1 and p53 genes have been found, and data suggest that genetic mutations in pluripotent mesenchymal stem cells give rise to malignant clones that differentiate along pathways that resemble normal histogenesis.2,3 There is a high incidence of germline mutations in patients with hereditary retinoblastoma, and the identification of germline mutations in p53 in the Li–Fraumeni syndrome support the significance of these cell regulatory genes in the pathogenesis of sarcoma.4,5 A follow-up study of members of Li–Fraumeni families with childhood rhabdomyosarcoma found 16 additional cancers, including carcinoma of the breast, soft tissue sarcomas, lung cancer, skin cancer, leukemia, pancreatic cancer and brain tumors.6 Table 2.1 Predisposing factors for development of soft tissue sarcoma. Genetic predisposition Neurofibromatosis Familial polyposis coli Li–Fraumeni syndrome Retinoblastoma Radiation exposure Lymphedema Chemical exposure

An autosomal dominant gene has been identified in 8–9% of children with soft tissue sarcomas.7 Survivors of hereditary retinoblastoma have a 13q chromosomal deletion and a high incidence of germline mutations. They often develop tumors later in life, with a high incidence of sarcomas, particularly osteosarcoma.8

Genetic predisposition A genetic predisposition to soft tissue sarcoma has been associated with neurofibromatosis.9,10 In a 42-year follow-up study of patients with neurofibromatosis, 47% of all malignancies were nervous system tumors,11 and, among these, approximately 46% of all patients with neurofibromatosis developed either a malignant tumor or a benign central nervous system tumor. The prevalence was slightly higher in those with a family history of neurofibromatosis than in sporadic cases, but was common in both. Even if there is no family history, relatives of these patients are also at risk of developing malignant tumors. The development of pheochromocytoma is a complication of neurofibromatosis,12 and approximately 5% of patients with neurofibromatosis develop malignant peripheral nerve sheath tumors.11 The genetic predisposition in familial adenomatous polyposis, 13 or Gardner’s syndrome, is commonly associated with the development of intra-abdominal desmoids,14 tumors that behave like low-grade fibrosarcomas. While the histopathologic classification and distinction between the desmoid tumor and aggressive fibromatosis has been debated, when managed inappropriately, their natural history of slow growth, with accompanying invasion of contiguous structures, increases the risk of mortality and morbidity.

Incidence, etiology

Molecular and gene biology Sarcoma has been a good model system in several laboratory settings and in human disease for increasing the understanding of molecular and gene biology of cancer. Indeed, the first evidence for the existence of oncogenes was obtained from a sarcoma model by Peyton-Rous in 1911.15 In contrast to the biology of carcinoma progression, sarcoma probably did not originate from preexisting benign lesions. It would therefore seem that acquisition of the overt malignant phenotype of mesenchymal precursors could be achieved by the accumulation of human mutations comparable to epithelial-derived carcinoma. Thus, molecules involved in several key regulatory programs, including RB and p53, are strongly associated with sarcoma. The well-understood natural history of sarcoma, together with experimental systems that are workable, have made sarcoma a model that is well suited to the study of tumorgenesis and tumor progression.

13

Cytogenetics Many, and probably most, sarcomas have recurrent chromosomal translocations which are specific for each particular tumor type (Table 2.2). These translocations may also be etiologic. Identification of these translocations has begun to yield insight into the pathogenesis and may be useful for molecular diagnosis.

Chromosomal translocations Chromosomal translocations have come to define many types of sarcoma. Synovial sarcoma Cytogenetic studies of synovial sarcoma have revealed a characteristic chromosomal translocation t(X;18)(p11;q11) in more than 90% of both biphasic and monophasic tumors.16 Cloning of the translocation breakpoints showed that t(X;18) results in the fusion of two novel genes designated SYT (at 18q11) and SSX (at Xp11). It appears that the

Table 2.2 Cytogenetic abnormalities in soft tissue sarcoma: recurrent chromosomal translocations specific for each tumor type. Sarcoma

Cytogenetic finding

Synovial cell sarcoma Liposarcoma (myxoid) Embryonal rhabdomyosarcoma (ERMS) Alveolar rhabdomyosarcoma (ARMS) Malignant fibrous histiocytoma (MFH) Malignant peripheral nerve tumor (MPNT) Extraskeletal myxoid chondrosarcoma Primitive neuroectodermal tumor (PNET) Hemangiopericytoma Uterine leiomyosarcoma

t(X;18)(p11.2;q11.2) t(12;16)(q13–14;p11) Trisomy 2q t(2;13)(q35–37;q14) 1q11, 3p12, 11p11 and 19p13 t(11;22)(q24;q11.2–12) t(9;15;22)(q31;q25;q12.2) t(11;22)(q24;q11.2–12) t(12;19)(q13;q13) t(12:14) and 12q15

14

Diagnosis and Management of Soft Tissue Sarcoma

Xp11 breakpoint involves either of two closely related genes, SSX1 and SSX2, both located in the vicinity of ornithine aminotransferase-like pseudogenes 1 and 2 respectively. Additional related SSX genes, apparently not involved by t(X;18), have been identified in Xp11.17 It has been suggested that in the molecular pathogenesis of synovial sarcoma, the t(X;18) subverts normal transcriptional regulation by direct SYT-mediated transcriptional activation to targets presumably recognized by the Cterminus of SSX and normally inhibited by the latter’s N-terminal transcriptional repressor domain. The genes normally repressed by SSXI and SSX2 and apparently activated by SYT–SSX gene product are not. We have reported16 the type of SYT–SSX fusion, as determined by reverse transcriptase polymerase chain reaction, with relevant clinicopathologic data in 45 patients with synovial sarcoma. The analysis suggests that 64% had an SYT–SSX1 fusion transcript and 36% had an SYT–SSX2 fusion transcript. All of the 12 biphasic synovial sarcomas had an SYT–SSX1 transcript, whereas 17 monophasic synovial sarcomas contained the SYT–SSX1 fusion transcript and 16 had an SYT–SSX2 fusion transcript. This was statistically significant, suggesting a stronger relationship between the histologic type and the presence of SSX1. It appeared in the initial analysis that patients with SYT–SSX1 had worse survival than those with SYT–SSX2. These data, however, await confirmation in a more standardized group, corrected for other prognostic factors for outcome, such as grade and size. The translocation of t(X;18)(p11;q11) has become an accurate diagnostic tool for the characterization of synovial sarcoma when there is doubt about histopathology. This analysis suggests an association with a low risk of early relapse in the SYT–SSX2 cohort,

while the cumulative risk of distant metastasis appears to be similar in both groups. This awaits confirmation. However, as late metastasis is not uncommon in synovial sarcoma, it is interesting to conjecture that the SYT–SSX2 characterization may be associated with a low risk of early metastasis and a high risk of late metastasis. Similar transcription factor fusion genes have been identified in rhabdomyosarcoma. In addition, the EWS–FL11 fusion transcript is thought to be a prognostic factor in Ewing’s sarcoma.18 Desmoplastic small round cell tumor (DSRCT) This recently recognized primitive type of sarcoma is characterized by a translocation t(11;22)(b13;q12). This translocation occurs between the ews gene, s22q12, and the Wilms tumor gene, wt1, 11p13, generating a fusion gene. This codes for trimeric RNA, resulting in an in-frame junction of ews axon 7 to wt1 axon 8 (Figure 2.14). This encodes a putative protein in which the RNA-binding domain of ews is replaced by three C-terminal zinc fingers of the wt1 DNA-binding domain. Wt1 functions as a stage-specific and tissuespecific transcription factor that acts as a

ews

wt1

ews/wt1

Figure 2.14 EWS/WT1 codes for trimeric RNA.

Incidence, etiology tumor suppressor. It is developmentally linked to several mesodermal tissues. This occurs most notably in the kidney but also in the gonads, spleen and mesothelia. This expression may be part of the reason why DSRCT occurs often on mesothelial surfaces. The DNA-binding domain of wt1 consists of four zinc-fingered domains. These interact with the DNA sequence 5´-GCG GGG GCG3´. This may provide insight into a possible mechanism for wt1, because binding of wt1 to this site adjacent to several growth-related genes results in transcription set with suppression. The physiologic in vivo targets of wt1 are unclear. The ews–wt1 transcripts include spliced forms of the zinc-fingered domain of wt1, allowing interaction with the full spectrum of the wt1 target genes. Conversely, some alterations of wt1, including mutation and deletions, turn wt1 into a transcriptional activator. DSRCT thus represents a unique in vivo system in which the effect of constitutive transactivation may provide possible insights into roles for these genes. Myxoid liposarcoma The t(12;16)(q13;p11) translocation occurs in about 75% of myxoid liposarcomas. The breakpoints on chromosome 12 involve the CHOP gene, which has a leucine zipper-type dimerization motif and a putative DNAbinding domain and may be involved in adipocyte differentiation. The normal protein may function in a dominant negative manner by dimerizing and inhibiting other transcription factors. The CHOP gene is rearranged with a gene of chromosome 16 designated TLS. TLS–CHOP seems to function as a transcriptional activator. It is interesting to note that some benign tumors with reported rearrangements of the 12q13,

15

including lipoma, have not shown rearrangement of TLS–CHOP. Thus it would seem that lipomas and myxoid liposarcomas are pathogenetically unrelated.

Radiation therapy The development of soft tissue and bone sarcoma as a result of exposure to radiation has been known since the 1920s.19 The development of sarcoma has been described after radiation therapy treatment of lymphoma,20 head and neck cancer,21 breast cancer22 and benign disease, including endometriosis and thymic enlargement. Most radiation-induced sarcomas are high-grade and are frequently osteosarcoma.23,24 Other histologic subtypes that have been observed include MFH and angiosarcoma.24 Data suggest that both ortho- and megavoltage radiation may be sarcomagenic at dose ranges of 880–7000 cGy.24,25 In a review from MSKCC,23 external radiation therapy had been given to 99% of 160 patients for antecedent diseases of breast and cervical cancer and lymphoma, and 14% received additional treatment with temporary or permanent radioisotope implantation. One patient inadvertently ingested radium. The subsequent tumor that developed was most commonly an osteogenic sarcoma, followed by soft tissue tumors, particularly MFH and angiosarcoma or lymphangiosarcoma (Figure 2.15). Antecedent malignancies for which radiation was delivered are shown in Figure 2.16.

Lymphedema Lymphedema has long been established as a factor in the development of lymphangiosarcoma. The most well-recognized association is with the post-mastectomy, post-irradiated

16

Diagnosis and Management of Soft Tissue Sarcoma MFH 16%

Osteogenic 21%

AS/LA 15%

Spindle cell 10%

Other 14%

Fibrosarcoma 7%

Desmoid 4%

Liposarcoma 6%

Chondrosarcoma 4% Leiomyosarcoma 5%

n=160 AS/LA, angiosarcoma/lymphangiosarcoma

Figure 2.15 Histopathologic type of sarcoma developed following delivery of external radiation therapy. From Brady et al.23

Lymphoma 25%

lymphedematous upper extremities of women described by Stewart and Treves, referred to above26 (Figure 2.17). This is not a radiationinduced sarcoma, because the lymphangiosarcoma develops in sites outside of the irradiated field, in the edematous extremity (Figure 2.18). Lower extremity lymphangiosarcoma has been observed in patients with congenital lymphedema or filariasis complicated by lymphedema27 (Figure 2.19).

Trauma A recent history of trauma is often described, especially by patients with extremity soft tissue sarcomas. Chronic inflammation has been suggested as a risk factor,28 but the interval between the trauma and the onset of the mass is usually short, making a causal relationship unlikely. Agents including shrapnel, bullets and foreign body implants

Breast 26%

Cervix 14%

Other 15%

H & N 5% RB 5%

Urothelial 3% Thyroid 3% Sarcoma 4%

n=160 H & N, head and neck RB, retinoblastoma

Figure 2.16 Antecedent malignancies for which radiation was delivered in patients developing sarcoma. From Brady et al.23

Figure 2.17 Post-mastectomy, post-irradiated lymphedematous upper extremity with lymphangiosarcoma (Stewart Treves Syndrome)

Incidence, etiology

17

Figure 2.19 Lower extremity lymphangiosarcoma has been observed in patients with congenital lymphedema or filariasis complicated by lymphedema.28

Chemical and environmental factors

Figure 2.18 Lymphangiosarcoma develops in sites outside of the irradiated field in the edematous extremity.

have also been implicated in the report. Often, a minor episode of injury draws attention to the presence of a mass, implying a causative association with trauma that is not real. Abdominal desmoid tumors commonly follow parturition.29 They can occur in the extremity and may be associated with antecedent vigorous physical activity. They may be multifocal.30

Reports about occupational exposure to phenoxyacetic acids found in some herbicides and chlorophenols found in some wood preservatives have been contradictory.31–37 The inherent problems in occupational epidemiology in relation to the source material for soft tissue sarcoma have been elucidated: (1) possible recall bias in self-reported exposure data; (2) soft tissue sarcomas are not consistently classified in the International Classification of Diseases (ICD), which is organ based; (3) there is variation in the operational definition of soft tissue sarcomas; and (4) because of their rarity, it is difficult to recruit sufficient patients for a case–control study, and cohorts would have to be extremely large to identify an increase in risk.38,39 Nevertheless, some studies have suggested a link between phenoxyherbicide exposure in forestry workers, farmers and railroad

18

Diagnosis and Management of Soft Tissue Sarcoma

workers and subsequent development of sarcoma,40,41 while other studies from the USA, New Zealand and Finland have not confirmed this relationship.33,35,42 An increased incidence of soft tissue sarcoma was seen in a cohort of 1520 industrial workers exposed for more than 1 year to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD),43 but other studies did not substantiate these findings.44,45 A population-based case–control study assessed the risk of soft tissue sarcoma in Vietnam veterans, including those potentially exposed to Agent Orange, which contains dioxin. No increased risk was found among any subset of veterans compared with control groups.46 Another study found no increased risk for Vietnam veterans compared with men who had never been in Vietnam.47 The risk for subgroups of veterans who were more likely to be exposed to Agent Orange, compared with their counterparts in Vietnam, was not statistically significant. Chemical carcinogens such as thorotrast, vinyl chloride and arsenic (including Fowler’s 1% arsenic solution) have an established role in the development of hepatic angiosarcomas.48–50 Although chemotherapy for pediatric malignancies has been associated with the subsequent development of osteogenic sarcomas,51 a relationship with the development of soft tissue sarcomas has not been demonstrated.

References 1. Greenlee RT, Murray T, Bolden S, Wing PH. Cancer Statistics, 2000. CA Cancer J Clin 2000;50:7–33. 2. Latres E, Drobnjak M, Pollack D et al. Chromosome 17 abnormalities and TP53 mutations in adult soft tissue sarcomas. Am J Pathol 1994;145:345.

3. Cance WG, Brennan MF, Dudas ME et al. Altered expression of the retinoblastomagene product in human sarcomas. N Engl J Med 1990;323:1457–62. 4. Malkin D. The Li-Fraumeni syndrome. In: Rosenberg S, ed. PPO Updates Vol. 7 (7). Philadelphia: JB Lippincott, 1995. 5. Li FP, Fraumeni JF. Soft tissue sarcomas, breast cancer and other neoplasms: a familial syndrome? Ann Intern Med 1969;71:747–52. 6. Li FP, Fraumeni JF. Prospective study of a family cancer syndrome. JAMA 1982;247:2692–4. 7. Williams WR, Strong LC. Genetic epidemiology of soft tissue sarcomas in children. In: Muller HJ and Weber W, eds. Familial Cancer. First International Research Conference. Basel: Karger, 1985:151. 8. Draper GJ, Sanders BM, Kingston JE. Second primary neoplasms in patients with retinoblastoma. Br J Cancer 1986;53:661–71. 9. D’Agostino AN, Soule EH, Miller RH. Sarcomas of the peripheral nerves and somatic soft tissues associated with multiple neurofibromatosis (von Recklinghausen’s disease). Cancer 1963;16:1015–27. 10. Heard G. Malignant disease in von Recklinghausen’s neurofibromatosis. Proc R Soc Med 1963;56:502–3. 11. Sorensen SA, Mulvihill JJ, Nielsen A. Longterm follow-up of von Recklinghausen’s neurofibromatosis. N Engl J Med 1986;314:1010–5. 12. Riccardi VM. von Recklinghausen’s neurofibromatosis. N Engl J Med 1981;305:1617–27. 13. Fraumeni JF, Vogel CI, Easton JM. Sarcomas and multiple polyposis in a kindred: a genetic variety of hereditary polyposis? Arch Intern Med 1968;121:57–61. 14. Posner MC, Shiu MH, Newsome JL et al. The desmoid tumor: not a benign disease. Arch Surg 1989;124:191–96. 15. Peyton-Rous P. A sarcoma of the fowl transmissible by an agent separate from the tumor cell. J Exp Med 1911;13:1397.

Incidence, etiology 16. Kawai A, Woodruff J, Healey JH et al. SYT–SSX gene fusion as a determinant of morphology and prognosis in synovial sarcoma. N Engl J Med 1998;338:153–60. 17. Ladanyi M. The emerging molecular genetics of sarcoma translocations. Diagn Mol Pathol 1995;4:162–73. 18. De Alava E, Kawai A, Healey JH et al. EWS–FL11 fusion transcript structure is an independent determinant of prognosis in Ewing’s sarcoma. J Clin Oncol 1998;16:1248–55. 19. Beck A. Zur frage des rontgensarkoms, zugleich ein beitrag zur pathogenese des sarkoms. Muench Med Wochenschr 1922;69:623–5. 20. Smith J. Postradiation sarcoma of bone in Hodgkin’s disease. Radiology 1987;16:524–32. 21. Coia LR, Fazekas JT, Kramer S. Postirradiation sarcoma of the head and neck: a report of three late sarcomas following therapeutic irradiation for primary malignancies of the paranasal sinus, nasal cavity, and larynx. Cancer 1980;46:1982–5. 22. Hatfield PM, Schulz MD. Postirradiation sarcoma, including five cases after x-ray therapy of breast carcinoma. Radiology 1970;96:593–602. 23. Brady MS, Gaynor JJ, Brennan MF. Radiation associated sarcoma of bone and soft tissue. Arch Surg 1992;127:1379–85. 24. Robinson E, Neugut AI, Wylie P. Clinical aspects of postirradiation sarcomas. J Nat Cancer Inst 1988;80:233–40. 25. Davidson T, Westbury G, Harmer CL. Radiation induced soft tissue sarcoma. Br J Surg 1986;73:308–9. 26. Stewart FW, Treves N. Lymphoangiosarcoma in postmastectomy lymphedema: a report of six cases of elephantiasis chirurgica. Cancer 1948;1:64. 27. Muller R, Hajdu SI, Brennan MF. Lymphangiosarcoma associated with chronic filarial lymphedema. Cancer 1987;59:179–83. 28. Brand KG. Foreign body induced sarcomas. In: Becker FF, ed. Cancer. New York: Plenum, 1975;485–9.

19

29. Pack GT, Ehrlich JE. Neoplasms of the anterior abdominal wall with special consideration of desmoid tumors: experience with 391 cases and collective review of literature. Int Abstracts Surg 1944;79:177–98. 30. Fong Y, Rosen PP, Brennan MF. Multifocal desmoids. Surgery 1993;114:902–6. 31. Hardell L, Sandstrom A. A case–control study: soft tissue sarcoma and exposure to phenoxyacetic acids or chlorophenols. Br J Cancer 1979;39:711–7. 32. Eriksson M, Hardell L, Ber NO et al. Soft tissue sarcomas and exposure to chemical substances: a case referent study. Br J Med 1981;38:27–33. 33. Smith AH, Pearce NE, Fisher DO et al. Soft tissue sarcoma and exposure to phenoxyherbicides and chlorophenols in New Zealand. J Nat Cancer Inst 1984;73:1111–7. 34. Balarajan R, Acheson ED. Soft tissue sarcomas in agriculture and forestry workers. J Epidemiol Community Health 1984;38:113–6. 35. Greenwald P, Kovasznay B, Collins DN et al. Sarcomas of soft tissue after Vietnam service. J Nat Cancer Inst 1984;73:1107–9. 36. Kang HK, Weatherbee L, Breslin P et al. Soft tissue sarcoma and military service in Vietnam: a case comparison group analysis of hospital patients. J Occup Med 1986;28:1215–8. 37. Hoar SK, Blair A, Holmes FF et al. Agricultural herbicide use and risk of lymphoma and soft tissue sarcoma. JAMA 1986;256:1141–7. 38. Kelly SJ, Guidotti TL. Phenoxyacetic acid herbicides and chlorophenols and the etiology of lymphoma and soft tissue neoplasms. Public Health Rev 1990;17:1–37. 39. Lynge E, Storn HH, Jensen OM. The evaluation of trends in soft tissue sarcoma according to diagnostic criteria and consumption of phenoxy herbicides. Cancer 1987;60:1896–901. 40. Hardell L, Eriksson M. The association between soft tissue sarcomas and exposure to phenoxyacetic acids: a new case referent study. Cancer 1988;62:652.

20

Diagnosis and Management of Soft Tissue Sarcoma

41. Wingren G, Fredrikson M, Noorlind BH et al. Soft tissue sarcoma and occupational exposures. Cancer 1990;66:806–11. 42. Riihimake V, Asp S, Hernberg S. Mortality of 2,4-dichlorophenoxyacetic acid and 2,4,5trichlorophenoxyacetic acid herbicide applicators in Finland: first report of an ongoing prospective cohort study. Scand J Work Environ Health 1982;8:37–42. 43. Fingerhut MA, Halperin WE, Marlow DA et al. Cancer mortality in workers exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin. N Engl J Med 1991;324:212–8. 44. Wiklund K, Holm LE. Soft tissue sarcoma risk in Swedish agricultural and forestry workers. J Nat Cancer Inst 1986;76:229–34. 45. Wiklund K, Dich J, Holm LE. Soft tissue sarcoma risk in Swedish licensed pesticide applicators. J Occup Med 1988;30:801–4. 46. Brann EA. The association of selected cancers with service in the US military in Vietnam. II.

47.

48.

49.

50.

51.

Soft tissue and other sarcomas. Arch Intern Med 1990;150:2485–92. Kang HK, Enziger F, Breslin P et al. Soft tissue sarcoma and military service in Vietnam: a case control study. J Nat Cancer Inst 1987;79:693–9. DaSilva HJ, Abbatt JD, DaMotta LC et al. Malignancy and other effects following the administration of thorotrast. Lancet 1965;2:201. Creech JL Jr, Makk L. Liver disease among polyvinyl chloride production workers. Ann NY Acad Sci 1975;246:88–94. Lander JJ, Stanley RJ, Summer HW. Angiosarcoma of the liver associated with Fowler’s solution. Gastroenterology 1975;68:1562. 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.

3 Pathologic classification (with James M Woodruff)

Soft tissue tumors (STT) may be benign or malignant, and a variety of borderline lesions are also recognized. The ratio of benign to malignant tumor is more than 100:1. Malignant STT arising from mesoderm are referred to as ‘sarcomas’. Developments in pathology suggest that some tumors, conventionally considered sarcoma, do not belong under the classical description. The conventional definition, in Webster’s International Dictionary, includes ‘any of various malignant tumors that begin in connective tissue or in tissue developed from the mesoblast’. According to this definition, some tumors treated as sarcomas, particularly by clinicians, such as primitive neuroectodermal tumor (PNET)/Ewing’s sarcoma and most malignant peripheral nerve sheath tumors, technically are not sarcomas. The histopathologic classification is clearly evolving, but because of current usage, the majority of lesions historically considered as sarcoma will continue to be described as such, despite identification of cells of origin other than the mesoblast. The precise pathogenesis of most sarcomas is uncertain. Unlike carcinomas, sarcomas do not demonstrate in situ changes, and nor does it appear that they originate from benign STT. In contrast, PNET/Ewing’s sarcoma and most malignant tumors of the peripheral nerve sheath (MPNST) are neuroectodermal tumors.

MPNST, for example, are thought to arise from Schwann cells, with the origin of a majority of MPNST from neurofibroma being well established. Designations of soft tissue neoplasms reflect their histologic diversity.1 STT are generally categorized according to the normal tissues they mimic.2 (Table 3.1) Several tumors that are considered sarcomas have no recognizable normal tissue counterpart (e.g. alveolar soft part tumor, Ewing’s sarcoma, epithelioid sarcoma). These tumors often have unique clinical features and usually are not graded. Although each malignant STT has distinguishing histologic characteristics, the different types have many common clinical and pathologic features. Malignant STT are characterized by local invasiveness; the pattern of metastasis is usually hematogenous; and lymph node metastases are uncommon, with the exception of selected types usually associated with childhood sarcoma (Table 3.2).3–5 The clinical behavior of most types of sarcoma is determined more by anatomic location, grade and size than by specific histologic pattern.6

Grading of sarcoma After establishing the diagnosis of malignant STT, the most critical piece of information the pathologist can provide to the clinician is

22

Diagnosis and Management of Soft Tissue Sarcoma

Table 3.1 Histologic classification of soft tissue tumors.2 I. Fibrous tumors A. Benign tumors and tumor-like conditions 1. Nodular fasciitis (including intravascular and cranial types) 2. Proliferative fasciitis and myositis 3. Atypical decubital fibroplasia (ischemic fasciitis) 4. Fibroma (dermal, tendon sheath, nuchal) 5. Keloid 6. Elastofibroma 7. Calcifying aponeurotic fibroma 8. Fibrous hamartoma of infancy 9. Fibromatosis colli 10. Infantile digital fibromatosis 11. Myofibromatosis (solitary, multicentric) 12. Hyalin fibromatosis 13. Calcifying fibrous pseudotumor 14. Solitary fibrous tumor B. Fibromatoses and locally aggressive myofibroblastic tumors 1. Superficial fibromatoses (a) Palmar and plantar fibromatosis (b) Penile (Peyronie’s) fibromatosis (c) Knuckle pads 2. Deep fibromatoses (desmoid tumor) (a) Abdominal fibromatosis (abdominal desmoid) (b) Extra-abdominal fibromatosis (extra-abdominal desmoid) (c) Intra-abdominal fibromatosis (intra-abdominal desmoid) (d) Mesenteric fibromatosis (including Gardner’s syndrome) (e) Infantile (desmoid-type) fibromatosis 3. Inflammatory myofibroblastic tumor C. Malignant tumors 1. Fibrosarcoma (a) Adult fibrosarcoma (b) Congenital or infantile fibrosarcoma (c) Malignant solitary fibrous tumor

II. Fibrohistiocytic tumors A. Benign tumors 1. Fibrous histiocytoma (a) Cutaneous fibrous histiocytoma (dermatofibroma) (b) Deep fibrous histiocytoma 2. Juvenile xanthogranuloma 3. Reticulohistiocytoma 4. Xanthoma 5. Angiomatoid fibrous histiocytoma B. Intermediate tumors 1. Atypical fibroxanthoma 2. Dermatofibrosarcoma protuberans (including pigmented form, Bednar tumor) 3. Giant cell fibroblastoma 4. Plexiform fibrohistiocytic tumor C. Malignant tumors 1. Malignant fibrous histiocytoma (MFH) (a) Storiform-pleomorphic MFH (b) Myxoid MFH (c) Giant cell MFH (malignant giant cell tumor of soft parts) (d) Xanthomatous (inflammatory type) MFH III. Lipomatous tumors A. Benign tumors 1. Lipoma (a) Cutaneous lipoma (b) Deep lipoma (i) Intramuscular lipoma (ii) Tendon sheath lipoma (iii) Lumbosacral lipoma (iv) Intraneural and perineural fibrolipoma (c) Multiple lipomas 2. Angiolipoma 3. Spindle cell or pleomorphic lipoma 4. Myolipoma 5. Angiomyolipoma 6. Myelolipoma 7. Chondroid lipoma

왘

Pathologic classification 8. Hibernoma 9. Lipoblastoma or lipoblastomatosis 10. Lipomatosis (a) Diffuse lipomatosis (b) Cervical symmetrical lipomatosis (Madelung’s disease) 11. Atypical lipomatous tumor B. Malignant tumors 1. Liposarcoma (a) Well-differentiated liposarcoma (i) Lipoma-like liposarcoma (ii) Sclerosing liposarcoma (iii) Inflammatory liposarcoma (b) Myxoid liposarcoma (c) Round cell (poorly differentiated myxoid) liposarcoma (d) Pleomorphic liposarcoma (e) Dedifferentiated liposarcoma (f) Liposarcoma with divergent myosarcomatous differentiation IV. Smooth muscle tumors A. Benign tumors 1. Leiomyoma (cutaneous, deep and pleomorphic) 2. Angiomyoma (vascular leiomyoma) 3. Epithelioid leiomyoma 4. Intravenous leiomyomatosis 5. Leiomyomatosis peritonealis disseminata B. Malignant tumors 1. Leiomyosarcoma 2. Epithelioid leiomyosarcoma 3. Gastrointestinal stromal tumor (GIST), including gastrointestinal autonomic nerve tumor V. Skeletal muscle tumors A. Benign tumors 1. Adult rhabdomyoma 2. Genital rhabdomyoma 3. Fetal rhabdomyoma 4. Intermediate (cellular) rhabdomyoma B. Malignant tumors 1. Rhabdomyosarcoma (a) Embryonal rhabdomyosarcoma

23

(b) Botryoid rhabdomyosarcoma (c) Spindle cell rhabdomyosarcoma (d) Alveolar rhabdomyosarcoma (e) Pleomorphic rhabdomyosarcoma 2. Rhabdomyosarcoma with ganglionic differentiation (ectomesenchymoma) VI. Tumors of blood and lymph vessels A. Benign tumors 1. Papillary endothelial hyperplasia 2. Hemangioma (a) Capillary (including juvenile) hemangioma (b) Cavernous hemangioma (c) Venous hemangioma (d) Epithelioid hemangioma (angiolymphoid hyperplasia, histiocytoid hemangioma) (e) Granulation-type hemangioma (pyogenic granuloma) (f) Tufted hemangioma 3. Deep hemangioma (intramuscular, synovial, perineural) 4. Lymphangioma 5. Lymphangiomyoma and lymphangiomyomatosis 6. Angiomatosis 7. Lymphangiomatosis B. Intermediate tumors 1. Hemangioendothelioma (a) Epithelioid hemangioendothelioma (b) Endovascular papillary angioendothelioma (Dabska tumor) (c) Spindle cell hemangioendothelioma C. Malignant tumors 1. Angiosarcoma and lymphangiosarcoma 2. Kaposi’s sarcoma VII. Perivascular tumors A. Benign tumors 1. Glomus tumor 2. Glomangiomyoma 3. Hemangiopericytoma B. Malignant tumors 1. Malignant glomus tumor 2. Malignant hemangiopericytoma

왘

24

Diagnosis and Management of Soft Tissue Sarcoma

VIII. Synovial tumors A. Benign tumors 1. Tenosynovial giant cell tumor (a) Localized tenosynovial giant cell tumor (b) Diffuse tenosynovial giant cell tumor (extra-articular pigmented villonodular synovitis, florid tenosynovitis) B. Malignant tumors 1. Malignant giant cell tumor of tendon sheath IX. Mesothelial tumors A. Benign tumors 1. Solitary fibrous tumor of pleura or peritoneum 2. Multicystic mesothelioma 3. Adenomatoid tumor 4. Well-differentiated papillary mesothelioma B. Malignant tumors 1. Malignant solitary fibrous tumor of pleura or peritoneum 2. Diffuse mesothelioma (a) Epithelial diffuse mesothelioma (b) Fibrous (spindled, sarcomatoid) diffuse mesothelioma (c) Biphasic diffuse mesothelioma X. Neural tumors A. Benign tumors 1. Traumatic neuroma 2. Morton’s neuroma 3. Nerve sheath ganglion 4. Mucosal neuromas 5. Neuromuscular hamartoma 6. Nerve sheath myxoma and neurothekeoma 7. Schwannoma (neurilemoma) (a) Cellular schwannoma (b) Plexiform schwannoma (c) Schwannomatosis 8. Melanocytic schwannoma 9. Neurofibroma (a) Solitary cutaneous neurofibroma

(b) Intraneural solitary neurofibroma (c) Plexiform neurofibroma (d) Diffuse neurofibroma 10. Granular cell tumor 11. Ectopic meningioma 12. Ganglioneuroma 13. Pigmented neuroectodermal tumor of infancy (retinal anlage tumor, melanotic progonoma) B. Malignant tumors 1. Malignant peripheral nerve sheath tumor (MPNST) (malignant schwannoma, neurofibrosarcoma) (a) Malignant triton tumor (MPNST with rhabdomyosarcoma) (b) Glandular MPNST (c) Epithelioid MPNST 2. Malignant melanocytic schwannoma 3. Primitive neuroectodermal tumor (PNET) and extraskeletal Ewing’s sarcoma 4. Malignant granular cell tumor XI. Extraskeletal cartilaginous and osseous tumors A. Benign tumors 1. Panniculitis ossificans and myositis ossificans 2. Fibro-osseous pseudotumor of the digits 3. Fibrodysplasia (myositis ossificans progressiva) 4. Extraskeletal chondroma or osteochondroma 5. Extraskeletal osteoma B. Malignant tumors 1. Extraskeletal chondrosarcoma (a) Well-differentiated chondrosarcoma (b) Myxoid chondrosarcoma (c) Mesenchymal chondrosarcoma 2. Extraskeletal osteosarcoma XII. Pluripotential mesenchymal tumors A. Benign tumors 1. Mesenchymoma

왘

Pathologic classification

25

7. Ossifying and non-ossifying fibromyxoid tumors 8. Palisaded myofibroblastoma of lymph node B. Malignant tumors 1. Synovial sarcoma 2. Alveolar soft part sarcoma 3. Epithelioid sarcoma 4. Malignant extrarenal rhabdoid tumor 5. Clear cell sarcoma (melanoma of soft parts) 6. Desmoplastic small cell tumor

B. Malignant tumors 1. Malignant mesenchymoma XIII. Miscellaneous tumors A. Benign tumors 1. Congenital granular cell tumor 2. Tumoral calcinosis 3. Myxoma (a) Cutaneous myxoma (b) Intramuscular myxoma (c) Juxta-articular myxoma 4. Angiomyxoma 5. Amyloid tumor 6. Parachordoma

XIV. Unclassified tumors

From Enzinger et al.2

Table 3.2 Histologic type and prevalence of lymph node metastasis in soft tissue sarcoma. Weingrada,4 Histopathology

5.1

54/215

25.1

0/162

0

3.3

84/823

10.2

8/316

2.5

12.2 10.6

201/1354 21/524

14.8 4

12/88 9/328

13.6 2.7

0 – – – 6.1 17 5.2

3/476 43/376 – – – 117/851 16/504

0.6 11.4 – – – 13.7 3.2

2/96 – 5/37 1/4 0/11 2/145 3/403

2.1 – 13.5 25.0 0 1.4 0.7

9.7 9.5 – 9.1

3/24 25/110 14/70 567/5257

12.5 22.7 – 10.8

0/13 15/222 2/12 46/1772

0 6.4 16.7 2.6

From a summary of 47 studies. From a summary of 122 studies. c Database includes only extraskeletal osteo- and chondrosarcomas. From Brennan et al.7 b

Fongc,3

No. of nodal % No. of nodal % No. of nodal % metastases/all of all metastases/all of all metastases/all of all sarcoma patients lesions sarcoma patients lesions sarcoma patients lesions

Fibrosarcoma 55/1083 Malignant fibrous histiocytoma 1/30 Embryonal rhabdomyosarcoma 108/888 Leiomyosarcoma 10/94 Neurofibrosarcoma (MPNT) 0/60 Vascular – Angiosarcoma – Lymphangiosarcoma – Osteosarcoma 20/327 Synovial sarcoma 91/535 Liposarcoma 15/288 Alveolar soft part sarcoma 6/62 Other 14/148 Epithelioid – Total 320/3515 a

Mazeronb,5

26

Diagnosis and Management of Soft Tissue Sarcoma

histologic grade. Pathologic features that define grade include cellularity, differentiation, pleomorphism, necrosis and mitotic activity. Criteria for grading have undergone numerous revisions;8,9 various attempts have been made to standardize grading according to fixed criteria.10 Unfortunately, these criteria are neither specific8,9,11 nor standardized. Several scales are used: a four-grade system (Broders’s),12 a three-grade system (low, intermediate, high) as recognized by the American Joint Commission on Cancer (AJCC),13 and a binary system (high versus low) as used at MSKCC. Even when there is agreement about the number of grades to be used, expert pathologists disagree about specific criteria for defining grade.8,11,14,15 The clinical implications are obvious. In adjuvant chemotherapy trials, ‘high grade’ has been defined differently at different centers, making comparison of results between trials, and combining results of multiple trials, potentially hazardous.16 In one trial, the Scandinavian Sarcoma Group adjuvant trial for high-grade extremity sarcoma, tumors of 240 patients who participated were reviewed by a panel of reference pathologists. A fourgrade system was used, and only patients with grade III or IV sarcomas were eligible. On review, 5% of the patients were considered ineligible because their tumors were actually low grade.17,18 There was considerable discordance between the original pathologists and the reference pathologists with regard to whether a lesion was grade III or IV, although eligibility was not influenced. A difference in survival was noted between patients with tumors of these two grades as assigned by the reference pathologists. The adjuvant regimen did not affect survival (see later). Mitotic activity and degree of necrosis are considered by pathologists to be the important pathologic features.19 The European

Organization for Research and Treatment of Cancer (EORTC) Soft Tissue and Bone Sarcoma Group studied the histologic features of tumors from 282 patients who participated in their adjuvant chemotherapy trial, and correlated the pathologic findings with outcome, in order to define a practical grading system.20 Mitotic count (less than 3, 3–20 and more than 20 mitoses/10 consecutive highpower fields), the presence or absence of necrosis and tumor size predicted survival in multivariate analysis. Although mutation of p53, nuclear overexpression of p53, and a high Ki-67 proliferation index are associated with high grade and poor survival,21 these biologic markers have not currently been shown to be independent indicators of prognosis, and cannot yet be used to grade malignant STT.

Differential diagnosis Sarcoma is a malignant growth derived from non-epithelial tissue of mesodermal embryonic origin, such as connective tissue, lymphoid tissue, cartilage and bone. The differential diagnosis of a soft tissue mass includes a variety of benign lesions in addition to sarcoma, as well as primary or metastatic carcinoma, melanoma, and lymphoma. Accurate diagnosis requires an adequate and representative biopsy of the tumor, and the tissue must be well fixed and well stained. Antibodies for immunohistochemical staining are available commercially, and this technique is readily applicable to paraffin-embedded tissues. Useful immunohistochemical markers are the intermediate filaments (e.g. vimentin, keratin), muscle markers (e.g. desmin, muscle common actin, smooth muscle actin and myogenin), epithelial membrane antigen, S-100 protein and leukocyte common antigen, outlined in Table 3.3.

Pathologic classification

27

Table 3.3 Immunohistochemical markers in the differential diagnosis of sarcoma. Vimentin Keratin or S-100 Desmin, Myoglobin/ CD34 CD31 013 HMB45 EMA actin myogenin antigen Carcinoma Leiomyosarcoma Rhabdomyosarcoma MPNST Synovial sarcoma Angiosarcoma PNET/Ewing’s sarcoma Clear cell sarcoma Alveolar soft part sarcoma Epithelioid sarcoma Soft tissue myxoid sarcoma

+/– + + + + + +

+ + +

+

+ + +

+ +

+

+ +/–

+ +

+

+ +

The pathologist should be prepared to process tissue from selected cases for electron microscopy, cytogenetic studies, or molecular analysis, provided that certain diagnoses are considered by the clinician, the diagnostic biopsy is obtained appropriately, and the clinician and pathologist communicate before the biopsy is performed to ensure that the pathologist is alerted to the need for such procedures. Cytogenetic analysis, which is laborintensive and requires short-term culture of the sarcoma cells, reveals clonal chromosome alterations in the majority of sarcomas,22 MPNST typically exhibit abnormalities of many chromosomes that vary from case to case. Fusion genes resulting from chromosomal rearrangements may be detected by reverse transcriptase polymerase chain reaction, a technique which has been quite effective in diagnosing and distinguishing small cell sarcomas. Fluorescent in situ hybridization uses probes to locate specific chromosomal

abnormalities and may become clinically useful, but is unavailable for routine diagnostic use at this time. There may be considerable disagreement among pathologists regarding specific histologic diagnoses in individual cases of a group of rare, diverse, but related tumors. In a study of 424 patients who entered into Eastern Cooperative Oncology Group (ECOG) sarcoma trials, pathologic material was reviewed by a panel of expert pathologists. Ten per cent of cases were rejected as not being sarcoma, and, there was disagreement with respect to the histologic subtype in 14% of the remaining cases.23 Of 216 patients in the Southeastern Cancer Group trial, 6% were determined not to have sarcoma, and in 27% the type of sarcoma was deemed incorrect by the reviewers.24 Similarly, the specific histologic diagnosis was disputed in 20% of patients entered into the Scandinavian Sarcoma Group trial.17 The three most common histopathologic subtypes are malignant fibrous histiocytoma

28

Diagnosis and Management of Soft Tissue Sarcoma

(MFH), liposarcoma, and leiomyosarcoma. The most common extremity sarcomas are liposarcoma, MFH, synovial sarcoma, and leiomyosarcoma, although a variety of other histologic types are seen, dependent on site (Figure 3.1). Some types of sarcoma occur with greater frequency in certain age groups or in specific locations that permit standardized treatment strategies. The distribution of common histologic types among different age groups is shown in Figure 3.2. The most frequent site of metastasis of extremity sarcoma is the lung (Figure 3.3).25 The data are derived from patients with first metastasis treated at

400

Memorial Sloan-Kettering Cancer Center (MSKCC). Clearly, for the extremity, lung is the most common site, and for the visceral primary tumor, liver is the most common site. Most retroperitoneal sarcomas are liposarcomas or leiomyosarcomas. In contrast to extremity sarcomas, local recurrence and intra-abdominal spread dominate the relapse pattern; liver metastases are also seen. The most commonly encountered chest wall tumors are desmoids, liposarcoma, and myogenic sarcomas.26 In the past, gastrointestinal sarcomas were usually classified as leiomyosarcomas or

Number of patients

Fibrosarcoma Leiomyosarcoma Liposarcoma MPNT

300

MFH Synovial

200

100

0 Lower extremity

Upper extremity

Retroperitoneal/ intra-abdominal

Visceral

n=3020

Figure 3.1 Predominant histopathology of soft tissue sarcoma by site, MSKCC, 7/82–12/00. MFH, malignant fibrous histiocytoma; MPNT, malignant peripheral nerve tumor.

Trunk

Pathologic classification Leiomyosarcoma n=808

Fibrosarcoma n=479

250 Number of patients

Number of patients

140 120 100 80 60 40 20

200 150 100 50 0

0

<20 20-29 30-39 40-49 50-59 60-69 70-79 80-89 90-99 Age (years)

<20 20-29 30-39 40-49 50-59 60-69 70-79 80-89 90-99 Age (years) Liposarcoma n= 839

250

Malignant fibrous histiocytoma n=809

200 Number of patients

Number of patients

29

200 150 100 50 0 <20 20-29 30-39 40-49 50-59 60-69 70-79 80-89 90-99 Age (years)

150 100 50 0

<20 20-29 30-39 40-49 50-59 60-69 70-79 80-89 90-99 Age (years)

Figure 3.2 Distribution of common histologic types among different age groups, MSKCC, 7/82–12/00.

80

Lung Liver Both Other

70

Percentage

60 50 40 30 20 10 0 Extremity n=742 n=461

Retoperitoneal n=248

Visceral/ gastrointestinal n=200

Visceral/ genitourinary n=70

Figure 3.3 Common sites of first metastasis by primary site. MSKCC, 7/82–12/00.

Visceral/ gynecologic n=201

30

Diagnosis and Management of Soft Tissue Sarcoma

leiomyoblastomas.27 It is now recognized that not all gastrointestinal sarcomas express markers of myogenic differentiation, and are better classified as gastrointestinal stromal tumors (GIST), or gastrointestinal autonomic nerve tumors (GANT) if they exhibit neural differentiation.28 Evidence suggests that both of these tumors are tumors of the pacemaker cell (interstitial cell of Cajal). The pattern of recurrence is intra-abdominal, including liver metastasis.27 In older patients, leiomyosarcoma is the most common type of genitourinary sarcoma,29 and arises in the bladder, kidney or prostate. In young men, rhabdomyosarcoma arises in paratesticular tissues. Four major types of uterine sarcoma are recognized: (1) leiomyosarcoma; (2) mesodermal mixed tumor (malignant mixed Mullerian tumors), a tumor composed of elements of carcinoma and sarcoma; (3) Mullerian adenosarcoma, a tumor composed of low-grade sarcoma and hyperplastic epithelium; and (4) endometrial stromal sarcoma, which is usually low grade and mainly locally aggressive. Leiomyosarcomas commonly arise from the myometrium, whereas the remaining three uterine sarcomas typically are endometrial in origin. Ewing’s original sarcoma concept has now evolved to a stage where the majority of these tumors are called ‘primitive neuroectodermal tumors (PNET)/extraskeletal Ewing’s sarcoma’.

Clinicopathologic features Tumors of fibrous origin Features of lesions that may be mistaken for sarcoma are summarized below. Benign tumors and tumor-like lesions of fibrous tissue must be distinguished from true fibrosarcoma. Among these lesions are reactive or reparative

processes. Although diverse fibrous proliferations of infancy and childhood resemble lesions in the adult, they are associated with a better prognosis.

Nodular fasciitis Also called pseudosarcomatous fasciitis, this is a benign lesion usually seen in adults aged 20–40, although it has been reported in both older and younger patients.30,31 The typical lesion grows rapidly over several weeks; growth is usually self-limited, and lesions are rarely larger than 5 cm. Tenderness or soreness is a common complaint. The upper extremity is the most common site, especially the volar aspect of the forearm. Nodular fasciitis generally arises in the subcutaneous fascia or the superficial portions of the deep fascia. Histologically, the lesions are nodular, nonencapsulated masses consisting of plump myofibroblasts arranged in short, irregular loose bundles or fascicles. Because of their rapid growth, cellularity, and high mitotic activity, these lesions may be mistaken for fibrosarcoma. Recurrence is uncommon after simple excision.

Keloid This is a benign proliferation of dermal and subcutaneous fibrous tissues, tending to develop in dark-skinned people. There is a congenital predisposition to keloids, although they most commonly arise from vaccination, injection, surgical incision, mosquito bite, scratching and burning. They may appear at all ages, but tend to be found in younger patients between 10 and 25 years old. They are most often found in the back, sternum, neck and ear lobes. In most cases, ablation by irradiation or surgical excision is required. Rapid and excessive recurrence follows both.1

Pathologic classification Fibroma This general term has been applied to a group of benign fibrous lesions, each of which has a specific designation. Fibroma of tendon sheath is a slowly growing dense fibrous nodule that is attached to the tendon sheath, found most frequently in the hands or feet.32 Most are effectively treated by simple excision, although there may be recurrence after local excision.

Elastofibroma This is a rare, slow-growing benign tumor that characteristically arises between the lower portion of the scapula and the chest wall of older persons (Figure 3.4a,b).33,34 The lesion is thought to be reactive, typically occurring in workers who have done repetitive manual tasks for years. Often measuring 5–10 cm in diameter, elastofibromas grow as ill-defined masses and may occur bilaterally. Rarely, there is a familial association. Histologically, the lesions consist of swollen eosinophilic collagen and elastic fibers, and stain intensely for elastins. Complete excision is usually curative,

31

although they may remain stable if untreated.

Retroperitoneal fibrosis This is characterized by proliferation of collagenous fibrous tissue around retroperitoneal and pelvic organs, with obstruction of the ureters, vena cava, and aorta. Some studies suggest the role of autoimmune processes and genetic predisposition in the development of this disease, primarily found in males in the fourth to sixth decades. Therapy is directed to relief of ureteral and vascular obstruction.

Inflammatory myofibroblastic tumor The concept of inflammatory myofibroblastic tumor arose from the initial descriptions of inflammatory pseudotumor, based on the recognition that it resembled a spindle cell sarcoma. The lesions are thought to be an exaggerated response to tissue injury without an obvious cause. The myofibroblast has been identified in a variety of soft tissue lesions, including nodular fasciitis and malignant

(b) (a) Figure 3.4 Elastofibroma is a rare slow-growing benign tumor. (a) H&E stain on light microscopy. (b) Elastin stain on light microscopy.

32

Diagnosis and Management of Soft Tissue Sarcoma

fibrohistiocytoma. It was eventually recognized as the main cell type in the inflammatory pseudotumor; hence the term.35,36

Fibromatoses Superficial fibromatoses are generally small and slow-growing, arising from the fascia or aponeurosis. Palmar fibromatosis is associated with flexion contractures. Dupuytren’s contracture, the most common form, afflicts as many as one in five persons aged 65 and older, occurs more often in men than in women, and tends to be familial. These benign lesions have a tendency to recur after simple excision. Plantar fibromatosis (Ledderhose’s disease) tends to occur in a somewhat younger age group, but may occur with greater frequency in patients with palmar fibromatosis. Penile fibromatosis (Peyronie’s disease), which causes pain and curvature of the penis on erection, is much less common. The fibrous mass in Peyronie’s disease primarily involves fascial structures, the corpus cavernosum, and, rarely, the corpus spongiosum. Peyronie’s disease is more common in men with palmar and plantar fibromatosis than in the general population. Subdermal fibromatosis affects predominantly male infants, although it may occur in children. Histologically composed of a mixture of proliferating fibroblastic adipose, vasoformative and muscle components, it has some resemblance to angiomyolipoma (see below). Fibromatosis colli or torticollis is a rare, congenital abnormality characterized by localized fibrous replacement of the muscle fibers of the sternocleidomastoid muscle, appearing usually during the first 2 weeks after birth.1 In most cases, the tumor gradually enlarges and then regresses in 5–6 months. Because of the fibrous shortening and thickening of the muscle, however, the

torticollis develops in a few months, but may remain undetected for years. Excision of the diseased muscle prior to age 2 or 3 results in most cases in complete restoration of muscle function. The lesions of digital fibromatosis tend to appear in the extensor surfaces of the distal phalanges of the fingers and toes of male infants or very young children. Recurrence is almost certain unless removal is complete, despite digital amputation. Fascial or congenital localized fibromatosis, while similar to fibromatosis colli, is not limited to any particular muscle group but is found most commonly in the arm and thigh, and is usually discovered soon after birth. Grossly, because of its considerable size and location, usually in deep muscle, it has an alarming appearance. Excision of the muscle with a clean surgical margin is the treatment of choice to prevent recurrence. Multifocal fibromatosis is an aggressive and deadly form of fibromatosis. Afflicted babies are usually born with multiple subcutaneous fibrous nodules. Mesenchymal tissues other than fibroblasts are also involved. Gingival fibromatosis is often familial and appears when permanent teeth erupt. Other anomalies such as hypertrichosis and neurofibromatosis have been reported in association with gingival fibromatosis. Surgical excision with clean margins is the best assurance against recurrence. Aponeurotic fibromatosis is an uncommon tumor-like proliferation of fibroconnective tissue cells with foci of calcification and ossification and areas of cartilaginous differentiation. Most commonly, it affects the palms and soles of small children and young adults, and resembles palmar and plantar fibromatoses in older people. There is a tendency for it to recur after limited surgical excision, but it can be controlled by conservative surgery.1

Pathologic classification Those examples in the mesentery are designated mesenteric fibromatosis. This is usually found in people older than 40 years and has no apparent sex predilection. Trauma, vasculitis and abnormal fat metabolism have been implicated in the etiology. There is general agreement that surgery should be limited to either complete removal or relief of mechanical obstruction. There is limited benefit to any palliative ‘debulking’ procedure. Mediastinal fibromatosis is often detected by signs of obstruction of the superior vena cava. It affects people of middle age, and the fibrous tissue is usually found over the aortic arch, trachea, bronchi, and the heart. Treatment focuses on relieving the obstruction of vital structures.

Desmoid tumors (deep-seated fibromatosis) Desmoid tumors provide a constant enigma for surgeons and patients. They are uncommon, slow-growing and considered histologically benign (Figure 3.5). Conversely, they are often locally aggressive, and tend to invade soft tissues, creating significant morbidity by their

Figure 3.5 Desmoid tumors.

33

presence and morbidity from procedures designed to arrest them. The desmoid was originally described as a tumor of the abdominal wall in women who had recently been pregnant, but these rare, slow-growing fibrous tumors may arise at any site in the body. As with sarcomas, site affects management, but it is unclear whether the distinction by site is biologically significant. Although desmoids do not metastasize, for clinical management these tumors are treated as locally invasive low-grade sarcoma. Based on clonal analysis, desmoids are believed to be true tumors, rather than inflammatory processes.37,38 They are classically described in three main anatomic sites: (1) truncal and extremity; (2) intra-abdominal, often associated with familial adenomatis polyposis39,40 and (3) abdominal wall, especially in women during and following pregnancy.41,42 The tumors have a high propensity for recurrent growth, and local recurrence rates have ranged from 24% to 77% in several series.43–48 The intraabdominal variety, often associated with familial adenomatis polyposis, has, if anything, a greater propensity for recurrence.50,51 An analysis of superficial and truncal desmoid tumors has been provided for 105 patients who presented primarily and were prospectively followed for a median time of 48.5 months (7–75 months).50 Of these, 74% were females and 26% males. The age range was 16–79 years, with a median of 35. A majority, 71%, presented with age <40. Anatomic distribution was 50% in the extremity, 23% on the chest wall and back, 20% on the abdominal wall, and 7% in the head and neck region. Twenty of the 21 patients who had abdominal wall tumors were female. In size, 34% were < 5 cm, 42% were 5–10 cm, and 24% were >10 cm. Local recurrence occurred in 24 patients at a median time of 17.8

34

Diagnosis and Management of Soft Tissue Sarcoma

months (4–181 months). Local recurrence was not dependent on site or size or a positive resection margin. Despite having a positive resection margin, only 22% developed local recurrence, compared with 24% of patients who developed a local recurrence in the absence of positive microscopic margins. Radiation has been utilized selectively in patients, but it does not appear to be an independent factor in our analysis of risk of local recurrence.

Fibrosarcoma These lesions are most commonly seen in persons aged 30–55 years, but may occur in patients of any age. The tumors have no characteristic clinical findings. Pathologically, they consist of elongated fibroblast-like cells arranged in a uniform, fasciculated growth pattern. Intersection or interlacing of the fascicles often yields a ‘herringbone’ pattern on light microscopy. Well-differentiated fibrosarcomas are rich in mature collagen.

Fibrohistiocytic tumors These tumors were originally thought to arise from histiocytes that had fibroblastic features, and the term fibrohistiocytic is merely descriptive of their appearance. They are a form of fibroblastic tumor.

Fibrous histiocytoma Usually, these benign tumors present as a solitary, slowly growing nodule, although up to one-third are multiple. Histologically, they consist of fibroblastic and histiocyte-like cells, often arranged in a cartwheel or storiform pattern. When the lesions occur in the skin, they are often called dermatofibromas and sometimes sclerosing hemangiomas. Superficially located lesions are usually cured by

simple excision,51 but deeper lesions should be resected with a wider margin of normal tissue to prevent local recurrence.52

Angiomatoid fibrous histiocytoma These lesions are characterized by a prominent hypervascularity as well as an often prominent lymphoid infiltration. Once considered as malignant, the tumor is now regarded as benign, but potentially locally aggressive.

Xanthoma Xanthoma refers to a collection of lipid-laden histiocytes and is seen in diseases associated with hyperlipidemia. These lesions, presumably reactive, generally occur in cutaneous or subcutaneous locations, but may involve deep soft tissues.

Dermatofibrosarcoma protuberans Considered a low-grade sarcoma,53,54 this lesion may occur anywhere in the body, but more than 50% present on the trunk, 20% in the head and neck, and 30% on the extremities. The tumor typically develops in early or mid-adult life, beginning as a nodular cutaneous mass. The pattern of growth is usually slow and persistent, and as the lesion enlarges over many years it becomes protuberant. Large lesions are often associated with satellite nodules. Dermatofibrosarcoma protuberans is histologically similar to benign fibrous histiocytoma, but grows in a more infiltrative pattern, showing a characteristic subcutaneous tissue spread and even deeper tissues. The central portion of the tumor consists of a uniform population of plump fibroblasts arranged in a typically disordered pattern. Unlike fibrous histiocytoma, the lesion usually stains positively for CD34.

Pathologic classification More than 75% have a ring chromosome, probably of chromosome 17 origin, superimposed on a normal karyotype.55 Up to 50% recur after simple excision.54,56 Occasional cases of dermatofibrosarcoma protuberans undergo transformation to classic fibrosarcoma. Metastases occur rarely to lung or to lymph nodes56 and usually come from dermatofibrosarcomas showing fibrosarcomatous differentiation. Because of their locally aggressive nature and extensive invasion, these lesions may ultimately lead to amputation or even death. The Bednar tumor, a variant with melanin pigmentation, is also recognized.57

Malignant fibrous histiocytoma In 1963, this term was used to describe a group of malignant STT with a fibrohistiocytic appearance,58 which have since become the most commonly diagnosed extremity sarcoma. A number of subtypes have been described including myxoid, giant cell, inflammatory, and pleomorphic. Because some subtypes of MFH, especially pleomorphic MFH, may be simulated by other sarcomas, including leiomyosarcoma, appropriate immunoreactions to rule out other sarcomatous tumors should be performed before accepting a diagnosis of MFH. Characteristically, MFH is a tumor of later adult life, with a peak incidence in the seventh decade, although it may occur in younger adults. MFH usually presents as a painless mass; the most common site is the lower extremity, followed by the upper extremity.

Tumors of adipose tissue Lipomas Lipomas are the most common benign tumors, arising in any location where fat is normally

35

present. They may be deep-seated in the mediastinum or retroperitoneum, where they may attain massive size. Multiple lipomas are occasionally seen in a familial pattern. Lipomatosis is a term applied to a poorly circumscribed overgrowth of mature adipose tissue that grows in an infiltrating pattern. Lipomas are composed of mature fat cells and are demarcated from surrounding fat by a thin fibrous lining. These tumors are usually found within subcutaneous fat. In spindle cell lipoma, mature fat is replaced by collagenforming spindle lipoma cells. This lesion typically arises in the posterior neck and shoulder in men between the ages of 45 and 65. Pleomorphic lipoma is a closely related lesion. Local excision of lipoma and these variants is generally curative. Lipomas with the presence of markedly atypical nuclei not otherwise classifiable as pleomorphic lipoma are designated ‘atypical lipomatous tumors’. When found in the groin, pelvis, retroperitoneum, or thorax, atypical lipomatous tumors are regarded as welldifferentiated liposarcomas.

Angiolipomas Angiolipomas present as subcutaneous nodules, usually in young adults, most commonly in the upper extremity. The tumors rarely reach more than 2 cm in size, but they are often painful, especially during their initial growth period. Microscopically, angiolipomas consist of adipocytes with interspersed vascular structures. Myxoid and fibroblastic angiolipomas are recognized.

Angiomyolipoma This term is used for a non-metastasizing renal tumor that is composed of fat, smooth muscle, and blood vessels. The tumor is typically

36

Diagnosis and Management of Soft Tissue Sarcoma

immunoreactive to muscle actins and HMB45. More common in women than in men, angiomyolipoma is seen in association with tuberous sclerosis. Although the tumor is usually well demarcated from normal kidney, it may extend into the surrounding retroperitoneum. Angiomyolipomas may be solitary or multicentric, and they may produce abdominal pain or hematuria. Angiomyolipomas of the liver and adrenal gland have also been described.59 Wide excision is curative.

Hibernoma This is a rare, slowly growing benign neoplasm that resembles the glandular, brown fat found in hibernating animals. The literature consists primarily of case reports. In most of these, the tumor presents in adults and arises within the thorax.60 Lesions of the trunk, retroperitoneum or extremities are also reported. Excision is generally curative.

Lipoblastoma and lipoblastomatosis

occur anywhere in the body. As with other adult sarcomas, there are no characteristic clinical findings. Several types of liposarcoma are recognized, and have different clinical outcomes.62 Well-differentiated liposarcoma is a nonmetastasizing lesion (Figure 3.6), usually of the retroperitoneum. Similar lesions located on the trunk and extremities are commonly designated atypical lipomatous tumor. Sclerosing liposarcoma, also a low-grade lesion, most commonly occurs in the retroperitoneum. Myxoid liposarcoma, a low- to intermediategrade lesion, accounts for 40–50% of all liposarcomas. The tumor consists of proliferating lipoblasts with a delicate capillary network and a myxoid matrix. The amount and distribution of the mucoid material may vary widely. Myxoid liposarcoma typically has a t(12;16)(q13–14;p11) translocation.63 Myxoid liposarcoma may show increased cellularity and develop areas where the nuclei are round and in contact. This is called a round cell liposarcomatous change, and, if present in 20% or more of the tumor, warrants designation as a high-grade sarcoma.

These tumors are peculiar variants of lipoma that occur almost exclusively in infancy and early childhood.61 They differ from lipoma by their cellular immaturity and their close resemblance to the myxoid form of liposarcoma.

Liposarcoma Liposarcoma is primarily a tumor of adults, with a peak incidence between ages 50 and 65. Along with MFH, it is the most commonly diagnosed soft tissue sarcoma in adults. The most common sites are the thigh and retroperitoneum, although liposarcoma may

Figure 3.6 Well-differentiated liposarcoma.

Pathologic classification Round cell liposarcoma has the same translocation seen in myxoid liposarcoma.64 Pleomorphic liposarcoma (Figure 3.7), as the name implies, is a distinctive form of liposarcoma and is a highly malignant lesion. Mitotic activity is high, and hemorrhage or necrosis is common. It is not unusual for large liposarcomas to consist of multiple nodules, some of which contain only low-grade elements and others of which contain intermediate- or highgrade elements. The term dedifferentiated liposarcoma65 refers to lesions seen most frequently in the retroperitoneum that begin as low-grade well-differentiated tumors, but progress to higher-grade tumors and show evidence of non-lipogenic differentiation, simulating MFH.66

Tumors of smooth muscle Leiomyoma Benign smooth muscle tumors are quite common in the uterus. Rare cutaneous leiomyomas arise from the pilar erector muscles of the skin. Some occur on a familial basis. These lesions are often multiple and

37

may be quite painful,67,68 typically developing in adolescence or early adult life as small discrete papules that eventually form nodules. The extensor surfaces of the extremities are most often affected, and the nodules may follow a dermatomal distribution. Histologically, these tumors are benign, but recurrences after surgical incision are seen frequently, and often the lesions are so numerous that surgical excision is not possible. Leiomyomata may also occur deep within the extremities, abdominal cavity, or retroperitoneum. Vascular or intravascular myomas are a group of neoplasms which are usually multiple, painful subcutaneous lesions and predominantly affect females of childbearing age. Pulmonary leiomyomas are exceedingly rare benign lung lesions seen most commonly in middle-aged females.1 Angiomyoma is a solitary form of leiomyoma that tends to occur on the extremity, more commonly in women, usually between the fourth and sixth decades of life. Intravenous leiomyomatosis is a rare condition in which nodules of benign smooth muscle tissue grow within the veins of the myometrium and may extend into the uterine and hypogastric veins.69 Rarely, these tumors extend up the inferior vena cava into the heart.70 Diffuse peritoneal leiomyomatosis is also recognized, often occurring in association with pregnancy.71 Leiomyomas and smooth muscle tumors of uncertain malignant potential in children have been associated with HIV infection.

Gastrointestinal stromal tumors Figure 3.7 Pleomorphic liposarcoma.

Sarcomas presumed to originate or differentiate as pacemaker cell tumors (Cajal cell tumors) arise in the intestinal tract and retroperitoneum (Figure 3.8a,b). The most

38

Diagnosis and Management of Soft Tissue Sarcoma

(a) (b) Figure 3.8 Sarcomas presumed to originate or differentiate as pacemaker cell tumors (Cajal cell tumors) arise in the intestinal tract and retroperitoneum: (a) gastrointestinal stromal tumor of jejunum; (b) gastrointestinal stromal tumor staining for c-kit. common site is within the stomach, where they tend to be in the proximal portion. Microscopically, they consist of nodules of short-spindled and rounded cells that characteristically grow in disarray. The cell found most commonly within these tumors, the short spindled cell, usually has an abundant, slightly eosinophilic cytoplasm. Recently, these tumors have been associated with expression of c-kit proto-oncogene and CD34+. These cells may blend with cells having epithelioid features. Size larger than 5.0 cm, hypercellularity, increased mitotic activity and epithelioid features correlate well with metastasis.72,73 Thus, tumors with <1 mitotic figure per 50 high-power field have a metastatic rate of 2%, compared to those with >10 mitoses per 50 high-power field, which commonly metastasize. Within the abdomen, about 20% will ultimately metastasize. Tumors that are histologically malignant should be treated with the same principles as leiomyosarcoma. Those that are benign should still be completely excised, and all patients should have ongoing follow-up.

Leiomyosarcoma This tumor presents insidiously with nonspecific symptoms and often reaches quite large proportions. Leiomyosarcoma may arise in any location, but the majority are located in retroperitoneal or intra-abdominal sites. Cutaneous leiomyosarcomas usually appear as small, solitary, extremity nodules.74 Deep extremity leiomyosarcoma most frequently arises in the thigh, possibly in association with medium or large veins.75 Although rare, leiomyosarcoma may arise in large vascular structures and present with symptoms of obstruction to the normal flow of blood. The most common arterial site is the pulmonary artery, and patients present with symptoms of decreased pulmonary outflow. Leiomyosarcoma of the inferior vena cava, which may present with Budd–Chiari syndrome, has also been described. The typical cell of the leiomyosarcoma is elongated and has an abundant cytoplasm. Multinucleated giant cells may be seen. Epithelioid changes, in which the cells become

Pathologic classification

Figure 3.9 Localization of muscle antigens by means of immunohistochemistry, muscle common actin, confirms the diagnosis of leiomyosarcoma (note the positive control vessel). rounded, with concomitant ‘clear cell’ changes in the neoplasm, may occur in otherwise typical leiomyosarcomas. When the tumor is predominantly or exclusively epithelioid, the term epithelioid leiomyosarcoma is used. Localization of muscle antigens by means of immunohistochemistry proves the diagnosis of leiomyosarcoma (Figure 3.9). Desmin and smooth muscle actin are the most common positive reactions. Grading of leiomyosarcoma, however, is difficult, although site of origin and mitotic activity appear to be the best indicators of prognosis.

Tumors of skeletal muscle Benign tumors of striated muscle (rhabdomyoma) are rare. Several types of rhabdomyosarcoma are recognized.

Embryonal rhabdomyosarcoma This is a small cell tumor that usually arises in the orbit or genitourinary tract in children.

39

The botryoid type of embryonal rhabdomyosarcoma, which frequently originates in mucosa-lined visceral organs such as the vagina and the urinary bladder, often grows as a polypoid tumor. These tumors may disseminate widely, but are very responsive to chemotherapy and radiation. Embryonal rhabdomyosarcomas occasionally arise in adults. Although regression of tumor in response to pediatric chemotherapy regimens usually occurs, age is an important prognostic factor for survival, with worse outcomes in older patients.76

Alveolar rhabdomyosarcoma Extremity rhabdomyosarcoma in adolescents and young adults often has an alveolar histology. Alveolar rhabdomyosarcoma is composed of ill-defined aggregates of poorly differentiated round or oval cells that frequently show central loss of cellular cohesion and formation of irregular ‘alveolar’ spaces. These tumors appear to have a worse prognosis than embryonal rhabdomyosarcoma in younger children. A specific translocation, t(2,13)(q37;q14) involving the PAX3 gene on chromosome 2 and the FKHR gene on chromosome 13 is seen in most alveolar rhabdomyosarcomas.76 In other patients, the translocated chromosome 2 locus is different.77 Many pediatric studies include all types of rhabdomyosarcoma seen in the pediatric population.

Pleomorphic rhabdomyosarcoma This is the most common form of rhabdomyosarcoma in adults. This high-grade lesion is not clinically distinguishable from other high-grade adult sarcomas.

40

Diagnosis and Management of Soft Tissue Sarcoma

Vascular tumors Several soft tissue tumors arise within and around blood vessels. These may be benign or malignant and may arise around arteries, veins or capillaries.

Hemangioma Hemangiomas are among the most common STT. Most are present at birth, and regress spontaneously. Rapid growth with impingement on vital structures may occur, however, and treatment with intralesional injection of interferon has been life-saving.78 Pulmonary hemangiomatosis, a rare disorder of diffuse microvascular proliferation in the lung, has been treated effectively with systemic interferon. Cavernous hemangioma refers to a benign lesion consisting of large dilated blood vessels with a flattened endothelium.

Lymphangioleiomyomatosis Pulmonary lymphangioleiomyomatosis is a disease of women of childbearing age. Patients present with cough, hemoptysis, and dyspnea. Grossly, the lungs demonstrate multiple small cystic lesions. On microscopic examination, there is proliferation of normal smooth muscle around the airways and the blood and lymphatic vessels. While tamoxifen does not appear to be useful, there have been responses to progestational agents.79

Epithelioid hemangioendothelioma Epithelioid hemangioendothelioma is an intermediate-grade malignant vascular tumor that has an epithelial appearance.80 It takes multiple forms. The lesion may appear as a solitary, slightly painful mass in either superficial or deep soft tissue. Metastases to

lung, regional lymph nodes, liver and bone have been reported. Another pattern, of a diffuse bronchoalveolar infiltrate or multiple small pulmonary nodules, has also been called IBVAT (intravascular, bronchiolar, and alveolar tumor of the lung).81 Patients may present with cough and hemoptysis. Epithelioid hemangioendothelioma can also arise in the liver, often presenting as an incidental finding, or during a work-up for mild elevation of liver enzymes or vague abdominal pain. Multiple liver nodules are usually found. Although such tumors can metastasize, they usually have an indolent course. Liver transplantation has sometimes been performed, even in patients with metastatic disease.82

Kaposi’s sarcoma Classical Kaposi’s sarcoma is an unusual vascular tumor occurring in the skin of the lower extremities of elderly men of Mediterranean or Jewish extraction.83 The disease is usually indolent, although it can spread to the lungs and the gastrointestinal tract. Cutaneous lesions can be palliated with radiation therapy when necessary. Kaposi’s sarcoma has also arisen in renal allograft recipients who are receiving immunosuppressant therapy.84 The term was first described in 1872 by Kaposi in five patients with unusual lesions affecting the lower extremity. Current evidence suggests that Kaposi’s sarcoma is a viral-associated or possibly viral-induced tumor. Although the well-established lesions of Kaposi’s sarcoma are neoplastic, the course for patients is greatly influenced by their immune status. Another form of Kaposi’s sarcoma occurs in black men in Africa; it may also occur in African children, in whom it runs a more aggressive course. The geographic distribution in Africa is very similar to that of

Pathologic classification Burkitt’s lymphoma, which is associated with Epstein–Barr virus. Epidemic Kaposi’s sarcoma is a complication of HIV infection. In addition, certain groups of AIDS patients who are coinfected with other viruses have a very high incidence of Kaposi’s sarcoma. It occurs in four clinical forms: (1) chronic Kaposi’s sarcoma; (2) lymphadenopathy-associated Kaposi’s sarcoma; (3) transplantation-associated Kaposi’s sarcoma; and (4) AIDS-related Kaposi’s sarcoma. Chronic Kaposi’s sarcoma This form is prevalent in Poland, Russia, Italy and equatorial Africa. It occurs classically in males in late adult life. There is no association of this form of Kaposi’s sarcoma with HIV infection. However, at least one-third of these patients have or subsequently develop a second malignant tumor, often leukemia or lymphoma. Because of this, the disease is characteristically prolonged and these lesions are often responsive to radiation therapy. Lymphadenopathy-associated Kaposi’s sarcoma This form occurs characteristically in young African children. The course of this disease is fulminant and often refractory to any kind of treatment. This form is probably not associated with HIV infection. Transplantation-associated Kaposi’s sarcoma This form occurs in renal transplant patients with a variable distribution depending on the patient population. In Western countries, the incidence of post-transplantation Kaposi’s sarcoma is <1%, whereas in the Near East it approaches 4%. This suggests that the genetic background of a patient influences the post-transplant risk. The clinical course

41

depends on both the stage of the disease and the ability to induce the immunosuppression.

AIDS-related Kaposi’s sarcoma Approximately 30% of patients with AIDS will develop Kaposi’s sarcoma. Indeed, diagnosis of Kaposi’s sarcoma frequently leads to clinical recognition of the syndrome. There is not an even distribution of Kaposi’s sarcoma among patients with AIDS, and it would seem that additional viral agents are responsible for the tumor. About 40% of homosexual patients with AIDS will develop Kaposi’s sarcoma, compared to <5% of those in the other recognized risk groups with AIDS. It frequently develops as a small, flat pink patch, and evolves into a classic blue papillar appearance. These tumors occur in any location; about one-half of the patients will have lymph node lesions, and about one-third develop gastrointestinal as well as skin lesions. The overall mortality rate of patients with Kaposi’s sarcoma is about 40%. A significant proportion of these patients die from co-morbid opportunistic infection. The treatment is often difficult. Operation is indicated for diagnosis. It has little application in treatment. Because this disease is often multifocal, radiation and chemotherapy are both often preferred. Drugs that have been used in treating this include etoposide, doxorubicin, vinblastin and interferon-α, all with variable effects.

Angiosarcoma These tumors manifest the properties of malignant endothelial cells. They are rare, and very difficult to manage. Angiosarcomas may arise in either blood or lymphatic vessels (Figure 3.10). They occur commonly within

42

Diagnosis and Management of Soft Tissue Sarcoma

the skin and superficial soft tissue. The prognosis is usually bad.85

(a)

(b)

(c) Figure 3.10 Angiosarcoma involving (a) skin, (b) lung metastasis, and (c) deep primary lesion.

Cutaneous lymphangiosarcoma may develop in chronically lymphedematous extremities.86 The classical presentation is the Stewart-Treves syndrome, which is lymphangiosarcoma in the chronically lymphedematous arms of women who have been treated for breast cancer with radical mastectomy, and, often, axillary irradiation.87 Angiosarcomas are usually located in the skin or superficial soft tissue. Multicentric angiosarcomas occur on the scalp and face of elderly men, where unrelenting progression can cause severe ulceration and infection.88 Angiosarcoma of the breast is often an aggressive lesion that recurs locally and may metastasize, primarily to lung; histologic grade has been of prognostic value.89 Angiosarcomas are known to occur in sites of prior irradiation without chronic lymphedema, in particular the pelvis of women who have received radiation therapy for gynecologic cancers.90 Soft tissue angiosarcoma, often with epithelioid features, may arise on the extremities or within the abdomen.91 The overall prognosis of cutaneous angiosarcoma is quite poor. There are several reasons for this. Part of this is delay in adequate treatment, which is consequent on delay in seeking advice and underestimating the extent of tumor. Death from disease may be due to local extension or metastasis. The tumor may metastasize to lymph nodes and also the lung and liver. Treatment of these tumors is often difficult and includes surgical resection, radiation and chemotherapy. Recent experience with taxol shows some promise.92

Perivascular tumors Glomus tumor Glomus tumors are distinctive neoplasms in which the cells resemble modified smooth

Pathologic classification muscle cells of the normal glomus body. The normal glomus body is a specialized arteriovenous anastomosis, important in thermal regulation. The glomus tumor commonly presents as a small, blue–red nodule in subcutaneous tissue or in the subungual region of a finger.93 The symptoms produced by glomus tumors are characteristic and often well out of proportion with regard to the size of the neoplasm. Paroxysmal pain, commonly brought on by change in temperature, is the hallmark. Essentially, all glomus tumors are benign and are adequately treated by wide excision. Only 10% will recur. Most of these probably represent persistent, rather than locally recurrent, disease.

Hemangiopericytoma These rare tumors usually arise in adults, most commonly in the lower extremity, pelvis or shoulder (Figure 3.11).The tumors occur predominantly in adult life at a median age of 45 years. They commonly present as an enlarged but painless mass. Hypoglycemia may occur in association with these tumors, in particular, large tumors located within the

Figure 3.11 Classical hemangiopericytoma.

43

pelvis and retroperitoneum.94 The cells of these tumors are thought to resemble pericytes, cells that are normally arranged along capillaries and venules. The tumors tend to be well circumscribed, and consist of tightly packed cells around thin-walled vascular channels of varying calibers. Hemangiopericytoma cells routinely stain for vimentin and occasionally focally for CD34. The most reliable method of identifying pericytic differentiation in these tumors is by an ultrastructural examination, looking for the presence of basement membrane. Monophasic synovial sarcoma is frequently mistaken histologically for hemangiopericytoma, so care should be taken to rule out that diagnosis before making a diagnosis of hemangiopericytoma. Most hemangiopericytomas have an indolent behavior, but are capable of distant metastasis.95 Treatment is again based on the cornerstone of complete excision.

Tumors of synovial tissue Nodular tenosynovitis A variety of tumor-like lesions arise from the synovium. Nodular tenosynovitis (tenosynovial giant cell tumor) is a giant cell tumor that may occur at any age but is usually seen between the ages of 30 to 50, somewhat more commonly in women. It occurs with greatest frequency in the hand, but is also seen in the ankles and knees, among other sites. These tumors grow slowly as circumscribed lobulated masses and are usually diagnosed when they are less than 5 cm in diameter. Because of their location, excision is often done with close margins. Local recurrence is seen in 10–20% of patients. A diffuse form of giant cell tumors occurs in and around joints, most commonly around the knee or ankle. In contrast to most giant cell tumors, this

44

Diagnosis and Management of Soft Tissue Sarcoma

neoplasm grows in expansive sheets without a mature capsule. Malignant giant cell tumors of the tendon sheath are also recognized.

Tumors of the peripheral nerves Neurofibroma Solitary neurofibromas are small, slowgrowing cutaneous or subcutaneous nodules that commonly arise by the third decade of life. These lesions may or may not be associated with neurofibromatosis. NF-1 (type 1 neurofibromatosis, peripheral neurofibromatosis, von Recklinghausen’s disease) is one of the most common genetic disorders, affecting approximately 1 in 3000 live births.96 An autosomal dominant mutation at the 17q11.2 locus has been identified.97 The clinical features of NF-1 include cafe au lait spots, multiple neurofibromas, and Lisch nodules (pigmented hamartomas) of the iris. Cutaneous neurofibromas – soft, fleshy growths – arise in the skin of most patients with NF-1. The cutaneous lesions generally range in size from a few millimeters to a few centimeters, and range in number in patients from few to hundreds. Subcutaneous neurofibromas are firm and nodular, and may be painful. A finding virtually pathognomic of NF-1 is the plexiform neurofibroma. Plexiform neurofibromas affect segments of a nerve, thickening and distorting the nerve into a sometimes large tortuous mass. They may cause severe dysesthetic pain.

Schwannoma Also called neurilemoma, this benign lesion presents most commonly in people aged 20–50 years. Common sites include the head and

neck and the flexor surfaces of the extremities. It grows slowly, and is usually smaller than 5 cm when the diagnosis is made. This encapsulated nerve sheath tumor is readily distinguished from neurofibroma, in that schwannoma usually consists of two components: a highly ordered cellular region bearing Verocay bodies (Antoni A area) and a hypocellular component (Antoni B area).

Cellular schwannoma This tumor is more cellular than classical schwannoma and is devoid of Verocay bodies. It may present at any age, and often affects paravertebral sites. Complete excision is curative.

Granular cell tumor The granular cell tumor (also called granular cell myoblastoma) is a rare tumor that is probably of neural origin. This tumor usually presents in adults as a small, poorly circumscribed subcutaneous nodule, although there are patients who have multiple lesions. This entity has a distinct histologic appearance, and stains positively for S-100 protein. Granular cell tumor usually has a benign course, but metastasizing malignant examples have been reported.

Malignant peripheral nerve sheath tumor This tumor has been called malignant schwannoma, neurofibrosarcoma or neurogenic sarcoma (Figure 3.12). The majority of MPNST are high grade and show scattered staining for the S-100 protein. The most common sites are the lower extremity in 50–70% of cases, the brachial plexus, upper

Pathologic classification

45

malignant triton tumor is a malignant peripheral nerve tumor with rhabdomyosarcoma elements.98

Gastrointestinal autonomic nerve tumor

Figure 3.12 Malignant peripheral nerve sheath tumor, high grade from sciatic nerve. extremity and paraspinal sites, but MPNST may arise anywhere in the body.98 The tumors originate from the nerve sheath, rather than from the nerve itself. Although higher estimates appear in the literature, approximately 2% of patients with NF-1 develop MPNST,99,100 often arising from a plexiform neurofibroma. About 55% of patients with MPNST have neurofibromatosis. After accounting for size and grade, the prognosis of patients with MPNST in the setting of NF-1 is not significantly different from that of patients without NF-1. The MPNST that develops in the patient with neurofibromatosis has historically been considered to have a poor prognosis compared with other extremity sarcomas. However, when other factors of known risk for outcome such as grade and size are accounted for, malignant peripheral nerve tumors arising both sporadically and in the presence of neurofibromatosis tend to have a similar outcome to other poor-prognosis peripheral sarcomas.101 MPNST tend to present with a greater preponderance of large size and high grade than other soft tissue sarcomas; hence their reputation for aggressiveness. The

The GANT (Figure 3.13), sometimes called plexosarcoma, is regarded as a form of gastrointestinal stromal tumor (GIST) (pacemaker cell or Cajal cell tumor) with ultrastructural neural features (cell processes

(a)

(b) Figure 3.13 The gastrointestinal autonomic nerve tumor (electron microscopy) showing (a) skeinoid fibers and (b) dense core granules.

46

Diagnosis and Management of Soft Tissue Sarcoma

with dense core granules and vesicles). Immunostaining is negative for muscle markers.

Extraskeletal cartilaginous and osseous tumors Myositis ossificans

Extraskeletal chondrosarcoma Myxoid chondrosarcoma (also called chordoid sarcoma) occurs most commonly in patients over the age of 35. More than twothirds occur in the extremity.102 This tumor usually grows slowly, but late recurrence and metastasis is common. A non-random reciprocal translocation has been shown in these tumors.103,104

This benign lesion is self-limiting, usually associated with trauma. Despite its name, myositis ossificans is not necessarily confined to the muscle, nor is inflammation a prominent feature. The condition usually presents in athletic young adults as a tender, soft tissue mass, which becomes firm or rockhard over a period of weeks. Radiographs show calcification several weeks before the lesion appears. Histologically, the mass consists of fibroblastic tissue, often with prominent mitotic activity. The process is benign, however, and may be managed conservatively. It is important to distinguish between myositis ossificans and sarcoma, especially extraosseous osteogenic sarcoma (Figure 3.14. Also see Figure 4.5).

These rare, high-grade sarcomas are defined by their production of malignant osteoid and bone (Figure 3.15). 105,106 By definition, they are not attached to the skeleton. Unlike typical osteogenic sarcoma of bone, these tumors rarely occur in patients under 20, and most patients are over 50 years of age.107,108 The tumors present like other soft tissue sarcomas. Most arise in the extremities, although osteosarcoma of other sites, including breast, retroperitoneum, urinary bladder, or other visceral organs, has been reported. There is considerable heterogeneity in the histologic appearance. Spindle cell varieties may

Figure 3.14 Myositis ossificans.

Figure 3.15 Extraosseous osteogenic tumor.

Extraskeletal osteogenic sarcoma

Pathologic classification

47

resemble MFH, MPNST or fibrosarcoma, whereas others have a more epithelioid appearance. Giant cells are a common feature. Some lesions that may contain bone or cartilage are hard to distinguish from MFH, but bone in MFH should be metaplastic in type. Nonetheless, extraosseous osteogenic sarcoma resembles MFH in terms of age, sites of distribution, and clinical behavior.

Miscellaneous tumors Myxoma Intramuscular myxoma is a rare tumor that occurs in adults, usually in the large muscles of the extremities. Myxomas consist of abundant mucoid material but few cells. Although these lesions often measure 5–10 cm in size, their clinical behavior is generally benign.109 Multiple intramuscular myxomas occur in association with fibrous dysplasia. Aggressive angiomyxoma (Figure 3.16)110 is a tumor that usually occurs in women, although male patients have been reported. The lesion generally presents as a mass in the perineal or pelvic area. Local recurrence can

Figure 3.17 Synovial sarcoma in a monophasic form.

result in considerable morbidity, given the location of these tumors, but distant metastases do not occur.

Mesenchymoma Malignant mesenchymoma is defined as a malignant tumor showing at least two types of malignant mesenchymal differentiation exclusive of fibrosarcoma, MFH or hemangiopericytoma. These rare tumors are generally thought to behave clinically in accordance with the predominant component, although a recent report suggests that their behavior is not as aggressive as might be expected.111

Synovial sarcoma

Figure 3.16 Pelvic angiomyxoma.

Current definitions suggest that synovial sarcoma does not arise from the synovium and that the use of the term is technically inappropriate. However, because of longstanding usage the term is still used, but the tumor is now classified among miscellaneous sarcomas. Synovial sarcoma usually occurs in young adults, either as a monophasic (Figure 3.17) or

48

Diagnosis and Management of Soft Tissue Sarcoma spindle cells, and a biphasic form in which the ovoid cells form glands. The tumor cells are often positive for keratin and epithelial membrane antigen. Synovial sarcomas contain a characteristic chromosomal translocation, t(X;18)(p11.2;q11.2); a hybrid transcript has been identified.113

Alveolar soft part sarcoma

Figure 3.18 Synovial sarcoma in a biphasic form.

a biphasic form (Figure 3.18)112 The most common site is around the knee, but sites of origin are widespread in the body. As opposed to most other soft tissue sarcomas, these lesions are occasionally painful. The tumor is composed of ovoid and spindle cells. Three growth patterns are noted: a monophasic form composed of sheets of spindle and ovoid cells, a biphasic form in which sheets or cords of ovoid cells wind through a background of

This rare tumor occurs most frequently in patients between 15 and 35 years of age. Women outnumber men, especially in patients under 20 years of age.114 Prognosis is better in those patients who present at a younger age. These tumors often present in the lower extremities as a slow-growing painless mass. Grossly, alveolar soft part sarcomas are poorly circumscribed. They typically grow in an organoid or nestlike arrangement. Alveolar spaces form due to cellular necrosis. Considerable controversy regarding histogenesis persists. A myogenic differentiation has been suggested but not proven.115 Lung, brain and bone are the most common sites of metastasis. Although this tumor tends to grow slowly, due to a metastatic proclivity, the ultimate prognosis is quite poor. Patients may remain asymptomatic over years, however, even with metastatic disease.

Epithelioid sarcoma

Figure 3.19 Epithelioid sarcoma: the lung is the most common site of distant metastases.

This is a tumor of adolescents and young adults, usually presenting as a small, firm nodule in the subcutaneous tissue of the distal extremities.116,117 Multiple recurrences, which grow along tendons and fascial planes, are a characteristic feature. Similar tumors arise from the perineum and paravaginal soft tissues. Unlike with most other sarcomas, lymph node metastases are common, and the tumor may appear more proximally in the

Pathologic classification

49

peritoneal implants. Because of its multifocal nature, complete resection is usually impossible. Chemotherapy regimens used in the treatment of Ewing’s sarcoma have induced responses in patients with this disease, but are rarely curative. A specific translocation between chromosomes 11 and 22 that is different from the translocation of Ewing’s sarcoma has been identified.119, 120

References Figure 3.20 Clear cell sarcoma.

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2.

extremity in transit to the regional nodes.3,117 Lung is the most common site of distant metastasis (Figure 3.19).

Clear cell sarcoma (malignant melanoma of soft parts) This tumor, also called clear cell sarcoma of tendons and aponeuroses, presents as a soft tissue mass (Figure 3.20). Because of the presence of intracellular melanin and the tendency for regional nodal metastasis, this entity is better considered a soft tissue melanoma rather than sarcoma. Despite these clinical features, clear cell sarcoma has a distinct chromosomal translocation, t(12;22)(q13;q13). Size is the most important prognostic factor. Treatment of the primary is similar to that of other sarcomas. There are few reported responses to chemotherapy.

Desmoplastic small cell tumor This newly appreciated entity is a tumor of adolescents and young adults.118 It usually presents in the abdomen, often with diffuse

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McCormick D, Mentzel T, Beham A et al. Dedifferentiated liposarcoma. Clinicopathologic analysis of 32 cases suggesting a better prognostic subgroup among pleomorphic sarcomas. Am J Surg Pathol 1994;18:1213–23. Tallini G, Erlandson RA, Brennan MF et al. Divergent myosarcomatous differentiation in retroperitoneal liposarcoma. Am J Surg Pathol 1993;17:546–56. Fisher WC, Helwig EB. Leiomyomas of the skin. Arch Dermatol (Chicago) 1963;88:510. Fox SR. Leiomyomatosis cutis. N Engl J Med 1960;263:1248. Norris HJ, Parmley TH. Mesenchymal tumors of the uterus. V. Intravenous leiomyomatosis: a clinical and pathologic study of 14 cases. Cancer 1975;36:2164–78. Suginami H, Kaura R, Ochi H et al. Intravenous leiomyomatosis with cardiac extension. Obstet Gynecol 1990;76:527–9. Tavassoli FA, Norris HJ. Peritoneal leiomyomatosis (leiomyomatosis peritonealis disseminata). Int J Gynecol Pathol 1982;1:59–74. Appleman HD, Helwig EB. Gastric epithelioid leiomyoma and leiomyosarcoma (leiomyoblastoma). Cancer 1976;38:708–28. Byard RW, Barr JR, Naidoo SP et al. Gastric stromal tumors with epithelioid features. Clinicopathologic features of 22 cases. Surg Pathol 1990;3:281. Stout AP, Hill WT. Leiomyosarcoma of the superficial soft tissues. Cancer 1958;11:844–54. Gustafson P, Willen H, Baldetorp B et al. Soft tissue leiomyosarcoma. Cancer 1992;70:114–9. LaQuaglia MP, Heller G, Ghavimi F et al. The effect of age at diagnosis on outcome in rhabdomyosarcoma. Cancer 1994;73:109–17. Davis RJ, D’Cruz CM, Lovell MA et al. Fusion of PAX7 to FKHR by the variant t(1;13)(p36;q14) translocation in alveolar

Pathologic classification

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80.

81.

82.

83.

84.

85.

86.

87.

88.

rhabdomyosarcoma. Cancer Res 1994;54:2869–72. White CW. Treatment of hemangiomatosis with recombinant interferon alfa. Semin Hematol 1990;27:15–22. Taylor JR, Ryu J, Colby TV et al. Lymphangioleiomyomatosis. Clinical course in 32 patients. N Engl J Med 1990;323:1254–60. Weiss SW, Ishak KG, Dail DH et al. Epithelioid hemangioendothelioma and related lesions. Semin Diagn Pathol 1986;3:259–87. Dail DH, Liebow AA, Gmelich JT et al. Intravascular, bronchiolar, and alveolar tumor of the lung (IBVAT). Cancer 1983;51:452–64. Kelleher MB, Iwatsuki S, Sheahan DG. Epithelioid hemangioendothelioma of liver. Clinicopathological correlation of 10 cases treated by orthotopic liver transplantation. Am J Surg Pathol 1989;13:999–1008. Reynolds WA, Winkelmann RK, Soule EH. Kaposi’s sarcoma: a clinicopathologic study with particular reference to its relationship to the reticuloendothelial system. Medicine (Baltimore) 1965;44:419–43. Stribling J, Wertzner S, Smith GV. Kaposi’s sarcoma in renal allograft recipients. Cancer 1978;42:442–6. Espat NJ, Lewis JJ, Leung D, Brennan MF. Confirmed angiosarcoma: prognostic factors and outcome in 50 prospectively followed patients. Sarcoma 2000;4:173–7. Woodard AH, Ivins JC, Soule EH. Lymphangiosarcoma arising in chronic lymphedematous extremities. Cancer 1972;30:562–72. Stewart FW, Treves N. Lymphangiosarcoma in postmastectomy lymphedema: a report of six cases of elephantiasis chirurgica. Cancer 1948;1:64–81. Holden CA, Spittle MF, Jones EW. Angiosarcoma of the face and scalp: prognosis and treatment. Cancer 1987;59:1046–57.

53

89. Rosen PP, Kimmel M, Ernsberger D. Mammary angiosarcoma: the prognostic significance of tumor differentiation. Cancer 1988;62:2145–51. 90. Nanus DM, Kelsen D, Clark DG. Radiation-induced angiosarcoma. Cancer 1987;60:777–9. 91. Fletcher CDM, Beham A, Bekir S et al. Epithelioid angiosarcoma of deep soft tissue: a distinctive tumor readily mistaken for an epithelial neoplasm. Am J Surg Pathol 1991;15:915. 92. Casper ES, Waltzman RJ, Schwartz GK et al. Phase II trial of paclitaxel in patients with soft tissue sarcoma. Cancer Invest 1998;16:442–6. 93. Shugart RR, Soule EH, Johnson EW. Glomus tumor. Surg Gynecol Obstet 1963;117:334–40. 94. Espat NJ, Lewis JJ, Leung D, Brennan MF. Conventional hemangiopericytoma: modern analysis of outcome. Submitted to Cancer. 95. Enzinger FM, Smith BH. Hemangiopericytoma. An analysis of 106 cases. Human Pathol 1976;7:61–82. 96. Riccardi VM. Neurofibromatosis: Phenotype, Natural History and Pathogenesis, 2nd edn. Baltimore: Johns Hopkins University Press, 1992. 97. Wallace MR, Marchuk DA, Andersen LB et al. Type I neurofibromatosis gene: identification of a large transcript disrupted in three NF1 patients. Science 1990;249:181–6. 98. Woodruff JM, Chernick NL, Smith MC et al. Peripheral nerve tumors with rhabdomyosarcomatous differentiation (malignant ‘Triton’ tumors). Cancer 1973;32:426–39. 99. Stout AP. Human Cancer: Etiologic Factors, Precancerous Lesions, Growth, Spread, Symptoms, Diagnosis, Prognosis, Principles of Treatment. Philadelphia: Lea & Febiger, 1932. 100. Stout AP. Tumors of the soft tissues. In: Atlas of Tumor Pathology, section 2, fascicle

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101.

102.

103.

104.

105.

106. 107.

108.

109. 110.

111.

Diagnosis and Management of Soft Tissue Sarcoma 5. Washington, DC: Armed Forces Institute of Pathology, 1953. Vauthey JN, Woodruff JM, Brennan MF. Extremity malignant peripheral nerve sheath tumors (neurogenic sarcomas): a 10-year experience. Ann Surg Oncol 1995;2:126–31. Enzinger FM, Shiraki M. Extraskeletal myxoid chondrosarcoma: an analysis of 34 cases. Human Pathol 1972;3:421. Orndal C, Carlen B, Akerman M et al. Chromosomal abnormality t(9;22)(q22;q12) in an extraskeletal myxoid chondrosarcoma characterized by fine needle aspiration cytology, electron microscopy, immunohistochemistry, and DNA flow cytometry. Cytopathology 1991;2:261–70. Turc-Carel C, Dal Cin P, Rao U. Recurrent breakpoints at 9q31 and 22q12.2 in extraskeletal myxoid chondrosarcoma. Cancer Genet Cytogenet 1988;30:145–50. Sordillo PP, Hajdu SI, Magill GB et al. Extraosseous osteogenic sarcoma. Cancer 1983;51:727–34. Chung EB, Enzinger FM. Extraskeletal osteosarcoma. Cancer 1987;60:1132–42. Bane BL, Evans HL, Ro JY, et al. Extraskeletal osteosarcoma. A clinicopathologic review of 26 cases. Cancer 1990;66:2762–70. Lee JSY, Fetsch JF, Wasdhal DA et al. A review of 40 patients with extraskeletal osteosarcoma. Cancer 1995;76:2253–9. Enzinger FM. Intramuscular myxoma. Am J Clin Pathol 1965;43:104. Steeper TA, Rosai J. Aggressive angiomyxoma of the female pelvis and perineum. Report of nine cases of a distinctive type of gynecologic soft tissue neoplasm. Am J Clin Pathol 1983;7:463–75. Newman PL, Fletcher CD. Malignant mesenchymoma. Clinicopathologic analysis of a series with evidence of low-grade

112.

113.

114.

115.

116.

117. 118.

119.

120.

behaviour. Am J Surg Pathol 1991;15:607–14. Brodsky JT, Burt ME, Hajdu SI et al. Tendosynovial sarcoma. Clinicopathologic features, treatment, and prognosis. Cancer 1992;70:484–9. Clark J, Rocques PJ, Crew AJ et al. Identification of novel genes, SYT and SSX, involved in the t(X;18)(p11.2;q11.2) translocation found in human synovial sarcoma. Nature Genet 1994;7:502–8. Lieberman PH, Brennan MF, Kimmel M et al. Alveolar soft-part sarcoma. A clinicopathologic study of half a century. Cancer 1989;63:1–13. Tallini G, Parham DM, Dias P et al. Myogenic regulatory protein expression in adult soft tissue sarcomas. A sensitive and specific marker of skeletal muscle differentiation. Am J Pathol 1994;144:693–701. Prat J, Woodruff JM, Marcove RC. Epithelioid sarcoma. Cancer 1978;41:1472–87. Chase DR, Enzinger FM. Epithelioid sarcoma. Am J Surg Pathol 1985;9:241–63. Gerald WL, Miller HK, Battifora H et al. Intra-abdominal desmoplastic small roundcell tumor: report of 19 cases of a distinctive type of high-grade polyphenotypic malignancy affecting young individuals. Am J Surg Pathol 1991;15:499. Rodriguez E, Sreekantaiah C, Gerald W et al. A recurring translocation, t(11;22)(p13;q11.2), characterizes intraabdominal desmoplastic small round-cell tumors. Cancer Genet Cytogenet 1993;69:17–21. Sawyer JR, Tryka AF, Lewis JM. A novel reciprocal chromosome translocation t(11;22)(p13;q12) in an intra-abdominal desmoplastic small round-cell tumor. Am J Surg Pathol 1992;16:411–6.

4 Clinical features, diagnosis and extent of disease evaluation

The majority of patients with extremity sarcoma present with a painless lump (Figure 4.1). A minority present with late-stage disease, including a fungating tumor (Figure 4.2) or an advanced posterior scapula lesion (Figure 4.3) or undifferentiated sarcoma in

(a)

(b)

the presence of lymphedema (Figure 4.4). Differential diagnosis includes a multitude of benign and potentially malignant lesions. The most common benign lesion is a lipoma, and the factors that suggest a soft tissue sarcoma in the presence of a clinically lipomatous mass

(c)

(d) (e) (f) Figure 4.1 The majority of patients present with a painless lump: (a) atypical lipomatous tumor of the posterior thigh; (b) schwannoma of foot; (c,d,e) lipoma of right thigh; (f) low-grade malignant fibrous histiocytoma (MFH) invading bone.

56

Diagnosis and Management of Soft Tissue Sarcoma

Figure 4.2 Late-stage disease: fungating tumor of thigh.

Figure 4.3 High-grade shoulder sarcoma: advanced posterior scapula lesion.

Figure 4.4 Undifferentiated sarcoma in the presence of chronic extensive lymphedema.

Figure 4.5 Myositis ossificans: plain radiograph of lower extremity showing discrete calcification.

must always be considered. These include variations in texture, large size, fixation to underlying structures and rapid recent growth. Often an antecedent history of trauma is suggested by the patient and thought to be the cause of a sarcoma. While injury is usually a factor that brings attention to the lesion, it is particularly true in the difficult differential

diagnosis of myositis ossificans. This diagnosis can usually be excluded by plain soft tissue films of the extremity showing calcification (Figure 4.5), or an MRI scan with the classical infiltration of the soft tissues rather than a discrete tumorous mass (Figure 4.6). However, it should be remembered that malignant soft tissue tumors such as extraskeletal

Clinical features, diagnosis and extent of disease evaluation

Figure 4.6 Myositis ossificans: MRI showing absence of discrete mass and intermuscular extension.

Figure 4.8 Elastofibroma at the lower border of the scapula.

chondrosarcoma or osteogenic sarcoma can show calcification (Figure 4.7). The diagnosis can usually be made by CT or MRI, while in myositis ossificans there is lack of a discrete mass and the presence of fluid in the interstices of the muscle in myositis.

57

Figure 4.7 Chondrosarcoma showing calcification.

Simple fibromata are not uncommon and must be considered. Elastofibroma, uncommon lesions, usually arise at the lower border of the scapula (Figure 4.8), and, on occasion, are bilateral, multiple, and familial. Most difficult are the superficial fibromatoses and desmoid tumors (see below). Nodular fasciitis, a benign but often recurrent lesion, is usually accompanied by tenderness and discomfort. When it arises in the deep subcutaneous fascia, forming a nodular encapsulated mass, it is often difficult to distinguish from true soft tissue tumors. Benign tumors of smooth muscle (leiomyoma) also occur and are much more common in the uterus and gastrointestinal tract but can occasionally be seen deep in the extremity or retroperitoneum. Some will contain vascular components and are considered angiomyomas. Angiomyxomas can occur in the paravaginal area (Figure 4.9). Other commonly seen benign tumors include hemangiomas (Figure 4.10). The majority in the extremities present at birth and regress spontaneously or persist as indolent lesions

58

Diagnosis and Management of Soft Tissue Sarcoma

(a) Figure 4.9 Angiomyxomas can occur in the paravaginal area.

Figure 4.10 Hemangioma of the entire right lateral chest and abdominal wall.

over many years. Some, e.g. hepatic hemangiomas, can become very large and undergo cavernous change. Imaging studies can often differentiate these lesions. Vascular malformations may be difficult to differentiate from vascular sarcomas clinically, but can usually be defined by MRI (Figure 4.11). In other sites outside the extremity, soft tissue sarcomas may be found incidentally

(b) Figure 4.11 Vascular malformations may be difficult to differentiate from vascular sarcomas clinically, but the diffuse involvement and lack of defined mass can be seen on MRI.

during imaging for non-specific symptoms (Figure 4.12) or in evaluation of cafe au lait spots which may draw attention to underlying neurofibroma or malignant peripheral nerve tumors (Figure 4.13). On rare occasions, other benign more aggressive lesions such as angiomyxoma and various cellular schwannomas can show invasive potential (Figure 4.14). This is particularly

Clinical features, diagnosis and extent of disease evaluation

59

Figure 4.12 Retroperitoneal sarcoma: in other sites outside the extremity, soft tissue sarcomas may be found incidentally during imaging for non-specific symptoms.

Figure 4.13 Cafe au lait spot and large left hip malignant peripheral nerve tumor.

Figure 4.14 Cellular schwannoma in the retroperitoneum showing extensive bone invasion.

Figure 4.15 Patient with a right-sided retroperitoneal liposarcoma displacing the kidney, 20 cm in maximum diameter at presentation.

true in the retroperitoneum, where patients undergo imaging for non-specific symptoms and a tumor of massive size may be detected (Figures 4.15–4.18.) Occasionally, visceral stromal tumors (GIST) can present with gastrointestinal bleeding. Retroperitoneal tumors involving the paravertebral region

and the psoas should always be considered in the differential diagnosis of non-specific neurologic symptoms, especially those involving the femoral nerve. In the retroperitoneum, other essentially benign lesions include angiomyolipoma (Figure 4.19), usually arising from the kidney or the renal

60

Diagnosis and Management of Soft Tissue Sarcoma

hilum or rarely involving the adrenal gland. Occasionally, large lymphangiomas occurring in the retroperitoneum can be mistaken for sarcoma or even lesions of the pancreas (Figure 4.20).

Sciatic nerve pain is a common presentation of a buttock lesion and is often missed and attributed to spinal pathology (Figure 4.21). Large intra-abdominal sarcomas can present in the perineum. Figure 4.22 shows the

Figure 4.17 Left upper quadrant liposarcoma, 15 cm in maximum diameter at presentation with early satiety. Figure 4.16 MRI, coronal section illustrating a large right-sided retroperitoneal tumor.

Figure 4.18 Left upper quadrant high-grade liposarcoma presenting as an abdominal mass.

Figure 4.19 An unusually large angiomyolipoma involving the renal hilum.

Clinical features, diagnosis and extent of disease evaluation

Figure 4.20 Lymphangioma in the retroperitoneum, simulating a retroperitoneal sarcoma or pancreatic mass.

61

Figure 4.21 Buttock sarcoma involving the sciatic notch and causing sciatic nerve pain.

Figure 4.22 Perineal presentation of pelvic sarcoma.

Figure 4.23 Intra-abdominal mass – a uterine sarcoma.

perineal presentation of a soft tissue buttock sarcoma contiguous with Figure 4.23, an intra-abdominal mass, which turned out to be a second primary sarcoma, a uterine sarcoma, causing pressure in the left iliac fossa and further presentation in the pelvic perineum.

Diagnostic imaging Diagnostic imaging provides a threedimensional image of soft tissue masses, together with anatomic relationships to surrounding structures. Non-invasive radiologic examination is almost always informative

62

Diagnosis and Management of Soft Tissue Sarcoma

enough to define the tumor and the extent of disease, and to facilitate treatment planning. Diagnostic imaging is used both to illustrate the primary tumor and to define the extent of disease. The choice of modality and extent of imaging should be in part dependent on the underlying biology of these tumors.

Imaging of the primary tumor CT and MRI have been used extensively and both are very reliable. The modern iterations of both of these modalities now enable extremely detailed visual resolution of tumor and anatomic structure. The comparative value of MRI versus CT was studied by the Radiology Diagnostic Oncology Group (RDOG) in an analysis of 367 eligible patients, examined with both CT and MRI within 4 weeks before operation.1 The CT scans of each patient were interpreted independently by two radiologists, and MRI images by two other radiologists at the enrolling institution. The CT and MRI were then interpreted together by two of those radiologists and subsequently re-read at other institutions. These findings were compared with operative and histopathologic findings. One hundred and thirty-three patients with primary soft tissue tumor were examined. There was no significant difference between CT and MRI in determining whether or not the tumor involved bone, joint or neurovascular structures. The variability between reviewers was similar. It would appear, therefore, that while MRI is often the preferred image for extremity lesions, at the present time high-quality CT and MRI are equivalent.

This study was done in the early 1990s, and the technology of both CT scanning and MRI have improved significantly since then in terms of their resolution. The two are often complementary, and useful information is gleaned from both. CT scanning is often the modality of choice when imaging the abdomen. MRI, which can be resolved in multiple anatomic planes between tumor and adjacent structures, may aid in defining a three-dimensional structure. One of the advantages of MRI is the ability to obtain images in several planes, including transverse, coronal, sagittal and parasagittal. Currently, CT has developed many of the threedimensional reconstructional capabilities. MRI can differentiate well between fat and non-fat tumors, given that fat has a short T1 relaxation time. In one study,2 preoperative MRI was tested for its ability to predict prognosis and outcome. While it was very good in terms of structural definition, it was not as reliable when compared to standard prognostic parameters, including grade and size. Bone invasion is an important issue and, while uncommon, is a bad prognostic sign and reflects aggressiveness of the lesion (Figure 4.24).We have tried to determine if MRI of soft tissue sarcoma allows us to predict local recurrence, distant metastases or diseasespecific survival. We evaluated 46 patients who we had treated, and correlated invasion of neurovascular structures and bone with outcome. We found that bone invasion did correlate with disease-specific survival but that neurovascular involvement did not impact on survival. Clearly, the finding of neurovascular involvement was quite important in terms of planning the operation and tailoring treatment for these patients. In the retroperitoneum and abdomen, CT is usually the modality most preferred for providing details of the primary tumor and

Clinical features, diagnosis and extent of disease evaluation

63

Figure 4.25 High-grade extremity lesions metastasize to lung. Figure 4.24 MRI of synovial sarcoma invading bones of foot.

evidence, or lack thereof, of liver metastases. More invasive studies, such as venography or angiography, are rarely indicated in the evaluation of soft tissue tumors. Occasionally, for patients presenting with primary gastrointestinal tumors, use of barium or gastrogaffin contrast studies may be useful.

Imaging as part of the extent of disease work-up With soft tissue tumors, the extent of disease can be evaluated once the primary site and biology are known. For example, high-grade extremity lesions predominantly metastasize to the lungs (Figure 4.25). Intra-abdominal lesions, when of visceral origin, predominantly metastasize to the liver (Figure 4.26), whereas retroperitoneal lesions have a greater predilection for the lungs.

Figure 4.26 Intra-abdominal lesions of visceral origin metastasize to liver.

Conversely, low-grade lesions have a low risk of metastasis, particularly in the extremity, and often require little more than a chest X-ray for evaluation (see Chapter 6). When a patient is suspected of having metastatic disease by chest X-ray, CT scan of the lung will often demonstrate a greater number of lesions.

64

Diagnosis and Management of Soft Tissue Sarcoma

Extremity low-grade

Chest X-ray

Extremity high-grade <5 cm >5 cm

suspicion

Chest CT

Visceral/ retroperitoneal

suspic

ion

Abdominal CT + chest X-ray

Figure 4.27 Algorithm for staging patients with metastasis of extremity tumors. Patients being staged for metastasis of extremity tumors undergo chest X-ray. Utilizing amber technology, the detection rate of standard chest X-ray is extremely high. CT scanning of the chest is used for patients with high-risk tumors that are more likely to metastasize.3 Both of these are used in ongoing follow-up of people with primary or metastatic disease. Figure 4.27 shows our current algorithm.

In theory, because tumors are avid glucose users, they will take up more glucose at a higher rate than normal tissue. Essentially, 2deoxyglucose is a non-metabolizable form of glucose, but is taken up by the same pathways as normal glucose. Initial studies4 addressed the issue of whether or not the size of the tumor could be determined by the rate of uptake of the label. A later study has suggested that PET can be used for detecting local recurrence of soft tissue sarcoma.5 It was claimed in this study that lesions as small as 1 cm could be identified. In soft tissue sarcoma, PET can often differentiate between a benign lesion such as lipoma with no normal accumulation of fluorodeoxyglucose (FDG) and a high-grade sarcoma (Figure 4.28). It is possible that PET can be of value in identifying active areas of high-grade tumor, e.g. in the retroperitoneum

Positron emission tomography (PET) There is a theoretical advantage in using radionuclides in the examination of tumors. Radionuclides are isotopes of common biological elements such as carbon, oxygen or nitrogen and are therefore readily traced in human tissue. Of the fluorinated biologicals, fluorine-18 is a frequently used radionuclide. The chemical attachment is to 2-deoxyglucose, a non-metabolized but avidly taken up form of glucose. The half-life of 18F-deoxyglucose, however, is relatively short, approximately 110 min. It therefore must be manufactured close to the site of utilization and requires an on-site cyclotron.

Figure 4.28 PET scan of patient with high-grade radiation-induced sarcoma of right supraclavicular area with metastatic disease in right and left buttock and right lower lobe.

Clinical features, diagnosis and extent of disease evaluation of patients with large lipomas. At present, PET will rarely be used for sarcoma identification, except in situations where very high-risk lesions are suspected and the potential therapy may be quite morbid. PET can identify unsuspected metastasis in sarcomas, and may be of value in assessing response to treatment.

Radionuclide scintigraphy Radionuclide scintigraphy has been evaluated in soft tissue sarcoma.6,7 A prospective study using gallium-67 scanning showed high sensitivity and specificity in detecting malignancy. However, gallium-67 is rarely used, as other modalities provide equal information for less cost and with greater definition. Radiolabeled sarcoma antibodies have been explored by a number of groups, and remain an investigational tool.

References 1. Panicek DM, Gatsonis C, Rosenthal DI et al. CT and MR imaging in the local staging of primary malignant musculoskeletal

2.

3.

4.

5.

6.

7.

65

neoplasms: report of the Radiology Diagnostic Oncology Group. Radiology 1997;202:237–46. Panicek DM, Go SD, Healey JH et al. Soft tissue sarcoma involving bone or neurovascular structures: MR imaging prognostic factors. Radiology 1997;205:871–5. Arca MJ, Sondak VK, Chang AE. Diagnostic procedures and pretreatment evaluation of soft tissue sarcomas. Semin Surg Oncol 1994;10:323–31. Kern KA, Brunetti A, Norton JA, et al. Metabolic imaging of human extremity musculoskeletal tumors by PET. J Nuclear Med 1988;29:181–6. Kole AC, Nieweg OE, van Ginkel RJ et al. Detection of local recurrence of soft tissue sarcoma with positron emission tomography using [18F] fluorodeoxyglucose. Ann Surg Oncol 1997;4:57–63. Schwartz HS, Jones CK. The efficacy of gallium scintigraphy in detecting malignant soft tissue neoplasms. Ann Surg 1992;215:78–82. Southee AE, Kaplan WD, Jochelson MS, et al. Gallium imaging in metastatic and recurrent soft tissue sarcoma. J Nuclear Med 1992;33:1594–9.

5 Staging

100 80 % surviving

Staging of soft tissue sarcoma has undergone considerable evolution over the last 25 years. Early staging systems were dependent upon grade and the presence or absence of metastasis. The classical system formalized by the American Joint Committee on Cancer (AJCC) was based on data from 1977 (Figure 5.1).1 Stages I–III were determined by grade, and stage IV by the presence of metastasis. Each stage was subdivided, depending on the size of the primary presenting tumor: subgroup A tumors were <5 cm in size, and those in subgroup B were *5 cm. Based on this system, survival graphs were produced

60 40

Stage I Stage II Stage III Stage IV

20 0 0

1

2 3 Time (years)

4

5

Figure 5.1 Based on 1977 AJCC system, survival curves were produced. From Russell et al.1

Table 5.1 AJCC staging system for soft tissue sarcomas, 1992. Stage

Grade

Tumor

Nodes

Metastasis

IA IB IIA IIB IIIA IIIB IVA IVB

G1 G1 G2 G2 G3,4 G3,4 any G any G

T1 T2 T1 T2 T1 T2 any T any T

N0 N0 N0 N0 N0 N0 N1 any N

M0 M0 M0 M0 M0 M0 M0 M1

T, primary tumor: T1, tumor 압5 cm; T2, tumor 암5 cm. G, histopathologic grade: G1, well differentiated; G2, moderately differentiated; G3, poorly differentiated; G4, undifferentiated. N, regional lymph nodes: N0, no regional lymph node metastasis; N1, regional lymph node metastasis. M, distant metastasis: M0, no distant metastasis; M1, distant metastasis. From Beahrs et al.2

Diagnosis and Management of Soft Tissue Sarcoma

(Figure 5.1). By 1992, the AJCC staging system was modified to include the presence or absence of metastasis in nodes2 (Table 5.1). With time, it became clear that tumors of small size presenting for primary management had a much more favorable prognosis than would be expected if they were assigned to stage III in the AJCC system with other highgrade tumors. An examination of outcome in small, <5 cm tumors of the extremity, presenting for the first time, was published.3 Risks for local and distant disease-free survival were far less than had been expected in the original staging systems (Figures 5.2 and 5.3). Over time, the significance of the depth of the tumor in staging became evident, and at MSKCC a system based on prognostic factors was developed (Table 5.2). Each factor was given equal weight, and outcome was determined by the number of unfavorable factors present. This system was validated in extremity lesions. Again, the presence of nodal metastasis defined a worse outcome group (Figure 5.4).4 The re-evaluation of the prognostic values of factors used in staging of localized soft

Local disease-free survival (%)

100 80 60 40 High grade Low grade

20 0 0

12

24

36

48 60 72 Time (months)

84

96

108 120

Figure 5.2 Outcome: risks for local disease-free survival in small <5 cm tumors of the extremity. From Geer et al.3

100 Distant disease-free survival (%)

68

80 60 40 High grade Low grade

20 0 0

12

24

36

48 60 72 Time (months)

84

96

108 120

Figure 5.3 Outcome: risks for distant disease-free survival in small <5 cm tumors less than expected in original staging systems. From Geer et al.3

tissue sarcoma was published by our group in 1992.4 The independent risk factors for distant metastasis and tumor mortality were clearly identified as high grade, deep location and size. Thus, a staging system based on the risk of developing a distant metastasis would assign equal prognostic value to grade, depth and size. The tumor grade effect during the initial 18 months, however, was of much greater magnitude than that for depth and size, and the effect of grade progressively disappeared beyond that time. In the staging system based on the risk of early metastatic spread, a larger prognostic value was assigned to grade and lesser but equal values to depth and size. This important observation that prognostic factors for outcome can vary with time continues to be examined and developed. A further staging system for benign and malignant musculoskeletal neoplasms was developed by Wolf and Enneking.5 In addition to grade, this system employed compartment extension and presence or absence of metastases in defining degrees of risk (Table 5.3).

Staging Table 5.2

1.00 Proportion free of distant metastasis

69

MSKCC staging system risk factors. Size Depth Grade

0.80

<5 cm versus *5 cm Superficial versus deep High versus low

0.60

0.40

0.20

0.00 0

36

72 108 144 180 Months from start of therapy

216

Figure 5.4 At MSKCC, the presence of nodal metastasis defined a worse-outcome group. From Gaynor et al.4 쏔, 0 (28 patients, 25 censored); 앪 , 1 (67 patients, 50 censored); 쑶, 2 (88 patients, 55 censored); or 앳, 3 (138 patients, 42 censored). 앰, nodal metastasis at presentation (20 patients, 3 censored). (Note: a freedom from extranodal metastasic curve for the 20 patients who presented with nodal metastasis is included.) A tick mark (|) indicates last follow-up.

A recent study compared three staging systems, those proposed by the American Joint Committee on Cancer/Union Internationale Contre le Cancer (AJCC/UICC), Memorial Sloan-Kettering Cancer Center (MSKCC), and the Musculoskeletal Tumor Society (MTS), for efficacy in predicting systemic outcome of patients with localized extremity soft tissue sarcoma.6 The authors found that depth, grade and size were significant prognostic indicators, and the two systems that incorporated these factors, MSKCC and AJCC/UICC, could be used to identify patients who might benefit from adjuvant systemic therapy. A somewhat more complicated staging system has been published by the AJCC (Table 5.4).7 Grade, size and depth are employed as features of staging to allow for much improved discrimination in survival. Again, this system is predicated upon grade, size and depth combinations, and stage IV includes any M1 or N1 disease.

Table 5.3 Staging of malignant lesions. Stage

Description

Grade

Site

Metastases

IA IB IIA IIB III

Low grade, intracompartmental Low grade, extracompartmental High grade, intracompartmental High grade, extracompartmental Any grade, metastatic

G1 G1 G2 G2 G1–2

T1 T2 T1 T2 T1–2

M0 M0 M0 M0 M1

From Wolf RE et al.5

70

Diagnosis and Management of Soft Tissue Sarcoma

Table 5.4 AJCC staging system for soft tissue sarcoma, 1997. Stage

Grade (G)

Tumor (T)

Nodes (N)

Metastasis (M)

IA

G1–G2 (low grade)

N0

M0

IB

G1–G2 (low grade) G1–G2 (low grade) G3–G4 (high grade)

T1a–T1b (small; superficial or deep) T2a (large; superficial) T2b (large; deep) T1a–T1b (small; superficial or deep) T2a (large; superficial) T2b (large; deep) Any T

N0

M0

N0

M0

N0

M0

N0

M0

N1 N0

M0 M1

IIA IIB

IIC III IV

G3–G4 (high grade) G3–G4 (high grade) Any G

T Primary tumor: TX, primary tumor cannot be assessed; T0, no evidence of primary tumor; T1, size )5 cm in greatest dimension – T1a, superficial tumor; T1b, deep tumor; T2, size >5 cm in greatest dimension – T1a, superficial tumor; T2b, deep tumor. G Histopathologic grade: GX, grade cannot be assessed; G1, well differentiated; G2, moderately differentiated; G3, poorly differentiated; G4, undifferentiated. N Regional lymph nodes: NX, regional lymph nodes cannot be assessed; N0, no regional lymph node metastasis; N1, regional lymph node metastasis. M Distant metastasis: MX, distant metastasis cannot be assessed; M0, no distant metastasis; M1, distant metastasis. From Fleming et al.7

It should be emphasized that these staging systems do not discriminate for local recurrence (Figures 5.5 and 5.6); that is, any risk factor combination has a similar risk of local recurrence. Further definitive validation is required other than the single database that we have utilized.

Significance of lymph node metastasis Lymph node metastasis is relatively infrequent in soft tissue sarcoma. This is particularly so in adult soft tissue sarcoma. For example, the

finding of lymph node metastasis in liposarcoma, not due directly to direct invasion by the tumor, is a rare event and may even raise a question as to the primary diagnosis. Overall, the presence of lymph node metastasis is less than 5% and it tends to occur primarily in sarcomas with epithelioid characteristics (Table 3.2).8–10 Figure 5.7 illustrates diseasespecific survival in patients presenting with lymph node metastases compared with patients presenting with other metastases; (that is, a lymph node metastasis has a similar risk of disease-dependent death as any other metastasis. A practical form for obtaining this information is shown in Figure 5.8.

Staging

Figure 5.5 Local recurrencefree survival: old 1992 AJCC staging system. MSKCC, 7/82–12/97.

1

0.8

Proportion surviving

71

0.6

0.4

1A n=140 1B n=221 3A n=272 3B n=426

0.2

p=NS

0 0

20

40

60

80

100 Months

120

140

160

180

200

n=1059

Figure 5.6 Local recurrencefree survival: new 1997 AJCC staging system. MSKCC, 7/82–12/97.

1

Proportion surviving

0.8

0.6

0.4

1A n=140 1B n=30 2A n=191 2B n=272 2C n=23 3 n=403

0.2

p=NS

0 0

20

40

60

80

100 Months

120

140

160

180

200

n=1059

Future directions in staging It is now clear, however, that the staging system will have to be further revised. This probably can be done only by a large single

institution database. When we examine the present staging systems (Table 5.4), it is clear that patients with stage 1, i.e. low-grade lesions that are large and superficial, make up a very small group of patients, approximately 3% of the total (Table 5.5). This is in

72

Diagnosis and Management of Soft Tissue Sarcoma Figure 5.7 Disease-specific survival in patients presenting with lymph node metastases compared with patients presenting with other metastases. MSKCC, 7/82–12/00.

1.0

Lymph node (n=160) Other (n=891)

Proportion surviving

0.8

0.6

0.4

0.2

0.0 0

40

80

120 Time (months)

n=1051

Patient identification _____________________________ Name _________________________________________ Address _______________________________________ Hospital or clinic number ________________________ Age _______ Sex __________ Race________________

Institution identification Hospital or clinic _________________________________ Address __________________________________________

Oncology Record Anatomic site of cancer __________________________ Histologic type _________________________________ Grade (G) _____________________________________ Date of classification ____________________________ Clin

Path

[ [ [ [ [ [ [ [

] ] ] ] ] ] ] ]

[ [ [ [ [ [ [ [

] ] ] ] ] ] ] ]

[ [ [

] ] ]

[ [ [

] ] ]

[ [ [

] ] ]

[ [ [

] ] ]

Distant Metastasis (M) MX Distant metastasis cannot be assessed M0 No distant metastasis M1 Distant metastasis

[ [ [ [ [

] ] ] ] ]

[ [ [ [ [

] ] ] ] ]

Histopathologic Grade (G) GX Grade cannot be assessed G1 Well differentiated G2 Moderately differentiated G3 Poorly differentiated G4 Undifferentiated

Clin

Path

[

]

[

]

[

]

[

]

[

]

[

]

[

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]

DEFINITIONS Primary Tumor (T) TX Primary tumor cannot be assessed T0 No evidence of primary tumor T1 Tumor 5 cm or less in greatest dimension T1a superficial tumor T1b deep tumor T2 Tumor more than 5 cm in greatest dimension T2a superficial tumor T2b deep tumor Superficial tumor is located exclusively above the superficial fascia without invasion of the fascia; deep tumor is located either exclusively beneath the superficial fascia, or superficial to the fascia with invasion of or through the fascia, or superficial and beneath the fascia. Retroperitoneal, mediastinal, and pelvic sarcomas are classified as deep tumors. Regional Lymph Nodes (N) NX Regional lymph nodes cannot be assessed* N0 No regional lymph node metastasis N1 Regional lymph node metastasis * Because of the rarity of lymph node involvement in sarcomas, the designation NX may not be appropriate and could be considered N0 if no clinical involvement is evident.

Stage Grouping Stage I A (Low grade, small, superficial and deep) B (Low grade, large, superficial) Stage II A (Low grade, large, deep) B (High grade, small, superficial, deep) C (High grade, large, superficial) Stage III (High grade, large, deep) Stage IV (any metastasis)

G1–2, T1a–1b, N0, M0 G1`–2, T2a, N0, M0 G1–2, T2b, N0, M0 G3–4, T1a–1b, N0, M0 G3–4, T2a, N0, M0 G3–4, T2b, N0, M0 any G, any T, N1, M0 any G, any T, N0, M1

Managed by _____________________________ M.D. ______________________________________ Registrar Date _________________________________________ Histopathologic Type

Figure 5.8 Data form for cancer staging.

(continued on next page)

160

200

240 p=0.1

Tumors included in the soft tissue category are listed below with the appropriate ICD-O morphology rubrics: Alveolar soft-part sarcoma (9581/3) Angiosarcoma (9120/3) Epithelioid sarcoma (8804/3) Extraskeletal chondrosarcoma (9220/3) Extraskeletal osteosarcoma (9180/3) Fibrosarcoma (8810/3) Leiomyosarcoma (8890/3) Liposarcoma (8850/3) Malignant fibrous histiocytoma (8830/3) Malignant hemangiopericytoma (9150/3) Malignant mesenchymoma (8890/3) Malignant schwannoma (9560/3) Rhabdomyosarcoma (8900/3) Synovial sarcoma (9040/3) Sarcoma, NOS (8800/3) The following histologic types of tumors are not included: Kaposi’s sarcoma, dermatofibrosarcoma (protuberans), fibrosarcoma grade I (desmoid tumor), and sarcoma arising from the dura mater, brain, parenchymatous organs or hollow viscera.

Staging

73

Table 5.5 Primary extremity soft tissue sarcoma. Distant metastases by stage. MSKCC, 7/92–12/97 (n=1059). Total (n) Old staging system (1992) 1A 1B 3A 3B New staging system (1997) 1A 1B 2A 2B 2C 3A 3B

Yes (%)

140 221 272 426

2 13 47 144

(1) (6) (17) (34)

140 30 191 272 23 208 195

2 3 10 47 4 57 83

(1) (10) (5) (17) (17) (27) (43)

From Brennan MF.11

contradistinction to the relatively uniform distribution of the other stages, with the exception of stage 2C, which is consistent with a paucity of large superficial lesions. When one examines the risk of distant metastasis in groups 1B and 2C, large, low grade and superficial, and large, high grade and superficial, respectively, the actual numbers involved, while small, have a relatively high risk of distant metastasis, 10% and 17%, respectively. Moreover, the 1992 AJCC staging system and the 1997 AJCC staging system do not discriminate for local recurrence (Figures 5.5 and 5.6), which, in the majority of patients, is approximately 10–20%. It is important to emphasize that staging systems are predominantly designed for systemic risk of death from disease, and so local recurrence is rarely included and one must turn to large populations to look at the actual risks for local recurrence (see Chapter 6).

When we examine discrimination in the 1992 AJCC staging system for distant metastasis, accepting that in our database there is no intermediate grade, then, in fact, there is a quite reasonable distinction between 1A,1B, 3A and 3B (Figure 5.9). In the 1997 AJCC staging system, with the addition of groups 2A and 2C, i.e. low grade, large and superficial, and high grade, large and superficial, the discrimination is worse than in the 1992 AJCC system and is dominated by the small numbers contained within groups 1B and 2C. This is also apparent when disease-specific survival is examined (Figure 5.10). It is clear, however, that even within stage 3, consisting of patients with high-grade large tumors, greater than 5 cm, size remains a factor in prognosis, and one might suggest that stage 3 be divided into 3A and 3B, i.e. >5 cm, <10 cm and >10 cm, to give further discrimination in survival.

74

Diagnosis and Management of Soft Tissue Sarcoma Figure 5.9 Discrimination in the old staging system for metastasis shows a reasonable distinction between 1A, 1B, 3A, and 3B. MSKCC, 7/82–12/97.

1

Proportion surviving

0.8

0.6

0.4

p=0.0001 0.2

1A n=140 1B n=221 3A n=272 3B n=426

0 0

20

40

60

80

100 Months

120

140

160

180

200

n=1059

Bearing in mind that the numbers of patients in stages 2A and 2C are markedly small, 2A can be easily included in a single stage 1, and the very small number of patients with 2C lesions can be combined with stage 2. In that circumstance, and dividing the highgrade large tumors, improved delineation of

distant metastasis-free survival can be obtained (Figure 5.11). It seems, therefore, that a revised simplified staging system which would include an appropriate representative number of patients in all groups would be preferable (Table 5.6). These suggestions have been summarized.11

Figure 5.10 Disease-specific survival in the new staging system. MSKCC, 7/82–12/97.

1

Proportion surviving

0.8

0.6

0.4

1A n=140 1B n=30 2A n=191 2B n=272 2C n=23 3 n=403

0.2

p=0.0001

0 0 n=1059

20

40

60

80

100 Months

120

140

160

180

200

Staging

Figure 5.11 Dividing the highgrade large tumors and combining 1A, 1B, 2A and 2B/2C, much improved distant metastasisfree survival can be delineated. MSKCC, 7/82–12/97.

1

Proportion surviving

0.8

0.6

0.4

p=0.0001 0.2

75

1A /1B/2A n=361 2B/2C n=295 3A n=208 3B n=195

0 0

20

40

60

80

100 Months

120

140

160

180

200

n=1059

Variation of prognostic factors with time All staging systems are static, i.e. they stage the patient at one moment in time. While this

would appear appropriate for survival, it is important to emphasize (see Chapter 6) that, over time, such factors for outcome may not retain the same power of prediction. A good example of the time factor would be the increasing influence of size over grade.11

Table 5.6 Staging system. AJCC 1977

AJCC 1997

Stage

Grade

Size

Grade

Size

Superficial/ deep

1A

LG

Small

1B IIA IIB

LG Intermediate Intermediate

Large Small Large

IIC IIIA IIIB IV

– HG HG

– Small Large

LG LG LG LG HG HG HG HG HG any N any M

Small Small Large Large Small Small Large Large Large

Superficial Deep Superficial Deep Superficial Deep Superficial Deep Deep

LG, low grade; HG, high grade; Small, <5 cm; Large, >5 cm.

Proposed

LG HG small HG large, superficial HG>5 cm, <10 cm, deep HG>10 cm, deep

76

Diagnosis and Management of Soft Tissue Sarcoma

Staging of non-extremity lesions: retroperitoneal and visceral sarcomas There is no adequate staging system for visceral and retroperitoneal sarcomas. The majority of patients present with large lesions and the majority of visceral sarcomas are high grade, although there are many clinicians and pathologists who prefer not to grade gastrointestinal stromal tumors. In the retroperitoneum, the very large tumors are often low-grade liposarcomas, many of which contain focal areas of high-grade histology. As opposed to extremity lesions, where local recurrence is rarely the cause of death, local recurrence of visceral and retroperitoneal tumors is often lethal. Staging, therefore, focuses on their large size and grade as the best predictor of outcome in the absence of known metastasis. The major predictor of survival is complete resection. Analysis of patients having complete resection shows only grade to be a secondary factor in long-term survival (see Chapter 6).

References 1. Russell WO, Cohen J, Enzinger F et al. A clinical and pathological staging system for soft tissue sarcoma. Cancer 1977;40:1562–70. 2. Beahrs OH, Henson DE, Hutter RVP, Kennedy BJ, eds. Manual for Staging Cancer. American Joint Committee on Cancer, 4th edn. Philadelphia: JB Lippincott, 1992. 3. Geer RJ, Woodruff J, Casper ES et al. Management of small soft tissue sarcoma of the extremity in adults. Arch Surg 1992;127:1283–7. 4. Gaynor J, Tan C, Casper ES et al. Refinement of clinicopathological staging for localized soft tissue sarcoma of the extremity: a study of 423 adults. J Clin Oncol 1992;10:1317. 5. Wolf RE, Enneking WF. The staging and surgery of musculoskeletal neoplasms. Orthop Clin North Am 1996;27:473–81. 6 Wunder J, Healey J, Davis AM, Brennan MF. A comparison of three staging systems for localized extremity soft tissue sarcoma. Cancer 2000;88:2721–30. 7. Fleming ID, Cooper JS, Henson DE et al. Soft tissue sarcoma. In: Fleming ID, Cooper JS, Henson DE, eds. AJCC Cancer Staging Manual. American Joint Committee on Cancer, 5th edn. Philadelphia: LippincottRaven, 1997;149–56. 8. Brennan MF, Casper ES, Harrison LB. Soft tissue sarcoma. In: DeVita VT, Hellman S, Rosenberg SA, eds. Cancer: Principles and Practice of Oncology, 5th edn. Philadelphia: Lippincott, 1997:1738–88. 9. Weingrad DN, Rosenberg SA. Early lymphatic spread of osteogenic and soft tissue sarcomas. Surgery 1978;84:231. 10. Mazeron JJ, Suit HD. Lymph nodes as sites of metastases from sarcomas of soft tissue. Cancer 1987;60:1800. 11. Brennan MF. Staging of soft tissue sarcomas. Ann Surg Oncol 1999;6:8–9.

6 Prognostic factors

Prognosis has been well defined for patients with soft tissue sarcoma. Several fundamental concepts are important. Soft tissue sarcomas are diverse, but tend to behave in a similar fashion when grouped together. Outcome variables must be carefully selected in terms of analyzing the impact of prognostic factors. Despite the evolution of several newer molecular markers and technologies, the best variables defining prognosis remain size, site and grade. The endpoints defining prognosis include local recurrence, metastatic recurrence, and tumor mortality. The relationship between these endpoints is complex and is certainly, at least in part, site-dependent.

statistical techniques to identify prognostic factors for the endpoints of local recurrence, metastatic recurrence, tumor mortality and post-metastasis survival. Ongoing analyses of this same group of patients confirmed the results. (Tables 6.1 and 6.2). It is clear that age greater than 50, recurrent presentation, positive microscopic margin and the histopathologic subtype of fibrosarcoma or malignant peripheral nerve tumor are factors in the multivariate analysis increasing the risk of local recurrence.

Site Total upper extremity 31%

Extremity and superficial trunk soft tissue sarcoma: prognostic factors for outcome in extremity lesions The two largest single-institution analyses of extremity lesions are from MSKCC, studies of 423 and 1041 patients.1,2 The latter study analyzed patients with extremity sarcoma who were treated between 1982 and 1994 (Figure 6.1). Patient, tumor and pathologic factors were analyzed by univariate and multivariate

Shoulder 7% Axilla 4%

Upper arm 7%

Forearm 7% Groin 5% Thigh 43% Knee 4% Lower leg 10% Foot 4% n=1041

Total lower extremity 69%

Figure 6.1 Prevalence of extremity sarcoma in 1041 patients. MSKCC, 7/82–8/94. From Pisters et al.2

78

Diagnosis and Management of Soft Tissue Sarcoma

Table 6.1 Prognostic factors for extremity soft tissue sarcoma. Outcome variable

Table 6.2 Prognostic factors in extremity soft tissue sarcoma – summary of significant adverse prognostic factors in disease-specific survival.

Factors prognostic by multivariate analysis

Local recurrence

High grade Size >5 cm Deep location Positive margins Local recurrence at presentation Lower extremity

Presentation with recurrent disease Positive surgical margins High histologic grade Deep location Size *5 cm Age * 60 years Time from presentation to metastasis Metastasis to sites other than single lung

Distant metastasis

Survival after metastasis

MSKCC, 1982–94. n=1041 localized extremity soft tissue sarcoma. From Pisters et al.2

From Pisters et al.2

The association between local recurrence and subsequent survival is both enigmatic and controversial.3 For local recurrence, high versus low grade has much less influence (Figure 6.2). High grade and size >5 cm are

also tumor factors in recurrence. It should be understood that grade and size are continuous variables, and the degree of grade is a continuum, just as size is a continuum. Depth is an independent predictor of survival but is

Figure 6.2 Extremity soft tissue sarcoma; local recurrence according to grade. MSKCC, 7/82–12/00.

1.0

Proportion surviving

0.8

0.6

0.4

0.2 High (n=970) Low (n=514)

0.0 0 n=1484

40

80

120 Time (months)

160

200

240 p < 0.4

Prognostic factors of less value (see Chapter 5) in an absolute staging system, mainly because large, superficial tumors are very uncommon. Multiple graphic representations of recurrence according to histopathology can be outlined. For example, malignant fibrous histiocytoma (MFH) and liposarcoma are

equally prevalent, but have a difference in disease-specific survival. In liposarcoma, disease-specific survival is clearly gradedependent (Figure 6.3). Fibrosarcoma, while having a lesser overall risk of disease-specific demise, shows a similar influence of grade (Figure 6.4). The high-grade variant of MFH Figure 6.3 Extremity liposarcoma; disease-specific survival according to grade. MSKCC, 7/82–12/00.

1.0

0.8

Proportion surviving

79

0.6

0.4

0.2 High (n=163) Low (n=172)

0.0 0

40

80

n=335

120 Time (months)

160

200

240 p < 0.01

Figure 6.4 Fibrosarcoma; disease-specific survival according to grade. MSKCC, 7/82–12/00.

1.0

Proportion surviving

0.8

0.6

0.4

0.2 High (n=32) Low (n=105)

0.0 0 n=137

40

80

120 Time (months)

160

200

240 p < 0.001

80

Diagnosis and Management of Soft Tissue Sarcoma

(Figure 6.5) has a much worse prognosis than high-grade liposarcoma (Figure 6.3) and fibrosarcoma (Figure 6.4), but the low-grade variety has a relatively good prognosis. While on occasion synovial cell sarcomas have been divided between high and low

grade, essentially they are all high grade, and the outcome in terms of disease-specific survival is shown in Figure 6.6. The influence of grade for all patients with extremity lesions is clearly demonstrated when overall survival is based on grade alone (Figure 6.7). This is

Figure 6.5 MFH; diseasespecific survival according to grade. MSKCC, 7/82–12/00.

1.0

Proportion surviving

0.8

0.6

0.4

0.2 High (n=270) Low (n=110)

0.0 0

40

80

120 Time (months)

n=380

160

200

240 p < 0.01

Figure 6.6 Synovial cell sarcoma; diseasespecific survival. MSKCC, 7/82–12/00.

1.0

Proportion surviving

0.8

0.6

0.4

0.2

0.0 0 n=169

20

40

60

80

100

120 140 Time (months)

160

180

200

220

240

Prognostic factors

Retroperitoneal and visceral sarcoma

equally dramatic when illustrated as diseasespecific survival (Figure 6.8). When diseasespecific survival is based on size within grade, clearly the larger tumors have a worse prognosis (Figure 6.9). Post-metastasis survival, regardless of site, remains the same (Figure 6.10).

Both of these tumors occur within the abdomen, and display some similarities in behavior, but are distinctive in their biology. Figure 6.7 Extremity soft tissue sarcoma; overall survival according to grade. MSKCC, 7/82–12/00.

1.0

0.8

Proportion surviving

81

0.6

0.4

0.2 High (n=970) Low (n=514)

0.0 0

40

80

n=1484

120 Time (months)

160

200

240 p < 0.01

Figure 6.8 Extremity soft tissue sarcoma; disease-specific survival according to grade. MSKCC, 7/82–12/00.

1.0

Proportion surviving

0.8

0.6

0.4

0.2 High (n=970) Low (n=514)

0.0 0 n=1484

40

80

120 Time (months)

160

200

240 p < 0.01

82

Diagnosis and Management of Soft Tissue Sarcoma Figure 6.9 Extremity soft tissue sarcoma; disease-specific survival according to size. MSKCC, 7/82–12/00.

1.0

Proportion surviving

0.8

0.6

0.4

0.2 <5 cm (n=450) >5,< 10 cm (n=423) >10 cm (n=408) 0.0 0

40

80

n=1281

120 Time (months)

160

200

240 p < 0.01

Figure 6.10 Post-metastasis survival, regardless of site, remains the same. MSKCC, 7/82–12/00.

1.0 Extremity/trunk (n=561) Visceral (n=179) Retroperitoneal/intra-abdominal (n = 98) Other (n=104)

Proportion surviving

0.8

0.6

0.4

0.2

0.0 0 n=942

40

80

120 Time (months)

We analyzed our experience with 500 patients with retroperitoneal soft tissue sarcoma and 200 patients with visceral soft tissue sarcoma.4,5

160

200

240 p < 0.02

Retroperitoneal soft tissue sarcoma The dilemma posed by the biology of these tumors is contingent on the anatomic location, with frequent late presentation and invasion of

Prognostic factors contiguous retroperitoneal structures. These factors often make treatment difficult, and this is integral to the prognostic factors. Five hundred patients with retroperitoneal soft tissue sarcoma (STS) who were admitted to MSKCC and treated between July 1982 and September 1997 were prospectively followed.4 Patient, tumor and treatment variables were analyzed for disease-specific and disease-free survival, determined with the Kaplan–Meier method. Statistical significance was evaluated

83

using log-rank test for univariate and Cox model stepwise regression for multivariate influence. Factors strongly associated with tumor mortality were stage at presentation, high histologic grade, unresectable primary tumor and positive gross margins. For patients with primary or locally recurrent tumors, unresectable disease, incomplete resection and high-grade tumors significantly reduced survival time.

Table 6.3 Analysis of local recurrence-free survival in 231 primary retroperitoneal sarcoma patients with resectable disease. N

Sex Female Male Age <50 years *50 years Grade Low High Size )10 cm >10 cm Histologic subtype Fibrosarcoma Leiomyosarcoma Liposarcoma Other Surgical resection margins Negative microscopic and gross margins Positive microscopic and negative gross margins Positive microscopic and gross margins aUnivariate

p-valuea (univariate)

p-value (multivariate)

Relative riskb (CI)

0.01

2.0 (1.2–3.4)

0.01

2.6 (1.5–4.6)

0.06 91 140 0.9 75 156 0.05 97 134 0.07 59 170 0.02 16 48 109 58 0.2 136 49 46

p refers to log-rank test of no difference versus any difference between categories. risk to other categories of the same factor. CI, confidence interval. From Lewis et al.4 bRelative

84

Diagnosis and Management of Soft Tissue Sarcoma

Local recurrence-free survival

Metastasis-free survival

Analysis of local recurrence-free survival is summarized in Table 6.3. Of the 500 patients in the analysis, 231 patients who presented to MSKCC with primary disease were resected. Local recurrence-free survival in these patients was 81% (CI 76–86%) at 2 years and 59% (CI 55–63%) at 5 years. Factors predictive for local recurrence included high histologic grade and histologic subtype of liposarcoma.

Metastasis-free survival was 88% at 2 years and 79% at 5 years. Sites of metastasis included the lung and the liver. Post-metastasis survival is shown in Figure 6.11. Median survival following metastasis was 13 months. Factors predictive of subsequent metastasis included high-grade tumors and positive microscopic and gross margins at the time of operation.

Table 6.4 Analysis of distant metastasis-free survival in 231 primary retroperitoneal sarcoma patients with resectable disease. N

Sex Female Male Age <50 years *50 years Grade Low High Size )10 cm >10 cm Histologic subtype Fibrosarcoma Leiomyosarcoma Liposarcoma Other Surgical resection margins Negative microscopic and gross margins Positive microscopic and negative gross margins Positive microscopic and gross margins aUnivariate

p-valuea (univariate)

p-value (multivariate)

Relative riskb (CI)

0.01

5.0 (1.7–15)

0.01

0.2 (0.07–0.7)

0.01

3.9 (1.6–9.5)

0.8 91 140 0.8 75 156 0.01 97 134 0.6 59 170 0.01 16 48 109 58 0.01 136 49 46

p refers to log-rank test of no difference versus any difference between categories. risk to other categories of the same factor. From Lewis et al.4

bRelative

Prognostic factors There are thus several differences between extremity and retroperitoneal tumors. Tumor mortality in extremity tumors, while associated with local recurrence, is almost always consequent on metastasis. In contrast, most patients who die from retroperitoneal sarcoma die from local recurrence. Analysis of distant metastasis-free survival in 231 primarily resected patients is shown in Table 6.4. 1 (n=28) Proportion surviving

0.8 0.6 0.4 0.2 0 0

20

40

60

80

Time (months)

Figure 6.11 Retroperitoneal sarcoma; post-metastasis survival. MSKCC, 7/82–9/97. From Lewis et al.4

85

Disease-specific survival Disease-specific survival following the first local recurrence is shown in Figure 6.12. Median survival following local recurrence was 28 months, similar to those patients presenting with local recurrence. Complete resection was a significant variable predicting post-local recurrence survival (Figure 6.13). Resection rate decreased after each subsequent local recurrence; thus, after the first local recurrence, 57% of patients underwent complete resection whereas after the second local recurrence, the rate went down to 22%, and after the third to 10% (Figure 6.14). Table 6.5 shows univariate and multivariate analyses of disease-specific survival. Unresectable disease, incomplete resection and high histologic grade were predictive factors for poor outcome. There was no significant difference in survival between patients who were unresectable and those who underwent incomplete resection in this group of retroperitoneal sarcomas.

1 Complete resection (n=35) Incomplete resection (n=26)

1 0.8 Proportion surviving

(n=61) Proportion surviving

0.8 0.6 0.4

0.6 0.4 0.2

0.2

p=0.01 0 0

0 0

20

40

60

80

20

40

60

80

Time (months)

Time (months)

Figure 6.12 Retroperitoneal sarcoma; disease-specific survival following the first local recurrence. MSKCC, 7/82–9/97. From Lewis et al.4

Figure 6.13 Retroperitoneal sarcoma; complete resection is a significant variable predicting post-local recurrence survival. MSKCC, 7/82–9/97. From Lewis et al.4

86

Diagnosis and Management of Soft Tissue Sarcoma

Table 6.5 Analysis of disease-specific survival in 231 primary retroperitoneal sarcoma patients with resectable disease. N

Sex Female Male Age <50 years *50 years Grade Low High Size )10 cm >10 cm Histologic subtype Fibrosarcoma Leiomyosarcoma Liposarcoma Other Surgical resection margins Negative microscopic and gross margins Positive microscopic and negative gross margins Positive microscopic and gross margins

p-valuea (univariate)

p-value (multivariate)

Relative riskb (CI)

0.001

3.0 (1.8–5.0)

0.4 91 140 0.1 75 156 0.001 97 134 0.04 59 170

2.0 (1.2–3.6) 0.2

16 48 109 58 0.001 136 49 46

0.03 0.001

1.9 (1.0–3.4) 5.5 (3.2–9.3)

aUnivariate

p refers to log-rank test of no difference versus any difference between categories. risk to other categories of the same factor. From Lewis et al.4

bRelative

The median survival of patients with highgrade tumors was 33 months compared with 149 months for patients with low-grade tumors (Figure 6.15). Size of the primary tumor did not appear to impact on survival.

Visceral tumors Gastrointestinal stromal tumors (GIST) comprise a heterogeneous group of malignant

visceral sarcomas, including leiomyosarcoma, gastrointestinal autonomic nerve tumor (GANT) and gastrointestinal stromal tumor not otherwise specified (GIST–NOS). No published data compare the biological behavior and prognosis of these entities. One paper5 analyzed experience with 200 patients with GIST presenting to MSKCC from July 1982 to February 1998, to identify prognosticators for recurrence and survival (Table 6.6).

Prognostic factors

median survival of 19 months. Patients with local recurrence and those who could not undergo complete resection had a median survival of 12 months. Complete resection was possible in 80 patients. For these patients, by univariate analysis, grade (for leiomyosarcoma) and size were important predictors of survival; by multivariate analysis, size was the dominant predictor. Margin status had no impact upon survival. The median disease-free interval after initial resection was 20 months, predicted by age and grade. Disease-specific survival was 88% at 1 year, 65% at 3 years and 54% at 5 years.

100 % complete resection

185 / 231 80 35 / 61

60 40

8 / 24

20

1/7

0 Primary

1st recurrence

2nd recurrence

3rd recurrence

Figure 6.14 Retroperitoneal sarcoma; complete resection rate decreases after each subsequent local recurrence. MSKCC, 7/82–9/97. From Lewis et al.4

Prognostic relevance of proliferation markers One study6 suggested that the analysis of proliferation marker Ki-67 by the monoclonal antibody Ki-S11 is an independent prognostic factor for survival and systemic progression in soft tissue sarcoma. Of 130 patients, 71 were admitted with primary lesions. Ninety-five per cent of the sarcomas had Ki-67 immunoreactivity. In this study, immunolabeling scores were used, i.e. the number of labeled nuclei calculated as a percentage of the total cell count.

Colorectal tumors comprised 16% of the total. The most common anatomic sites of tumor origin were the stomach (39%) and the small intestine (32%). More than two-thirds of patients had tumors >5 cm in size. The predominant histologic type was leiomyosarcoma (67%) and 88% of these were high grade. Of the remaining tumors, 20% were GIST–NOS and 14% were GANT. Overall survival for all patients in the study was 35% at 5 years. Those with metastasis had a

1

Figure 6.15 Retroperitoneal sarcoma; diseasespecific survival in patients with highand low-grade tumors. MSKCC, 7/82–9/97. From Lewis et al.4

Low (n=110) High (n=168)

Proportion surviving

0.8 0.6 0.4 0.2 0 0

20

40

60

80

100

Time (months)

87

120

140

160

180 p=0.0001

88

Diagnosis and Management of Soft Tissue Sarcoma

Table 6.6 Gastrointestinal stromal tumors; association of factors with survival.a Entire population (n=200) Univariate Multivariate Presentation Primary Local recurrence Metastasis Age )50 >50 Sex Female Male Size )5 cm >5 cm, )10 cm >10 cm Surgical margins –Gross –Micro –Gross +Micro +Gross/unresectable

RR (CI)

Completely resected primary presentation (n=80) Univariate Multivariate RR (CI)

0.01

0.08

0.4

0.08

0.3 0.04

1.6 (1.0–2.6)

0.01

0.04 0.01 0.01

2.8 (1.3–6.2) 4.4 (2.0–9.8)

0.01

0.01

2.5 (1.2–5.5)

0.4

0.01

3.9 (2.4–6.2)

NA

aIn

the entire population and in those with primary presentation who underwent complete resection. RR, relative risk; CI, confidence interval; NA, not applicable. From DeMatteo et al.5

Five-year freedom from distant metastasis with a Ki-67 score of <20 was 70% versus 50% for a score of >20. Overexpression of p53 or of mdm2 did not correlate with an increased risk of distant metastasis.7 We have also studied the expression of cyclin D1.8 Binding of G1 cyclins to cyclin-dependent kinases results in phosphorylation of the RB protein and progression through the G1 and S phases of the cell cycle. We studied expression of cyclin D1 in 84 patients with extremity soft tissue sarcoma. We found that overexpression of cyclin D1 was significantly associated with a

worse overall survival for the entire group of patients as well as for the subset with highgrade tumors. Conversely, cyclins E and A did not correlate in terms of overexpression and survival. While this particular study had a relatively short follow-up time (with a mean of 2.4 years), it is strongly suggestive that expression of cell cyclin regulatory gene products correlates with prognosis. In another study,9 we studied the INK4A and INK4B genes with PCR and SSCP (single strand conformation polymorphism) analysis. We found that the overall frequency of gene

Prognostic factors alteration (deletion or rearrangement) was approximately 15% for the INK4A and INK4B genes, with these changes restricted to high-grade sarcomas. We found associations between combined INK4A/INK4B deletions or alterations and poor survival. Thus, coincident homozygous deletion of the INK4A and INK4B genes may be associated with more aggressive biological behavior. Despite the fact that all of these studies have generated new information regarding molecular mechanisms and molecular correlation with prognosis,10 none of them is as powerful as traditional definition of grade by light microscopy and tumor size. Thus, the welldefined clinical prognostic variables for soft tissue sarcoma are predictive and reliable, while the relevance of molecular proliferation markers remains investigational.

References 1. Gaynor J, Tan C, Casper ES et al. Refinement of clinicopathological staging for localized soft tissue sarcoma of the extremity: a study of 423 adults. J Clin Oncol 1992;10:1317–29. 2. Pisters PWT, Leung DHY, Woodruff J et al. Analysis of prognostic factors in 1,041 patients with localized soft tissue sarcoma of the extremities. J Clin Oncol 1996;14:1679–89.

89

3. Lewis JJ, Leung D, Heslin M et al. Association of local recurrence with subsequent survival in extremity soft tissue sarcoma. J Clin Oncol 1997;15:646–52. 4. Lewis JJ, Leung D, Woodruff JM, Brennan MF. Retroperitoneal soft tissue sarcoma: analysis of 500 patients treated and followed at a single institution. Ann Surg 1998;228:355–65. 5. De Matteo RP, Lewis JJ, Leung D et al. Two hundred gastrointestinal stromal tumors – recurrence patterns and prognostic factors of survival. Ann Surg 2000;231:51–8. 6. Rudolph P, Kellner V, Chasseventa A et al. Prognostic relevance of a novel proliferation marker, Ki-S11, for soft tissue sarcoma. A multivariate study. Am J Pathol 1997;150:1997–2007. 7. Heslin MJ, Cordon-Cardo C, Lewis JJ et al. Ki-67 detected by MIB-1 predicts distant metastasis and tumor mortality in primary, high grade extremity soft tissue sarcoma. Cancer 1998;83:490–7. 8. Kim SH, Lewis JJ, Brennan MF et al. Overexpression of cyclin D1 is associated with poor prognosis in extremity soft tissue sarcomas. Clin Cancer Res 1998;4:2377–82. 9. Orlow I, Drobnjak M, Zhang ZF et al. Alterations of INK4A and INK4B genes in adult soft tissue sarcomas: effect on survival. J Nat Cancer Inst 1999;91:73–9. 10. Antonescu CR, Leung DH, Dudas M et al. Alterations of cell cycle regulators in localized synovial sarcoma: a multifactorial study with prognostic implications. Am J Pathol 2000;156:977–83.

7 Clinical and pathologic correlates

The desmoid tumor Diagnosis The natural history of the desmoid tumor is enigmatic.1 The clinical behavior often resembles that of a low-grade fibrosarcoma; that is, the lesion can be infiltrative and persistent, but essentially never metastasizes. Like most other suspected sarcomas, the desmoid presents as a localized firm to hard

Retroperitoneal/ intra-abdominal 9% Abdominal wall 17%

25 47 108

Extremity 40%

94

Other 34% n=274

Figure 7.1 Desmoids by body site. MSKCC, 7/82–12/00.

mass, usually in the proximal extremity or the abdominal wall (Figure 7.1). Characteristics that may suggest a desmoid diagnosis include site (the abdominal wall in a parturient female, the retroperitoneum in a patient with familial polyposis, or a muscular insertion in an athlete) and a prolonged history of slow growth.

Desmoids in the presence of familial polyposis Clinical desmoids occur in approximately 10% of all patients with familial adenomatous polyposis (FAP). Intra-abdominal desmoids are highly unpredictable, but, as opposed to desmoids in the extremity, can ultimately result in the death of the patient. Unfortunately, the morbidity of operation, radiation and chemotherapy in such patients is very significant. Overall, approximately 2% of desmoids are FAP-associated, and the patients have approximately a 1000-fold increased risk of developing a desmoid, compared with the general population. It has been suggested that desmoid-associated death in FAP ranges from 10% to 50%.2 Indeed, in patients with FAP, desmoids and periampullary carcinoma are the two commonest causes of death following prophylactic colectomy.

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Diagnosis and Management of Soft Tissue Sarcoma

Treatment The primary treatment of the desmoid tumor is surgical resection. The extent of the resection, however, remains controversial. It is now clear that the first attempt at resection invariably defines the likelihood of recurrence.

Adjuvant treatment Multiple pharmacologic agents have been used in the treatment of desmoid tumors, based on anecdotal reports of response, the correlation of estrogen levels in growth, and the clinical observation of the higher incidence of desmoid tumors in young parturient females. The spontaneous regression of desmoids after menopause or oophorectomy has been reported.3–5 Attempts have been made to identify and characterize estrogen receptor and anti-estrogen binding sites in desmoid tumors, with variable results.6,7 Subsequently, anecdotal reports have suggested that the use of various anti-estrogens can result in regression of such tumors.8–11 These reports are very difficult to interpret, as the numbers are small, the response rate is variable, and follow-up is almost always short. It does seem practical, however, to consider the use of anti-estrogens or other agents before moving to radical, aggressive surgery, radiation or chemotherapy. Non-steroidal anti-inflammatory drugs are commonly used, and response rates have varied from 0% to 50%.2 An impressive response to such treatment is shown in Figure 7.2. Other reports have suggested benefit from vitamin K, coumadin, and vitamin C, showing the variability of observation, much of it obfuscated by natural history. The issue of whether or not radiation therapy should be used uniformly is difficult. We have used it very selectively at MSKCC, and it would appear that, with selective use of

radiation, local recurrence rates in patients with positive margins can be reduced to rates similar to those in patients with negative margins. Conversely, as patients with negative margins recur, the use of radiation should be carefully judged, based on potential morbidity. This is also true, as mentioned above, in the use of radical surgical resection. An extensive review of the use of chemotherapy has been provided by the MD Anderson Medical Center.12 They examined, over a 20-year period, 180 patients who had a histologically confirmed diagnosis of a desmoid tumor. From that entire spectrum, 11 patients received chemotherapy consisting of doxorubicin (60–90 mg/m2) and dacarbazine (750–1000 mg/m2)-based regimens for a median of five cycles. Six of nine patients who were evaluated had an objective response. It was suggested that two had a complete response, and four a partial response. In this group, five patients were alive with no evidence of disease, and four were alive with disease. The authors concluded that chemotherapy should at least be considered before embarking on more radical operations, a not unreasonable approach if treatment must be embarked upon because of symptoms. A later paper13 described 47 patients with unresectable desmoid tumors who were treated with chemotherapy. These authors found that a combination of methotrexate with vinblastine and etoposide was effective in yielding longterm control. However, the natural difficulties in following such patients over a long period of time make the meaning of response much more difficult to evaluate. It does appear in chemotherapeutic regimens that response rates of the order of 40–45% can be expected to be maintained for about 4 years, while, conversely, as many patients can remain indolent for that period of time. An impressive response to chemotherapy is shown in Figure 7.3.

Clinical and pathologic correlates

(a)

(b)

(c)

(d)

Figure 7.2 An impressive response to non-steroidal anti-inflammatory drugs (a,b,c) November 1997; (d) January 1999.

(a)

(b)

Figure 7.3 An impressive response to chemotherapy is shown (a) July 1998; (b) March 1999.

93

94

Diagnosis and Management of Soft Tissue Sarcoma

Rare patients have undergone aggressive resection of small bowel desmoids with visceral auto-transplantation. This should be considered highly experimental and should be reserved for those patients with no alternatives, i.e. patients with very aggressive lesions, associated necrosis and vascular compromise.14

Prognostic factors for outcome The risk of local recurrence is addressed in analyses of prognostic factors for outcome. Local recurrence has been reported to be greater in women over 3015 or in patients under the age of 30.16 In the main, however, it is unlikely that sex or age are factors in recurrence. In contradistinction to other sarcomas, we have not found any factors to be predictive of local recurrence in primarily treated patients. Factors analyzed include age, sex, depth, size and site. The relationship of positive microscopic margins to local recurrence is the subject of considerable debate (Table 7.1).1 The effect of surgical resection margin on local recurrence rates is difficult to evaluate, as the series are usually small and many of the patients have received adjuvant therapy. It is clear, however,

from our own experience, that while positive microscopic margins appeared to predict local recurrence rates in patients not treated with radiation therapy, positive margins in a second series did not predict local recurrence rates.1 Presumably, there must have been some impact from the very selective use of radiation therapy in patients with positive microscopic margins. We used external beam radiation therapy selectively in margin-positive patients, and increased use of radiation therapy in microscopically positive patients may have reduced the local recurrence rate in these patients to that of the microscopically negative patients. As expected, patients with recurrent disease have a greater risk of subsequent local recurrence.16 This is not surprising, as recurrent disease could be seen as the ultimate defined positive margin. It is clear, however, that many patients with positive margins do not necessarily recur (Figure 7.4). Conversely, even patients with negative margins are at risk for local recurrence, usually within the first 2 years after initial resection. When feasible, the preferred approach is a re-resection that has some possibility of having at least gross, and preferably microscopic, margin negativity. However, mutilating operations should be deferred until symptoms persist despite other treatment.

Table 7.1 Local recurrence of extremity and trunk desmoids. Author Posner (MSKCC) McKinnon Miralbell Pritchard Merchant Overall

Year 1989 1989 1990 1996 1998

n 128 32 26 44 105

Tumor types Primary and recurrent Primary and recurrent Primary Primary Primary

Margins defined as ‘close’ included in positive.

Margins Negative

Positive

15% 5% – 15% 24% 17%

51% 43% 20% 48% 22% 43%

Median follow-up 88 24 70 48 49

Clinical and pathologic correlates No patient in our series with an extremity desmoid died of the disease. In one analysis of our study,1 24 of 105 patients presenting with primary untreated extremity desmoids developed a local recurrence. Of these, 22 were re-resected and 19 remained without disease at a median follow-up of 67 months (10–146 months) that is, it is possible to obtain ‘cure’ in greater than 90% of patients treated appropriately initially. There were no patients in the extremity group who died of disease, with follow-up of 48.5 months. The 2- and 5-year local recurrence-free survival rates were 80% and 75% respectively.

Percentage free of recurrence

1.0 Positive (n=43)

0.8

Negative (n=58)

0.6

0.4

0.2

0.0 0

50

The very long natural history of the desmoid tumor makes investigation and documentation of these patients quite difficult. Local recurrence-free survival is also site dependent, with local recurrence being less in the abdominal wall lesions compared with other sites (Figure 7.5). In an analysis of 105

150

200

Figure 7.5 Desmoid tumors: local recurrencefree survival is site dependent (p=0.06). MSKCC, 12/82–12/00.

1.0

0.8

Proportion surviving

100 Months

Figure 7.4 Desmoid tumors: local recurrence-free survival and microscopic resection margin. A positive resection margin (solid line, n=43), negative resection margin (dashed line, n=58) (p=0.51). From Merchant et al.1

Results

0.6

0.4 Extremity (n=108) Abdominal wall (n=47) 0.2

Retroperitoneal/intra-abdominal (n= 25) Other (n=94)

0.0 0 n=274

95

40

80

120 Time (months)

160

200

240 p=0.06

96

Diagnosis and Management of Soft Tissue Sarcoma

patients with primary desmoid of the extremity, 5-year local recurrence-free survival was 75% (Figure 7.6). In our report, a group of patients were followed whose only therapeutic option was amputation, and over several years with no further treatment there was no progression. Similarly, Rock et al17 followed 68 patients with recurrent desmoids by observation only (Figure 7.7). In 60 of the 68, the tumor remained stable with minimal, if any, symptoms over a follow-up period of greater than six years. In other studies,18 multivariate analysis has identified the involvement of the pathologic resection margin as a significant factor contributing to local recurrence. After median follow-up of 47 months, 31 (49%) of the 63 patients who had an initial adequate surgical resection developed local recurrence, remarkably similar to the 23% local recurrence rate of those patients that we treated primarily.1 Interestingly, the median time to local recurrence was 83 months in patients who had

Percentage with local recurrence

1.0

0.8

0.6

0.4

0.2

0.0 0

50

100 Months

150

200

Figure 7.6 In an analysis of 105 patients with primary desmoid of the extremity, 5-year local recurrence was 25%. From Merchant et al.1

Desmoid tumors 153 Local recurrence Operation

85 No evidence of disease

68 Local recurrence >6 years

2 Increased

60 No change

6 Decreased

Figure 7.7 Desmoid tumors: follow-up from Rock et al.17

negative pathologic resection margins, emphasizing the importance of long-term follow-up. Conversely, local recurrence occurred within 13 months in patients with positive margins. The study further reinforces the fact that adequate initial operations remain the best opportunity for patients to be rendered disease-free and not develop local recurrence. However, once recurrence has occurred the benefit of aggressive treatment must be balanced against morbidity. In summary, the role of surgical therapy should be a non-mutilating operation designed to ensure complete gross resection and microscopically negative margins when possible. Radiation therapy should be used selectively for people with high risk of recurrence when it can be applied with minimal morbidity. Amputation should be reserved for patients with functionless extremities or incapacitating symptoms.

Clinical and pathologic correlates Cytotoxics should be used sparingly and only as an alternative to limb loss.

97

age was 38.5 years (range 12–79 years). Eightyseven patients (55%) were male and 72 (45%) were female. The overall 5-year recurrence-free survival was 75% during a median follow-up time of 57 months. The median recurrence-free survival was 228 months (Figure 7.8).

Dermatofibrosarcoma protuberans Diagnosis

Pathology

Dermatofibrosarcoma protuberans (DFSP) is a rare dermal fibroblastic soft tissue sarcoma which may constitute a difficult management problem. The mainstay of treatment for DFSP is surgical resection. The biggest difficulty with this disease is local recurrence, and as many as 60% of patients may recur locally. DFSP is not considered a lethal disease and rarely metastasizes. It is, however, important to note that the DFSP–fibrosarcoma variant is more aggressive and indeed may metastasize and result in death. We have studied 159 patients with DFSP who underwent treatment at MSKCC.19 The median

DFSP has a distinct morphologic appearance. These are classically storiform whorls and fascicles of spindle cells with round to oval nuclei and eosinophilic cytoplasm. This pattern is frequently infiltrating. When there are areas of high-grade fibrosarcomatous change in at least 5% of the lesion, it is subclassified as FS-DFSP. These fibrosarcomatous areas are recognized by a fascicular , herringbone pattern of growth and increased cellularity and cytologic atypia. Immunohistochemistry for CD34 being utilized as an antigen expressed by DFSP may help with the diagnosis.20

Figure 7.8 DFSP: overall 5year recurrence-free survival and median recurrencefree survival. MSKCC, 7/50–7/98. From Bowne et al.19

1.0 Tick mark (I) indicates last follow-up.

Proportion free of recurrence

0.8

0.6

0.4

0.2

0 0 n=159

24

48

72

96

120

144

168

192

216

240

264

288

312

336

98

Diagnosis and Management of Soft Tissue Sarcoma

The Bednar tumor is a rare pigmented variant of DFSP and is usually clearly identified by its characteristic findings of dispersal of melanin-containing cells in an otherwise typical DFSP.21

Tumor mortality Classic DFSP does not metastasize and does not cause mortality. Conversely, the FS-DFSP variant may metastasize and lead to tumorrelated mortality. When these tumors metastasize, they frequently metastasize to the lung. In our series of 159 patients, two patients died from pulmonary metastases.

Treatment Treatment is governed by the biology of this tumor. It is important to remember that DFSP is a deceptively invasive dermal tumor and that clinically undetectable tumor invasion occurs primarily on a horizontal plane. The very first report with regard to DFSP from MSKCC in 1967 by McPeak et al 22 emphasized the need for wide surgical resection, and these same principles apply today. Wide resection will often extend to 2 cm beyond the tumor, depending on the anatomic location. Thus, for a tumor of the thigh, a wide margin would be fully acceptable. Frozen section is notoriously unreliable in documenting margin status and one must wait for the final section. In the event of unsuspected positive margin, if there is the capability to perform a re-resection with low morbidity, this should be done. Conversely, if morbidity is going to be high (e.g. in the face), then the positive margin may be accepted and the patient closely followed. Clearly, the ultimate therapeutic approach would be complete surgical removal of all disease. However, experience has

demonstrated recurrence despite wide resection. It is worth trying to stratify a treatment approach. All patients with the FS-DFSP variation should undergo aggressive treatment which will ensure removal of all disease. In contrast, those patients with recurrent classical DFSP without evidence of adverse histologic features may benefit from conservative management, especially in a setting of potentially unresectable disease and high morbidity from treatment. In those patients with classic DFSP exhibiting increased mitotic index or cellularity, the treatment should be intensified to attempt to remove all residual disease. The role of Mohs micrographic surgery is evolving.23

Adjuvant treatment Adjuvant radiation therapy has demonstrated some value in microscopic residual disease. Again, the morbidity of the treatment has to be weighed against the usual indolent nature of this disease.

Prognostic factors for local recurrence (Table 7.2) The overall 5-year local recurrence rate for classical DFSP is 19%. Conversely, it is 72% for those with the FS-DFSP variant. Microscopic margins of resection are important predictors of local recurrence. This is clearly shown in Figure 7.9. Local failure is significantly associated with close (<1 mm) and positive margins of resection. Other factors that are associated with recurrence include the mitotic rate and cellularity as seen under the microscope and patient age >50 years.

Clinical and pathologic correlates

99

Table 7.2 Analysis of local recurrence-free survival in patients with dermatofibrosarcoma protuberans. N Sex Male Female Age >50 years <50 years Presentation Primary Local recurrence Symptoms Yes No Histologic subtype Classical DFSP Fibrosarcomatous variant Site Extremities Trunk Head and neck Trunk and extremities Size (cm) <5 5–10 >10 Depth Superficial Deep Unknown Mitosis per 10 hpf (all) Low Intermediate High Mitosis per 10 hpf (FS-DFSP) Low Moderate High Cellularity (grade) Low Moderate High Microscopic margins Negative Positive Very close to <1 mm Invasion None Muscle Nerve Muscle and nerve Bone and nerve aUnivariate p refers to bRelative risk to other

Univariate Pa

Selection into Cox model (multivariate P)

Relative riskb (CI)

<0.001

5.3 (2.6–12)

<0.001 <0.001

12.5 (4.7–34) 7.8 (2.2–27)

0.8 87 72 0.03 117 42 0.2 111 48 0.9 50 112 <0.001 134 25 0.8 76 56 25 2 0.7 134 21 4 0.9 121 36 2 <0.001 129 16 14 0.4 3 14 9 0.02 12 82 65 <0.001 93 51 15 0.1 123 28 2 5 1

log-rank test of no difference versus any difference between categories. categories of the same factor. CI, 95% confidence intervals; hpf, high-power fields; all, dematofibrosarcoma protuberans and fibrosarcomatous variant. From Bowne et al.19

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Diagnosis and Management of Soft Tissue Sarcoma

% Local recurrence by margin status

50 24/51 40 5/15

30 20 10

5/93

0 Positive

Very close <1 mm

decrease the recurrence rate from 11% to 2.4% with wide local excision only.23 In a series from the Massachusetts General Hospital,26 radiation therapy was utilized in 18 patients. Local control was realized in three patients treated with radiation therapy alone, while there were three local failures in 15 patients treated with radiation plus operation.

Negative

Figure 7.9 Rate of local recurrence following surgical resection for primary or recurrent dermatofibrosarcoma protuberans as related to the microscopic margin status. From Bowne et al.19

Results Of 159 patients studied at MSKCC, 134 (84%) had DFSP and 25 had the FS-DFSP variant (16%). The 5-year recurrence-free survival rates were 81% and 28% respectively. On univariate and multivariate analysis, very close to positive microscopic margins and FS-DFSP were unfavorable prognostic factors.19 FS-DFSP represents an uncommon form of DFSP, but with a much worse prognosis. In a review of 34 patients, local recurrence occurred in 58%, with metastasis in seven: five to lung, one to bone and one to soft tissue, with two patients dying of disease.24 In another study of 35 patients with DFSP, no patient developed lymphatic or distant metastasis but the overall rate of local recurrence was as high as 57%. All of these were attributed to inadequate margins at the time of initial operation, and when complete resection was obtainable, there was a local recurrence rate of 8%.25 Utilization of Mohs micrographic surgery has been suggested to

Malignant fibrous histiocytoma Diagnosis Of soft tissue sarcomas of the extremity, malignant fibrous histiocytoma (MFH) is the second most frequent histopathology, behind liposarcoma. It was first described in 1964 by O’Brien and Stout,27 who suggested that this was a distinct soft tissue tumor with a mixed pattern, as described in Chapter 3. However, arguments have been made that this tumor is a subtype of fibrosarcoma, and it is progressively being reclassified.28,29 Modern immunohistochemistry showing unexpected antigen expression has resulted in tumors originally diagnosed as MFH being reclassified as other sarcomas, or even melanoma or anaplastic carcinoma. As reported previously,30 MFH is a common histopathology seen in radiation-induced soft tissue sarcoma. Malignant fibrous histiocytoma can occur in rare sites such as small bowel, chest wall, and liver. Rare cases have been reported in association with artificial hip replacement.31 In this situation, the development of malignant tumor would be suspected if aggressive radiographic osteolysis occurred. Other unusual sites for MFH include the lacrimal sac, corneal sclera and brain. These tumors present in the typical fashion for soft tissue sarcoma. This is usually as a

Clinical and pathologic correlates lump, often first noticed by the patient after some minor injury. The diagnosis is based on biopsy. For small tumors (<5 cm), an excisional biopsy may often be performed. For larger tumors (>5 cm), an incisional biopsy should be performed. As discussed in Chapter 8, the initial approach should be with a tru-cut® biopsy. If the pathologist’s interpretation of this is equivocal, an incisional biopsy should be performed, always orienting the incision along the longitudinal axis of the limb, encompassable by a definitive procedure. The diagnosis is based on the classic findings under the microscope that include the features of fibroid sarcoma with some myxoid elements.

Treatment Complete surgical resection remains the primary form of curative treatment. These tumors are treated according to the same principles as for other histologic subtypes. These include resection, radiation, and chemotherapy appropriate for the biological risk of the individual tumor.

101

underwent complete surgical excision between July 1982 and July 1996.32 Of 239 patients, 135 were men and 104 were women, with a median age of 62 years. One hundred and ninety-seven presented with a primary lesion, and 42 presented with a local recurrence without metastatic disease, after excision of the primary tumor at another institution. Median follow-up for those patients alive was 61 months. Fifty-one per cent (122 patients) had no further evidence of disease during the follow-up period. One hundred and seventeen patients (49%) developed recurrent disease. Isolated local recurrence developed in 33 (14%), isolated metastatic disease without local recurrence in 71 (30%), and combined local and metastatic disease in 13 (5%) (Figure 7.10). In all, 84 (35%) developed metastatic disease, and 77 of the 84 had a tumor-related mortality. Disease-specific survival for all 239 patients was 65% at 5 years and 59% at 10 years. The factors associated with local recurrencefree survival, metastasis-free survival, and

Adjuvant treatment The indications for radiation therapy are the same as for other soft tissue sarcomas. Local recurrence can be decreased in patients with lesions >5 cm who receive radiation therapy. Adjuvant chemotherapy has not been shown to have proven benefit, but should be considered in investigational trials in high-risk patients.

Prognostic factors for outcome We have recently reviewed our experience with patients with MFH of the extremity who

239

No recurrence 122 (51%)

Local only 33 (14%)

Recurrence 117 (49%)

Metastatic only 71 (30%)

Local and metastatic 13 (5%)

Figure 7.10 Presentation of MFH at MSKCC. From Salo et al.32

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Diagnosis and Management of Soft Tissue Sarcoma

disease-specific survival are shown in Table 7.3. Presentation with locally recurrent disease, age >50, location on the upper extremity and a distal site were the factors associated with risk of local recurrence. We did not show an

association of local recurrence with grade, depth, size or status of microscopic margin, in contradistinction to studies of other sarcomas in our overall database.

Table 7.3 Factors associated with survival in malignant fibrous histiocytoma of the extremity. Factor Local recurrence-free survival Age >50 years Presentation with recurrence Upper extremity location Distal extremity site Tumor size High grade Deep location Positive microscopic margin Metastasis-free survival Age >50 years Presentation with recurrence Upper extremity location Distal extremity site Tumor size 5–10 cm >10 cm High grade Deep location Positive microscopic margin Disease-specific survival Age >50 years Presentation with recurrence Upper extremity location Distal extremity site Tumor size 5–10 cm > 10 cm High grade Deep location Positive microscopic margin From Salo et al.32

Univariate 0.002 0.009 0.006 0.03 0.5 0.8 0.3 0.4 0.06 0.04 0.9 0.3 0.0001

0.009 0.0001 0.7 0.04 0.02 0.8 0.3 0.0001

0.02 0.0001 0.6

Cox model

Relative risk

0.004 0.06 0.02 0.04

4.5 2.0 1.9

0.02

1.8

0.0002

0.02 0.03

2.0 3.4 3.5 2.6

0.008

2.0

0.0002

0.04 0.02

2.3 3.7 2.6 2.8

Clinical and pathologic correlates 100

103

100

Low grade (n=33)

90

90 Size <5 cm (n=96)

80

80 70

High grade (n=206)

60

Survival (%)

Survival (%)

70

50 40

Size 5–10 cm (n=76)

50 40

30

30

20

20

10

10

0

Size >10 cm (n=67) Size <5 cm versus size 5–10 cm p=0.0004 Size 5–10 cm versus size >10 cm p=0.029 Overall log-rank p=0.0001

0

0 p=0.018

1

2 3 4 5 6 7 8 Post-resection survival time (years)

9

10

Figure 7.11 MFH: DSS. Post-resection disease-specific survival was predicted by tumor grade. From Salo et al.32 (a)

0

1

2

3 4 5 6 7 8 Disease-specific survival time (years)

9

10

Figure 7.12 MFH: DSS. Overall, tumor size was the most important factor predicting disease-specific survival. From Salo et al.32 (b)

1.0

1.0

0.9

0.9

Extremity/trunk

0.8

0.8

0.7

0.7

0.6 0.5

Retroperitoneal/visceral

0.4 0.3

Proportion surviving

Proportion surviving

60

0.6 Retroperitoneal/visceral

0.5 0.4 0.3

0.2

0.2

0.1

0.1

0.0

Extremity/trunk

0.0 0

12

24 36 Months

48

60

0

12

24

36 Months

48

60

(a) (b) Figure 7.13 Liposarcoma: retroperitoneal and intra-abdominal sarcomas clearly have a worse prognosis than extremity and superficial truncal liposarcoma. Kaplan–Meier survival curves after complete resection of extremity/trunk (n=301) and retroperitoneal/visceral (n=159) liposarcoma. (a) LRfree survival (p=0.001) and (b) DSS (p=0.001) measured in months. From Linehan et al.35

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Diagnosis and Management of Soft Tissue Sarcoma

Results Distant metastasis was predicted by tumor grade in terms of both metastasis-free and diseasespecific survival, as shown in Figure 7.11. The 10-year disease-specific survival was 86% for patients with low-grade lesions and 55% for patients with high-grade lesions. Overall, tumor size was the most important factor predicting metastasis-free and disease-specific survival (Figure 7.12). Ten-year disease-specific survival was 83% for lesions less than 5 cm, 47% for

lesions 5–10 cm, and 37% for those greater than 10 cm. Multivariate analysis suggests that tumor size was by far the most important factor in predicting outcome for both metastasis-free and disease-specific survival (Table 7.3).

Liposarcoma Diagnosis Liposarcoma includes a broad group of tumors that can occur in any site throughout the body.

(a)

(b)

(c)

(d)

Figure 7.14 A large atypical lipomatous tumor of the right thigh: (a) clinical appearance; (b) MRI coronal; (c) operative specimen; (d) operative field indicating extent from femoral artery anteriorly to sciatic nerve posteriorly.

Clinical and pathologic correlates

105

It is very clear that they are both anatomically and biologically diverse. Retroperitoneal and intra-abdominal sarcomas clearly have a worse prognosis than extremity and superficial truncal liposarcoma (Figure 7.13). Diagnosis is made in standard fashion. In the extremity, with a large mass lesion, the difficulty lies in the distinction between a lipoma (Figure 4.1c), an atypical lipomatous tumor (Figure 7.14) and a low-grade liposarcoma (Figure 7.15). Tru-cutR biopsy may be inaccurate in this situation, and open biopsy may be required. Atypical lipomatous tumors are, in the main,

treated as very low-grade liposarcoma, i.e. clinically with the risk of local recurrence low, and the risk of metastasis rare. When diagnosed in the retroperitoneum, they are frequently typed as low-grade liposarcoma. In the retroperitoneum and intra-abdominal sites, liposarcoma may be huge in size and provide considerable technical challenge (Figure 7.16).

(a)

(b)

(c)

(d)

Treatment Complete surgical resection remains the primary treatment for all liposarcomas. In the

Figure 7.15 A low-grade liposarcoma of the right thigh: (a) clinical picture; (b) MRI cross-section; (c) operative specimen; (d) operative field, showing resection from femoral artery anteriorly to sciatic nerve posteriorly.

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Diagnosis and Management of Soft Tissue Sarcoma

(a)

(b)

(c)

(d)

Figure 7.16 In the retroperitoneum and intra-abdominal sites, liposarcoma may be huge in size. (a) clinical appearance; (b) computed tomography; (c) intraoperative appearance; (d) post-resection appearance. extremity, care should be taken to ensure complete excision, but in those tumors that are very low grade or have atypical lipomatous components, neurovascular preservation should be the goal, with functional limbsparing the aim. It is important to recognize that proximal thigh lesions can arise in the retroperitoneum and track with the psoas into the thigh (Figure 7.17). In the retroperitoneum, resection is often limited by massive size, and, in general, complete resection translates into long-term survival benefit. Additional resection, i.e.

taking adjacent organs beyond a complete resection, does not translate into survival benefit.33 At the time of the recurrent disease, the recurrence may be multifocal, limiting the options for cure (Figure 7.18). It has also been suggested that even palliative resections may translate into survival benefit.34

Adjuvant treatment For the extremity, the indications for radiation therapy are the same as for other soft tissue sarcomas. Local recurrence can be decreased

Clinical and pathologic correlates

107

(a)

(b)

(c)

Figure 7.17 Iliopsoas liposarcoma. Patients who present with groin sarcomas should always be carefully examined for the possibility of intra-abdominal origin. As illustrated here, the intra-abdominal component is extensive and the thigh component small. Alternative incisions are outlined. (a) computed tomography showing both retroperitoneal and proximal thigh components; (b) clinical appearance, alternate incisions shown by the dotted line; (c) operative specimen.

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Diagnosis and Management of Soft Tissue Sarcoma

(a)

(b)

(d) (c) Figure 7.18 Recurrent retroperitoneal low-grade multifocal liposarcoma. (a) computed tomography; (b) intraoperative appearance; (c) operative specimens; (d) histopathology. in patients with lesions >5 cm who receive radiation therapy. Adjuvant chemotherapy has not been shown to have proven benefit, but should be considered in investigational trials in high-risk patients. Given the results in myxoid round cell liposarcoma these patients are candidates for trials of preoperative chemotherapy. Differentiation agents such as troglitazone, a PPAR (peroxisome proliferator activator receptor) ligand, and oral hypoglycemic agents have been under investigation. Intraoperative radiation therapy remains a subject of investigation. For retroperitoneal

sites, sufficient external beam dosage has not been able to be given without significant toxicity.

Prognostic factors for outcome Site is clearly a factor in survival in liposarcoma. Death from local recurrence in the extremity is extraordinarily rare but clearly occurs with retroperitoneal and intraabdominal lesions. A recent examination of 720 patients with liposarcoma,35 463 of

Clinical and pathologic correlates whom had completely resected primary or locally recurrent disease, allowed an analysis of prognostic factors for outcome. Sixty-five per cent of the patients (n=301) had extremity or truncal lesions, and 35% were retroperitoneal or intra-abdominal visceral lesions (n=162). With a median follow-up of 42 months (range 1–194), multivariate analysis concluded that age >50, high grade, retroperitoneal or visceral site, size >10 cm and initial recurrence were factors in subsequent local recurrence (Table 7.4). For disease-specific survival, retroperitoneal or visceral site, recurrence at presentation, size >10 cm and high grade were all issues in recurrence following complete resection (Table 7.5). It is important, therefore, to note that site is at least as important as the normally considered prognostic variables, i.e. grade, in survival from these tumors.

109

It should be emphasized that of those patients who died with retroperitoneal or intra-abdominal visceral tumors, 80% had local disease only at the time of death, without distant metastasis. In this site, therefore, local recurrence can be a cause of death.

Results We have previously examined the survival rates and the recurrence rates for the various histologic subtypes of liposarcoma,36 using a then accepted histopathologic differentiation: well-differentiated, myxoid, fibroblastic, lipoblastic, and pleomorphic, in which the first two are low-grade lesions, the last two highgrade lesions, and the fibroblastic types have a variable presentation, but are usually high

Table 7.4 Multivariate analysis of factors affecting local recurrence (LR) in 460 cases of completely resected liposarcoma. E/T (n=301) 5-year LR-free survival

RP/V (n=159)

p-value RR (CI)a

5-year LR-free survival

p-value RR (CI)

Low grade High grade

85% 73%

0.06 1.7 (1–3)

49% 25%

0.01 1.9 (1–3)

Size )10 cm Size >10 cm

77% 79%

0.9

38% 42%

0.5

Negative micromargin Positive micromargin

80% 60%

0.1

42% 47%

0.5

Primary presentation Recurrent

82% 64%

0.05 2 (1–4)

47% 35%

0.03 1.8 (1–3)

Superficial Deep

81% 79%

0.5

N/A

N/A

LR, Local recurrence; E/T, Extremity/trunk; RP/V, Retroperitoneal/visceral; N/A, not applicable. aRelative risk with 95% confidence intervals. From Linehan et al.35

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Diagnosis and Management of Soft Tissue Sarcoma

Table 7.5 Multivariate analysis of factors affecting disease-specific survival (DSS) in 460 cases of completely resected liposarcoma. E/T (n=301)

RP/V (n=159)

5-year DSS

p-value RR (CI)*

5-year DSS

p-value RR (CI)*

Low grade High grade

93% 73%

0.001 3.5 (2–7)

68% 40%

0.01 2.6 (1.5–5)

Size )10 cm Size >10 cm

87% 76%

0.001 2.7 (1.5–5)

56% 61%

0.8

Negative micromargin Positive micromargin

82% 82%

0.6

65% 35%

0.03 2 (1–4)

Primary presentation Recurrent

84% 77%

0.03 2.3 (1–5)

73% 35%

0.001 2.5 (1.5–5)

Superficial Deep

93% 80%

0.3

N/A

N/A

E/T, Extremity/trunk; RP/V, Retroperitoneal/visceral. *Relative risk with 95% confidence intervals. From Linehan et al.35

grade. The results for recurrence and survival were clearly different (Figure 7.19a,b). Overall survival for primary extremity liposarcoma is illustrated in Figure 7.20. This compares well with the survival given for extremity liposarcoma seen at MD Anderson,37 (Figure 7.21) and can be compared with the distant metastasis rate illustrated in Chang et al36 (Figure 7.19c). Unusual presentations of recurrence from liposarcoma do occur and the patterns of recurrence in extremity sarcoma have recently been defined.35 In a 13-year study period, 122 patients with intermediate- or high-grade extremity liposarcoma were identified. With a median follow-up of 70 months, the 5-year survival rate for all intermediate- and highgrade tumors presenting with primary disease (n=85) was 74%. Local recurrence-free

survival at 5 years was 93%. Interestingly, of 102 of the patients defined as having myxoid tumors, 33 had distant recurrence, and 31 of the 33 were at extrapulmonary soft tissue sites such as retroperitoneum and chest wall, and two were at lung only, a clearly very different pattern from that seen with other high-grade sarcomas. This would justify a different approach in evaluating patients with extremity liposarcoma, particularly myxoid liposarcoma, where extrapulmonary sites of metastasis are common. It is now clear that a unique translocation exists for myxoid liposarcoma. This t(12;16)(q13;p11) fusion product (TLS(FUS)–CHOP ) is seen in 75% of these lesions. Utilization of these data35 has now shown that these liposarcomas of unusual multiple site presentation are more likely metastatic and not multifocal disease.

Clinical and pathologic correlates

111

Percentage local disease free

100 90 80 70 60 50 40 30 20

Low grade High grade

10 0

0

1

p=0.0015 2

3

4

5

Years

(a) 100

Percentage distant disease free

100

Percentage surviving

90 80 70 60 50

Well-differentiated Myxoid Pleomorphic Fibroblastic Lipoblastic

40 30 20 10 0

0

1

p=0.003

2

3

4

90 80 70 60 50 40 30 20

Low grade High grade

10 0

5

0

p=0.0005

1

2

Years

3

4

5

Years

(c)

(b)

Figure 7.19 (a) Liposarcoma: local recurrence rates of primary localized extremity liposarcoma as a function of grade. (b) Liposarcoma: survival rates of primary localized extremity liposarcomas of various histologic subtypes. (c) Liposarcoma: distant metastasis rate. From Chang et al.36 Figure 7.20 Overall survival for primary extremity liposarcoma. MSKCC, 7/82–12/00.

1.0

Proportion surviving

0.8

0.6

0.4

0.2

0.0 0

20

40

60

80

100

120

140

Time (months) n=335

160

180

200

220

240

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Diagnosis and Management of Soft Tissue Sarcoma

Leiomyosarcoma Diagnosis Leiomyosarcomas are an uncommon subgroup that are frequently aggressive, with a high rate of recurrence and metastasis. They are diagnosed based on the presence of smooth muscle actin that is detected by immunohistochemistry. They present in the typical fashion for soft tissue sarcoma, either in the extremity (Figure 7.22) or in the retroperitoneum (Figure 7.23). The diagnosis is based on biopsy and the typical findings of the pathologist. It is important to separate out leiomyosarcomas that are cutaneous and superficial from those that are deeper. They behave in a very different biological fashion. The superficial ones are frequently much more benign in their behavior. Conversely, as mentioned, the deeper leiomyosarcomas are frequently aggressive and refractory to many forms of treatment.38

(a)

Proportion surviving

1 0.8 0.6 Myxoid (n=71) 0.4 Pleomorphic (n=14) 0.2 p=0.01 0 0

24

48

72

96

120 144

168

192

216

Time (months)

Figure 7.21 Overall survival in extremity liposarcoma seen at MD Anderson. Overall survival is shown for 97 patients with pleomorphic or myxoid extremity liposarcoma who presented with primary localized disease. p<0.01, myxoid subtype versus pleomorphic subtype. From Pearlstone et al.37

(b) Figure 7.22 Leiomyosarcoma of the calf (MRI).

Clinical and pathologic correlates

(a)

113

(b)

(d) (c) Figure 7.23 High-grade leiomyosarcoma involving the inferior vena cava and right renal vein: (a) intraoperative pre-resection; (b) intraoperative post-resection; (c) surgical specimen; (d) operative field with repaired IVC.

Treatment Complete surgical resection is the primary and cornerstone treatment for leiomyosarcoma. The same algorithm as for extremity soft tissue sarcoma applies to leiomyosarcoma.

Adjuvant treatment For the extremity, the indications for radiation therapy are the same as for other soft tissue sarcomas. Local recurrence can be decreased in patients with lesions >5 cm who receive

radiation therapy. There are several anecdotal reports and experiences suggesting that leiomyosarcoma is less responsive to adjuvant systemic chemotherapy. This also applies to treatment of metastatic disease. Adjuvant chemotherapy has not been shown to have proven benefit, but should be considered in investigational trials in high-risk patients. For retroperitoneal sites, sufficient dosage has not been able to be given without significant toxicity. Intraoperative radiation therapy remains a subject of investigation.

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Diagnosis and Management of Soft Tissue Sarcoma

Prognostic factors for outcome Cutaneous leiomyosarcomas may recur frequently but otherwise remain biologically non-aggressive. In contrast to other soft tissue sarcomas, grade seems not to be an independent predictor of disease mortality. Part of this is because grading of leiomyosarcomas can be difficult, and uniform criteria are not as evenly applied as in other soft tissue sarcomas. Perhaps the biological behavior of leiomyosarcoma is different from that of other histologic subtypes of soft tissue sarcoma. Nevertheless, this fact emphasizes that even with the detection of different or abnormal protein products by immunohistochemistry or Western immunoblotting, we are still far away from understanding the behavior of some soft tissue sarcomas.

Results Visceral leiomyosarcoma is discussed in Chapter 10. For those with extremity leiomyosarcoma, the overall actuarial diseasespecific survival is 70%. For patients with primary tumor size >5 cm, the 5-year survival is 42%. Similarly, for those with deep tumors, the survival is 45%, and for those with positive microscopic margins, the survival is 51%. As noted above, grading of leiomyosarcomas can be difficult. While patients with high-grade tumors do worse, these results are blurred because of the difficulty in grading. Conversely, superficial cutaneous leiomyosarcomas very rarely metastasize and very rarely result in tumor-related mortality.

Fibrosarcoma Diagnosis Fibrosarcoma represents a wide spectrum of soft tissue sarcomas. Diagnosis is essentially made as with any other soft tissue sarcoma. The site distribution is as in Figure 3.1, and the age distribution as previously described in Figure 3.2. Often there are a number of other associated pathologic subtypes, such as inflammatory fibrosarcoma, inflammatory pseudo-tumor, or inflammatory myofibroblastic tumor. It is important to make the diagnosis, because, despite their appearance, inflammatory tumors often have an excellent prognosis following complete resection. Increasingly, the myxofibrosarcoma variant has been diagnosed, to include many lesions previously classified as MFH (Figure 7.24). This differential diagnosis is consistent with the concept of an exuberant repair process and clinically often blends into some aspects of the fibromatoses, although the primary cell type involved is the myofibroblast.

Treatment As with other sarcomas, complete surgical resection is the treatment of choice, and adjuvant radiation therapy, particularly in the extremity, is of value in both low- and highgrade lesions.

Adjuvant treatment For the extremity, the indications for radiation therapy are the same as for other soft tissue sarcomas. Local recurrence can be decreased in patients with lesions >5 cm who receive radiation therapy. Adjuvant chemotherapy has not been shown to have proven benefit, but should be

Clinical and pathologic correlates

115

(a)

(b)

(c)

Figure 7.24 Myxofibrosarcoma of the buttock, following prior incomplete resection, with extensive hemorrhage: (a) preoperative; (b) postoperative; (c) operative specimen.

considered in investigational trials in high-risk patients. For retroperitoneal sites, sufficient dosage has not been able to be given without significant toxicity. Intraoperative radiation therapy remains a subject of investigation.

Prognostic factors for outcome Fibrosarcomas of the extremity are often low grade. As with other tumors, size, grade and margins remain statistically significant.

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Diagnosis and Management of Soft Tissue Sarcoma

Results See overall results by histopathology at end of chapter.

Inflammatory fibrosarcoma Diagnosis Inflammatory fibrosarcoma is a rare entity39 which usually occurs in the retroperitoneum or the mesentery. Historically, these tumors have been given a wide variety of names, including inflammatory pseudo-tumors and inflammatory myofibroblastic tumors, most of which are descriptive of the histologic appearance of the tumors. However, some patients present with systemic symptoms characterized by significant fever, anemia, and weight loss, which resolves following removal of the tumor. Such tumors are usually thought to be aggressively locally recurrent, but metastases have been reported.

Treatment Primary treatment for all these lesions is complete surgical resection.

Adjuvant treatment Because of the usual site of these tumors, adjuvant radiation is difficult to deliver. Where this can be delivered safely, it should be applied.

Results In a review from the Armed Forces Institute of Pathology, 38 cases of inflammatory fibrosarcoma were described, with a median age of 8.5 years (2 months to 74 years), the majority

with symptoms of pain, anemia, fever or gastrointestinal obstruction.39 The majority occurred in the mesentery or retroperitoneum, with only rarely identified tumors elsewhere. Approximately one-third of the patients had a local recurrence, and 10% had histologically proven distant metastases. Characteristically, a patient who first presented with an inflammatory pseudo-tumor and then developed severe pain and fever was shown to have an inflammatory fibrosarcoma still containing residual elements of the more benign-appearing low-grade pseudo-tumor (Figure 7.25). Some characteristic immunophenotypic findings have been described;40 the intralesional myofibroblast stained for vimentin, smooth muscle actin, cytokeratin, and occasionally desmin. The currently most accepted term would be an inflammatory myofibroblastic tumor which may go on to inflammatory fibrosarcoma.

Angiosarcoma Diagnosis Angiosarcoma is an uncommon vascular tumor that comprises approximately 2% of all soft tissue sarcomas and only 0.7% of all malignancies. At the time of diagnosis, 10–25% of patients will already have developed metastatic disease.41 Tumors can occur following radiation to the breast42 or in the form of lymphangiosarcoma following surgery and radiation for breast cancer.43 The most common sites are the head, neck and skull, occurring in approximately one-third of patients. Figure 7.26 shows the sites of angiosarcoma as seen in our database.44 Other unusual sites include presentations in the breast, lung and heart, often associated with antecedent radiation therapy or toxic chemical exposure.45–47

Clinical and pathologic correlates

117

(a)

(b)

(c)

(d)

(e)

Figure 7.25 Inflammatory fibrosarcoma is a rare entity which usually occurs in the retroperitoneum: (a) CT scan; (b) gallium scan; (c) operative specimen; (d) low-grade component; (e) high-grade component.

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Diagnosis and Management of Soft Tissue Sarcoma

Adjuvant treatment

Head and neck 32%

Thoracic 8% 4

16

4 5 8 Extremity 16%

6

Viscera 8%

Pelvic/ retroperitoneal 10%

7

Trunk 14%

Breast 12%

n=50

Figure 7.26 Sites of angiosarcoma as seen at MSKCC, 7/82–2/98. From Espat et al.44

The association of lymphangiosarcoma with chronic postoperative edema in the extremity following radical mastectomy and postoperative radiation was originally described by Stewart and Treves.43 An example is shown in Figure 2.17. In angiosarcoma local recurrence is common, particularly in the head and neck: as many as two-thirds of these patients had a local recurrence. Tumor grade is difficult to characterize in angiosarcoma, but the majority will be considered high grade. Diagnosis should be suspected based on antecedent risk factors and on a characteristic vascular appearance to the lesion. Median age at presentation in our series44 (n=73) is 56 years (range 18–84).

Treatment Complete surgical resection remains the primary form of curative treatment.

Radiation therapy alone, without prior surgical resection, rarely, if ever, controls disease adequately.47 Adjuvant radiation therapy is commonly utilized, particularly in extensive angiosarcoma of the scalp. The important issue is the ability to determine margins. Margins are poorly delineated in most angiosarcomas and peripheral biopsies are often needed to ensure that the radiation field is adequate. Rotational arc electron beam and conventional radiation therapy have both been utilized.48,49 Technical issues of radiation therapy to the scalp have been studied. In the main, this requires detailed three-dimensional planning with rotational techniques to ensure uniform distribution of the dose.50

Prognostic factors for outcome Positive gross margins and positive microscopic margins predict subsequent local recurrence and survival. Most lesions are considered high grade, and grade, age and sex have not been shown to be predictive of survival.

Results Unfortunately, long-term results, even with aggressive surgery and radiation therapy, are poor, with recurrence rates in the range 60–70%.50 With a median follow-up of 17 months (1–179 months), 14% of patients developed local recurrence, and 25% metastatic disease. Patients with extremity lesions were the most likely to develop metastasis (46%) followed by those with tumors in the retroperitoneum and gastrointestinal tract (29%). Overall, 58% of patients died of

Clinical and pathologic correlates disease. It is clear that patients can die with angiosarcoma from local progression as well as metastatic disease, an uncommon event in most other sarcomas of the extremity. Even in angiosarcoma, this is reflective of site, as the patients most likely to die were those with head, neck and scalp, thoracic or intra-abdominal lesions. Overall, 2- and 5-year survival rates are 50% and 33% (Figure 7.27).

Hemangiopericytoma Diagnosis Hemangiopericytoma is usually a wellcircumscribed lesion, often with a pseudo-

119

capsule, but not infrequently at presentation satellite nodules are found. Historically angiosarcoma, lymphangiosarcoma and hemangiopericytoma have been grouped as vascular soft tissue sarcomas. At the present time, angiosarcoma and lymphangiosarcoma are considered to be classical vascular sarcomas, as they arise from the endothelium, differentiating them histologically from hemangiopericytoma, which appears to arise from the pericytes which surround the blood vessels.51 Hemangiopericytomas are distributed throughout the body, with approximately one-third of patients being seen with extremity lesions and one-third with intra-abdominal lesions (Figure 7.28). The remaining third are

1.0 0.9 0.8

Proportion surviving

0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 0

12

24

36

48

60

72

84

96

108

Months

Figure 7.27 Angiosarcoma: overall survival, n=50. From Espat et al.44

120

132

144

156

168

180

192

120

Diagnosis and Management of Soft Tissue Sarcoma

(a)

(b)

(c)

(d)

Figure 7.28 Low-grade hemangiopericytoma of the axilla: (a) clinical presentation, post-biopsy; (b) CT scan, showing extensive lesion; (c) operative dissection; (d) clinical specimen. made up of head and neck, trunk and thoracic lesions equally. The majority are high-grade lesions with approximately similar distribution to other sarcomas, i.e. one-third <5 cm, one-third 5–10 cm, and one-third >10 cm. Most are deep-seated lesions. The median age at presentation is 48 years.

Treatment Surgical resection remains the primary modality for potentially curative treatment.

Adjuvant treatment Radiation therapy is primarily used in a palliative role for metastatic hemangiopericytoma, particularly metastasis to bone. Some data suggest that preoperative use of radiation therapy may diminish the very significant potential hemorrhage from such lesions.52 In the majority of patients, radiation therapy should be considered as an adjunct to limit local recurrence.53 Adjuvant chemotherapy has not been shown to have proven benefit, but should be

Clinical and pathologic correlates considered in investigational trials in high-risk patients.

Prognostic factors for outcome As with other sarcomas, negative microscopic margins diminish local recurrence. Complete resection results in long-term survival.

Results Approximately 20% of all patients will develop metastasis following complete resection of the primary, and a majority of these will go on to die of the disease. Overall 2- and 5-year survival rates in our series were 82% and 64%.54

Malignant peripheral nerve sheath tumors Tumors of the peripheral nerves are usually classified based on an assumed origin from a cell component usually associated with the normal nerve. As each peripheral nerve is composed of one or more nerve fascicles, there are contained within these, nerve fibers or axons surrounded by Schwann cells. The Schwann cell is thought of as a neural crest cell, whose function is support of the axon. Conceptually, the axon is surrounded by a myelin sheath, with a Schwann cell surrounding that. In addition, there are other supporting fibroblasts and capillary and endothelial cells which also help surround the axon. Each nerve consists of a series of fascicles, which are surrounded by a distinct layer of perineurial cells and this layer is called the perineurium. It would appear, therefore, that the Schwann cell and the perineurial cell are different and can be

121

recognized as such. For our understanding of malignant peripheral nerve tumors, it is important to note that Schwann cells express the S-100 protein, but not epithelial membrane antigen (EMA). The perineurial cells, however, express EMA but not S-100 protein.55 We can therefore classify the major peripheral nerve sheath tumors (Table 7.6) based on the origin from the underlying cell (see Chapter 3). Malignant peripheral nerve sheath tumors (MPNST) therefore can arise from the neurofibroma, the schwannoma, or the ganglioneuroma. This explains the often-used terms, ‘malignant schwannoma’ and ‘neurofibrosarcoma’, all of which are malignant peripheral nerve tumors in essence only really defined by their cell of origin. The majority are thought to arise from the Schwann cell, and the use of the term, ‘malignant peripheral nerve sheath tumor’ gets away from the suggestion that the malignant schwannoma arises from a benign schwannoma, thought to be a very unlikely event. Table 7.6 Peripheral nerve sheath tumors. Schwannoma Cellular schwannoma Melanotic schwannoma Schwannoma Neurofibroma Cutaneous Intraneural Plexiform Diffuse Perineurioma Soft tissue Intraneural Malignant peripheral nerve sheath tumor (MPNST) From neurofibroma From schwannoma From ganglioneuroma

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Diagnosis and Management of Soft Tissue Sarcoma

Diagnosis

Treatment

Diagnosis is usually suspected by a mass lesion. Approximately one-half to two-thirds of all patients with MPNST will be seen in association with an underlying neurofibroma. This explains the high prevalence of patients with neurofibromatosis as the background to the development of MPNST. Most patients are between 20 and 40 years of age at the time of onset. The tumors are uncommon in children. Patients with neurofibromatosis-1 (NF-1) usually develop tumors at an earlier age. Patients present with a firm to hard mass, often with some central necrosis. Histologic patterns (see Chapter 3) are diverse: various subtypes have been described, including the epithelioid type, the malignant triton tumor, usually reserved for the peripheral nerve tumor that has rhabdomyosarcomatous differentiation. In a review of our own experience, the median age at presentation was 33 years,56 with a predominance of 24 males to 9 females. They all presented with a mass lesion, with some having neurologic symptoms, usually pain on pressure over the tumor. At the time of presentation, the tumor was large (median 9.5 cm) and the majority (66%) were located in the lower extremity. In our experience, an obvious nerve as a source of origin was found in two-thirds of the patients. As these tumors can involve large nerves, such as the sciatic and the brachial plexus, the morbidity of treatment can be high. The vast majority of all MPNST are high-grade lesions which may, given their large size, have been responsible for the previous suggestion indicating their bad behavior. However (see below), once corrected for known risk factors, their behavior is similar to that of other large, highgrade sarcomas.

The majority of patients require complete surgical resection, with the goal of limb-sparing operations wherever possible. In our series, however, one-third of patients came to amputation because of the extensive nature of the lesion involving a major nerve. Often, to obtain negative margins, the nerve needs to be resected. The margins were negative in all patients in whom the major nerve was sacrificed in our series, but five patients with preserved nerve had positive margins.

Adjuvant treatment The indications for radiation therapy are the same as for other soft tissue sarcomas. Local recurrence can be decreased in patients with lesions >5 cm who receive radiation therapy. Adjuvant chemotherapy has not been shown to have proven benefit, but should be considered in investigational trials in high-risk patients.

Prognostic factors for outcome In terms of disease-free survival, a positive margin is a predictor (Figure 7.29).

Results Amputation did not seem to improve survival in a non-random study (Figure 7.30), and patients have a similar outcome in terms of survival compared with other patients with other extremity sarcomas, once corrected for their large size and high-grade nature (Figure 7.31). We were not able to show a difference in terms of disease-free survival for patients who had MPNST in association with neurofibromatosis, as has been suggested previously.

Clinical and pathologic correlates 1 Negative n=22 Positive n=9

0.8

Proportion surviving

Proportion surviving

1

0.6 0.4 0.2

Limb sparing n=13 Amputation n=8

0.8 0.6 0.4 0.2 0

0 0

20

40

p=0.02

60 Months

80

100

1

p=0.37

0.2 0 60 80 Months

100

120

60 Months

80

100

120

Figure 7.30 MPNST: amputation does not seem to improve survival (non-random comparison). From Vauthey et al.56

Number of patients

0.4

40

40

100

0.6

0 20 p=0.1

20

n=309

Non-MPNST n=458 MPNST n=31

0.8

0

120

Figure 7.29 MPNST: in terms of disease-free survival, a positive margin is a predictor of survival. From Vauthey et al.56

Proportion surviving

123

140

Figure 7.31 MPNST: patients have a similar outcome in terms of survival as other patients with other extremity sarcomas, once corrected for their large size and high-grade nature. From Vauthey et al.56

Synovial sarcoma Diagnosis Synovial sarcoma comprises approximately 7% of all adult patients with sarcoma. However, it is a disease of the younger age

80 60 40 20 0 <20 20-29 30-39 40-49 50-59 60-69 70-79 80-89 90-99 Age (years)

Figure 7.32 Synovial sarcoma: age distribution in our adult population. MSKCC, 7/82–12/00.

group and so is often seen in adolescents and children. The age distribution in our adult population is shown in Figure 7.32. The median age at presentation (n=226) is 36 years. Although considered synovial in origin, there is no evidence that the tumor itself results from the synovia, although it is

124

Diagnosis and Management of Soft Tissue Sarcoma

(a)

(c) (b) Figure 7.33 Synovial sarcoma presents as an isolated mass. High-grade synovial sarcoma, posterior flank: (a) clinical picture showing prior biopsy, and extent from rib cage to iliac crest; (b) CT scan showing extensive psoas and spinal musculature involvement; (c) CT scan showing retroperitoneal extension.

Clinical and pathologic correlates commonly seen in association with joint spaces. Like other tumors, it presents as an isolated mass (Figure 7.33). It can be seen in unusual sites such as the diaphragm. A site distribution of synovial sarcoma according to our experience is shown in Figure 7.34. (See section on genetics of sarcoma.) The lesions are often extensive and present after attempted prior resections and after prior metastatic resection (Figure 7.35). Synovial sarcoma is a high-grade tumor associated with a poor prognosis. Tumors such as epithelioid, clear cell and chordoid sarcomas, which were broadly characterized as tendosynovial sarcomas in the past, are presently separated from synovial sarcomas. These tumors are diagnosed by typical histology (in most biphasic synovial sarcomas) or in conjunction with immunohistochemical techniques (in all monophasic synovial sarcomas). EMA and keratins (CAM 5.2 and AE1:AE3) typically define the immunopathologic differentiation of these tumors. In some cases, with atypical histology and non-contributory immunoprofile, additional

Upper Extremity 24% Lower extremity 55%

73 172 32 Other 10% 19 58

Trunk 6% Retroperitoneal/ intra-abdominal 3%

n=309

Visceral 2%

Figure 7.34 Site distribution of synovial sarcoma, according to our experience. MSKCC, 7/82–12/00.

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studies that may aid the diagnosis include ultrastructural detection of epithelial-type cellular junctions and/or the presence of translocation t(X;18) by molecular techniques. This results in the fusion protein, SYT–SSX, which may have etiologic and prognostic significance.57

Treatment Treatment, as with other sarcomas, is complete surgical resection. These tumors are commonly treated by multimodality therapy. There is anecdotal experience that their response rate to chemotherapy is higher than that of other types of soft tissue sarcoma. They commonly occur around the proximal limb girdles, and operation may frequently involve dissection in and around the neurovascular structures. Thus, it is not unusual to have to do a neurovascular dissection when removing these tumors from the shoulder and axilla. Similar principles apply in the groin.

Adjuvant treatment The same principles of adjuvant radiation therapy as are applicable to other soft tissue sarcomas apply to synovial sarcoma. Because all synovial sarcomas are high grade, the addition of adjuvant brachytherapy is utilized in patients with tumors >5 cm to limit local recurrence. Chemotherapy has been much more liberally used in synovial sarcoma than in some other high-grade sarcomas, presumably because of the propensity for young adolescents to develop the disease. Some suggestion of improved survival has been made in uncontrolled studies.58–60 In our own

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Diagnosis and Management of Soft Tissue Sarcoma

(a)

(b)

(c)

(d)

Figure 7.35 Recurrent high-grade synovial sarcoma post-pneumonectomy for pulmonary metastasis: (a) chest CT; (b) clinical recurrence; (c) operative specimen; (d) postoperative appearance.

studies, 42 patients (37%) received adjuvant chemotherapy in a non-random fashion. We were not able to demonstrate a survival benefit for patients receiving chemotherapy. Because of anecdotal experience with high response rates to chemotherapy, we frequently treat patients with synovial sarcomas that are >5 cm with adjuvant chemotherapy. In those presenting with larger tumors involving neurovascular structures, neoadjuvant chemotherapy is often worthwhile and may frequently facilitate subsequent resection.

Prognostic factors for outcome One analysis57 has suggested that the SYT-SSX gene fusion product may have significance in prognosis. A review of the early studies60 from MSKCC shows the changes that have taken place in the outcome for these lesions. In earlier time periods, the incidence of pulmonary metastases was 65% and the overall 5-year survival was 24%. In the present studies,

Clinical and pathologic correlates overall disease-specific survival was 72%. As with other sarcomas, size, age, anatomic site, margins and histologic subtype have all been cited as prognostic factors for outcome. In our most recent analysis, age was not a significant variable for prognosis. An analysis of 126 patients with primary extremity synovial sarcoma seen at MSKCC was recently completed.61 The median age of the patients was 35, with an equal distribution between male and female. The majority of patients presented with a small lesion <5 cm (55%) involving the lower extremity. Of the 112 patients treated by us primarily, eight have had local recurrences, with a median follow-up of 57 months (range 1–182 months), and 32

127

(29%) have developed metastatic disease. As with other extremity lesions, the lung is the primary site of metastatic disease: 28 of the 32 distant recurrences that we have seen occurred in the lung. Only 8% of all patients experienced local recurrence within five years, in marked contradistinction to early studies in the 1950s, when local recurrence was a very common event. However, adjuvant radiation therapy is liberally used in high-grade lesions, particularly those that are >5 cm in size. Overall survival is shown in Figure 7.36. We found that tumor size >5 cm and bone or neurovascular invasion were independent adverse prognostic factors. When patients

1.0 0.9 0.8

Proportion alive

0.7 0.6 0.5 0.4 0.3 STRATA

0.2

No risk factors (n=54)

0.1

1 risk factor

(n=52)

2 risk factor

(n=6)

0.0 0 p=0.0009

12

24

36

48

60

72

84

96

108

120

132

144

156

168

Months from surgery

Figure 7.36 Synovial sarcoma: overall survival by risk factors (see text). From Lewis et al.61

180

192

128

Diagnosis and Management of Soft Tissue Sarcoma

were stratified by these factors into three groups – patients with no risk factors, patients with one risk factor, and patients with two risk factors – we found that the 5-year tumor mortality was 14% in those with no risk factors, 34% in those with one risk factor, and 60% in those with two risk factors. The 5-year actuarial mortality for the entire group of patients with synovial sarcoma is approximately 25%.

6.5 cm (1.2–24 cm). Sixty-five per cent of patients (48) presented with stage IV disease, and 34 of these had solitary foci, with the lung predominant in 30. Brain metastases are a late feature of alveolar soft part sarcoma and can occur in as many as 20% of patients with metastatic disease. However, they occur only in the presence of antecedent or concurrent metastatic disease elsewhere.

Results

Treatment

Despite optimal current multimodality therapy, 40% of patients will develop distant metastases by 5 years, and 25% will die. The actuarial 5-year local recurrence rate is approximately 12%. However, as can be seen, long-term survival is possible in patients treated primarily, and overall survival is of the order of 75%.

Treatment continues to be complete surgical resection in those who present with primary disease alone. Unfortunately, 25% will present with metastasis at the time of diagnosis. Local recurrence following surgical treatment is relatively infrequent (15–20%).

Alveolar soft part sarcoma

The majority of patients will undergo local excision, although adjuvant radiation therapy is given in some. We have not been able to show a benefit to chemotherapy.

Diagnosis Alveolar soft part sarcoma is a rare malignancy with an often prolonged clinical course which provides considerable confusion for both patient and physician. The lesion is itself rare, with unusual features, commonly discussed. The median age at diagnosis is young (usually 20-25). The lesion usually presents as a mass lesion, commonly in the extremity.62 A recent retrospective review described 70 patients seen consecutively with localized and metastatic alveolar soft part sarcoma over a 40-year period.63 Forty-four (60%) presented in the extremity, 15 (20%) in the trunk, 9 (12%) in the head and neck, and 6 (8%) in the retroperitoneum. Median tumor size was

Adjuvant treatment

Prognostic factors for outcome Younger patients have better long-term survival. Metastasis at the time of presentation is clearly a bad prognostic event and is probably the factor that explains the improved prognosis for the younger age group, who tend to present without metastases.

Results As with other extremity lesions, the most common site of metastasis is the lung, although a greater frequency of bone

Clinical and pathologic correlates metastasis is encountered in alveolar soft part sarcoma than in other high-grade extremity sarcomas. For 22 patients treated and followed for localized alveolar soft part sarcoma,62 the 5-year local recurrence-free survival was 87%, distant recurrence-free survival was 84%, disease-free survival was 71%, and overall survival was 87%. With a long period of follow-up (median, 9 years), 3 of the 22 patients with initial localized disease developed metastatic disease to lung (Figure 7.37). Long-term survival is certainly possible. In our analysis of 102 patients,62 patients tended to die from disease over a period of 25 years.

1.0 0.9

Survival probability

0.8 0.7 0.6

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Epithelioid sarcoma Epithelioid sarcoma is a rare histologic subtype.64–67 It primarily affects young adults and is set apart from other types of sarcoma by a high rate of local recurrence and incidence of nodal metastasis.

Diagnosis The clinical presentation is varied and often leads to delay in diagnosis. The median age at diagnosis is 30 years. These tumors frequently present as a nodule or ulcerated lesion on a distal extremity, although they can arise anywhere. In our experience, the primary sites of presentation are the extremities, followed by the trunk, including the buttock, perineum or vulva (Table 7.7 and 7.8).64 Primary tumors presented as ulcerated distal lesions in some patients, and as masses in others. In all patients, the diagnosis was made by biopsy, although several patients had been misdiagnosed as having had a wart or dermatofibroma.

0.5 0.4 0.3

No metastases (69)

0.2 Metastases (22)

0.1 0.0 0

5

10 15 20 Years from diagnosis

25

30

Figure 7.37 Survival after diagnosis in 69 patients with alveolar soft part sarcoma without distant metastases at presentation (continuous line), and 22 patients with metastases at presentation (dashed line). From Lieberman et al.62

Table 7.7 Primary sites of epithelioid sarcoma, 1 July 1982 to 30 June 1999. Site

%

Upper extremity Lower extremity Perineal buttock, vulva, perineum Head and neck

29 36 32 3

From Ross et al.64

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Diagnosis and Management of Soft Tissue Sarcoma

Table 7.8 Natural history of 16 patients with epithelioid sarcoma. Age at diagnosis (years)

Primary site

Local recurrence

Nodal metastasis

Distant metastasis (months)

20 16 37 39 32 38 36 27 30 33 26 66 24 31 52 19

Vulva Buttock Buttock Buttock Perineum Perineum Perineum Calf Calf Shin Toe Thigh Wrist Finger Forearm Forearm

None 8 months None 19 months 24 months 34 months None None None 21 months Multiple None 11 months 3 months 56 months None

None 5 months None 19 months 24 months None None None None 52 months 29 months None None 3 months None At present

None Pulmonary Pulmonary Pulmonary None None None Pulmonary Pulmonary None Pulmonary None None None None At present

Status (months)

(9) (24) (19)

at present at present (40)

NED (105) AWD (96) DOD (49) DOD (44) NED (33) NED (10) NED (3) AWD (1) DOD (14) NED (69) DOD (89) NED (54) AWD (3) NED (86) NED (61) DOD (10)

NED, no evidence of disease; AWD, alive with disease; DOD, dead of disease. From Ross et al.64

Treatment All of these tumors are high grade. Treatment is governed by similar principles as for other sarcomas, except that these tumors tend to spread along tendon sheaths or via lymphatics into lymph nodes. All patients should undergo wide local excision of their primary, as dictated by the anatomic site. When these tumors present in an extremity digit, this will often necessitate a primary amputation. Because of the propensity to spread to regional lymph nodes, it is obviously important to examine these patients carefully. In our experience,64 44% of patients will develop metastases to regional lymph nodes during the course of their disease. In patients who are node

negative, there is no role for prophylactic lymphadenectomy. While there is no firm evidence, it may well be worthwhile performing sentinel lymph node mapping on patients presenting with primary lesions. If the sentinel lymph node is negative, no further treatment needs to be given to the regional nodes. Conversely, if the sentinel lymph node is positive, the regional lymph nodes should be removed.

Adjuvant treatment In tumors that are greater than 5 cm or where margins are positive, adjuvant radiation should be administered. As with other soft tissue sarcoma, there is no defined role for neoadjuvant or adjuvant chemotherapy.

Clinical and pathologic correlates

Prognostic factors for outcome Patients who develop pulmonary metastases show a significantly reduced rate of survival. Conversely, patients with nodal disease do not have the same bad prognosis. Similarly, there is no difference in survival between patients who develop local recurrence and those who do not. The only factor that we have found to be associated with decreased survival is male gender.

Results The median survival of patients ranges from 84 to 88 months.64,65 (Table 7.8). Approximately 70% of patients will develop local recurrence, and 40% will develop lymph node metastases. Neither of these impact on tumor mortality. Pulmonary metastases will develop in 21–40% of patients, and this is the predominant cause of death in these patients.

Desmoplastic small round cell tumors Diagnosis Desmoplastic small round cell tumors are rare, very aggressive tumors, usually occurring in adolescence and early adulthood. Our experience has been described.68 The median age at diagnosis is 22 years. Most patients present with non-specific symptoms, usually confined to the abdomen, with increasing abdominal girth, malaise, and palpable mass. The majority have an intra-abdominal or pelvic origin, and, at the time of presentation, disease will be very extensive, involving all of the peritoneal surfaces, the

131

lymph nodes, and, often, discontiguous organs. These tumors are predominantly a disease of young males: in our experience,68 96% of 30 patients were male, and the primary site was the abdominopelvis in 97%. The tumors display phenotypic characterization with a consistent chromosomal translocation t(11;22)(p13;q12), which reflects a fusion of EWS (Ewing’s sarcoma gene) with WT1 (Wilms tumor gene).69 This overlap between desmoplastic small round cell tumor and Ewing’s sarcoma/peripheral primitive neuroectodermal tumor (PNET) continues. Isolated reports describe the EWS/ERG fusion transcipt, i.e. the characteristic of Ewing’s sarcoma or PNET, rather than the more classical EWS–WT1 primary transcript typical of the desmoplastic small round cell tumor.70 In one study of 39 patients, 32 were men and the mean age was 25 years (10–41). Survival was poor, with a mean of 25 months, with widespread metastasis.71 The author identified 37 of the 39 patients who were positive for cytokeratin markers.72 The study confirmed that epithelial, mesenchymal and neural phenotypes are all expressed with a wide variation of prevalence. The author suggests that it is unlikely, because of the immunohistochemistry, that the tumor is of mesothelial or skeletal muscle origin. While histogenesis remains uncertain, the tumor presumably originates from an early stem cell with multiple phenotypic capacity for differentiation outcome.

Treatment The majority of patients in our experience receive chemotherapy, with surgery reserved for complications of the disease, or, following chemotherapy, in an effort to provide complete resection or maximum cytoreduction.

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Diagnosis and Management of Soft Tissue Sarcoma

Adjuvant treatment With intensive chemotherapy, isolated reports of complete clinical remissions have been obtained. In those patients with a good response to chemotherapy, surgical debulking has resulted in progression-free survival in a small number of patients. However, toxicity is high and death from toxicity is a real phenomenon.

Prognostic factors for outcome

(a)

As the majority of patients present with extensive disease, only response to chemotherapy and the ability to undergo complete gross resection translate into survival benefit.

Results Only those patients who underwent complete response to multimodality therapy are longterm survivors. Overall median survival is approximately 17 months.68

Extraskeletal chondrosarcoma Diagnosis Extraskeletal chondrosarcoma was first described in 1953, with the myxoid variant being defined by Enzinger and Shiraki in 1972.73 The diagnosis is based on specific histopathologic findings of immature chondrocytes within a soft tissue, extraosseous location. The plain film often shows extraskeletal calcification, and the extension can be significant, to involve neurovascular structures (Figure 7.38). Unlike chondrosarcoma of bone, differentiated cartilage cells are rare.

(b) Figure 7.38 Extraskeletal chondrosarcoma: (a) extraskeletal calcification in a patient with chondrosarcoma; (b) MRI – extensive soft tissue mass involving the entire popliteal fossa, making conservative operation difficult, if not impossible. The patient underwent amputation after recurrence following conservative operation and is alive with no evidence of disease 2 years later.

Clinical and pathologic correlates

Treatment The treatment principles for these tumors are the same as for other extremity soft tissue sarcomas. The goal of operation is to effect complete resection.

Adjuvant treatment Adjuvant treatment is applied in the same fashion as for other tumors. Of note is that in our experience in treating these tumors, the presence of positive microscopic margins is not an adverse prognostic factor for recurrence, but all of those patients with positive margins received adjuvant radiation therapy.

Prognostic factors for outcome Several studies have suggested that, if followed for long enough, most patients with this disease will develop recurrence and many of these patients will die from metastatic disease. In one analysis of our experience, we found an actuarial overall survival of 80% at 5 years.74 Furthermore, the actuarial metastasis and local recurrence rates of survival were also 80% at 5 years. Thus, extraskeletal and myxoid chondrosarcoma should be regarded as a low-grade sarcoma, with a propensity for both local recurrence and metastasis over the long term.

Extraskeletal osteogenic sarcoma Primary osteogenic sarcoma occurring in the soft tissue is a rare entity. There have been many single case reports of unusual sites such

133

as the kidney, liver, larynx,75 spermatic cord, tongue, mediastinum, penis, breast, heart and nasopharynx. Our own experience is very limited. Among over 4000 cases of soft tissue sarcoma admitted to MSKCC, we have seen 15 patients with this unusual variant.76 The proximal thigh is by far the most common site, accounting for 93% (14 of 15) of the patients. At the last follow-up, nine of the patients were dead of disease (60%), emphasizing the relatively poor prognosis for this lesion. However, it would appear that it is not very different from other large, high-grade, deep lesions, which, essentially, all of these tumors tend to be.

Rhabdomyosarcoma Diagnosis Rhabdomyosarcoma is a tumor believed to arise from cells committed to a skeletal muscle lineage. While it is the most common sarcoma in the pediatric population, it is very uncommon in adults. In our experience, it constitutes approximately 2% of all adult sarcomas seen. It has a wide site of anatomic distribution, and the majority are visceral, in particular the genitourinary system, with the testes and prostate being the most common subsites (Figure 7.39). Other sites include the head and neck and extremity, each of these accounting for approximately one-third of patients seen.77 There are four pathologic subtypes: embryonal, alveolar, pleomorphic and botryoid. In our experience, embryonal is the most common, accounting for about 50% of patients seen. Alveolar is the next most common, accounting for about 30%, while pleomorphic is seen in 17%. The botryoid subtype is exceedingly rare in adults.

134

Diagnosis and Management of Soft Tissue Sarcoma translation of the success in children to adults has been difficult.

Prognostic factors for outcome

Treatment The management of adult patients has often been extrapolated from the experience with pediatric rhabdomyosarcoma. Results from controlled trials have led to effective adjuvant chemotherapy regimens for pediatric patients, with survival rates approaching 70%. Unfortunately, similar treatment of adults has not resulted in this level of success. Surgical resection remains the mainstay of therapy. We often treat younger adults with a pediatric multidose regimen of chemotherapy, utilizing the P-6 protocol.

Results The median disease-specific survival is 22 months, and the 5-year survival is 35% (Figure 7.40). Predictors of improved diseasespecific survival include: age at diagnosis <20 years, localized disease, tumor size <5 cm, and 1.0

n=84 Median follow-up = 5.6 years

0.9 0.8

Proportion surviving

Figure 7.39 Rhabdomyosarcoma involving the ischiorectal fossa

Patient age, extent of disease, tumor size and margins are significant predictors of diseasespecific survival. The most important predictor is complete resection. Histologic subtype does not predict patient survival but does vary with patient age. It is notable that the proportion of patients with the pleomorphic subtype increases with advancing age, accounting for over 40% of rhabdomyosarcoma in patients over the age of 40.

0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 0

Adjuvant treatment The principle of adjuvant radiation is the same as that for other histologic subtypes. Results seen in adults have been different from those seen in the pediatric population, and

20

40

60

80 100 Months

120

140

160

180

Figure 7.40 Adult rhabdomyosarcoma: median diseasespecific survival and 5-year survival. From Hawkins et al.77

Clinical and pathologic correlates a negative surgical margin. When patients older than 20 years are subdivided by decades, all groups have similarly poor survival. Patients diagnosed prior to age 20 have not yet reached median disease-specific survival, whereas those greater than 20 years of age have a median disease-specific survival of 15 months.

Clear cell sarcoma (malignant melanoma of soft parts) The original report of this unusual soft tissue neoplasm was provided by Enzinger in 1965.78 Since that time, a number of reports have suggested the melanocytic-like origin of this tumor. Further emphasis has been provided by the finding that the S-100 protein may be of value in the diagnosis,79 and the known marker of melanoma, HMB-45, has also been observed in the same tumors.

135

Metastasis may occur in a large percentage of patients. The association of gene product abnormalities has also been suggested, related to an abnormal gene product similar to that seen in some small round cell tumors.80 These tumors commonly occur in the extremity and, like other sarcomas, present as a non-painful mass. Primary treatment, as for other sarcomas, is complete surgical resection, and in patients with close or potentially positive margins, radiation therapy has been applied.

Results A review of the Dutch experience with 29 patients suggests that 13 developed regional lymph node metastasis, 8 of 23 developed local recurrence, and 14 of 18 patients who developed distant metastases died of disease.81 Overall survival was 54% at 5 years, and 65% for those patients presenting with localized tumors. As with other sarcomas, survival was related to size.

Table 7.9 Analysis of local recurrence-free survival in 951 sarcoma patients presenting to MSKCC with primary disease of the extremities, 7/82–7/98. Local recurrence-free survival Prognostic factor Histology

Fibrosarcoma Leiomyosarcoma Liposarcoma MFH MPNT Synovial sarcoma

aUnivariate

N

Events

53 98 297 315 45 143

8 7 52 48 10 12

log-rank p-value. (Cox) p-value. cRelative risk estimates with (95% CI). bMultivariate

Pa

Pb

0.03

0.95 0.05 0.82 Baseline 0.03 0.28

RRc 0.45 (0.2,1.0)

2.2(1.1,4.4)

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Diagnosis and Management of Soft Tissue Sarcoma

Overall prognostic factors for outcome, based on histology We reviewed 951 patients with primary extremity soft tissue sarcoma and analyzed outcome based on histology alone. For local recurrence-free survival (Table 7.9), considering the commonest histopathology of MFH, 85%

local recurrence-free survival at 5 years, as a baseline, improved local recurrence-free survival is found in liposarcoma, synovial sarcoma, and leiomyosarcoma, with a worse survival for malignant peripheral nerve tumor (MPNT). Only the poorer survival of MPNT and the better survival of leiomyosarcoma are statistically significant. This is consistent with the descriptions above, where leiomyosarcomas in the extremity can often be superficial lesions,

Table 7.10 Analysis of disease-specific survival in 951 sarcoma patients presenting to MSKCC with primary disease of the extremities, 7/82–7/98. Disease-specific survival Prognostic factor Histology

Fibrosarcoma Leiomyosarcoma Liposarcoma MFH MPNT Synovial sarcoma

N

Events

53 98 297 315 45 143

3 25 52 67 17 35

Pa

Pb

RRc 0.3 (0.1,0.9) 1.6 (1.0,2.5) 0.6 (0.4,0.9)

<0.001

0.03 0.05 0.01 Baseline 0.07 0.71

1.7 (1.0,3.1)

aUnivariate

log-rank p-value. (Cox) p-value. cRelative risk estimates with (95% CI). bMultivariate

Table 7.11 Analysis of metastasis-free survival in 951 sarcoma patients presenting to MSKCC with primary disease of the extremities, 7/82–7/98. Distant recurrence-free survival Prognostic factor Histology

Fibrosarcoma Leiomyosarcoma Liposarcoma MFH MPNT Synovial sarcoma

aUnivariate

N

Events

53 98 297 315 45 143

6 29 59 76 19 48

log-rank p-value. (Cox) p-value. cRelative risk estimates with (95% CI). bMultivariate

Pa

Pb

RRc 0.5 (0.2,1.0) 1.7 (1.1,2.5) 0.6 (0.4,0.9)

<0.001

0.06 0.03 0.01 Baseline 0.3 0.51

Clinical and pathologic correlates whereas malignant peripheral nerve tumors are essentially all high grade and usually deep. In terms of disease-specific survival, using the same approach (Table 7.10), liposarcoma has significantly improved 5-year survival, as does fibrosarcoma, whereas leiomyosarcoma and MPNT have worse 5-year disease-specific survival. This is all consistent with distant recurrence-free survival (Table 7.11), where the improvement in liposarcoma is seen and the poorer prognosis for leiomyosarcoma and MPNT identified. Because of the tendency of fibrosarcoma to recur locally rather than systemically, fibrosarcoma also has an improved distant relapse-free survival.

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Clinical and pathologic correlates

44.

45. 46.

47.

48.

49.

50.

51. 52.

53.

54.

postmastectomy lymphedema: a report of six cases of elephantiasis chirurgica. Cancer 1948;1:64. Espat NJ, Lewis JJ, Leung D, Brennan MF. Confirmed angiosarcoma: prognostic factors and outcome in 50 prospectively followed patients. Sarcoma 2000;4:173–7. Lewis JJ, Brennan MF. Soft tissue sarcomas. Current Problems Surg 1996;33:817–80. Mark RJ, Tran LM, Sercarz J et al. Angiosarcoma of the head and neck. The UCLA experience 1955 through 1990. Arch Otolaryngol Head Neck Surg 1993;119:973–8. Bullen R, Larson PO, Landeck AE et al. Angiosarcoma of the head and neck managed by a combination of multiple biopsies to determine tumor margin and radiation therapy. Report of three cases and review of the literature. Dermatol Surg 1998;24:1105–10. Brand CU, Yawalkar N, von Briel C, Hunziker T. Combined surgical and X-ray treatment for angiosarcoma of the scalp: report of a case with a favorable outcome. Br J Dermatol 1996;134:763–5. Kinard JD, Zwicker RD, Schmidt-Ullrich RK et al. Total craniofacial photon shell technique for radiotherapy of extensive angiosarcomas of the head. Br J Radiol 1996;69:351–5. Morrison WH, Byers RM, Garden AS et al. Cutaneous angiosarcoma of the head and neck. A therapeutic dilemma. Cancer 1995;76:319–27. Enzinger FM, Weiss SW. Soft Tissue Tumors, 3rd edn. St Louis: Mosby-Year Book, 1995. Uemura S, Kuratsu J, Hamada J et al. Effect of radiation therapy against intracranial hemangiopericytoma. Neurol Med Chirurg 1992;32:328–32. Staples JJ, Robinson RA, Wen BC, Hussey DH. Hemangiopericytoma – the role of radiotherapy. Int J Radiation Oncol Biol Physics 1990;19:445–51. Espat NJ, Lewis JJ, Leung D, Brennan MF. Conventional hemangiopericytoma: modern analysis of outcome. Cancer (submitted).

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55. Woodruff JM. Pathology of the major peripheral nerve sheath neoplasms. Int Acad Pathol 1996;161:129–60. 56. Vauthey JN, Woodruff JM, Brennan MF. Extremity malignant peripheral nerve sheath tumors (neurogenic sarcomas): a 10–year experience. Ann Surg Oncol 1995;2:126–31. 57. Ladanyi M. The emerging molecular genetics of sarcoma translocations. Diagn Mol Pathol 1995;4:162–73. 58. Ladenstein R, Treuner J, Koscielniak E et al. Synovial sarcoma of childhood and adolescence: report of the German CWS-81 study. Cancer 1993;71:3647–55. 59. 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;12:2360–6. 60. Pack GT, Ariel IM. Synovial sarcoma (malignant synovioma). Report of 60 cases. Surgery 1950; 28:1047–84. 61. Lewis JJ, Antonescu CR, Leung D et al. Synovial sarcoma: A multivariate analysis of prognostic factors in 112 patients with primary localized tumors of the extremity. J Clin Oncol 2000;18:2087–94. 62. Lieberman PH, Brennan MF, Kimmel M et al. Alveolar soft-part sarcoma. A clinicopathologic study of half a century. Cancer 1989;63:1–13. 63. Pontera C Jr, Ho V, Patel SR et al. Alveolar soft part sarcoma (ASPS): clinical course and pattern of metastasis in 70 patients treated at a single institution. Cancer 2001;91:585–91. 64. Ross HM, Lewis JJ, Woodruff JM, Brennan MF. Epithelioid sarcoma: clinical behavior and prognostic factors of survival. Ann Surg Oncol 1997;4:491–5. 65. Prat J, Woodruff JM, Marcove R. Epithelioid sarcoma: an analysis of 22 cases indicating the prognostic significance of vascular invasion and regional lymph node metastasis. Cancer 1978;41:1472–87. 66. Chase DR, Enzinger FM. Epithelioid sarcoma: diagnosis, prognostic indicators, and treatment. Am J Surg Pathol 1985;9:241–63.

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67. Bos GD, Pritchard DJ, Reiman HM et al. Epithelioid sarcoma: an analysis of fifty-one cases. J Bone Joint Surg 1988;70:862–70. 68. Schwarz RE, Gerald WL, Coit DG et al. Desmoplastic small round cell tumors: prognostic indicators and results of surgical management. Ann Surg Oncol 1998;5:416–22. 69. Leuschner I, Redig K, Harms D. Desmoplastic small round cell tumor. Semin Diagn Pathol 1996;13:204–12. 70. Ordi J, de Alava E, Torne A et al. Intraabdominal desmoplastic small round cell tumor with EWS/ERG fusion transcript. Am J Surg Pathol 1998;22:1026–32. 71. Ordonez NG. Desmoplastic small round cell tumor: I: a histopathologic study of 39 cases with emphasis on unusual histological patterns. Am J Surg Pathol 1998;22:1303–13. 72. Ordonez NG. Desmoplastic small round cell tumor: II: An ultrastructural and immnohistochemical study with emphasis on new immunohistochemical markers. Am J Surg Pathol 1998;22:1314–27. 73. Enzinger FM, Shiraki M. Extraskeletal myxoid chondrosarcoma: an analysis of 34 cases. Human Pathol 1972;3:421. 74. Lewis JJ, Brennan MF. Soft tissue sarcoma. In: Cameron JL, ed. Current Surgical Therapy, 6th edn. Chicago: Mosby, Inc., 1998;1033–8.

75. Myssiorek D, Patel M, Wasserman P, Rofeim O. Osteosarcoma of the larynx. Ann Otol Rhinol Laryngol 1998;107:70–4. 76. McCarter MD, Lewis JJ, Antonescu CR, Brennan MF. Extraskeletal osteosarcoma: analysis of outcome of a rare neoplasm. Sarcoma 2000;4:119–23. 77. Hawkins WG, Hoos A, Antonescu CR et al. Clinicopathologic analysis of adult patients with rhabdomyosarcoma 2(RMS). Cancer 2001;91:794–803. 78. Enzinger FM. Clear-cell sarcoma of tendons and aponeuroses: an analysis of 21 cases. Cancer 1965;18:1163–74. 79. Weiss SW, Langloss JM, Enzinger FM. Value of S-100 protein in the diagnosis of soft tissue tumors with particular reference to benign and malignant schwann cell tumors. Lab Invest 1983;49:299–308. 80. Fujimora Y, Ohno T, Siddique H et al. The EWS-ATF-1 gene involved in malignant melanoma of soft parts with t(12;22) chromosome translocation, encodes a constitutive transcriptional activator. Oncogene 1996;21:963–70. 81. Deenik W, Mooi WJ, Rutgers EJ et al. Clear cell sarcoma (malignant melanoma) of soft parts: a clinicopathologic study of 30 cases. Cancer 1999;86:969–75.

8 Principles of management

Management of extremity and superficial trunk soft tissue sarcoma The majority of soft tissue sarcomas present as a clinically suspicious mass (Figure 8.1). The initial evaluation requires a standard approach to the historical possibilities of predisposing factors, as outlined in Chapter 6. Given the association of familial syndromes with the subsequent development of soft tissue sarcoma, obtaining the family history is

important. Clinical evaluation is then performed, to characterize the nature of the mass, specific site, relationship to neurovascular structures and clinical size. Prior history of trauma may raise the possibility of myositis ossificans (see Chapter 4). As benign lipomatous lesions are the most common form of soft tissue tumor, these provide the most difficult diagnostic conundrum. Features such as rapidity of growth, change in texture, fixation or the presence of a long-standing mass can often be helpful. Nevertheless, atypical lipomatous tumors, infiltrating lipomas and intramuscular lipomas can often lead to diagnostic difficulty (Figure 8.1).

Biopsy

Figure 8.1 Patient with a soft tissue mass, coming from beneath the clavicle, subsequently shown to be a lipoma.

Once the size of a lesion is characterized, further evaluation and biopsy is justified. For lesions <5 cm, excisional biopsy, particularly of superficial lesions, is the preferred approach. For lesions >5 cm or more deeply seated lesions, core needle (e.g. tru-cut®) biopsy has become the approach of choice. Historically, open biopsy has been recommended to obtain tissue for definition of malignancy and grade. Disadvantages of this technique are the operating room costs, potential morbidity with any open procedure, and the associated time required. When utilized, open biopsy should be carefully

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orientated with regard to subsequent treatment required (Figure 8.2). Transverse incisions in the extremity are to be avoided (Figure 8.3). Often, for small lesions, excisional biopsy can be recommended as the primary approach. Frozen section analysis at the time of definitive operation gives a rapid diagnosis but does not allow for preoperative multitreatment planning, and therefore it cannot be recommended if decisions about preoperative therapy are to be made. Modern immunohistochemical tests are able to differentiate on small samples, and core needle biopsy has become the procedure of choice in the initial diagnosis of suspicious soft tissue tumors. At MSKCC, core needle (tru-cut®) biopsy has been shown to be highly accurate in making a diagnosis of benign versus malignant and in differentiating sarcoma from carcinoma. In an evaluation of 164 primary extremity soft tissue masses before biopsy,1 93% of 60 core

Figure 8.3 Major transverse incisions in the extremity are to be avoided. This incision effectively commits the patient to a much more extensive procedure than necessary.

needle (tru-cut®) specimens were adequate to make a diagnosis, and, of these, 95%, 88%, and

Preoperative biopsy

Benign

Malignant

Malignant

Excise

Sarcoma

Other

Low grade

>5 cm

Wide excision

± ERT

Figure 8.2 Open biopsy should be carefully orientated with regard to subsequent required treatment, i.e. a longitudinal incision capable of being encompassed at the definitive procedure.

<5 cm

High grade

<5 cm

>5, <10 cm

>10 cm

Wide excision

± preoperative chemotherapy

No further treatment

Wide excision Plan BRT

Figure 8.4 Management algorithm. ERT, external beam radiation therapy; BRT, brachytherapy; ±, consider. From Heslin et al.1

Principles of management 75%, respectively, correlated with the final resection diagnosis for malignancy, grade, and histologic subtype. Of the frozen section biopsy specimens, 94% were adequate and 88% provided accurate diagnostic results of malignancy. However, 62% were correct for grade, and 47% were correct for histologic subtype. It was found that core needle biopsy was more cost effective and more time effective, with a lower rate of morbidity, compared with open biopsy. We concluded that accurate diagnostic information for malignancy and grade can be provided by core needle biopsy when read by an experienced pathologist. As always, should definitive diagnosis not be clear or in the absence of adequate tissue, open biopsy should be done (Figure 8.4).

Resection When the size, underlying histopathology and grade of the lesion have been established, a secondary approach can be developed (Figure 8.5). For small, <5cm low-grade lesions, wide local excision is the standard approach. Occasionally, a patient with a positive microscopic margin or close juxtaposition to a neurovascular bundle will be treated with adjuvant radiation therapy alone, although reexcision should be considered. For high-grade lesions <5 cm, wide excision with a margin aimed at 2 cm of normal tissue is the desired goal. If there is close juxtaposition to neurovascular bundles, adjuvant radiation therapy can be considered. A maximum of 25% of patients would be candidates for radiation therapy. The results of surgical management alone (see below) justify this approach. For soft tissue sarcoma of the extremity greater than 5 cm but less than 10 cm, again, a differentiation between low- and high-grade lesions is made. Current recommendations for

143

Soft tissue sarcoma Suspicious mass

Biopsy

Histopathology grade

Size

<5 cm

>5 cm

Figure 8.5 Once the size, histopathology and grade of the lesion have been established, a secondary approach can be developed.

high-grade lesions >10 cm include preoperative systemic chemotherapy, usually with a regimen containing ifosfamide and adriamycin for at least three courses. Currently, considerable debate exists as to whether this approach should be applied to patients who have lesions between 5 and 10 cm. It is our strong opinion that chemotherapy is not indicated for lesions <5 cm. In fact, it would appear that 8 cm is a more realistic dividing point for patients with high risk of recurrence (see below). Therefore, for patients with high-grade lesions between 5 and 10 cm, chemotherapy would be considered as an investigative approach. All patients with high-grade lesions >5 cm, we believe, should receive adjuvant radiation therapy to minimize local recurrence. This, in our hands, is usually performed by the brachytherapy route with or without a boost of external beam therapy. There is no proof that external beam therapy is either superior or inferior to the delivery of brachytherapy.

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Diagnosis and Management of Soft Tissue Sarcoma

Preoperative radiation therapy (see below) can be applied and is the preferred approach in the hands of many. Conversely, though no data exist currently to prove that preoperative adjuvant radiation therapy is either superior or inferior to the use of postoperative adjuvant therapy, a study suggests that the wound complication rate is increased by preoperative compared to postoperative radiation therapy.2 Treatment of recurrent disease in patients with initial lesions <5 cm depends on the presence of local and/or distant recurrence. If the recurrence is local and the lesion remains resectable, then resection is the objective. If the lesion remains low grade, then surgery alone is preferred, but usually with adjuvant radiation therapy by the external beam route. If the patient has a local recurrence of a high-grade lesion, on some occasions preoperative chemotherapy will be justified, depending upon the extent of the recurrence. These patients would then go on to resection with brachytherapy, usually as the adjuvant form of radiation therapy. Should patients not be

Recurrent high-grade extremity soft tissue sarcoma

resectable, then systemic chemotherapy and alternative treatment should be considered. Some patients with a resectable lesion and distant metastasis may undergo preoperative chemotherapy, and, depending on their response, resection where feasible, of both the primary and the metastatic disease. For patients who are clearly unresectable in terms of the primary lesion, systemic treatment should be considered. The pathways would be similar in the treatment of subsequent local and systemic recurrence, but with much more liberal use of systemic therapy, even for those lesions potentially resectable. Chemotherapy for treatment of relapse in patients with high-grade lesions >5 cm is almost always uniformly applied, in resectable patients as a preoperative adjuvant to resection and in non-resectable patients as a systemic treatment (Figure 8.6). Patients referred with a prior operation should be considered for re-excision, if it is possible without major neurovascular resection or amputation. If either amputation or major neurovascular resection would be required to improve a positive microscopic margin, we believe external beam adjuvant therapy to be the modality of first choice.

Distant + Local

Resectable

Unresectable

Preoperative chemotherapy

Chemotherapy

Resection

+ Postoperative chemotherapy

Figure 8.6 Treatment of distant recurrence.

Technical aspects of operation The principles of operative resection of soft tissue sarcomas are as follows. First, wherever practical, function and limbsparing procedures should be performed. Second, the surgical objective should be complete removal of the tumor with negative margins and maximum preservation of function. Third, where possible, tumor should be excised with 2–3 cm of normal tissue, because of the propensity for unappreciated

Principles of management microscopic spread. Fourth, neurovascular and bone structures should be identified and, where possible, preserved. The surgical procedure should be thoroughly planned preoperatively. These resections are non-anatomic, and therefore careful thought and consideration must be given to the three dimensions of resection, with a thorough knowledge of how this superimposes on the underlying normal anatomy. Moreover, the normal anatomy is often distorted, being pushed or pulled by the abnormal tumor. Resections should encompass the skin, subcutaneous tissue, and soft tissue that is around the tumor. Enough skin should be removed to encompass removal of the site of previous biopsy and to ensure that the skin flaps are viable after removal of the tumor (Figure 8.7). Often this will involve converting a poorly placed transverse incision into a longitudinal incision by an S-shaped approach. The guiding principle for resection is visualizing the tumor and surrounding anatomic structures in three dimensions. This

145

is depicted in Figure 8.8. A useful way to conceptualize this is to divide these three dimensions into north–south, east–west, and depth. The initial part of the resection usually involves definition of the north–south and east–west dimensions. Once these are ascertained, attention can be paid to depth. Again, the guiding principle is definition of the normal structures and, in particular, structures that should be left behind. Resection is done in a progressive and sequential fashion. This is depicted in Figure 8.8. It is important to reaffirm constantly the three-dimensionality of the tumor and surrounding structures. This is done by constant re-evaluation by visualization and palpation as the resection is done.

Drains We employ suction drainage in the extremities to avoid subsequent major seroma formation. Drains should be placed distally close to the incision to allow the drain site to be included

(a) (b) (c) Figure 8.7 (a) prior incision; (b) prior incision marked with lateral proximal drain site; (c) modified incision to encompass a poorly placed prior drain site.

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Diagnosis and Management of Soft Tissue Sarcoma

E N S

W

n. a. v. E

N

Figure 8.8 The guiding principle for resection is visualizing the tumor and surrounding structures in three dimensions.

W

E

N

W

S

S

2 cm

in a radiation field if necessary, and to allow limitation of proximal treatment should amputation ever be necessary (Figure 8.9).

Closure Layered cosmetic closure is preferred. With small lesions, subcuticular absorbable sutures can be used to provide cosmetics. In very large resections, interrupted removal sutures are preferred.

2 cm

Amputation While amputation was historically the preferred method of treatment for extremity soft tissue sarcoma, it is now clear that both long-term survival and freedom from local recurrence can be equally well achieved for the majority of patients by a limb-sparing operation. Currently, limb-sparing operations are performed on more than 95% of patients with soft tissue sarcoma presenting to our institution (Figure 8.10).

Principles of management However, there are indications for amputation (for technique, see Chapter 10). These, in the main, include patients who, in the absence of systemic disease, cannot be rendered diseasefree without amputation. Often, although radical and ablative, this can be both lifesaving and a major improvement in patient symptomatology, even in the presence of advanced disease.

Post-treatment follow-up Post-treatment follow-up regimens remain poorly defined. Approximately one-half of all patients who experience recurrence notice an abnormality that brings them to their surgeon, rather than such recurrence being detected by the surgeon in routine scheduled follow-up. At MSKCC, patients with soft tissue sarcoma are followed according to their risk of

147

recurrence.3 This is predicated upon the site, size and grade of the primary tumor (Table 8.1). The details that follow are guidelines and are usually followed, although there may be exceptions. It is essential to emphasize that follow-up programs are largely based on opinion rather than on fact, and few studies are directed to evaluating the benefits of specific follow-up programs.4 Patients with primary extremity tumors that are <5 cm, and completely excised receive clinical follow-up every 6 months for 5 years, and every 12 months thereafter. These patients would also undergo chest X-ray examination every 12 months. Patients with primary extremity tumors *5 cm and low-grade histology would receive the same follow-up. Patients with high-grade histology and primary extremity tumors need closer follow-up. Patients with tumors 5–10 cm and high-grade

Suction drain

(a) (b) Figure 8.9 (a,b) Drains should be placed distally close to the incision to allow the drain site to be included in a radiation field if necessary, and to allow limitation of proximal treatment should amputation ever be necessary.

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Diagnosis and Management of Soft Tissue Sarcoma

120 110

LSS Amputation

100

Number of patients

90 80 70 60 50 40 30 20 10 0 1968 69 70 71 72 73 74 75 76 77 78 82 83 84 85 86 87 88 89 90 91 92 93 94 94 96 97 98 99 2000 Year

Figure 8.10 Primary operation for localized extremity sarcoma. Currently, limb-sparing operations are performed on more than 95% of patients. MSKCC, 1968–2000. LSS, limb-sparing surgery.

histology would receive clinical follow-up every 3–4 months for 3 years and every 6 months thereafter. In addition, they would undergo chest X-ray examination every 6 months. Patients with tumors >10 cm and high-grade histology are followed clinically and by chest X-ray every 3–6 months indefinitely. We do not routinely obtain a chest CT scan to survey for lung metastases. In patients receiving postoperative radiation or chemotherapy, routine follow-up would be interdigitated with the follow-up required for radiation or chemotherapy. Many follow-up programs include screening blood tests. However, these are essentially useless unless specific symptomatology is identified. In addition, the patient is often falsely reassured by ‘normal blood work’, when blood tests rarely, if ever, identify recurrent sarcoma.3

Management of local recurrence At least one-third of patients will develop recurrent disease, despite optimal multimodality therapy, with a median disease-free interval of 18 months.4 At MSKCC, the mainstay of our monitoring for local recurrence is physical examination, not routine radiologic surveillance. Local extremity recurrence presents as a nodular mass or series of nodules arising in the surgical scar. If local recurrence is suspected, a CT scan, MRI or fine needle aspiration biopsy may be obtained. After extent of disease work-up, patients with isolated local recurrence should undergo re-resection. Resection principles are similar to those outlined for dealing with the primary

Principles of management

149

Table 8.1 Routine soft tissue sarcoma follow-up. Chest CTa

Abdominal CTa

Every 12 months

a

a

Every 12 months

Every 6 months for 5 years, thereafter every 12 months

Every 12 months

a

a

Every 12 months

Extremity 5–10 cm high grade

Every 3–4 months for 3 years, thereafter every 6 months

Every 6 months

a

a

Every 12 months

Extremity >10 cm, high grade

Every 3–4 months

Every 3–4 months

a

a

Every 12 months

Retroperitoneal, high grade

Every 3–4 months for 3 years, thereafter every 6 months

a

a

Every 3–4 months for 3 years, thereafter every 6 months

Every 3–4 months Every 6 months

Retroperitoneal low grade

Every 3–4 months for 3 years, thereafter every 6 months

a

a

Every 3–4 months for 3 years, thereafter every 6 months

Every 3–4 monthsb Every 6 monthsb

GI/visceral

Every 3–4 months for 3 years, thereafter every 6 months

a

a

Every 3–4 months for 3 years, thereafter every 6 months

Every 3–4 months Every 6 months

Office visit

Chest X-ray

Extremity <5 cm

Every 6 months for 5 years, thereafter every 12 months

Extremity *5 cm low grade

CBC, LFTs

15–20% of extremity patients will undergo CT/MRI for suspected local recurrence. 5–10% of extremity patients will undergo FNAB for suspected local recurrence. aThese imaging studies are performed when indicated. bOnly a percentage (±80%) of these patients will undergo laboratory testing at each follow-up visit. CBC, complete blood count; LFT, liver function test; FNAB, fine needle aspirate biopsy.

tumor. Adjuvant radiation therapy should be utilized after surgery, depending upon the method and extent of previous radiation. Two-thirds of these recurrent patients experience long-term survival.

Management of distant metastases Chest X-ray is a crucial component in the follow-up of patients with extremity soft tissue

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Diagnosis and Management of Soft Tissue Sarcoma

sarcoma, since the most common site of metastasis is the lung.5 It is the only site of recurrence in approximately half of all patients. An abnormal or new finding on chest X-ray is verified by chest CT scan. Extrapulmonary metastases are uncommon and occur as a late manifestation of widely disseminated disease. We do not utilize technetium-99m bone scanning or liver imaging as routine practice, and do not perform a metastatic survey unless indicated. Patients who have no extrathoracic disease, and are medically fit, should undergo thoracotomy with the intent of resecting all disease.5,6 Patients with unresectable pulmonary metastases or extrapulmonary metastatic sarcoma have a uniformly poor prognosis and are best treated with systemic chemotherapy. The combination of mesna, ifosfamide, doxorubicin and dacarbazine (MAID) has been shown to have a 47% response rate and a 10% complete response rate.7 Trials are currently underway evaluating MAID and other ifosfamide–doxorubicin combinations with cytokine support.

Management of retroperitoneal and visceral soft tissue sarcoma The management of retroperitoneal sarcomas is dependent on complete resection. Technical aspects of this are illustrated in Chapter 11. A similar approach is employed for visceral sarcomas. With a few exceptions (recurrent retroperitoneal liposarcoma), only complete resection translates into any long-term survival benefit.8 Therefore, the object should always be complete resection, reserving incomplete resections only for palliation of major symptoms, which are relatively infrequent in both retroperitoneal and visceral sarcoma.9,10

Post-treatment follow-up The vigor and frequency of follow-up depends on the risk of recurrence from the primary lesion and, in part, on the philosophy of the following surgeon. If the policy is aggressive retreatment, including operation for all detected recurrences, then follow-up is frequent. However, if there is a reluctance by the patient or surgeon to act on new recurrences in the absence of symptoms, then follow-up, especially with regard to imaging, is much less vigorous. Patients with retroperitoneal and gastrointestinal/visceral sarcomas are usually followed clinically every 3 months for the first 3 years.11 In addition, these patients would undergo abdominopelvic CT scans every 6 months. After 3 years, patients would be followed clinically and by CT scan every 6 months. In patients with completely resected tumors, the 5-year actuarial survival ranges between 54% and 64%.12,13 Survival for patients who are incompletely resected ranges from 10% to 36%. Local recurrence occurs in the majority of these patients, with rates reported between 53% and 68%.12 The median time to recurrence is 16 months. Based on these data, patients should be followed postoperatively every 3–4 months for the first 3 years. CT is commonly performed at 3–6 month intervals. Complete resection of recurrent disease is possible in about 44% of patients and may be associated with prolonged 5-year survival of up to 50%.13 The issue of follow-up and treatment of recurrence is highly dependent on the philosophy of the following physician. How often to offer repeat resection to asymptomatic patients with recurrent retroperitoneal sarcoma is a difficult question. What is clear is that, as with primary retroperitoneal sarcoma, operation should only be offered for palliation or if there is potential for complete resection.

Principles of management In patients with retroperitoneal or visceral sarcoma, local recurrence usually presents with non-specific symptoms, often only after recurrence has reached a substantial size. (Table 8.1).12

Management of local recurrence After work-up for extent of disease, patients with isolated local recurrence undergo reresection, and two-thirds of these patients experience long-term disease-free survival. Adjuvant radiation therapy should be considered, if practical, depending on the method and extent of previous radiation and the site of recurrence. Unfortunately, with many intraperitoneal and retroperitoneal recurrences, the recurrences are discontiguous and leave radiation therapy as an unrealistic option.

Recurrent gastrointestinal/ visceral sarcomas Despite complete resection, recurrence rates are still high, ranging from 42% to 90%, with a median time to recurrence of 18–24 months.14,15 Most patients present with recurrent disease in the liver (50–65%), with about 30% of patients presenting with intraperitoneal recurrence and 8% with distant metastases.14 If the intra-abdominal recurrence is completely resected, survival is improved, and this should be attempted in patients who are a good operative risk.12,16,17 Extent of disease may limit the application of resection, and certainly when contemplating hepatic resection, anything less than complete resection is not indicated.12 Resectional operation should be offered only for palliation or if there is potential for

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complete resection. Most patients with gastrointestinal/visceral sarcomas present with local recurrence and/or metastatic disease in the liver. Current studies are addressing the use of intraperitoneal therapy and new genespecific drugs (see Chapter 11).

References 1. Heslin MJ, Lewis JJ, Woodruff JM et al. Core needle biopsy for diagnosis of extremity soft tissue sarcoma. Ann Surg Oncol 1997;4:425–31. 2. Lewis JJ. Soft tissue sarcoma. In: Johnson FE and Virgo KS, eds. Cancer patient follow-up: surveillance strategies after primary treatment of cancer. St Louis: Mosby, 1997:249–54. 3. Brennan MF. Follow-up is valuable and effective: true, true and unrelated? Ann Surg Oncol 2000;7:2–3. 4. Brennan MF, Casper ES, Harrison LB et al. The role of multimodality therapy in soft tissue sarcoma. Ann Surg 1991;214:328–33. 5 Gadd MA, Casper ES, Woodruff J et al. Development and treatment of pulmonary metastases in adult patients with extremity soft tissue sarcoma. Ann Surg 1993;218:705–12. 6. Roth JA, Pass HI, Wesley MN et al. Comparison of median sternotomy and thoracotomy for resection of pulmonary metastases in patients with adult soft tissue sarcomas. Ann Thorac Surg 1986;42:134–8. 7. Elias A, Ryan L, Aisner J, Antman KH. Mesna, doxorubicin, ifosfamide, dacarbazine (MAID) regimen for adults with advanced sarcoma. Semin Oncol 1990;17:41–9. 8. Bevilacqua RG, Rogatko A, Hajdu SI, Brennan MF. Prognostic factors in primary retroperitoneal soft-tissue sarcomas. Arch Surg 1991;126:328–34. 9. Lewis JJ, Leung D, Heslin M et al. Association of local recurrence with subsequent survival in extremity soft tissue sarcoma. J Clin Oncol 1997;15:646–52. 10. Shibata D, Lewis J, Leung D et al. Is there a role for incomplete resection in the

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11.

12.

13.

14.

Diagnosis and Management of Soft Tissue Sarcoma

management of retroperitoneal liposarcomas? J Am Coll Surg. 2001;193:373–9. Lewis JJ, Brennan MF. The management of retroperitoneal soft tissue sarcoma. Adv Surg 1999;33:329–44. Jaques DP, Coit DG, Hajdu SI, Brennan MF. Management of primary and recurrent soft tissue sarcoma of the retroperitoneum. Ann Surg 1990;212:51–9. Dalton RR, Donohue JH. Management of retroperitoneal sarcomas. Surgery 1989;106:725–33. Ng EH, Pollock RE, Akinson EN et al. Prognostic factors influencing survival in

gastrointestinal leiomyosarcomas. Implications for surgical management and staging. Ann Surg 1992;215:68–77. 15. McGrath PC, Neifel JP, Lawrence W Jr et al. Gastrointestinal sarcomas: analysis of prognostic factors. Ann Surg 1987;206:706–10. 16. Jaques DP, Coit DG, Casper ES et al. Hepatic metastases from soft tissue sarcoma. Ann Surg 1995;221:392–7. 17. Demers ML, Roh MS, Ellis LM. Liver resection improves survival for metastatic sarcoma. Proc Soc Surg Oncol 1995;181.

9 Adjuvant management

Radiation therapy Prospective randomized trials 1–3 have confirmed the benefit of adjuvant radiation therapy in extremity sarcoma, primarily as an adjunct to surgical resection. We randomized 164 patients to receive or not receive adjuvant radiation therapy by the brachytherapy

technique.1 Patients were stratified for size, grade, depth, site and primary versus recurrent and received postoperative adjuvant brachytherapy (42–45 Gy) on the sixth day. In this study, local disease-free survival was improved in those patients receiving brachytherapy (Figure 9.1). Benefit in local disease-free survival was confined to the

Proportion free of local recurrence

1.0

0.8

0.6

0.4

0.2

BRT (n=78) No BRT (n=86)

0.0 0 n=164

20

40

60

80

100

120 140 Time (months)

160

180

200

Figure 9.1 Local disease-free survival: brachytherapy (BRT) versus no brachytherapy. MSKCC, 7/82–7/92 (follow-up to 12/00).

220

240 p=0.039

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Diagnosis and Management of Soft Tissue Sarcoma

patients who had high-grade lesions (Figures 9.2 and 9.3). Distant disease-free survival, however, was not influenced (Figure 9.4). Follow-up of these studies is as of 31 December 2000. Two studies from the National Cancer Institute (NCI) have confirmed the benefits from radiation therapy by the external beam route in diminishing local recurrence of lowgrade tumors.2,3 In the study of Yang et al,3 141 patients underwent randomization to receive (n=70) or not receive (n=71) postoperative external beam radiation therapy. A dramatic reduction in local recurrence was found (Figure 9.5). Again, there was a differential response between lowgrade tumors and high-grade tumors. The 91 patients with high-grade tumors who had undergone a limb-sparing operation within the

previous 4 months were randomized to receive chemotherapy alone (n=47) or concurrent chemotherapy and radiation therapy (n=44). The chemotherapy employed was doxorubicin, 70 mg/m2, in intravenous bolus and cyclophosphamide, 700 mg/m2 intravenous infusion. Five cycles were given on a 28-day basis. Radiation concurrent with the chemotherapy consisted of 4500 cGy to a wide field, followed by an 1800 cGy boost to the tumor bed given in 100 cGy fractions over 5 days/week for a total of 6 or 7 weeks. In these patients (Figure 9.6), local recurrence-free survival was markedly in favor of those patients receiving radiation. Fifty patients with low-grade tumors were similarly randomized to receive or not receive radiation therapy. This resulted in a marked improvement in local recurrence-free survival

Proportion free of local recurrence

1.0

0.8

0.6

0.4

0.2

BRT (n=56) No BRT (n=63)

0.0 0 n=119

20

40

60

80

100

120 140 Time (months)

160

180

200

220

240 p=0.002

Figure 9.2 Local disease-free survival: BRT versus no BRT; high-grade patients only. MSKCC, 7/82–7/92 (follow-up to 12/00).

Adjuvant management

155

1.0

Proportion free of local recurrence

0.8

0.6

0.4

BRT (n=23) No BRT (n=22)

0.2

0.0 0

20

40

60

80

100

n=45

120 140 Time (months)

160

180

200

220

240 p=0.5

Figure 9.3 MSKCC response with X-ray therapy to low-grade lesions. MSKCC, 7/82–7/92 (follow-up to 12/00).

Proportion free of local recurrence

1.0

0.8

0.6

0.4

BRT (n=74) No BRT (n=85)

0.2

0.0 0 n=159

20

40

60

80

100

120 140 Time (months)

160

180

200

220

240 p=0.9

Figure 9.4 Distant disease-free survival: BRT versus no BRT. MSKCC, 7/82–7/92 (follow-up to 12/00).

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Diagnosis and Management of Soft Tissue Sarcoma

100 Radiation

Percentage without local recurrence

90 80 70

No radiation 60 50 40 30 20 10 0 2

4

6

8

10

12

Follow-up (years)

p=0.0001

Figure 9.5 Local recurrence-free survival: radiation versus no radiation. From Yang et al.3

100 Radiation Percentage without local recurrence

90 80 No radiation

70 60 50 40 30 20 10 0 2

p=0.003

4

6

8

10

12

Follow-up (years)

Figure 9.6 Local recurrence-free survival: radiation versus no radiation; high-grade patients only. From Yang et al.3

Adjuvant management

157

Radiation

100 Percentage without local recurrence

90 80 No radiation

70 60 50 40 30 20 10 0 2

4

6

8

10

12

Follow-up (years)

p=0.016

Figure 9.7 Local recurrence-free survival: radiation versus no radiation; low-grade patients only. From Yang et al.3 100 Percentage without distant recurrence

90 Radiation

80 70

No radiation

60 50 40 30 20 10 0 2

p=0.64

4

6 8 Follow-up (years)

10

12

Figure 9.8 Metastatic disease-free survival: high-grade tumors; surgery, chemotherapy and X-ray therapy versus none. From Yang et al.3

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Diagnosis and Management of Soft Tissue Sarcoma

100 90 Radiation

80 Percentage survival

70

No radiation

60 50 40 30 20 10 0 2

4

p=0.71

6 8 Follow-up (years)

10

12

Figure 9.9 Overall survival: high-grade extremity. From Yang et al.3

(Figure 9.7). This was in contradistinction to the study from our own institution using brachytherapy for patients with low-grade lesions (Figure 9.3). Overall, in the NCI study, metastatic disease-free survival for patients with highgrade extremity sarcoma was not different (Figure 9.8). Overall survival in patients with high-grade lesions was similarly not improved (Figure 9.9).

Technical aspects of external beam radiation Technical aspects of external beam radiation therapy have been described.4 One issue has been the concept of the ‘shrinking field technique’. This involves wide irradiation

5–7 cm around the tumor bed, to 5000 cGy, and then a reduced field to a total dose of >6000 cGy to as much as 7000 cGy for highgrade tumors. Inclusion of the surgical scar and drain sites has been repeatedly emphasized. This is of importance surgically, as the drain site should always be placed to minimize the need for extending the radiation field to encompass the site (Figure 9.10). In similar fashion, the placement of the drain site distally will ensure adequate ability either to perform further surgery or to encompass the field. Considerable pains have been taken to avoid total limb circumferential radiation, which would thereby create disabling and extensive peripheral edema.5,6 The aim is to diminish the radiation such that at least one-third of the circumference of the limb is spared.

Adjuvant management

159

Because of the relative success of adjuvant brachytherapy, the issue of the extent of the radiation field remains unclear. It would appear that, for low-grade tumors, external beam radiation therapy remains the treatment of choice.

Brachytherapy The technique of brachytherapy can be utilized, as we did in our prospective randomized study, as a solitary modality, or as an adjunct to external beam treatment. A very important issue is that brachytherapy only treats the tumor bed with a very limited margin (<2 cm), with no directed attempt to treat more extensive margins, the scar or peripheral drain sites. One advantage is the ability to deliver the entire radiation dose in 4–6 days, in contrast to external beam radiation, which takes 6–8 weeks. Another is the ability to deliver brachytherapy at the time of initial resection, such that the entire treatment, surgery and radiation therapy, can be completed within 10 days of the initial operation. The cost benefit of this has been demonstrated and confirmed in the literature.7 The technique for brachytherapy has been described elsewhere.8,9 It basically consists of placing afterloading catheters over the surgical bed, with the catheter sewn in place with absorbable sutures. Catheters are spaced at approximately 1-cm intervals and extend to approximately 2 cm from the edge of the resected margin. We prefer to use a suction drainage placed over the catheters so as to elevate the skin, at least in part, away from the actual catheters. The preferred isotope is usually iridium-192, although iodine-125 is utilized when the site is close to reproductive organs. It is possible to place the catheters directly over major extremity nerves (Figure 9.10).

Figure 9.10 Catheters can be placed directly over major extremity nerves.

It is important to emphasize the delay until the sixth postoperative day before loading the afterloading catheters, as we have demonstrated clearly.10,11 Wound healing impairment is increased when catheter loading takes place before the sixth day. This is based on multiple wound healing studies in animals.12 We have had similar experiences with the addition of radiation therapy by the external beam route when there is concern about the margin, particularly for patients who have positive margins. The addition of radiation to patients with positive microscopic margins in the extremity tends to bring the results of local control closer to those of patients who have negative margins, although this does not necessarily translate into long-term survival. Patients with positive microscopic margins continue to have a worse disease-free interval, whether or not external beam radiation is used. It is essential to emphasize that poorly applied radiation therapy, like poorly applied operations, results in unacceptable complications and long-term and severe morbidity.

160

Diagnosis and Management of Soft Tissue Sarcoma

Preoperative radiation therapy We have had limited experience with preoperative radiation therapy, mainly because of logistic restraints. Several groups have developed and, indeed, have used it as their routine approach, even for clearly resectable lesions. In a study examining preoperative versus postoperative radiation, O’Sullivan et al13 showed that there was no difference in local recurrence but that there was increased wound morbidity in those receiving preoperative radiation therapy.

Intraoperative radiation therapy Intraoperative radiation therapy can be applied particularly for those patients who have residual microscopic disease which is low grade in nature and in whom external beam therapy cannot be given at an adequate dose to limit further progression. Patients known to have high-grade

tumors at the time of referral, usually after percutaneous tru-cut® biopsy, can be considered for investigational preoperative chemotherapy as is given for large, high-grade extremity lesions (see above). After biopsy is obtained, patients who are unresectable will enter a preoperative chemotherapeutic regimen or an investigational trial. In uncommon situations (<5%), where complications of the disease, such as obstruction or bleeding, are encountered, palliative operations may be considered.

Radiation therapy as a definitive treatment for sarcoma Radiation therapy alone is rarely used for the definitive management of soft tissue sarcoma. Where surgical operation is not possible, and when tumors are unresectable, or are marginally resectable, then radiation therapy as a primary modality should be considered. In some situations, as many as 30% of patients can be locally controlled by definitive radiation therapy.7

Complications of local treatment

Figure 9.11 Appropriate placement of early biopsy incisions so that more appropriate tissue coverage can be provided for re-resection.

Because of the large size and extensive nature of some tumors, wound complications in major resections can be significant. Specific issues revolve around appropriate placement (i.e. longitudinal) of early biopsy incisions, so that more appropriate tissue coverage can be provided at re-resection. In selected instances, it will be important for rotational flaps and microvascular free flaps to be placed, to ensure adequate wound healing (Figures 9.11 and 9.12).

Number of patients

Adjuvant management

161

Wound complications Primary healing

6 5 4 3 2 1 0 5-10

Figure 9.12 Rotational flaps and microvascular free flaps are placed to ensure adequate wound healing.

1700 1600 1500 1300 Grams to disrupt wound

1200 1100 1000 900 800 700 600 500 400 300 200 100

ADR (day) 0 +7 0 -7 0 XRT (day) 0 0 0 0 -7

0 0 +7 +7 0 0 -7 -7 0 +7 -7 0 +7 -7 0 -7 0 -7 0 +7 +7 +7

Figure 9.13 Wound breaking strength in response to ADR and XRT. -7, 0 or +7 = day of treatment: 0/ = no treatment; ADR, adriamycin. From Devereux.12

The overall incidence of wound complications in patients not undergoing radiation therapy should be less than 10%. Animal

11-20 21-30 Skin dose (Gy)

31-40

Figure 9.14 Wound complications in patients receiving brachytherapy, by dose. From Ormsby et al.11

experiments12 have shown that adjuvant therapy, both radiation therapy and chemotherapy, has a time-dependent effect on the impairment of wound healing (Figure 9.13). Based on animal data, it became very clear that the application of radiation therapy less than 5 days from the time of operation was accompanied by an unacceptable postoperative complication rate.10 Based on these experiments, a change was instituted so that no radiation was delivered to patients until 5 or more days after operation. A major difference was noted: significant wound complications were found in 14% of 21 patients receiving brachytherapy, and in 10% of 29 patients who did not receive radiation (Figures 9.14 and 9.15).11 It is clear that these complications were time-dependent, rather than dosedependent, in terms of the time of application in relationship to the initial wound. Delayed healing can be severe (Figure 9.16), with complications of infection, necrosis, and long-term breakdown (Figure 9.17). The majority of these patients do not heal well, and progressively greater attempts at primary coverage by rotational and free flaps must be encouraged (Figure 9.12). Most of our studies of radiation-associated injury have been a

162

Diagnosis and Management of Soft Tissue Sarcoma

Number of patients with wound complications

12

Brachytherapy No brachytherapy

10 8 6 4

consequence of the brachytherapy technique. Other studies, however,11 have shown significant impairment of wound healing when external beam radiation therapy is also applied.

2 0 1982-85 (54)*

1985-87 (50)*

Period of study *Total number of patients

Figure 9.15 Wound complications in patients receiving and not receiving brachytherapy, by time. From Ormsby et al.11

Figure 9.16 Delayed healing in the groin after brachytherapy and operation.

Figure 9.17 Complications from delayed healing.

The effect of radiation therapy on local and systemic recurrence The results of randomized trials of adjuvant therapy, either by brachytherapy or by the external beam route, firmly establish that radiation can diminish local recurrence.1,2 However, questions arise about the role of radiation therapy in the overall management of the patient with soft tissue sarcoma. In particular, should all patients with positive microscopic margins receive radiation therapy? Do all patients need radiation therapy?

Should all patients with positive microscopic margins receive radiation therapy? Recently, we examined our database from July 1982 to December 2000. During that time, 1235 new patients with extremity soft tissue sarcoma presented and were treated primarily at MSKCC. We examined the entire cohort of 1235 patients. Of these, 622 (50%) never received radiation therapy. Of the 613 (50%) patients who did receive radiation therapy (Figure 9.18), 278 (45%) received brachytherapy, 264 (43%) received external beam therapy and 71 (12%) received a combination of both. For patients who underwent resection, negative margin was clearly a factor in local-only recurrence (Figure 9.19) (p<0.01) and in disease-specific survival

Adjuvant management

benefit (Figure 9.20) (p<0.01). The question is, however, does radiation therapy impact on patients who have positive margins? Based on the prospective randomized trial of all patients, whether with positive margins or negative margins, radiation therapy clearly diminishes local recurrence but does not translate into disease-specific survival benefit. However, in the present database of 1235 patients, the addition of radiation therapy did not significantly (p=0.1) improve local recurrence in patients with positive microscopic margins (Figure 9.21). This implies that the positive microscopic margin was as much a harbinger of biology as it was an entity that could be improved by a further local modality. In those patients who received radiation therapy,

Primary extremity n=1235

RT n=613 (50%)

No RT n=622 (50%)

ERT n=264 (43%)

BRT n=278 (45%)

BRT/ERT n=71 (12%)

Figure 9.18 Patients who received radiation therapy for extremity soft tissue sarcoma at MSKCC, 7/82–12/00.

Proportion free of local recurrence

1.0

0.8

0.6

0.4

Positive (n=249) Negative (n=974)

0.2

0.0 0 n=1223

20

40

60

80

163

100

120 140 Time (months)

160

180

200

220

240

p<0.01

Figure 9.19 Primary extremity sarcoma: local recurrence versus margin. MSKCC, 7/82–12/00.

164

Diagnosis and Management of Soft Tissue Sarcoma 1.0

Disease-specific survival

0.8

0.6

0.4

0.2

Positive (n=249) Negative (n=974)

0.0 0

20

40

60

80

100

n=1223

120 140 Time (months)

160

180

200

220

240 p<0.01

Figure 9.20 Primary extremity sarcoma: disease-specific survival versus margin. MSKCC, 7/82–12/00.

Proportion free of local recurrence

1.0

0.8

0.6

0.4

0.2

RT (n=144) No RT (n=105)

0.0 0 n=249

20

40

60

80

100

120 140 Time (months)

160

180

200

220

240 p=0.1

Figure 9.21 Primary extremity sarcoma: addition of radiation therapy did not improve local recurrence in patients with positive micromargins (p=0.1). MSKCC, 7/82–12/00.

Adjuvant management

165

Proportion free of local recurrence

1.0

0.8

0.6

0.4

0.2

Positive (n=144) Negative (n=467)

0.0 0

20

40

60

80

100

n=611

120 140 Time (months)

160

180

200

220

240 p=0.6

Figure 9.22 Primary extremity sarcoma: for patients who received radiation therapy, positive margins did not impact on local-only recurrence. MSKCC, 7/82–12/00.

positive margins did not impact on local-only recurrence (p=0.6) (Figure 9.22). This would imply that the addition of radiation therapy to patients with positive margins diminished local recurrence. Looked at in a different way, localonly recurrence, while not significant, did decrease with the addition of radiation therapy in the presence of a positive microscopic margin, which implies that the patients receiving radiation therapy may have been more appropriately selected for that modality. Nevertheless, in the context of previous experience, it would seem prudent that patients with a positive microscopic margin should receive radiation therapy as an added modality in local control; that is, patients with a positive

microscopic margin can have the same results in local control as patients with a negative microscopic margin. No significant difference has been shown in patients with positive microscopic margins in terms of the way in which the radiation therapy has been delivered (Figure 9.23). In terms of disease-specific survival, if we look at patients with a positive microscopic margin who receive radiation therapy and thereby have a local recurrence rate that approximates that of patients with a negative margin, we can see that a positive microscopic margin translates into a worse disease-specific survival (Figure 9.20). It might be expected that, with positive microscopic margins, the diminution of the

166

Diagnosis and Management of Soft Tissue Sarcoma

Proportion free of local recurrence

1.0

0.8

0.6

0.4 No RT (n=105) ERT (n=66) BRT (n=53) BRT/ERT (n=25)

0.2

0.0 0

20

40

60

80

100

n=249

120 140 Time (months)

160

180

200

220

240 p=0.3

Figure 9.23 There was no significant difference in patients with positive margins in terms of the way in which radiation therapy was delivered. MSKCC, 7/82–12/00. margin might translate into disease-specific survival benefit, but this clearly is not so. Local recurrence can be minimized in patients with positive margins with radiation therapy, whether it is given by brachytherapy, external beam or brachytherapy plus external beam therapy. This, however, does not translate into disease-specific survival difference.

Do all patients need radiation therapy? Analysis of data from MSKCC14 suggested that the low prevalence of local recurrence (10–12% over 12 years) for small lesions (<5 cm) obviates both the indications for, and benefits from, radiation therapy for small lesions. Even for patients with positive margins, the local recurrence rate is less than 40%.

Quality of life Very few quality of life studies have been performed in patients receiving radiation therapy for soft tissue sarcoma. In the randomized study by Yang et al,3 quality of life was studied for patients receiving and not receiving radiation therapy. The authors emphasized the significantly decreased joint motion in the affected limbs compared with patients not given radiation therapy, in followup 6, 12, 24 and 36 months after operation. Muscle strength was lower 12 months after operation with adjuvant X-ray therapy, but this was of borderline significance. There was no difference between patients receiving and not receiving radiation therapy in global quality of life measurements or in performance of activities of daily living.

Adjuvant management

Chemotherapy (with Ephraim S Casper) Control of the primary site can be achieved in the majority of cases of extremity soft tissue sarcoma, but nearly half of all patients ultimately experience distant metastases or progressive localized disease. The role of systemic chemotherapy as part of primary therapy for patients with high-risk soft tissue sarcoma is under active investigation. As is the case for patients with other advanced solid tumors, systemic chemotherapy offers patients with advanced soft tissue sarcoma the possibility of tumor control and palliation of symptoms. Nonetheless, therapeutic responses are seen in fewer than 50% of patients, and durable complete regressions are rare. Optimal management of patients with soft tissue sarcoma requires an appreciation of the natural history of the disease, an understanding of potential risks and benefits of the available treatment options, and close attention to the individual patient. Multidisciplinary treatment planning should precede initiation of any therapy, and should involve an experienced team to evaluate pathologic material and imaging studies, and to coordinate the integration of surgical resection, radiation, and systemic therapy. A discussion of the results of preoperative and postoperative adjuvant chemotherapy trials follows an overview of chemotherapy for patients with advanced disease.

Treatment of patients with advanced disease Single agents The activity of commercially available chemotherapeutic agents is summarized in

167

Table 9.1.15–77 Doxorubicin and ifosfamide are the two most active agents in patients with soft tissue sarcoma. The activity of doxorubicin has been recognized for 25 years. In older trials, approximately 30% of patients were reported to have experienced major responses, defined as 50% or greater tumor shrinkage.15–18 In later randomized series, however, the frequency of response has been between 17% and 25%. 20,21,23,24 Subset analysis of patients with soft tissue sarcoma from a broad phase II trial in which patients were randomized to receive various doses of doxorubicin demonstrated a steep dose–response relationship;18 patients treated with doses below 60 mg/m2 rarely responded. Ifosfamide, an analog of cyclophosphamide, demonstrated activity in patients with sarcoma during its early evaluation, but extensive testing was limited by profound urothelial toxicity. Following the introduction of mesna, a disulfide uroprotective agent, extensive phase I and II study was possible. In a randomized phase II trial, 18% of patients treated with ifosfamide 5 gm/m2 experienced major responses, in contrast to 12% of patients treated with cyclophosphamide 1.5 gm/m2.31 This occurred in spite of greater myelosuppression with the latter agent. In a large American phase II trial, 17 of 99 patients with soft tissue sarcoma responded to ifosfamide 8 gm/m2.36 All patients had previously been treated with doxorubicinbased therapy, suggesting a degree of non-crossresistance. Responses to higher doses of ifosfamide (>12 gm/m2) had been observed in patients who progressed on doses below 8 g/m2, supporting the concept of a dose–response relationship for this agent as well.77 In a randomized trial, the response to 9 g/m2 (17.5%) was superior to the 3% response observed among patients treated with 5 g/m2.78 The reason for the low response to the lower dose was unclear. In a subsequent trial by the

168

Diagnosis and Management of Soft Tissue Sarcoma

Table 9.1 Activity of commercially available agents in adults with soft tissue sarcoma. Agent Antibiotics Doxorubicin

Mitomycin C Bleomycin Actinomycin D Alkylating agents Cyclophosphamide Hexamethylmelamine Ifosfamide

Cisplatin

Dose/schedule comments 60/90 mg/m2q3w 60 mg/m2q3w 60–75 mg/m2q3w 25–75 mg/m2q3w 70 mg/m2q3w 70 mg/m2q3w 15 mg/m2q3w 70 mg/m2q3w 75 mg/m2q3w 80 mg/m2q3w 75 mg/m2q3w Daily 75 mg/m2q3w 60 mg/m2q3w 12 mg/m2q3w

1.5 g/m2

1.25–2.5 g/m2 × 5d 5–8 g/m2 × 24h 5 g/m2 × 24h 2 g/m2 × 4d 2–4.5 g/m2 × 5d 1–6.3 g/m2 × 5d 2.5–3.5 g/m2 × 5d 4 g/m2 × 3d 2 g/m2 × 6d 2 g/m2 × 7d (continuous infusion) 2 g/m2 × 7d (bolus) 200 mg/m2 75 mg/m2 100 mg/m2 120 mg/m2 120 mg/m2 80 mg/m2 100 mg/m2

Evaluable patients

Responding patients

Response rate (%)

Reference no.

64 25 15 75a 54b 94b 89b 148b 83 90b 240b 41b 18 28b,c 34 32 30

21 10 1 21 16 17 15 26 21 18 56 7 1 7 0 0 5

33 40 7 28 30 18 17 17 25 20 23 17 5 25 0 0 17

15 16 17 18 19 20 20 21 22 23 24 25 26 27 28 29 30

67 26 40 13 40 68b 95 20d 16 8 36 13e 45

8 0 3 5 15 12 17 7 5 3 12 13 8

12 0 7 38 36 18 18 35 31 38 33 100 17

31 32 33 34 35 31 36 37 38 39 40 41 42

11 40 42 13 36 26 8 17

5 6 3 2 2 1 0 0

45 15 7 15 6 4 0 0

43 44 45 46 47 48 49 50

씰

Adjuvant management

169

Table 9.1 (Continued) Agent

Carboplatin Antimetabolites Methotrexate

Dose/schedule comments

Etoposide

Gallium nitrate Mitoxantrone

Paclitaxel

Vinblastine Topotecan Docetaxel aRandomization

Response rate (%)

Reference no.

96f 12g 50

13 5 6

13 42 12

51 52 53

Various Low dose 40 mg/m2/week 2–4g/m2q4w 3–7.5 g/m2/week *5 g/m2q2w w/vincristine 50–300 mg/kg w/vincristine

41 19 21 18 9 14

15 2 0 1 0 2

36 10 0 5 0 14

54 55 56 57 58 59

6

1

17

60

8

1

12

61

44 53 15

8 9 4

18 17 27

62 63 64

25

1

4

65

26

1

4

66

26 24 53 61 29f 10 48 22 )15h 16 29

0 0 0

0 0 0 2 0 0 12 5 0 12 17

67 68 69 70 71 72 73 74 75 76 77

1.2g/m2 300 mg/m2× 10–14d 50 mg/m2PO daily × 21d 130 mg/m2/d × 5 q3w 120 qod × 3 q3w 700 mg/m2

200 mg/m2 250 mg/m2 250 mg/m2 1.5 mg/m2/d × 5

to one of five dose levels. arm of a randomized trial. cUterine leiomyosarcoma only. dSubset of phase I trial. eSynovial sarcoma only. fUterine leiomyosarcoma and mixed mesodermal sarcoma. gUterine mixed mesodermal sarcoma only. hIncludes soft tissue and bone sarcoma. bOne

Responding patients

50 mg/m2 75–100 mg/m2 320–400 mg/m2

5-Fluorouracil Other Dacarbazine

Evaluable patients

0 0 6 1 0

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Diagnosis and Management of Soft Tissue Sarcoma

same investigators, the response to 12 g/m2 was only 14%.79 Higher response rates have been reported using 10–20 g/m2 with hematopoietic growth factor support, but thrombocytopenia, as well as neurologic and renal toxicity, are often dose-limiting.37 Other agents appear to be less useful than doxorubicin or ifosfamide. The activity of dacarbazine (DTIC) was recognized in the 1970s,63 and was confirmed in a later phase II trial.62 Dacarbazine was rapidly integrated into combination chemotherapy regimens, but its contribution to response and survival is uncertain. Both cisplatin44–50 and carboplatin53 have produced responses in occasional patients in phase II trials. The taxanes, paclitaxel,73,74,80,81 and docetaxel,77 have demonstrated activity in phase II trials, but appear to be marginally active at best. Vinca alkaloids have also produced response in single-arm phase II trials,75,82,83 but their role in sarcoma therapy is not established.

Combination chemotherapy Combination chemotherapy regimens have been used widely in the management of patients with soft tissue sarcoma (Table 9.2). High response rates have been reported in a number of single-arm phase II trials. Most of the regimens tested included an anthracycline (either doxorubicin or, in Europe, epirubicin), an alkylating agent, and/or dacarbazine. Overall, response rates to combination regimens have been higher in single-arm trials than in large, randomized studies. The combination of doxorubicin plus dacarbazine (AD) has been studied extensively by the Southwest Oncology Group (SWOG). This regimen was initially reported to yield responses in 41% of patients,84 but the reported response frequency in SWOG trials has declined over time. In a large randomized

trial in which this combination was given either by rapid or prolonged intravenous infusion, responses were seen in only 17% of patients on either schedule.85 For over a decade, the CyVADIC regimen (cyclophosphamide, vincristine, doxorubicin, and dacarbazine)86 was widely accepted as the standard of care. Variations of this four-drug regimen yielded responses in the range of 38–71%.80,87,88 In a prospective randomized trial, however, CyVADIC was not superior to doxorubicin alone.24 Doxorubicin (or epirubicin) plus ifosfamide combinations have consistently yielded responses in over 25% of patients in single-arm trials. The MAID regimen (mesna, doxorubicin, ifosfamide, dacarbazine) yielded an overall response rate in 47% of patients in a large phase II trial.89 In a randomized comparison of AD versus MAID,90 the response to MAID was 32%, compared to a 17% response with the two-drug regimen (p <0.002). However, there were eight toxic deaths in this trial, seven among the 170 patients treated with MAID. All treatmentrelated deaths occurred in patients older than 50 years. Toxicity forced a reduction in the original doses of MAID during that study. There was no advantage in survival for patients treated with MAID compared to patients who received the two-drug regimen. In fact, a nonsignificant survival advantage was seen for the two-drug regimen (median 13 versus 12 months), perhaps because of less toxicity, and successful second-line therapy with ifosfamide. Although cisplatin appears to have minimal activity, and the activity of mitomycin C has not been explored extensively, a combination using modest doses of mitomycin C, doxorubicin, and cisplatin induced responses in 43% of patients in a single-arm trial,91 and had an effect similar to that of doxorubicin plus ifosfamide in a randomized phase III study.23

Adjuvant management

171

Table 9.2 Commonly used chemotherapy combinations for patients with soft tissue sarcoma. Regimen

Dose

Schedule

Doxorubicin Ifosfamide

60–90 mg/m2 5 g/m2 2–3 g/m2d

Bolus or continuous infusion over 3–4 days q3w 24-h continuous infusion with mesna q3–4w Bolus or continuous infusion with mesna for 4d q3–4w

AD Doxorubicin Dacarbazine

60 mg/m2 750–1000 mg/m2

Bolus or over 4 days by continuous infusion q3w

CyVADIC Cyclophosphamide Vincristine Doxorubicin Dacarbazine

500 mg/m2 1.5 mg/m2 days 1 and 5 50 mg/m2 250 mg/m2d × 5

Bolus administration q3w

AI Doxorubicin Ifosfamide MAID Doxorubicin Ifosfamide Dacarbazine

50–75 mg/m2 5–7.5 g/m2

Bolus or divided doses over 2–3d q3w 24–72-h continuous infusion with mesna q3w

60 mg/m2

Bolus, or divided over 3 d by continuous infusion q3–4w Daily × 3 d by continuous infusion with mesna q3–4w Bolus or over 3 d by continuous infusion q3–4w

2–2.5 g/m2 900–1000 mg/m2

Randomized trials of combination chemotherapy are summarized in Table 9.3. In eight trials, combination chemotherapy was compared to treatment with doxorubicin alone. In some of the trials, a higher frequency of response is seen with combination therapy, but there are no randomized trials in which a significant survival advantage has been shown. Complete responses are uncommon, and do not appear to translate into prolonged survival. Kaplan–Meier plots of survival are virtually superimposable within each trial, and, indeed, from trial to trial. Approximately 20–25% of patients entered into such trials are alive 2 years after therapy is initiated.

These data suggest that not all patients need immediate treatment, and that the impact of treatment of survival is limited. The non-hematologic toxicities (cardiac, neurologic and renal) of the agents most active in soft tissue sarcoma prevent dramatic dose escalation. However, the availability of hematopoietic growth factors has facilitated study of modestly higher doses of doxorubicin and ifosfamide chemotherapy. In sequential EORTC trials, a regimen of doxorubicin 92 75 mg/m2 + ifosfamide 5 g/m2 was superior to doxorubicin 50 mg/m2 + ifosfamide 5 g/m2.93 However, in a prospective randomized trial comparing the two regimens, there was no

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Diagnosis and Management of Soft Tissue Sarcoma

Table 9.3 Randomized trials of combination chemotherapy. Trial

Regimen 94

GOGa

95

GOGa

GOG27

96

ECOGa

ECOG25

ECOG19 ECOG20

EORTC21

CALGB and SWOG23

A AD A ACy A ActL ActLV ActLCyclo A CyAV CyActV A A ADIC A AVd A AI MAP A AI CyVADIC AD AID

Patients 120 106 50 54 41 25 26 26 54 56 58 94 88 92 148 143 90 88 84 240 231 134 170 170

Complete response rate (%) 16 24 19 19 17 4 0 0 30 21 12 18 17 30 17 18 20 34 32 23 28 28 17 32

(6) (10) (4) (8) (2)

(7) (5) (2) (5) (3) (6) (4) (6) (2) (3) (7) (4) (5) (8) (2) (2)

Median survival (months) 7.7 7.3 11.6 10.9 8.5 8.1 11.5 5.1 8.6 7.9 9.5 8.0 8.4 8.0 9.4 9.0 <9 11 9 12.0 12.6 11.7 13.3 11.9

CALGB, Cancer and Acute Leukemia Group B; ECOG, Eastern Cooperative Oncology Group; EORTC, European Organization for Research and Treatment of Cancer; GOG, Gynecologic Oncology Group; SWOG, Southwest Oncology Group. A, doxorubicin; Act, actinomycin D; Cy, cyclophosphamide; Cyclo, cycloleucine; DIC, dacarbazine; I, ifosfamide; L, L-PAM (L-phenylalanine mustard); M, mitomycin C; P, cisplatin; V, vincristine; VD, vindesine. aUterine sarcoma only; response rates are only for subset of patients with measurable disease.

difference in response rate or survival.97 Response rates approaching 70% have been reported in studies in which moderately high doses of doxorubicin 75–90 mg/m2 are administered with moderately high doses of ifosfamide (>10 g/m2).98 Duration of response

is not easily assessed in these pilot trials, because many patients undergo surgical resection of marker lesions. Not all trials have shown such a dramatic improvement in response to dose intensification. For example, in a randomized trial, in spite of increased

Adjuvant management toxicity, 25% escalation in doses of MAID did not improve outcome over treatment with standard doses of MAID.99 It has been suggested that the duration of ifosfamide infusion may affect response.100 Superior response rates have been reported with regimens that employ short (1–4-h) infusions of ifosfamide rather than 24-h continuous infusions. Pharmacokinetic studies show that ifosfamide has a long half-life,101 so the reason for schedule dependence, if real, is not obvious. There is limited experience using high-dose chemotherapy with autologous stem cell or marrow rescue for adults with soft tissue sarcoma.102,103 Although reports of pilot trials are optimistic, the extent to which such results can be generalized is not known.

Factors predicting response to chemotherapy The variation in reported response rates to similar chemotherapy regimens, and the recognition that the soft tissue sarcomas are a heterogeneous group of clinicopathologic entities, suggest that one might be able to identify features that predict for response to therapy. In an analysis of 1742 patients with soft tissue sarcoma who participated in EORTC trials, only two factors were confirmed in multivariate analysis to be independently prognostic for response — the absence of liver metastases, and young age.104 This observation was confirmed in an analysis of later EORTC trials as well,105 and is consistent with observations in American trials. For example, gastrointestinal leiomyosarcoma, which represents the majority of sarcomas metastatic to liver, is resistant to standard chemotherapy regimens. In contrast, uterine leiomyosarcoma does appear

173

to be responsive to doxorubicin/ifosfamide combinations.90 Leiomyosarcoma accounts for up to 50% of patients entered into large prospective sarcoma trials.20,23,85 Thus, the results of individual trials may be heavily influenced by the proportion of patients with gastrointestinal sarcoma. Similarly, evidence from single-agent and combination chemotherapy trials suggests that synovial sarcoma is particularly sensitive to ifosfamide.23,41 Synovial sarcoma tends to arise in younger individuals who are unlikely to have comorbid conditions, and usually have a good performance status. Single-arm trials of aggressive chemotherapy regimens are most likely to be offered to young, fit individuals. Thus, the pretreatment characteristics of patients with sarcoma may have a major impact on the observed outcome of clinical trials, especially when trials are small and non-randomized.

Treatment recommendations The goal of chemotherapy for most patients with metastatic soft tissue sarcoma is palliation. This is of paramount importance in selecting therapy for individual patients. For good performance status patients with rapidly progressive disease or worsening symptoms, combination chemotherapy with an anthracycline/ifosfamide combination is indicated. For most patients, especially those with other significant medical conditions, sequential single-agent therapy is less toxic, and not inferior in terms of survival. All patients should be considered for clinical trials of novel agents or combinations, especially those with metastatic sarcoma of the gastrointestinal tract, in whom responses to conventional agents are rare. Periods of watchful waiting may be appropriate for many

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Diagnosis and Management of Soft Tissue Sarcoma

patients with metastatic sarcoma who are asymptomatic or who have only minimal symptoms.

Adjuvant therapy Osteogenic sarcoma and pediatric small cell sarcoma provide striking examples of diseases in which combined modality therapy of localized disease significantly improves survival compared to the results with surgical resection alone. Small non-randomized trials suggested that postoperative adjuvant chemotherapy also impacts favorably on the outcome of adult patients with soft tissue sarcoma. The National Cancer Institute (NCI) conducted a series of adjuvant trials using the combination of cyclophosphamide, doxorubicin, and high-dose methotrexate. In a pilot trial, this combination resulted in improved survival compared to historical controls. In a subsequent prospective randomized trial, there appeared to be a difference in both diseasefree and overall survival in comparison with patients randomized to observation alone. However, at 7.5 years, the difference was no longer statistically significant.93 Similar NCI trials in patients with sarcoma of other sites included small numbers of patients; no survival advantage was seen in patients with retroperitoneal, head and neck, or breast primaries.106,107 The EORTC conducted a study in which patients were randomized to observation versus chemotherapy with CyVADIC.108 Accrual of 468 patients made this the largest randomized trial performed. However, 32% of randomized patients were ineligible, and only 52% of the eligible patients randomized to chemotherapy received the planned eight cycles of treatment. Distant metastases

occurred with similar frequency in both arms, and the difference in overall survival was not statistically significant. A much smaller trial using the same regimen claimed a dramatic difference in survival between treated and untreated patients.109 In total, 13 prospective trials have been published in which patients were randomized to observation alone or to receive postoperative chemotherapy following resection of a primary or recurrent soft tissue sarcoma. In six, the chemotherapy consisted of doxorubicin alone; in the others, combination chemotherapy was studied, often the CyVADIC regimen. Only two trials demonstrated a significant survival advantage for chemotherapy-treated patients. In some of the trials, however, there was either a trend or a significant advantage in disease-free survival, especially among patients with highgrade extremity sarcoma. Analyses of the pooled results of the published literature are consistent with this observation.110,111 Most of these trials included fewer than 100 patients, and even the largest trial was inadequately powered to detect a 15% difference in survival. Finally, none of the published trials have involved an ifosfamide-containing combination. A formal meta-analysis of individual data from 1568 patients who participated in these trials (plus an additional unpublished trial) has been carried out by the Sarcoma Meta-analysis Collaboration (SMAC).112 Although not all data were available for all patients, the analysis demonstrated a significant reduction in the risk of local or distant recurrence. The overall hazard ratio for distant relapse-free survival was 0.70. That is, the risk of distant relapse (metastasis) was reduced by 30% in treated patients. The absolute benefit at 10 years was 10%, so that the recurrence-free survival at 10 years was improved from 60% to 70%. The hazard ratio for overall survival, however, was 0.89, and did not meet the

Adjuvant management criteria for statistical significance (Figure 9.24). In absolute terms, there was a possible improvement in survival from 50% to 54% at 10 years. Subset analysis failed to show that the effects of chemotherapy differed by primary site, although the best evidence for an effect of adjuvant chemotherapy was in patients with extremity sarcoma. To address the question of ifosfamide-based therapy, there had been an attempt to conduct a large prospective randomized trial of postoperative chemotherapy with the MAID regimen in the USA, but patient accrual was insufficient, and the trial was aborted. An Italian cooperative group, however, has conducted a trial in which patients aged 18–65, with high-grade extremity sarcoma larger than 5 cm, were randomized to postoperative chemotherapy with epirubicin plus ifosfamide, or to observation alone. The trial had been planned for 200 patients, but was interrupted after accrual of 104 patients, when an interim analysis showed a significant survival advantage for the chemotherapytreated group.113 As the data have matured, the difference has become less dramatic, and further follow-up will be needed. Neoadjuvant, or preoperative, chemotherapy has been studied at several institutions. At the MD Anderson Cancer Center, a retrospective analysis of 76 patients with stage IIIB soft tissue sarcoma was summarized.114 Most patients received doxorubicin-based therapy; the overall response rate was 27%. In contrast to the previous experience at that center,115 in the later analysis comparison of responding and non-responding patients did not show any significant difference in local relapse, diseasefree survival or overall survival. A prospective trial conducted at MSKCC, assessed two cycles of chemotherapy with cyclophosphamide, doxorubicin and DTIC before definitive surgery and radiation.116

175

Compared to historical controls, there was no impact on survival, but many patients received only those first two cycles of therapy. In contrast, a high frequency of response was seen in patients with primary extremity lesions treated with a schedule in which MAID chemotherapy was alternated with radiation.117 These preliminary results provided the background for a subsequent phase II trial being conducted by the RTOG. The EORTC is conducting a prospective randomized trial of neoadjuvant doxorubicin/ifosfamide followed by surgery, versus immediate surgery, but accrual has been poor and the trial may fail as a consequence. At this point in time, there is a body of evidence to suggest that patients with high-risk lesions do benefit from chemotherapy applied before or after treatment of the primary. Nonetheless, the data are not definitive. Ideally, such therapy should be offered within the context of clinical trials. As was demonstrated in the USA, and currently is being demonstrated in Europe, neither patients nor doctors appeared to be comfortable with randomization to an aggressive course of chemotherapy in the adjuvant setting for a primary soft tissue sarcoma versus observation alone. It is interesting that the biases on the two sides of the Atlantic do not always run in the same direction. We currently employ neoadjuvant chemotherapy in high-risk patients with high grade, >10 cm tumors (Figure 9.9). Chemotherapy with combinations of anthracycline and ifosfamide is associated with significant morbidity, especially in older patients. The available data suggest that the patients most likely to benefit from adjuvant or neoadjuvant systemic chemotherapy are young, medically fit patients who have high-risk lesions. Outside the context of a prospective clinical trial, decisions regarding adjuvant therapy should be based on the prognosis, general medical condition and desires of the individual patient.

176

Diagnosis and Management of Soft Tissue Sarcoma Events/Total entered Chemotherapy Control

O–E

Variance

Hazard Hazardratio retio

Local RFI GOG MDA Mayo NC14 NC15 NC16 EORTC DFCI/MGH Bergonie SSG Rizzoli IGSC SAKK

20/112 2/18 4/22 2/17 8/28 0/21 30/193 3/21 6/28 19/121 1/16 6/40 0/12

16/109 5/17 5/23 4/8 9/41 0/20 51/188 3/25 8.26 13/119 6/22 8/46 0/12

1.25 –1.61 –0.66 –2.49 0.09 0.00 –12.25 0.23 –2.31 2.59 –1.96 –0.93 0.00

8.97 1.75 2.24 1.11 0.00 0.00 20.16 1.49 3.33 7.94 1.71 3.49 0.00

Total

101/659

128/656

–18.05

56.42

GOG MDA Mayo NC14 NC15 NC16 EORTC DFCI/MGH Bergonie SSG Rizzoli IGSC SAKK

21/112 8/18 6/22 4/17 12/38 7/21 51/193 6/21 8/28 41/121 6/16 4/40 3/12

36/109 8/17 6/23 3/8 16/41 10/20 56/188 7/25 14/26 53/119 10/22 13/46 4/12

–8.70 –1.10 –0.01 –1.10 –1.51 –2.12 –3.43 –0.20 –5.00 –7.87 –1.-5 –4.14 –0.44

14.20 3.70 3.00 1.38 6.98 4.20 26.73 3.24 5.29 22.97 3.86 4.24 1.75

Total

177/659

236/656

–36.65

101.54

0

Distant RFI

0

0.5

1.0

0.5

1.0

Chemotherapy better

1.5

2.0

1.5

2.0

Control better

Figure 9.24112 Meta-analysis of effects of adjuvant chemotherapy versus control. Squares represent hazard ratios; area is proportional to amount of information available in trial; bars, 95% CI (inner limit) and 99% CI (outer limit); diamonds, overall hazard ratios for results of all trials combined (extremes of diamond give 95% CI). Trial group abbreviations: Bergonie, Institut Bergonie; DFCI, Dana-Farber Cancer Institute; ECOG, Eastern Cooperative Oncology Group; EORTC, European Organization for Research and Treatment of Cancer; GOG, Gynecologic Oncology Group; IGSC, Intergroup Sarcoma Committee; Mayo, Mayo Clinic; MDA, MD Anderson Cancer Center; MGH, Massachusetts General Hospital; NCI4, 5 and 8, National Cancer Institute; Rizzoli, Instituti Ortopedica Rizzoli; SAKK, Swiss Group for Clinical Cancer Research; SSG, Scandinavian Sarcoma Group. RFI, recurrence-free interval; RFS, recurrence-free survival, 0–E, observed–expected. 씰

Adjuvant management Events/Total entered Chemotherapy Control

O–E

Variance

Overall RFS GOG MDA Mayo NC14 NC15 NC16 EORTC DFCI/MGH ECOG Bergonie SSG Rizzoli IGSC SAKK

52/113 12/18 12/22 9/17 22/38 9/21 92/193 7/21 9/24 11/28 65/121 7/16 14/40 4/12

62/112 15/17 11/23 5/8 24/41 11/20 105/188 8/25 11/23 19/26 69/119 13/22 25/46 4/12

–6.75 –4.65 0.21 –1.42 –0.33 –2.00 –13.31 –0.20 –1.70 –7.60 –5.35 –2.10 –5.09 0.08

28.42 5.88 5.71 2.64 11.47 4.90 48.84 3.74 4.96 6.96 32.73 4.85 9.73 2.00

Total

325/684

382/682

–50.21

172.83

GOG MDA Mayo NC14 NC15 NC16 EORTC DFCI/MGH ECOG Bergonie SSG Rizzoli IGSC SAKK

51/113 15/26 14/28 9/17 23/38 8/21 94/234 6/21 9/24 10/33 57/121 12/34 16/43 5/14

55/112 20/28 12/29 5/8 23/41 9/20 96/233 7/25 10/23 18/32 57/119 25/43 23/49 3/15

–1.37 –3.13 1.46 –1.57 1.32 –1.01 –0.60 0.15 –1.29 –5.94 –1.30 –5.83 –2.72 1.55

26.43 8.65 6.45 2.54 11.15 4.21 47.47 3.22 4.69 6.82 28.48 9.19 9.72 1.94

Total

328/767

363/777

–20.29

170.95

Overall RFI

177

Hazard ratio

0

0.5

1.0

1.5

2.0

0

0.5

1.0

1.5

2.0

0

0.5 1.0 1.5 Chemotherapy better Controlbetter better Chemotherapy better Control

2.0

Figure 9.24 continued

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Adjuvant management 67. Welt S, Magill GB, Sordillo PP et al. Phase II trial of VP-16-213 in adults with advanced soft tissue sarcomas. Proc Am Soc Clin Oncol 1983;2:234 (abstract). 68. Saiki J, Stephens R, Fabian C et al. Phase II evaluation of gallium nitrate (NSC-15200) in soft tissue and bone sarcomas. Proc Am Assoc Cancer Res 1981;22:525. 69. Presant C, Gams R, Bartolucci A. Treatment of metastatic sarcomas with mitroxantrone. Cancer Treat Rep 1984;68:813–14. 70. Bull FE, Von Hoff DD, Balcerzak SP et al. Phase II trial of mitoxantrone in advanced sarcomas. A Southwest Oncology Group study. Cancer Treat Rep 1985;69:231–3. 71. Muss HB, Bundy BN, Adcock L et al. Mitoxantrone in the treatment of advanced uterine sarcoma. A phase II trial of the Gynecologic Oncology Group. Am J Clin Oncol 1990;13:32–4. 72. Gian V, Lynch J, McCarley D et al. Taxol in the treatment of recurrent or metastatic soft tissue or osteosarcomas. Proc Am Soc Clin Oncol 1995;14:516 (abstract). 73. Balcerzak SP, Benedetti J, Weiss GR et al. A phase II trial of paclitaxel in patients with advanced soft tissue sarcomas. Cancer 1995;76:2248–52. 74. Waltzman R, Schwartz GK, Shorter S et al. Lack of efficacy of paclitaxel (taxol) in patients with advanced soft tissue sarcoma Am Soc Clin Oncol 1996 (abstract). 75. Yap BS, Benjamin RS, Plager C et al. A randomized study of continuous infusion vindesine versus vinblastine in adults with refractory metastatic sarcomas. Am J Clin Oncol 1983;6:235–8. 76. Eisenhauer EA, Wainman N, Boos G et al. Phase II trials of topotecan in patients with malignant glioma and soft tissue sarcoma. Proc Am Soc Clin Oncol 1994;13:A488 (abstract). 77. Van Hoesel QG, Verweij J, Catimel G et al. Phase II study with docetaxel (Taxotere) in advanced soft tissue sarcomas of the adult. EORTC Soft Tissue and Bone Sarcoma

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Group. Ann Oncol 1994;5:539–42. 78. van Oosterom AT, Krzemienlecki K, Nielsen OS et al. Randomized phase II study of the EORTC Soft Tissue and Bone Sarcoma (STSBS) group comparing two different ifosfamide (IF) regimens in chemotherapy untreated advanced soft tissue sarcoma (STS) patients. Proc Am Soc Clin Oncol 1997;16:496a. 79. Nielsen OS, Judson I, van Hoesel Q et al. Effect of high dose ifosfamide (HDI) in advanced soft tissue sarcoma (STS). A multicenter phase II study of the EORTC Soft Tissue and Bone Sarcoma Group. Proc Am Soc Clin Oncol 1998;17:517a. 80. Gian VG, Johnson TJ, Marsh RW et al. A phase II trial of paclitaxel in the treatment of recurrent or metastatic soft tissue sarcomas or bone sarcomas. J Exp Ther Oncol 1996;1:186–90. 81. Patel SR, Linke KA, Burgess MA et al. Phase II study of paclitaxel in patients with soft tissue sarcomas. Sarcoma 1997;1:95–8. 82. Sordillo PP, Magill GB, Gralla RJ. Phase II evaluation of vindesine sulfate in patients with advanced sarcomas. Cancer Treat Rep 1981;65:515–16. 83. Fidias P, Demetri G, Harmon DC. Navelbine shows activity in previously treated sarcoma patients: phase II results from MGH/Dana Farber/Partner’s Cancercare study. Proc Am Soc Clin Oncol 1998;17:513a. 84. Gottlieb JA, Baker LH, Quagliana JM et al. Chemotherapy of sarcomas with a combination of adriamycin and dimethyl triazeno imidazole carboximide. Cancer 1972;30:1632–8. 85. Zalupski M, Metch B, Balcerzak S et al. Phase III comparison of doxorubicin and dacarbazine given by bolus versus infusion in patients with soft tissue sarcomas: a Southwest Oncology Group study. J Nat Cancer Inst 1991;83:926–32. 86. Yap B, Baker LH, Sinkovics JG et al. Cyclophosphamide, vincristine, adriamycin and DTIC (CYVADIC) combination

182

87.

88.

89.

90.

91.

92.

93.

94.

95.

Diagnosis and Management of Soft Tissue Sarcoma

chemotherapy for the treatment of advanced sarcomas. Cancer Treat Rep 1980;64:93–8. Pinedo HM, Bramwell VHC, Mouridsen HT et al. CYVADIC in advanced soft tissue sarcoma: a randomized study comparing two schedules. Cancer 1984;53:1825–32. Pfeffer MR, Sulkes A, Biran S. Treatment of advanced soft tissue sarcomas with a modified CYVADIC protocol. Oncology 1984;41:308–13. Elias A, Ryan L, Sulkes A et al. Response to mesna, doxorubicin, ifosfamide, and dacarbazine in 108 patients with metastatic or unresectable sarcoma and no prior chemotherapy. J Clin Oncol 1989;9:1208–16. Antman K, Crowley J, Balcerzak SP et al. An intergroup phase III randomized study of doxorubicin and dacarbazine with or without ifosfamide and mesna in advanced soft tissue and bone sarcomas. J Clin Oncol 1993;11:1276–85. Edmonson JH, Long HJ, Richardson RL et al. Phase II study of a combination of mitomycin, doxorubicin and cisplatin in advanced sarcomas. Cancer Chemother Pharmacol 1985;15:181–2. Schutte J, Mouridsen HT, Steward W et al. Ifosfamide plus doxorubicin in previously untreated patients with advanced soft tissue sarcoma. Cancer Chemother Pharmacol 1993;31(suppl 2):S204–9. Steward WP, Verweij J, Somers R et al. Doxorubicin plus ifosfamide with rhGM-CSF in the treatment of advanced adult soft tissue sarcomas: Preliminary results of a phase II study from the EORTC Soft Tissue and Bone Sarcoma Group. J Cancer Res Clin Oncol 1991;117(suppl 4):S193–7. Rosenberg SA, Chang AE, Glatstein E. Adjuvant chemotherapy for treatment of extremity soft tissue sarcoma: review of the National Cancer Insitute experience. Cancer Treatment Symposia 1985;3:83. Chang AE, Kinsella T, Glatstein E et al. Adjuvant chemotherapy for patients with high

96.

97.

98.

99.

100.

101.

102.

103.

grade soft tissue sarcomas of the extremity. J Clin Oncol 1988;6:1491. Muss HB, Bundy B, DeSaia PJ et al. Treatment of recurrent or advanced uterine sarcoma. A randomized trial of doxorubicin versus doxorubicin and cyclophosphamide (a phase II trial of the Gynecologic Oncology Group). Cancer 1985;55:1648. Nielsen OS, Judson I, Van Hoesel Q et al. Effect of high dose ifosfamide in advanced soft tissue sarcoma: a multi-center phase 2 study of the EORTC Soft Tissue and Bone Sarcoma Group. Eur J Cancer 2000;36:61–7. Patel SR, Vadhan-Raj S, Burgess MA et al. Dose intense therapy does improve response rates – updated results of studies of adriamycin (A) and ifosfamide with growth factors in patients (pts) with untreated soft tissue sarcomas (STS). Proc Am Soc Clin Oncol 1997;16:499a. Bui NB, Demaille MC, Chevreau C et al. qMAID vs MAID + 25% with G-CSF in adults with advanced soft tissue sarcoma (STS). First results of a randomized study of the FNCLCC Sarcoma Group. Proc Am Soc Clin Oncol 1998;17:517a. Patel SR, Benjamin RS. Ifosfamide in sarcomas: is it a schedule-dependent drug? Cancer Invest 1996;14:290–1. Singer JM, Hartley JM, Brennan C et al. The pharmacokinetics and metabolism of ifosfamide during bolus and infusional administration; a randomized cross-over study. Br J Cancer 1998;77:978–84. Dumontet C, Biron P, Bouffet E et al. High dose chemotherapy with ABMT in soft tissue sarcomas: a report of 22 cases. Bone Marrow Transplant 1992;10:405. Bokemeyer C, Franzke A, Hartmann JT et al. A phase I/II study of sequential, doseescalated, high dose ifosfamide plus doxorubicin with peripheral blood stem cell support for treatment of patients with advanced soft tissue sarcomas. Cancer 1997;80:1221–7.

Adjuvant management 104. Van Glabbeke M, van Oosterom AT, Oosterhuis JW et al. Prognostic factors in advanced soft tissue sarcoma (STS): an overview of 1742 patients treated with doxorubicin containing first line chemotherapy by the EORTC Soft Tissue and Bone Sarcoma Group. Proc Am Soc Clin Oncol 1994;13:474 (abstract). 105. Van Glabbeke M, Van Oosterom AT, Nielson OS et al. Prognostic factors for first line high dose chemotherapy outcome in advanced soft tissue sarcoma (STS): an overview of 759 patients included in studies of the EORTC Soft Tissue and Bone Sarcoma Group. Proc Am Soc Clin Oncol 1998;17:512a. 106. Glenn J, Kinsella T, Glatstein E et al. A randomized prospective trial of adjuvant chemotherapy in adults with soft tissue sarcomas of the head and neck, breast and trunk. Cancer 1985;55:1206–14. 107. Glenn J, Sindelar W, Kinsella T et al. Results of multimodality therapy of resectable soft tissue sarcomas of the retroperitoneum. Surgery 1985;97:316–25. 108. Bramwell V, Rousse J, Steward W et al. Adjuvant CYVADIC chemotherapy for adult soft tissue sarcoma: reduced local recurrence but no improvement in survival: a study of the European Organization for Research and Treatment of Cancer, Soft Tissue and Bone Sarcoma Group. J Clin Oncol 1994;12:1137–49. 109. Ravaud A, Bui NB, Coindre J et al. Adjuvant chemotherapy with CYVADIC in high risk soft tissue sarcoma: a randomized prospective trial. In: Salmon SE, ed. Adjuvant Therapy of Cancer, VI. Philadelphia: WB Saunders, 1990:556–66. 110. Zalupski MM, Ryan JR, Hussein ME et al. Defining the role of adjuvant chemotherapy

111.

112.

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116.

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for patients with soft tissue sarcoma of the extremities. In: Salmon SE, ed. Adjuvant Therapy of Cancer, VII. Philadelphia: JB Lippincott, 1993:385–92. Tierney JF, Mosseri V, Stewart LA et al. Adjuvant chemotherapy for soft-tissue sarcoma: review and meta-analysis of the published results of randomised clinical trials. Br J Cancer 1995;72:469–75. Sarcoma Meta-analysis Collaboration. Adjuvant chemotherapy for localised resectable soft-tissue sarcoma of adults: meta-analysis of individual data. Lancet 1997;350:1647–54. Frustaci S, Gherlinzoni F, De Paoli A et al. Preliminary results of an adjuvant randomized trial on high risk extremity soft tissue sarcomas (STS). The interim analysis. Proc Am Soc Clin Oncol 1997;16:496a. Pisters PW, Patel SR, Varma DG et al. Preoperative chemotherapy for stage IIIB extremity soft tissue sarcoma: long-term results from a single institution. J Clin Oncol 1997;15:3481–7. Pezzi CM, Pollock RE, Evans HL et al. Preoperative chemotherapy for soft tissue sarcomas of the extremities. Ann Surg 1990;211:476–81. Casper ES, Gaynor JJ, Harrison LB et al. Preoperative and postoperative adjuvant combination chemotherapy for adults with high grade soft tissue sarcoma. Cancer 1994;73:1644–51. Spiro I, Gebhardt MC, Jennings LC et al. Prognostic factors for local control of sarcomas of the soft tissue managed by radiation and surgery. Semin Oncol 1997;24:540–6.

10 Special sites

Head and Neck Diagnosis and presentation Head and neck sarcomas are rare. They represent <5% of all sarcomas seen and treated at MSKCC. All types of soft tissue sarcoma are seen in the head and neck, particularly fibrosarcoma, malignant fibrous histiocytoma, and synovial sarcoma. A particularly difficult type of head and neck sarcoma is the irradiation-induced sarcoma seen in patients with previously treated retinoblastoma. As with other sites, CT and MRI are the mainstays in determining tumor extent at the time of initial surgical approach. Perhaps even more than in other sites, prior operation distorts special planes and makes evaluation of recurrence difficult, even with excellent CT. As differential diagnosis in the head and neck may be difficult, a complete examination, including all the lymph node-bearing areas, oral cavity, larynx and pharynx, for potential primary sources should be carried out. Where appropriate, fine needle aspiration cytology can be considered, as can tru-cut® biopsy if there is concern about the histology. If the lesion is small and can be safely encompassed, then it can be treated much as an extremity lesion, with local excision and appropriate application of external beam radiation therapy.

Unfortunately, in many situations there are limitations as to what can be performed because of proximity of the major neurovascular structures. Radiation therapy, therefore, is much more commonly applied even with very small superficial lesions <5 cm, where the margin is rarely adequate. For patients with clinically unresectable disease, chemotherapy is utilized in an effort to render the patient operable. Treatment The management of sarcoma of the head and neck is often complicated by the close juxtaposition of tumors to important major structures. The general algorithm allows more liberal use of radiation therapy, often employed when margin status is difficult to assess, even in small tumors. However, the basic principles remain, of encompassing excision with negative margins wherever possible. Adjuvant treatment For large, high-grade lesions, and even, on occasion, lesions <5 cm, preoperative chemotherapy may be considered in an effort to gain a local effect and allow less destructive resection. In similar fashion, the use of adjuvant external beam radiation therapy, or brachytherapy, is much more liberally applied to smaller lesions in the head and neck compared to other sites.

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Studies have utilized preoperative and postoperative radiation therapy with varying benefit.1 We have not vigorously used chemotherapy, although it has been evaluated in a number of studies. In the prospective randomized trial of adjuvant chemotherapy for patients with soft tissue sarcoma of the head and neck, breast and trunk, Glenn et al2 examined 31 patients in a randomized prospective study testing the efficacy of adjuvant chemotherapy after aggressive local treatment. In this study, patients had complete resection of gross tumor, postoperative radiation therapy, 60–63 Gy over 8 weeks, and adjuvant chemotherapy with doxorubicin (<550 mg/m2), cyclophosphamide (<5500 mg/m2), and methotrexate (<1000/mg/kg). In that study, 3-year actuarial survival in the chemotherapy arm was 77%, compared to 49% in the no-chemotherapy arm (p=0.075). Three-year overall actuarial survival, however, was not different, at 68% in both the treated and the control arms (p=0.38). In that study, local control was achieved in 81% of patients. Significant doxorubicin-induced cardiomyopathy was seen in the study, and so chemotherapy cannot be recommended as primary adjuvant treatment for high-grade sarcomas of the head and neck but remains a subject for further investigation.

(MPNT). An update of our experience is given in Figure 10.1. All types were represented. The commonest site was on the face, followed by the neck, scalp, and oropharynx. The majority presented to the institution having had previous treatment, and the tumors were in the main <5 cm in size. Forty-three patients had tumors <5 cm, and nine patients had tumors >5 cm, with indeterminate tumor size in the remaining eight patients because of prior treatment. Approximately two-thirds were high grade, as is seen in other sites. The most common presenting symptom was a painless mass, which occurred in 80% of patients. Head and neck presents a unique problem, in that negative margins are difficult to obtain. In this experience, 35 of 60 patients had negative margins following operation at MSKCC, including two patients who had had previous operations elsewhere. Two patients had

MPNT 5%

Liposarcoma 6% Synovial sarcoma 8% 9

12

Other 22%

15 44

19

Leiomyo sarcoma 10%

22 ERMS 11% 42

Results A review of the MSKCC experience has been published.3 Sixty patients identified in a 7-year period with soft tissue sarcoma of the head and neck were retrospectively reviewed after having been obtained from the prospective database. Excluding embryonal rhabdomyosarcoma as a tumor of children, the commonest type was malignant fibrous histiocytoma (MPH), followed by fibrosarcoma, leiomyosarcoma, and malignant peripheral nerve tumor

33 Fibrosarcoma 21%

MFH 17%

n=196

Figure 10.1 Histology of head and neck tumors. ERMS, embryonal rhabdomyosarcoma; MPNT, malignant peripheral nerve tumor; MFH, malignant fibrous histiocytoma. MSKCC, 7/82–12/00.

Special sites pathologic evidence of metastatic lymph node disease, i.e. approximately 3%. Twenty-nine patients received postoperative external beam radiation therapy, with doses ranging from 43 Gy to 70 Gy, and with a median dose of 60 Gy. At the time of completion of the study, 60% had no evidence of recurrence, 13 patients had local recurrence only, 3 had local and distant recurrence, 1 had local and regional recurrence, 2 had regional recurrence, and 5 had distant metastases. Of 24 patients who recurred, 23 recurred within 3 years of completion of treatment. Disease control with low-grade tumors was greater (88%) than in high-grade tumors (60%). Interestingly, 12 of 23 patients (52%) with close or positive margins did not recur locally. Metastatic disease was almost exclusively confined to those patients (10 of 11) who had high-grade lesions. Overall survival was 71%, and diseasefree survival was 60%. Multivariate analysis based on the Cox proportional hazard model suggested that margin status is the only factor in predicting local control, and grade and margins were factors in subsequent metastatic and disease-specific survival.

Thoracic Chest wall Diagnosis and presentation Primary soft tissue sarcomas of the chest wall are very uncommon.4 The majority of primary sarcomas that occur in the chest wall originate in the soft tissue. They therefore involve the bony thorax in a relatively minor proportion of cases. The most common sarcoma is MFH, which, in the main, requires chest wall resection for complete eradication. As with other sites, outcome is dependent on size and grade and complete resection is mandatory.

187

Treatment Surgical resection is the predominant major modality of treatment. Technical issues of resection of the chest wall have been well summarized (see Chapter 11). When a primary chest wall tumor is quite large, an incisional biopsy is done, and thorough evaluation is planned with all disciplines prior to definitive operation. For example, reconstruction can require specialized skin flaps or tumors encroaching on the spine, and require neurosurgical consultation. Adjuvant treatment Radiation and chemotherapy are applied, using the same principles as for extremity. Thus, tumors >5 cm would be given radiation, and those >10 cm would be given radiation and considered for chemotherapy. Results In a recent review, our experience at MSKCC was examined.4 Of 189 patients, pathologic material was available for analysis for 149 patients. Sixty per cent of tumors were high grade and 40% were low grade, as is consistent with the distribution seen in other sites in the extremity and superficial trunk. We included desmoid tumors (21% of these patients), as these are common tumors of the chest wall and make up a majority of the ‘low-grade’ lesions seen in this site. Histopathology is listed in Table 10.1. Local recurrence occurred in 27% and metastasis in 35%. If one excludes the desmoid, then metastasis occurred in 52 of 117 or 44% of the non-desmoid lesions. This was reflected in 5-year survival rates of 50% for high-grade lesions and 90% for low-grade lesions. These data are consistent with results seen in other areas of the trunk and superficial extremity (Figure 10.2).

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Diagnosis and Management of Soft Tissue Sarcoma

Table 10.1 Histologic types of chest wall soft tissue sarcomas: average age of patient, grade of tumor, and distribution by sex. Histologic type

No.

Desmoid 32 Liposarcoma 23 Rhabdomyosarcoma 18 Fibrosarcoma 17 Embryonal rhabdomyosarcoma 14 Malignant peripheral nerve tumor 13 Malignant fibrous histiocytoma 11 Spindle cell sarcoma 4 Tenosynovial sarcoma 3 Hemangiopericytoma 3 Alveolar soft-part sarcoma 3 Dermatofibrosarcoma protuberans 2 Leiomyosarcoma 2 Primitive neuroectodermal tumor 1 Giant cell sarcoma 1 Unclassified 2 Total 149

%

No. by grade Low High

Mean age (years)*

No. male No. female

21 15 12 11

32 16 0 1

0 7 18 16

33 56 44 44

13 20 13 12

19 3 5 5

9

0

14

17

7

7

9

4

9

49

10

3

7 3 3 3

1 2 0 1

10 2 3 2

44 45 37 38

8 3 3 3

3 1 0 0

3

0

3

20

2

1

1 1

2 0

0 2

52 62

1 2

1 0

1 1 1

0 0 0 59

1 1 2 90

16 52 33 41

0 1 2 100

1 0 0 49

*Overall median age, 38 years. From Gordon et al.4

Breast sarcoma Primary sarcomas of the breast constitute <5% of all soft tissue sarcomas and <1% of all breast tumors5 (Figure 10.3). The majority of conventional sarcomas are stromal sarcomas.

Cystosarcoma phyllodes Diagnosis and presentation Cystosarcoma phyllodes is a rare entity thought to arise from fibroadenoma and is essentially benign, although a malignant

subtype can occur in up to 50% of patients with the phyllodes tumor (PT). In one study, 90% of the patients were premenopausal,6 and a retrospective study of 84 patients found the median age of patients with benign PT to be 34 years, compared with 52 years for those with malignant tumors.7 Predominantly a large painless breast mass, it is often associated with rapid tumor growth and can reach enormous size. The tumor is usually grossly bosselated, with a sticky surface of various colors from gray to red. There are often cystic areas with associated polypoid tumor masses. In many tumors, myxoid

Special sites

Proportion surviving

1 0.8 0.6 0.4 0.2

High Grade (n=90) Low grade (n=59)

0 0

20

40

60 80 Time (months)

100

120

p=0.0001

Figure 10.2 Overall survival in chest wall by tumor grade. Patients with high-grade tumors had 5- and 10-year survival rates of 49% and 39%, respectively, compared to 5- and 10-year surival rates of 90% and 82%, respectively, among patients with low-grade tumors. From Gordon et al.4

Upper extremity 13% Retroperitoneal/ intra-abdominal 15%

593

degeneration may be observed and there may be necrotic areas. The differentiation of benign from malignant can be quite difficult, with malignancy usually confined to tumors with high mitotic activity.8 Clear malignant features of soft tissue invasion are not often seen, and it has been suggested that another factor suggestive of malignancy is if the soft tissue component is more prominent than the epithelial component. The malignant type is more like an anaplastic or high-grade fibrosarcoma. On occasion, neoplastic dystrophic tissue containing cartilage or bone can be identified. Axillary lymph node metastasis is rare, although, because of the necrosis in the tumor, clinical axillary lymph enlargement may be suspicious. Distant metastatic disease has occurred in reported series, ranging from 3% to 17%.9 A probable risk of malignant histiosarcoma is 5–10%. As with other extremity and superficial truncal lesions, the lung is the primary site for metastasis. A genetic study of PTs has been reported.10 In this study, abnormalities of chromosome 1q and 10q were found to consistently occur in patients with this disease.

Trunk 8% Thoracic 6%

379 282

354 687 306 137 196 89 73

1400 Lower extremity 32%

189

n=4496

Visceral/ gastrointestinal 8% Visceral/ gynecologic 7% Visceral/ genitourinary 3% Head & Neck 4% Breast 2% Unknown 2%

Figure 10.3 Sarcomas of breast constitute < 5% of all soft tissue sarcomas. MSKCC, 7/82–12/00.

Treatment Treatment is similar to that of other sarcomas; that is, complete resection is mandatory. This often requires mastectomy, total or simple, with limited low axillary lymph node sampling.

Adjuvant treatment The primary treatment is surgical; only rarely will adjuvant therapy be used, usually radiation therapy, where margins are positive or close and further operation is not possible or appropriate.

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Diagnosis and Management of Soft Tissue Sarcoma

Results In a clinicopathologic study of 45 patients, this rare malignancy in adolescents and young women has been reported8 from our institution. Forty-five patients were studied, 34 benign cases and 11 malignant cases. The majority underwent local excision or mastectomy. The mean age of this group ranged from 10 to 24 years (mean 17.7), with tumors varying in size from 1.4 to 10.2 cm. There was no breast predominance in terms of laterality. Thirty-two patients were able to be treated by local excision, and only four underwent mastectomy. In follow-up on 36 patients for a mean of 58 months, local recurrence occurred in 6 of the 36 cases (4 were benign and 2 malignant). Only one patient had a systemic metastasis, and that was from a high-grade tumor with some rhabdomyosarcomatous stromal differentiation. Thirty-four of 36 patients were alive with no evident disease at most recent follow-up. The authors suggest quite strongly that cystosarcoma phyllodes in adolescent girls and young women is not more aggressive than in older patients. As with other sarcomas, an infiltrative border is the strongest pathologic predictor of malignant behavior. Again, conservation of breast tissue is possible in these lesions. Another comprehensive study7 examined 84 patients with cystosarcoma phyllodes for prognosis and outcome. The median age of the patients with benign tumors was 34, and the median age of patients with malignant disease was 52 years. Malignant tumors were larger than benign tumors (7.25 cm versus 3 cm). Median follow-up was 6.6 years, and all patients with benign lesions showed no evidence of recurrence. Twelve of the 15 patients with malignant tumors underwent mastectomy, and only one patient went on to die of systemic disease. Overall, then, the recommendations for the management of PTs

would be complete surgical excision. For tumors >5 cm in size, this may well require mastectomy. On rare occasions, it has been reported that the resection of solitary metastases can provide long-term survival and possibly cure.

Other tumors of the breast Diagnosis and presentation Granulocytic sarcoma of the breast is a rare tumor and can be multicentric.11 Radiationinduced sarcomas certainly occur (see Chapter 2).12 Angiosarcoma following development of lymphedema (Stewart–Treves syndrome)13 is a serious and devastating entity. Diagnosis is usually made with fine needle aspiration biopsy, and the most common histologic subtypes are MFH, liposarcoma, and fibrosarcoma. Treatment The principles of treatment are the same as for sarcoma on the superficial trunk and other anatomic locations. The operative principles include a wide resection of the primary tumor, with the goal being to obtain negative microscopic margins. Depending on the relative proportion of tumor compared to breast size, this may necessitate a partial or total mastectomy. Axillary lymph node dissection is not indicated for patients with clinically normal axilla. Adjuvant treatment As with other trunk lesions, tumors that are >5 cm should benefit from adjuvant radiation. Results The outcome of primary non-phyllodes sarcoma of the breast is predicated upon

Special sites

191

histologic type, degree of differentiation and tumor size. Recurrences are primarily local as an early event and, somewhat later in the course of the disease, distant to the lung.5

heart transplantation without a clear incidence of increased tumor recurrence.17

Cardiac sarcoma

The role of adjuvant therapy is not well defined. Virtually all patients would be candidates for adjuvant systemic chemotherapy.

Diagnosis and presentation The heart is an infrequent site of either primary or metastatic soft tissue sarcoma.14–16 Treatment While rare, cardiac sarcomas are usually situated such that primary resection is technically difficult if not impossible. These tumors had not been considered for orthotopic heart transplantation, because of the concern about recurrence as a consequence of immunosuppression. However, a number of patients who have been treated for breast cancer and Hodgkin’s disease have undergone subsequent

Adjuvant treatment

Results In a review17 at least 11 patients underwent cardiac transplantation for malignant sarcoma (Table 10.2).17–25 While isolated patients are alive, the majority have recurred and died. The majority had already received extensive chemotherapy, and some received postoperative adjuvant therapy, usually doxorubicin-based. We see, therefore, that it is possible to consider cardiac transplantation in patients with lowgrade malignant lesions. In patients with highgrade lesions, with high risk of metastasis, this should be a rare event.

Table 10.2 Cardiac transplantation for cardiac sarcoma. Author

(ref. no.) Age

Sex

Tumor

Outcome

RA angiosarcoma RV neurofibrosarcoma LV fibrosarcoma RA angiosarcoma Recurrent biatrial malignant fibrohistiocytoma RA angiosarcoma RA angiosarcoma Recurrent RA and RV synovial sarcoma Recurrent LA spindle cell sarcoma Recurrent myxofibrosarcoma Myofibrosarcoma

Died 15 months, metastasis Alive, NED 5.5 years Alive, NED 12 months Alive, NED 33 months Died 18 months, recurrence Died 8 months, metastasis Died 9 months, metastasis

Horn Aravot Aufiero Baay Bacher

(19) (20) (21) (22) (23)

13 43 31 34 35

M F F M M

Crespo

(24)

31 32 31

M M F

42 49 64

F F M

Siebenmann (25) Michler

(17)

NED, no evidence of disease. Modified from Michler and Goldstein.17 RV, right ventricle; LV, left ventricle; RA, right atrium; LA, left atrium.

Died 2 months, metastasis Alive, NED 6 months Alive 38 months, metastasis Died 3 months

192

Diagnosis and Management of Soft Tissue Sarcoma

Primary sarcomas of the mediastinum

year survival was 49% for complete resection and 3-year survival was 18% for incomplete or no resection (p=0.001).

Diagnosis and presentation

Lung

In our experience with 47 patients with a diagnosis of primary sarcoma of the mediastinum,26 the median age was 39 years (range 2.5–69), the male/female ratio was 1.6, and the most common presentation was pain and dyspnea. All varieties of sarcoma were identified, but the most common were MPNT (26%), spindle cell sarcoma (15%), leiomyosarcoma (9%) and liposarcoma (9%). Treatment The primary modality of treatment was operation in 72%, with 22 patients undergoing complete resection. As with other sites in the body, the major factor determining survival was the ability to obtain complete resection. Adjuvant treatment Local recurrence in the mediastinum is common, with over 60% of patients in this series reporting recurrence. As a consequence, the primary goal should be complete surgical resection, but because of the limitations of margins, external beam radiation therapy is recommended as a surgical adjuvant, given the results for adjuvant radiation therapy in other sites. Results The overall 5-year survival was 32%, with high-grade lesions having a significantly decreased survival compared with low-grade lesions. High-grade 5-year survival was 27%, and low-grade 5-year survival was 66%. Five-

Diagnosis and presentation Primary lung sarcoma is extremely rare. Histologic subtypes include MFH, synovial sarcoma, and leiomyosarcoma, but, because of the rarity, the true incidence compared to other sites is difficult to assess. The most common presentation is dyspnea, hemoptysis, or chest pain. Definitive diagnosis is usually made after biopsy. Treatment The only potentially curative treatment is operation. Two studies27,28 both reported an actuarial 5-year survival rate for patients who underwent resection of 60–70%. In order to obtain this, operations ranging from lobectomy to chest wall resection, pneumonectomy, were necessary, and often extended resection, including the pulmonary artery, pulmonary vein, or atrial wall. Adjuvant treatment There is no defined role for adjuvant treatment in these tumors. Some of the principles for sarcoma in other sites are applicable. Thus, there is a role for adjuvant radiation in patients with positive margins. The role of chemotherapy is less well defined. Results The 5- and 10-year actuarial survival after complete resection ranges from 60% to 70%.

Special sites Size and grade have not been found to correlate with survival, but the numbers being studied are very small. The 5-year actuarial survival of patients with unresectable tumors was 30%. For the entire group, the median survival is less than 2 years.

Abdomen/pelvis Retroperitoneal soft tissue sarcomas Diagnosis and presentation In 1954, the first report from MSKCC on retroperitoneal tumors was published.29 The original emphasis in that report on the need for aggressive management holds true today. Most tumors in the retroperitoneum are malignant. About one-third are soft tissue sarcomas. Because of the anatomic location of these tumors, patients present in advanced stages of disease with frequent invasion of contiguous retroperitoneal structures, factors which make surgical resection difficult. Because chemotherapy has not been effective to date, and radiation is limited by toxicity to surrounding structures, complete surgical resection, when feasible, remains the most effective modality for selected primary and recurrent disease. Most patients present with an asymptomatic abdominal mass (Figure 10.4). Symptoms which might be present include pain, gastrointestinal bleeding and incomplete obstruction. Neurologic symptoms relate to retroperitoneal invasion of neurovascular structures. Neurologic symptoms identified in 27% of these patients were related primarily to an expanding retroperitoneal mass.30 The primary modality for evaluation of retroperitoneal and visceral sarcomas is

193

computed tomography (CT). A CT scan of the abdomen and pelvis usually encompasses the primary lesion and the most likely source of metastasis. While the most likely site of visceral metastasis is the liver, the incidence of metastatic disease to the liver is low for retroperitoneal lesions. Leiomyosarcoma and liposarcomas are the predominant histopathologic types. Most retroperitoneal tumors that are leiomyosarcomas are high grade; retroperitoneal liposarcoma is often predominantly low grade and is the more common tumor. However, retroperitoneal tumors frequently have mixed cellularity and grade. Treatment Primary surgical resection is the dominant therapeutic modality. Because many tumors will involve the retroperitoneum, evaluation of contralateral adequate renal function allows nephrectomy where appropriate. Resection of adjacent organs is common, but more extensive resection of adjacent organs does not seem to impact on long-term survival. The major issue in resection is adequate exposure. Complete resection is usually possible in about two-thirds of patients presenting with a recurrence. Should adjacent organs be involved by tumor, they should be resected, although organs not involved should not be resected if they are not the limiting factor in the margins. The use of debulking for recurrent lesions does not significantly enhance long-term survival, nor do more extended resections. Since complete resection benefits survival, operation determines outcome. Incomplete resection should be undertaken only for symptom relief. In the setting of liposarcoma, there may be a role for incomplete resection in the asymptomatic patient.31 The concept,

194

Diagnosis and Management of Soft Tissue Sarcoma

(a)

(b)

(c)

(d)

Figure 10.4 Retroperitoneal soft tissue sarcoma: (a) most patients present with an asymptomatic abdominal mass; (b) CT scan; (c) intraoperative view; (d) operative specimen. however, should be that unless palliation can be achieved, operation should be reserved for those patients for whom complete resection is at least possible. The basis for unresectability is usually the presence of peritoneal implants or extensive vascular involvement. When patients are clinically resectable, one should proceed directly to operation. Preoperative biopsy is not mandatory, as it will not change the procedure. Patients who undergo a complete R0 or R1 (positive microscopic margin) and have low-grade tumors will be followed. Patients with low-grade tumors in whom disease is left behind (R2) will be treated

based on symptoms, as progression can be prolonged, or they will enter investigative protocols designed for local treatment. Adjuvant treatment There is no clearly defined role for adjuvant radiation or chemotherapy. Local recurrence is very common, and local failure is frequently the cause of death. It would therefore seem that being able to deliver an adequate dose of radiation would improve the prognosis in these patients. To date, there is no evidence that adjuvant or neoadjuvant treatment in any

Special sites way affect the prognosis. Several studies have evaluated techniques to deliver radiation therapy, either preoperatively or intraoperatively, at high dose,32,33 but none of these have shown any survival benefit. Similarly, chemotherapy has been shown to have no benefit. Results Median survival is 72 months for patients with primary disease, 28 months for those with local recurrence, and 10 months for those with metastases (see Figures 6.11–14). Local

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recurrence occurs in the majority of these patients, with rates of 53–68%.34,35 The median time to recurrence is 16 months. Patients should therefore be followed postoperatively every 3 months for the first 3 years, every 6 months for the next 2 years, and annually thereafter.

Gastrointestinal sarcomas Gastrointestinal stromal tumors Gastrointestinal sarcomas are uncommon, comprising about 2–4% of sarcoma cases. The most common histologic subtypes include

(a)

(b)

(c)

(d)

Figure 10.5 Gastric sarcomas present frequently with dsypepsia or bleeding: (a) CT scan; (b,c) operative specimen; (d) histopathology.

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Diagnosis and Management of Soft Tissue Sarcoma

(a)

(b)

(c)

(d)

(e)

Figure 10.6 GIST of the distal duodenum may be resected by partial duodenectomy: (a) CT scan; (b) intraoperative view; (c) operative specimen; (d,e) histopathology.

Special sites

Diagnosis and presentation In terms of distribution, the stomach is the most common site, representing approximately 50% of all primary GIST. The clinical presentation of gastrointestinal sarcoma is similar to that of a corresponding carcinoma in the same portion of the gastrointestinal tract. Thus, gastric sarcomas present frequently with dyspepsia or bleeding (Figure 10.5), intestinal sarcomas present often with abdominal pain, hemorrhage or obstruction, and rectal sarcomas present with rectal bleeding or tenesmus.36,37 The diagnosis of gastrointestinal sarcoma is often made at the time of laparotomy. In marked contrast to gastrointestinal carcinomas, gastrointestinal sarcomas rarely spread to regional lymph nodes. The majority of tumors are usually characterized as high grade, although great debate exists as to the ability to differentiate grade with primary gastrointestinal stromal tumors. Treatment The operative approach is predicated on the tumor size, the anatomic site, and the biological requirement of attaining negative margins without the necessity of performing a regional lymph node removal. For localized gastric lesions, a wedge resection with negative margins is the procedure of choice. This results in both disease-free and overall survival comparable to those obtained with more extensive gastrectomy.38 Larger gastric sarcomas may require more extensive surgery including a total gastrectomy and en bloc resection of adjacent organs. Duodenal sarcomas may be amenable to local resection (Figure 10.6), or, if extensive, will require

pancreaticoduodenectomy.35 Small and large bowel lesions may be resected segmentally. A study from our institution36 examined the initial experience with 38 patients presenting with primary lesions. Of those, 70% underwent complete resection at the time of presentation. Resection is the most important factor in prolonged survival (Figure 10.7). For patients undergoing complete resection, the grade of the tumor is the most important factor. Adjuvant treatment There is no proven adjuvant treatment for GIST. The overall poor survival, in particular in highrisk patients, suggests that experimental adjuvant treatments should be considered under protocols for clinical investigation. Studies have focused on the evaluation of mitoxantrone as an intraperitoneal adjuvant.39 However, the response to a new drug directed at the c-kit receptor on these tumors shows dramatic initial promise. Results The overall actuarial survival of these patients is 28%.36 Univariate analysis of survival 1 Proportion surviving

leiomyosarcoma, GIST (gastrointestinal stromal tumor) and GANT (gastrointestinal autonomic nerve tumor).

197

Complete resection (n=27) Incomplete resection/biopsy (n=10)

0.8 0.6 0.4 0.2 0 0

20

40

60 80 Time (months)

100

Figure 10.7 Resection is the most important factor in survival in gastrointestinal sarcomas. p=0.005. From Conlon et al.36

120

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suggests that tumor size <5 cm, low-grade tumors, localized disease and complete resection are favorable prognostic factors.36,38 Multivariate analysis suggests that complete resection is the most significant favorable prognostic factor. For patients undergoing complete resection, grade becomes the major prognostic factor. In this study, the median survival of patients undergoing complete resection was 46 months, compared to 21 months for those undergoing incomplete resection. This is similar to the data reported for colorectal sarcoma, where incomplete resection and high grade are unfavorable prognostic factors.40 Despite complete resection, recurrence rates are still high, ranging from 42%–90% with a median time to recurrence of 18–24 months.40–42 Most patients who present with recurrent disease experience recurrence in the liver (50–65%), with about 30% of patients presenting with intraperitoneal recurrence and 8% with distant metastases.43 If the intra-abdominal recurrence is completely resected, survival is improved, and this should be attempted in patients who represent a good operative risk.41,43,44 Extent of disease may limit the application of resection, and certainly when contemplating hepatic resection, anything less than complete resection is not indicated.44

A study by MSKCC examined approximately 298 patients with GIST. Figure 10.8 shows that approximately 50% of patients present with the primary lesion intact, 22% with metastasis, and a small proportion with local recurrence alone. Of the patients who present with the primary intact, at least one-third will go on to develop either local or metastatic recurrence. An examination of outcome

GIST n=298

Present primary n=150 (50%)

Develop metastases n=29 (19%)

Present local recurrence n=22 (7%)

Present metastases n=67 (22%)

Present primary and metastases n=33 (11%)

Present local and metastases n=26 (9%)

Develop Develop local local recurrence and n=12 metastases (8%) n=3 (2%)

Figure 10.8 GIST: presentation and outcome. MSKCC, 7/82–12/00.

Table 10.3 Ultrastructural features of gastrointestinal stromal tumors.

Leiomyosarcoma GANT (Gastrointestinal autonomic nerve tumor) GIST–NOS (Gastrointestinal stromal tumor – not otherwise specified)

Immunohistochemistry Smooth muscle actin

Electron microscopy Neurofibrils

+

–

–

+

–

–

Special sites suggests metastasis to be a dominant factor in survival (Figure 10.9). Patients who present with metastasis or develop metastasis have an approximately 20% 5-year survival rate, whereas those who never developed metastasis have at least a 40% survival rate. As best as we can tell, the various types of GIST, i.e. leiomyosarcoma, gastrointestinal stromal tumors (not otherwise characterized) and GANT, are not different (Figure 10.10) in terms of overall survival. Those presenting with local recurrence would appear to have the worst survival (Figure 10.11) although the number who present with local recurrence alone is quite small. These data are better described in Table 10.3.

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Unfortunately, as the numbers for solitary tumors are small, it is difficult to identify important issues. Clearly, it appears that the disease-free interval is an important factor in outcome, and patients who have a disease-free interval greater than 20 months have much improved survival over patients with a diseasefree interval of less than 20 months (Table 10.4). It is important to note that prolonged survival can occur even with metastasis at the time of presentation, although ultimate death from disease appears inevitable (Figure 10.12). Therefore, there is a great opportunity to look at mechanisms limiting both local recurrence and metastatic disease at the time of primary treatment. The high-risk group is clearly

1.0 Never developed metastases (n=139) Presented with metastases (n=126) Developed metastases (n=33)

Proportion surviving

0.8

0.6

0.4

0.2

0.0 0 n=298

20

40

60

80

100

120

140

160

180

Time (months)

Figure 10.9 GIST: metastasis is a dominant factor in survival. MSKCC, 7/82–12/00.

200

220 p<0.01

240

200

Diagnosis and Management of Soft Tissue Sarcoma 1.0 Leiomyosarcoma (n=149) GI stromal tumors (n=119) GI autonomic nerve tumors (n=30)

Proportion surviving

0.8

0.6

0.4

0.2

0.0 0 n=298

20

40

60

80

100

120

140

160

180

Time (months)

200

220

240

p=0.25

Figure 10.10 GIST versus GANT; overall survival. MSKCC, 7/82–12/00.

Table 10.4 Gastrointestinal stromal tumors; disease-free survival. Institution (ref. no.)

Mayo MSKCC MCV MDACC MSKCC

(45) (38) (46) (47) (48)

Years

Total patients (n)

Complete resection (n)

5-year survival (%)

1950–74 1949–73 1951–84 1957–97 1982–98

108 38 51 191 200

52 20 30 99 80

50 65 63 48 54

Mayo, Mayo Clinic; MCV, Medical College of Virginia; MDACC, MD Anderson Cancer Center.

Special sites

201

1.0 Primary (n=150) Local recurrence (n=22)

Proportion surviving

0.8

0.6

0.4

0.2

0.0 0 n=172

20

40

60

80

100

120

140

160

180

200

Time (months)

220

240

p=0.07

Figure 10.11 GIST patients with local recurrence have the worst survival. MSKCC, 7/82–12/00.

identified, i.e. those presenting with local recurrence or those unable to undergo complete resection.

Management of gastrointestinal or visceral sarcoma The algorithm for the management of visceral sarcoma is essentially the same as for retroperitoneal sarcoma (Figure 10.13). Patients who are clinically completely resectable proceed to operation. Patients who are clinically unresectable undergo a biopsy, and then will be considered either for palliative operations for symptom relief or investigational

or chemotherapeutic regimens. As outlined in the algorithm, we reserve radiation therapy for lesions <5 cm (see Results). For patients with low-grade tumors, external beam radiation therapy is the preferred approach, and for patients with high-grade lesions, we prefer brachytherapy with additional external beam radiation therapy if appropriate.

Primary liver sarcomas Diagnosis and presentation Primary liver sarcomas are rare and often undifferentiated. Thorotrast, arsenic and vinyl

202

Diagnosis and Management of Soft Tissue Sarcoma 1.0

Proportion surviving

0.8

0.6

0.4

0.2

0.0 0 n=126

20

40

60 Time (months)

80

100

120

Figure 10.12 GIST. Metastasis at presentation: disease-specific survival. MSKCC, 7/82–12/00.

Diagnosis suspected

CT Scan

Operation

Complete resection

Incomplete resection

Consider IP chemotherapy Investigational approaches

Figure 10.13 Management of visceral sarcomas. IP, intraperitoneal.

chloride have been associated as etiologic agents, and it has been suggested that the p53 mutations associated with prior vinyl chloride exposure are common and consistent and different from the rarely seen p53 mutations in sporadic angiosarcoma.49 It is difficult, on occasion, when patients present with a liver tumor, to decide whether or not the tumor is primary or metastatic. Multiple different rare pathologies have been identified as primary sarcomas of the liver, including MFH and hemangiopericytoma. Epithelioid hemangiosarcomas can occur as either primary or secondary tumors. A review50 of 25 patients with primary sarcoma of the liver found that the majority were either angiosarcoma or undifferentiated tumors.

Special sites Treatment Primary liver resection, whenever possible, is the treatment of choice.51 This is often not possible, and hepatic transplantation has been attempted, but in the few cases that it has been performed, rapid recurrence has been the norm. Adjuvant treatment On rare occasions, for unresectable lesions, embolization has been attempted, but as the tumors are usually large and often multiple, hepatic necrosis is a serious problem. Chemotherapy has been of very limited value but can be attempted in some lesions. The majority of patients are candidates for investigational treatment, with angiogenesis inhibitors of theoretical appeal.

Sarcomas of the genitourinary tract Diagnosis and presentation Sarcomas of the genitourinary tract are uncommon.52 In our prospective database, 92 patients were seen, with the following distribution: bladder 16, kidney 19, prostate 22, testicular 35. Median age was 50 years with a median follow-up of 27 months. Diseasespecific survival was 72 months, with differing medians: 130 months for bladder; 27 months for kidney; 28 months for prostate; and 72 months for paratesticular. As expected, leiomyosarcoma was the predominant histopathology, appearing in 39% of patients, and 78% of the tumors were high grade. Twentyeight per cent of patients presented with metastasis at the time of diagnosis, of whom 70% are already dead of disease.

203

The composition of these tumors is usually similar to those of visceral sarcomas, in terms of histopathologic type. However, on occasion, low-grade liposarcoma can encompass, in particular, the kidney or bladder, and can be involved in the inguinal area of the spermatic cord as a low-grade lesion, essentially behaving as a retroperitoneal or pelvic liposarcoma. The preferred radiologic investigation is CT or MRI, which can clearly discriminate the tumors from the surrounding tissue. Other high-grade lesions arising from the true visceral component of the genitourinary tract behave much as do visceral sarcomas and should be treated similarly. Important differentials in diagnosis arise, however, particularly for lesions that are associated with the scrotum and testis, such that, on occasion, it is appropriate to measure testicular tumor markers. Treatment As with other visceral and organ-based sarcomas, complete resection is the effective therapy. Once complete resection is accounted for, only grade predicts subsequent survival. Adjuvant treatment No proven adjuvant treatment currently exists. For advanced disease, standard chemotherapy would involve an adriamycin–ifosfamide combination. Results We analyzed 43 patients with soft tissue sarcoma arising from the urinary tract and the male genital tract (urologic sarcoma).53 This comprised 2.7% of the cases that we had treated at that time. The most common site was paratesticular (44% of cases), and the

Diagnosis and Management of Soft Tissue Sarcoma

Gynecologic tumors Diagnosis and presentation Uterine leiomyomas, or fibroids, are by far the most common cause of benign uterine

Kidney 34% Bladder 7%

16

23

21 Spermatic cord 15% n=137

Margin negative (n=25) Margin positive (n=5) Not resected (n=3)

0.8 0.6

Margin negative (70%) 0.4 Not resected (10%)

0.2

Margin positive (25%)

0 0

20

40

60 80 Time (months)

100

120

Figure 10.15 Urologic sarcoma: survival. Influence of margins. From Russo et al.53

1 Low grade (100%) 0.8 0.6 High grade (48%)

0.4 0.2

High Grade (n=37) Low grade (n=6)

0 0

20

40

60 80 Time (months)

100

120

p<0.02

Figure 10.16 Urologic sarcoma: survival. Influence of grade. From Russo et al.53

46

10 Other 12%

1 Proportion surviving

most common histopathologic type was leiomyosarcoma. Other histopathologies included rhabdomyosarcoma and liposarcoma. The majority of tumors were high grade and more than half were >5 cm. (An update of sites of urological sarcomas is shown in Figure 10.14.) Twenty per cent of the patients presented with metastatic disease, most commonly rhabdomyosarcoma. As with other sites, the results were improved with complete surgical resection, which was possible with negative margins in 58% of the patients. Disease-free survival at 3 and 5 years was 55% and 40%, respectively. Again, margin positivity in terms of actual survival was clearly demonstrated (Figure 10.15), and patients with low-grade tumors did well (Figure 10.16).

Proportion surviving

204

21

Prostate/seminal vesicle 17%

Testis15%

Figure 10.14 Urologic sarcoma: site. MSKCC, 7/82–12/00.

enlargement, and are seen in 20% of all women, with a high incidence in black females. Sarcomas may arise from the endometrium, myometrium, cervix, uterine blood vessels, or a leiomyoma. They are most frequently seen in the fifth decade. A very rare sarcoma of the cervix, sarcoma botryoides, is seen in infants and not in adults. The incidence of sarcoma within the body of the uterus is much higher than that within the cervix. These patients frequently present with an abdominal

Special sites mass. They may also present with rapid uterine enlargement with abnormal bleeding.

Uterine sarcomas Diagnosis and presentation Uterine sarcomas are uncommon and comprise <5% of uterine malignancies. The most common subtype is leiomyosarcoma and, more rarely, patients may present with endometrial stromal tumors or mixed mesodermal tumors. The diagnosis is usually made based on the presentation and staging. Patients may present either with an abdominal mass or with abdominal or pelvic pain or vaginal bleeding. The diagnosis is usually made by biopsy or dilatation and curettage. In some patients, these tumors are indistinguishable from a retroperitoneal sarcoma. Treatment All of these patients should undergo preoperative imaging either with a CT or MRI scan. The principles of treatment are similar to those for other retroperitoneal and visceral sarcomas. For patients with localized disease, a total abdominal hysterectomy and bilateral salpingo-oophrectomy is usually indicated. Often, when the mass is larger, there is involvement of contiguous organs. The goal of the operation is always complete resection, but consideration is given to the structure and preservation of function. Where indicated, this should include a resection of adjacent organs. Thus, it may be necessary to do an en bloc bowel resection or partial cystectomy. Many institutions recommend adjuvant radiation for patients with uterine sarcoma. There are no randomized prospective data on which to base this.

205

Patients who are completely resectable are often diagnosed after the fact, following total abdominal hysterectomy for suspected large leiomyomas. In the main, they will have earlystage disease and often will have had bilateral salpingo-oophorectomy. As with other visceral sarcomas, progression and relapse are common and curative treatment is unlikely. Some uterine sarcomas, including the endometrial stromal sarcoma and leiomyosarcoma, can present as a low-grade variant, with complete cure expected by complete resection. On occasion, there is very late (>10 years) relapse of low-grade and somewhat indolent lesions. The principles of management are the same as for other visceral sarcomas. Thus, where possible, tumor should be excised together with contiguous structures in order to try and get negative margins. Adjuvant treatment Retrospective comparisons of radiation therapy have not demonstrated any significant difference in survival. Similarly, no benefit to adjuvant chemotherapy has been demonstrated. Thus, as with other intraabdominal sarcomas, there is limited role for adjuvant chemotherapy or radiation therapy outside of clinical trials. Although recent reports have suggested that the addition of radiation therapy in early-stage disease could improve results in the management of uterine sarcoma,54 other groups have not shown a benefit and, in fact, some have shown a detriment.55 Unfortunately, no interpretable randomized trial has demonstrated efficacy, so radiation should be used with great selectivity. Results More recent data have clearly shown improvement, with overall survival of the order of

206

Diagnosis and Management of Soft Tissue Sarcoma

50–60%.54 Most of the differences in results are dependent on variations in stage presentation and underlying histopathology.

Inferior vena cava Leiomyosarcoma of the inferior vena cava (IVC) is a rare entity. In a 20-year report for the University of California at Los Angeles,56 14 patients were treated with attempted wide resection. As with other sites with visceral sarcoma, the ability to perform complete resection was the primary factor in determining outcome. Adjuvant radiation therapy in this small series appeared to improve median survival. However, this was not a randomized trial. Overall, seven patients have survived for 5 years, similar to the authors’ experience with resection of leiomyosarcomas of different origin. Of interest was the fact that seven patients had an interposition graft placed, while five had primary repair of the IVC, all of which were patent at last follow-up. It is important to emphasize that only patients who actually had a patent IVC at the time of initial exploration were resected, since, unfortunately, a number of patients presented with the IVC already occluded and with extensive collateral circulation. An international registry of IVC leiomyosarcoma has been maintained.57 It is difficult to evaluate outcome in a meaningful sense in these patients, because of the rarity of the disease and the lack of ability to perform prospective studies. In our own experience, since July 1982, we have seen 14 lesions of the IVC, 11 of which have undergone resection.

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48.

49.

50.

51.

52.

53. 54.

55.

56.

57.

Prognostic factors influencing survival in gastrointestinal leiomyosarcomas. Implications for surgical management and staging. Ann Surg 1992;215:68–77, De Matteo RP, Lewis JJ, Leung D et al. Two hundred gastrointestinal stromal tumors – recurrence patterns and prognostic factors of survival. Ann Surg 2000; 231:51–8. Soini Y, Welsh JA, Tshak KG, Bennett WP. P53 mutations in primary hepatic angiosarcomas not associated with vinyl chloride exposure. Carcinogenesis 1995;16:2879–81. Forbes A, Portmann B, Johnson P, Williams R. Hepatic sarcomas in adults: a review of 25 cases. Gut 1987;28:668–74. Vennarecci G, Ismail T, Gunson B, McMaster T. L’angiosarcoma primativo del fegato. Minerva Chir 1997;52:1141–6. Gong MC, Grimaldi G, Brennan MF, Russo P. Sarcoma of the genitourinary tract. Presented at the American Urological Association, San Diego, CA, 1998 (abstract). Russo P, Brady MS, Conlon K et al. Adult urological sarcoma. J Urol 1992;147:1032–7. Knocke TH, Kucera H, Dorfler D et al. Results of postoperative radiotherapy in the treatment of sarcoma of the corpus uteri. Cancer 1998;83:1972–9. Olah KS, Gee H, Blunt S et al. Retrospective analysis of 318 cases of uterine sarcoma. Eur J Cancer 1991;27:1095–9. Hines OJ, Nelson S, Quinones-Baldrich WJ, Eilber FR. Leiomyosarcoma of the inferior vena cava. Prognosis and comparison with leiomyosarcoma of other anatomic sites. Cancer 1999;85:1077–83. Mingoli A, Sapienza P, Cavallaro A et al. The effect of extent of caval resection in the treatment of inferior vena cava leiomyosarcoma. Anticancer Res 1997;17:3877–81.

11 Special techniques

Head and neck Posterior neck resection This 61-year-old male presented with a recurrent 3-cm high-grade fibrosarcoma. It is often easier to position the patient in the lateral position in order to gain full access to the posterior and anterior neck. An incision is made to incorporate resection of the previous biopsy site (Figure 11.1), and is usually

Figure 11.1 Posterior neck resection: an incision is made to incorporate resection of the previous biopsy site.

extended in a transverse direction in order to be oriented within the lines of Langer. This is gauged individually in order to get a tensionfree closure. Flaps are developed superiorly and inferiorly, exposing the underlying tumor and posterior neck muscles (Figure 11.2). The

Figure 11.2 Posterior neck resection: flaps are developed superiorly and inferiorly, exposing the underlying tumor and posterior neck muscles.

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depth of resection is down to the deep layer of the investing fascia (Figure 11.3), with care being taken to identify and preserve the spinal accessory nerve. The wound is then closed cosmetically.

Chest wall resection The patient is a 70-year-old man with a large recurrent desmoid, involving his distal sternotomy incision (Figure 11.4). Considerable pending skin loss is evident, requiring an extensive resection of skin and chest wall. As with other sites, the object is complete surgical resection. If possible, a single normal muscular fascial plane beyond the tumor should be obtained. If skin coverage by rotational flaps is required, the flap must be planned prior to

Figure 11.3 Posterior neck resection: the depth of resection is down to the deep layer of the investing fascia.

resection. An extensive dissection is then performed, removing the lower sternum and adjacent ribs (Figure 11.5). To secure adequate closure and prevent paradoxical movement when the diaphragm is involved, replacement of the defect with marlex mesh has worked well: (1) two pieces of marlex mesh are cut slightly larger than the skeletal defect (Figure 11.6); (2) the methyl methacrylate is mixed until it begins to set; (3) it is then spread with a tongue blade over one layer of the mesh to a size slightly smaller than the defect; (4) steel mesh is added to prevent fragmentation of the hardened methyl methacrylate; (5) the second piece of mesh is pressed into the paste, and the sandwich can then be molded to conform to body contours; and (6) when the sandwich has hardened, the mesh surrounding the methyl methacrylate is sutured to the edge of the defect, preferably to the bony structures. Muscle and skin closures are carried out in routine fashion. This provides excellent coverage of the chest wall defect. Other prosthetics such as polypropelene (prolene) or polytetrafluoroethylene (Gore-tex®) can be

Figure 11.4 Chest wall resection: the patient is a 70-yearold man with a large recurrent desmoid, involving his distal sternotomy incision.

Special techniques utilized. Methylmethacrylate or bone cement can be injected into the sternal marrow space to firmly anchor or re-create the sternum. This prosthesis is radiolucent and does not interfere with subsequent radiologic evaluation.

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The patient is a young woman with a radiation-induced soft tissue tumor. It is uncertain whether it has arisen in bone or is involving bone secondarily to the site of previously irradiated Hodgkin’s disease. The

Clavicular resection Soft tissue tumors rarely involve bone; however, on occasion they can extend to bone, particularly in areas of confined space, such as the base of the neck. In addition, the resection of the clavicle gives excellent exposure to the brachial plexus and subclavian/axillary neurovascular bundle. The morbidity of such a procedure is quite low, and it is certainly a procedure that should be in the armamentarium of every soft tissue tumor surgeon.

Figure 11.5 Chest wall resection: an extensive dissection is performed, removing the lower sternum and adjacent ribs.

Figure 11.6 Chest wall resection: two pieces of marlex mesh are cut slightly larger than the skeletal defect.

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first approach is a linear incision along the margin of the clavicle, extending from the coracoid process to the suprasternal notch (Figure 11.7). The platysma muscle is divided (Figure 11.8) and the bone exposed. The clavicular attachment of pectoralis major is removed, with care being taken not to injure the cephalic vein in the deltopectoral groove unless it is involved. The deltoid muscle is detached from the lateral aspect of the clavicle and the inferior border of the clavicle mobilized. The subclavius muscle is detached from its medial attachment and, depending on the extent of the tumor, the pectoralis minor muscle may need to be detached from the

coracoid process. The neurovascular bundle is clearly identified and, if appropriate, the cephalic vein is divided as it enters into the subclavian vessels, the brachial plexus running superiorly, to begin to embrace the neurovascular bundle. The extent of the more proximal dissection depends on the extent of the tumor. The clavicle can then be disarticulated by entering the sternoclavicular joint medially, and laterally dividing the attachments at the acromioclavicular joint (Figure 11.9). This then completely encompasses and removes the tumor and provides excellent access to the neurovascular bundle and the brachial plexus. The wound is closed cosmetically with drainage.

(a) (b) Figure 11.7 Clavicular resection: the first approach is a linear incision along the margin of the clavicle extending from the coracoid process to the suprasternal notch.

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(a) (b) Figure 11.8 Clavicular resection: the platysma muscle is divided (a), and the bone exposed (b).

(a) (b) Figure 11.9 Clavicular resection: the clavicle can be disarticulated by entering the sternoclavicular joint medially, and laterally dividing the attachments at the acromioclavicular joint.

Breast sarcoma The patient is a 51-year-old woman who developed a spindle cell sarcoma in the right breast approximately 6 cm in size, but occupying the majority of the breast.

Essentially, this will be a total mastectomy. The tumor is identified, the margins are clearly outlined, and standard superior and inferior flaps developed (Figure 11.10). Previous biopsy sites are encompassed, and upper and lower flaps developed (Figure 11.11).

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(a) (b) Figure 11.10 Breast sarcoma: spindle cell sarcoma in the right breast – margins are clearly outlined and standard superior and inferior flaps developed.

Utilization of cautery or sharp dissection with the knife allows access to the anterior aspects of the pectoral muscle superiorly and inferior to the anterior muscle (Figure 11.12). The lesion was sitting deep to the nipple and was encompassed in standard fashion with

wide mobilization of the flaps, and essentially a simple mastectomy was performed (Figure 11.13). Axillary lymph nodes were not dissected, but the axillary tail was completely taken with the specimen. Primary closure was obtained.

(a) (b) Figure 11.11 Breast sarcoma: previous biopsy sites are encompassed and upper and lower flaps developed.

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(a) (b) Figure 11.12 Breast sarcoma: utilization of cautery or sharp dissection with the knife allows access to the anterior aspects of the pectoral muscle superiorly and inferior to the anterior muscle.

(b) (a) Figure 11.13 Breast sarcoma: the lesion was sitting deep to the nipple and was encompassed in standard fashion with wide mobilization of the flaps, and essentially a simple mastectomy was performed.

Abdominal wall A 58-year-old patient underwent a total abdominal hysterectomy and bilateral salpingooopherectomy for a moderately differentiated adenocarcinoma of the cervix 10 years earlier. This was followed by external beam radiation therapy. Within the last several months, she noted a mass in the lower abdominal wall. This was incised as an infection, only to reveal a

draining sinus. This persisted until she presented with a 5×3 × 2 cm mass consistent with a radiation induced sarcoma. This was excised en bloc (Figure 11.14), taking the anterior fascia of the abdominal wall, and then with wide local margins primary closure was subsequently obtained (Figure 11.15). Synthetic reconstruction was avoided, and a reinforcing layer of absorbable mesh was placed deep to the abdominal wall fascia.

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Figure 11.14 Abdominal wall: a recurrent mass, with central draining sinus, was excised en bloc taking the anterior fascia of the abdominal wall.

Figure 11.15 Abdominal wall: the excised specimen.

Resection of posterior back

removed (Figure 11.20). Often this fascial plane is not invaded and the main spinal musculature can be preserved. Once that is encompassed, then hemostasis can be ensured, drains placed, and the incision closed cosmetically.

The patient has a large posterior back tumor sitting in the paraspinal musculature. A long linear incision is placed (Figure 11.16), encompassing the previous biopsy site, and medial and lateral flaps developed to the palpated spinal processes and portions of trapezius muscles resected (Figure 11.17). The attachments of the trapezius medially to the spine are divided and the tumor can be completely encompassed (Figure 11.18). Deep to the trapezius muscle, the rhomboideus minor and major need to be resected and detached from the medial border of the scapula (Figure 11.19). Once those are divided, access to the true paraspinal musculature is identified and those portions of involved muscle, including medially the spinalis and laterally the longissimus, are resected. These all lie deep to the lumbodorsal fascia and deep to the rhomboids and the serratus, and the tumor is

Retroperitoneal soft tissue sarcoma This 37-year-old woman presented with an asymptomatic large left upper quadrant lesion involving the superior pole of the kidney, which raises the question of whether a primary renal neoplasm or adrenocortical neoplasm or primary sarcoma is the definitive histopathology. Splenic ilium is involved; attachment to the diaphragm is suspected (Figure 11.21). Close juxtaposition of the left lateral segment of the liver is also seen (Figure 11.22). The operative procedure requires access to the left upper quadrant, where attachment to the diaphragm is identified and a large

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(a) (b) Figure 11.16 (a,b) resection of posterior back: a long linear incision is placed, encompassing the previous biopsy

(a) (b) Figure 11.17 (a,b) resection of posterior back: medial lateral flaps are developed to the palpated spinal processes and portions of trapezius muscles resected.

(a) (b) Figure 11.18 (a,b) resection of posterior back: the attachments of the trapezius medially to the spine are divided and the tumor can be completely encompassed.

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Figure 11.19 Resection of posterior back: deep to the trapezius muscle, the rhomboideus minor and major need to be resected and detached from the medial border of the scapula.

Figure 11.20 Resection of posterior back: the excised specimen.

resection involving the spleen, kidney, central portion of the diaphragm and adrenal is required (Figures 11.23 and 11.24). The costal margin is elevated, and the abdomen is opened, with identification of the tumor extending above the spleen and across to the edge of the

liver. Figure 11.25 shows elevation of the pancreas, with the pancreatic tail up and off the tumor, and with division of the proximal splenic artery and vein. Resection of the diaphragm allows access so as to completely encompass the tumor after ligation of the renal

Figure 11.21 Retroperitoneal soft tissue sarcoma: splenic ilium is involved: attachment to the diaphragm is suspected.

Figure 11.22 Retroperitoneal soft tissue sarcoma: close juxtaposition of the left lateral segment of the liver is also seen.

Special techniques

Figure 11.23 Retroperitoneal soft tissue sarcoma: resection includes the diaphragm.

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Figure 11.24 Retroperitoneal soft tissue sarcoma: a large resection involving the spleen, kidney, central portion of the diaphragm and adrenal is required.

or

Figure 11.25 Retroperitoneal soft tissue sarcoma: elevation of the pancreas, with the pancreatic tail up and off the tumor, and with division of the proximal splenic artery and vein.

Figure 11.26 Retroperitoneal soft tissue sarcoma: reconstruction of the diaphragm by Gore-tex® (PTPE) mesh is obtained prior to closure. Insert shows alternative incisions.

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(b)

(d)

(c) Figure 11.27 Retroperitoneal liposarcoma: massive recurrent dedifferentiated liposarcoma invading into the iliac bone. (a) mass, outlined by dotted line, proposed incision; (b) MRI showing bone invasion; (c) showing resection with preservation of iliac vessels and ureter; (d) specimen.

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artery vessels. The specimen is removed. Reconstruction of the diaphragm by Gore-tex® mesh is obtained prior to closure, and Figure 11.26 shows the reconstructed diaphragm.

Retroperitoneal liposarcoma A similar example shows a massive recurrent dedifferentiated liposarcoma invading into the iliac bone (Figure 11.27). Bone invasion is rarely seen in low-grade liposarcoma, and usually reflects either dedifferentiation or previous periosteal resection. A further example of how large a low-grade sarcoma can grow before becoming symptomatic is shown in Figure 11.28.

(a)

Right lower quadrant retroperitoneal tumor As with all retroperitoneal tumors, it is important that the patient undergo a thorough bowel preparation preoperatively. In addition, it is important to document bilateral renal function on CT nephrogram so that, if indicated, one of the kidneys can be removed in contiguity with the en bloc resection. The overwhelming majority of retroperitoneal tumors should be approached through a midline abdominal laparotomy incision. The patient is therefore positioned supine. After entering the abdomen, exploration should validify the preoperative findings and confirm resectability. This includes an examination of the liver and remainder of the retroperitoneum and peritoneum in order to exclude metastatic disease. Once this is done, the tumor can be assessed in terms of its resectability. This often requires mobilization of surrounding structures in order to get a sense of resectability.

(b)

(c) Figure 11.28 Retroperitoneal liposarcoma: (a) CT scan showing renal vascular encasement; (b) operative view; (c) specimen.

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In the right lower quadrant, this often includes mobilization of the right colon and distal small bowel. Any components of the bowel that are directly involved with or close to the tumor should be resected. After mobilization of these structures, ureter and kidney are identified and again, in a sense, assessed in terms of the relationship of the tumor to the ureter. It is often possible to dissect the tumor away from the ureter, but again, if it is directly involved with ureter or kidney, and in the presence of normal contralateral function, an en bloc resection of the ureter and kidney should be done. The pelvic component of the tumor is next dissected, and frequently the most dangerous component of the operation is dissection of the pelvic sidewall veins. There are many different ways of performing this, and this is usually determined by the relationship of the tumor to the surrounding pelvic visceral and sidewall structures. It is often easiest to identify the artery first, as this is usually palpable. The artery is also usually much easier to dissect, and this is done in the adventitial plane. Having identified the artery, the veins are then identified under direct vision. The anatomic relationships are often distorted by the tumor, necessitating meticulous attention to detail and an understanding of the three-dimensional relationships. In this patient, the right common iliac, external and internal iliac vessels were pushed towards the midline, and even the left side of the patient. All these structures were dissected under direct vision, with great care being taken to expose all structures as much as possible. Right lower quadrant tumors are often related to the lumbosacral plexus. It is again important to take this into account when dissecting posteriorly, especially in and around the posterior attachments of the psoas and iliacus muscles. It is usually easier to dissect

these structures under direct vision, but with large tumors, as in this example, it is frequently very difficult. It is therefore important, again, to have a three-dimensional sense of the anatomy, in particular given that it may be distorted by the tumor. Thus, the plan of dissection posteriorly may involve partial muscle resection, with careful attention to preservation of the lumbosacral nerves when appropriate.

Visceral sarcoma The patient is a 40-year-old man who presented with an acute episode of abdominal pain and was shown to have, by CT, hemorrhage in a recurrent gastrointestinal stromal tumor (Figure 11.29). Because of an ascites on his initial CT scan, laparoscopy was performed first to exclude the possibility of disseminated disease. However, none was found. We proceeded through a long midline incision to mobilize the right colon, enter into the lesser sac, take the omentum with the lesion, and then, with a GIA stapler, resect with negative margins the lesion from the mid-stomach. Apart from a somewhat reduced gastric remnant, the complete resection subsequently resulted in excellent nutritional status.

Algorithm for the management of visceral sarcoma Patients usually present with abdominal pain or with the feeling of an abdominal mass. Once the diagnosis is suspected, CT scan is usually the examination of choice. CT scan should focus on the site of the origin of the tumor, the most common being the stomach. In addition, the most common site of

Special techniques

(a)

(b)

(c)

(d)

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Figure 11.29 Visceral sarcoma: (a) CT of hemorrhage in a recurrent gastrointestinal stromal tumor; (b) mass outlined; (c) operative appearance; (d) histopathology.

metastasis, i.e. the liver, can be evaluated on the scan. Pulmonary metastasis is far less common and usually occurs only in the presence of established extensive intraabdominal disease. For patients who have undergone rupture prior to presentation, multiple sites of intra-abdominal recurrence should be expected. The primary operation is designed to completely resect the tumor. Investigational approaches are reserved for the incompletely resected, or for those with

residual microscopic disease. In some situations, high-risk patients (patients with tumors >10 cm and central necrosis) can be considered for intraperitoneal therapy as an adjuvant but this is far from being established. Current studies focus on the value of a new drug (STI-571, Gleevec®) as an adjuvant to resection for those GIST that express c-kit protooncogene.

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Upper extremity Axilla A 27-year-old female developed a mass 8 months earlier. She sought medical attention 5 months prior to referral, at which time an 8 × 7 cm mass was discovered, and 2 months later she was seen with a 10 × 10 cm mass involving the subscapularis infraspinatus, the proximal biceps and coracobrachialis muscles. A biopsy was consistent with a high-grade synovial cell sarcoma, which was 8 ×12 cm by the time of presentation (Figure 11.31). She did not respond to three courses of mesna, doxorubicin, ifosfamide, dacarbazine (MAID) chemotherapy and was referred for operation. An extensive multiloculated lesion was resected, including the portion of skin beneath the original biopsy with a skeletonization of the axillary neurovascular bundle. The lesion was completely excised. A nodular excrescence was clearly identified. Afterloading catheters were placed for brachytherapy and primary closure was obtained (Figure 11.32).

Figure 11.30 Axilla: the tumor was a high-grade synovial cell sarcoma, 8 ×12 cm.

Upper arm The patient is positioned supine and the arm prepped with a free drape. It is important to understand the neurovascular relationships prior to operation, and to have a good sense of where these structures are in terms of distortion by the tumor. An incision is made to incorporate sites of previous biopsy, and flaps are raised in the usual fashion (Figure 11.33). In this particular example, the tumor is within the biceps and brachialis muscles. Complete mobilization is done in two planes and the muscles are divided proximally and distally. It is usually easiest to identify the neurovascular bundle by palpation of the brachial artery. The brachial artery starts as a continuation of the axillary artery at the border of teres major. The distal extent of the artery is usually palpable within the antecubital fossa. Once the artery is identified, the surrounding nerves can be dissected. These are usually easily visible, but should there be any doubt, a nerve stimulator is useful to confirm the presence of nerves. When dissecting around the nerve, care

Figure 11.31 Axilla: afterloading catheters were placed for brachytherapy and primary closure was obtained.

Special techniques

Figure 11.32 Upper arm: an incision is made to incorporate sites of previous biopsy, and flaps are raised in the usual fashion.

should be taken and monopolar diathermy coagulation used. Figure 11.33 illustrates the formation of the median, ulnar and radial nerves around the brachial artery. It is very unusual for sarcoma to invade into the neurovascular bundle, and, provided one follows the plane of the adventitia, the margin is usually microscopically negative.

Forearm The patient is positioned with the arm free draped and on an arm board. It is important to understand the anatomic relationship of the underlying neurovascular structures. An incision is made in the longitudinal axis. Flaps are developed around the tumor, taking care to be aware of where the ulnar nerve courses. The ulnar nerve is identified as it curves around the medial epichondyle. Dissection is continued in all three dimensions, down to the level of the interosseous membrane. The tumor is removed

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Figure 11.33 Upper arm: the formation of the median, ulnar and radial nerves around the brachial artery.

en bloc, and drains are brought out distally. The wound is closed in a layered fashion, making sure that there is no tension on the skin edges.

Lower extremity Gluteal/buttock

(Figure 11.34)

The patient is positioned either prone or semiprone. It is important to have a clear definition of the bony landmarks, including the sacrum, coccyx, iliac crest, anterior/superior iliac spine and trochanter of the femur. The direction of incision is frequently within the lines of Langer. This should be done to include removal of the sites of previous biopsy. The layer of fat is variable, and the plane for development of a flap should be within the superficial fascia, then entering in a subcutaneous flap. Flaps are developed in superior and inferior directions to extend at least 2 cm beyond the palpable edge of the tumor. The sciatic nerve courses through the gluteal region medially. Complete

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(a)

(b)

(c)

(d)

Figure 11.34 Buttock: a large buttock lesion: (a) oblique incision; (b) MRI showing extent of gluteal involvement; (c) excised specimen; (d) histopathology of high grade sarcoma. mobilization is done away from the nerve, and the gluteus maximus muscle divided by diathermy down to a level below the deepest point of the palpable edge of the tumor. Mobilization is completed in both side-to-side and superior/inferior directions. Again, 2-cm margins of normal muscle and soft tissue are taken around the palpable edge of the tumor. A suction drain is placed and brought out in a lateral direction and the wound closed in the usual fashion.

Posterior thigh

(Figure 11.35)

An incision is marked out to incorporate resection of the site of previous biopsy and oriented in a longitudinal fashion (Figure 11.36). Depicted in this figure is the extent of the tumor, marked by dotted lines. It is useful to conceptualize the three-dimensionality of the tumor, two dimensions showing here in the north–south and east–west axes. Flaps are then developed in each of these axes. This is shown in

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Extent of skin flaps

Skin incision Previous biopsy site

Figure 11.35 Posterior thigh: an 8-cm high-grade malignant fibrous histiocytoma of the distal posterior thigh.

Figure 11.36 Posterior thigh: an incision is marked out to incorporate resection of the site of previous biopsy and oriented in a longitudinal fashion.

Figure 11.37. Dissection of flaps is always aided by traction with skin hooks at 90° to the plane of dissection. This tumor wrapped around the distal thigh neurovascular structures. It is usually easiest to identify the artery by palpation. In order to identify the distal

superficial femoral artery, the soft loose areola tissue of the Hunterian canal is dissected (Figure 11.38). The artery and vein are encircled with vessel loops, and dissection is performed on the plane of the adventitia of both vessels. In order to fully mobilize these vessels, several branches

Figure 11.37 Posterior thigh: flaps are then developed in each of these axes.

Figure 11.38 Posterior thigh: the soft loose areola tissue of the Hunterian canal is dissected, to identify the distal femoral, proximal popliteal artery.

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and tributaries are divided. As this is done, the deep attachments of the tumor are loosened and dissection continued in a side-to-side fashion. Having identified the artery and vein, the sciatic nerve and its branches into the posterior tibula and peroneal nerve are next identified. The plane of dissection is on the peripheral nerve areola connective tissue. The third dimension of resection, the deep margin, is effected by completely exposing the entire length of the nerve (Figure 11.39). Once this is done, the specimen is removed en bloc, exposing the underlying neurovascular bundle.

Proximal medial thigh

Figure 11.40 Proximal medial thigh: coronal MRI showing a massive tumor in the medial compartment of the right thigh. Note proximal extension through the obturator foramen.

This massive tumor was in the medial thigh compartment, extending from the femoral neurovascular bundle anteriorly to the sciatic nerve posteriorly (Figures 11.40 and 11.41). The tumor extended through the obturator foramen proximally. The patient is positioned supine with the abdomen, pelvis and perineum prepped. The thigh and leg are placed in a free

Figure 11.39 Posterior thigh: the third dimension of resection, the deep margin, is effected by completely exposing the entire length of the nerve, artery and vein.

Figure 11.41 Proximal medial thigh: tumor extends from the femoral neurovascular bundle anteriorly to the sciatic nerve posteriorly.

Special techniques drape. An incision is made in the longitudinal axis to incorporate resection of the previous site of biopsy. Flaps are dissected in the subcutaneous plane in order to extend beyond the tumor margin. Again, a 2-cm margin is ideal. It is crucial to visualize the course of the femoral neurovascular bundle while doing the dissection. The easiest way of doing this is to palpate the artery at the midfemoral point and visualize the superficial femoral artery running towards the abductor tubercle. While doing the dissection, it is important to frequently palpate for the arterial pulse at the anterior extent of the dissection. This is usually straightforward, and the anterior extent of dissection can be safely done in terms of preserving the artery, nerve and vein. When the tumor is close to the artery, it is often technically easier to dissect along the plane of the adventitia. The same applies to the vein. Posteriorly, it may be difficult to visualize the sciatic nerve. It is useful to do this component of the dissection without muscle relaxation. The reason for this is that one can use either a nerve stimulator or get a sense from the electrocautery of nerve conduction. Once the nerve is identified, it is usually straightforward to dissect in a plane that is away from the nerve. The medial extent of dissection is often along the femur. It is unusual for any soft tissue sarcoma to invade through the periosteum, and every attempt should be made to preserve this in order to reduce the risk of fracture in patients who will be receiving adjuvant radiation. Once the tumor is completely encompassed, it is removed en bloc. Primary closure can virtually always be obtained. The same principles of drain placement apply as for other extremity lesions.

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Lateral leg/knee The patient is positioned supine with a free leg drape. An incision is marked out in a longitudinal axis, incorporating the site of previous biopsy (Figure 11.42). Flaps are dissected in the subcutaneous plane, in order to extend 2–3 cm beyond the palpable area of tumor (Figure 11.43). There is no palpable artery within the lateral compartment, and it is easy to identify the peroneal nerve through bony landmarks at the knee. Thus, the nerve can usually be easily identified as it curves around the neck of the fibula (Figure 11.44). If possible, the nerve should be preserved; however, it may be sacrificed with good functional recovery. Similarly, the peroneal muscles can be resected again with good functional recovery. The depth of resection may include complete removal of all the lateral compartment muscles. Thus, after complete en bloc removal, the muscles of the anterior and posterior compartment, together with the fibula, are visible. Despite loss of some eversion of the foot, the functional recovery in these patients is usually excellent.

Figure 11.42 Lateral leg: an incision is marked out in a longitudinal axis, incorporating the site of previous biopsy.

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Figure 11.43 Lateral leg: flaps are dissected in the subcutaneous plane, in order to extend 2–3 cm beyond the palpable area of tumor.

Figure 11.44 Lateral leg: the peroneal nerve can usually be easily identified as it curves around the neck of the fibula.

Forequarter amputation Forequarter amputation, a mutilating and disabling operation, is used less and less in modern sarcoma surgery. However, there are still occasions when the procedure is appropriate, e.g. when the patient presents with a disabling local problem without metastatic disease (Figure 11.45). The primary goal of the operation, where possible, is early vascular control to minimize blood loss and allow the procedure to proceed satisfactorily. The only exception is when the tissue of the amputated forearm is to be used for the coverage of the extensive primary lesion.

Technique The patient is positioned, usually on an inflatable air mattress angled at 45º to the

Figure 11.45 Forequarter amputation: massive proximal recurrent sarcoma involving the neurovascular bundle.

operating table, with the arm prepped free and the chest draped beyond the midline to the base of the hairline to the mandible and below the inframammary crease. The majority of patients will have a coverage flap based on the skin over the deltoid. Any prior biopsy sites are included

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in the amputation site, and the flap will be modified according to the site of the primary tumor. On occasions, the flap has to be based on the medial aspect of the inner upper arm to cover lesions at the base of the neck. We like to commence the anterior incision at the sternoclavicular joint, and then extend along the clavicle, and out over the deltoid musculature, to outline the flap (Figure 11.46). The incision then comes back to the posterior axillary fold, and down into the axilla, and is angled appropriately to encompass any prior incisions. Anteriorly, (Figure 11.47) the incision extends above the breast line to the sternoclavicular joint. We prefer to start the incision anteriorly, mobilizing the medial flap and dissecting down to the sternoclavicular joint or just lateral to it. On occasions, it is simpler either to divide the clavicle, leaving the medial onethird, with a Gigli saw, or to divide the pectoralis major along the anterior chest wall, usually as far medial as the sternum, adjusting as appropriate. More lateral division can be maintained, particularly in retaining the contour of the female breast. The pectoralis minor muscle is exposed and detached, the sternocleidomastoid divided at the medial end of the clavicle, and the

sternoclavicular joint opened if the mid-third of the clavicle is not to be divided. In either event, it is important to clearly identify the axillary artery and vein. The division is made lateral to the innominate vessels. The artery is isolated with care, coming from beyond the scalenus anticus muscle to preserve the phrenic nerve. Cords of the brachial plexus are clearly identified at this site. Where there is no contraindication, ligation of the artery, and, subsequently, the vein, with suture ligation, is then achieved. This gives vascular control for the remainder of the procedure. All tissue can then be swept to the axilla and the posterior flap developed. This is usually accomplished by the assistant mobilizing and rotating the arm forward, such that the posterior flap can be enveloped, and the trapezius muscle detached. The latissimus dorsi is divided inferiorly, including its attachment to the inferior border of the scapula. The medial musculature, the levator scapulae and rhomboid muscles along with the accessory vessels are then divided. The flap is then elevated upward and forward. With this detachment completed inferiorly, the amputation can be completed. The flap is then mobilized to give appropriate coverage.

Figure 11.46 Forequarter amputation: posterior incision.

Figure 11.47 Forequarter amputation: anterior incision.

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Hindquarter amputation

Technique

Hindquarter amputation is a major procedure with a number of variations, including anterior flap hemipelvectomy, posterior flap hemipelvectomy, extended hemipelvectomy with sacral resection, limited hemipelvectomy with preservation of the iliac wing, and hip disarticulation. One of the early proponents of this operation was Dr George Pack of MSKCC, who reviewed his experience in 1956.1 With the advent of limb-sparing surgery, hindquarter amputation is less and less indicated. Major indications for this operation are based on the anatomic site of the sarcoma, involving extensive lesions with neurovascular encasement, or bone invasion that prevents a lesser procedure. If the lesion is confined to the proximal thigh, hip disarticulation is occasionally an alternative. In the main, however, if a tumor is so proximally situated that hip disarticulation can be considered, hemipelvectomy would prove to be a more satisfactory operation.

The patient is positioned with the pelvis elevated at a 45º angle to the operating room table, usually with the advantage of an inflatable pneumatic mattress. A foley catheter is in place and a suture is placed in the anus. The scrotum is sutured to the contralateral side, and the leg is prepped and draped completely free to allow full mobilization. Incision is usually commenced just above the inguinal ligament from the pubic tubercle to just above the iliac crest (Figure 11.48). This allows early assessment of the retroperitoneum, with regard to the proximal extent and suitability for resection of tumors. The posterior flap is extended down over the buttock, and we prefer initially to make this flap longer than may appear necessary, so as to gauge blood supply and to allow adequate tension-free coverage (Figure 11.49). Medially, the incision extends along the lateral margin of the scrotum and then into the groin crease, and superiorly and medially to the symphysis pubis.

Figure 11.48 Hindquarter amputation: incision is usually commenced just above the inguinal ligament from the pubic tubercle to just above the iliac crest.

Figure 11.49 Hindquarter amputation: the posterior flap is extended down over the buttock, and we prefer initially to make this flap longer than may appear necessary.

Special techniques

233

Figure 11.50 Hindquarter amputation: closure is completed by uniting the large posterior flap to the abdominal wall.

Figure 11.51 Hindquarter amputation: we employ suction drainage to avoid any hematoma.

Anteriorly, the inguinal ligament is detached and divided, the rectus abdominis is divided and the retroperitoneum is entered. The spermatic cord is preserved from harm, unless involved by tumor. The common iliac artery is identified, the ureter preserved from harm, and ligatures placed to encompass the vessels which are ligated and divided. Rarely, it may be appropriate to divide the external iliac vessel just distal to the internal iliac. Care should always be taken to avoid injury to the superior gluteal vessel as it passes through the iliac notch. The psoas muscle is then divided above the vessel transection down to the sacroiliac joint. The posterior flap is then developed, down to the overlying gluteus maximus, extended as far posterior on the sacrum as is necessary to allow separation of the gluteus from the sacrum. The gluteus is detached from the sacrum to identify the pyriformis muscle, gemelli, sacrotuberous ligament and sciatic nerve. We then divide the symphysis pubis sharply with a knife. If the knife does not enter

freely into the symphysis pubis, then the pubis can be divided with a Gigli saw. In the male, care must be taken not to damage the prostatic venous plexus, which can cause considerable hemorrhage. With the pubis divided, the entire hemipelvis can be rotated, opening clearly the anterior aspect of the sacroiliac joint. This, too, can be divided with a knife unless an extended resection is required. Medially, the attachments of the levators are divided and the entire extremity is removed. Closure is completed by uniting the large posterior flap to the abdominal wall (Figure 11.50). We employ suction drainage to avoid any hematoma (Figure 11.51).

Extended hemipelvectomy On occasion, if the tumor involves bone and extends into the sacroiliac joint, then the sacral division is beyond the sacroiliac joint, and with a chisel the sacrum is taken through the sacral foramina.

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Diagnosis and Management of Soft Tissue Sarcoma

Anterior flap hemipelvectomy If the lesion is posteriorly situated, this involves a long anterior flap with ligation of the femoral artery and nerve distally in the thigh with the flap mobilized, with the femoral vessels as the base of the flap, elevating it from all tissues deeply. Posteriorly, the flap can be extended as high as is appropriate on the sacroiliac crest.

Hip disarticulation This operation is progressively becoming less common for soft tissue tumors. Essentially it involves an incision similar to that for hemipelvectomy, placed 4–7 cm more distally. The anterior femoral vessels are ligated and divided, as is the femoral nerve. This operation is much simpler, requiring detachment of the muscles from their attachments to the pelvis,

with similar extension posteriorly to divide the gluteal muscles at the level of the skin incision coming down just onto the greater tuberosity. All the median muscles can then be divided, including the gluteus medius, piriformis and gemelli. Posteriorly, the sciatic nerve is sharply divided. Liberal use of rotation of the hip will make this procedure quite simple. The head of the femur is easily dislocated from the acetabulum, and the round ligament divided. Primary closure of muscle to muscle can be obtained, and skin sutures over suction drains appropriately placed.

References 1. Pack GT. Major XR articulations for malignant neoplasms of the extremities: Interscapulothoracic amputation, hip joint disarticulation, and interileoabdominal amputation. J Bone Joint Surg 1956;38:249–62.

12 Treatment of recurrence

Extremity soft tissue sarcoma Failure to obtain microscopically negative resection margins during surgery precedes high rates of local failure, or recurrence, at the primary resection site.1 Moreover, re-excision of persistent disease may not be feasible, because of tumor size or anatomic location. While, historically, amputation was expected to translate into survival advantage by eliminating positive margins, a randomized, prospective trial at the National Cancer Institute2 found no difference in diseasespecific survival between limb-sparing surgery and amputation. For the past 20 years, limbsparing surgery has been the treatment of choice at MSKCC (Figure 8.10). Although adjuvant radiation therapy has been shown to improve local control over surgery alone, this has not resulted in improved survival. At MSKCC, in a prospective trial, 126 patients with completely resected extremities and superficial trunk sarcomas were randomized to receive adjuvant brachytherapy or no further therapy. The local recurrence rate in the group receiving adjuvant brachytherapy was 18%, compared with 33% in the group receiving no further therapy, and after 5 years there was no difference in the rate of distant metastases or disease-specific survival.3

In a study of 911 patients with extremity soft tissue sarcoma from MSKCC, factors predictive of local recurrence, metastasis and survival were analyzed.4 Independent predictive risk factors for local recurrence were age >60 years, upper extremity, leiomyosarcoma subtype, and positive microscopic margins. By multivariate analysis, positive microscopic margins were the significant factor for the development of local recurrence (Table 12.1). Patients with high-grade or deep location extremity lesions were more likely to develop systemic disease. The lung was the site of metastasis in 38 patients who developed systemic disease. Unfavorable predictors of disease-specific survival after local recurrence were size >5 cm, high-grade histology, deep location, leiomyosarcoma or fibrosarcoma subtypes, and positive margins (Table 12.2).

Retroperitoneal soft tissue sarcoma For patients with retroperitoneal soft tissue sarcoma, there is a direct relationship between local recurrence and tumor mortality.1 Surgical resection of retroperitoneal soft tissue sarcoma is often difficult because of the anatomic location and frequent invasion of multiple contiguous structures. Moreover,

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Diagnosis and Management of Soft Tissue Sarcoma

Table 12.1 Analysis of local recurrence (n=116) in primary extremity soft tissue sarcoma patients. Variable Age *60 years Female sex Size 5–10 cm Size >10 cm Deep location Upper extremity site Liposarcoma MFH Synovial sarcoma Fibrosarcoma Leiomyosarcoma MPNT Positive microscopic margins

Univariate P value

Cox model P value

Relative risk

Confidence interval

0.0001 0.74 0.29 0.87 0.45 0.0013 0.32 0.70 0.13 0.21 0.02 0.26 0.0036

0.0001

1.02

1.011–1.034

0.018

0.25

0.080–0.79

0.019

1.6

1.1–2.5

MFH, malignant fibrous histiocytoma; MPNT, malignant peripheral nerve tumor. From Lewis et al.4

Table 12.2 Analysis of disease-specific survival (n=34) in primary extremity soft tissue sarcoma patients who had local recurrence. Variable Age *60 years Female sex Size 5–10 cm Size >10 cm High grade Deep location Upper extremity site Liposarcoma MFH Synovial sarcoma Fibrosarcoma Leiomyosarcoma MPNT Positive microscopic margins

Univariate P value 0.8 0.9 0.01 0.07 0.004 0.04 0.7 0.5 0.2 0.5 0.02 0.02 0.02 0.4

Cox model P value

Relative risk

Confidence interval

0.01

3.2

1.2–8.4

0.007

3.7

1.4–9.5

MFH, malignant fibrous histiocytoma; MPNT, malignant peripheral nerve tumor. From Lewis et al.4

Treatment of recurrence current chemotherapy is not effective, and radiation is limited by organ toxicity. Complete surgical resection is the most effective treatment for patients with both primary and recurrent disease. The MSKCC study of 500 patients with primary or recurrent retroperitoneal sarcoma has been cited previously5 (Table 12.3). Histologic grade and liposarcoma subtype were predictive factors for local recurrence.

237

Disease-specific survival after the first local recurrence was similar to that of patients initially presenting with local recurrence. Only 231 of the 500 patients had resectable disease at presentation, and complete resection was a significant factor in predicting survival after local recurrence. Unresectable disease, incomplete resection and high-grade histology were significant for disease-specific death, by both univariate and multivariate analysis.

Table 12.3 Analysis of local recurrence-free survival in 231 primary retroperitoneal soft tissue sarcoma patients with resectable disease. Variable Sex Male Female Age >50 years <50 years Grade High Low Size >10cm )10cm Histological subtype Liposarcoma Others Leiomyosarcoma Fibrosarcoma Surgical resection margins Negative microscopic and gross margins Positive microscopic and negative gross margins Positive microscopic and gross margins aUnivariate

N

P valuea (univariate)

P value (multivariate)

Relative riskb(CI)

0.01

2.0 (1.2–3.4)

0.01

2.6 (1.5–4.6)

0.06 140 91 0.9 156 75 0.05 134 97 0.07 170 59 0.02 109 58 48 16 0.2 136 49 46

P refers to log-rank test of no difference versus any difference between categories. risk to other categories of same factor. CI, confidence interval. From Lewis et al.5 bRelative

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Diagnosis and Management of Soft Tissue Sarcoma

Local recurrence differences between extremity and retroperitoneal sarcomas Control of local recurrence after resection of extremity soft tissue sarcoma can be accomplished surgically, with or without adjuvant radiation, and tumor mortality is almost always a consequence of systemic disease. Most patients who die of retroperitoneal sarcoma die of local recurrence, in the absence of metastasis (Figure 12.1). The difference in tumor mortality in extremity soft tissue sarcoma compared with retroperitoneal soft tissue sarcoma depends on both anatomic location and tumor biology.

Management of metastatic disease It is important to differentiate sites of metastatic disease of soft tissue sarcoma: the site may be pulmonary only, isolated, solitary other metastasis (usually soft tissue), or multiple sites of metastasis.

Associated Extremity STS

Local recurrence

Death

Retroperitoneal STS

Local recurrence

Death

Figure 12.1 The biological significance of local recurrence in extremity versus retroperitoneal soft tissue sarcoma (STS). From Espat and Lewis.1

Pulmonary-only lesions For pulmonary-only lesions, all previous studies have suggested a benefit of pulmonary resection6–11 (Table 12.4). Median survival is approximately 2 years, and 20–30% of patients can be expected to survive for 3 years. It is important to emphasize, however, that not all patients with apparent pulmonary-only metastasis are resectable. In a review from MSKCC12 of a total of 716 patients with primary extremity soft tissue sarcoma, 135, or 19%, developed isolated pulmonary metastasis. Of these, 23 (17%) had locally recurrent resectable disease, while 112 (83%) had isolated pulmonary metastatic disease. Fourteen of the 112 previously had a local recurrence prior to the development of pulmonary metastasis, that is, 31% presented with synchronous pulmonary metastasis and 69% metachronous. The median disease interval between treatment of the primary tumor and the development of metachronous pulmonary metastasis was 14 months (range 1–152 months). In 72% of patients who developed metachronous pulmonary metastasis, it occurred within the first 2 years after treatment of the primary tumor. In 20% it developed between years 2 and 5, and in 6% beyond 5 years. We have seen only one patient who developed a pulmonary metastasis more than 10 years after primary tumor management. The most common histopathologic types in patients developing pulmonary metastatic disease are liposarcoma, malignant fibrous histiocytoma and synovial sarcoma. It is clear, however (Table 12.5), that the risk of developing pulmonary metastasis is greater in synovial sarcoma than in liposarcoma, although more patients present initially with a primary diagnosis of liposarcoma. It is of interest that patients with liposarcoma are the group least likely to be completely resectable.

Treatment of recurrence

239

Table 12.4 Reports of survival after complete resection of pulmonary metastases from adult soft tissue sarcoma. Author (years) Creagan (1950–76)8

No. of No. of patients extremity sites

No. with No. with pulmonary surgical metastases treatment

112

NS

112

112

Putnam/Roth (1974–82)9,10 487

52

93

68

Casson (1981–85)7

68

45

68

68

Jablons (1982–87)11

74

58

57

57

Verazin (1970–86)6

78

51

78

716

716

135

MSKCC (1983–90)12

No. with complete resection 64 (57%) 51 (75%) 58 (85%) 49 (86%) 61 (78%) 65 (83%)

78

Median 3-year survival survival (months) (%) 18a

0a

23

32

25

42

27

35

21

21.5b

19

23

NS, not stated in text. aOverall. bFive-year survival. From Gadd et al.12

Table 12.5 Soft tissue extremity sarcomas: histologic type in 716 adult patients (MSKCC 1983–90) and 135 patients with pulmonary metastases. Histologic type

Overall

Liposarcoma Malignant fibrous histiocytoma Tendosynovial sarcoma Leiomyosarcoma Malignant peripheral nerve tumor Rhabdomyosarcoma Extraskeletal chondrosarcoma Fibrosarcoma Angiosarcoma Spindle cell sarcoma Extraskeletal osteosarcoma Hemangiopericytoma Alveolar soft part sarcoma

213 184 103 53 44 30 23 20 16 14 8 4 4

Values are no. (%). From Gadd et al.12

(30) (26) (14) (7) (6) (4) (3) (3) (2) (2) (1) (1) (1)

With pulmonary metastases 25 36 30 7 7 9 3 1 4 9 4 0 0

(18) (27) (22) (5) (5) (5) (2) (1) (3) (7) (3)

p value 0.002 0.86 0.006 0.36 0.75 0.18 0.18 0.07 0.19 <0.001 0.04 0.43 0.43

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Diagnosis and Management of Soft Tissue Sarcoma

Fifty-eight per cent of patients presenting with pulmonary-only metastasis at MSKCC were considered surgically resectable. Of 73 patients operated on, 83% had completely resectable disease, thus, the predictability of the probability of complete resection is quite high.

Survival after resection For pulmonary-only lesions, only complete resection is of value in changing survival. This is consistent with experience in other metastatic sites (Figure 12.2), with no long-term survivors of incomplete resection of pulmonary metastasis.

Treatment Complete resection n=65 Incomplete resection n=13 Non-surgical therapy n=38

Proportion surviving

1 0.8

Adjuvant therapy following resectable disease In patients with resectable disease, adjuvant therapy should be considered because of the high probability of subsequent recurrence, but is not of proven benefit. Current studies involve isolated lung perfusion and adjuvant trials, usually of immunotherapeutic agents (see below).

Management of other isolated sources of metastasis Hepatic metastasis

0.6 0.4 0.2 0 0

24

48 72 Time (months)

96

120 p=0.005

Figure 12.2 For pulmonary-only lesions, only complete resection is of value in changing survival. From Gadd et al.12

While the liver is a relatively uncommon site overall for patients with soft tissue sarcoma, it is the second site to lung in overall metastatic sites.13 The majority of hepatic metastases from soft tissue sarcoma will be gastrointestinal stromal tumors, and, rarely, angiosarcoma and rhabdomyosarcoma. Virtually all will be high grade (Table 12.6), and the vast majority will come from an intra-abdominal site, most commonly visceral (Table 12.7).

Table 12.6 Hepatic metastases from soft tissue sarcoma: distribution by histologic type and grade. Histologic type Leiomyosarcoma Angiosarcoma Rhabdomyosarcoma Liposarcoma Malignant fibrous histiocytoma From Jaques et al.13

No. of patients (%) 55 5 3 1 1

(85%) (8%) (5%) (1%) (1%)

No. of high grade (%) 48 5 3 1 1

(87%) (100%) (100%) (100%) (100%)

No. of low grade (%) 7 (13%) 0 0 0 0

Treatment of recurrence

241

Table 12.7 Hepatic metastases from soft tissue sarcoma: incidence by primary site. Primary site

No. of patients

Extremity/trunk Trunk Lower extremity Upper extremity Buttock Abdomen Retroperitoneum Viscera Gynecologic Genitourinary Other Breast Head and neck Thoracic Total

No. of hepatic metastases

637 124 384 100 29 272 149 56 47 20 72 6 51 15 981

3 0 3 0 0 61 24 35 1 1 1 0 0 1 65

(0.5%) (0%) (0.8%) (0%) (0%) (22%) (16%) (62%) (2%) (5%) (1%) (0%) (0%) (7%) (6.6%)

From Jaques et al.13

1 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0

survival is rare, however (Figure 12.3), and chemotherapy has not been shown to improve survival, although some delay in disease progression may be possible (Figure 12.4).

Proportion surviving

Proportion surviving

Hepatic resection can delay ultimate recurrence. Candidates for resection are those with a very long disease-free interval with completely resectable disease. In highly selected patients with long disease-free intervals, isolated 5-year survivors from hepatic resection can be identified. Long-term

1 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0

Hepatic reaction n=14 Unresectable n=51

0 0

10

20

30 40 Time (months)

50

Figure 12.3 Long-term survival is rare after hepatic resection. From Jaques et al.13

60

10

20

30 40 Time (months)

50

60

Figure 12.4 Some delay in disease progression may be possible after hepatic resection. From Jaques et al.13

242

Diagnosis and Management of Soft Tissue Sarcoma

Brain metastasis

References

Brain metastases from sarcoma are very rare, and very few data exist as to management, other than limited surgical resection. In very selected patients, surgical resection can be considered if other effective therapy is lacking. Survival is poor, and such resection, we believe, should be reserved for symptomatic relief. Virtually all patients have associated metastases in other sites. The addition of radiation therapy to resection does not appear to prolong survival significantly, although rare patients have survived to 5 years. In a review of 25 patients who had brain metastases from sarcoma,14 median age at the time of diagnosis was 25 years, and median time from the primary diagnosis to diagnosis of brain metastases was 26.7 months. In 19 of these patients (76%), pulmonary metastases were also present. Overall survival following resection from craniotomy was 7 months. Forty per cent were alive at 1 year, and 16% at 2 years (Figure 12.5).

1. Espat NJ, Lewis JJ. The biological significance of failure at the primary site on ultimate survival in soft tissue sarcoma. Semin Radiation Oncol 1999;9:369–77. 2. Rosenberg SA, Tepper J, Glatstein E et al. The treatment of soft tissue sarcoma of the extremities: prospective randomized evaluations of (1) limb-sparing surgery plus radiation therapy compared with amputation and (2) the role of adjuvant chemotherapy. Ann Surg 1982;196:305–15. 3. Brennan MF, Hilaris B, Shiu MH et al. Local recurrence in adult soft tissue sarcoma: a randomized trial of brachytherapy. Arch Surg 1987;122:1289–93. 4. Lewis JJ, Leung D, Heslin M et al. Association of local recurrence with subsequent survival in extremity soft tissue sarcoma. J Clin Oncol 1997;15:646–52. 5. Lewis JJ, Leung D, Woodruff JM, Brennan MF. Retroperitoneal soft tissue sarcoma: analysis of 500 patients treated and followed at a single institution. Ann Surg 1998;228:355–65. 6. Verazin GT, Warneke JA, Driscoll DL et al. Resection of lung metastases from soft tissue sarcomas: a multivariate analysis. Arch Surg 1992;127:1407–11. 7. Casson AG, Putnam JB, Natarajan G et al. Five-year survival after pulmonary metastectomy for adult soft tissue sarcoma. Cancer 1992;69:662–8. 8. Creagan ET, Fleming TR, Edmonson JH et al. Pulmonary resection for metastatic nonosteogenic sarcoma. Cancer 1979;44:1908–12. 9. Putnam JB, Roth JA, Wesley MN et al. Analysis of prognostic factors in patients undergoing resection of pulmonary metastases from soft tissue sarcomas. J Thorac Cardiovasc Surg 1984;87:260–8. 10. Roth JA, Putnam JB, Wesley MN et al. Differing determinants of prognosis following

100

Survival from primary diagnosis median 38.8 months Survival from craniotomy median 7.0 months

Proportion surviving (%)

90 80 70 60 50 40 30 20 10 0 0

12

24

36 48 60 72 Survival (months)

84

Figure 12.5 Brain metastases. From Wronski et al.14

96

Treatment of recurrence resection of pulmonary metastases from osteogenic and soft tissue sarcoma patients. Cancer 1985;55:1361–6. 11. Jablons D, Steinberg SM, Roth J et al. Metastasectomy for soft tissue sarcoma. Further evidence for efficacy and prognostic indicators. J Thorac Cardiovasc Surg 1989;97:695–705. 12. Gadd MA, Casper ES, Woodruff J et al. Development and treatment of pulmonary

243

metastases in adult patients with extremity soft tissue sarcoma. Ann Surg 1993;218:705–12. 13. Jaques DP, Coit DG, Casper ES et al. Hepatic metastases from soft tissue sarcoma. Ann Surg 1995;221:392–7. 14. Wronski M, Arbit E, Burt M et al. Resection of brain metastases from sarcoma. Am Surg Oncol 1995;2:392–9.

13 Future directions

Isolated lung perfusion The lung is the primary site for metastasis from extremity lesions and is often the solitary site. While resection is the preferred approach when possible, many patients cannot undergo pulmonary resection, and those that do have a high probability of further recurrence in the lung. Isolated lung perfusion has been investigated since the late 1950s. 1 This approach is theoretically very attractive for patients with metastatic sarcoma in efforts to eradicate all disease with high-dose chemotherapeutic agents. A recent report from our group established the maximum tolerated dose of adriamycin in isolated lung perfusion to be 40 mg/m2. Doses in excess of this are accompanied by unacceptable toxicity.2 This approach, although done in a phase I setting, did not show significant response, except in a single patient (12%). However, the technique of isolated lung perfusion is an ideal one for the investigation of new biological agents and, indeed, of other chemotherapeutic agents. As well as being a therapeutic approach for unresectable disease, isolated lung perfusion can serve as an adjuvant for patients who have already undergone resection. The majority of these tumors will recur, and the majority of these will recur in the lung. At present, no significant effect has been shown from isolated lung perfusion, but it remains a model with

potential for testing biological agents or other chemotherapeutic agents whose systemic toxicity at this dosage is unacceptable.

Immunotherapy We are exploring several new approaches to the treatment of soft tissue sarcomas. There has been little recent progress in the prevention or treatment of metastatic disease. One approach that we are investigating is the use of vaccination to delay or prevent progression of disease, particularly in minimal residual disease settings in patients with high-risk sarcomas. However, little is known about potential molecular targets on soft tissue sarcomas. Despite current optimal multimodality treatment, approximately 50% of patients with soft tissue sarcoma will experience recurrence and die of their disease. There is, therefore, a clear need for expanded treatment in these high-risk patients. Most of these patients have been rendered disease-free or have minimal residual disease on completion of treatment. Tumor vaccines have a significant potential role in the adjuvant context of minimal or no residual disease. Considerable recent advances in molecular and tumor immunology are defining potential novel approaches for tumor vaccines, making it feasible to develop vaccine strategies on a molecular basis. Little is known about antigens

246

Diagnosis and Management of Soft Tissue Sarcoma

in sarcoma. We are currently extending our knowledge of known and unknown antigens. Known immunogenic antigens of sarcoma cells include the cell membrane gangliosides GM2, GD2 and GD3.3 In addition, studies have suggested that sarcoma patients are capable of mounting a cytotoxic T-lymphocyte (CTL) response against HLA-restricted antigens.4 SYT–SSX chimeric transcriptional proteins are present in nearly all patients with synovial sarcoma. These fusion proteins strongly correlate with tumor phenotype and are associated with proliferative rate and clinical course. Induction of an immune response against these potentially unique proteins may improve disease-free survival and overall survival in patients with synovial sarcoma. This would be a model system for utilization of other translocation proteins in soft tissue sarcoma as antigen targets, such as TLS–CHOP in myxoid liposarcoma, EWS–ATF1 in clear cell sarcoma, and EWS–CHN in extraskeletal myxoid chondrosarcoma. There is very limited information on T-cell recognition of human sarcomas. One study has shown that sarcoma patients are capable of mounting a CTL response against potential differentiation antigens. Slovin et al have previously demonstrated that lymphocytes from sarcoma patients are capable of mediating cytotoxicity against autologous tumor cells in an HLA-A2-restricted fashion.5 Not only can isolated lymphocyte clones recognize and kill autologous tumor cells in vitro, but they can also kill HLA-A2-matched allogeneic tumor cells, suggesting that shared differentiation antigens on sarcomas can also be recognized by T-cells.4 Studies from the Surgery Branch of the National Cancer Institute have also supported the existence of shared sarcoma antigens, including antigens shared by Ewing’s sarcomas and melanomas.4 We have been able to demonstrate that

malignant fibrous histiocytoma (MFH) sarcoma cells stimulated autologous CD4+ Tcells and that proliferation could be blocked by a monoclonal antibody (mAb) against HLA-DR. In addition, an allogeneic sarcoma (epithelioid) cell line induced proliferation of these same CD4+ T-cells. The epithelioid cell line was HLA-DR11–DR2+, and this response was blocked by a mAb against HLA-DR. We are currently evolving several strategies to develop immunotherapy for sarcoma. In one of these, we will investigate immune recognition of SYT–SSX transcriptional proteins in patients with synovial sarcoma. Patients will be selected for this study following surgical resection and appropriate adjuvant therapy for primary localized synovial sarcoma of the extremities. As shown in Table 13.1, an HLA homology search identified multiple HLA-binding sequences in both the SSX1 and SSX2 regions of each fusion peptide within a 158 amino acid region of the SYT–SSX1/2 breakpoint. The initial phase I clinical trial will evaluate and compare T-cell and antibody responses elicited by vaccination with peptide plus adjuvant versus DNA immunization with a minigene.6 Patient eligibility for this study will be determined by the identification of either an SYT–SSX1 or SYT–SSX2 translocation and/or expression of untranslocated SSX1 or SSX2. A second strategy will include immunizing patients with GM2 ganglioside covalently attached to keyhole limpet hemocyanin (GM2-KLH), GD2-KLH and GD3 lactone (GD3L)-KLH, and/or GM2, GD2 and GD3L covalently attached to a purified fraction of meningococcal outer membrane proteins (OMP) mixed with the adjuvant QS21. We have vaccinated one patient, who has myxofibrosarcoma metastatic to his lungs, with GD2-KLH + GM2-KLH + QS21. He developed a significant response to GM2, with a maximum titer of 1:160.

Future directions

247

Table 13.1 HLA binding motifs6 according to gene haplotype and serologic haplotype, indicating the location of the HLA-binding motif. HLA gene

HLA serology

HLA-A*0201 HLA-A*3302 HLA-A68.1 HLA-B*2702 HLA-B*2705 HLA-B*3902 HLA-B60 HLA-B62 HLA-DRB1*0101 HLA-DRB5*0101

A2 A33 A28 B27 B39 B60 B62 DRB10101 DRB50101

Epitope position: SYT–SSX1

Epitope position: SYT–SSX2

137–145 116–124 134–142 73–81a, 136–144,138–146 136–144 130–138 – 20–28, 38–46, 52–60, 68–76 96–104 76–84a

137–145 – 134–142, 116–124 73–81a, 136–144, 138–146 136–144 – 130–138 20–28, 38–46, 52–60, 68–76 96–104 76–84a

The indicated MHC class I and class II epitopes are located in the SSX region of the fusion protein, except for the four HLA-B62 epitopes located in the SYT region of the fusion protein.a Novel epitopes created across the SYT–SSX fusion region. Patient eligibility for this study will be determined by the identification of either an SYT–SSX1 or SYT–SSX2 translocation and/or expression of untranslocated SSX1 or SSX2.

This trial is designed to assess antibody titers. We also plan to obtain preliminary data on the impact of these antibodies on recurrence rate and survival, comparing actuarial progression and survival curves generated from our sarcoma database. The intention ultimately is to provide data correlating antibody response to clinical outcome and to provide a possible new treatment modality for testing for formal efficacy in an inter-institutional, randomized clinical trial, perhaps in a cooperative setting, e.g. sarcoma groups of the American College of Surgeons and the EORTC. Recognizing the difficulties of antigen identification requiring tumor-specific T-cell clones, the group of Sahin et al7 developed the SEREX technique as a modified strategy to identify tumor antigens. SEREX is an acronym which stands for serologic analysis of tumor

antigens by recombinant cDNA expression cloning. The principle of this technique relies on the ability of antibodies in autologous serum to recognize and bind to immobilized recombinant tumor proteins. This will then facilitate detection of the encoding cDNA clone. SEREX is highly efficient in detecting tumor antigens that elicit both a humoral and a cellular immune response.8 We are currently applying this technology to identification of novel sarcoma molecules and antigens. We hope to apply these to future clinical trials in soft tissue sarcoma.

Hyperthermic isolated limb perfusion (HILP) HILP is an investigational technique that has been tested in the treatment of extremity soft tissue sarcoma. In theory, patients with locally

248

Diagnosis and Management of Soft Tissue Sarcoma

advanced tumors not resectable without amputation, or locally advanced lesions in which there are known metastases, could be considered for HILP. A multicenter phase II trial evaluated 55 patients with unresectable extremity soft tissue sarcoma, using tumor necrosis factor alpha, interferon gamma and Melphalan as the profusaid. Complete responses were seen in 20 (36%) and partial responses in 28 (51%). Regional toxicity was low and there were no treatment-related deaths. Amputation was avoided in 84% of patients.9 The EORTC has currently developed a prospective trial for this therapy. Unfortunately, in the USA, tumor necrosis factor is difficult, if not impossible, to obtain at the present time.

Whole-body hyperthermia Whole-body hyperthermia combined with ifosfamide and carboplatin has been used for refractory small cell sarcoma.10 Hyperthermia was achieved by extracorporeal heating. Whole-body hyperthermia has been proposed as a treatment for metastatic sarcoma.11,12 The approach has been utilized as a phase I and phase II study combining whole-body hyperthermia with ifosfamide, carboplatin and etoposide. There were two complete responses and six partial responses to the treatment. An alternative approach, regional hyperthermia with electromagnetic field application in conjunction with ifosfamide and etoposide, has also been employed in the treatment of patients with locally advanced sarcoma.13 Such studies remain highly investigational, but, for advanced or unresponsive systemic disease, deserve further investigation.

Chemotherapy A variety of new approaches hold the promise of improvement in the outcome for patients

with metastatic sarcoma, and for patients who have resectable disease, but are at risk for relapse. As we learn more about the biology of cancer, and about sarcoma in particular, novel strategies come closer to reality. New agents that influence signal transduction are becoming available, and may find a role as single agents or in combination with traditional chemotherapeutic drugs. Antiangiogenic compounds, vaccines, gene therapy and other biological approaches may also become useful agents in this group of diseases. Patients with sarcoma may have much to gain by participating in clinical trials of these innovative therapies.

Electronically enhanced drug delivery It has been suggested that electronically enhanced drug delivery, electrochemotherapy, can be utilized to perform cytoreduction on small tumors.14 The basic premise is that postelectrical fields are utilized to increase the effectiveness of antineoplastic agents by increasing cell membrane permeability. It has already been applied to subcutaneous or cutaneous malignancies such as melanoma.15

Use of differentiation agents It has been suggested that the induction of terminal differentiation is a possible approach to treatment of malignancy. In soft tissue sarcoma, this is being addressed by the utilization of ligands for peroxisome proliferator-activated receptor gamma (PPAR gamma) and retinoid X receptor alpha (RXR alpha). These receptors are expressed at high levels in the majority of soft tissue sarcomas.16

Future directions Troglitazone has been evaluated in a phase III trial, in non-insulin-dependent diabetics, but has been withdrawn because of hepatic toxicity. In human liposarcoma cell lines, liposarcoma cells can be forced to undergo terminal differentiation by treatment with a PPAR gamma ligand, pioglitazone. As of now, there are far fewer side-effects in terms of hepatic toxicity.

4.

5.

STI–571 Perhaps the most exciting and recent drug development has been the development of a specific agent, STI–571 (Novartis; Basel, Switzerland), a specific c-abl tyrosine kinase inhibitor. This drug, showing dramatic responses in chronic myelogenous leukemia, also inhibits c-kit, though at lower affinity than c-abl. It does, however, inhibit the mutant c-kit seen in GI stromal tumors at much higher affinity, and early testing in phase II stages has shown dramatic responses in advanced GI stromal tumors, up to 65% having a partial response and 25% having stable disease in a disease almost inevitably progressive under all previous forms of treatment. Current trials are being developed to examine the value of using this as an adjuvant to patients with high-risk, primarily resected, GI stromal tumors.

References 1. Creech O, Krementz ET, Ryan RF, Winblad JN. Chemotherapy of cancer: regional perfusion utilizing an extracorporeal circuit. Ann Surg 1958;148:616–32. 2. Burt M, Liu D, Abolhoda A et al. Isolated lung perfusion for patients with unresectable metastases from sarcomas: a phase I trial. Ann Thorac Surg 2000;69:1542–9. 3. Livingston PO. Approaches to augmenting the immunogenicity of melanoma gangliosides

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8. 9.

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from whole melanoma cells to gangliosideKLH conjugate vaccines. Immunol Rev 1995;145:147–50. Shamamian P, Mancini M, Kwakami Y et al. Recognition of neuroectodermal tumors by melanoma-specific cytotoxic T lymphocytes: evidence for antigen sharing by tumors derived from the neural crest. Cancer Immunol Immunother 1994;39:73–6. Slovin SF, Lackman RD, Ferrone S et al. Cellular immune response to human sarcomas: cytotoxic T cell clones reactive with autologous sarcomas. I. Development, phenotype, and specificity. J Immunol 1986;137:3042–7. Rammensee HG, Friede T, Stevanoviic S. MHC ligands and peptide motifs: first listing. Immunogenetics 1995;41:178–80. Sahin U, Tureci O, Pfreundschuh M. Serological identification of human tumor antigens. Current Opin Immunol 1997;9:709–10. Old LJ, Chen YT. New paths in human cancer serology. J Exp Med 1998;187:1163–7. Eggermont AMM, Shraffordt Koops H, Lienard D et al. Isolated limb perfusion with high-dose tumor necrosis factor-alpha in combination with interferon-v and melphalan for nonresectable extremity soft tissue sarcomas: a multicenter trial. J Clin Oncol 1996;14:2653–65. Wiedemann GJ, d’Oleire F, Knop E et al. Ifosfamide and carboplatin combined with 41.8°C whole-body hyperthermia in patients with refractory sarcoma and malignant teratoma. Cancer Res 1994;54:5346–50. Wiedemann GJ, Robins HI, Katschinski DM et al. Systemic hyperthermia and ifosfamide, carboplatin and etoposide ( ICE) chemotherapy for sarcoma patients. Rationale and clinical status. Anticancer Res 1997;17:2899–902. Wiedemann GJ, Robins HI, Gutsche et al. Ifosfamide, carboplatin and etoposide (ICE) combined with 41.8°C whole body hyperthermia in patients with refractory sarcoma. Eur J Cancer 1996;32:888–92.

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13. Issels RD, Prenninger SW, Nagele A et al. Ifosfamide plus etoposide combined with regional hyperthermia in patients with locally advanced sarcomas: a phase II study. J Clin Oncol 1990;8:1818–29. 14. Hyacinthe M, Jaroszeski MJ, Dang VV et al. Electrically enhanced drug delivery for the treatment of soft tissue sarcoma. Cancer 1999;85:409–17. 15. Heller R, Jaroszeski MJ, Reintgen DS et al.

Treatment of cutaneous and subcutaneous tumors with electrochemotherapy using intralesional bleomycin. Cancer 1998;83:148–57. 16. Tontonoz P, Singer S, Forman BM et al. Terminal differentiation of human liposarcoma cells induced by ligands for peroxisome proliferator-activated receptor gamma and the retinoid X receptor. Proc Nat Acad Sci 1997;94:237–41.

Index 5-Florouracil, 169 Abdomen/pelvis sarcomas, 193–206 Abdominal wall, resection, 215–16 Actinomycin activity, 168 combination chemotherapy, 172 Adipose tissue tumors, clinicopathologic features, 35–7 Adjuvant management, 153–83 Adjuvant therapy, and resectable disease, 240 Age, distribution by, 29, 123 Agent Orange, 18 Alkylating agents, activity, 168–70 Alveolar rhabdomyosarcoma, clinicopathologic features, 39 Alveolar soft part sarcoma clinical and pathologic correlates, 128–9 clinicopathologic features, 48 diagnosis, 128 prognostic factors for outcome, 128 results, 128–29 survival, 129 treatment, 128 Amputation, 146, 147 forequarter, 230–1 hindquarter, 232–3 Angiolipomas, clinicopathologic features, 35 Angiomatoid fibrous histiocytoma, clinicopathologic features, 34 Angiomyolipoma clinical features, 59 clinicopathologic features, 35–6 Angiomyomas, clinical features, 58 Angiomyxomas, clinical features, 57 Angiosarcoma chemical predisposing factors, 18 clinical and pathologic correlates, 116–19

clinicopathologic features, 41–2 diagnosis, 116–18 hepatic metastases, 240 and mastectomy, 116, 118 metastasis, 116, 240 prognostic factors for outcome, 118 radiation induced, 15 radiation therapy, 118 recurrence, 118–19 results, 118–19 sites, 116, 118 survival rates, 118–19 treatment, 118 Anterior flap hemipelvectomy, 234 Anthracycline, combination chemotherapy, 175 Antibiotics, activity, 168 Antimetabolites, activity, 169 Aponeurotic fibromatosis, 32 Arms, resection, 224–5 Axilla, resection, 224 Back tumor, resection, 216–18 Biopsy, 141–3, 160 Bleomycin, activity, 168 Blood vessel tumors, classification, 23 Brachytherapy (BRT), 153–9 and wound healing, 161 Brain metastasis, 242 Breast sarcoma, 188–91 resection, 213–15 BRT see Brachytherapy Budd–Chiari syndrome, leiomyosarcoma and, 38 Buttock, resection, 235–6 Cafe au lait spots, clinical features, 58, 59 Cajal cell tumors, clinicopathologic features,

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Diagnosis and Management of Soft Tissue Sarcoma

37–8 Carboplatin, activity, 169 Carcinoma, terminology, 1–5 Cardiac sarcoma, 191 Catheters, brachytherapy, 159 Cellular schwannoma, 121 clinical features, 58–9 clinicopathologic features, 44 Chemical exposure, predisposing factor, 12, 17–18 Chemotherapy, 167–77 combination chemotherapy, 170–7 desmoid sarcoma, 92–3 drug delivery, 248 evolution, 5 factors predicting response to, 173 fibrosarcoma, 114–15 future direction, 248 goal, 173 head and neck, 185–6 leiomyosarcoma, 173 meta-analysis, 174–7 and radiation therapy, 154–8 randomized trials, 172 role, 167 single agents, 167–70 synovial sarcoma, 125–6, 173 treatment recommendations, 173–4 Chest wall sarcomas, 187–8 diagnosis, 187 presentation, 187 resection, 210–12 results, 187–8 treatment, 187 Chondrosarcoma clinical features, 56–7 radiation induced, 16 see also Extraskeletal chondrosarcoma CHOP gene, 15 Chromosomal translocations, 13–15 Cisplatin activity, 168–70 combination chemotherapy, 172

Classification, pathologic see Pathologic classification Clavicular resection, 211–12 Clear cell sarcoma, 135 clinicopathologic features, 49 Clinical correlates, 91–140 Clinical features, 55–65 Clinicopathologic features, 30–49 Combination chemotherapy, 170–7 Complications, wound, 160–2 Congenital localized fibromatosis, 32 CT scanning management of recurrence, 150 v MRI, 62–4 visceral sarcoma, 202 Cyclophosphamide activity, 168 combination chemotherapy, 170–2, 174–5 Cystosarcoma phyllodes, 188–90 Cytogenetics, 13 CyVADIC regimen, combination chemotherapy, 170–1, 174–5 Dacarbazine activity, 169, 170 combination chemotherapy, 170–2 Deep-seated fibromatosis see Desmoid sarcoma Dermatofibrosarcoma protuberans (DFSP) clinical and pathologic correlates, 97–100 clinicopathologic features, 34–5 diagnosis, 97 FS-DFSP, 97–100 pathology, 97–8 prognostic factors for local recurrence, 98–100 recurrence, 98–100 results, 100 treatment, 98 tumor mortality, 98 Desmoid sarcoma chemotherapy, 92–3 clinical and pathologic correlates, 91–7

Index clinicopathologic features, 33–4 diagnosis, 91 and FAP, 91 NSAIDs, 92–3 parturition and, 17, 92 prognostic factors for outcome, 94–5 radiation induced, 16 radiation therapy, 92 recurrence, 94–7 resection, 210–11 results, 95–7 sites, 91 treatment, 92–4 Desmoplastic small round cell tumor (DSRCT) chromosomal translocation, 14–15 clinical and pathologic correlates, 131–3 clinicopathologic features, 49 diagnosis, 131 prognostic factors for outcome, 132 results, 132 treatment, 131–2 DFSP see Dermatofibrosarcoma protuberans Diagnostic imaging, 61–5 CT v MRI, 62–4 primary tumor, 62–3 Differential diagnosis, 26–30 Differentiation agents, future direction, 248–9 Digital fibromatosis, 32 Dioxin, 18 Disease-specific survival, retroperitoneal soft tissue sarcoma, 85–7 Docetaxel, activity, 169, 170 Doxorubicin, 154–7, 167 activity, 167, 168 combination chemotherapy, 170–5 Drain site placement, STT resection, 145–6 Drug delivery, future direction, 248 DSRCT see Desmoplastic small round cell tumor Duodenum, 197 Dupuytren’s contracture, 32

253

Elastofibroma clinical features, 57 clinicopathologic features, 31 Electronically advanced drug delivery, 248 Embryonal rhabdomyosarcoma (ERMS), 186 clinicopathologic features, 39 Environmental factors, predisposing factor, 17–18 Epirubicin, combination chemotherapy, 170–2 Epitheloid hemangioendothelioma, clinicopathologic features, 40 Epitheloid sarcoma clinical and pathologic correlates, 129–31 clinicopathologic features, 48–9 diagnosis, 129–30 prognostic factors for outcome, 131 results, 131 sites, 129–30 treatment, 130 ERMS see Embryonal rhabdomyosarcoma Etiology, 9–18 Etoposide, activity, 169 Ewing’s sarcoma see Primitive neuroectodermal tumor /Ewing’s sarcoma Extended hemipelvectomy, 233 External beam radiation, technical aspects, 158–9 Extraskeletal cartilaginous tumors classification, 24 clinicopathologic features, 46–7 Extraskeletal chondrosarcoma clinical and pathologic correlates, 132–3 clinical features, 56–7 clinicopathologic features, 46 diagnosis, 132 prognostic factors for outcome, 133 treatment, 133 Extraskeletal osteogenic sarcoma, 133 clinicopathologic features, 46–7 Extremity sarcoma management, 141–50 prevalence, 77

254

Diagnosis and Management of Soft Tissue Sarcoma

prognostic factors, 77–81 recurrence, 238 recurrence treatment, 235 Extremity STT, resection, 143–50, 224–34 Familial adenomatous polyposis (FAP), 91 predisposing factor, 12 Familial polyposis coli, predisposing factor, 12 Family histories, 141 FAP see Familial adenomatous polyposis Fascial fibromatosis, 32 Fibrohistiocytic tumors classification, 22 clinicopathologic features, 34 Fibroma, clinicopathologic features, 31 Fibromatoses clinicopathologic features, 32–3 deep-seated see Desmoid sarcoma Fibromatosis colli, 32 Fibrosarcoma chemotherapy, 114–15 clinical and pathologic correlates, 114–16 clinicopathologic features, 34 diagnosis, 114 distribution by age, 29 head and neck, 186, 209–10 incidence, 9 inflammatory fibrosarcoma, 116, 117 neck, 209–10 prognostic factors, 79–80 prognostic factors for outcome, 115 radiation induced, 16 recurrence, 114–15 results, 136 retroperitoneal, 115 survival, 136, 137 treatment, 114–15 Fibrous histiocytoma, clinicopathologic features, 34 Fibrous tumors classification, 22 clinicopathologic features, 30–5

Follow-up, post-treatment extremity STT, 147–8 visceral STT, 155 Forequarter amputation, 230–1 Future directions, 245–9 Gallium nitrate, activity, 169 GANT see Gastrointestinal autonomic nerve tumors Gardner’s syndrome, predisposing factor, 12 Gastrointestinal autonomic nerve tumors (GANT) classification, 30 clinicopathologic features, 45–6 incidence, 9 prognostic factors, 86–7 ultrastructural features, 198 v GIST, 199–200 Gastrointestinal sarcomas, 195–203 Gastrointestinal stromal tumors (GIST), 196–202 classification, 30 clinicopathologic features, 37–8 diagnosis, 197 incidence, 9 management, 201 metastasis, 199, 202 presentation, 196, 197 prognostic factors, 87–8 recurrence, 200–1 resection, 197, 222–3 results, 197–201 survival, 200–1, 202 treatment, 197 ultrastructural features, 198 v GANT, 199–200 Gastrointestinal stromal tumors – not otherwise specified (GIST–NOS) incidence, 9 prognostic factors, 86–7 ultrastructural features, 198 Gene and molecular biology, predisposing factor, 13–15

Index

255

Genetic predisposition, 12 Genitourinary tract sarcomas, 203–4 Gingival fibromatosis, 32 GIST see Gastrointestinal stromal tumors GIST–NOS see Gastrointestinal stromal tumors – not otherwise specified Glomus tumors, clinicopathologic features, 42–3 Gluteal resection, 225 Gore-tex® (polytetraflouroethylene), chest wall resection, 210–11 Grade, incidence by, 7, 10 Grading, sarcoma, 21–6, 67–76 Granular cell tumors, clinicopathologic features, 44 Granulocytic sarcoma, 190 Gynecologic tumors, 204–6

classification, 26 incidence, 7, 10 leiomyosarcoma, 113 radiation induced, 15 recurrence, 77–81 resection, 143–6 staging, 67–76 synovial sarcoma, 124–5 HILP see Hyperthermic isolated limb perfusion Hindquarter amputation, 232–3 Hip disarticulation, 234 Historical perspectives, 1–6 Hyperthermia, whole-body, 248 Hyperthermic isolated limb perfusion (HILP), 247–8 Hypertrichosis, and gingival fibromatosis, 32

Head and neck, chemotherapy, 185–6 Head and neck sarcomas, 185–7 diagnosis, 185 presentation, 185 resection, 209–10 results, 186–7 treatment, 185–6 Hemangioma clinical features, 57 clinicopathologic features, 40 Hemangiopericytoma clinical and pathologic correlates, 119–21 clinicopathologic features, 43 diagnosis, 119–20 presentation, 119–20 prognostic factors for outcome, 121 results, 121 treatment, 120–1 Hemipelvectomy, 233 Hepatic metastasis, 240–1 Herbicides, occupational exposure, 17–18 Hexamethylmelamine, activity, 168 Hibernoma, clinicopathologic features, 36 High grade tumours biopsy schema, 142–3

Ifosfamide, 167 activity, 167, 168 combination chemotherapy, 170–5 and synovial sarcoma, 173 Iliopsoas liposarcoma, 107 Immunohistochemical markers, differential diagnosis, 26–7 Immunohistochemical tests, 142 Immunotherapy, future direction, 245–7 Incidence, 7–9 Inferior vena cava (IVC), 206 Inflammatory fibrosarcoma diagnosis, 116 results, 116 retroperitoneal, 116 treatment, 116 Inflammatory myofibroblastic tumors, clinicopathologic features, 31–2 INK4A/B genes, proliferation markers, 88–9 Intraoperative radiation therapy, 160 Iodine-125, 159 Iridium-192, 159 Isolated lung perfusion, 245 IVC see Inferior vena cava

256

Diagnosis and Management of Soft Tissue Sarcoma

Kaposi’s sarcoma, clinicopathologic features, 40–1 Keloid tumors, clinicopathologic features, 30 Ki-67 proliferation marker, 87–8 Lateral leg resection, 229 Ledderhose’s disease (plantar fibromatosis), 32 Leiomyoma clinical features, 57–8 clinicopathologic features, 37 Leiomyosarcoma chemotherapy, 173 classification, 30 clinical and pathologic correlates, 112–14 clinicopathologic features, 38–9 diagnosis, 112 distribution by age, 29 head and neck, 186 hepatic metastases, 240 histopathology, 27–8 incidence, 7, 9, 11 IVC, 206 metastasis, 112, 240 presentation, 112 prognostic factors for outcome, 114 radiation induced, 16 recurrence, 112, 114 results, 114 retroperitoneal, 113 survival, 136–7, 199–200 treatment, 113 ultrastructural features, 198 uterine, 205 Li–Fraumeni syndrome, predisposing factor, 12 Lipoblastoma, clinicopathologic features, 36 Lipoblastomatosis, clinicopathologic features, 36 Lipomas clinical features, 55 clinicopathologic features, 35 presentation, 141

Lipomatous tumors benign, 141 classification, 22–3 clinical features, 55, 104 treatment, 105–8 Liposarcoma clinical and pathologic correlates, 104–11 clinical features, 60–1 clinicopathologic features, 36–7 diagnosis, 104–5 distribution by age, 29 hepatic metastases, 240 histopathology, 27–8 iliopsoas liposarcoma, 107 incidence, 7, 9, 11 liposarcoma, 109–10 metastasis, 109–10, 240 myxoid liposarcoma, 15, 110–11, 113 neck, 209 prognostic factors, 79–80 prognostic factors for outcome, 108–9 radiation induced, 16 recurrence, 108–11 results, 109–11 retroperitoneal, 106–9 survival rates, 109–11, 112, 136, 137 Liver sarcomas, 201–3 Local recurrence-free survival, retroperitoneal soft tissue sarcoma, 84 Low grade tumours biopsy schema, 142–3 classification, 26 incidence, 7, 10 liposarcoma, 105 recurrence, 77–81 resection, 143–6 staging, 67–76 Lower extremities, resection, 225–34 Lung perfusion, isolated, 245 Lung sarcoma, 192–3 metastatic disease, 238–40 Lymph node metastasis histologic type, 25

Index prevalence, 25 signficance, 70–2 Lymph vessel tumors, classification, 23 Lymphangioleiomomatosis, clinicopathologic features, 40 Lymphangioma, clinical features, 60 Lymphangiosarcoma, radiation induced, 15, 16, 17, 116, 118 Lymphedema clinical features, 56 predisposing factor, 12, 15–16 MAID see Mesna, ifosfamide, doxorubicin, dacarbazine Malignant fibrous histiocytoma (MFH) clinical and pathologic correlates, 100–4 clinical features, 55 clinicopathologic features, 35 diagnosis, 100–1 distribution by age, 29 head and neck, 186 hepatic metastases, 240 histopathology, 27–8 immunotherapy, 246 incidence, 7, 9, 11 presentation, 101 prognostic factors, 79–80 prognostic factors for outcome, 101–3 radiation induced, 15, 16 recurrence, 101–4 results, 104 retroperitoneal, 103 survival factors, 101–4 survival rates, 136 thigh, 227 treatment, 101 Malignant melanoma of soft parts, clinicopathologic features, 49 Malignant peripheral nerve tumors (MPNT) classification, 21 clinical and pathologic correlates, 121–3 clinicopathologic features, 44–5 diagnosis, 122

257

head and neck, 186 prognostic factors for outcome, 122–3 results, 122–23 survival rates, 136, 137 treatment, 122 Management, principles of see Principles of management Markers, immunohistochemical, 26–7 Marlex mesh, chest wall resection, 210–11 Mastectomy and angiosarcoma, 116, 118 post-irradiated lymphedematous tissue, 16 Mediastinal fibromatosis, 33 Mediastinum, primary sarcomas, 192 Melothelial tumors, classification, 24 Mesenchymoma, clinicopathologic features, 47 Mesenteric fibromatosis, 33 Mesna, ifosfamide, doxorubicin, dacarbazine (MAID), 150 combination chemotherapy, 170–3, 175 Metastasis angiosarcoma, 116, 240 brain, 242 GIST, 199, 202 hepatic, 240–1 leiomyosarcoma, 112, 240 liposarcoma, 109–10, 240 Lymph node, 25, 70–2 management of distant, 149 myxoid liposarcoma, 109–10 pulmonary, 238–40 resection and, 143–4 retroperitoneal tumors, 62–4 sites of first, 29 and staging, 70–6 Metastasis-free survival, retroperitoneal soft tissue sarcoma, 84–5 Metastatic disease, management, 238–40 Methotrexate activity, 169 combination chemotherapy, 174–7 Methylmethacrylate, chest wall resection, 210–11

258

Diagnosis and Management of Soft Tissue Sarcoma

MFH see Malignant fibrous histiocytoma Microscopic margins, and radiation therapy, 162–6 Miscellaneous tumors classification, 25 clinicopathologic features, 47–9 Mitomycin activity, 168 combination chemotherapy, 172 Mitoxantrone, activity, 169 Mobilization, tumor, 210 Molecular and gene biology, predisposing factor, 13–15 MPNT see Malignant peripheral nerve tumors MRI, v CT scanning, 62–4 Mullerian tumors, 30 Multifocal fibromatosis, 32 Muscle tumors skeletal, 23, 39 smooth, 23, 37–9 Musculoskeletal neoplasms, staging, 69–70 Myositis ossificans clinical features, 56, 57 clinicopathologic features, 46 Myxofibrosarcoma, 115 Myxoid liposarcoma chromosomal translocation, 15 metastasis, 109–10 survival, 112 Myxoma, clinicopathologic features, 47 Neck and head sarcomas see Head and neck sarcomas Neck, resection, 209–10 Negative microscopic margins, and radiation therapy, 162–5 Neural tumors, classification, 24 Neurofibroma, 121 clinicopathologic features, 44 Neurofibromatosis and gingival fibromatosis, 32 predisposing factor, 12

Nodular fasciitis, clinicopathologic features, 30 Nodular tenosynovitis, clinicopathologic features, 43–4 Non-steroidal anti-inflammatory drugs (NSAIDs), desmoid sarcoma, 92–3 Osseous tumors classification, 24 clinicopathologic features, 46–7 Osteogenic sarcomas adjuvant therapy, 174 chemical predisposing factors, 18 extraskeletal, 46–7, 133 radiation induced, 16 P53 gene, predisposing factor, 12, 13 Pacemaker cell tumors, clinicopathologic features, 37–8 Paclitaxel, activity, 169, 170 Palmar fibromatosis, 32 Parturition, desmoid sarcoma and, 17, 92 Pathologic classification, 21–54 clinicopathologic features, 30–49 differential diagnosis, 26–30 grading of sarcoma, 21–6 Pathologic correlates, 91–140 Pediatric small cell sarcoma, adjuvant therapy, 174 Penile fibromatosis (Peyronie’s disease), 32 Peripheral nerves tumors, 121–3 clinicopathologic features, 44–6 see also Malignant peripheral nerve tumors Perivascular tumors classification, 23 clinicopathologic features, 42–3 Peroxisome proliferator-activated receptor gamma (PPAR gamma), 248–9 PET see Positron emission tomography Peyronie’s disease (penile fibromatosis), 32 Phenoxyherbicides, occupational exposure, 17–18 Pioglitazone, 249

Index Plantar fibromatosis (Ledderhose’s disease), 32 Pleomorphic rhabdomyosarcoma, clinicopathologic features, 39 Plexosarcoma see Gastrointestinal autonomic nerve tumors Pluripotential mesenchymal tumors, classification, 24–5 PNET see Primitive neuroectodermal tumor /Ewing’s sarcoma Polypropelene (prolene), chest wall resection, 210–11 Polytetraflouroethylene (Gore-tex®), chest wall resection, 210–11 Positive microscopic margins, and radiation therapy, 162–6 Positron emission tomography (PET), 64 Post-treatment follow-up extremity STT, 147–8 visceral STT, 150 PPAR gamma see Peroxisome proliferatoractivated receptor gamma Predisposing factors, 9–18, 116 Preoperative radiation therapy, 160 Prevalence extremity sarcoma, 77 by site and type, 7–9, 10 Primitive neuroectodermal tumor (PNET)/Ewing’s sarcoma classification, 21, 30 DSRCT, 131 Principles of management, 141–52 extremity soft tissue sarcoma, 141–50 retroperitoneal STT, 150–1 superficial trunk soft tissue sarcoma, 141–50 visceral STT, 150–1 Prognostic factors, 77–89 Proliferation markers, prognostic relevance, 87–9 Prosthetics, chest wall resection, 210–12 Pseudosarcomatous fasciitis, 30 Pulmonary-only lesions, metastatic disease, 238–40

259

Quality of life, and radiation therapy, 166 Radiation exposure, predisposing factor, 12, 116 Radiation-induced sarcoma, 15, 16, 17, 116, 118, 185 Radiation therapy, 153–66 and chemotherapy, 154–7 as definitive treatment, 160 external beam radiation, 158–9 head and neck, 185–6 intraoperative, 160 and microscopic margins, 162–6 predisposing factor, 15 preoperative, 160 preoperative/postoperative, 143 and recurrence, 162–6 survival, disease free, 153–8 Radionuclide scintigraphy, 65 RB-1 gene, predisposing factor, 12, 13 Recurrence extremity STT, 149 extremity v retroperitoneal sarcomas, 238 high grade v low grade, 77–81 local/distant, 143–4 management of local, 148, 149 and radiation therapy, 162–6 survival, 154–7, 236–7 treatment, 235–7 visceral STT, 150–1 Resection Abdominal wall, 215–16 arms, 224–5 axilla, 224 back tumor, 216–18 breast sarcoma, 213–15 buttock, 225–6 chest wall, 210–12 clavicular, 211–12 desmoid sarcoma, 210–11 extremity STT, 143–50, 224–34 GIST, 197, 222–3 gluteal, 225

260

Diagnosis and Management of Soft Tissue Sarcoma

high grade tumors, 143–6 lateral leg, 229 low grade tumors, 143–6 lower extremities, 225–34 metastasis and, 143–4 neck, 209–10 retroperitoneal liposarcoma, 220–1 retroperitoneal soft tissue sarcoma, 216–21 retroperitoneal STT, 150–1 superficial trunk STT, 143–50 thigh, 226–8 visceral sarcoma, 222–3 Retinoblastoma, predisposing factor, 12 Retinoid X receptor alpha (RXR alpha), 248–9 Retroperitoneal liposarcoma, resection, 220–1 Retroperitoneal soft tissue sarcoma, 193–5 diagnosis, 193 disease-specific survival, 85–6 fibrosarcoma, 115 leiomyosarcoma, 113 liposarcoma, 106–9 local recurrence-free survival, 84 metastasis-free survival, 84–5 MFH, 103 presentation, 193–4 prognostic factors, 82–6 recurrence, 238 recurrence treatment, 235–7 resection, 221–5 results, 195 treatment, 193–5 treatment, recurrence, 235–7 Retroperitoneal STT, management, 150–1 Retroperitoneal STT, resection, 150 Retroperitoneal tumors clinical features, 59–60 metastasis, 62–4 prognostic factors, 81–6 staging, 76 Rhabdomyosarcoma, 39, 186 clinical and pathologic correlates, 133–5

diagnosis, 133–4 hepatic metastases, 240 prognostic factors for outcome, 134 results, 134–5 treatment, 134 RXR alpha see Retinoid X receptor alpha Sarcoma grading, 21–6 terminology, 1–5 Schwannoma, 121 clinical features, 55, 58–9 clinicopathologic features, 44 SEREX technique, immunotherapy, 247 Sex, distribution by, 8 Sites abdomen/pelvis, 193–206 angiosarcoma, 116, 118 breast sarcoma, 188–91 cardiac sarcoma, 191 chest wall sarcomas, 187–8 desmoid sarcoma, 91 epitheloid sarcoma, 129–30 gastrointestinal sarcomas, 195–203 head and neck sarcomas, 185–7 histopathology, STT, 28 liver sarcomas, 201–3 lung sarcomas, 192–3 mediastinum, 192 metastasis, 29 prevalence by, 7–9, 10 retroperitoneal sarcomas, 193–5 special, 185–208 synovial sarcoma, 125 thoracic sarcomas, 187–91 Size, distribution by, 7, 11 Skeletal muscle tumors classification, 23 clinicopathologic features, 39 Smooth muscle tumors classification, 23 clinicopathologic features, 37–9 Soft tissue tumours (STT)

Index biopsy, 141–3 classification, 21–6 management, 141–52 staging, 67–76 Special sites, 185–208 Special techniques, 209–34 Spindle cell sarcomas breast, 213–14 radiation induced, 16 Staging, STT, 67–76 future directions, 71–6 and metastasis, 70–6 retroperitoneal tumors, 76 visceral sarcomas, 76 STT see Soft tissue tumours Subdermal fibromatosis, 32 Superficial trunk STT, resection, 143–50 Survival disease-free, 153–8 disease-specific, 85–7 local recurrence, 236–7 pulmonary metastasis, 239–40 recurrence-free, 154–7 Synovial sarcoma age distribution, 123 axilla, 224 chemotherapy, 125–6, 173 chromosomal translocation, 13–14 clinical and pathologic correlates, 123–8 clinicopathologic features, 43–4, 47–8 diagnosis, 123–5 diagnostic imaging, 63 head and neck, 186 and ifosfamide, 173 incidence, 9 presentation, 124 prognostic factors, 80–2 prognostic factors for outcome, 126–8 recurrence, 126–8 results, 128

261

sites, 125 survival, 126–7, 136 treatment, 125–6 Synovial tumors, classification, 24 Technical aspects, operative resection, STT, 144–6 Techniques, special, 209–34 Thigh, resection, 226–8 Thoracic sarcomas, 187–91 Topotecan, activity, 169 Torticollis, 32 Translocations, chromosomal, 13–15 Trauma, predisposing factor, 16–17 Treatment, evolution, 5 Troglitazone, 249 Type, prevalence by, 7–9 Uterine sarcomas, 205–6 clinical features, 61 types, 30 Vascular tumors clinical features, 58 clinicopathologic features, 39–42 Vinblastine, activity, 169 Vincristine, combination chemotherapy, 170–2 Vindesine, combination chemotherapy, 172 Visceral sarcomas management, 150–1 prognostic factors, 81–6 resection, 222–3 staging, 76 Visceral tumors, prognostic factors, 86–7 Whole-body hyperthermia, 248 Wound complications, radiation therapy, 160–2 Xanthoma, clinicopathologic features, 34