Non-Surgical Treatment of Keratinocyte Skin Cancer

Non-Surgical Treatment of Keratinocyte Skin Cancer Gregor B. E. Jemec Lajos Kemeny Donald Miech (Eds.) Non-Surgical ...

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Non-Surgical Treatment of Keratinocyte Skin Cancer

Gregor B. E. Jemec Lajos Kemeny Donald Miech (Eds.)

Non-Surgical Treatment of Keratinocyte Skin Cancer

Prof. Donald Miech Marshfield Clinic Dept. Dermatology 1000 N. Oak Ave. Marshfield WI 54449 USA [email protected]

Dr. Gregor B. E. Jemec University of Copenhagen Roskilde Hospital Dept. of Dermatology Køgevej 7-13 4000 Roskilde Denmark [email protected] Prof. Lajos Kemeny University of Szeged Dept. Dermatology & Allergology Korányi Fasor 6 Szeged 6720 Hungary [email protected]

ISBN: 978-3-540-79340-3

e-ISBN: 978-3-540-79341-0

DOI: 10.1007/978-3-540-79341-0 Springer Heidelberg Dordrecht London New York Library of Congress Control Number: 2009929700 © Springer-Verlag Berlin Heidelberg 2010 This work is subject to copyright. All rights are reserved, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilm or in any other way, and storage in data banks. Duplication of this publication or parts thereof is permitted only under the provisions of the German Copyright Law of September 9, 1965, in its current version, and permission for use must always be obtained from Springer. Violations are liable to prosecution under the German Copyright Law. The use of general descriptive names, registered names, trademarks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. Product liability: The publishers cannot guarantee the accuracy of any information about dosage and application contained in this book. In every individual case the user must check such information by consulting the relevant literature. Cover design: eStudio Calamar, Figueres/Berlin Printed on acid-free paper Springer is part of Springer Science+Business Media (www.springer.com)

Preface

Books mark the progress of Man since they were invented. Through them we are able to gain insight into the minds of our predecessors better than through any other medium. They describe how the delicate interplay between practice and ideal, which is better known as evolution, has brought forward the societies in which we now live. A book marks the synthesis of knowledge in a different way from individual papers. A certain maturity and volume of understanding and knowledge is necessary before the material is suitable for a book. The timing of the cognitive and analytical synthesis represented by a book is therefore crucial; too soon and it is lost in speculation, too late and it is old news. Non-melanoma skin cancer is common; it causes morbidity, it causes a burden on society, and treatment has been traditionally almost exclusively surgical. Decades of medical science have however now brought forward a number of techniques which may help both the diagnosis and treatment of skin cancer without physically removing it, either alone or in combination in treatment programs tailored to the individual patients. This book is an attempt at providing a timely synthesis of knowledge about the burden of non-melanoma skin cancer, the nonsurgical options for treatment and the range of adjuvant therapies available. The Editors are greatly indebted to the many eminent scholars who have kindly contributed their insight and understanding of this complex area to this review of the state of the art. The insight is theirs, any oversight is ours. We hope that the readers’ academic enthusiasm will make them bring some of the ideas presented here both to their research and their patients, so that the book may stimulate a broad move forward in this important area. Gregor B. E. Jemec Donald Miech Lajos Kemény

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Contents

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From Precursor to Cancer: Field Cancerization and the Opportunities for Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Gillian M. Murphy

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When Is a Skin Cancer a Cancer: The Histopathologist’s View . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Dirk M. Elston

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Epidemiology of Non-Melanoma Skin Cancer . . . . . . . . . . . . . . . . . . . . . Annette Østergaard Jensen, Anna Lei Lamberg, and Anne Braae Olesen

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Genetics of Non-Melanoma Skin Cancers and Associated Familial Syndromes. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Khanh P. Thieu and Hensin Tsao

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Environmental Risk Factors for Non-Melanoma Skin Cancers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Vishal Madan

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Accuracy in the Diagnosis of Non-Melanoma Skin Cancer . . . . . . . . . . . Mette Mogensen and Gregor B. E. Jemec

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Cure Rates Following Surgical Therapy – The Golden Standard . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Roland Kaufmann and Markus Meissner

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Pharmacological Therapy: An Introduction . . . . . . . . . . . . . . . . . . . . . . . Donald J. Miech

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Systemic Chemotherapy of Non-Melanoma Skin Cancer . . . . . . . . . . . . Robert Gniadecki

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Contents

10 Intralesional Agents to Manage Cutaneous Malignancy . . . . . . . . . . . . . Whitney A. High

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11 Topical Chemotherapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Donald J. Miech

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12 Immunotherapy: An Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 103 Lajos Kemény 13 Intralesional Interferon in the Treatment of Basal Cell Carcinoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 107 Stanislaw Buechner 14 Interleukin-2 for Nonmelanoma Skin Cancer. . . . . . . . . . . . . . . . . . . . . . 113 Arpad Farkas 15 Topical Imiquimod. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 123 Lajos Kemény 16 Photodynamic Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 133 Gregor B. E. Jemec 17 Critical Evidence-Based Review of Current Experience and Possible Future Developments of Topical PDT . . . . . . . . . . . . . . . . . 137 Olle Larkö and Ann-Marie Wennberg 18 Electrochemotherapy in Treatment of Cutaneous Tumors . . . . . . . . . . . 143 Gregor Sersa 19 Radiotherapy: At a Glance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 151 Renato Panizzon 20 Prevention and Adjuvant Therapy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 159 Veronique del Marmol and Gregor B. E. Jemec 21 Sunscreens. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 167 Hans Christian Wulf 22 Skin Cancer: Antioxidants and Diet . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 177 Daniela Göppner and Harald Gollnick 23 Retinoids in the Management of Non-Melanoma Skin Cancer . . . . . . . . 187 Mohamed Badawy Abdel-Naser and Christos C. Zouboulis

Contents

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24 PDT for Cancer Prevention. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 197 C. A. Morton 25 Dermabrasion, Laser Resurfacing, and Photorejuvenation for Prevention of Non-Melanoma Skin Cancer. . . . . . . . . . . . . . . . . . . . . 205 Annesofie Faurschou and Merete Hædersdal 26 To Cut or Not, That Is the Question. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 211 Barbara Jemec and Gregor B. E. Jemec Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 215

Contributors

Mohamed Badawy Abdel-Naser Departments of Dermatology and Venereology, Ain Shams University, Cairo, Egypt Anne Braae Olesen Department of Dermatology, Aarhus Sygehus, Aarhus University Hospital, 8000 Aarhus C., Denmark [email protected] Stanislaw Buechner Department of Dermatology, Blumenrain 20, 4059 Basel, Switzerland [email protected] Dirk M. Elston Geisinger Medical Center, 100 N. Academy Avenue, Danville, PA 17822, USA [email protected] Arpas Farkas Department of Dermatology and Allergology, University of Szeged, Hungary [email protected] Annesofie Faurschou Department of Dermatology, University of Copenhagen, Bispebjerg Hospital, Bispebjerg Bakke 23, 2400 Copenhagen NV, Denmark [email protected] Robert Gniadecki University of Copenhagen, Department of Dermatology, Bispebjerg Hospital, Bispebjerg bake 23, 2400 Copenhagen, Denmark [email protected] Harald Gollnick Department of Dermatology und Venerology, Otto-von-Guericke-University Magdeburg, Leipziger Straße 44, 39120 Magdeburg, Germany [email protected] Daniela Göppner Department of Dermatology und Venerology, Otto-von-Guericke-University Magdeburg, Leipziger Straße 44, 39120 Magdeburg, Germany Merete Hædersdal Department of Dermatology, University of Copenhagen, Bispebjerg Hospital, Bispebjerg Bakke 23, 2400 Copenhagen NV, Denmark [email protected] Whitney A. High Department of Dermatology and Pathology, University of Colorado Health Sciences Center, P.O. Box 6510, Mail Stop F703, Aurora, CO 80045-0510, USA [email protected] xi

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Barbara Jemec Department of Plastic Surgery, Chelsea and Westminster Hospital, London, U.K. [email protected] Gregor B. E. Jemec Deptartment of Dermatology, Faculty of Health Sciences, University of Copenhagen, Roskilde Hospital, Køgevej 7-13DK-4000 Roskilde, Denmark [email protected] Roland Kaufmann Department of Dermatology, Goethe-University Hospital, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany [email protected] Lajos Kemény Department of Dermatology and Allergology, University of Szeged, Hungary [email protected] Anna Lei Lamberg Department of Dermatology, Aarhus Sygehus, Aarhus University Hospital, 8000 Aarhus C., Denmark [email protected] Olle Larkö Department of Dermatology, Sahlgrenska Academy at Gothenburg University, Sahlgrenska University Hospital, 413 45 Gothenburg, Sweden [email protected] Vishal Madan The Dermatology Centre, Salford Royal Hospitals NHS Trust, Hope Hospital, Stott Lane, Salford, M6 8HD, UK [email protected] Véronique del Marmol Université Libre de Bruxelles, Hopital Erasme, Service de Dermatologie, 808, route de Lennik, 1070 Bruxelles, Belgium v.marmol @skynet.be Markus Meissne Department of Dermatology, Goethe-University Hospital Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany [email protected] Donald J. Miech Marshfield Clinic, Marshfield, Wisconsin 54449 [email protected] Mette Mogensen Deptartment of Dermatology, Faculty of Health Sciences, University of Copenhagen, Roskilde Hospital, Køgevej 7-13, 4000 Roskilde, Denmark [email protected] C. A. Morton Department of Dermatology, Stirling Royal Infirmary, Livilands, Stirling, Scotland, FK8 2AU, UK [email protected] Gillian M. Murphy Director National Photobiology Centre, Beaumont and Mater Misericordiae Hospitals, Dublin, Ireland [email protected] Annette Østergaard Jensen Department of Dermatology, Aarhus Sygehus, Aarhus University Hospital, 8000 Aarhus C., Denmark [email protected]

Contributors

Contributors

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Renato Panizzon Department of Dermatology, CHUV Lausanne, Switzerland [email protected] Gregor Sersa Department of Experimental Oncology, Institute of Oncology Ljubljana, Zaloska 2, 1000 Ljubljana, Slovenia [email protected] Khanh P. Thieu Harvard Medical School, 25 Shattuck Street, Boston, MA, USA Hensin Tsao Massachusetts General Hospital, Department of Dermatology, Bartlett Hall 622, 50 Blossom Street, Boston, MA 02114 Wellman Center for Photomedicine, Massachusetts General Hospital, Boston, MA, USA [email protected] Ann-Marie Wenneberg Department of Dermatology, Sahlgrenska Academy at Gothenburg University, Sahlgrenska University Hospital, 413 45 Gothenburg, Sweden Hans Christian Wulf Bispebjerg Hospital, University of Copenhagen, Department of Dermatology, D42, Bispebjerg Bakke 23, 2400 Copenhagen NV, Denmark [email protected] Christos C. Zouboulis Departments of Dermatology, Venereology, Allergology and Immunology Dessau Medical Center, Auenweg 38, 06847 Dessau, Germany [email protected]

From Precursor to Cancer: Field Cancerization and the Opportunities for Therapy Gillian M. Murphy

Key Points

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Ultraviolet radiation is a complete carcinogen due to its ability to initiate, promote and induce progression of skin cancer in human skin. The evolution of cancer in the skin is a multistep sequence needing at least seven genetic events for it to develop. Areas of the skin receiving excess amounts of ultraviolet radiation either early in life or as a cumulative dose with advancing years may be primed for the development of skin cancers with genetic alteration of irradiated skin. Subclinical genetic damage accumulates and leads to later emergence of skin cancers due to failure of local immunosuppressant mechanisms. Field cancerization makes a cogent argument for the treatment of not only the visible malignant and pre-malignant lesions but also the underlying genetic accumulated derangement not visible to the eye.

G. M. Murphy Consultant Dermatologist and Senior Lecturer, Director National Photobiology Centre, Beaumont and Mater Misericordiae Hospitals, Dublin, Ireland e-mail: [email protected]

Non-melanoma skin cancer (NMSC), predominantly basal cell carcinoma (BCC) and squamous cell carcinoma (SCC), accounts for 90% of all skin cancers in the populations of Western European countries and North America. Skin type is classified into different categories with greater or lesser tendency to sunburn in an effort to predict reactions to photochemotherapy [1]. The risk of skin cancers is greatest in white-skinned individuals of Fitzpatrick skin type (Table 1.1) I and II, though darker-skinned individuals of skin type III and IV [2] also may develop skin cancer, more usually basal cell carcinoma or malignant melanoma. Individuals with brown or black skin rarely develop skin cancer and if they do, it is usually due to genetic susceptibility or it is unrelated to sun exposure. Genetic syndromes with defective DNA repair or cancer susceptibility genes such as mutated patched gene or other tumour suppressor genes may lead to skin cancer even in darker skin types. Immunosuppressed individuals such as organ transplant recipients (exposed to immunosuppressant medication over years) also readily develop skin cancers with increased risk, orders of magnitude greater than the risk in the general population (see Fig. 1.1). The main factors leading to skin cancer are pale skin Fitzpatrick skin types I and II > III and IV [2], ultraviolet radiation (UVR) and immunosuppression [3]. Much is now understood about the mechanisms underlying skin cancer from the study of rare genetic syndromes such as xeroderma pigmentosum, Gorlin’s syndrome and Li Fraumeni syndrome and chronically immunosuppressed individuals [3]. Ultraviolet radiation is absorbed by DNA; the absorption spectrum of DNA, the action spectrum for the formation of thymine dimers and the human erythema action spectrum all virtually coincide [4]. Cyclobutane pyrimidine dimers are repaired by the DNA repair complex, defects in individual components of

G. B. E. Jemec et al. (eds.), Non-Surgical Treatment of Keratinocyte Skin Cancer, DOI: 10.1007/978-3-540-79341-0_1, © Springer-Verlag Berlin Heidelberg 2010

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2 Table 1.1 Fitzpatrick skin type Skin type I Skin type II Skin type III Skin type IV Skin type V Skin type VI

G. M. Murphy

Response to 30 min noonday sun at 420 latitude North (Boston, USA) Always burns, never tans Always burns, tans with difficulty Sometimes burns, tans with ease Never burns, always tans (Mediterranean/Hispanic) Asian/Indian (brown) African (black)

Fig. 1.1 Hand of organ transplant patient

which lead to the various complementation groups of xeroderma pigmentosum or defects of post replication DNA repair (XP variant). Such enzyme-dependent DNA repair is error prone, even with normal enzyme function and vestiges of DNA damage may remain. DNA damage induced by UVR often occurs in crucial genes such as the p53 gene and other tumour suppressing genes; if this damage is not repaired, the p53 gene function is altered from the normal function of the gene (a tumour suppressor gene) to that of a tumour-promoting gene [5]. In response to incident UV on the skin which leads to DNA lesions, the function of p53 is to halt the cell in S phase, permitting repair of such DNA damage. If the cell has too much DNA damage to be repaired, the p53 gene triggers a series of events through the caspase pathway which culminates in cell suicide (so-called programmed cell death or apoptosis), a non-inflammatory, harmless way of eliminating cells which are beyond repair. Apoptosis therefore is an error-free method of removing cells with significant UV-induced DNA damage. In the Li Fraumeni syndrome, no p53 is produced; patients with such syndrome are prone to multiple cancers including malignant melanoma. In knock-out mice with no p53

function, apoptosis does not occur in response to UVR exposure and carcinogenesis is facilitated. The p53 gene has been dubbed the ‘Guardian of the genome’ because its function is so integral to maintenance of genetic integrity [6].

1.1 Actinic Keratoses and Squamous Cell Carcinoma Repeated UVR exposure of the skin in man leads to clones of cells accumulating which contain mutated p53. These cells contain p53 functioning in its mutated form as a tumour promoter. With ongoing UV exposure, the p53 patches become more numerous [7] and with chronic UVR exposure the immunosuppressive effects of UVR sooner or later overwhelm the immune surveillance mechanisms of the skin, and actinin keratoses (AKs) become clinically overt. Both UVB and UVA seem to be able to induce similar mutations [8]. Carcinogenesis is a multi-step process where mutations occur in genes which suppress cancer cells converting those genes to tumourpromoter genes and induce oncogenes which drive the cancer cells faster [9]. Where the damage is retained in basal cells the cancer process is more effective [10]. Actinic keratoses first present on sites of maximum UVR exposure and along with solar elastosis are the first objective clinical evidence of cellular dysplasia within the epidermis. Actinic keratoses, histologically, are seen as partial thickness dysplasia, usually the lower third of the epidermis. Progression to full thickness dysplasia may occur and an estimated one in 50 AKs progress to squamous cell carcinoma (SCC); the true rate of progression of AKs to SCC in any one person is unknown. Squamous cell carcinoma in situ is full thickness dysplasia and is a very common skin cancer of the elderly. It is not recorded in many national cancer registers and many lesions are treated topically, so the true incidence is not documented. Frequently multifocal squamous cell carcinoma is associated with the presence of human papilloma virus (HPV) and is especially common in immunosuppressed individuals [11]. Frequently, plane warts, multi-focal Bowen’s disease and HPV infection are seen on the lower legs of women with considerable UV exposure and fair skin type. Nowadays, the multi-focal Bowen’s disease is less common which used to be a consequence of previous arsenic exposure which was prevalent in iron tonics in Europe until the 1950s.

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From Precursor to Cancer: Field Cancerization and the Opportunities for Therapy

Disseminated superficial actinic porokeratosis is a peculiar, often genetically influenced, clonal expansion of epidermal cells leading to UV-distributed subtle annular lesions which may occasionally be pre-malignant. More frequently porokeratosis of Mibelli, a much larger variant, leads to squamous cell carcinoma. Porokeratosis is seen more frequently in immunosuppressed individuals. Squamous cell carcinoma is directly related to total UVR dose. The larger the dose of UVR, the paler the colour of the skin: the earlier the onset of SCC. Actinic keratoses occur in childhood in XP. In this genetic disease, failure of the DNA repair mechanism leads to retention of UV-induced DNA lesions and, as a consequence, accelerated photo-ageing and pre-malignant lesions occur together with malignant skin cancers at a rate 1,000-fold greater than the general public. Thus, from this collection of diseases, we understand the importance of the DNA repair complex. Skin cancer may develop in early adult life in skin type I or albinism in equatorial/tropical regions where exposure of a skin without the ability to absorb incident UVR is particularly detrimental. Eumelanin (which is black melanin) has the ability to absorb UVR without augmenting its effects. Phaeomelanin (red-yellow melanin) found in skin type I and II in relatively greater amounts appears to act as a photosensitiser, actually generating free radicals and augmenting the effects of UVR exposure. In albinism in sub-Saharan Africa, skin without the ability to pigment is overwhelmed by UVR and readily develops basal and particularly squamous cell carcinoma in a multi-focal distribution. The other group of patients who develop very large numbers of skin cancers are the long-term immunosuppressed individuals, specifically those with pale skin, with onset of skin cancer and 20–30 years earlier than equally exposed normal adults even in high latitude countries. Thus, within all these diseases, the importance of DNA repair, pale skin and immunosuppression are highlighted dramatically as important components of photoprotective mechanisms in human skin. In parallel with the effects of UVR on DNA, both direct and indirect, an additional contributory factor leading to persisting DNA damage is the presence of human papilloma virus of various types in the skin. Mucosal skin is well recognised as harbouring oncogenic HPV known to interfere with the function of p53, through the E6 protein. Cutaneous immunosuppression caused by ultraviolet radiation (which leads

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to both local and systemic immunosuppression) and immunosuppressing systemic drugs (as in the case of the long-term immunosuppression given to organ transplant recipients) leads to the presence of large amounts of HPV of low and moderate oncogenic potential. This has relatively recently been recognised as contributing to cancer risk by blocking apoptosis via a p53 independent pathway [12]. In addition to blocking apoptosis, HPV appears to contribute to the immortalisation of the cells which carry DNA damage so that they persist in the skin accumulating until overt cancers develop [13]. The exact role of HPV in carcinogenesis is still being elucidated but it seems to assume greater importance in sun-exposed skin of systemically immunosuppressed individuals. Chronically sunexposed skin thus harbours myriads of DNA lesions insufficiently repaired, with additional impairment of the error-free mechanism of elimination of cells (apoptosis) with consequent significant additional DNA damage apart from that directly induced by UVR. Additionally, the local immunosuppression which UVR induces in exposed skin encourages the proliferation of HPV, augmenting the whole process. Thus, the stage is set for the ready development of skin cancer in fair-skinned UVR-exposed systemically immunosuppressed individuals. The emergence of AKs in the immunosuppressed is of much greater significance than in the general population as those transplant patients with AKs will almost certainly develop skin cancer in due course. By the time AKs are present, the skin has accumulated much subclinical DNA damage such as p53 patches. Actinic keratoses thus may be regarded as a major warning that much subclinical cellular damage has been accumulated and just treating visible lesions does not solve the carcinogenic risk which the patients is now harbouring. The use of treatments which are preferentially sequestered in DNA-damaged cells gives a clue to the scale of the subclinical damage. Thus, clinicians treating patients with systemic 5-fluorouracil for colon cancer may be surprised by the inflammatory reactions occurring in sun-exposed sites of sun-damaged people, but what they witness is the unmasking of field change, dubbed ‘field cancerization’. The other way of unmasking field cancerization is to introduce systemic immunosuppression to those with significant actinic keratoses: Within weeks or months squamous cell carcinomas are likely to emerge. The last brake holding the skin cancers in check clearly

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was immune surveillance and when this is impaired by drugs with immunosuppressive properties such as azathioprine and calcineurin inhibitors which both immunosuppress via a T cell-mediated mechanism and also have the ability to further block apoptosis, it is not surprising that the consequence is emergence of skin cancers. Thus, only treating visible skin lesions in sundamaged individuals and especially those also on immunosuppressant drugs does not address the problem of disease recurrence. Treatment of the whole area to eliminate underlying genetically compromised cells is the only way of preventing recurrence.

1.2 Basal Cell Carcinoma The pathogenesis of basal cell carcinoma (BCC) is different from that of SCC; it is a consequence of defects in the patched gene which leads to Smoothin and Hedgehog signalling defects [14]. In Gorlin’s syndrome this is a genetic defect and unrelated to UVR exposure. In sporadic BCCs, the defect in patchedgene function is acquired usually through intermittent childhood or young adult sun exposure and the genetic mutations are UV-signature mutations occurring regardless of the phenotype of the sporadic BCC [15]. The mutated cell is activated decades later by deficient immune surveillance either sun-induced or drug-induced immunosuppression. Defects in DNA repair also promote BCC development. DNA repair also declines with age, so all of these factors may contribute to later development of BCCs. Not infrequently a family history of BCCs is obtained, so some genetic predisposition seems relevant even in sporadic BCCs. Does the concept of field change apply also to BCCs? Basal cell carcinomas may recur even if fully removed. This is because BCCs may be multi-focal, 30% of those with one BCC may expect a second BCC to occur within a 3-year time frame and often in the same anatomical area. Clearly, subclinical lesions were initiated and promoted and then emerged over time either with ongoing immunosuppression from the sun and/or from systemic immunosuppression. Do we have any proof of this? The rate of BCCs is increased after renal transplantation with a standardised incidence rate (SIR) of 16 [16]. The photoprotection field studies of Adele Greene give some trends towards the reduction of BCCs by introducing sunscreen use to patients with

G. M. Murphy

previous skin cancers; smaller studies also suggested a reduction of BCCs with sunscreen use though to date it is not statistically significant [17]. The concept of field cancerization also should be extended to BCCs.

1.3 Malignant Melanoma Malignant melanoma is a complex cancer though often melanomas are discussed as if there is only one type. In reality, there are subsets of melanoma each with different epidemiology and behaviour (see Table 1.2). Patterns of UVR exposure determine the type of genetic mutations seen in melanoma: early exposure to UVR induces BRAF mutations whereas later exposure predisposes to NRAS mutations [18]. Analysis of different patterns of UV exposure shows that multiple primary melanomas are related to increased UV exposure both in childhood and later as an adult. Thus, reduction of UV after diagnosis of melanoma is likely to reduce the risk of a second primary [19]. Lentigo maligna is most analagous to actinic keratoses and squamous cell carcinoma in that it is linked directly to cumulative UVR exposure rather than Table 1.2 Subtypes of malignant melanoma Lentigo maligna (pigmented and amelanotic)

Melanoma in situ pigmented/ amelanotic Superficial spreading melanoma pigmented/ amelanotic Nodular melanoma Includes desmoplastic melanoma and amelanotic Intradermal naevus melanoma Blue naevus melanoma Mucosal melanomas Melanoma of childhood

Ocular melanoma

Non-cutaneous melanoma

Comment Occurs in very sun-damaged skin in elderly, may progress to lentigo maligna melanoma Relatively little solar elastosis Radial spread

Vertical spread

Unrelated to UVR Mainly occurs in giant congenital naevi Very rare de novo May be linked with cutaneous melanoma in cancer families Melanoma primary may occur in CNS or gut

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From Precursor to Cancer: Field Cancerization and the Opportunities for Therapy

intermittent UVR exposure which is more implicated in superficial spreading and nodular melanoma and BCCs. Elderly sun-damaged individuals may present with irregularly pigmented macules which on biopsy turn out to have atypical melanocytes and solar elastosis, sometimes classified as solar lentigines. Years later, such lesions turn out to be the first manifestation of early melanoma. Therefore, there is a continuum through continuous junctional atypical melanocytic hyperplasia, lentigo maligna, lentiginous melanoma and in situ melanoma. Where one begins and the other ends may be a function of lesion sampling, patient age, body site and amount of associated solar elastosis. Lentigo maligna is a tumour caused by cumulative sun damage; it is frequently seen with adjacent actinic keratoses and flat seborrhoeic keratoses in the elderly on exposed sites in outdoor individuals. In the temperate zones, such as in Ireland, it is the commonest form of malignant melanoma [20]. Melanoma in situ occurs in younger individuals and does not show such associated solar damage. Complete excision of lentigo maligna often is followed by recurrence in a multi-focal distribution because of the field change induced by chronic UVR exposure. About 5% of lentigo maligna patients develop invasive melanoma [21]. The recurrence rate following a 5-mm margin is 8–20% [21]. The recurrence rate after Mohs’ microgaphic surgery is 5% [21]. Use of immunostain mel-5 to detect single cell spread outside the main lesion improves this to 0.5% [22]. Whether such radical excision of lentigo maligna is warranted should be balanced by the age and wishes of the patient together with the feasibility of reconstruction and co-morbidities given the low rate of invasive melanoma. The use of Mohs’ micrographically controlled surgery is therefore impracticable, in some patients with large lesions with single cell spread centimetres from the main lesion, though sometimes advocated. Ultraviolet radiation is a major risk factor in the pathogenesis of malignant melanoma. Exposure to blistering sunburn early in life either as a child or as a young adult seems to be an important mechanism. Malignant melanoma may occur de novo without a pre-existing lesion or as a malignant transformation of a pre-existing naevus (40%). The larger the mole, the more numerous the moles, the greater the risk for malignant melanoma. Individuals who freckle in response to UV exposure are also predisposed to malignant melanoma. Genetic predisposition accounts for about 10% of melanomas. Defects in CDKN2 or P16

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or P53 or Brac, all predispose to melanoma as do polymorphisms of the MC1R gene. The SIR for malignant melanoma in renal transplant patients is 6–8 in Ireland and the UK [23]. Immunosuppression is thus also important in permitting malignant melanoma to emerge. Nearly 3–6% of people with melanoma may expect to develop a second primary melanoma. Those with a family history of melanoma and multiple large atypical naevi are most at risk. The good news about skin cancer is that now we have tools which enable early detection of skin cancer such as dermoscopy in which patterns of pigmentation and vascularisation enable distinguishing benign from malignant lesions with greater accuracy than the unaided eye.

1.4 Treatment of Field Change Over the past few decades treatments both systemic and topical have been developed and assessed to treat early sun damage and recurrent skin cancers even in high-risk patients (see Table 1.3 ). Systemic and topical 5-fluorouracil relatively specifically lead to selective destruction of cells harbouring DNA damage as cellular turnover is increased in these lesions (AKs, SCCs and BCCs). Subclinical lesions are also affected and so there is often significant surrounding cellular necrosis with associated inflammation. Imiquimod acts through the Toll-like receptor 7 and unless basal cells and actinic keratoses express these receptors the drug may not be effective. Significant associated local inflammation occurs which leads to destruction of cells with the production locally of interferon. Imiquimod is undoubtedly effective in lentigo maligna, though cases of invasive melanoma have occurred detected on complete

Table 1.3 Systemic treatments for skin cancer Isotretinoin Acetretin 5 fluorouracil (IV) Capecitabine Photodynamic therapy (systemic)

Topical treatments for skin cancer Diclofenac 5 Fluorouracil (topical) Imiquimod ALA PDT ALA-ester PDT Intralesional interferon (not licenced) T4 endonuclease V (not licenced)

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excision of the lesion. Intralesional interferon likewise has been shown to be an effective way of eradicating BCCs. Multiple clinical trials have demonstrated the efficacy of imiquimod which is widely licenced for treatment of AKs and BCCs. Photodynamic therapy rests on the principle of generation of protoporphyrin IX by applying aminolaevulinic acid or related ester (e.g. Metvix®) topically, allowing it to penetrate through to the cancer cells beneath. Cancer cells are relatively iron-deficient compared with surrounding non-cancerous skin and therefore the porphyrin pathway has a rate-limiting step as there is insufficient iron to convert protoporphyrin IX into haem. Protoporphyrin IX thus accumulates, highly photosensitises and irradiates the area with visible light, whether red blue or green and leads to death of the cell by generation of free radicals in the presence of oxygen. Multiple clinical trials have shown efficacy for AKs and superficial BCCs. Squamous cell carcinoma and precursor lesions express COX 2 more so with neovascularisation associated with tumour spread [24] so blockade of COX-2 expression leads to regression of these lesions, usually in the absence of much inflammation. The use of topical diclofenac with formulation designed to aid penetration through the stratum corneum has proved highly popular with patients wanting a relatively easy way of inducing regression of AKs. Repeated treatments are however needed as complete cessation of use leads to recurrence of AKs after variable intervals of time. Treatment with T4 endonuclease V, a topically applied liposomal enzyme which reduces UV-induced DNA damage, has been shown to reduce AKs and SCC in XP [25] but further studies are awaited to confirm these results in other skin cancer-prone groups. Systemic 5-flourouracil pro-drug capecitabine is an oral formulation being trialled for prevention of recurring SCCs in organ transplant patients currently. Results are awaited before recommending this drug. Systemic sirolimus is being substituted in organ transplant patients for calcineurin inhibitors, early results are promising for this drug which leads to regression of Kaposi’s sarcoma and fewer SCCs. Retinoids used systemically have proved useful [26] together with reduction of the level of immunosuppressive drugs in organ transplant recipient patients [27]. In Gorlin’s syndrome and xeroderma pigmentosum, oral retinoids have proved useful for those with recurring skin cancers.

G. M. Murphy

In tandem with all these approaches to reduction of field cancerization is the value of photoprotection, using sunscreens as an adjunct to UV-avoiding behaviour. Greene showed reduction of AKs and SCCs and a trend in the reduction of the numbers of BCCs [17]. Thus, sunscreens should be regarded as an essential part of the management of field cancerization. The old approach of cryotherapy to individual lesions would now not be regarded as sufficient with the availability of a wide variety of field change treatments including sunscreens. Patients often prefer the rapid response achieved with cryotherapy, but in order to reduce recurrence of AKs and skin cancers they should be advised to additionally use treatments likely to reduce skin cancer. Trials showing the efficacy of such topical treatments are lacking apart from the sunscreen trial but should be undertaken to demonstrate not only AK reduction but also long-term skin cancer reduction.

References 1. Parrish JA, Fitzpatrick TB, Tanenbaum L, Pathak MA. Photochemotherapy of psoriasis with oral methoxsalen and longwave ultraviolet light. N Engl J Med. 1974 Dec 5; 291(23):1207–11 2. Fitzpatrick TB. The validity and practicality of sun-reactive skin types type I through VI. Arch Dermatol. 1988;124: 869–71 3. Ho WL, Murphy GM. Update on the pathogenesis of posttransplant skin cancer in renal transplant recipients. Br J Dermatol. 2008 Feb;158(2):217–24 4. Young AR, Chadwick CA, Harrison GI, Nikaido O, Ramsden J, Potten CS. The similarity of action spectra for thymine dimers in human epidermis and erythema suggests that DNA is the chromophore for erythema. J Invest Dermatol. 1998;111:982–8 5. Piercall WE, Mukhopadhyay T, Goldberg LH, Ananthaswamy HN. Mutations in the p53 tumour suppressor gene in human cutaneous squamous cell carcinomas. Mol Carcinog. 1991; 4(6):445–9. 6. Lane DP. Cancer p53 guardian of the genome. Nature. 1992;358(6381):15–6 7. Jonason AS, Kunala S, Price GJ, Restifo RJ, Spinelli HM, Persing JA, Leffell DJ, Tarone RE, Brash DE. Frequent clones of p53-mutated keratinocytes in normal human skin. Proc Natl Acad Sci USA. 1996;93(24):14025–9 8. Kappes et al Short and long wave UV light (UVB and UVA) induce similar mutations. JID. 2006 Mar;126(3):667–75 9. Nijhof JG, Mulder AM, Speksnijder EN, Hoogervorst EM, Mullenders LH, de Gruijl FR. Growth stimulation of UV-induced DNA damage retaining basal cells gives rise to clusters of p53 overexpressing cells. DNA repair (Amst). 2007;6(11):1642–50

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From Precursor to Cancer: Field Cancerization and the Opportunities for Therapy

10. Lee S, Chari NS, Kim HW, Wang X, Roop DR, Cho SH, DiGiovanni J, McDonnell TJ. Cooperation of Ha-ras and Bcl-2 during multistep skin carcinogenesis. Mol Carcinog. 2007 Dec;46(12):949–57 11. Moloney FJ, de Freitas D, Conlon PJ, Murphy GM. Renal transplantation, immunosuppression and the skin: an update. Photodermatol Photoimmunol Photomed. 2005 Feb;21(1):1–8 12. Jackson S, Harwood C, Thomas M, Banks L, Storey A. Role of Bak in UV-induced apoptosis in skin cancer and abrogation by HPV E6 protein. Genes Dev. 2000;14(23):3065–73 13. Bedard KM, Underbrink MP, Howie HL, Galloway DA. The E6 oncoproteins from human betapapillomaviruses differentially activate telomerase through an E6AP-dependent mechanism and prolong the lifespan of primary keratinocytes. J Virol. Apr 15, 2008;82(8):3894–902 14. Tsao H. Genetics of nonmelanoma skin cancer. Arch Dermatol. 2001;137:1486–92 15. Heitzer E, Lassacher A, Quehenberger F, Kerl H, Wolf P. UV fingerprints predominate in the PTCH mutation spectra of basal cell carcinomas independent of clinical phenotype. J Invest Dermatol. 28 June 2007;doi:10.1038/sj.jid.5700923 16. Moloney FJ, Comber H, Conlon PJ, Murphy GM. The role of immunosuppression in the pathogenesis of basal cell carcinoma. Br J Dermatol. 2006 Apr;154(4):790–1 17. Green A, Williams G, Neale R, Hart V, Leslie D, Parsons P, Marks GC, Gaffney P, Battistutta D, Frost C, Lang C, Russell A. Daily sunscreen application and betacarotene supplementation in prevention of basal-cell and squamous-cell carcinomas of the skin: a randomised controlled trial. Lancet. 1999;354: 723–9 18. Thomas NE et al Number of nevi and early-life ambient UV exposure are associated with BRAF-mutant Melanoma. Cancer Epidemiol Biomarkers Prev. 2007 May;16(5):991–7 19. Kricker A, Armstrong BK, Goumas C, Litchfield M, Begg CB, Hummer AJ, Marrett LD, Theis B, Millikan RC, Thomas

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N, Culver HA, Gallagher RP, Dwyer T, Rebbeck TR, Kanetsky PA, Busam K, From L, Mujumdar U, Zanetti R, Berwick M. For the GEM Study Group. Ambient UV, personal sun exposure and risk of multiple primary melanomas. Cancer Causes Control. 2007 Apr;18(3):295–304. Epub 2007 Jan 6 20. http://www.ncri.ie/ncri/index.shtml 21. McKenna JK, Florell SR, Goldman GD, Bowen GM. Lentigo maligna/lentigo maligna melanoma: current state of diagnosis and treatment. Dermatol Surg. 2006 Apr;32(4): 493–504 22. Bhardwaj SS, Tope WD, Lee PK. Mohs micrographic surgery for lentigo maligna and lentigo maligna melanoma using Mel-5 immunostaining: University of Minnesota experience. Dermatol Surg. 2006 May;32(5):690–6 23. Laing ME, Moloney FJ, Comber H, Conlon P, Murphy GM. Malignant melanoma in renal transplant recipients. Br J Dermatol. 2006 Oct;155(4):857 24. O’Grady A, O’Kelly P, Murphy GM, Leader M, Kay E. COX-2 expression correlates with microvessel density in non-melanoma skin cancer from renal transplant recipients and immunocompetent individuals. Hum Pathol. 2004 Dec;35(12):1549–52 25. Yarosh DKJ, O’Connor A, Hawk J, Rafal E, Wolf P. Effect of topically appliedendonucleaseV in liposomes on skin cancer in xeroderma pigmentosum: a randomised study. Lancet. 2001;357:926–9 26. McKenna DB, Murphy GM. Skin cancer chemoprophylaxis in renal transplant recipients: 5 years of experience using low-dose acitretin. Br J Dermatol. 1999 Apr;140(4):656–60 27. Moloney FJ, Kelly PO, Kay EW, Conlon P, Murphy GM. Maintenance versus reduction of immunosuppression in renal transplant recipients with aggressive squamous cell carcinoma. Dermatol Surg. 2004 Apr;30(4 Pt 2):674–8

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When Is a Skin Cancer a Cancer: The Histopathologist’s View Dirk M. Elston

Key Points

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In the initial phase of field cancerization, a patch of abnormal cells arises from a genetically altered stem cell. With molecular techniques, precancerous clonal fields that are 7 cm and greater in diameter have been detected in oral and esophageal mucosae. No data exist regarding the skin. Individual cells in an AK may be every bit as atypical as those in an invasive SCC. A specimen that provides adequate depth is key to a correct diagnosis. Once a tumor has invaded, there is little consensus as to what histologic features should be cited in the pathology report. In SCC carcinoma type, Breslow thickness, level of invasion, ulceration, growth pattern, and mitotic index may be relevant histological features. Molecular techniques may aid the histopathological diagnosis.

D. M. Elston Geisinger Medical Center, 100 N. Academy Avenue, Danville, PA 17822, USA e-mail: [email protected]

2.1 Field Cancerization from the Dermatopathologist’s Point of View Non-melanoma skin cancers typically develop on a background of “sun damage” characterized by solar elastosis as well as varying degrees of epithelial atypia and architectural disorder. Molecular data from both skin and other organs suggest that these observations are manifestations of field cancerization. The presence of widespread actinic keratoses (AKs) and the high incidence of multiple primary cutaneous cancers in patients with severe sun damage are the most obvious manifestations of field cancerization in the skin. The finding of cutaneous squamous cell carcinomas (SCCs) arising within actinic keratoses (Fig. 2.1) is evidence of multistage carcinogenesis where progressive genetic aberrations eventually result in an invasive cancer arising on a background of field cancerization. This chapter examines the concept of field cancerization from the dermatopathologist’s point of view as well as histologic and

Fig. 2.1 Invasive SCC arising in an actinic keratosis

G. B. E. Jemec et al. (eds.), Non-Surgical Treatment of Keratinocyte Skin Cancer, DOI: 10.1007/978-3-540-79341-0_2, © Springer-Verlag Berlin Heidelberg 2010

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10 Table 2.1 Histologic and molecular evidence supporting field cancerization in NMSC SCCs commonly arise in AKs AKs demonstrate a spectrum of cytologic changes similar to SCC Cytologic features of the actinic keratosis typically resemble those of the invasive component Shared molecular aberrations that impart a growth advantage to both cell populations, including p53 mutations and phosphorylation, upregulation of cyclooxygenase (COX)-2 expression, and E-cadherin gene promoter hypermethylation Multiple p53 mutations in adjacent normal-appearing skin Cytogenetic evidence that multiple primary tumors represent distinct clones arising on a background of atypical cells

molecular methods to determine when a proliferation of atypical cells crosses the threshold to a malignancy competent to produce metastatic disease (Table 2.1). The concept of field cancerization was first proposed by Slaughter in 1953 to explain the histological alterations in the mucosa surrounding oral squamous cell carcinoma. The concept has evolved to encompass a spectrum of multifocal neoplastic or preneoplastic changes. Field cancerization has been described in a variety of tissues that include the oral mucosa, esophagus, stomach, colon, anal mucosa, cervix, bladder, and skin. In the initial phase of field cancerization, a patch of abnormal cells arises from a genetically altered stem cell. Mutations such as p53 that impart a growth advantage allow the patch to create an expanding precancerous field. With molecular techniques, precancerous clonal fields that are 7 cm and greater in diameter have been detected in oral and esophageal mucosae [1]. Ultimately, additional mutations lead to clonal divergence and the development of cancers within the precancerous field. Field cancerization helps explain the presence of multifocal tumors and the formation of new tumors in an area where one cancer has been resected. Multiple p53 mutations can be detected by DNA sequence analysis in normal-appearing skin adjacent to non-melanoma skin cancer of the head and neck [2]. Cytogenetic analyses of basal cell carcinomas have indicated that some tumors are composed of multiple cytogenetically unrelated clones, suggesting that field cancerization can result in clinically inapparent “collision tumors” [3]. Psoralen and ultraviolet A (PUVA) therapy may increase risk of non-melanoma skin cancer through p53 and other mutations that lead to field

D. M. Elston

cancerization. Signature PUVA-induced mutations differ from those produced by ultraviolet light alone [4]. The presence of field cancerization has been used to explain the high incidence of second tumors in patients with head and neck cancer. In one study, 21 patients with head and neck cancer, infusions of iododeoxyuridine and/or bromodeoxyuridine followed by monoclonal antibody staining identified epithelial disorder with suprabasal S-phase nuclei in tissue surrounding the cancer, supporting field cancerization [5]. Clonal expansion has been demonstrated in tissue surrounding gastric carcinomas by identification of mitochondrial DNA mutations through laser-capture microdissection and polymerase chain reaction [6]. Selective growth advantage of clones of normal-appearing cells surrounding both colon and head and neck cancers is imparted by TGFBR1*6A, a variant of the type I transforming growth factor (TGF)-beta receptor (TGFBR1). The highest ratio of abnormal to normal allele is present at the tumor edge, but extends at least 2 cm from the tumor [7]. 14–3–3 sigma, a cell cycle regulating protein, is often lost in cancers as a result of hypermethylation or induction of a ligase that targets the protein for proteasomal degradation. Loss is also noted in the surrounding apparently normal tissue, suggesting a role in field cancerization. The normal protein acts as a tumor suppressor through binding to eukaryotic initiation factor 4B. In the absence of the protein, aberrant mitotic translation often results in binucleate cells or aneuploidy [8]. About 72% of the mucosal biopsies adjacent to squamous cell carcinoma of the head and neck demonstrate aberrations in protein expression similar to the adjacent cancers [9]. Methylation of O-6-methylguanine-DNA methyltransferase (a DNA repair gene) is frequently found in colorectal cancer as well as the apparently normal adjacent mucosa [10]. In patients with lung cancer, evidence of allelic imbalance and alterations in p53 and cyclin D1 expression are found in 83% of specimens from histologically normal areas of the bronchi of the upper and lower lobes [11]. Telomeres stabilize the chromosome. When telomere shortening reaches a critical threshold, chromosomal instability results in “genomic crisis” with widespread cell death and the potential for immortal clones. Telomere measurement via quantitative fluorescence in situ hybridization has identified telomere shortening in esophageal squamous cell carcinomas, but also in nearby non-neoplastic esophageal epithelium [12]. Evidence of altered telomeres as well as unbalanced allelic loci are

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When Is a Skin Cancer a Cancer:- The Histopathologist’s View

present in breast tumors and adjacent normal-appearing tissue extending at least 1 cm beyond the tumor [13]. The evidence supporting field cancerization in the skin and other organ systems is overwhelming. It explains the presence of fields of AKs in sun-damaged skin and the eventual progression to invasive SCC. It remains for the dermatopathologist to determine when that transition takes place.

2.2 Histologic Diagnosis of Skin Cancers Clinical misdiagnosis of SCC as “hypertrophic AK” is particularly common on the dorsal hands, ears, and scalp. Various new technologies, including dermoscopy, spectroscopy, confocal microscopy, ultrasonography, computed tomography, magnetic resonance imaging, optical coherence tomography, fluorescence imaging, positron emission tomography, and terahertz imaging have been investigated as means of noninvasive tests to improve clinical diagnosis of possible skin cancers, but to date none has replaced biopsy as the gold standard [14]. Both AK and SCC can demonstrate a spectrum of cytologic changes from mild to high-grade atypia. Features of high-grade atypia include a high nuclear to cytoplasmic ratio, nuclear hyperchromasia, prominent nucleoli, red nucleoli, nucleoli with stems, and the presence of a thick irregular nuclear envelope. Individual cells in an AK may be every bit as atypical as those in an invasive SCC, and karyometric analysis has not been successful in distinguishing the two [15]. Actinic keratoses with high-grade atypia are likely to give rise to invasive SCC, and the cytologic features of the actinic keratosis typically resemble those of the invasive component. I will not dwell on the debate regarding nomenclature for actinic keratoses. Suffice it to say that some believe that all actinic keratoses should be termed keratinocytic intraepithelial neoplasia (KIN) or SCC in situ. Others feel that these designations are not an improvement over the term actinic keratosis and do little to improve the care of patients. Regardless of what terms we use, the molecular data cited above suggest that tumorigenesis in skin is a multistep process in which clones of cells gain a growth advantage that allows them to expand over large areas of skin. Successive

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aberrations eventually lead to competence for invasion and metastasis. The focus of my discussion will be on how the pathologist determines when a population of atypical squamous cells gains competence to invade and metastasize. An adequate specimen is critical for the accurate diagnosis of non-melanoma skin cancers. In a study of 57 consecutive patients with penile squamous cell carcinoma, the interpretation of the initial biopsy was discordant with staging at the time of penectomy in 30% of cases. In two patients, a diagnosis of cancer could not be established in the initial biopsy material. The depth of invasion could not be determined in 91% of the biopsy specimens [16]. In contrast, a retrospective study of 40 consecutive periocular tumors found the biopsy results to be concordant with the excisional specimen in 19 of 20 incisional biopsy specimens and 17 of 20 punch biopsy specimens [17]. A specimen that provides adequate depth is key to a correct diagnosis. Histologic invasion is characterized by irregular islands of cells or single keratinocytes that breach the basement membrane zone and extend between collagen bundles into the zone of solar elastosis. Hyperplastic AKs demonstrate a complex pattern of budding that extends into an expanded papillary dermis, but not the reticular dermis or the zone of solar elastosis. Step sections may be required to demonstrate the area of invasive carcinoma. Once a tumor has invaded, there is little consensus as to what histologic features should be cited in the pathology report. Synoptic reporting modules for nonmelanoma skin cancer exist, just as they do for melanoma, but they are seldom used [18]. A study of 184 patients with cutaneous squamous cell carcinoma evaluated carcinoma type, Breslow thickness, level of invasion, ulceration, growth pattern, and mitotic index as risk factors for recurrence or metastasis. Ulceration was a significant risk factor for metastasis, as were level and thickness. Mitotic index and degree of differentiation were somewhat important [19]. Cassarino, Derienzo, and Barr separate cutaneous squamous cell carcinomas into categories with a low (£ or = 2%), intermediate (3–10%), or high (>10%) risk of metastasis. Low-risk SCCs include those tumors arising in actinic keratosis, HPV-associated tumors, trichilemmal carcinoma, and SCCs unassociated with radiation. The intermediate-risk category includes acantholytic SCC, intraepidermal epithelioma with invasive carcinoma, and lymphoepithelioma-like carcinoma. The high-risk types include those in immunosuppressed

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patients, anaplastic invasive carcinoma originating in Bowen’s disease, de novo SCC, adenosquamous carcinoma, malignant proliferating pilar tumors, and SCC arising in radiation ports and burn scars [20, 21].

2.3 Advanced Diagnostic Techniques The number of silver-stained nucleolar organizer regions (AgNORs) becomes progressively higher with tumor progression from AK to SCC (P < 0.001) [22]. Interpretation requires experience and pathologists must be careful that they are counting AgNORs rather than nucleoli. A study of nuclear Ki-67 (MIB-1) expression 15 actinic keratoses and seven invasive squamous cell carcinomas showed staining of basal and suprabasal nuclei in actinic keratoses to the mid-zone of the epidermis. In invasive squamous cell carcinomas, MIB-1 positivity was variable in all layers of the epidermis [23]. In a study of expression of markers associated with tumor progression, p53 was moderately expressed in AKs and strongly expressed in SCCs, p63 staining was variable in SCC, but strong in AK, survivin was confined to the basal layer in AKs but more diffusely expressed in eight of ten SCCs, and and hTERT was strongly expressed in both [24]. In another study, iImmunoperoxidase staining for p53 and bcl-2 protein expression was greater in invasive SCC than in AK [25] (Table 2.2). Oh et al. found that nuclear expression of p27 is decreased in invasive squamous cell carcinoma. Ki-67 expression is increased and is more likely to be seen in tumor islands while it is restricted to the basal layer in AKs [26]. Fas ligand expression increases in both T cells and epithelial cells with progression from AK to SCC. In one study, FasL-expressing tumor cells were present in nine of 18 SCCs, compared with only one of 20 AKs (P < 0.005) [27].

Table 2.2 Histologic features that distinguish invasive SCC from AK Irregular islands Single-file keratinocytes Cells breach the basement membrane zone Cells extend between collagen bundles Cells extend into the zone of solar elastosis

D. M. Elston

A study of cyclin A and beta-catenin expression by immunohistochemistry in actinic keratoses and invasive SCC found that diffuse cyclin A expression was more common in poorly differentiated tumors (P < 0.0001) and reduced or absent membranous beta-catenin staining was found more often in SCC than in AK (P = 0.03) [28]. A study of protein and mRNA expression of RPE65 in actinic keratosis and squamous cell carcinoma found that mRNA expression was reduced in both. Protein expression was reduced and quite irregular in AK and absent in invasive SCC [29]. Some authors have found that the intensity of p16 protein expression is greater in SCC than in AK and progression from actinic keratosis to SCC of the skin is correlated with deletion of the 9p21 region encoding p16 [30–32]. Aberrant expression of nuclear lamins A and C is noted in skin tumors, and the staining with lamin C tends to be more diffuse in SCC than in AK [33]. Expression of the retinoblastoma protein p16 INK4a is weak in AK, and stronger in invasive SCC with strongest staining toward the center of the tumor [34]. Metalloproteinase-2 expression is predictive of the aggressiveness of cutaneous SCCs [35]. Staining intensity correlates with cellular atypia, neovascularization, inflammation, and the invasive tumor front. Other molecular techniques have shown little value in distinguishing SCCs from AKs. In an immunohistochemical study of p53 phosphorylation state in 44 AKs and 62 SCCs, overexpression was similar in both, suggesting it is an early change in the pathogenesis of SCC and has little value in differentiating AK from SCC [36] (Table 2.3). Similarly, analysis of promoter hypermethylation of death-associated protein kinase Table 2.3 Promising advanced diagnostic tests to distinguishing invasive SCC from AK AgNOR counts p63 expression Survivin expression p53 expression bcl-2 protein expression p27 expression Ki-67 expression Fas ligand expression Cyclin A expression Beta-catenin expression RPE65 expression p16 expression Lamin expression Metalloproteinase expression

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When Is a Skin Cancer a Cancer:- The Histopathologist’s View

Table 2.4 Advanced diagnostic tests that do not appear to distinguish invasive SCC from AK p53 phosphorylation state Promoter hypermethylation of death-associated protein kinase Promoter hypermethylation of p16 tumor suppressor gene (COX)-2 expression E-cadherin gene promoter hypermethylation Expression of endothelin

and p16 tumor suppressor gene were each found in one of seven SCCs and none of nine AKs, making it unlikely that these markers will be helpful in distinguishing the two. Cyclooxygenase (COX)-2 expression is upregulated in both AKs (31%), and SCC (40%) [37]. E-cadherin gene promoter hypermethylation was detected in six of seven cases of invasive squamous cell carcinoma, and four of nine AKS [38]. A study using quantitative polymerase chain reaction to measure the level of gene transcription of three endothelin proteins and two endothelin receptors found no significant increase in expression in AK, Bowen’s disease, or SCC, suggesting these assays are of little value in predicting tumor progression for cutaneous squamous cancers [39] (Table 2.4). While molecular techniques have improved our ability to distinguish SCCs from AKs, they have also reinforced the concept that non-melanoma skin cancers arise through a complex series of aberrations at the molecular level. Actinic keratoses represent a spectrum along the continuum to invasive cancer. They are the most visible manifestation of field cancerization which creates a population of atypical cells with the potential to progress to invasive malignancy capable of metastasis.

References 1. Braakhuis BJ, Tabor MP, Kummer JA, Leemans CR, Brakenhoff RH. A genetic explanation of Slaughter’s concept of field cancerization: evidence and clinical implications. Cancer Res. 2003 Apr 15;63(8):1727–30 2. Kanjilal S, Strom SS, Clayman GL, Weber RS, el-Naggar AK, Kapur V, Cummings KK, Hill LA, Spitz MR, Kripke ML, et al p53 mutations in nonmelanoma skin cancer of the head and neck: molecular evidence for field cancerization. Cancer Res. 1995 Aug 15;55(16):3604–9 3. Mertens F, Heim S, Mandahl N, Johansson B, Mertens O, Persson B, Salemark L, Wennerberg J, Jonsson N, Mitelman F. Cytogenetic analysis of 33 basal cell carcinomas. Cancer Res. 1991 Feb 1;51(3):954–7

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4. Stern RS, Bolshakov S, Nataraj AJ, Ananthaswamy HN. p53 mutation in nonmelanoma skin cancers occurring in psoralen ultraviolet a-treated patients: evidence for heterogeneity and field cancerization. J Invest Dermatol. 2002 Aug;119(2):522–6 5. Kotelnikov VM, Coon JS, Taylor S, Hutchinson J, Panje W, Caldareill DD, LaFollette S, Preisler HD. Proliferation of epithelia of noninvolved mucosa in patients with head and neck cancer. Head Neck. 1996 Nov-Dec;18(6):522–8 6. McDonald SA, Greaves LC, Gutierrez-Gonzalez L, RodriguezJusto M, Deheragoda M, Leedham SJ, Taylor RW, Lee CY, Preston SL, Lovell M, Hunt T, Elia G, Oukrif D, Harrison R, Novelli MR, Mitchell I, Stoker DL, Turnbull DM, Jankowski JA, Wright NA. Mechanisms of field cancerization in the human stomach: the expansion and spread of mutated gastric stem cells. Gastroenterology. 2008 Feb; 134(2): 500–10 7. Bian Y, Knobloch TJ, Sadim M, Kaklamani V, Raji A, Yang GY, Weghorst CM, Pasche B. Somatic acquisition of TGFBR1*6A by epithelial and stromal cells during head and neck and colon cancer development. Hum Mol Genet. 2007 Dec 15;16 (24):3128–35 8. Wilker EW, van Vugt MA, Artim SA, Huang PH, Petersen CP, Reinhardt HC, Feng Y, Sharp PA, Sonenberg N, White FM, Yaffe MB. 14–3–3sigma controls mitotic translation to facilitate cytokinesis. Nature. 2007 Mar 15;446(7133):329–32 9. Roesch-Ely M, Nees M, Karsai S, Ruess A, Bogumil R, Warnken U, Schnölzer M, Dietz A, Plinkert PK, Hofele C, Bosch FX. Proteomic analysis reveals successive aberrations in protein expression from healthy mucosa to invasive head and neck cancer. Oncogene. 2007 Jan 4;26(1):54–64 10. Shen L, Kondo Y, Rosner GL, Xiao L, Hernandez NS, Vilaythong J, Houlihan PS, Krouse RS, Prasad AR, Einspahr JG, Buckmeier J, Alberts DS, Hamilton SR, Issa JP. MGMT promoter methylation and field defect in sporadic colorectal cancer. J Natl Cancer Inst. 2005 Sep 21;97(18):1330–8 11. Sikkink SK, Liloglou T, Maloney P, Gosney JR, Field JK. In-depth analysis of molecular alterations within normal and tumour tissue from an entire bronchial tree. Int J Oncol. 2003 Mar;22(3):589–95 12. Kammori M, Poon SS, Nakamura K, Izumiyama N, Ishikawa N, Kobayashi M, Naomoto Y, Takubo K. Squamous cell carcinomas of the esophagus arise from a telomere-shortened epithelial field. Int J Mol Med. 2007 Dec;20(6):793–9 13. Heaphy CM, Bisoffi M, Fordyce CA, Haaland CM, Hines WC, Joste NE, Griffith JK. Telomere DNA content and allelic imbalance demonstrate field cancerization in histologically normal tissue adjacent to breast tumors. Int J Cancer. 2006 July 1;119(1):108–16 14. Mogensen M, Jemec GB. Diagnosis of nonmelanoma skin cancer/keratinocyte carcinoma: a review of diagnostic accuracy of nonmelanoma skin cancer diagnostic tests and technologies. Dermatol Surg. 2007 Oct;33(10):1158–74 15. Ranger-Moore J, Bozzo P, Alberts D, Einspahr J, Liu Y, Thompson D, Stratton S, Stratton MS, Bartels P. Karyometry of nuclei from actinic keratosis and squamous cell cancer of the skin. Anal Quant Cytol Histol. 2003 Dec;25(6):353–61 16. Velazquez EF, Barreto JE, Rodriguez I, Piris A, Cubilla AL. Limitations in the interpretation of biopsies in patients with penile squamous cell carcinoma. Int J Surg Pathol. 2004 Apr;12(2):139–46 17. Rice JC, Zaragoza P, Waheed K, Schofield J, Jones CA. Efficacy of incisional vs punch biopsy in the histological

14 diagnosis of periocular skin tumours. Eye. 2003 May;17(4): 478–81 18. Khanna M, Fortier-Riberdy G, Dinehart SM, Smoller B. Histopathologic evaluation of cutaneous squamous cell carcinoma: results of a survey among dermatopathologists. J Am Acad Dermatol. 2003 May;48(5):721–6 19. Petter G, Haustein UF. Squamous cell carcinoma of the skin--histopathological features and their significance for the clinical outcome. J Eur Acad Dermatol Venereol. 1998 July;11(1):37–44 20. Cassarino DS, Derienzo DP, Barr RJ. Cutaneous squamous cell carcinoma: a comprehensive clinicopathologic classification. Part one. J Cutan Pathol. 2006 Mar;33(3):191–206 21. Cassarino DS, Derienzo DP, Barr RJ. Cutaneous squamous cell carcinoma: a comprehensive clinicopathologic classification–part two. J Cutan Pathol. 2006 Apr;33(4):261–79 22. Aroni K, Mastoraki A, Kyriazi E, Liossi A, Ioannidis E. Silver-stained nucleolar organizer regions and immunoglobulins in cutaneous squamocellular tumors. Pathol Res Pract. 2007;203(12):857–62 23. Bordbar A, Dias D, Cabral A, Beck S, Boon ME. Assessment of cell proliferation in benign, premalignant and malignant skin lesions. Appl Immunohistochem Mol Morphol. 2007 June;15(2):229–35 24. Park HR, Min SK, Cho HD, Kim KH, Shin HS, Park YE. Expression profiles of p63, p53, survivin, and hTERT in skin tumors. J Cutan Pathol. 2004 Sept;31(8):544–9 25. Hussein MR, Al-Badaiwy ZH, Guirguis MN. Analysis of p53 and bcl-2 protein expression in the non-tumorigenic, pretumorigenic, and tumorigenic keratinocytic hyperproliferative lesions. J Cutan Pathol. 2004 Nov;31(10):643–51 26. Oh CW, Penneys N. P27 and mib1 expression in actinic keratosis, Bowen disease, and squamous cell carcinoma. Am J Dermatopathol. 2004 Feb;26(1):22–6 27. Satchell AC, Barnetson RS, Halliday GM. Increased Fas ligand expression by T cells and tumour cells in the progression of actinic keratosis to squamous cell carcinoma. Br J Dermatol. 2004 July;151(1):42–9 28. Brasanac D, Boricic I, Todorovic V, Tomanovic N, Radojevic S. Cyclin A and beta-catenin expression in actinic keratosis, Bowen’s disease and invasive squamous cell carcinoma of the skin. Br J Dermatol. 2005 Dec;153(6):1166–75 29. Foedinger D. Expression of RPE65, a putative receptor for plasma retinol-binding protein, in nonmelanocytic skin tumours. Br J Dermatol. 2005 Oct;153(4):785–9

D. M. Elston 30. Tyler LN, Ai L, Zuo C, Fan CY, Smoller BR. Analysis of promoter hypermethylation of death-associated protein kinase and p16 tumor suppressor genes in actinic keratoses and squamous cell carcinomas of the skin. Mod Pathol. 2003 July;16(7):660–4 31. Hodges A, Smoller BR. Immunohistochemical comparison of p16 expression in actinic keratoses and squamous cell carcinomas of the skin. Mod Pathol. 2002 Nov;15(11): 1121–5 32. Mortier L, Marchetti P, Delaporte E, Martin de Lassalle E, Thomas P, Piette F, Formstecher P, Polakowska R, Danzé PM. Progression of actinic keratosis to squamous cell carcinoma of the skin correlates with deletion of the 9p21 region encoding the p16(INK4a) tumor suppressor. Cancer Lett. 2002 Feb 25;176(2):205–14 33. Tilli CM, Ramaekers FC, Broers JL, Hutchison CJ, Neumann HA. Lamin expression in normal human skin, actinic keratosis, squamous cell carcinoma and basal cell carcinoma. Br J Dermatol. 2003 Jan;148(1):102–9 34. Nilsson K, Svensson S, Landberg G. Retinoblastoma protein function and p16INK4a expression in actinic keratosis, squamous cell carcinoma in situ and invasive squamous cell carcinoma of the skin and links between p16INK4a expression and infiltrative behavior. Mod Pathol. 2004 Dec;17(12): 1464–74 35. Fundyler O, Khanna M, Smoller BR. Metalloproteinase-2 expression correlates with aggressiveness of cutaneous squamous cell carcinomas. Mod Pathol. 2004 May;17(5): 496–502 36. Matsumoto M, Furihata M, Kurabayashi A, Ohtsuki Y. Phosphorylation state of tumor-suppressor gene p53 product overexpressed in skin tumors. Oncol Rep. 2004 Nov; 12(5):1039–43 37. Nijsten T, Colpaert CG, Vermeulen PB, Harris AL, Van Marck E, Lambert J. Cyclooxygenase-2 expression and angiogenesis in squamous cell carcinoma of the skin and its precursors: a paired immunohistochemical study of 35 cases. Br J Dermatol. 2004 Oct;151(4):837–45 38. Chiles MC, Ai L, Zuo C, Fan CY, Smoller BR. E-cadherin promoter hypermethylation in preneoplastic and neoplastic skin lesions. Mod Pathol. 2003 Oct;16(10):1014–8 39. Zhang Y, Tang L, Su M, Eisen D, Zloty D, Warshawski L, Zhou Y. Expression of endothelins and their receptors in nonmelanoma skin cancers. J Cutan Med Surg. 2006 NovDec;10(6):269–76

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Epidemiology of Non-Melanoma Skin Cancer Annette Østergaard Jensen, Anna Lei Lamberg, and Anne Braae Olesen

Key Points

› › › › › ›

Non-melanoma skin cancer (NMSC) is the most common cancer among fair-skinned people. NMSC incidence increases with age; approximately 90% of all NMSCs occur in individuals aged 50 years and older. The most common body site for NMSC is the chronically sun-exposed head and neck region. Mortality from NMSC is generally very low. NMSC patients have a higher risk of new NMSC and other cancers compared with the background population. NMSC is a disease with a substantial economical and social impact.

an increasing economic and social impact on the individual level as well as on the public health level. The prognosis of NMSC is relatively good and can be assessed by estimating morbidity rates and mortality rates. There are several potential methodological problems in studying NMSC. In many countries, NMSC information is not routinely or only partly collected. Moreover, the registration is often incomplete. New studies have added important details concerning the epidemiology of NMSC. However, the methodological problems may limit some of our interpretations of the NMSC epidemiological results.

3.2 Descriptive Epidemiology 3.1 Introduction Epidemiology is the study of frequency, distribution, causal determinants, prognosis, and mortality of diseases. Non-melanoma skin cancer (NMSC) is the most common cancer among fair-skinned people, and the frequency of the disease is often expressed by the number of new cases per 100,000 of the population per year (i.e., incidence rate). NMSC incidence has been increasing during the past 4 decades, and these cancers, i.e., basal cell carcinoma (BCC) and squamous cell carcinoma (SCC), represent

A. Ø. Jensen () Department of Dermatology, Aarhus Sygehus, Aarhus University Hospital, 8000 Aarhus C, Denmark e-mail: [email protected]

NMSC, including BCC and SCC, is the most common cancer among Caucasians. The incidence increases exponentially with age, and men generally have higher incidence rates than women (Fig. 3.1) [1–3]. The incidence of NMSC varies throughout the world, and the NMSC is estimated to far exceed even the most frequent cancers registered by the American Cancer Society [4]. For example, prostate cancer has the highest incidence among registered cancers by the American Cancer Society; however, it was projected to account for 218,890 cases in 2007. In contrast, NMSC is estimated to account for over one million cases, although it is not routinely registered (Table 3.1) [4]. On average, the NMSC incidence has increased 3–8% per year over the last 4 decades [5–7] among the Caucasian population [8]. In Denmark, there has been almost a threefold increase in incidence since the 1970s (Fig. 3.2). Furthermore, it is estimated that one in six Americans will develop skin cancer during

G. B. E. Jemec et al. (eds.), Non-Surgical Treatment of Keratinocyte Skin Cancer, DOI: 10.1007/978-3-540-79341-0_3, © Springer-Verlag Berlin Heidelberg 2010

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Fig. 3.1 Age-and sex-specific incidence rates of NMSC per 100,000 persons in Denmark in 2003

1200 Male Female 1000

incidence

800

600

400

200

0 0-

5- 10- 15- 20- 25- 30- 35- 40- 45- 50- 55- 60- 65- 70- 75- 80- 80+ age

Table 3.1 Estimated incidence of NMSC in the USA compared with the most common cancers registered by The American Cancer Society in 2007 Type Estimated new cases/ year/US in 2007 NMSC (estimated) 1 million Cancer all sites (excl. NMCS) 1.4 million Prostse 218,890 Lung and bronchus 213,380 Breast 178,480 Colon bladder 153,760 Urinary bladder 67,160 Non-Hodgkin lymphoma 63,190 Melanoma 59,940 Source: www.cancer.org/downloads/STT/CAFF2007PWSecured. pdf

their lifetime [9]. As such, NMSC represents and will continue to represent a significant burden to public health resources.

3.3 Incidence

sunlight exposure on skin. Finland reports some of the lowest incidence rates of 49 and 45 cases per 100,000 for men and women, respectively [10]. In contrast, the highest incidence of BCC is found in northern Australia with incidence rates of 2,145 and 1,259 cases per 100,000 for men and women, respectively (Table 3.2) [3, 11–13]. While NMSC is not routinely recorded by cancer registries in Australia, the incidence has been monitored using a series of household surveys, the latest of which was conducted in 2002 [3]. This survey reported an over threefold difference in BCC incidence from the south to the north of the country (Table 3.2) [3].

3.3.1.1 Gender and Age Distribution BCC incidence increases with age, and approximately 90% of all BCC occur in individuals aged 50 years and older [14, 15]. Generally, men have an approximately 1.1–1.9 times higher incidence of BCC than women. However, among those aged less than 50 years, incidence rates for women exceed those for men [3, 5, 14, 16].

3.3.1 Basal Cell Carcinoma 3.3.1.2 Trends in BCC Incidence BCC is approximately two to four times more common than SCC (Table 3.2). The geographic distribution of BCC varies with latitudes due to the impact of

A consistent increase in BCC of 2–10% per year has been observed over the last 4 decades among Caucasians

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Epidemiology of Non-Melanoma Skin Cancer

Fig. 3.2 Age-standardized incidence rates of NMSC per 100,000 persons per year in Denmark from 1943 to 2003 (world age-standardized)

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80 Male Female

70 60

incidence

50 40 30 20 10 0 1940

1950

1960

1970 year

1980

1990

Table 3.2 Age-standardized incidence rates of BCC and SCC in Europe, North America, and Australia Year of study Incidence rate of BCC Incidence rate of SCC per 100,000 per 100,000 Male Female Male Female Europe Scotland [16] Northern Ireland [14] Finland [10] Switzerland, Canton of Vaud [7] North America New Hampshire [6] Arizona [2] New Mexico [15] Australia North region(<29°S) Central region (29°S–37°S) South region (>37°S) [3]

Nambour, Queensland [12]

2000

Standard population

2001–2003 1993–2002 1991–1995 1995–1998

61 94 49 75

47 72 45 67

24 46 7 29

9 23 4 17

1993–1994 1996 1998–1999

310 936 930

166 497 486

97 271 356

32 112 150

USA, 1970 USA, 1970 USA, 2000

2002

2,145

1,259

1,240

429

World

1985–1992

1,088 646 2,074

843 462 1,579

473 306 1,035

400 171 472

World

[17]. The annual percent change in BCC rates increases with age for men, but not for women. Two US studies have reported an increase in incidence rate among younger females [6, 18]. This may explain why incidence rates in women aged less than 50 years have surpassed those of men [5].

World World World World

In New Hampshire (USA), the highest annual increase was observed among women aged 45–54 years compared with the other age groups [6]. In Olmsted County Minnesota, an increase between 1976 and 2003 was seen in the younger population (those aged <40 years), driven by an increase in BCC

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incidence among women but not men [18]. This increase in the younger population is not consistent, however. Encouraging data has been reported in Australia, where sun-protection programs have been in operation since 1985 [19]. Between 1985 and 2002, BCC rates in Australia for people younger than 60 years showed no substantial increase despite overall increases in the age-standardized rates of BCC [3].

3.3.1.3 Body-Site Distribution and Histological Classiﬁcation of BCC BCC most frequently localizes to the head and neck in both genders; however, there has been a change in tumor localization over the last 30 years. Whereas the largest increase of tumors was seen in the head and neck region, the proportion of BCCs in the head and neck region relative to that on the trunk, arms, and legs has decreased over time for both genders. This pattern is particularly evident among younger age groups [5, 6, 20]. BCC is divided into subtypes with different clinical behavior and most likely different aetiology [20]. Nodular BCC is the most common subtype of BCC followed by superficial BCC and the less common morphea subtype. The proportional distribution between the subtypes is not consistent worldwide, but in general, nodular BCCs account for 50–80% of all lesions, and superficial BCCs account for 15–25% of all lesions [21]. Nodular BCC is most frequently seen on body sites prone to chronic sun exposure, such as the head and neck region. Superficial BCC is dominant on areas exposed to intermittent sunlight, such as on the trunk, but is also highly prevalent on the extremities. Superficial BCC more frequently presents in younger female patients than nodular BCC [20].

3.3.2 Squamous Cell Carcinoma Similar to BCC, the geographic distribution of SCC varies by latitude. Again, Finland has the lowest recorded incidence rates. In 1991–1995 the rates were estimated at seven and four cases per 100,000 for men and women, respectively [10]. Similar to BCC, Australia has the highest incidence rates. In 2002 in North Australia, the

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rates were estimated at 1,240 and 429 cases per 100,000 for men and women, respectively [3].

3.3.2.1 Gender and Age Distribution The incidence increases dramatically with age for both men and women [2, 6, 14]. Men have a 1.1–2.9 times higher incidence of SCC than women (Table 3.2). Rates are consistently higher among men than women, except among those aged < 40 years, where several studies report no significant gender variation [2, 6, 14].

3.3.2.2 Body-Site Distribution For both genders, the most common body site for SCC is the chronically sun-exposed head and neck region, but there is substantial variation in site of the cancer localization in men and women. In women, only approximately 46% of lesions are located on the head and neck region, while approximately 65% of lesions in men present at these sites [2]. The second most common site is the upper limbs, especially on the dorsum of the hand, which accounts for approximately 20–25% of the cases [2, 13]. The percentage of lesions on the lower limbs is significantly higher in women (15%) than men (2–4%). These patterns are consistent across studies from America, Europe, and Australia [2, 3, 6, 13].

3.3.2.3 Trends in SCC Incidence Trends in SCC incidence are not consistent. In Arizona (USA), there were no significant changes in the ageadjusted incidence rates for any age group in either gender between 1985 and 1996. Furthermore, no substantial changes in body-site distribution were seen [2]. In contrast, the incidence rates for SCC in New Hampshire, USA, between 1979–1980 and 1993–1994, have increased by 235% in men and 350% in women, a far more rapid increase than the changes seen in BCC. Although the absolute increase in rates was largest for tumors in the head and neck region, the relative increase in terms of percentages, was largest for those of the lower limbs in women and the trunk in men [6]. The same increasing trend has been reported in Australia. Between 1985 and 2002, a twofold increase

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Epidemiology of Non-Melanoma Skin Cancer

was reported; however, no significant increase was found in the incidence rate of SCC among individuals aged less than 50 years [3]. In Europe data from the Cancer Registry in the Swiss Canton of Vaud, also reports an increase in incidence between 1976 and 1990, but between 1990 and 1997, a decline has been noted for both sexes [7].

3.4 Methodological Problems in Studying NMSC Incidence It is essential to be aware of the limitations in studying NMSC incidence. Worldwide, data on NMSC are not routinely collected by many cancer registries; in some cancer registries only SCCs are recorded, while in others BCCs and SCCs are recorded as one entity [22]. Likewise, in the Danish Cancer Registry, registration of NMSC is incomplete [23–28]. In 1995, a Danish nationwide cohort was established by prospectively recording all patients with NMSC seen by Danish dermatologists and collaborating dermatopathologists. Comparing the number of first primary cases of NMSC registered in this prospective cohort with the number of first primary cases registered in the Danish Cancer Registry, an incomplete registration of 11–12% was found [29], but it has been estimated as high as 40% [30]. The reasons for this incomplete registration include (1) underreporting due to the high cure rate, leading clinicians to regard these skin cancers as trivial; (2) the large number of these cancers threatens to overwhelm cancer surveillance systems; and (3) difficulties in ascertaining cases, since multiple lesions are often diagnosed simultaneously and many people have multiple lesions in their lifetime [12, 31]. Therefore, the true incidence and prevalence of NMSC is unknown and comparisons of occurrence data over time, or between different populations must be interpreted with caution [32].

3.5 NMSC Prognosis and Mortality Mortality from BCC is very low and reports have shown that the mortality rate may have dropped further from 1980 to 2000 [33]. Mortality from SCC is approximately 12 times higher than for BCC. The mortality

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rate in Denmark is 0.8 per 100,000 per year [1], but inaccuracies in death certificate information may overestimate the actual mortality [34–36]. Several factors may influence the outcome of NMSC. The simplest way to assess health outcome in a particular population, is by estimating morbidity (diseases) and mortality (deaths). More complex health indicators include discomfort such as disfigurement, disability, and dissatisfaction (quality of life) [37]. Prognostic factors for NMSC can be divided into NMSC-related factors, treatment factors, and patient factors [38]. NMSC-related factors cover type of NMSC and the risk profile of the tumor. For SCC a higher mortality is seen in tumors located on the lip, ears, and anogenital region [36]. Other high-risk predictors include tumor size (>2 cm), poor differentiation, and deep invasion [39]. For BCC, aggressiveness of the tumor is also dependent on tumor location: head and neck tumors (especially those located on the ear and eyelid) are more commonly metastatic [36]. Markers of high risk for BCCs also include tumor size (>2 cm) and histological subtype (morphea-form BCC is more malignant than noduloulcerative and superficial BCC) [39]. In any case, BCCs with squamous metaplasia are more aggressive in nature and can cause mortality [39]. Treatment-related factors impact on NMSC patient management may be modified by the clinical performance of the treating physician, and the patient’s acceptance of the treatment plan. As regards outcome, total tumor removal is most important. However, an optimal cosmetic result is often given a higher priority than total removal due to the slow growth and low metastatic rate of these tumors. The consequences are increased morbidity and in worst case, higher mortality [36, 40]. Patient-related factors encompass general demographic characteristics, such as age, gender, and race, which have been reported to predict the prognosis of NMSC. Higher mortality is seen with increasing age and male gender among Caucasians [36]. A patient’s physical performance and immune status, in particular, prior to NMSC diagnosis is important. The presence of chronic comorbid conditions impacts on the prognosis of most diseases [41]. It is well known that NMSCs, particularly SCC, are extremely aggressive and account for the vast majority of deaths among organ transplant recipients [42]. Patient lifestyle may also have an impact on physical performance, i.e., a healthy lifestyle avoiding smoking and alcohol may improve the patients’ physical

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performance and thereby the outcome of NMSC. The individual patient’s compliance according to diagnosis is also important. Some patients can delay presenting for treatment, given the slow-growing nature of their tumor which can significantly worsen prognosis.

3.6 All-Cause Mortality In both Denmark and the USA, a high degree of misclassification regarding the cause of death from skin cancer has been found among NMSC patients [33, 35, 36]. This causes an overestimation of the mortality rate of these cancers. In general, mortality of NMSC from other causes other than skin cancer is not clear, although information about this may contribute to a better understanding of the aetiology and clinical course of NMSC. A Danish study examined the 10-year total and causespecific mortality of all BCC and SCC patients registered by Danish dermatologists in 1995 compared to that of the general Danish population [43]. For BCC, they found a slight reduction in total mortality (mortality rate ratio (MRR), 0.89; 95% confidence interval (CI): 0.83–0.95) with decreased MRRs for cardiovascular diseases and diseases of the digestive tract. Death from malignant melanoma was increased. In contrast, among SCC patients, they observed an increased total mortality (MRR, 1.61; 95% CI: 1.27–2.02) with elevated MRRs for cardiovascular diseases, chronic obstructive pulmonary diseases (COPD), and cancer [43]. These findings indicate that the reduced mortality among patients with BCC is likely explained by a healthy lifestyle, avoiding smoking and seeking sun exposure. In contrast, the increased mortality among patients with SCC is likely explained by an increased mortality related to causes associated with smoking and impaired immune function.

3.7 Risk of De Novo Occurrence of NMSC As the skin is the body’s largest organ and mortality from NMSC is low, de novo occurrences are commonly seen among NMSC patients. A recent study reported a risk of 44% at 3 years of a new BCC among those with a history of BCC and a risk of 18% at 3 years of a new SCC after an earlier SCC diagnosis [44]. The risk of

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SCC after BCC was only 6% at 3 years whereas the risk of BCC after SCC was 43% at 3 years [44].

3.7.1 Risk of Other Malignancy After NMSC There is substantial evidence that the risk of developing a second primary cancer following a diagnosis of NMSC is increased [23, 24, 45–48], and that a history of NMSC may worsen the prognosis in patients with a second primary cancer [49, 50]. Explanations generally focus on a common predisposing factor for NMSC and the subsequent cancer. These include immune suppression either induced by UV-light or immunosuppressive therapies [23, 51], infection with human papilloma virus (HPV) [52] and Epstein-Barr virus (EBV) [53], cigarette smoking [23], and poor DNA repair capacity due to either genetic or environmental factors [54, 55].

3.7.2 Risk of Other Malignancy After BCC Several European, Australian, and American studies have found an increased risk of cancer of the lip, mouth, pharynx, lung, malignant melanoma, breast, and nonHodgkin’s lymphoma among patients with a previous history of BCC [24, 45, 47, 50, 56]. An increased risk of cancer of the lip and mouth may be associated with UV-light and attributable, at least in part, to smoking, although the smoking association is not a consistent finding [6]. The increased risk for cancer of the lung and pharynx may also have smoking as the common aetiological factor [24], but more recent research has attributed the association between BCC and pharynx, lung and breast cancer with a reduced DNA repair capacity [55]. An increased risk of malignant melanoma was the most convincing (with a relative risk between 2 and 3) and consistent finding reported in patients with a history of BCC. UV-light, skin phenotype, and UV-light exposure pattern most likely explain the link between BCC and malignant melanoma. The association between BCC and a subsequent diagnosis of Non-Hodgkin’s lymphoma has been linked to general immunosuppression which is a risk factor for both BCC and Non-Hodgkin’s lymphoma [57]. Immunosuppression due to UV-light

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Epidemiology of Non-Melanoma Skin Cancer

has also been suggested, however, in 2005, a Swedish study found that a history of high UV-light exposure was associated with a reduced risk of non-Hodgkin’s lymphoma. Therefore, the positive association between BCC and non-Hodgkin’s lymphoma is unlikely to be mediated through UV-light exposure [58]. Although a generally increased risk of a second primary cancer following BCC has been found, a reduced risk of oesophageal, stomach, rectal, and pancreas cancers was found in patients with a history of BCC [50]. This protective finding among BCC patients has been associated with different social class correlates or other general lifestyle factors, more than an actual underlying biological mechanism. However, a hypothesis of a link between UV-B-light exposure and reduction of cancer risk through photo production of vitamin D in the skin has been postulated [59, 60]. To investigate this hypothesis, a multinational study examined the joint occurrence of skin cancers and other primary cancers in a cohort from 11 different cancer registries, divided into sunny countries (Australia, Singapore, and Spain) and less sunny countries (Canada, Sweden, Denmark, Finland, Island, Norway, Scotland, and Slovenia). By comparing the incidence of primary cancers between the sunny and less sunny countries they found evidence that vitamin D production in the skin reduces the risk of digestive cancers, as well as lung, breast, prostate, bladder, and kidney cancers [60].

3.7.3 Risk of Other Malignancies After SCC An increased risk of cancer of the lip, mouth, malignant melanoma, Non-Hodgkin’s lymphoma, Hodgkin’s lymphoma, and myeloma has been found among patients with a previous history of SCC [23, 45, 46, 48, 50]. An increased risk of cancer of the lip, mouth, and lung may likely be associated with smoking, since smoking in an American study was found to be a risk factor for SCC [6]. As for BCC, malignant melanoma and SCC share a common risk factor in UV-light exposure. However, the pattern of exposure is different; SCC is associated with cumulative UV-light exposure, whereas BCC and malignant melanoma are associated with recreational and intermittent UV-light exposure [61, 62]. The risk for malignant lymphomas among patients with a previous history of SCC has been

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associated with general immunosuppression [23, 45, 60]. This association may be linked through two different pathways: either by increasing the risk of acquiring infection with an oncogenic virus, such as HPV or EBV [52, 53], or reducing the body’s ability to mount defenses against a developing tumor, irrespective of the presence or absence of infection.

3.8 Methodological Problems in Studying Relative Effects of NMSC The incomplete registration of NMSC also provides methodological problems in studying the relative effects of NMSC, if registered and unregistered NMSC patients differ according to risk factors and outcome variables. Such differential data completeness will lead to bias in the estimates of relative effects [32]. Patients are usually followed closely after a cancer diagnosis and could be subject to surveillance bias leading to the diagnosis of a second primary cancer. This could explain the association between NMSC and the increased risk of another primary cancer. However, one Australian study examined the presence of this type of bias by examining the tumor stage of the second primary cancer. If surveillance bias were present they would expect that NMSC patients would be diagnosed with their second cancer at an earlier stage. Their results, however, did not support this type of bias as an explanation [50]. Results from mortality studies and second primary cancer studies suggest a different aetiology and clinical course of BCC and SCC, which supports the appropriateness of regarding BCC and SCC as two separate disease entities. Beyond that, there may be several other factors explaining the different mortality and cancer pattern observed among these BCC and SCC patients. The incomplete registration may be differential according to prognostic factors, such as socioeconomic status (SES) and comorbidities associated with the skin cancer. It is widely known that both SES and comorbidity level affects mortality [41, 63–67]. Individuals with higher SES may have a higher tendency to seek health care increasing their chance of diagnosis and registration of a skin cancer. In particular, for BCC patients, it was found that low SES and infrequent physician visits were associated with late diagnosis and large BCC lesions [68]. Similarly, physicians may be less likely to register BCCs

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among patients with severe comorbidities due to the triviality of the BCC compared with this other disease. Such differential registration would lead to an underestimation of the mortality and second cancer estimates. This may explain the reduced mortality and the reduced risk of digestive cancers among BCC patients. This phenomenon could also explain the positive effect by vitamin D found particularly among BCC patients. The differential registration may be less likely to occur among SCC patients because the SCC is regarded to have a worse prognosis by both patients and physicians.

3.9 Economic and Social Impact Given the high incidence and prevalence, and risk of de novo occurrences among patients with NMSC, the economic cost of this disease is high. In America, the estimated cost of treatment of NMSC is more than US$ 2 billion each year [69]. NMSC therefore ranks fifth in terms of health expenditure in the USA, after lung, and bronchus, prostate, colon and rectal, and breast cancers [70]. The economic impact of NMSC worldwide depends on the setting in which the cancer management takes place. A recent study from the USA reported that maintaining care of NMSC in office-based settings was more cost-efficient than utilizing ambulatory surgical centers or hospital operating rooms [71]. In addition, the rate of complications after treatment in office-settings was lower because of fewer nosocomial infections, thus reducing the cost of treatment [71]. Although mortality is low, disability and disfigurement may result from NMSC leading to subsequent treatment with resultant economic and psychosocial implications. A few studies have evaluated the quality of life (QOL) among NMSC patients, mainly measured as change in quality of life before and after treatment for NMSC [72– 74]. One recent study concluded that quality of life generally improved after treatment but the improvement depended on the type of treatment – with Mohs surgery and excision regarded as optimal [72].

3.10 Take Home Pearls Non-melanoma skin cancer (NMSC), including BCC and SCC, is the most common cancer among Caucasians. The incidence increase of this cancer has been

A. Ø. Jensen et al.

substantial during the last 4 decades. Around 90% of all NMSC occur in people older than 50 years, and are most often located at chronically sun-exposed body sites. Fortunately, the prognosis after NMSC is good. The mortality is low; however, NMSC patients have a higher risk of a new NMSC and another cancer after their first skin cancer.

References 1. Cancer Incidence and Mortality in the Nordic Countries, version 3.1. Association of Nordic Cancer Registries. Danish Cancer Society. Available at http://www.ancr.nu 2. Harris RB, Griffith K, Moon TE. Trends in the incidence of nonmelanoma skin cancers in southeastern Arizona, 1985– 1996. J Am Acad Dermatol. 2001;45:528–36 3. Staples MP, Elwood M, Burton RC, Williams JL, Marks R, Giles GG. Non-melanoma skin cancer in Australia: the 2002 national survey and trends since 1985. Med J Aust. 2006;184: 6–10 4. American Cancer Society. Cancer facts & figures, 2007. Available at http://www.cancer.org 5. de Vries E, Louwman M, Bastiaens M, de Gruijl F, Coebergh JW. Rapid and continuous increases in incidence rates of basal cell carcinoma in the southeast Netherlands since 1973. J Invest Dermatol. 2004;123:634–8 6. Karagas MR, Greenberg ER, Spencer SK, Stukel TA, Mott LA. Increase in incidence rates of basal cell and squamous cell skin cancer in New Hampshire, USA. New Hampshire Skin Cancer Study Group. Int J Cancer. 1999;81: 555–9 7. Levi F, Te VC, Randimbison L, Erler G, La Vecchia C. Trends in skin cancer incidence in Vaud: an update, 1976– 1998. Eur J Cancer Prev. 2001;10:371–3 8. Diepgen TL, Mahler V. The epidemiology of skin cancer. Br J Dermatol. 2002;146(Suppl 61):1–6 9. Gloster HM, J., Brodland DG. The epidemiology of skin cancer. Dermatol Surg. 1996;22:217–26 10. Hannuksela-Svahn A, Pukkala E, Karvonen J. Basal cell skin carcinoma and other nonmelanoma skin cancers in Finland from 1956 through 1995. Arch Dermatol. 1999;135: 781–6 11. Staples M, Marks R, Giles G. Trends in the incidence of non-melanocytic skin cancer (NMSC) treated in Australia 1985–1995: are primary prevention programs starting to have an effect? Int J Cancer. 1998;78:144–8 12. Green A, Battistutta D, Hart V, Leslie D, Weedon D. Skin cancer in a subtropical Australian population: incidence and lack of association with occupation. The Nambour Study Group. Am J Epidemiol. 1996;144:1034–40 13. Buettner PG, Raasch BA. Incidence rates of skin cancer in Townsville, Australia. Int J Cancer. 1998;78:587–93 14. Hoey SE, Devereux CE, Murray L, Catney D, Gavin A, Kumar S, Donnelly D, Dolan OM. Skin cancer trends in Northern Ireland and consequences for provision of dermatology services. Br J Dermatol. 2007;156:1301–7 15. Athas WF, Hunt WC, Key CR. Changes in nonmelanoma skin cancer incidence between 1977–1978 and 1998–1999 in

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Northcentral New Mexico. Cancer Epidemiol Biomarkers Prev 2003;12(10):1105–8. 16. Brewster DH, Bhatti LA, Inglis JH, Nairn ER, Doherty VR. Recent trends in incidence of nonmelanoma skin cancers in the East of Scotland, 1992–2003. Br J Dermatol 2007 Jun; 156(6):1295–300. 17. Karagas MR, Weinstock MA, Nelson HH. Keratinocyte carcinomas. In: Schottenfeld FJD (ed) Cancer epidemiology and prevention, third edition. Oxford: Oxford University Press, 2006, pp. 1230–50 18. Christenson LJ, Borrowman TA, Vachon CM, Tollefson MM, Otley CC, Weaver AL, Roenigk RK. Incidence of basal cell and squamous cell carcinomas in a population younger than 40 years. JAMA. 2005;294:681–90 19. Montague M, Borland R, Sinclair C. Slip! Slop! Slap! and SunSmart, 1980–2000: Skin cancer control and 20 years of population-based campaigning. Health Educ Behav. 2001;28: 290–305 20. Bastiaens MT, Hoefnagel JJ, Bruijn JA, Westendorp RG, Vermeer BJ, Bouwes Bavinck JN. Differences in age, site distribution, and sex between nodular and superficial basal cell carcinoma indicate different types of tumors. J Invest Dermatol. 1998;110:880–4 21. Raasch BA, Buettner PG, Garbe C. Basal cell carcinoma: histological classification and body-site distribution. Br J Dermatol. 2006;155:401–7 22. Cancer Incidence in five continents, vol. VII. International Agency for Research on Cancer (IARC), Lyon, 1997 23. Frisch M, Melbye M. New primary cancers after squamous cell skin cancer. Am J Epidemiol. 1995;141:916–22 24. Frisch M, Hjalgrim H, Olsen JH, Melbye M. Risk for subsequent cancer after diagnosis of basal-cell carcinoma. A population-based, epidemiologic study. Ann Intern Med. 1996; 125:815–21 25. Bower CP, Lear JT, Bygrave S, Etherington D, Harvey I, Archer CB. Basal cell carcinoma and risk of subsequent malignancies: a cancer registry-based study in southwest England. J Am Acad Dermatol. 2000;42:988–91 26. Lucke TW, Hole DJ, Mackie RM. An audit of the completeness of non-melanoma skin cancer registration in Greater Glasgow. Br J Dermatol. 1997;137:761–3 27. Frentz G, Olsen JH. Malignant tumours and psoriasis: a follow-up study. Br J Dermatol. 1999;140:237–42 28. Magnus K. The Nordic profile of skin cancer incidence. A comparative epidemiological study of the three main types of skin cancer. Int J Cancer. 1991;47:12–9 29. Jensen A.Ø. Personal communication. Århus, 2006 30. Frentz G. General skin cancer. Quantity, treatment and quality. Ugeskr Laeger. 1996;158:7202 31. Adami HO, Hunter D, Trichopoulos D. Textbook of cancer epidemiology. Oxford: Oxford University Press, 2002, p. 282 32. Sorensen HT, Sabroe S, Olsen J. A framework for evaluation of secondary data sources for epidemiological research. Int J Epidemiol. 1996;25:435–42 33. Lewis KG, Weinstock MA. Nonmelanoma skin cancer mortality (1988–2000): the Rhode Island follow-back study. Arch Dermatol. 2004;140:837–42 34. Weinstock MA. Nonmelanoma skin cancer mortality in the United States, 1969 through 1988. Arch Dermatol. 1993;129: 1286–90

23 35. Osterlind A, Hjalgrim H, Kulinsky B, Frentz G. Skin cancer as a cause of death in Denmark. Br J Dermatol. 1991;125:580–2 36. Weinstock MA, Bogaars HA, Ashley M, Litle V, Bilodeau E, Kimmel S. Nonmelanoma skin cancer mortality. A population-based study. Arch Dermatol. 1991;127:1194–7 37. Fletcher RW, Fletcher SW. Clinical epidemiology the essentials. Philadelphia, PA: Lippincott Williams & Wilkins, 2005 38. Sackett DL, Haynes RB, Guyatt GH, Tugwell P. Clinical epidemiology: a basic science for clinical medicine, 2nd ed. Boston, MA: Little, Brown, 1991 39. Rigel DS, Friedman RJ, Dzubow LM, Reintgen DS, Bystryn J, Marks R. Cancer of the skin, 2nd ed., Philadelphia, PA: Elsevier Saunders, 2005 40. Robins P, Albom MJ. Recurrent basal cell carcinomas in young women. J Dermatol Surg. 1975;1:49–51 41. Charlson ME, Pompei P, Ales KL, MacKenzie CR. A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chronic Dis. 1987;40:373–83 42. Ong CS, Keogh AM, Kossard S, Macdonald PS, Spratt PM. Skin cancer in Australian heart transplant recipients. J Am Acad Dermatol. 1999;40:27–34 43. Jensen AO, Olesen AB, Dethlefsen C, Sorensen HT. Ten year mortality in a cohort of nonmelanoma skin cancer patients in denmark. J Invest Dermatol. 2006; 126:2539–41 44. Marcil I, Stern RS. Risk of developing a subsequent nonmelanoma skin cancer in patients with a history of nonmelanoma skin cancer: a critical review of the literature and meta-analysis. Arch Dermatol. 2000;136:1524–30 45. Karagas MR, Greenberg ER, Mott LA, Baron JA, Ernster VL. Occurrence of other cancers among patients with prior basal cell and squamous cell skin cancer. Cancer Epidemiol Biomarkers Prev. 1998;7:157–61 46. Wassberg C, Thorn M, Yuen J, Ringborg U, Hakulinen T. Second primary cancers in patients with squamous cell carcinoma of the skin: a population-based study in Sweden. Int J Cancer. 1999;80, 511–5 47. Levi F, La Vecchia C, Te VC, Randimbison L, Erler G. Incidence of invasive cancers following basal cell skin cancer. Am J Epidemiol. 1998;147:722–6 48. Levi F, Randimbison L, La Vecchia C, Erler G, Te VC. Incidence of invasive cancers following squamous cell skin cancer. Am J Epidemiol. 1997;146:734–9 49. Hjalgrim H, Frisch M, Storm HH, Glimelius B, Pedersen JB, Melbye M. Non-melanoma skin cancer may be a marker of poor prognosis in patients with non-Hodgkin’s lymphoma. Int J Cancer. 2000;85:639–42 50. Nugent Z, Demers AA, Wiseman MC, Mihalcioiu C, Kliewer EV. Risk of second primary cancer and death following a diagnosis of nonmelanoma skin cancer. Cancer Epidemiol Biomarkers Prev. 2005;14:2584–90 51. Hemminki K, Vaittinen P, Kyyronen P. Age-specific familial risks in common cancers of the offspring. Int J Cancer. 1998; 78:172–5 52. Bouwes Bavinck JN, Feltkamp M, Struijk L, ter Schegget J. Human papillomavirus infection and skin cancer risk in organ transplant recipients. J Investig Dermatol Symp Proc. 2001;6:207–11

24 53. Hemminki K, Dong C. Primary cancers following squamous cell carcinoma of the skin suggest involvement of EpsteinBarr virus. Epidemiology. 2000;11:94 54. Rosenberg CA, Greenland P, Khandekar J, Loar A, Ascensao J, Lopez AM. Association of nonmelanoma skin cancer with second malignancy. Cancer. 2004;100:130–8 55. Brewster AM, Alberg AJ, Strickland PT, Hoffman SC, Helzlsouer K. XPD polymorphism and risk of subsequent cancer in individuals with nonmelanoma skin cancer. Cancer Epidemiol Biomarkers Prev. 2004;13:1271–5 56. Adami J, Frisch M, Yuen J, Glimelius B, Melbye M. Evidence of an association between non-Hodgkin’s lymphoma and skin cancer. BMJ. 1995;310:1491–5 57. Karagas MR, Cushing GL, Jr, Greenberg ER, Mott LA, Spencer SK, Nierenberg DW. Non-melanoma skin cancers and glucocorticoid therapy. Br J Cancer. 2001;85:683–6 58. Smedby KE, Hjalgrim H, Melbye M, Torrang A, Rostgaard K, Munksgaard L, Adami J, Hansen M, Porwit-MacDonald A, Jensen BA, Roos G, Pedersen BB, Sundstrom C, Glimelius B, Adami HO. Ultraviolet radiation exposure and risk of malignant lymphomas. J Natl Cancer Inst. 2005;97: 199–209 59. Grant WB, Holick MF. Benefits and requirements of vitamin D for optimal health: a review. Altern Med Rev. 2005;10: 94–111 60. Tuohimaa P, Pukkala E, Scelo G, Olsen JH, Brewster DH, Hemminki K, Tracey E, Weiderpass E, Kliewer EV, PompeKirn V, McBride ML, Martos C, Chia KS, Tonita JM, Jonasson JG, Boffetta P, Brennan P. Does solar exposure, as indicated by the non-melanoma skin cancers, protect from solid cancers: vitamin D as a possible explanation. Eur J Cancer. 2007;43:1701–12 61. Gallagher RP, Hill GB, Bajdik CD, Coldman AJ, Fincham S, McLean DI, Threlfall WJ. Sunlight exposure, pigmentation factors, and risk of nonmelanocytic skin cancer. II. Squamous cell carcinoma. Arch Dermatol. 1995a;131:164–9 62. Gallagher RP, Hill GB, Bajdik CD, Fincham S, Coldman AJ, McLean DI, Threlfall W J. Sunlight exposure, pigmentary factors, and risk of nonmelanocytic skin cancer. I. Basal cell carcinoma. Arch Dermatol. 1995b;131:157–63 63. Pappas G, Queen S, Hadden W, Fisher G. The increasing disparity in mortality between socioeconomic groups in the United States, 1960 and 1986. N Engl J Med. 1993;329:103–9

A. Ø. Jensen et al. 64. Huisman M, Kunst AE, Andersen O, Bopp M, Borgan JK, Borrell C, Costa G, Deboosere P, Desplanques G, Donkin A, Gadeyne S, Minder C, Regidor E, Spadea T, Valkonen T, Mackenbach JP. Socioeconomic inequalities in mortality among elderly people in 11 European populations. J Epidemiol Community Health. 2004;58:468–75 65. Mackenbach JP, Bos V, Andersen O, Cardano M, Costa G, Harding S, Reid A, Hemstrom O, Valkonen T, Kunst AE. Widening socioeconomic inequalities in mortality in six Western European countries. Int J Epidemiol. 2003;32: 830–7 66. Charles AJ, Jr, Otley CC, Pond GR. Prognostic factors for life expectancy in nonagenarians with nonmelanoma skin cancer: implications for selecting surgical candidates. J Am Acad Dermatol. 2002;47:419–22 67. Extermann M. Measuring comorbidity in older cancer patients. Eur J Cancer. 2000;36:453–71 68. Robinson JK, Altman JS, Rademaker AW. Socioeconomic status and attitudes of 51 patients with giant basal and squamous cell carcinoma and paired controls. Arch Dermatol. 1995;131:428–31 69. Chuang TY. Skin cancer II: non melanoma skin cancer. In: The challenge of dermato-epidemiology. Boca Raton, FL: CRC, 1997, pp. 209–22 70. Housman TS, Feldman SR, Williford PM, Fleischer AB, Jr, Goldman ND, Acostamadiedo JM, Chen GJ. Skin cancer is among the most costly of all cancers to treat for the Medicare population. J Am Acad Dermatol. 2003;48:425–9 71. John Chen G, Yelverton CB, Polisetty SS, Housman TS, Williford PM, Teuschler HV, Feldman SR. Treatment patterns and cost of nonmelanoma skin cancer management. Dermatol Surg. 2006;32:1266–71 72. Chren MM, Sahay AP, Bertenthal DS, Sen S, Landefeld CS. Quality-of-life outcomes of treatments for cutaneous basal cell carcinoma and squamous cell carcinoma. J Invest Dermatol. 2007;127:1351–7 73. Rhee JS, Matthews BA, Neuburg M, Logan BR, Burzynski M, Nattinger AB. The skin cancer index: clinical responsiveness and predictors of quality of life. Laryngoscope. 2007;117:399–405 74. Rhee JS, Matthews BA, Neuburg M, Smith TL, Burzynski M, Nattinger AB. Quality of life and sun-protective behavior in patients with skin cancer. Arch Otolaryngol Head Neck Surg. 2004;130:141–6

4

Genetics of Non-Melanoma Skin Cancers and Associated Familial Syndromes Khanh P. Thieu and Hensin Tsao

Key Points

Informative Box

›

Clinical criteria for Familial Cancer Syndromes:

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› › ›

›

Cancer is fundamentally a genetic disorder of somatic cells. Mutations can be inherited or arise as a result of chemical carcinogens, inaccuracies in DNA replication, or errors in genomic repair. Oncogenes usually promote cellular proliferation or survival. Tumor suppressor genes either restrict proliferation or induce apoptosis. Gatekeeper genes encode gene products that directly regulate cellular proliferation and prevent growth of potential cancers by inhibiting the cell cycle progression, down-regulating growth signals, or promoting cell death. Caretaker genes encode gene products that maintain genomic stability and integrity. Cancers can occur as sporadic, familial, or inherited. Familial cancer syndromes (FCS) represent a clustering of malignancies within kindreds in higher expected frequencies than those in the general population. Inherited cancers occur due to well-described genetic mechanisms.

H. Tsao () Associate Professor of Dermatology, Massachusetts General Hospital, Department of Dermatology, Bartlett Hall 622, 50 Blossom Street, Boston, MA 02114, USA e-mail: [email protected]

1. Early age of onset for a cancer within the family 2. Increased frequency of one or several specific cancers within several members of the family 3. Multiple tumors developing at one organ 4. Multiple primary tumors at different sites 5. The presence of a distinctive clinical phenotype (e.g., polyposis coli) or congenital abnormalities

4.1 Introduction to Cancer Genetics Cancer is fundamentally a genetic disorder of somatic cells. Although genetic injury via mutagenesis can often be lethal to the cell, rarely, mutations can confer survival or growth advantages that allow the cell to clonally expand without regard for normal physiologic restrictions, and it is under these conditions that the cells become cancerous. Mutations can be inherited or arise as a result of chemical carcinogens, inaccuracies in DNA replication, or errors in genomic repair [1]. Gene studies have revealed that mutations at any of a long list of cellular targets can support sustained cancer growth and evasion of apoptosis [2]. A tumor’s characteristics (e.g., growth rate, ability to invade, etc.) depend in part on the cumulative set of mutations that it has acquired [3]. The growth regulatory genes that are typically targeted in cancer can be divided into two broad categories: oncogenes and tumor suppressor genes. Oncogenes usually promote cellular proliferation or survival and can thus be perpetually “turned-on” with certain mutations, thus supporting uninhibited tumor growth [2].

G. B. E. Jemec et al. (eds.), Non-Surgical Treatment of Keratinocyte Skin Cancer, DOI: 10.1007/978-3-540-79341-0_4, © Springer-Verlag Berlin Heidelberg 2010

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Oncogenes are typically genetically dominant, so an activating mutation in one copy is sufficient to induce tumor development. The second category of genes, the tumor suppressor genes, either restrict proliferation or induce apoptosis and, when inactivated by mutations, lose their ability to keep malignant growth in check [4]. Typically, tumor initiation requires that both alleles be inactivated, because normal tumor suppressor gene function in one allele is sufficient to avert tumorigenesis [5]. Most tumor suppressor genes can be broadly categorized into two groups: gatekeepers and caretakers [6]. Gatekeeper genes encode gene products that directly regulate cellular proliferation and prevent growth of potential cancers by inhibiting the cell cycle progression, down-regulating growth signals, or promoting cell death. These genes are rate-limiting for tumor growth, and thus their complete inactivation is often required for tumor formation. Clinically, gatekeeper defects may lead to tissue-specific cancers. Inactivation of the Adenomatous Polyposis Coli (APC) gene, for example, particularly predisposes patients to colorectal cancer [7–9]. In contrast, caretaker genes encode gene products that maintain genomic stability and integrity. Inactivation of caretakers leads to genetic instabilities and increased mutation rates in other genes that eventually promote tumor growth [6]. The increased mutagenesis can target gatekeeper tumor suppressor genes, other caretaker tumor suppressor genes, and oncogenes, and therefore, can greatly accelerate tumorigenesis. Xeroderma pigmentosum represents a set of disorders in which caretaker genes responsible for the repair of ultraviolet radiation (UVR)-induced lesions are deficient, leading to an increased predisposition for various skin cancers [10].

4.1.1 Genetic Basis of Familial Cancer Syndromes Familial cancer syndromes (FCS) represent a clustering of malignancies within kindreds in higher expected frequencies than those in the general population [11]. These syndromes can individually encompass a heterogeneous group of cancers, as seen for example in familial breast cancer. The genetic basis for FCSs is often difficult to verify, since confounding environmental exposures shared among family members can

K. P. Thieu and H. Tsao

sometimes lead to a clustering of sporadic malignancies within families. Fortunately, clinical clues exist that can suggest a true genetic basis for an FCS: (1) early age of onset for a cancer within the family, (2) increased frequency of one or several specific cancers within several members of the family, (3) multiple tumors developing at one organ, (4) multiple primary tumors at different sites, and (5) the presence of a distinctive clinical phenotype (e.g., polyposis coli) or congenital abnormalities [11, 12]. Overall, familial cancer syndromes account for a tiny fraction of most incident cases of human cancers and are responsible for less than 1% of new cases of non-melanoma skin cancers [13]. However, their importance is profound in research, and genetic studies of these syndromes have greatly elucidated cellular pathways involved in human cancers, particularly the contribution of tumor suppressor genes to tumorigenesis. The inheritance of a predisposition to malignancies that define FCS is best explained by Knudson’s two-hit hypothesis. From studying familial and sporadic retinoblastoma, Knudson postulated that two mutational events were required for tumor development [14]. In familial cancer syndromes, a predisposed individual inherits the first hit – a germline mutation from the affected parent – at conception, and the second hit – a somatic, inactivating mutation in the wild-type allele inherited from the unaffected parent – occurs later to initiate tumor development (Fig. 4.1). Development of sporadic cancers requires the acquisition of both “hits” in the same cell; this phenomenon occurs rarely and explains the decreased frequency and later onset seen compared to familial cancers. Knudson’s model, originally developed to describe retinoblastoma, has been confirmed in numerous other cancers involving the loss of tumor suppressor genes (e.g., APC in colorectal cancer) [15]. At the molecular level, Knudson’s hypothesis is illustrated by the loss of heterozygosity (LOH) within a tumor cell. Loss of heterozygosity in the context of oncogenesis represents the loss of normal function of one allele of a tumor suppressor gene when the other allele has already been inactivated or deleted; this produces a complete deficiency of the tumor suppressor function and assures tumorigenesis. Loss of heterozygosity can arise via several mechanisms, including gene deletion, chromosome loss, and mitotic recombination [16]. Moreover, loss of heterozygosity is noted in cancers by observing the presence of heterozygosity

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Genetics of Non-Melanoma Skin Cancers and Associated Familial Syndromes

27

a Sporadic Cancer: 2 acquired mutations

Wild-type tumor suppressor genes

Germ line: 2 normal genes

Somatic cell: 1st hit

Somatic cell: 2nd hit

Germ line: 1 inherited mutation (1st hit)

Somatic cell: 2nd hit

Tumor

b Familial Cancer: 1 inherited mutation 1 acquired mutation

Inherited mutated tumor suppressor gene

Fig. 4.1 Knudson’s two-hit hypothesis for tumorigenesis involving tumor suppressor genes in sporadic versus familial cancers One pair of chromosomes is depicted: the white rectangles represent the intact tumor suppressor gene, and the black rectangles represent a “hit” (e.g., deletion or mutation) to the same gene. (a) In sporadic cancers, the individual receives two wild-type copies of the tumor suppressor genes from its parents. Two independent

at a genetic locus in an individual’s germline DNA and the absence of heterozygosity at that corresponding locus in the malignant cells [16].

4.2 Genetic Targets in Sporadic NonMelanoma Skin Cancers (NMSCs) 4.2.1 TP53 in NMSCs The gene TP53 encodes for the protein p53, which has a staggering array of functions in the cell. It is upregulated by a variety of cellular stressors and activates transcription of a large number of genes that potentially link many otherwise independent cellular pathways. P53 has been called the guardian of the genome for its role in sensing genetic insults and executing necessary protective responses [17]. P53 recognizes genomic injury (e.g., DNA damage from UV exposure) through encoding several DNA-damage recognition factors and

mutational hits to this gene – to cause complete or partial inactivation of the tumor suppressor gene – must occur in the same cell before tumorigenesis can occur. (b) By contrast, in familial cancers, the individual inherits a defective copy of the tumor suppressor gene from one parent upon fertilization. Therefore, every postzygotic cell already has the first hit. A cell only needs one additional hit for tumor development to occur

responds to such injury by elevating global genomic repair pathways [18, 19]. It can also activate genes to halt cell cycle progression, thus allowing more time for the cell to repair its DNA damage [17, 20, 21]. Lastly, when the injury is too severe for repair, p53 can induce an apoptotic response to remove these defective and potentially malignant cells [22, 23]. Given TP53’s central role, alterations in this tumor suppressor gene play a prominent role in most human cancers. In many of these cancers, mutations in p53 typically occur late in tumorigenesis and correlates with the shift from benign to malignant tumor growth [24].

4.2.1.1 p53 in BCCs Mutations of TP53 have been reported with varying frequency in BCCs, ranging from 20% to 60% [25]. Notably, most of the mutations are dipyrimidine transitions (CCTT) that are specific for UVB damage, suggesting a role for UVB radiation in the carcinogenesis of sporadic BCCs [26].

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4.2.1.2 p53 in SCCs Mutations in TP53 have been described in actinic keratoses (AKs), in situ squamous cell carcinomas (SCCs), and invasive SCCs. In a seminal case series, 58% of a total of 24 invasive SCC were found to have mutations in the p53 [27]. Mice deficient in p53 give rise to lesions resembling SCC when exposed to UV irradiation [28, 29]. Interestingly, patients with Li-Fraumeni syndrome have germline mutations in TP53 gene but have not been shown to be predisposed to developing SCCs [30]. Therefore, it appears that mutations in TP53 may play a role in the genesis of AKs and eventual SCCs but are not the rate-limiting step in tumorigenesis.

4.2.2 RAS in NMSCs RAS mutations are common in a variety of human tumors and probably comprise one of the most frequent

p14/ARF: splice mutations, rare deletions. Familial melanoma +/- neural tumors

oncogenic lesions in all human malignancies. The RAS family of oncogenes encode G-protein which plays central roles in transducing cell growth and survival signals. Activating mutations in RAS occur infrequently in BCCs [31–34], although one study reported finding such mutations in 31% of BCCs [35]. Like TP53, UVB-induced mutations of RAS have also been described in AKs and in SCCs [31, 35, 36]. The rate of RAS mutations in SCCs has been reported to be as high as 46% [35].

4.2.3 CDKN2A in NMSCs CDKN2A encodes two distinct proteins by alternative splicing, p16 INK4a and p14ARF, which both act concertedly through different pathways to suppress cell growth. Loss of p16 and p14ARF leads to functional inactivation of p53 and pRB – the two critical gatekeeper proteins in apoptosis and cell cycle progression, respectively (Fig. 4.2) [37–39]. Although most studies

p16/INK4a: >100 mutations Familial melanoma +/- pancreatic ca

CDK4: 2 mutations Phenotype ª p16INK4a Ubiquitinated

Fig. 4.2 CDKN2A gene products and their effects on tumor suppressor pathways The CDK N2A gene encodes two proteins, p16INK4a and p14ARF, that act as tumor suppressors via distinct cell cycle regulatory pathways. CDKN2A consists of four exons: E1b, E1a, E2, and E3. However, the gene is alternatively spliced to yield two different transcripts containing either E1b or E1a. Exons E2 and E3 are common to both transcript variants. The transcript containing E1b encodes p14ARF, and the one containing E1a transcript encodes p16INK4a. p14ARF inhibits cell growth by binding to HDM2 and promoting its

Phosphorylated

rapid degradation. Since HDM2 normally inhibits and promotes the degradation of the crucial tumor suppressor p53, the functional consequence of p14ARF is to enhance the ability of p53 to halt cell cycle progression. p16INK4a inhibits CDK4, which normally inactivates Rb’s downstream activity; thus, the overall effect of p16INK4a is to promote Rb activity. Rb is an important tumor suppressor gene that can arrest cells during progression from G1 to S phase of the cell cycle *Abbreviations: HDM2, human homologue of mouse double minute 2; Rb, retinoblastoma

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Genetics of Non-Melanoma Skin Cancers and Associated Familial Syndromes

have focused on CDKN2A’s role in familial melanoma, increasing attention has been paid to alterations of the 9p21 (CDKN2A) locus in NMSC. Loss of this locus has now been well-documented in cutaneous SCCs and BCCs in high percentages: up to 76% of SCCs [40–42] and 69% of BCCs [43]. Moreover, Pacifico et al. demonstrate loss of expression of CDKN2A’s gene products, p16INK4a and p14ARF, in 38 and 39 of 40 NMSCs samples, respectively [44]. Inactivation of CDKN2A appears to occur more commonly through deletions rather than inactivating mutations, similar to genetic observations made in melanomas. Overall, deletions in CDKN2A may be a contributing event to NMSC progression, particularly for more aggressive lesions [43, 44].

4.3 Cancer Syndromes with Established Genetic Defects

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4.3.1.1 Cutaneous Findings Basal cell carcinomas are the most common finding in this syndrome and are indistinguishable histologically from typical sporadic BCCs. A study by Kimonis et al. in 1997 found that affected white individuals develop BCCs at the median age of 21 years, and 90% of them had it by age 35 years [48]. However, black and Asian patients with BCNS develop BCCs at a lower rate and at an earlier age compared to their white counterparts [48–50]. Unlike their white counterparts. In countries with high ultraviolet radiation exposure, such as Australia, individuals develop BCCs significantly earlier than affected individuals in less-UV exposed countries [51]. The malignant lesions may present as any kind of clinical variant of BCCs and can mimic the appearance of benign cutaneous lesions such as milia, vascular lesions, melanocytic nevi, or skin tags (Fig. 4.3). BCCs are most commonly found on the face, neck, and trunk but can occur at any site and are

4.3.1 Basal Cell Nevus Syndrome (OMIM 109400) Basal cell nevus syndrome (BCNS, nevoid basal cell carcinoma syndrome or Gorlin’s syndrome) is an autosomal dominant disorder characterized by the rapid development of numerous BCCs in early adulthood. The disease displays complete penetrance but variable expressivity. Approximately one third of cases arise from de novo mutations. Disease prevalence ranges from one in 56,000 to one in 164,000 in the general population [45, 46]. Although BCCs are thought to be the most common cancer in the white population, BCNS accounts for less than 0.5% of patients with BCCs [47]. Refer to Table 4.1 for diagnostic criteria for BCNS.

Fig. 4.3 Numerous BCCs are observed on the neck of a child with basal cell nevus syndrome Source: Reproduced from [11]. With permission. Copyright Elsevier 2000

Table 4.1 Diagnostic criteria for basal cell nevus syndrome (BCNS) (Requires two major or one major and one minor criteria) Major criteria Minor criteria

• More than two BCCs or one before the

• Macrocephaly (adjusted for height)

age of 20 years • Multiple palmar or plantar pits

• Other head and neck abnormalities: cleft lip or palate, frontal bossing,

• Biopsy-proven odontogenic keratocysts

• Other skeletal abnormalities: unilateral elevation of scapula, signifi-

coarse face, hypertelorism of the jaw

cant pectus deformity, marked syndactyly

• Bifid, fused, or splayed ribs

• Radiological abnormalities: bridging of sella turcica, vertebral anoma-

• Bilamellar calcification of falx cerebri • First-degree relative with BCNS

lies (e.g., fusion/elongation of vertebral bodies), modeling defects of hands and feet, flame-shaped lucencies of hands or feet • Medulloblastoma • Ovarian fibroma

Source: From [48].

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K. P. Thieu and H. Tsao

craniofacial features include macrocephaly (50% of patients), frontal bossing (25% of patients), and a widened nasal bridge [48, 51, 52]. If head imaging is pursued, intracranial calcifications of the falx cerebri (65% of patients) may be seen. Other skeletal abnormalities such as polydactyly, pectus excavatum, pectus carinatum, and kyphoscoliosis are more commonly seen in BCNS patients. In addition to BCCs, patients face higher risks of other malignancies including medulloblastoma (1–4% of patients) [58], ovarian fibromas (14–24% of women) [48, 51, 52], and more rarely cardiac fibromas [45].

4.3.1.3 Patched Gene and Sonic Hedgehog Fig. 4.4 Clusters of 1–3 mm discrete red pits are seen on the palmar surface of the hand of a patient with basal cell nevus syndrome

relatively increased in sun-protected areas. Individuals with BCNS usually develop multiple BCCs (median of 8) ranging from a few to thousands, with sizes between 1–10 mm in diameter [48, 52]. Consequently, nonsurgical treatment modalities, such as topical 5-fluorouracil or imiquimod and photodynamic therapy, are often employed to minimize scarring [53–55]. While most BCCs remain nonaggressive, exceptional cases of metastasis have been reported [51]. Palmar and/or plantar pits occur in 65–87% of individuals with BCNS, usually arising before patients reach 10 years of age (Fig. 4.4) [51]. The pits are often subtle, and immersion of the hands or feet in water for 10 min before examination may facilitate their identification by highlighting the telangiectatic appearance of the pits [56]. Rarely, BCCs can arise within these pits [51]. Other cutaneous findings include facial milia and epidermal cysts (both described in about 50–60% of patients) [51, 52] and rare findings of hairy patches of skin reported in one case report [57].

4.3.1.2 Extracutaneous Findings Jaw cysts are a common occurrence, developing in 74–80% of patients [45, 48]. These odontogenic keratocysts begin to develop in the 1st decade and peak in incidence in the 2nd and 3rd decades [48, 51]. Jaw cysts occur most frequently in the mandible and are usually asymptomatic although they may cause pathologic fractures, swelling, or tooth detachment. Characteristic

Linkage analyses of BCNS pedigrees led to the demonstration of germline Patched (PTC) mutations [46, 59]. The PTC gene, located on chromosome 9q22.3, was first elucidated in fruit flies, and has since been shown to play crucial developmental roles in a wide range of animals including mammals. The gene product is a transmembrane protein which plays a key role as a negative regulator of the Sonic Hedgehog (SHH) signaling cascade [60]. Normally, SHH binds PTC, which then relieves the PTC-mediated inhibition of signaling through the Smoothened (PTC) gene product [60, 61]. Downstream PTC signaling is growth promoting, so functional PTC gene products keep this cascade and cell growth in check (Fig. 4.5). Therefore, mutations that inactivate PTC function [62, 63] lead to heightened activation of PTC [64] with consequent growth signaling and tumor formation. The wide-ranging activity of the SHH-PTC-SMO cascade accounts for the constellation of findings in patients with BCNS. Mutations in the tumor suppressor gene PTC are found in about 60% of pedigrees exhibiting two or more clinical features of BCNS [65].

4.3.2 Xeroderma Pigmentosum (OMIM 194400, 278700–278800) Xeroderma pigmentosum (XP) refers to a set of autosomal recessive disorders characterized by severe sun sensitivity that leads to degenerative changes in the sun-exposed skin and eyes and early onset of cutaneous BCCs, SCCs, and cutaneous melanomas. Nearly 20% of patients display neurological abnormalities [66].

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31

Fig. 4.5 The Sonic Hedgehog (SHH) – Patched (PTC) – Smoothened (SMO) pathway in basal cell nevus syndrome SMO’s downstream signals lead to the eventual activation of proteins involved in cell proliferation and tumor formation, including the Gli family of proteins. PTC normally inhibits SMO through direct contact, but this inhibitory interaction is abolished if SHH binds to PTC. Mutations that lead to uncontrolled signaling via SMO, either as inactivating mutations in PTC or activating mutations in SMO, have been observed in human cancers. Inactivating PTC mutations are well-described in BCNS *Abbreviations: HHIP, hedgehog-interacting protein; FU, fused; SUFU, suppressor of fused; GLI, gliomaassociated oncogene

The disease prevalence is about one in one million in the United States and Europe, though it occurs more commonly in Japan (1 in 100,000) [67]. Although the disease does not contribute significantly to the skin cancer burden at the population level, genetic studies of XP patients have illuminated the role of UV radiation in skin cancer formation.

population [68]. The NMSCs occur in sites of greatest UV exposure, with 90% of BCCs and SCCs developing on the face, head, and neck [67, 68]. Patients with XP suffer significant morbidity and mortality from skin cancers, with only a 70% survival rate by 40 years of age [66].

4.3.2.2 Extracutaneous Findings 4.3.2.1 Cutaneous Findings The initial manifestations of XP include photosensitivity reactions and photodistributed freckling, which present at a median age of 1–2 years [66]. The common changes of photo-aging (including actinic lentigines and poikiloderma) become prominent early in childhood. Xeroderma pigmentosum is also marked by early development of pre-malignant actinic keratoses and skin cancers; these usually present at a median age of 8 years [68]. Affected individuals have at least a 1,000-fold increased risk of BCCs, SCCs, and cutaneous melanomas compared to the general

Ocular abnormalities occur in 40% patients with XP and typically affect the UV-exposed sites such as the lids, cornea, and conjunctiva [66]. Early symptoms include photophobia and conjunctivitis, but ectropion, keratitis, and corneal opacificiation are also often seen [66, 67]. Progressive damage can eventually result in complete blindness [69]. Ocular cancers (usually SCCs and BCCs) occur in 10–20% of patients with XP and are limited to the photo-exposed sites [66]. Xeroderma pigmentosum patients also have a 10- to 20-fold increased risk of internal malignancies, such as leukemia, primary brain tumors, lung tumors, and

32

gastric carcinomas suggesting that the DNA reparative machinery deficient in XP is not restricted to the correction of UV-induced lesions [67, 68, 70, 71]. Neurological abnormalities also occur in about 20% of XP patients and are characterized by progressive mental deterioration and retardation, sensorineural deafness, ataxia, and hyporeflexia [66]. The severity of neurological disease is proportional to the sensitivity of the cultured XP fibroblasts to UV radiation [72].

4.3.2.3 Nucleotide Excision Repair Pathways Xeroderma pigmentosum is a multigenic, heterogeneous group of diseases characterized by an impaired ability to repair UV-induced DNA lesions [73]. Eight genes responsible for the XP phenotype have been identified on various chromosomes (Table 4.2). Seven of these genes (designated XPA to XPG) are components of the UV-responsive DNA repair system known as the nucleotide excision repair (NER) pathway [74]. The NER apparatus is mostly responsible for correcting base damage caused by UV photoproducts. It recognizes damaged nucleotides based on structural or chemical irregularities, excises them, thereby allowing DNA polymerase and DNA ligase to synthesize the proper sequence from the unaffected strand (Fig. 4.6). Defects in different XP genes lead to variable degrees of impairment in the DNA repair rates experimentally observed in cells (Table 4.2). About 80% of XP results from defects in any one of the seven genes involved in NER, and the resulting phenotype varies depending on which gene is affected [67, 75]. For example, XP complementation group A (XP-A) is the most clinically severe variant, with frequent skin symptoms and neurological disorders. Xeroderma pigmentosum complementation group C

Table 4.2 Properties of xeroderma pigmentosum genes Gene Chromosome Function

K. P. Thieu and H. Tsao

(XP-C) is the most common form, often referred to as the classic form of XP, and it usually demonstrates only cutaneous and ocular disorders and rare neurological findings. Xeroderma pigmentosum complementation group D (XP-D) is the second most common form; clinical symptoms vary significantly, but about 50% of patients eventually exhibit neurological abnormalities. XP groups B, E, F, and G are all very rare. The remaining 20% of XP patients encompass a clinically heterogeneous group and are considered variants because the implicated gene (designated XPV) is not involved in NER but rather encodes a polymerase that permits error-free replication of UV-irradiated DNA [76]. Current investigations are underway to link common polymorphisms in XP genes with risk for various cancers, including lung cancer, melanoma, and sarcomas [77–81].

4.3.3 Muir-Torre Syndrome (OMIM 158320) Muir-Torre syndrome (MTS) is an autosomal dominant disorder characterized by at least one sebaceous tumor or keratoacanthoma and at least one internal malignancy. A little over 200 cases have been reported thus far [82], although this likely represents an underreporting since families with MTS often exhibit significant phenotypic variability and may be difficult to recognize [83]. MTS is considered a subtype of the more common hereditary nonpolyposis colorectal cancer syndrome (HNPCC), where the cutaneous features serve as the distinguishing characteristic [84], and a recent study reported that only 5 of 538 HNPCC patients screened demonstrated clinical criteria diagnostic for MTS [85].

Residual DNA repair ratea

XPA 9q22.3 Binds and stabilizes damaged DNA <2% XPB 2q21 3¢–5¢ DNA helicase 3–40% XPC 3p25 Recognizes and binds damaged DNA 10–25% XPD 19q13.2–q13.3 5¢–3¢ DNA helicase 25–55% XPE 11p12–p11 May bind damaged DNA 50% XPF 16p13.3 Endonuclease (5’ DNA incisions) 15–30% XPG 13q33 Endonuclease (3’ DNA incisions) <5–25% XPV 6p21.1–p12 Post-replication repair Normal a Amount of residual DNA synthesis observed (as percentage of synthesis in normal cells) when deficient in the gene.

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Genetics of Non-Melanoma Skin Cancers and Associated Familial Syndromes

4.3.3.1 Cutaneous Findings The hallmark cutaneous manifestation of MTS is the development of sebaceous tumors, encompassing adenomas (68%), epitheliomas (27%), and carcinomas (30%) [86]. These sebaceous tumors most commonly develop on the face and can precede (29%), occur concurrently, or appear after the diagnosis of the patient’s initial visceral malignancy [82, 86]. The median age for development of these skin cancers is 53 years [86]. More than 20% of MTS patients have at least one keratoacanthoma, but this finding does not reliably diagnose MTS if sebaceous and/or internal malignancies are absent [86]. Overall, sebaceous tumors are rare and should alert the clinician to the possibility of MTS and its associated internal neoplasms. 4.3.3.2 Extracutaneous Findings Colorectal carcinoma (CRC) is the most common visceral malignancy in MTS, accounting for one half of all internal tumors, and is the first malignancy to appear in 47% of patients [86]. Lesions are usually located in the proximal colon and arise from isolated colonic polyps in the same manner as those found in HNPCC [11, 82, 87]. The median age at diagnosis of CRC in MTS patients is 50 years, which is 10 years earlier than the corresponding

Fig. 4.6 The role of XP gene products in the nucleotide excision repair (NER) pathway in eukaryotes UV irradiation creates mutagenic agents that damage the bases of a DNA strand. A complex containing protein XPC recognizes and attaches to the damaged DNA region. This is followed by the binding of several other proteins: XPA and TFIIH initially, followed by XPF and XPG. XPA is believed to bind the damaged DNA and further stabilize this region as the large NER complex forms. TFIIH is a large complex comprising multiple subunits; it contains XPB and XPD, both of which mediate DNA helicase activity to unwind duplex DNA near the damaged bases. The endonucleases, XPF and XPG, are eventually recruited to complete the assembled NER multiprotein complex. XPF and XPG make incisions on the damaged strand at positions 5’ and 3’ to the site of base damage, respectively. The damaged fragment is then excised from the original DNA. DNA polymerase and other accessory replication proteins are recruited to carry out repair synthesis of the gap. DNA ligase restores the covalent linkages on the newly synthesized fragment. Finally, the DNA is restored to its native configuration *Abbreviations: UV, ultraviolet; TFIIH, transcription factor IIH; XP, xeroderma pigmentosum

33

onset age of the general population [86]. Other cancers in MTS, in descending frequency encountered, include genitourinary cancers (21%), breast cancers (12%), hematological cancers (9%), and head & neck cancers (4%) [86]. Nearly one half of MTS patients develop two or more internal malignancies [86].

34

4.3.3.3 Mismatch Repair Pathways Genetic studies of kindreds expressing the MTS phenotype have identified inherited germline mutations in DNA mismatch repair gene (MMR). The major MMR genes involved are hMLH1 and hMSH2, which are known to cause disease in HNPCC [88, 89]. The vast majority of alterations (>90%) in MTS are seen in hMSH2 [90]. The MMR genes encode a class of caretaker proteins involved in maintaining genome integrity by repairing nucleotide–nucleotide mismatches and small insertions and deletions [11]. Defective MMR activity leads to an increased rate of mutagenesis which encourages oncogenesis. The MMR genes also play a role in preserving stability of microsatellite sequences [91]. Microsatellites are common repetitive stretches of DNA 1–6 base pairs long found dispersed throughout the human genome [92]. During DNA replication, slippage between the DNA strands occurs more frequently within these repetitive sequences, giving rise to mutations, insertions, or deletions within microsatellites [92]. Thus, cells deficient in MMR exhibit the hallmark finding of microsatellite instability, defined by microsatellites of varying lengths within the genome. Microsatellite instability has been noted in 71% of MTS-associated skin tumors in a recent study by Ponti and colleagues [91], and the loss of expression of MMR gene products was detected in 80% of similar lesions by Popnikolov et al. [93]. Thus, either immunohistochemical or genetic analysis of sebaceous tumors or keratoacanthomas can serve as useful diagnostic tools in the workup of suspected MTS cases.

K. P. Thieu and H. Tsao

dominant, due to the absence of male-to-male transmission, and has been mapped to chromosome Xq24– 27 [97]. Oley et al. reported a four-generation pedigree in 1992 with multiple BCCs, coarse, sparse hair, and milia on face and extremities [98]. Originally thought to be a separate entity, the pedigree is now thought to be consistent with Bazex syndrome [99].

4.4.2 Rombo Syndrome (OMIM 180730) Michaelsson et al. described the only pedigree of this syndrome and observed autosomal dominant transmission of a constellation of skin abnormalities across four generations. Members exhibited cyanosis in childhood and later developed multiple facial milia-like papules and follicular atrophy on cheeks [100]. Basal cell carcinomas were frequently seen and developed around 35 years of age [100]. The syndrome shares similarities with Bazex syndrome with the exception that male-to-male transmission was observed [100]. Since Michaelsson’s original report in 1981, two sporadic cases matching the clinical findings of Rombo symdrome have also been described [101, 102].

4.4.3 Syndromes with Squamous Cell Carcinomas 4.4.3.1 Multiple Self-Healing Squamous Epithelioma (OMIM 132800)

4.4 Cancer Syndromes Without Established Genetic Defects 4.4.1 Syndromes with Basal Cell Carcinomas 4.4.1.1 Bazex Syndrome (OMIM 301845) This is an extremely rare disorder characterized by the triad of multiple BCCs developing in the 2nd and 3rd decades, pitting of the skin (follicular atrophoderma) presenting in early infancy, and congenital hypotrichosis [94–96]. Inheritance is believed to be X-linked

Multiple self-healing squamous epithelioma (MSSE) is an autosomal dominant disorder that is also known as Ferguson–Smith syndrome. The syndrome is characterized by multiple, recurrent epithelial tumors resembling SCCs clinically and histologically that resolve spontaneously, leaving pitted scars [103–105]. Most tumors occur on photoexposed areas (face and scalp being most common), but they have also been reported on the anus, scrotum, and anterior abdomen [104]. Age of onset is highly variable, ranging from the 1st decade to the 6th decade of life with a mean of around 25 years old [104]. Ferguson–Smith syndrome has been mapped to chromosome 9q31 but disease-causing mutations have not been identified [106]. Bose et al. recently

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Genetics of Non-Melanoma Skin Cancers and Associated Familial Syndromes

demonstrated loss of heterozygosity of the MSSE region in 5 out of 12 tumors, providing evidence that MSSE acts as a tumor suppressor gene [106].

4.4.3.2 Epidermodysplasia Verruciformis (OMIM 226400) Epidermodysplasia verruciformis (EV) is an extremely rare inherited disorder characterized by marked susceptibility to cutaneous human papillomavirus (HPV) infections and increased risk of cutaneous SCCs [13, 107]. Human papillomavirus infection results in childhood onset of disseminated plane wart-like and pityriasis versicolor-like lesions [13]. About half of these lesions, especially those in photodistributed areas, progress to in situ and invasive SCCs [13]. The mode of inheritance remains unclear and is further muddled by the frequent finding of parental consanguinity in reported families. Recently, Ramoz et al. identified mutations in either of two adjacent genes (EVER1 and EVER2) located at the 17q25 locus in kindreds with EV [108]. The role of these genes remains to be elucidated.

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68. Kraemer KH, Lee MM, Andrews AD, Lambert WC. The role of sunlight and DNA repair in melanoma and nonmelanoma skin cancer. The xeroderma pigmentosum paradigm. Arch Dermatol. 1994;130(8):1018–21 69. Bhutto AM, Shaikh A, Nonaka S. Incidence of xeroderma pigmentosum in Larkana, Pakistan: a 7-year study. Br J Dermatol. Mar 2005;152(3):545–51 70. Kraemer KH, Lee MM, Scotto J. DNA repair protects against cutaneous and internal neoplasia: evidence from xeroderma pigmentosum. Carcinogenesis. 1984:511–4 71. Mamada A, Miura K, Tsunoda K, Hirose I, Furuya M, Kondo S. Xeroderma pigmentosum variant associated with multiple skin cancers and a lung cancer. Dermatology. 1992;184: 177–81 72. Andrews AD, Barrett SF, Robbins JH. Xeroderma pigmentosum neurological abnormalities correlate with colonyforming ability after ultraviolet radiation. Proc Natl Acad Sci USA. Apr 1978;75(4):1984–8 73. Tsao H. Genetics of nonmelanoma skin cancer. Arch Dermatol. Nov 2001;137(11):1486–92 74. Cleaver JE, Thompson LH, Richardson AS, States JC. A summary of mutations in the UV-sensitive disorders: xeroderma pigmentosum, Cockayne syndrome, and trichothiodystrophy. Hum Mutat. 1999;14(1):9–22 75. Somoano B, Tsao H. Genodermatoses with cutaneous tumors and internal malignancies. Dermatol Clin. Jan 2008; 26(1):69–87, viii 76. Masutani C, Kusumoto R, Yamada A, et al The XPV (xeroderma pigmentosum variant) gene encodes human DNA polymerase eta. Nature. June 17 1999;399(6737):700–4 77. Kiyohara C, Yoshimasu K. Genetic polymorphisms in the nucleotide excision repair pathway and lung cancer risk: a meta-analysis. Int J Med Sci. 2007;4(2):59–71 78. Tse D, Zhai R, Zhou W, et al Polymorphisms of the NER pathway genes, ERCC1 and XPD are associated with esophageal adenocarcinoma risk. Cancer Causes Control. May 14 2008;19:1077–83 79. Wang F, Chang D, Hu FL, et al DNA repair gene XPD polymorphisms and cancer risk: a meta-analysis based on 56 case-control studies. Cancer Epidemiol Biomarkers Prev. Mar 2008;17(3):507–17 80. Zhang D, Chen C, Fu X, et al A meta-analysis of DNA repair gene XPC polymorphisms and cancer risk. J Hum Genet. 2008;53(1):18–33 81. Povey JE, Darakhshan F, Robertson K, et al DNA repair gene polymorphisms and genetic predisposition to cutaneous melanoma. Carcinogenesis. May 2007;28(5):1087–93 82. Ponti G, Ponz de Leon M. Muir-Torre syndrome. Lancet Oncol. Dec 2005;6(12):980–7 83. Ponti G, Ponz de Leon M, Losi L, et al Different phenotypes in Muir-Torre syndrome: clinical and biomolecular characterization in two Italian families. Br J Dermatol. June 2005; 152(6):1335–8 84. Lynch HT, Lynch PM, Pester J, Fusaro RM. The cancer family syndrome. Rare cutaneous phenotypic linkage of Torre’s syndrome. Arch Intern Med. Apr 1981;141(5): 607–11 85. Ponti G, Losi L, Pedroni M, et al Value of MLH1 and MSH2 mutations in the appearance of Muir-Torre syndrome phenotype in HNPCC patients presenting sebaceous gland tumors

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or keratoacanthomas. J Invest Dermatol. Oct 2006; 126(10): 2302–7 Cohen PR, Kohn SR, Kurzrock R. Association of sebaceous gland tumors and internal malignancy: the MuirTorre syndrome. Am J Med. 1991;90:606–13 Hansen SK, Szpara ML, Serafini TA. Regulation of pontine neurite morphology by target-derived signals. Brain Res Mol Brain Res. May 19 2004;124(2):165–77 Kruse R, Lamberti C, Wang Y, et al Is the mismatch repair deficient type of Muir-Torre syndrome confined to mutations in the hMSH2 gene? Hum Genet. Dec 1996;98 (6):747–50 Bapat B, Xia L, Madlensky L, et al The genetic basis of Muir-Torre syndrome includes the hMLH1 locus. Am J Hum Genet. Sept 1996;59(3):736–9 Mangold E, Pagenstecher C, Leister M, et al A genotypephenotype correlation in HNPCC: strong predominance of msh2 mutations in 41 patients with Muir-Torre syndrome. J Med Genet. July 2004;41(7):567–72 Ponti G, Losi L, Di Gregorio C, et al Identification of MuirTorre syndrome among patients with sebaceous tumors and keratoacanthomas: role of clinical features, microsatellite instability, and immunohistochemistry. Cancer. Mar 1 2005;103(5):1018–25 Umar A, Risinger JI, Hawk ET, Barrett JC. Testing guidelines for hereditary non-polyposis colorectal cancer. Nat Rev Cancer. Feb 2004;4(2):153–8 Popnikolov NK, Gatalica Z, Colome-Grimmer MI, Sanchez RL. Loss of mismatch repair proteins in sebaceous gland tumors. J Cutan Pathol. Mar 2003;30(3):178–84 Viksnins P, Berlin A. Follicular atrophoderma and basal cell carcinomas: the Bazex syndrome. Arch Dermatol. 1977;113 (7):948–51 Gould DJ, Barker DJ. Follicular atrophoderma with multiple basal cell carcinomas (Bazex). Br J Dermatol. Oct 1978; 99(4):431–5 Kidd A, Carson L, Gregory DW, et al A Scottish family with Bazex-Dupre-Christol syndrome: follicular atrophoderma, congenital hypotrichosis, and basal cell carcinoma. J Med Genet. June 1996;33(6):493–7 Vabres P, Lacombe D, Rabinowitz LG, et al The gene for Bazex-Dupre-Christol syndrome maps to chromosome Xq. J Invest Dermatol. 1995;105(1):87–91 Oley CA, Sharpe H, Chenevix-Trench G. Basal cell carcinomas, coarse sparse hair, and milia. Am J Med Genet. 1992;43(5):799–804 Vabres P, de Prost Y. Bazex-Dupre-Christol syndrome: a possible diagnosis for basal cell carcinomas, coarse sparse hair, and milia. Am J Med Genet. Mar 15 1993; 45(6):786 Michaelsson G, Olsson E, Westermark P. The Rombo syndrome: a familial disorder with vermiculate atrophoderma, milia, hypotrichosis, trichoepitheliomas, basal cell carcinomas and peripheral vasodilation with cyanosis. Acta Derm Venereol. 1981;61(6):497–503 Ashinoff R, Jacobson M, Belsito DV. Rombo syndrome: a second case report and review. J Am Acad Dermatol. June 1993;28(6):1011–4 van Steensel MA, Jaspers NG, Steijlen PM. A case of Rombo syndrome. Br J Dermatol. June 2001;144(6):1215–8

38 103. Ferguson-Smith J. Multiple primary, self-healing squamous epithelioma of the skin. Br J Dermatol. 1948;60:315–9 104. Ferguson-Smith MA, Wallace DC, James ZH, Renwick JH. Multiple self-healing squamous epithelioma. Birth Defects Orig Artic Ser. 1971;7(8):157–63 105. Rajka G. Multiple keratoacanthoma (self-healing squamous epithelioma according to Ferguson-Smith). Acta Derm Venereol. 1971;51(3):232–3 106. Bose S, Morgan LJ, Booth DR, Goudie DR, FergusonSmith MA, Richards FM. The elusive multiple self-healing

K. P. Thieu and H. Tsao squamous epithelioma (MSSE) gene: further mapping, analysis of candidates, and loss of heterozygosity. Oncogene. Feb 2 2006;25(5):806–12 107. Majewski S, Jablonska S. Epidermodysplasia verruciformis as a model of human papillomavirus-induced genetic cancer of the skin. Arch Dermatol. Nov 1995;131 (11):1312–8 108. Ramoz N, Rueda LA, Bouadjar B, Montoya LS, Orth G, Favre M. Mutations in two adjacent novel genes are associated with epidermodysplasia verruciformis. Nat Genet. Dec 2002;32(4):579–81

5

Environmental Risk Factors for Non-Melanoma Skin Cancers Vishal Madan

Key Points

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Besides genetic susceptibility, several environmental risk factors play an important role in the pathogenesis of non-melanoma skin cancer (NMSC). Role of ultraviolet radiation (UVR) in pathogenesis of NMSC in general is well established; however, its effect on the pathogenesis of different basal cell carcinoma (BCC) subtypes is still a matter of research. Ultraviolet radiation in the wavelengths 290– 320 nm (UVB) is the most carcinogenic range of terrestrial UVR. In contrast to squamous cell carcinomas (SCCs), intermittent rather than chronic sun exposure may be more important in the development of superficial BCC. The ratio of SCC to BCC in the setting of iatrogenic immunosuppression reverses as SCC occurs more frequently in the transplant recipients.

V. Madan MBBS (Hons), MD, MRCP Laser and Dermatological Surgery Fellow and Specialist Registrar in Dermatology, The Dermatology Centre Salford Royal Hospitals NHS Trust Hope Hospital, Stott Lane, Salford, M6 8HD, UK e-mail: [email protected]

Despite increasing awareness about the role of sun exposure in cutaneous carcinogenesis, the incidence of non-melanoma skin cancers (NMSC, syn: keratinocyte carcinomas) continues to rise. While the role of sun exposure in the causation of NMSC has been long established, several other factors appear to influence this risk. For example, frequent occurrence of basal cell carcinomas (BCCs) on nonsun-exposed sites supports the role of non-solar co-carcinogens in cutaneous tumourogenesis. Constitutional (genotypic and phenotypic) susceptibility and environmental factors are fundamental in the genesis of NMSC. An individual’s risk of developing NMSC is thus determined by several wellestablished and hitherto unknown environmental factors. In this chapter, the potential role of environmental factors contributing to NMSC pathogenesis is discussed (Table 5.1).

5.1 Solar Ultraviolet Radiation Solar radiation has historically been regarded as a major risk factor for NMSC. In 1896, Unna described the changes of skin cancer among sailors exposed to the sun [1, 2]. The fact that sunlight is the major cause of skin cancer was also noted by Blum in 1948 [1]. Since then, several epidemiological studies have evaluated and confirmed the causative role of sun exposure, implicating it as the single, most important factor for NMSC. The observations that NMSCs are more frequent in residents of high ambient solar irradiance, in sun-sensitive people, those with high sun exposure and in those with benign sun-related skin conditions, occur mainly on sun-exposed body sites, and are reduced by protection of carcinogenic effects of

G. B. E. Jemec et al. (eds.), Non-Surgical Treatment of Keratinocyte Skin Cancer, DOI: 10.1007/978-3-540-79341-0_5, © Springer-Verlag Berlin Heidelberg 2010

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40 Table 5.1 Environmental risk factors for non-melanoma skin cancers Solar ultraviolet radiation Human papilloma virus Immunosuppression – iatrogenic and acquired immunodeficiency syndrome PUVA therapy UVB Ionising radiation Occupational factors Arsenic Tobacco smoking and diet

sunlight, provide indirect but crucial evidence of the role of ambient solar radiation in the causation of NMSC [3]. Furthermore, confirmatory data associating ultraviolet radiation (UVR) in the causation of skin cancer come from investigations of UV-induced carcinogenesis in experimental animals [4]. The most biologically active component of sunlight appears to be UVR. UVR in the wavelengths 290–320 nm (UVB) is the most carcinogenic range of terrestrial UVR, but the range 320–400 nm (UVA) has also been implicated to a lesser extent [5, 6]. UV effects deoxyribonucleic acid (DNA) damage and oxidation of membrane lipids and amino acids [7]. UVB directly damages DNA and ribonucleic acid (RNA) by inducing formation of covalent bonds between adjacent pyrimidines, leading to the generation of mutagenic photoproducts such as cyclopyrimidine dimers (TT) and pyrimidine–pyrimidine (6–4) lesions [8]. On the other hand UVA, which is 10,000 times less mutagenic than UVB, predominantly causes indirect damage to DNA via a ‘photooxidative-stress’mediated mechanism [9]. Reactive oxygen species thus produced, interact with lipids, proteins and DNA to generate intermediates that combine with DNA to form adducts [10, 11]. A variety of complex DNA repair systems are therefore needed to prevent the deleterious effects of these premutagenic adducts [11]. UVR is also a local immunosuppressant in skin giving rise to the suggestion that this may compromise local antitumour activity [13]. Further evidence strengthening the relationship between sun exposure and skin cancer may be obtained from consideration of geographic variation in skin cancer incidence in relation to ambient solar irradiance and ethnic characteristics. The incidence of BCC in Australia in 1990 increased threefold from latitudes

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south of 37°S to latitudes north of 29°S [13]. Incidence of skin cancer within countries appears to increase with proximity to the equator with similar gradients for men and women and for all ages [13, 14]. An inverse gradient with latitude for both BCC and SCC (squamous cell carcinoma) was found in a national survey of eight geographically diverse locations in the USA [14]. Indeed, it has been estimated that, should the amount of exposure to UVB increase by 30%, the incidence of skin cancer will increase by 60% in males and 45% in females [15]. Analysis of incidence rates of NMSC in Arizona showed that these are three to six times more common in patients with similar skin type and living in regions of higher latitude [16]. The inverse relation of NMSC to latitude gradient suggests a strong association of UVR on NMSC development. The thinner ozone layer and the shorter distance for UVB to traverse at lower latitudes make residents of lower latitudes more vulnerable to the effects of UVB [17, 18]. Furthermore, from studies conducted in Australia, it was observed that incidence rates of NMSC were higher in people born there as compared with migrants of similar genetic background and from countries with lower ambient solar radiation [12, 19–21]. It has also been observed that amongst migrants the risk is higher if migration occurs in childhood rather than later in life [20]. The rarity of NMSC in dark-skinned individuals as explained by the protection conferred by melanin against solar radiation provides further evidence of the causative role of sun exposure against NMSC. The relative rarity of NMSC in young individuals and a progressive increase in its incidence with age, and the observation that they are more common in men are consistent with the effects of more or less continuous exposure to the sun throughout life and a greater prevalence of outdoor work in men than in women [22]. Kricker et al. reviewed the epidemiologic evidence linking sun exposure and skin cancer from both descriptive studies in populations and analytical studies involving estimates of exposure in individuals [22]. It was clear from the descriptive studies that compared with SCC, BCC was infrequent in heavily pigmented races, less consistently distributed on exposed body sites, and occurred less frequently among patients with cutaneous sensitivity to the sun, e.g. in xeroderma pigmentosum and albinism. Thus, a difference in the pathogenesis of these NMSC was clearly apparent. The same authors also found that although UVR is the most important risk factor in the genesis of both SCC and BCC, there is

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Environmental Risk Factors for Non-Melanoma Skin Cancers

a proportionately greater effect of increasing sun exposure on the risk of developing SCC [23]. Even in the pathogenesis of BCC, although exposure to UVR is essential, its relationship with risk remains unclear and epidemiological studies suggest its quantitative effect is modest. The evidence linking reported total (occupational and non-occupational) sun exposure to BCC has been weak [3]. Earlier reports of strong associations came from studies where confounding of the association by age and gender was likely [22]. In a Western Australian study, the relative risk of BCC of the head and neck and the limbs fell with increasing lifetime total exposure, but, on the trunk, it increased with increasing total exposure [24]. A large European case-control study has shown only a twofold increase in BCC risk with increased sun exposure [25] while recent studies suggest that intermittent rather than cumulative sun exposure is more important [23]. On the other hand, cumulative lifetime sun exposure, showed a strong dose–response relationship with SCC [25, 26] although this was not a consistent observation [22]. Thus, most authors now agree that while chronic sun exposure is the most important cause of SCC [27], it may be less important for the development of BCC [22, 28]. Kennedy et al. also found that lifetime sun exposure was associated with an increased risk of SCC and to a lesser degree with nodular and superficial multi-focal BCC, where intermittent sun exposure may be more important. Recall of painful sunburns before the age of 20 years was associated with an increased risk of both BCC and SCC [29, 30]. Additionally, a German case-control study of patients with sporadic BCC assessing the risk of occupational and leisure-time sun exposure behaviour found that any sunburn sustained 20 years before occurrence of sporadic BCC seems to be an important risk factor related to recreational UV exposure behaviour [31]. Further, it has been suggested that exposure between ages 0 and 19 is more important than lifetime exposure [22]. Clearly, UV exposure is a major influence on NMSC but its relationship to clinical phenotype remains unclear, as the distribution of lesions does not correlate well with the area of maximum exposure to UVR [32]. BCC are common on the eyelids, at the inner canthus and behind the ear, but uncommon on the back of the hand and forearm and compared with SCC, BCC are relatively more common on less-exposed sites such as the trunk. Thus, although exposure to UVR remains critical, patients often develop BCC at sites generally

41

believed to be relatively less sun exposed. Approximately 20% of all BCC arise on non-sun-exposed skin. The basis of this difference in susceptibility of skin at different sites to BCC development is unknown, but may be related to the association of BCC with intermittent UV exposure [33]. Kricker et al. found this to be true, in particular, regarding skin cancer at sites of sunburns sustained during holidays in late teenage years [24]. It is possible that people who develop NMSC in sunprotected areas of the body may have a decreased DNA repair capacity. Alternatively, UV radiation may cause a systemic as well as a local immunosuppressive effect.

5.2 Human Papilloma Virus Human papilloma viruses (HPV) are now well recognised as important human carcinogens. There is overwhelming evidence from both epidemiological and functional studies implicating HPV in high-risk mucosal cancers. HPV are characterised into phylogenetic genera alpha, beta, gamma, mu and nu, and are associated with both benign and malignant proliferative skin disorders [34, 35]. Mucosal HPV types 16, 18, 31 and 33 are strongly associated with anogenital carcinomas [36]. Beta or cutaneous HPVs are suspected in the aetiology of NMSC because of estimates that up to 90% of NMSC from immunocompromised individuals and up to 50% of those from immunocompetent individuals contain DNA from cutaneous or beta HPV types [37–39]. Such cutaneous HPV types 5 and 8 are associated with epidermodysplasia verruciformis (EV), a rare autosomal disorder that is characterised by diminished cellmediated immunity and predisposition to cutaneous warts and multiple, early-onset keratinocyte cancers [37]. A quarter of the HPV genotypes that are completely sequenced today belong to the EV-associated HPV [40]. NMSC developing in immunocompetent individuals also frequently contain EV–HPV [41–42]. The association between EV–HPV infection and SCC risk has been further strengthened by seroepidemiological studies [43–45]. Immunocompetent patients with positive serology for HPV-8 had a threefold risk of developing SCC and the same study also found a modest increase in risk if the patients had positive serology for HPV-15 [45]. In another recent study, SCC risk was specifically associated with HPV 5 and, to a lesser extent, with HPV 20 [46].

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Furthermore, localisation of HPV DNA to malignant keratinocytes in SCC as well as EV–HPV gene transcription in almost 40% of tumours has been found by in situ hybridisation technique, thus providing further evidence of the role of HPV in pathogenesis of SCC [47]. It has been demonstrated that persistent skin infections with high-risk genital HPV types may also represent a risk factor for NMSC in immunocompetent patients [48]. Although HPV has been associated strongly with malignant progression of warts to SCC, different oncogenic subtypes of the virus have been found in 60% of BCCs from immunosuppressed patients in contrast to 36% of BCCs from immunocompetent patients, suggesting that these viruses may also be involved in the development of BCC [49]. However, recent studies have found that risk for SCC and not BCC was associated with seropositivity to HPV [46]. It has also been suggested that PUVA therapyinduced immunosuppression may play an important role in PUVA-related carcinogenesis by affecting the extent and pathogenicity of HPV infection [50]. The ‘early’ transforming protein E 6, from HPV 8 has been shown to inhibit DNA repair of UV-B-induced damage by altering the G1 phase cell cycle checkpoint and by interacting with single-strand break repair protein XRCC1 to reduce its repair activity [51, 52]. The E7 gene codes for a product that targets and binds to the tumour suppressor retinoblastoma gene product, phosphorylating and therefore inactivating this protein. The net result of both viral products, E6 and E7, is dysregulation of the cell cycle, allowing cells with genomic defects to enter the S-phase (DNA replication phase) [53]. Proteins of some beta HPVs have been shown to target and abrogate Bak, a cellular protein involved in signalling apoptosis in the skin in response to UV-B damage [46]. Beta HPVs may therefore increase the risk of NMSC by promoting cell division with a concomitant reduction in DNA repair and resistance to UV-induced apoptosis [46]. In contrast, in other HPVinduced malignancies, viral proteins directly inactivate critical tumour suppressor proteins. The lack of cancer development in every patient infected with high-risk HPV coupled with a long latency period prior to malignant transformation suggests that other events are required for full transformation. Host genetic factors including polymorphisms and

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susceptibility loci; immunosuppression, as evidenced by organ transplant recipients; associated environmental co-factors including tobacco, UV and ionising radiation, diet and obesity; co-infection with other viral and bacterial pathogens including herpes simplex virus 2 and Chlamydia trachomatis are all known to contribute to HPV oncogenesis [54]. For example, cytokine production induced by UV radiation can have both positive and negative regulatory effects on HPV replication, thus facilitating HPV oncogenesis in the skin [55].

5.3 Immunosuppression 5.3.1 Iatrogenic Immunosuppression Immunosuppressed transplant recipients are at considerably higher risk of developing both BCC and SCC than the general population, with the risk of SCC being higher than BCC. The ratio of SCC to BCC in the setting of iatrogenic immunosuppression reverses as SCC occurs more frequently in transplant recipients [56] whereas in the general populations BCC is three to six times more frequent than SCC [57]. SCCs are more immunogenic than BCCs and effective immune response directed against SCC tumour cells, may lead to a partial control of these tumours in immunocompetent hosts. The less immunogenic BCC may escape this immunosurveillance mechanism. HLA mismatching in organ transplant recipients may also influence the risk of development of SCC. A diminished response to skin application of dinitrochlorobenzene was found in patients with SCC but not in those with BCC, supporting the notion that the incidence of BCC is not affected by immune status to the same extent as SCC [58]. The incidence of these cancers increases substantially with the extended survival after transplantation [59] and it has been shown that in heart transplant recipients, the number of skin cancers is significantly correlated with both age at transplantation and duration of follow-up [60]. Time-to-event analysis showed that one of five heart transplant recipients will develop SCC, and one of eight will develop BCC within 10 years after transplantation [61]. In a European study, 40% of renal transplant recipients develop skin cancer within 20 years after grafting [62]. As transplant recipients are living longer their

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Environmental Risk Factors for Non-Melanoma Skin Cancers

risk of developing NMSC is also on the rise. The degree of immunosuppression also influences the risk as heart transplant recipients who receive higher doses of immunosuppression are at a greater risk than renal transplant recipients [63]. The risk of SCC in organ transplant recipients might be associated with the global immunosuppression rather than with a specific immunosuppressive drug [61]. As in the general population, hosts’ genotypic and phenotypic features, history of cumulative sun exposure and other environmental risk factors also contribute to cutaneous carcinogenesis in organ transplant recipients. Transplant recipients have a high risk of infection with HPV and, consequently, an increased risk of HPV-mediated oncogenesis. Both ‘low’ and ‘high cancer-risk’ HPV types are found in SCC developing in renal transplant recipients [64–67].

5.3.2 Acquired Immunodeﬁciency Syndrome (AIDS) The incidence of cutaneous and extra-cutaneous malignancies increases in human immunodeficiency virus (HIV) patients. This may be secondary to a variety of different mechanisms including increased TH2 cytokine production which may enhance HIV proliferation, immune evasion, angiogenesis, and transcription of certain oncogenes and reduce apoptosis, antigen presentation and overall patient survival [68–71]. HIV proteins, e.g. tat, can regulate chemokines, resulting in dysregulated angiogenesis and net protein decreases major histocompatibility complex class 1 resulting in poor detection of deranged self-cells [71, 72]. The oncogenic potential of certain viruses, e.g. HPV, may be enhanced and tumour surveillance reduced by HIVinduced dysfunction in cell-mediated immunity [73]. The risk of developing NMSC in patients with AIDS increases three- to fivefold except in HIV positive haemophiliac patients in whom BCCs are reported to be 11.4 times more common. In addition to immunosuppression, risk factors for NMSC in these patients remain unchanged as they frequently have blue eyes, blonde hair, family history and extensive prior sun exposure [74, 75]. In contrast to the transplant population, the ratio of BCC to SCC in these patients remains unchanged and these present identically to those seen in immunocompetent patients [71].

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The most common morphological type of BCC in this population is the superficial type; however, more aggressive forms may be seen [71]. These may be multiple and present most commonly on the trunk. The reason why HIV-induced immunosuppression increases the risk of BCC, whereas pharmaceutical immunosuppression does not, remains unclear. Depletion of CD4 lymphocytes by HIV may lead to a more pervasive defect in adaptive anti-tumour immunity that may only be functionally suppressed by iatrogenic immunosuppression. Highly active antiretroviral therapy induced reduction in the incidence and spontaneous regression of BCC in an HIV-positive patient with Gorlin’s syndrome has been described, which further supports the critical role of immunomodulation in skin cancer susceptibility [76]. In contrast, SCC in HIV patients are more aggressive, develop rapidly, occur at a younger age, are more common on the head and neck and have a high risk of local recurrence, metastasis and mortality [77]. Patients with SCC have a later-stage HIV disease than those with BCC. Surprisingly, the aggressive nature of these SCCs is not correlated with the CD4 counts and HPV does not appear to be a risk factor in the development of NMSC in HIV [77]. Instead, p53 over-expression has been seen, suggesting the crucial role of UV exposure in the genesis of NMSC in the HIV patients.

5.4 Phototherapy 5.4.1 Psoralen and Ultraviolet-A (PUVA) Therapy For the past three decades, oral methoxsalen photochemotherapy, i.e. psoralen and ultraviolet-A light (PUVA), has been widely used as one of the most effective treatment of psoriasis. PUVA treatment is mutagenic and carcinogenic and patients exposed to high doses of PUVA therapy have a significantly increased risk of cutaneous SCC [78]. PUVA is immunosuppressive, which explains its carcinogenic effect on the skin during active treatment, in a pattern similar to that observed with iatrogenic immunosuppression in organ transplant recipients [78]. It would be expected that the risk of developing NMSC would be highest in those with previous exposure to

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other carcinogens and would diminish if treatment is stopped. However, there is a persistent and substantial increase in the risk of SCC in patients following highdose exposure to PUVA. This risk pertained to all patients with substantial exposure to PUVA, even those without substantial exposure to other carcinogens and with little exposure to PUVA in recent years [78]. Even though PUVA is a complete carcinogen, a co-factor role of HPV has been suggested by the reversal of the BCC to SCC ratio; similar to that observed in organ transplant recipients [79]. PUVA may lead to immunosuppression and /or increased HPV replication. Analysis of hair samples of psoriasis patients receiving PUVA showed a significantly increased incidence of HPV DNA [80]. HPV DNA has also been detected in 75% NMSCs in patients treated with high-dose UVA (500 J/cm2) [79]. Thus, the prevalence and type of HPV infection in cutaneous lesions from PUVA-treated patients is similar to that reported in renal transplant associated skin lesions [79]. Reported incidence of SCC in PUVA treated patients varies from one to four per 1,000 person-years. For patients exposed to high-dose PUVA, the incidence rate can be as high as 65 per 1,000 person-years [81]. The risk increases 30-fold after 200–300 PUVA exposures [82]. PUVA treatment has also been associated with a dose-dependent and persistently increased risk of genital SCC among men. A 90-fold increased risk of genital tumours has been observed in men exposed to high doses of PUVA [83]. Unlike oral PUVA, bath PUVA with 8-methoxypsoralen and trioxsalen have not been associated with an increased risk of NMSC [84, 85]. The relationship between the risk of BCC and exposure to PUVA is different from that observed for SCC. Overall, the incidence of BCC is only modestly elevated. Only patients exposed to very high levels of PUVA have a substantially increased risk of BCC, and the magnitude of this increase in risk is much lower than that seen for SCC [78].

5.4.2 Ultraviolet-B Phototherapy Although not extensively studied, the risk of developing NMSC after UVB phototherapy is significantly less than PUVA and increases with the number of treatments. High-dose UVB exposure (×300 treatments)

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increases the risk of developing an SCC or BCC in a given year by about 40% [86]. The attributable risk associated with high UVB exposure is about 30% for both SCC and BCC. This increase in relative risk is most apparent among individuals not previously treated with large amounts of PUVA therapy and on anatomic sites typically exposed during phototherapy, and rare to only those intermittently exposed to sunlight [86]. Overall, the carcinogenic risk of a single PUVA treatment is estimated to be about seven times greater than a single UVB treatment [86]. An early (median 4 years) follow-up study of the photocarcinogenecity of narrowband UVB (TL-01), found a small but significant increase in the risk of BCC. However, the authors acknowledged the potential for diagnostic bias in their study. In the same study cohort the risk of SCC was not increased [87]. Exposure to artificial UV radiation as generated from tanning beds and lamps is also carcinogenic, and accounts for a large number of NMSC especially in the young population.

5.5 Ionising Radiation The carcinogenic effect of ionising radiation became recognised in the early years of the twentieth century when skin cancers were frequently found on the hands of doctors, dentists or technicians who were exposed to X-rays or point sources of radiation during the administration of radiotherapy. Further evidence that ionising radiation is carcinogenic comes from reports of increased incidence of NMSC developing in several radiation-exposed groups including uranium miners and patients treated with X-rays in childhood [88–91]. Epidemiologic studies have since then provided confirmatory evidence that prior radiation therapy is related to an increased risk of developing new BCC [92, 93]. Radiation therapy for acne, for example, was found to be associated with approximately a threefold risk of a new BCC while radiation received for tinea capitis in childhood increases this risk by four- to sixfold [90–92]. However, the risk of SCC was not increased in these studies. Additionally, a stronger excess risk for BCC than SCC was also noted among atomic bomb survivors of Hiroshima and Nagasaki [94]. A modest increase in SCC risk after ionising radiation has been found by some, but this was confined to patients whose skin was likely to burn after sun exposure [93]. Non-diagnostic

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Environmental Risk Factors for Non-Melanoma Skin Cancers

radiation exposure also leads to 5.7- and 4.8-fold increased risk of BCC and SCC [95]. Interestingly, it has been suggested that the risk of NMSC may be higher among those who received radiation therapy at an earlier age and the latency period from first ionising radiation to NMSC development is presumed to be approximately 20 years [91, 92, 94]. The risk of NMSC remains confined to the body site/s exposed to ionising radiation and it is estimated that the total dose of radiation required for NMSC development is 30 Gy [93]. Thus, in contrast to PUVA therapy, which is associated with an increased risk of SCC, the risk of BCC and less so SCC is increased with ionising radiation.

45 Table 5.2 High-risk occupations for non-melanoma skin cancer Causative agent Occupation Ultraviolet irradiation

Outdoor work, e.g. agriculture, groundskeepers, gardeners driving, fishing and construction Welding Laser exposure Certain printing processes Miners and quarrymen

Polycyclic hydrocarbons

Distillation of coal tar Coal, iron and steel foundries Roofing, road paving or wood impregnation Manufacture of coal gas Working with shale oil, creosote, asphalt and chimney soot

Ionising radiation

Nuclear plant operations Diagnostic X-ray work Uranium mining Radon mining

Burn

Welding

5.6 Occupational Factors In 1775, Sir Percival Pott, a London surgeon, made the link between occupation and skin cancer as he observed the occurrence of scrotal SCC in chimney sweeps. Since then several such observations have been made in workers exposed to products of distilling tar and pitch (polycyclic aromatic hydrocarbons [PAHs]), shale oil extraction workers, creosote-exposed wood impregnators, chimney sweeps, roofers and asphalt workers [96, 97]. As discussed in previous section, carcinogenic effects of ionising radiation on the skin have been recognised since the early years of the twentieth century. Several occupational groups remain at a high risk of developing NMSC (Table 5.2). In a recent population-based case-control study of agricultural occupations, in particular, groundskeepers and gardeners were found to have significantly elevated risks for both BCC and SCC [98]. Farmers had a more than two-fold risk of BCC, but no apparent elevation in SCC risk. It was speculated that sun exposure and exposure to insecticides, herbicides, fungicides and seed control treatments might be responsible for the increased risk of NMSC in this group. The same study found that men employed in unspecified management-related occupations were also at increased risk for both BCC and SCC, partly explained by detection bias [98]. A similar association for BCC has also been seen in patients who are employed in social science and social work [99]. In keeping with previous studies implicating occupational exposure to PAHs as a possible risk factor for NMSC, an increased BCC risk was noted among truck

Arsenic

Manufacture of insecticide or herbicide Agricultural exposure to pesticide Smelting of copper, lead, zinc Mining of arsenic Coal burning power plants Source: Adapted from Gawkrodger [96].

drivers, roofers, men employed at garages and kitchen workers, further supporting a potential role of occupational PAHs in NMSC pathogenesis. Higher risk of BCC has also been documented in workers exposed to fiberglass dust, dry-cleaning agents, luminous paint and arsenic [99, 100]. A multi-centre case-control study found a higher risk of BCC in railway engine drivers, firemen, farmers, salesmen, miners and quarrymen, secondary education teachers and masons. The same study found an increased risk of SCC among workers in direct contact with livestock [101]. Exposure to PAHs, ionising radiation, arsenic and burns were thought to play a role in genesis of NMSC in these patients. Despite the above evidence, exposures to pesticides, PAHs and asbestos were not found to be important risk factors for NMSC in another study [102]. It would seem, therefore that whilst certain outdoor occupations pose a definite hazard in terms of increasing the risk of NMSC, the evidence linking other occupations to NMSC is conflicting and at best limited.

46

5.7 Arsenic Exposure to high doses of arsenic has been implicated in the causation of NMSC and precancerous skin lesions like Bowen’s disease. Arsenical keratoses are punctate keratotic lesions seen on the palms and soles, and represent hallmark lesions of chronic arsenic exposure, which can eventuate into aggressive SCC. Chronic arsenic exposure is also associated with BCC. Arsenic modulates cellular signalling pathways and alters growth factors and diverse processes such as cell proliferation, oxidative stress, differentiation, apoptosis, chromosomal abnormality and genotoxic damage. Furthermore, like PAHs, arsenic may increase cancer risk through tumour promotion, hormonal action and immunotoxicity [103, 104]. Arsenic results in p53 dysfunction and in combination with UVB are proapoptotic and antiproliferative and therefore may act as a co-carcinogen. In addition, chronic arsenism results in cellular immune dysfunction with a decrease in peripheral CD4 + and Langerhan cell counts [104]. Rather than transdermal route, systemic absorption via ingestion is believed to be the mode of exposure and drinking water is perhaps the most common source of exposure to inorganic arsenic. Epidemiologic data from southwest of Taiwan with high levels of well water arsenic concentrations (1,220 mg/l), suggested the role of arsenic in causation of NMSC [105]. Further studies have corroborated this evidence [102, 106]. Occupational exposure to arsenic can also occur from other sources as listed in Table 5.2. Besides, exposure to arsenic also occurs from burning of coal in unventilated indoor stoves and tobacco smoking.

5.8 Tobacco Smoking and Diet The evidence linking tobacco smoking and NMSC remains sparse and at best inconclusive. One hospitalbased case-control study found tobacco smoking to be an independent risk factor for cutaneous SCC. They found a dose-response relationship with number of cigarettes and pipes smoked and SCC [107]. However, a nationwide cohort study from Sweden found no association between smoking tobacco and SCC risk. Interestingly, snuff use was associated with a decreased risk of SCC [108]. Like smoking, the association of dietary factors with NMSC remains inconclusive. On analysis of two major dietary patterns, meat and fat pattern was found

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to be positively associated with development of SCC whereas a higher consumption of green leafy vegetables appeared to substantially decrease SCC risk. No association was seen between the dietary patterns and BCC [109, 110]. The protective role of green leafy vegetables in SCC was confirmed by another Australian study, which also found consumption of unmodified dairy products, such as whole milk, cheese and yoghurt, to increase SCC risk in susceptible persons [111]. The role of dietary supplements in protection against NMSC also remains controversial. While vitamins A, C and E; folate; or carotenoids were not found to play a protective role against SCC in one study, another study found a substantial protective effect of vitamin E on SCC development [110, 112]. Dietary vitamin and antioxidant supplementation have also been found to be ineffective in reducing BCC risk [113, 114]. Thus far, there are no consistent data supporting the role of a tobacco smoking, specific form of diet or lack of specific nutrients in causation of, and dietary supplementation in protection against NMSC.

5.8.1 Take Home Messages 1. Besides ultraviolet radiation the role of most other environmental factors in the pathogenesis of NMSC is poorly studied. 2. Whilst the role of HPV, PUVA, immunosuppression and arsenic in NMSC causation is clear, the mechanisms by which these co-factors interact at molecular level, remains to be fully determined. 3. Quantitative effects of UV radiation in the pathogenesis of NMSC subtypes vary and are a matter of further research. 4. For development of NMSC, an individual’s susceptibility seems to be determined by a combination of their genetic status and the quantum of risk imposed by their occupation. 5. Evidence linking the association of smoking and diet with NMSC remains speculative.

5.9 Conclusions Although NMSCs are the commonest cancers affecting humans, apart from the role of the major environmental risk factors our understanding of the aetiological

5

Environmental Risk Factors for Non-Melanoma Skin Cancers

factors for these tumours has been poor and speculative. That UV radiation plays a pivotal role in the pathogenesis of both BCC and SCC has been long known and confirmed by several epidemiological and experimental studies. However, the quantitative effect of UV radiation in each of these NMSC subtypes differs and has been unravelled by the data provided in good quality epidemiological studies. Whilst the role of HPV, PUVA, immunosuppression and arsenic in NMSC causation is clear, the mechanisms by which these co-factors interact at molecular level, remains a matter of intensive research. Although occupational studies have identified several high-risk occupations, an individual’s susceptibility for NMSC seems to be determined by a combination of their genetic status and the quantum of risk imposed by their occupation. Finally, despite several attempts to define the role of smoking and diet in NMSC, studies have produced conflicting results and the evidence establishing this link remains speculative.

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syndrome is associated with increased serum levels of IL10, or the IL10 promoter -592 C/C genotype. Clin Immunol. 2003;109:119–29 69. Dalgleish AG, O’Byrne KJ. Chronic immune activation and inflammation in the pathogenesis of AIDS and cancer. Adv Cancer Res. 2002;84:231–76 70. Weiss E, Mamelak AJ, La Morgia S, et al The role of interleukin 10 in the pathogenesis and potential treatment of skin diseases. J Am Acad Dermatol. 2004;50:657–75 71. Wilkins K, Turner R, Dolev JC, et al Cutaneous malignancy and human immunodeficiency virus disease. J Am Acad Dermatol. 2006;54:189–206 72. Piguet V, Wan L, Borel C, et al HIV-1 Nef protein binds to the cellular protein PACS-1 to downregulate class I major histocompatibility complexes. Nat Cell Biol. 2000;2:163–7 73. Robertson P, Scadden DT. Immune reconstitution in HIV infection and its relationship to cancer. Hematol Oncol Clin North Am. 2003;17:703–16 74. Lobo DV, Chu P, Grekin RC, et al Nonmelanoma skin cancers and infection with the human immunodeficiency virus. Arch Dermatol. 1992;128:623–7 75. Maurer TA, Christian KV, Kerschmann RL, et al Cutaneous squamous cell carcinoma in human immunodeficiency virusinfected patients. A study of epidemiologic risk factors, human papillomavirus, and p53 expression. Arch Dermatol. 1997;133:577–83 76. Chan SY, Madan V, Helbert M, et al Highly active antiretroviral therapy-induced regression of basal cell carcinomas in a patient with acquired immunodeficiency and Gorlin syndrome. Br J Dermatol. 2006;155:1079–80 77. Nguyen P, Vin-Christian K, Ming ME, et al Aggressive squamous cell carcinomas in persons infected with the human immunodeficiency virus. Arch Dermatol. 2002;138:758–63 78. Stern RS, Liebman EJ, Väkevä L. Oral psoralen and ultraviolet-A light (PUVA) treatment of psoriasis and persistent risk of nonmelanoma skin cancer. PUVA Follow-up Study. J Natl Cancer Inst. 1998;90:1278–84 79. Harwood CA, Spink PJ, Surentheran T, et al Detection of human papillomavirus DNA in PUVA-associated nonmelanoma skin cancers. J Invest Dermatol. 1998;111:123–7 80. Wolf P, Seidl H, Back B, et al Increased prevalence of human pap-illomavirus in hairs plucked from patients with psoriasis treated with psoralen-UV-A. Arch Dermatol. 2004;140: 317–24 81. Stern RS, Lunder EJ. Risk of squamous cell carcinoma and methoxsalen (psoralen) and UV-A radiation (PUVA). A meta-analysis. Arch Dermatol. 1998;134:1582–5 82. Lindelöf B, Sigurgeirsson B, Tegner E, et al PUVA and cancer: a large-scale epidemiological study. Lancet. 1991;338 (8759):91–3 83. Stern RS, Bagheri S, Nichols K; PUVA Follow Up Study. The persistent risk of genital tumors among men treated with psoralen plus ultraviolet A (PUVA) for psoriasis. J Am Acad Dermatol. 2002;47:33–9 84. Hannuksela-Svahn A, Sigurgeirsson B, Pukkala E, et al Trioxsalen bath PUVA did not increase the risk of squamous cell skin carcinoma and cutaneous malignant melanoma in a joint analysis of 944 Swedish and Finnish patients with psoriasis. Br J Dermatol. 1999;141:497–501 85. Hannuksela-Svahn A, Pukkala E, Koulu L, et al Cancer incidence among Finnish psoriasis patients treated with

49 8-methoxypsoralen bath PUVA. J Am Acad Dermatol. 1999;40: 694–6 86. Lim JL, Stern RS. High levels of ultraviolet B exposure increase the risk of non-melanoma skin cancer in psoralen and ultraviolet A-treated patients. J Invest Dermatol. 2005; 124:505–13 87. Man I, Crombie IK, Dawe RS, et al The photocarcinogenic risk of narrowband UVB (TL-01) phototherapy: early follow-up data. Br J Dermatol. 2005;152:755–7 88. Sevcova M, Sevc J, Thomas J. Alpha irradiation of the skin and the possibility of late effects. Health Phys. 1978; 35: 803–6 89. Matanoski GM, Seltser R, Sartwell PE, et al The current mortality rates of radiologists and other physician specialists: specific causes of death. Am J Epidemiol. 1975;101: 199–210 90. Shore RE, Albert RE, Reed M, et al Skin cancer incidence among children irradiated for ringworm of the scalp. Radiat Res. 1984;100:192–204 91. Ron E, Modan B, Preston D, et al Radiation-induced skin carcinomas of the head and neck. Radiat Res. l991;125: 3l8–25 92. Karagas MR, McDonald JA, Greenberg ER, et al Risk of basal cell and squamous cell skin cancers after ionizing radiation therapy. For the Skin Cancer Prevention Study Group. J Natl Cancer Inst. 1996;88:1848–53 93. Lichter MD, Karagas MR, Mott LA, et al Therapeutic ionizing radiation and the incidence of basal cell carcinoma and squamous cell carcinoma. The New Hampshire Skin Cancer Study Group. Arch Dermatol. 2000;136:1007–11 94. Thompson DE, Mabuchi K, Ron E, et al Cancer incidence in atomic bomb survivors. Part II: solid tumors, 1958–1987. Radiat Res. l994;137:SI7–67 95. Gallagher RP, Bajdik CD, Fincham S. Chemical exposures, medical history, and risk of squamous and basal cell carcinoma of the skin. Cancer Epidemiol Biomarkers Prev. 1996; 5: 419–24 96. Gawkrodger DJ. Occupational skin cancers. Occup Med (Lond). 2004;54:458–63 97. Boffetta P, Jourenkova N, Gustavsson P. Cancer risk from occupational and environmental exposure to polycyclic aromatic hydrocarbons. Cancer Causes Control. 1997;8: 444–472 98. Marehbian J, Colt JS, Baris D, et al Occupation and keratinocyte cancer risk: a population-based case-control study. Cancer Causes Control. 2007;18:895–908 99. Gallagher RP, Bajdik CD, Fincham S, et al Chemical exposures, medical history, and risk of squamous and basal cell carcinoma of the skin. Cancer Epidemiol Biomarkers Prev. 1996;5:419–24 100. Kennedy C, Bajdik CD, Willemze R, et al Chemical exposures other than arsenic are probably not important risk factors for squamous cell carcinoma, basal cell carcinoma and malignant melanoma of the skin. Br J Dermatol. 2005; 152: 194–97 101. Suárez B, López-Abente G, Martínez C, et al Occupation and skin cancer: the results of the HELIOS-I multicenter case-control study. BMC Public Health. 2007, 26;7:180 102. Kennedy C, Bajdik CD, Willemze R, et al Chemical exposures other than arsenic are probably not important risk factors for squamous cell carcinoma, basal cell carcinoma

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110.

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6

Accuracy in the Diagnosis of Non-Melanoma Skin Cancer Mette Mogensen and Gregor B. E. Jemec

Key Points

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Early diagnosis is a key factor in the overall prognosis for skin cancer patients. By increasing diagnostic accuracy, a potential decrease in morbidity and mortality of non-melanoma skin cancer (NMSC) can be achieved. A variety of non-invasive technologies aimed at diagnosing and quantifying skin cancer have been developed during the past decades. Accurate diagnostic test assessment involves several phases and should ideally be performed prior to the clinical introduction of new test or technologies. Dermoscopy is currently the most widely accepted and most frequently used imaging tool in dermatology. Ultrasound imaging has also gained a wide clinical acceptance. Well-established medical imaging technologies such as magnetic resonance imaging (MRI), computed tomography (CT), and positron emission tomography (PET-scanning) have been used for diagnosis and staging of patients with NMSC.

M. Mogensen () Department of Dermatology, Faculty of Health Sciences, University of Copenhagen, Roskilde Hospital, Køgevej 7-3, 4000 Roskilde, Denmark e-mail: [email protected]

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The new in vivo high resolution imaging techniques such as confocal microscopy (CM), optical coherence tomography (OCT), and multiphoton microscopy imaging (MPMI) provide the potential for real-time delineation and diagnosis of NMSC.

Non-melanoma skin cancer (NMSC) is the most prevalent cancer in the Western world. The majority of tumours are of low-grade malignancy, but serious morbidity can result due to misdiagnosis, suboptimal therapy, or underestimation of the biological potential of the primary tumor. Early diagnosis, therefore, remains a key factor in the overall prognosis for the patients. A test or technology capable of increasing diagnostic accuracy could potentially decrease morbidity and mortality in NMSC, especially in patients affected by multiple lesions or field cancerization where biopsies from all lesions/whole area are not always feasible. The range of potentially diagnostic tests and technologies in NMSC is steadily increasing [1] and resolution and penetration depth are also ever increasing [2]. This chapter presents a review of accuracy studies of well-established as well as upcoming and bench technologies for NMSC/keratinocyte carcinoma diagnosis. All diagnostics tests can be accredited with precision and accuracy. Precision, also known as reliability, reproducibility, or repeatability refers to agreement of the test: If the test is performed multiple times on the same subject with the same result, then it is precise. Accuracy describes whether the diagnostic test yields a

G. B. E. Jemec et al. (eds.), Non-Surgical Treatment of Keratinocyte Skin Cancer, DOI: 10.1007/978-3-540-79341-0_6, © Springer-Verlag Berlin Heidelberg 2010

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correct or incorrect answer by correlating the test result with the truth. Thus, the accuracy of a test tells us how efficient it is in arriving at the correct diagnosis. The accuracy of a diagnostic test is usually reported in terms of its sensitivity, specificity, and predictive values. The truth, the correct diagnosis, cannot always unequivocally be reached, and for that reason, a “gold standard” or reference standard is chosen to represent the truth. In skin cancer, a biopsy obtained for histopathologic examination is considered as the reference standard. Biopsy, however, may be a time-consuming, expensive, potentially mutilating, and painful experience to the patient and carries a risk of infectious wound complications [3]. It is estimated that 3% of presumed benign lesions are actually malignant [4] and this misclassification can result in serious morbidity. On the other hand, a large number of biopsies from lesions with low degree of clinical suspicion of malignancy will increase the potential morbidity related to the biopsy procedure and health care expenses. A fast, reliable noninvasive diagnostic test can have a large clinical impact. Furthermore, noninvasive diagnostics would be valuable as new noninvasive emerging treatment strategies for NMSC call for noninvasive diagnostics. Accurate diagnostic test assessment involves four phases [5]: (1) determining the normal range of values for a diagnostic test through observational studies in healthy people, (2) diagnostic accuracy assessment through case-control studies, (3) assessment of clinical consequences of introducing a diagnostic test through randomized trials, and (4) determining the effects of introducing a new diagnostic test into clinical practice by surveillance in large cohort studies [6]. Unfortunately, many diagnostic tests and technologies are still introduced into the clinic without prior bona fide diagnostic accuracy assessment.

6.1 Clinical/Physical Examination Despite being the most accessible and used test, precision and accuracy of the clinical, naked-eye examination are often not known. The precision in clinical examination can be described as intra- and interobserver differences. The examination for NMSC can be performed by an expert, by a general practitioner, or by the patient himself or herself. Precision estimates must be generated in a blinded fashion; this is feasible in

M. Mogensen and G. B. E. Jemec

interobserver observations, but as lesions change over time intra-observer differences must be estimated from evaluation of pictures of skin lesions assessed at two different times [7, 8]. Results from representative studies [4, 7–15] are presented in Table 6.1. The overall sensitivity for clinical diagnosis of NMSC is 56–90% and specificity is 75–90%, with highest accuracy values for BCC diagnosis. Both false-negative and the false-positive diagnostic rates matter; it was demonstrated in a study in which 3% of lesions assessed as benign proved malignant and 40% of suspected malignancies were benign [4]. Two large studies [16, 17] considered diagnostic accuracy in delineating tumor borders after excision of BCC and SCC: In 2,141 BCCs, overall rate of incomplete excision was 11.2%, and in 517 SCCs incomplete excision rate was 6.3%. Patients themselves may also be involved in the diagnosis of cancer. In a study, patients with high risk of cutaneous malignant melanoma assessed changing lesions by performing a skin self-examination (SSE) and comparing it to a baseline digital total body photography of the skin: three of the four SCCs, and two of the four BCCs were noted by the patients on skin self-examination. SSE helped detect new and subtly changing melanomas, which did not satisfy the classical clinical features of melanoma and also helped detect NMSC [18]. The three strongest predictors of SSE performance in a study of 200 high-risk skin cancer patients were positive attitude toward SEE, having dermatology visits with skin biopsies, and at least one skin malignancy in the previous 3 years (P < 0.0001) [19]. These factors must be taken into account when planning SSE education programs.

6.2 Biopsy Techniques Shave and punch biopsies have been compared in a study including 86 biopsy specimens and subsequent total excision of the tumor [20]. Punch biopsy was accurate in determining BCC in 81% of cases, and shave biopsy correctly identified 76% of cases. In a systematic review of exfoliative cytology in diagnosis of BCC, a meta-analysis showed the pooled sensitivity to be 97% (CI 95%: 94–99%) and specificity to be 86% (CI 95%: 80–91%) [21, 22]. Another study compared diagnostic performance of scrape cytology using two different cytological staining techniques in

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Accuracy in the Diagnosis of Non-Melanoma Skin Cancer

Table 6.1 Diagnostic accuracy of clinical diagnosis Authors Group studied Number of participants Leffell D.J. et al., 1993

Two dermatologists

Whited J.D. et al., Dermatologists 1995 blinded to the patient history Whited J.D. et al., Primary care 1997 physicians (PCP) and dermatologists Hallock C.G. Plastic surgeons et al., 1998

Har-Shai Y et al., 2001 Morrisin A. et al., 2001

Oliveria S.A. et al., 2004

Davis D.A. et al., 2005

Plastic surgeons Dermatologists and family practitioners (FP) Patients

77 pathologists

Schwartzberg J.B. Dermatologists et al., 2005 complete a questionnaire before biopsy, confidence level 1–3 was plotted Ek E.W. et al., Plastic surgeons 2005

Westbrook R.H. et al., 2006

GPs, dermatologists, and pathologists

Tan et al., 2007

Prospective, observational study of 477 SCC patients

53 patients with 143 NMSC lesions 50 NMSC patients

190 NMSC patients

53

Question

Result

Observer agreement

Kappa 0.78 in AK and 0.38 in SCC [11] (See Box 6.1)

Does history Kappa values -0.04 (blinded) and 0.76 influence the (with history) [7] (See Box 6.1) clinical diagnosis? Diagnostic accuracy Sensitivity of the PCPs was 57% (95% CI 44–68%) and specificity was 88% (95% CI 81–93%) [153]

2,058 lesions in Diagnostic accuracy 809 NMSC patients referred for tumor excision

Three-fourth of benign lesions were identified (sensitivity 93% and specificity 86%). Only 60% of malignant lesions were identified (sensitivity 73% and specificity 90%). 3% of presumed benign lesions were malignant [4] Sensitivity of 91% and a PPV of 71% [12] FPs diagnosed 22% of skin cancer prior to biopsy, dermatologists diagnosed 87% correctly [10]

835 lesions in 778 patients 493 NMSC patients

Diagnostic accuracy

50 patients with dysplastic nevi

Diagnostic accuracy in selfexamination

Choose between a diagnosis of either AK or SCC in 15 slides 141 patients with BCC lesions

Observer agreement

Effect of additional data

PPV was 80% [9] when additional data was presented

2,582 NMSC lesions excised from 1,223 patients 283 NMSC cases

Diagnostic accuracy

BCC and SCC was diagnosed with a sensitivity of 89% and 56%, and a PPV of 65% (p = 0.001) [13]

Diagnostic accuracy

GPs diagnosed SCC in 70, dermatologists in 24, 53 suspected SCC were biopsied, 13 of these were confirmed SCC by pathologists [155] Overall incomplete excision rate 6.3%. Highest rate among ear, reexcisions, and invasive lesions

517 excised SCC lesions

Diagnostic accuracy

Ability to delineate tumor borders, estimated as incomplete excision of SCC

The accuracy was significantly higher (p = 0.001) with the aid of a digital photography. Sensitivity without photo was 60% and specificity was 96% compared to sensitivity of 72% with photo and specificity of 98% [154] ICC was 0.96 for dermatopathologists and anatomic pathologists and 0.65 for fellows [14] (see Box 6.2)

(continued)

54

M. Mogensen and G. B. E. Jemec

Table 6.1 (continued) Authors Group studied

Number of participants

Question

Result

Ability to delineate tumor borders, estimated as incomplete excision of BCC

Overall incomplete excision rate 11.2%. Highest rate among morpheic BCC, lesions larger than 20 mm, multiple lesions, and more

Su et al., 2007

Prospective study

1,214 excised BCC lesions

Youl et al., 2007

Prospective comparative study of 104 GPs and 50 skin cancer clinic doctors involving 28,755 patient encounters

GPs excised or biopsied 3,175 skin lesions. Clinic doctors excised or biopsied 7,941 skin lesions

Box 6.1 The kappa statistics is a measure of the agreement level beyond what might be expected by chance alone. The kappa values vary from –1 (perfect disagreement) to + 1 (perfect agreement).

Box 6.2 Intra class correlation coefficient (ICC) is an estimate of the interobserver reliability by two-way analysis of variance. Standard criteria for ICC are: 0.40 = poor; 0.40–0.59 = fair; 0.60–0.74 = good; 0.75–1.00 = excellent correlation between observers.

50 BCC and 28 AK, from 41 and 25 patients, respectively. The smears were stained with Papanicolaou (Pap) or May-Grünwald-Giemsa (MGG) stains. All cytological specimens were examined in random order by pathologists without knowledge of the histology. Cyto-diagnosis agreed with histopathology in 48 (Pap) and 47 (MGG) of the 50 BCC cases, and in 26 of 28 (Pap) and 21 of 26 (MGG) AK cases, yielding sensitivities of 96%, 94%, 93%, and 81%, respectively. No significant difference in sensitivity between the two staining methods was found [23]. However, cytology does not give any information about subtype and tumor borders.

Overall, sensitivity for diagnosing any skin cancer was similar for skin cancer clinic doctors (0.94) and GPs (0.91), although higher for skin cancer clinic doctors for BCC (0.89 versus 0.79; P < 0.01) and melanoma (0.60 versus 0.29; P < 0.01)

6.3 Histopathology and Molecular Markers Histopathology is a subjective assessment by a dermatopathologist conforming to certain classification systems. Ideally, histopathological classification of NMSC should identify subtypes that correlate with clinical behavior and treatment requirements. In addition, the classification should be easy to use and reproducible. Determining diagnostic accuracy of the reference standard itself is hampered by the fact that there are several classification systems for NMSC [24, 25]. Difficulties also confront pathologists reporting BCCs: Many BCCs have more than one growth pattern and published data have varied with regard to number necessary to designate the presence of a specific subtype. Furthermore, the accuracy of reporting different subtypes has not been extensively investigated [24]. In general, interobserver differences cannot be neglected as a potential source of error, with potential clinical consequences for the patient, but also diagnostic-research-wise, as all other skin cancer diagnostic techniques must be compared to histopathology. The interobserver differences in this review range from 1.2% to 7% [26–31] (see Table 6.2). Interobserver reliability of the histopathologic diagnosis of BCC and SCC was assessed in a study by blinded review of histopathologic slides by two dermatopathologists [32]. Overall interobserver agreement between the two dermatopathogists was k = 0.69

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Accuracy in the Diagnosis of Non-Melanoma Skin Cancer

55

Table 6.2 Diagnostic accuracy of histopathology and molecular markers Authors Group studied Number of cases Question

Results

Lind A.C. et al., 1995

Two pathologists

2,694 slides

Interobserver differences

Olhoffer I.H. et al., 2002

DPs and other physicians (including pathologists) 20 pathologist diagnosing pigmented skin lesions and NMSC 77 pathologists (both dermatoand anatomic)

336 cases

Interobserver differences

48 slides

Interobserver differences

Overall sensitivity was 87% (range 55–100%) and specificity was 94% (range 83–100%) [28]

15 SCC and AK slides

Interobserver differences

Trotter M.J. et al., 2003

Two pathologists

Interobserver differences

Biesterfield S. et al., 2002

MIB-1 immunohistometry for the differential diagnosis between KA and SCC Doing reverse transcriptase – polymerase chain reaction (RT-PCR) to amplify keratin19,

Blinded review of 592 histopathology slides 49 keratoacanthomas and 48 SCC

Average ICC (see Box 6.2) was 0.97 for all pathologists. Agreement was above 70% for 11 of 15 slides [156] Agreement was found in more than 93% of cases [31]

26 lymph nodes 10 had histologically proven metastasis, 16 had none

This method showed a detection Molecular marker: sensitivity of one tumor cell in Micrometastasis of 106 lymphocytes [29] SCC in lymph nodes

Brochez et al., 2002

Renshaw A.A. et al., 2002

Kamiya M. et al., 2003

(95% confidence interval [CI] 0.67–0.69). The interobserver agreement was highest for basal cell carcinoma at k = 0.88 (95% CI 0.84–0.91) and for a diagnostic category in the SCC-actinic keratosis spectrum at k = 0.80 (95% CI 0.73–0.86). The largest disagreements between the two dermatopathologists were regarding the categories of invasive SCC at k = 0.62 (95% CI 0.52–0.72), SCC in situ at k = 0.42 (95% CI 0.29–0.56), and actinic keratosis k = 0.51 (95% CI 0.40–0.62. The

Molecular marker: Proliferation marker MIB-1

Thirty-two major errors were found, involving 1.2% of cases reviewed [26]. Errors were divided into 4 types: (1) major: errors in diagnosis that could directly affect patient care; (2) diagnostic discrepancies: errors in diagnosis that should not affect patient care; (3) minor: correct diagnosis rendered, but report correction required to add supportive information; (4) clerical: typographical and grammatical errors. Discordance in 5.7% of cases. New management in 18 of 19 severe cases [27]

If specificity 85% is required sensitivity decreases to 56%. MIB-1 is currently of limited value in SCC diagnosis [30]

morphea subtype of basal cell carcinoma was the only reliably diagnosed subtype (k = 0.79, 95% CI 0.51– 1.00) (Fig. 6.1). A current research goal is to define skin cancer by its phenotype in terms of molecular abnormalities as a reference standard for NMSC diagnosis [24, 25, 33–36]. To date a molecular marker with a high diagnostic accuracy in NMSC diagnosis has not been identified.

56

a

b

M. Mogensen and G. B. E. Jemec

c

0.20 mm 0.40 mm 0.60 mm 0.80 mm 1.00 mm 1.20 mm 1.40 mm 1.60 mm 1.80 mm 2.00 mm 2.20 mm

Fig. 6.1 Ulcerating basal cell carcinoma (BCC) on the forehead 1a: Clinical photo of a BCC lesion. 1b: OCT scan of BCC lesion shown in 1a. The convex upper dark area corresponds to the ulceration in the histopathology image. 1c: Histopathology slide

from the same area of the lesions scanned by OCT. (HE stain, 20× magnifications). The base of the BCC tumor is pointed out by a fat arrow in both 1b and 1c. Image courtesy to Dr. Birgit M. Nurnberg, Dept of Pathology, Roskilde Hospital, Denmark

6.4 High Frequency Ultrasonography and Doppler Sonography

(see Table 6.3 and Fig. 6.2). In HFUS images skin tumors generally appear as a homogeneously echopoor area in comparison to the surrounding echo-rich dermis. Because all skin tumors appear echo-poor, HFUS alone is not suitable for differential diagnosis [60]. Overestimation of tumor thickness appears to be a general problem because fibrosis and inflammation generally have the same echogenecity as NMSC. Skin tumor vascularization studies using Doppler techniques have also been performed. HFUS in NMSC diagnosis is to some extent capable of revealing the three-dimensional size, margins, and relation to adjacent vessels of a suspicious skin lesion. Information on quality (such as solid, cystic, or combined) and information about the inner structure (homogeneous, inhomogeneous, hypo/hyperechoic, calcification, or necrosis) can be

The principle in high frequency ultrasonography (HFUS) is the emission of a pulsed ultrasound from a transducer, and registration of the intensity of the echo backscattered from the tissue. The amplitude of the curve reproduces the intensity and time delay of the returning US, and is called A-scan. A B-scan is created when the transducer is moved laterally creating a twodimensional image. Penetration depth and resolution of US is inversely related to the frequency, which makes HFUS suitable in dermatology. Axial resolution at 20 MHz is 50 mm and lateral resolution is 350 mm. The sonographic characteristics of skin tumors have been widely investigated during the past decades [37–59]

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Accuracy in the Diagnosis of Non-Melanoma Skin Cancer

Table 6.3 Diagnostic accuracy of high frequency ultrasonography Authors Number and Question asked pathology of patients Stucker M. et al., 1999

16 BCC lesions and 27 MM

Laser Doppler perfusion imaging

Schroder R.J. et al., 2001

81 Clinically malignant tumors

Karaman G.C. et al., 2001

19 benign and 32 BCC, 15 SCC

Moore J.V. et al., 2003

181 patients with BCC

Lont A. et al., 2003

33 SCC patients

Desai et al., 2007

50 superficial and nodular BCCs

Uhara et al., 2007

29 BCC, 56 malignant melanomas

Laser Doppler perfusion imaging study with and without contrast Power Doppler (Doppler independent of angle) Thickness of the lesions before and after PDT treatment HFUS Diagnosis of SCC of the penis compared to MRI Ability of HFUS to delineate tumor borders Assessment of diagnostic value of HFUS features in BCC

57

Results

Tumor perfusion values higher than surrounding skin. BCC perfusion values similar in the whole tumor as opposed to MM, where it was higher in the tumor center [157] Sensitivity of 0.75 and specificity of 0.79 if three to five vessels were visible in the tumor, and sensitivity of 0.58 and specificity of 0.88 if a parameter called “percentage vessel area” exceeded 5% [158] Specificity of 63% and sensitivity of 88% in diagnosis based on vascular patterns alone in the lesions [38] BCC thickness predicts outcome 1 year after photodynamic therapy with ALA [39] In SCC of the penis HFUS provide diagnostic value in staging the disease. PPV for corpus cavernosum infiltration: 67% (HFUS) and 75% (MRI) [159, 160] 45/50 BCC were clear after margin assessment with HFUS, which also detected one subclinical BCC extension Multiple hypersonographic spots in BCC may differentiate BCC from MM using HFUS. Present in 0/56 MM and in 27/29 BCC

a

Fig. 6.2 Comparison of OCT and ultrasound imaging for tumor thickness measurement 2a is an OCT image of a BCC lesion. The thickness is measured and marked by a white bar and indicated by white numbers next to the bar in all images 2a–2d. 2b is a 20 MHz ultrasound image of the same lesion as in 2a. 2c is an OCT image of another BCC lesion and 2d is a 20 MHz ultrasound image of the same lesion as in 2c. The figures illustrate a common tendency over high-frequency ultrasound to overestimate tumor thickness compared to OCT imaging

b 0.422 mm

0.816 mm

OCT image of BCC c 0.310 mm

Histology of BCC

Ultrasound image of BCC

58

obtained [61]. Tumor depth measurement in NMSC using HFUS corresponds well with tumor depth measured in HE stains slides from the excised tumor [58].

6.5 Elastography Benign skin tumors are often softer than malignant tumors. This characteristic is imaged by elastography: it uses conventional US to create a sonogram combined with another dimension: compression. When recording the elastography the skin is compressed with the US probe. Thus, the elastography image captures the echoes of the sound waves in this compressed state. Since a malignant tumor behaves differently from a benign tumor under compression, the computer-generated combination of the first image with the compression image may contain more information. A few pilot studies on human skin supports this [62–64]. Melanomas can be discriminated from benign pigmented nevi in a pilot study [65]. No studies on NMSC were identified.

6.5.1 Optical Diagnostic Technologies To understand optical imaging it is important to acknowledge the optical properties of the anatomical layers of the normal skin [66]. Stratum corneum consists of a number of layers of keratin-impregnated cells that vary considerably in thickness. Apart from scattering the light it is optically neutral. The epidermis is largely composed of keratinocytes and it also contains Langerhans and dendritic cells, melanocytes and their product melanin. Melanin strongly absorbs light in the blue and ultraviolet part of the spectrum. Within the epidermal layer there is very little scattering, with the small amount that occurs being forwarddirected. The result being that all light not absorbed can be considered to pass into the dermis. Dermis consists mainly of fibroblasts which are embedded in a network of collagen fibers and, in contrast to epidermis, dermis contains vessels. Hemoglobin acts as a selective absorber of light. The papillary dermis has smaller-size collagen fiber bundles than the reticular layer. All light from the papillary dermis is backscattered, and the scatter is greatest at the infrared spectrum where also absorption of melanin and

M. Mogensen and G. B. E. Jemec

hemoglobin is negligible. The scatter is forwarddirected in the reticular layer. Adnex structures, such as hair follicles and glands situated in dermis, have great variation in refractive index, and cause random scattering, which decrease light penetration into tissue [67].

6.6 Dermoscopy/Dermatoscopy/ Epiluminiscence Microscopy/ Incident Light Microscopy/ Skin Surface Microscopy In dermoscopy the lesion is examined with a 10–100× magnification lens placed directly against skin to which immersion oil has been applied to remove scatter of light at the air-skin boundary. Dermoscopy has had the largest clinical impact regarding new skin cancer diagnostic technologies, especially in diagnosis of pigmented skin lesions, but it has also been studied and used in NMSC. Interobserver agreement among five observers in dermoscopic diagnosis of pigmented BCC had “very good” to “good” agreement on three recognized dermoscopy features as spoke-wheel areas (kappa value 0.85, 0.72, and 0.49) and total agreement on absence of pigment network [68]. Concerning AK four, essential features combined in 95% of cases produced a strawberry appearance which may prove helpful in the diagnosis of facial AK [69]. Diagnostic accuracy regarding vessels characteristics in BCC and Bowen’s disease seems promising and sensitivity for BCC diagnosis ranges from 87% to 96% and specificity from 72% to 92% (see Table 6.4). Dermoscopic features of BCC are: Arborizing vessels are defined as stem vessels with a large diameter, branching irregularly into the finest terminal capillaries. The diameter of the vessels can be up to 0.2 mm, branching irregularly into capillaries of 10 mm [70]. Grey-brown lumps, often ovoid in shape and amber-colored crusts are other dermoscopy features in BCC. In Bowen’s disease dermoscopic features are glomerular vessels (90%) and scaly surface (90%) [71]. Glomerular vessels are dotted vessels often distributed in clusters mimicking the glomerular apparatus of the kidney. Compressing the blood vessels renders them invisible. Magnification by 30 times or more must be applied to visualize vessels down to 10 mm [72].

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Accuracy in the Diagnosis of Non-Melanoma Skin Cancer

Table 6.4 Diagnostic accuracy of dermoscopy Authors Number and pathology of patients Aregnziano et al., 2007

59

Question asked

Zalaudek et al., 2004, 2005

Ability of primary care physicians to improve diagnostic accuracy using dermoscopy Internet study regarding 165 lesions (including 20 diagnostic accuracy A BCC, otherwise mostly three-point checklist pigmented lesions) 150 dermatologists and (asymmetry, atypical other doctors network, blue-white structures) Assessment of dermoscopic diagnostic features in AK 21 SCC in situ (Bowen’s Characteristic dermoscopy disease) features

Argenziano et al., 2004

531 lesions (117 BCC) from 517 patients

Diagnostic features: vascular structures

Chin et al., 2003

111 skin samples (including 20 SCC, 50 BCC) 7 BCC patients

Blood vessels counted after immunohistochemistry

Peris et al., 2002

56 pigmented BCCs

Interobserver agreement among five observers in dermoscopic diagnosis of pigmented BCC

Kreusch J.F., 2002

BCC patients, number not retrieved

Diagnostic features: vascular structures

Zalaudek et al., 2006

Zalaudek et al., 2006

Otis et al., 2004

Menzies S.W 2002

73 physicians evaluated 2,522 lesions

Diagnostic features: vascular structures with capillaroscopy 71 pigmented BCC lesions Characteristic dermoscopy features

6.7 Optical Coherence Tomography OCT is a novel, noninvasive optical imaging technology that provides cross-sectional tomographic images of skin in situ and in real time. OCT works in analogy to ultrasound; the reflection of infrared light (instead of acoustical waves) from the skin is measured and the signal strength is imaged as a function of position. A low-power infrared light illuminates the tissue, and the signal obtained from the scan is amplified, demodulated, and stored in a digital form. The OCT probe is applied directly to the skin after application of ultrasound gel. OCT is well-suited for in vivo skin imaging with a resolution in the 8–20 µm range and a penetration depth of

Results Significant increase in sensitivity and specificity

Sensitivity for BCC was 86.7% (CI 95%: 76.9–92.7%) and specificity 71.9% (CI 95%: 56.6–83.3%) [161]

Four essential features combined produced a strawberry appearance in 95% of AK Glomerular vessels with a patchy distribution and scaly surface was found in 90% of all lesions [71, 162] Arborizing vessels were seen in 82% of BCC, with a PPV of 94% (p < 0.001) [70] SCC in situ:13 out of 16 lesions showed glomerular vessels, PPV 62% Significant difference between the groups, and also between BCC and SCC [163] Micro vessel area fraction were increased 4.9-fold in BCC and 2.5-fold in AK compared to normal skin Arborizing vessels are detected in 52%, sensitivity was 93% and specificity was 89–92% [164] “Very good” to “good” agreement on three recognized dermoscopy features as spoke-wheel areas, (kappa value 0.85, 0.72 and 0.49) and total agreement on absence of pigment network Sensitivity of 96%, specificity of 91% [72]

approximately 2 mm. Characteristics other than the intensity of backscattered and reflected light can be imaged by OCT. Some tissues such as muscle and collagen are birefringent and in polarization-sensitive (PS)OCT the birefringence of tissue can be measured [73]. OCT images can also be enhanced by 2D and 3D Doppler function [74–76]. In the past decade OCT has been widely investigated for imaging of NMSC [67, 77–89] (see Table 6.5). A breakup of the characteristic layering of normal skin [90, 91] is found in both OCT images of NMSC [67, 79, 83, 86, 87, 89] and MM [92] lesions. However, this disruption of layering is also seen in various benign lesions as sebhorreic keratosis [86] and benign melanocytic

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M. Mogensen and G. B. E. Jemec

Table 6.5 Optical coherence tomography Authors Study type

Number of patients

OCT resolution in tissue (axial/lateral, penetration)

Korde et al., 2007

Clinical study

112 patients with skin on forearm assessed as normal, sun-damaged, and actinic keratosis

17 mm axial, 12 mm lateral

Olmedo et al., 2007

Clinical study

23 patients with 49 lesions (27 BCC, 10 SCC, 7 AK, 2 SK, 2 MM, 1 nevus)

12 mm in depth

Gambichler et al., 2006

Clinical study

38 patients with 43 lesions (23 nodular BCC, 10 sup. and 10 inf. BCC

Olmedo et al. [83], 2006

Clinical pilot study

23 patients with 27 BCC lesions

Abuzahra et al. [77], 2006 Strasswimmer et al. [98], 2004

Pilot study Pilot study

1 patient with a Mb. Bowen lesion 2 patients with invasive BCC lesions

Bechara et al. [80], 2004

Clinical pilot study

Buchwald et al. [97], 2003

Clinical pilot study

Steiner et al. [67], 2003

pilot study

Barton et al. [79], 2003

Clinical pilot study

3 patients with BCC, 3 patients with MM 35 patients with 38 eye-lid lesions (BCC 4/38, AK 1/38 and other benign and malignant lesions BCC lesion and malignant melanoma lesion 20 patients with actinic keratosis (AK)

Petrova G. et al. [96], 2003

Clinical study

Welzel J. et al. [86], 2001

Review

Welzel J. et al. [165], 1997

Clinical pilot study

12 mm in depth 1 mm

Penetration depth 1 mm 12 um

118 patients with various skin diseases, five skin cancer patients (erythrodermic T-cell lymphoma) Some BCCs and a malignant melanoma

nevi [92]. Several other NMSC features in OCT images have been described, the most important are: focal changes including thickening of epidermis (AK) [79, 93]; dark rounded areas, sometimes surrounded by a white area (BCC basaloid island cell clusters and surrounding stroma); and increased penetration depth in OCT images [80, 83, 94]. SCC has mainly been studied on oral mucosal surfaces using OCT [95], but changes similar to BCC have been described. In a study of 49 BCC lesions [83], there was an excellent match between histological features seen on light microscopy and 20 OCT images of superficial, nodular, micronodular, and infiltrative BCCs. In another study, OCT images from three superficial BCCs and

15 um. Penetration depth of 0.5–1.5 mm

three MM lesions were compared with histology. The size, allocation, and form of BCC nests seemed to be similar to those in histological images; the MM lesions were less well-defined [80]. In a study of nine patients with 12 BCC lesions, some lesions were well-defined in OCT-images, but BCC subtypes could not be identified in OCT images [82]. Accuracy was assessed in three OCT studies [79, 93, 96]; identification of dark band in epidermis enabled detection of AK with sensitivity of 86% and specificity of 83% in a study of more than 100 patients. The dark band in OCT images corresponds to keratin deposits in thickened SC in AK lesions. The study also reported sensitivity of 73% and specificity of 65% in diagnosis of AK from ROC-curves

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Accuracy in the Diagnosis of Non-Melanoma Skin Cancer

Table 6.5 (continued) Diagnostic Accuracy assessment

61

Conclusion

Identification of diagnostic features (dark band in AK can be distinguished from undiseased skin with 86% sensitivity epidermis). And assessment of diagnosis of AK and 83% specificity. AK can be distinguished from sun-damaged from ROC-curves displaying quantitative data from skin with sensitivity of 73% and specificity of 65% (ROC-curves) OCT images of AK and sun-damaged skin Comparison of thickness of 20 BCC lesions measured by OCT is a promising method for BCC depth measurement in lesions OCT and microscopy. Correlation for tumors < 1.2 <1.2 mm. mm (17/20), r = 0.95 (p > 0.001). No correlation or coefficient of variation data for thicker lesions 3 main OCT features identified. No subtype characteris- OCT morphology correlated well with histopathology. No statistical tic features identified significant difference between features among subtypes – small sample size 20/27 OCT-scans matched histopathology. No statistical BCC subtypes as superficial and nodular could be identified in OCT elaboration of significance of OCT features images. Small sample size None Differential diagnosis of neoplasia not possible No statistical elaboration of data. The birefringence Tumor tissue was distinguished from normal skin by PS-OCT also signal was quantified, and both BCC lesions indicating an ability of PS-OCT to delineate tumor borders demonstrated a 3–10-fold power signal than normal skin No statistical elaboration of data. Morphological match In 2 OCT-images a match between morphological structures in the of histopathology and OCT images image and histopathology structures were demonstrated Morphological and quantitative (relative reflectivity) tumor margins could not be determined by OCT, but cystic lesions comparison of OCT images and 30 MHz ultrasound. were visualized with higher resolution compared to ultrasound No statistical elaboration of data None OCT is matched morphologically to histpathology in various dermatosis and suggested a potentially diagnostic tool A model for diagnosing AK on the basis of thickness AK lesions were not biopsied but clinically diagnosed. No observerand signal intensity of SC and epidermis/dermis was blinded evaluation, only statistical models. High diagnostic developed. Sensitivity of 77–84%. Specificity of accuracy of features is promising 42–100%. Sensitivity of 62% and specificity of 91%, kappa 0.63 Application of Glycerol improves image quality and diagnostic (CI 0.58–0.65) accuracy. Overall diagnostic accuracy from 76% to –94%. Kappa up to 0.69 None BCCs show a characteristic homogeneous signal distribution in OCT-images. Lateral tumor borders can be identified None Promising new imaging method for visualization of morphologic changes of superficial layers of the human skin

displaying quantitative data from OCT images of AK and sun-damaged skin [93]. In an earlier smaller pilot study, Barton et al. [79] had described sensitivity of 100% and specificity of 70% for diagnosing AK from dark bands in SC in OCT images. Another study [96] included patients with a variety of dermatoses including five T-cell lymphomas. OCT images were blindly evaluated by nine dermatologists. Sensitivity of 62% and specificity of 91% and a kappa value of 0.63 were demonstrated in differentiating between psoriasis and erythrodermic T-cell lymphoma. No other skin cancers were included in the study. A study compared OCT and HFUS in diagnosis of eye-lid tumors. Examination of 38 patients (four BCC,

one AK and other benign and malignant tumors) showed that OCT was superior in detecting cystic lesions, but due to low penetration of the OCT system in the skin, tumor margins could not be determined [97]. In PS-OCT images, a non-birefringent, homogeneous band [88] has been described in the upper part of the image corresponding to epidermis and papillar dermis. A gradual transition from normal-appearing tissue to tumor tissue could be detected by PS-OCT at the BCC borders, indicating an ability of PS-OCT to delineate tumor borders [98]. OCT and PS-OCT from 104 patients were studied by observer-blinded evaluation of OCT images from 64 BCC, 1 baso-squamous

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carcinoma, 39 AK, two malignant melanomas, and nine benign lesions, in a recent study by Mogensen et al. [99]. Sensitivity was 79–94% and specificity was 85–96% in differentiating normal skin from lesions. Important features were absence of well-defined layering in OCT and PS-OCT images and dark lobules in BCC. Discrimination of AK from BCC had an error rate of 50–52%. Conclusively, OCT features in NMSC were identified, but AK and BCC could not be differentiated. OCT diagnosis is thus less accurate than clinical diagnosis, but high accuracy in distinguishing lesions from normal skin was obtained, crucial for delineating tumor borders. OCT has some advantages over en face technologies like confocal microscopy (CM) and multiphoton microscopy imaging (MPMI) despite its lower resolution. Accurate assessment of skin layers or tumor thickness is more difficult in cross-sectional images, even though B-scans can be generated from en face images. Compared to CM and MPM, OCT has a larger field of view and penetration depth and offers cross-sectional images of the skin similar to histopathology sections. OCT has therefore been called “the optical biopsy” [100].

6.8 Confocal Microscopy Reflectance confocal microscopy (CM) or confocal laser scanning microscopy has the second highest resolution of optical techniques used in NMSC diagnostic research [101]. Current CM systems have an axial resolution of 0.5–5 mm and a lateral resolution of 0.5–1 mm. The penetration depth maximum is 300 mm. CM uses a point source light to illuminate a small spot within a tissue. The pinhole minimizes out-of-focus light reaching the detector, and only confocal light is detected. For in vivo imaging, a plastic cap filled with water has to be adapted to the skin. CM has proved a potentially valuable diagnostic aid in BCC, AK, and SCC diagnosis, both ex vivo and in vivo [102–105] (see Table 6.6). Characteristic CM features of NMSC in BCC are described as abundant blood vessels juxtaposed to BCC cells, sometimes in tightly packed nests, rolling of leucocytes and lymphocytes along the endothelial lining. BCC cells appeared to be oval, elongated with a prominent, monomorphic polarized nucleus. Tumor cells had a high refractive index with dark-appearing

M. Mogensen and G. B. E. Jemec

nuclei, the cytoplasm appeared bright [106, 107]. In pigmented BCC, morphology has been described as aggregations of tightly packed cells with palisading forming cordlike structures and nodules with irregular borders and variable brightness (nests of pigmented basaloid tumor cells on histopathology and blue-gray ovoid areas on dermoscopy). Tumor nests were associated with bright dendritic structures, identified histologically as either melanocytes or Langerhans cells, together with numerous bright oval-to-stellate-shaped structures with indistinct borders representing melanophages, and with highly refractile granules of melanin [108]. In SCC recognized CM features are irregular epithelial mass with a variable proportion of normal and atypical keratinocytes, along with areas of anaplasia. In AK, CM imaging was able to describe well-known hyperkeratosis, lower epidermal nuclear enlargement, and pleomorphism [102]. Some features seen in CM images (e.g., uniform polarization of BCC nuclei, margination, and rolling of leucocytes) are morphological features not recognized in BCC histologypathology [106, 107]. A diagnostic accuracy study demonstrated an overall sensitivity and specificity of 91% and 99%, respectively in differentiating malignant melanomas, BCC, benign nevi, and seborrheic keratosis [104] in an observer-blinded setting. Classification and regression analysis based on three diagnostic features facilitated a correct classification of 96% MM, of 99% benign nevi, and 100% of BCC and seborrheic keratosis. In a CM study on AK, with blinded evaluation by two independent investigators, 98% of 44 AKs were correctly identified and 2% were incorrectly identified as normal skin [105]. CM comes with a learning curve, but also CM novices have a high diagnostic accuracy when using five CM-criteria for in vivo BCC diagnosis (e.g., presence of nests of elongated monomorph nuclei). A sensitivity of 96% and specificity of 83% were found using three criteria in a large multicenter trial, and sensitivity of 94% and specificity of 78% using five criteria [109]. In Mohs’ micrographic surgery (MMS) CM might have a role to play in analyzing untreated fresh biopsy specimens. This has been done in a study of 20 BCC patients. Several CM diagnostic criteria (e.g., elongation of tumor cell nuclei) yield a sensitivity ranging from 44% to 100% and a specificity of 100% for all five criteria. In a study of 92 BCC and 23 SCC, despite

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Table 6.6 Diagnostic accuracy of confocal microscopy Authors Number and Question asked pathology of patients Ulrich et al., 2007

Sequra et al., 2007

44 Caucasians (SPT I-III) with a minimum of one actinic keratosis lesion 3 pigmented BCC

Marra et al., 2005

3 BCC

Gerger et al., 2005

20 BCC

Nori S. et al., 2004

152 lesions (83 BCC and benign)

Chung V.Q. et al., 2004

92 BCC, 23 SCC

Tannous Z. et al., 2003

5 BCC

Gonzalez S. et al., 2002 Sauermann K. et al., 2002 Aghassi D. et al., 2000

5 BCC 12 BCC 6 AK, 1 SCC

Results

CM evaluation parameters included parakeratosis, architectural disarray, and keratinocyte pleomorphism Proliferation of large dendritic-shaped cells has been associated with the diagnosis of MM. Occurrence in pigmented BCC studied CM compared to histopathology Diagnostic accuracy CM in MMS untreated fresh biopsies Diagnostic accuracy of five CM-criteria for in vivo BCC diagnosis Ex vivo CM of stage 1 MMS excisions Diagnostic accuracy in vivo CM aluminium chloride contrast In vivo CM compared to histopathology Diagnostic value of CM vascular pattern CM diagnostic features

difficulties in recognizing SCC in situ in CM and poor image quality, CM was considered a promising diagnostic adjunct to MMS frozen sections [103]. Aluminium chloride might provide an excellent contrast between BCC cells and surrounding tissue in CM. In a pilot study of four patients with BCC undergoing MMS, a high diagnostic accuracy has been found, but a limitation is the inflexible, large tissue ring, which makes imaging of convex and small surfaces unfeasible [110]. Another study found excellent match between florescent CM images of NMSC and histopathology using Toluiden blue and Methylen red ex vivo [111]. CM has also been used ex vivo to locate Merkel cells in the skin [112]. A BCC patient was followed by weekly CM during Imiquimod treatment of a BCC lesion, after 9 weeks there was neither CM nor clinical

Following blinded evaluation by two independent investigators, 97.7% of all skin samples were identified as AK using CM and 2.3% were incorrectly identified as normal skin by CM Highly refractive dendritic structures within tumor nests correlated with the presence of melanocytes in BCC

Characteristic CM features in all specimens Sensitivity ranging from 44–100% and a specificity of 100% for all five criteria [166] Sensitivity of 93.9% and specificity of 78.3% was found using three criteria, and 95.7% and 82.9% respectively [109] CM may be an alternative to frozen sections in large nodular BCC. Difficulties in recognizing SCC in situ and poor image quality [103] 100% sensitivity in stage I MMS and 80% sensitivity in stage II [110] Characteristic CM features in all specimens [106] Vascular pattern of BCC in CM can be used diagnostically [167] CM able to distinguish pathological features of epidermal neoplasms: 100% show nuclear enlargement and pleomorphism [168]

signs of BCC [113]. In general, depth of penetration is a major limiting factor for CM, and especially in hypertrophic and hyperkeratotic lesions. Fluorescence fiber-optic CM in vivo is a novel CM technique where fluorophore distribution in the skin may illustrate morphological changes in the epidermis. An application that holds great promise for fluorescence CM is the ability to image fluorescent markers that target specific subcellular molecules including proteins, and therefore, to monitor specific pathological and immune processes over time [114]. CM offers benefits both in ex vivo and in vivo. Ex vivo it can be used to analyze tissue samples morphologically and functionally and guide further testing. In vivo it can study normal or pathological processes over time and potentially diagnose NMSC.

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6.9 Near Infrared (NIR), Diffuse Reﬂectance and Raman Spectroscopy Light that penetrates the skin surface is variably absorbed by different skin components termed chromophores. The skin components, which subsequently emit radiation, are termed flourophores. Optical measurements of the skin can therefore be based on the interactions of nonionizing electromagnetic (EM) radiation and the skin [101]: The absorbed energy may be dissipated as heat (tissue absorption), reemitted as EM radiation of lower energy with a longer wavelength (fluorescence) or even reemitted as radiation of higher energy (Raman scattering), the latter being the least probable event. A spectroscope separates the returned light into individual wavelengths and assesses it. Raman spectroscopy provides molecular information of a sample irradiated with laser light as a small fraction is shifted in frequency (Raman Effect). Several studies have described a characteristic Raman spectra in NMSC [115–124]. A sensitivity of 97% and specificity of 98% was found in this study of 48 BCCs. In vivo Raman spectroscopy is possible but the precision of the spectra is low. Two ex vivo studies found distinct Raman band differences between BCC and normal skin. Ten samples of BCC suggested this from direct observations of spectral differences, after reducing endogenous autofluorescence by a confocal device, and the two groups were significantly different from each other [125]. In an in vitro study of 15 BCCs, Raman pseudo color maps were compared to skin biopsies. Pseudo color maps assign areas with similar spectra with the same color, and are generated by multivariate statistical analysis and clustering analysis of spectra. A prediction model could classify new tissue samples from BCC lesions from their Raman spectra with a sensitivity of 100% and specificity of 93% [118]. Another study suggested that neural network analysis of near-infrared Fourier transform Raman spectra may show some potential for ex vivo NMSC diagnosis [115] An in vivo study of 195 patients with a variety of malignant and benignant skin lesions (33 AK, 32 BCC) showed promising results for the screening of skin lesions with NIR spectroscopy. Spectra were compared to histopathology in all lesions, univariate

M. Mogensen and G. B. E. Jemec

statistics showed significant differences between spectra and healthy skin (normal skin versus AK, BCC, dysplastic nevi, lentigines, benign nevi, and seborrheic keratosis), and also between the spectra themselves. However, significant differences are not always diagnostic differences. A pattern recognition technique was applied and successfully discriminated lesions with accuracy higher than 80% [117].

6.10 Fluorescence Spectroscopy Specific autofluorescence emitted from malignant tissue upon radiation with a laser, xenon light or halogen lamp has been used to distinguish normal tissue from cancerous tissue in the head and neck region [126]. Fluorescence imaging is an attractive potential diagnostic technique for skin tumor demarcation. In a study of 21 patients with 80 BCC, the fluorescence intensity from BCC was significantly lower than surrounding, normal skin [127] In a study of 18 patients with 25 NMSC lesions (20 BCC and 5 SCC) a fiber-optic-based fluorimeter collected spectral data in vivo and microscopic fluorescence ex vivo [128]. The fluorescence of tryptophan moieties in BCC was 2.9 +/−1.9 SD and for SCC 2 +/−0.9 SD times larger. A marked loss of fluorescence in the middle of the tumor region was noticed in 78% of the NMSC lesions due to a decrease in collagen and elastin crosslinks. Another study of 49 patients (BCC, SCC, AK, and normal skin) compared diagnostic accuracy in laserinduced fluorescence spectroscopy for skin types I–III (Pathak) to determine the skin colors’ effect on the results [120]. Melanin absorbs fluorescence strongly. Typically, normal skin exhibited stronger fluorescence emission than BCC and SCC. The accuracy of classifying NMSC was higher (93%) in type I skin. It has also been suggested that due to the large variation in fluorescence intensities developing an algorithm for NMSC is not possible [129]. Bispectral fluorescence imaging combines skin autofluorescence with d-aminolaevulinic acid (ALA) fluorescence. The agreement between bispectral fluorescence images and the histopathological tumor boundary of ill-defined BCC in 12 patients with an aggressive BCC undergoing MMS was examined [122]. Only five patients had good correlation between histopathology and bispectral images of the tumor, not significant (p = 0.057). Another study applied two different algorithms in data analysis of bispectral fluorescence,

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and showed promising results in demarcation of skin lesions in 15 BCC patients [130]. Also two different fluorescence systems showed a clear demarcation of BCC in two patients with several BCC lesions [131]. In an in vivo study, 55 patients with oral SCC were studied with respect to endogenous fluorescence. The intensity of the fluorescence significantly corresponded with the pathological tumor (T) and node (N) categories of SCC (p < 0.01) [119, 132].

studied in freshly excised specimens from 14 patients [136]. Traditional histopathological criteria such as bowenoid dysplasia, multinucleated cells, or hyperkeratosis in squamous cell carcinoma in situ (SCCIS) (five specimens), and peripheral palisading of tumor cells in superficial basal cell carcinoma (SBCC) (six specimens) were clearly discerned. The morphologic features differed significantly between these lesions and perilesional skin. However, characteristic tumor aggregates were found in only one of the three investigated nodular basal cell carcinomas (NBCCs) due to limited imaging depth. In addition, speckled perinuclear fluorescence was observed in both lesions and normal perilesional skin. In conclusion, MMI could potentially be applied for noninvasive diagnostics of SCC and superficial BCC, whereas the ability to characterize NBCC was unclear.

6.11 Multiphoton or Two-Photon Microscopy Imaging (MPMI) MPMI has the highest resolution of optical techniques used in NMSC diagnosis imaging research. Multiphoton laser imaging is a novel tool for the noninvasive evaluation of cellular and molecular structures. Collagen is able to generate second harmonics and elastin has an excitation maximum in the blue spectral range, therefore, both components can ideally be excited at 820 nm by two-photon processes. A filter system can be used for the separate measurement of elastin and collagen. In FLIM the sample is illuminated with a wavelength around twice the wavelength of the absorption peak of the fluorophore being used. Essentially no excitation of the fluorophore will occur at this wavelength. However, if a high peak-power, pulsed laser is used to avoid damage to the specimen scanned, two-photon events will occur at the point of focus. At this point the photon density is sufficiently high that two photons can be absorbed by the fluorophore essentially simultaneously and fluorophore excitation will only occur at the point of focus. Thereby, eliminating excitation of out-of-focus fluorophore and optical sectioning is achieved. In Spectrally Resolved Multiphoton Imaging autofluorescence from both cellular and extracellular structures, second-harmonic signal from collagen, and a narrowband emission related to Raman scattering of collagen can be detected. A study showed that discrimination of tissue structures such as epidermal keratinocytes, lipid-rich corneocytes, intercellular structures, hair follicles, collagen, elastin, and dermal cells morphological and spectral differences between excised tissues were possible [133]. Multiphoton imaging in general is a promising technology that provides nanometer resolution of skin [134, 135]. Morphologic features in NMSC were

6.12 Spectrophotometric Intracutaneous Analysis (SIA), SIAscopy A SIAscope emits light in the spectrum 400–1,000 nm. The light is reflected or absorbed by the skin up to the depth of papillar dermis. All remitted light is received by the unit and processed by the computer software. Known models of light interaction with skin allow the application of complex mathematical calculations, producing parametric maps of the skin lesion in seconds, illustrating the melanin, blood and collagen in the area of concern. These three windows are shown together with a dermascopic image of the lesion. In a clinical study of 302 patients, SIAscope images from 363 lesions (152 NMSC lesions) were analyzed together with clinical data. Using logistic regression analysis a predictive model was constructed with three SIAscope features (branched vessels, paleness, and flare), and demonstrated sensitivity of 98% and specificity of 96% in diagnosing BCC and SCC (only three included in dataset) [137]. A later study was performed to prospectively assess the accuracy of NMSC diagnosis by the SIAscope compared to the clinician. Diagnostic accuracy for the clinician and SIAscope was compared. Sensitivity, specificity, and positive and negative predictive values for clinical diagnoses were 95.6%, 75.8%, 0.79, and 0.95, respectively. Results for SIA diagnoses were 97.5%, 86.7%, 0.88,

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and 0.97. Statistically significant higher specificity for the SIAscope was demonstrated [138]. Twenty-one pigmented BCC were studied using both SIAscopy and dermoscopy. Dermoscopy correctly identified 90% of lesions. SIAscopy demonstrated no diagnostic advantage over dermoscopy; on the contrary, pigmented BCC showed SIAscopy features previously described in malignant melanomas (dermal melanin and collagen holes) [139].

6.13 Terahertz Imaging Terahertz Pulsed Imaging (TPI) is a novel, noninvasive imaging modality. It uses pulses of electromagnetic radiation in the frequency range of 0.1–10 Terahertz (THz). Water has strong absorption over the entire THz range, and water content in the skin is a source of image contrast [140]. TPI has potential use in NMSC diagnosis. A significant difference between the response of THz radiation in normal skin and BCC has been reported [141, 142]. In a study of 18 BCCs, both in vivo (5 BCC) and ex vivo TPI analysis were done. In vivo regions of contrast were seen in all THz images, and correlated well with histology [143].

6.14 Electrical Impedance The impedance of the skin is an electrical entity, which can be described in complex numbers by resistance and reactance. A pilot study had found statistical difference in electrical impedance values between BCC and normal skin [144]. This was confirmed in a study of 34 BCC patients [145]. Statistical difference in electrical impedance values was found between BCC and normal skin; however diagnostic accuracy could not be assessed. The electrical impedance system was elaborated further, and the probe equipped with microinvasive electrodes to bypass the barrier function of the high impedance of stratum corneum. The lesions were 99 benign nevi, 28 BCC, and 13 MM [146]. Sensitivity for separation of BCC from benign nevi was 96% and specificity was 86%, when using the noninvasive probe. The invasive probe had higher diagnostic accuracy only in MM. The choice of electrode can be considered application-dependent. A study of 35 BCC patients compares electrical impedance, transepidermal water

M. Mogensen and G. B. E. Jemec

loss (TEWL), and laser Doppler (LD) in diagnosing nodular and superficial BCC [147]. LD devices send a monochromatic laser beam toward the target and collect the reflected radiation. According to the Doppler Effect the change in wavelength of the reflected radiation is a function of the targeted object’s relative velocity. The velocity of the object can be calculated by measuring the change in wavelength of the reflected laser light. LD can be configured to act as flow meters. In accordance with other studies, statistically significant differences between electrical impedance and BCC were found (p < 0.001), but no differences between subtypes were found. In addition TEWL and laser Doppler values had similar p-values in discriminating BCC from normal skin. Increased TEWL values are ascribed to the decreased barrier function of the skin due to the pathological processes of BCC. The assumption is that the increased LD values are due to increased angiogenesis and vasodilation in BCC.

6.15 CT, PET, and MR CT is based on the X-ray principal, whereas positron emission tomography (PET) is an imaging technique that detects positron release from radioactive substances and provides cross-sectional physiological information. PET imaging commonly uses 2-deoxy2–18F-fluoro-d-glucose (FDG), a positron-imaging agent, to measure the metabolic rate of tissue noninvasively. Tumors can be metabolically more active than normal tissue, thus mobilization of the image tracer can be detected by PET-scanning. FDG-PET has been investigated in diagnosis of NMSC [148]. Six patients with BCC larger than 1 cm were examined by PETscanning. BCC could only be identified in three out of six patients. Another study compared FDG-PET NMSC diagnosis in patients with head and neck tumors with physical examination, ultrasonography, and Computed Tomography (CT) [149]. In a group of 56 patients (43 SCC) detecting the primary tumor site with PET had a sensitivity of 95% (CI 95%: 80–98%) and a specificity of 100% (CI 95%: 62–100%). There was no statistical difference between PET and CT diagnosis. Magnetic resonance imaging (MRI) makes use of the magnetic properties of hydrogen nucleus (the protons). MRI has been applied to studies of SCC, morphological information about the shape, the depth, and the location of the tumor between MRI and

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histopathology are in good agreement [150]. A retrospective study of 33 NMSC patients (20 BCC, 12 SCC, 1 mixed) estimated accuracy of MRI and computed tomography (CT) and the findings were compared to histopathology [151]. Patients were seen for both primary assessment and follow-up. MR and CT localized the lesions in 29 out of 33 patients; of the four tumors not identified three fourth of patients had mean disease-free survival at 33 months and the fourth patient developed recurrence at 52 months. In a study of 35 patients of whom 18 had perineural spread of BCC and SCC, based on clinical and histopathological investigation, CT and MR [152] showed that positive perineural spread inversely correlated with 5-year survival rate. Patients who were imaging positive had a 5-year survival of 50% and for imaging negative patients it was 86% (p = 0.049). In this study MRI seems to be informative in estimating prognosis.

depth of OCT and the cellular information, morphological as well as functional from MMI and CM.

Core Messages

› › ›

›

6.16 Conclusion An amazingly varied specter of diagnostic technologies has been studied in NMSC. Some of these novel technologies have the potential to become clinically available for noninvasive diagnosis of NMSC. The reference standard, skin biopsy, and histopathological assessment are, however, not yet to be replaced. Stateof-the-art diagnostic research has only been conducted in the most well-established diagnostic methods and technologies. Many of these technologies seem to offer an adequate diagnostic accuracy, especially as a supplement to clinical diagnosis. Regarding all areas of novel noninvasive diagnostic tests and technologies in NMSC the clinical role remains to be established in larger, multicenter independent studies. But in course of time our understanding of the dynamic nature of tumor growth and regression will change and we will be able to image every step in the tumor process using a nanometer resolution as offered in MMI. The optical imaging technologies as OCT may be compared to lower magnification microscopy for orientation and architecture, whereas CM or MMI may be compared to high magnification microscopy suited for cytological detail. In the future, the combination of CM, MMI, and OCT may therefore be a promising technology for overcoming the scarcity of cellular information in OCT images and benefiting from the larger penetration

›

›

The reference standard, skin biopsy, and histopathological assessment is presently not to be replaced by novel imaging or other methods. To date a molecular marker with a high diagnostic accuracy in NMSC diagnosis has not been identified. The well-established medical imaging technologies such as MRI, CT, and PET-scanning have been used for staging of patients with NMSC, and provide a high diagnostic accuracy but relatively low resolution. The novel in vivo imaging techniques such as confocal microscopy (CM), optical coherence tomography (OCT), and multiphoton imaging microscopy (MPMI) have the highest resolution and provide the potential for real-time delineation and diagnosis of NMSC, but are still bench technologies. Currently, it seems that the combination of technologies such as CM, OCT, and MPMI is a way to overcome scarcity of cellular information in OCT images, but benefiting from the larger penetration depth of OCT and the cellular information, morphological as well as functional, provided by MPMI and CM. Regarding all areas of novel noninvasive diagnostic tests and technologies in NMSC the clinical role remains to be established in large independent multicenter studies.

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43. Gropper CA, Stiller MJ, Shupack JL, et al Diagnostic highresolution ultrasound in dermatology. Int J Dermatol. 1993;32:243–50 44. Jemec GB, Gniadecka M, Ulrich J. Ultrasound in dermatology. Part I. High frequency ultrasound. Eur J Dermatol. 2000;10:492–7 45. Lassau N, Spatz A, Avril MF, et al Value of high-frequency US for preoperative assessment of skin tumors. Radiographics. 1997;17:1559–65 46. Marques J, Cueto L, Roldan F, et al Ultrasound study of skin tumors. Radiologia. 2002;44(2):55–60 47. Vaillant L, Grognard C, Machet L, et al High resolution ultrasound imaging to assess skin tumors prior to cryosurgery. Annales de Dermatologie et de Venereologie. 1998; 125(8):500–4 48. Gross U, Suter L, Hundeiker M. 20-MHz sonography as a planning aid in the therapy of skin tumours. Aktuelle Dermatologie. 1993;19(1–2):32–5 49. Costa P, Ghillani M, Papadia F, et al Superficial ultrasound in the assessment of skin tumours: indications and limitations. Rivista Italiana di Chirurgia Plastica. 1992; 24(3): 263–9 50. Nitsche N, Hoffmann K, Iro H. Ultrasound diagnosis of skin tumours. HNO 1992;40(3):97–100 51. Edwards C, Al-Aboosi MM, Marks R. The use of A-scan ultrasound in the assessment of small skin tumours. Br J Dermatol. 1989;121(3):297–304 52. Hoffmann K, Stucker M, el-Gammal S, et al Digital 20 MHz sonography of basalioma in the B-scan. Hautarzt. 1990; 41:333–9 53. el Gammal S, Auer T, Hoffmann K, et al Non-invasive methods of the skin, chapter 5.6 “high-resolution ultrasound of the human epidermis”. Boca Raton, FL: CRC, 1995 54. el Gammal S, El Gammal C, Altmeyer PJ, et al Highresolution sonography of the skin. Chapter 30 non-invasive methods of the skin, 2nd edn. Boca Raton, FL: CRC/Taylor & Francis, 2006 55. Serup J, Keiding J, Fullerton A, et al High-frequency ultrasound examination of the skin. Chapter 56 non-invasive methods of the skin epidermis, 2nd edn. Boca Raton, FL: CRC/Taylor & Francis, 2006 56. Wortsman XC, Holm EA, Wulf HC, et al Real-time spatial compound ultrasound imaging of skin. Skin Res Technol. 2004;10:23–31 57. Bessoud B, Lassau N, Koscielny S, et al High-frequency sonography and color Doppler in the management of pigmented skin lesions. Ultrasound Med Biol. 2003;29: 875–9 58. Desai TD, Desai AD, Horowitz DC, et al The use of highfrequency ultrasound in the evaluation of superficial and nodular basal cell carcinomas. Dermatol Surg. 2007;33: 1220–7 59. Uhara H, Hayashi K, Koga H, et al Multiple hypersonographic spots in basal cell carcinoma. Dermatol Surg. 2007;33:1215–9 60. Ruocco E, Argenziano G, Pellacani G, et al Noninvasive imaging of skin tumors. Dermatol Surg. 2004;30:301–10. 61. Schmid-Wendtner MH, Burgdorf W. Ultrasound scanning in dermatology. Arch Dermatol. 2005;141:217–24 62. Miga MI, Rothney MP, Ou JJ. Modality independent elastography (MIE): potential applications in dermoscopy. Med Phys. 2005;32:1308–20

63. Langevin HM, Rizzo DM, Fox JR, et al Dynamic morphometric characterization of local connective tissue network structure in humans using ultrasound. BMC Syst Biol. 2007;1:25 64. Deprez JF, Cloutier G, Schmitt C, et al 3D Ultrasound elastography for early detection of lesions. Evaluation on a pressure ulcer mimicking phantom. Conf Proc IEEE Eng Med Biol Soc. 2007;1:79–82 65. Dr. Nakajima. The evaluation method of elastography. 2007 66. Claridge E, Cotton S, Hall P, et al From colour to tissue histology: physics-based interpretation of images of pigmented skin lesions. Med Image Anal. 2003;7:489–502 67. Steiner R, Kunzi RK, Scharffetter KK. Optical coherence tomography: clinical applications in dermatology. Med Laser Appl. 2003;18(3):249–259 68. Peris K, Altobelli E, Ferrari A, et al Interobserver agreement on dermoscopic features of pigmented basal cell carcinoma. Dermatol Surg. 2002;28:643–5 69. Zalaudek I, Giacomel J, Argenziano G, et al Dermoscopy of facial nonpigmented actinic keratosis. Br J Dermatol. 2006;155:951–6 70. Argenziano G, Zalaudek I, Corona R, et al Vascular structures in skin tumors: a dermoscopy study. Arch Dermatol. 2004;140:1485–9 71. Zalaudek I, Argenziano G, Leinweber B, et al Dermoscopy of Bowen’s disease. Br J Dermatol. 2004;150:1112–6 72. Kreusch JF. Vascular patterns in skin tumors. Clin Dermatol. 2002;20:248–54 73. Hee MR, Huang D, Swanson EA, et al Polarization-sensitive low-coherence reflectometer for birefringence characterization and ranging. J Opt Soc Am. 1992;B 9: 903–8 74. Aalders MC, Triesscheijn M, Ruevekamp M, et al Doppler optical coherence tomography to monitor the effect of photodynamic therapy on tissue morphology and perfusion. J Biomed Opt. 2006;11:044011 75. Gambichler T, Moussa G, Sand M, et al Applications of optical coherence tomography in dermatology. J Dermatol Sci. 2005;40:85–94 76. Thomas MW, Grichnik JM, Izatt JA. Three-dimensional images and vessel rendering using optical coherence tomography. Arch Dermatol. 2007;143:1468–9 77. Abuzahra F, Baron JM. Optical coherence tomography of the skin: a diagnostic light look. Hautarzt. 2006;57:646–7 78. Andretzky P, Lindner MW, Herrmann JM, Schultz A, Konzog M, Kiesewetter F, Hausler G. Optical coherence tomography by spectral radar: dynamic range estimation and in vivo measurements of skin. SPIE. 1998;3567: 78–87 79. Barton JK, Gossage KW, Xu W, et al Investigating sun-damaged skin and actinic keratosis with optical coherence tomography: a pilot study. Technol Cancer Res Treat. 2003; 2:525–35 80. Bechara FG, Gambichler T, Stucker M, et al Histomorphologic correlation with routine histology and optical coherence tomography. Skin Res Technol. 2004;10: 169–73 81. Gladkova ND, Petrova GA, Nikulin NK, et al In vivo optical coherence tomography imaging of human skin: norm and pathology. Skin Res Technol. 2000;6:6–16 82. Jensen LK, Thrane L, Andersen PE, Tycho A, Pedersen F, Andersson-Engels S, Bendsoe N, Svanberg S, Svanberg K. Optical coherence tomography in clinical examination of non-pigmented skin malignancies. Proc SPIE-OSA Biomedical Optics, SPIE 2003;5140:160–7

70 83. Olmedo JM, Warschaw KE, Schmitt JM, et al Optical coherence tomography for the characterization of basal cell carcinoma in vivo: a pilot study. J Am Acad Dermatol. 2006;55:408–12 84. Olmedo JM, Warschaw KE, Schmitt JM, et al Correlation of thickness of basal cell carcinoma by optical coherence tomography in vivo and routine histologic findings: a pilot study. Dermatol Surg. 2007;33:421–5 85. Welzel J, Lankenau E, Birngruber R, et al Optical coherence tomography of the human skin. J Am Acad Dermatol. 1997; 37:958–63 86. Welzel J. Optical coherence tomography in dermatology: a review. Skin Res Technol. 2001;7:1–9 87. Pierce MC, Strasswimmer J, Park BH, et al Advances in optical coherence tomography imaging for dermatology. J Invest Dermatol. 2004;123:458–63 88. Strasswimmer J, Pierce MC, Park B, et al Characterization of basal cell carcinoma by multifunctional optical coherence tomography. J Invest Dermatol. 2003;121:156 89. Gambichler T, Orlikov A, Vasa R, et al In vivo optical coherence tomography of basal cell carcinoma. J Dermatol Sci. 2007;45:167–73 90. Gambichler T, Matip R, Moussa G, et al In vivo data of epidermal thickness evaluated by optical coherence tomography: effects of age, gender, skin type, and anatomic site. J Dermatol Sci. 2006;44:145–52 91. Mogensen M, Morsy HA, Thrane L, et al Morphology and epidermal thickness of normal skin imaged by optical coherence tomography. Dermatology. 2008;217:14–20 92. Gambichler T, Regeniter P, Bechara FG, et al Characterization of benign and malignant melanocytic skin lesions using optical coherence tomography in vivo. J Am Acad Dermatol. 2007 93. Korde VR, Bonnema GT, Xu W, et al Using optical coherence tomography to evaluate skin sun damage and precancer. Lasers Surg Med. 2007;39:687–95 94. Gambichler T, Orlikov A, Vasa R, et al In vivo optical coherence tomography of basal cell carcinoma. J Dermatol Sci. 2007;45(3):167–73 95. Wilder-Smith P, Jung WG, Brenner M, et al In vivo optical coherence tomography for the diagnosis of oral malignancy. Lasers Surg Med. 2004;35:269–75 96. Petrova GA, Derpalyek E, Gladkova N, Feldchtein F, Nikulin N, Donchenko E, Gelikonov V, Kamensky V. Optical coherence tomography using tissue clearing for skin disease diagnosis. Proc SPIE 5140, 2003, pp. 168–186 97. Buchwald HJ, Muller A, Kampmeier J, et al Optical coherence tomography versus ultrasound biomicroscopy of conjunctival and eyelid lesions. Klinische Monatsblatter fur Augenheilkunde. 2003;220(12):822–829 98. Strasswimmer J, Pierce MC, Park BH, et al Polarizationsensitive optical coherence tomography of invasive basal cell carcinoma. J Biomed Opt. 2004;9:292–8 99. Mogensen M, Joergensen TM, Nürnberg BM, Morsy HA, Thomsen JB, Thrane L, Jemec GB. Assessment of optical coherence tomography imaging in the diagnosis of non-melanoma skin cancer and benign lesions versus normal skin: observer-blinded evaluation by dermatologists and pathologists. Dermatol Surg. 2009;35:1–8

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135. Skala MC, Riching KM, Bird DK, et al In vivo multiphoton fluorescence lifetime imaging of protein-bound and free nicotinamide adenine dinucleotide in normal and precancerous epithelia. J Biomed Opt. 2007;12:024014 136. Paoli J, Smedh M, Wennberg AM, et al Multiphoton laser scanning microscopy on non-melanoma skin cancer: morphologic features for future non-invasive diagnostics. J Invest Dermatol. 2007;128(5):1248–55 137. Tehrani H, Walls J, Price G, et al A novel imaging technique as an adjunct to the in vivo diagnosis of nonmelanoma skin cancer. Br J Dermatol. 2006;155:1177–83 138. Tehrani H, Walls J, Price G, et al A prospective comparison of spectrophotometric intracutaneous analysis to clinical judgment in the diagnosis of nonmelanoma skin cancer. Ann Plast Surg. 2007;58:209–11 139. Terstappen K, Larko O, Wennberg AM. Pigmented basal cell carcinoma – comparing the diagnostic methods of SIAscopy and dermoscopy. Acta Derm Venereol. 2007;87: 238–42 140. Pickwell E, Cole BE, Fitzgerald AJ, et al In vivo study of human skin using pulsed terahertz radiation. Phys Med Biol. 2004;49:1595–607 141. Woodward RM, Cole BE, Wallace VP, et al Terahertz pulse imaging in reflection geometry of human skin cancer and skin tissue. Phys Med Biol. 2002;47:3853–63 142. Woodward RM, Wallace VP, Pye RJ, et al Terahertz pulse imaging of ex vivo basal cell carcinoma. J Invest Dermatol. 2003;120:72–8 143. Wallace VP, Fitzgerald AJ, Shankar S, et al Terahertz pulsed imaging of basal cell carcinoma ex vivo and in vivo. Br J Dermatol. 2004;151:424–32 144. Emtestam L, Nicander I, Stenstrom M, et al Electrical impedance of nodular basal cell carcinoma: a pilot study. Dermatology. 1998;197:313–6 145. Aberg P, Nicander I, Holmgren U, et al Assessment of skin lesions and skin cancer using simple electrical impedance indices. Skin Res Technol. 2003;9:257–61 146. Aberg P, Geladi P, Nicander I, et al Non-invasive and microinvasive electrical impedance spectra of skin cancer – a comparison between two techniques. Skin Res Technol. 2005;11:281–6 147. Kuzmina N, Talme T, Lapins, et al Non-invasive preoperative assessment of basal cell carcinoma of nodular and superficial types. Skin Res Technol. 2005;11:196–200 148. Fosko SW, Hu W, Cook TF, et al Positron emission tomography for basal cell carcinoma of the head and neck. Arch Dermatol. 2003;139:1141–6 149. Sigg MB, Steinert H, Gratz K, et al Staging of head and neck tumors: [18F]fluorodeoxyglucose positron emission tomography compared with physical examination and conventional imaging modalities. J Oral Maxillofac Surg. 2003;61:1022–9 150. Querleux B. Nuclear Magnetic Resonance (NMR) examination of the skin in vivo. Chapter 36 non-inasive methods of the skin., 2nd edn. Boca Raton, FL: CRC/Taylor & Francis, 2006 151. Lanka B, Turner M, Orton C, et al Cross-sectional imaging in non-melanoma skin cancer of the head and neck. Clin Radiol. 2005;60:869–77 152. Williams LS, Mancuso AA, Mendenhall WM. Perineural spread of cutaneous squamous and basal cell carcinoma:

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7

Cure Rates Following Surgical Therapy – The Golden Standard Roland Kaufmann and Markus Meissner

Key Points

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Among surgical treatment options, microscopically controlled margin-free excisions (Mohs micrographic surgery, MMS) provide highest cure rates with maximal preservation of normal tissue. Mohs micrographic surgery is the treatment of choice for non-melanoma skin cancers in highrisk areas, and for those with aggressive behaviour, recurrent growth or ill-defined borders. Every alternative treatment option has to be compared with Mohs micrographic surgery for its effectiveness.

different established ways of three-dimensional histological work-up of the excised tissue volume is called Mohs micrographic surgery (MMS). This procedure is required whenever a complete removal of the entire lesions has to be ensured and offers best long-term results with lowest recurrence rates reported for different types of epithelial and other non-melanoma skin cancers. Moreover, it best accomplishes the relevant purposes of any surgical treatment: to eliminate the entire tumour, to guarantee a high cure rate and to best preserve uninvolved surrounding tissue. Therefore, MMS can be considered the ‘gold-standard’ of treatment and should serve as control group with any other treatment option [1].

7.1 Technical Aspects of MMS Though early or superficial stages (less than 1–2 mm depth) of non-melanoma skin cancer (NMSC) can be easily and effectively treated by an increasing variety of non-surgical techniques – including photodynamic therapy or more recent approaches of immunomodulators – surgical removal is still considered the most frequent choice especially in more advanced or recurrent tumour growth. Apart from thermally destructive methods (electrosurgery, cryosurgery, laser vaporisation), surgical techniques for skin cancer removal encompass ablative techniques (e.g. shave excisions, laser ablation) and scalpel excisions. A special multi-step procedure with

R. Kaufmann () Professor and Chair of Dermatology,Department of Dermatology, Goethe-University Hospital, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany e-mail: [email protected]

Mohs micrographic surgery is a technique of tumour excision leading to complete extirpation of the cutaneous malignancy by using frozen section assessment of the entire margins. Already in 1849, the Scottish pathologist John Hughes Bennett suggested examining the surrounding tissue of a tumour to determine if it is free of any tumour cells using a microscope in the operating theatre prior to wound closure [2]. It was only in 1936 that Dr. Frederic Mohs (1910– 2002) developed the concept of micrographic surgery. The first used technique was the so-called chemosurgery, which makes use of zinc chloride paste for in vivo fixation of the lesion that is microscopically examined in horizontal sections for margin clearance after excision [3]. The procedure of in vivo fixation was very painful, time consuming and was associated with an intense tissue inflammation limiting the use of this procedure. In 1974, Stegman and Tromovitch developed a

G. B. E. Jemec et al. (eds.), Non-Surgical Treatment of Keratinocyte Skin Cancer, DOI: 10.1007/978-3-540-79341-0_7, © Springer-Verlag Berlin Heidelberg 2010

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frozen fresh tissue technique eliminating inflammation and pain and allowing a quick 1-day procedure [4]. In contrast to a traditional surgical excision, in Mohs micrographic surgery the incision is typically made at an angle of 45° on the skin resulting in a more conical specimen alleviating the further histological processing. The specimen is colour-coded with different dyes for orientation purposes and if necessary further subdivided. The specimen is then flipped upside down, pressed onto a glass slide and then freeze-mounted. Finally, horizontal sections are cut with a cryostat containing the entire peripheral margins of the specimen including the base of the lesion. The slides can then be stained by haematoxylin and eosin and histologically interpreted. By this procedure the exact area of possible residual tumour is detectable and the residual cancer can be excised. This routine is repeated until all surgical margins are free of tumour. Finally, the defect can be managed according to its size and configuration by either primary closure, skin flaps, grafting or simply by second intention healing, especially with smaller defects in flexural areas. The frozen tissue technique is the standard procedure in many countries. However, the histological interpretation in frozen sections is often much more difficult and as a result residual tumour might be challenging to identify. Therefore, many surgeons, especially in Europe, use formalin-fixed, paraffin-embedded histology as an effective and cheaper alternative to the frozen tissue technique, with the advantage of providing permanent, high-quality histological sections. The drawback of this method is the delay between the first micrographic procedure and the final closure even with accelerated processing techniques, and therefore the method is also called ‘Slow Mohs’. Meanwhile, there are many different procedures and variants of Mohs micrographic surgery, mainly differing in the type of surgical excision made as there are vertical, bowel-shaped or square excisions, to mention only some examples [5].

7.2 Cure Rates of ‘Gold Standard’ in Special Indications MMS has two major goals, namely to (1) decrease recurrence rates of the respective tumour, and (2) to preserve maximum amount of normal tissue by removing the tumour with the smallest margin necessary. Since it

R. Kaufmann and M. Meissner Table 7.1 Recurrence rates in NMSC after surgical treatment Tumours 5-year recurrence 5-year recurrence rate micrographic rate surgical surgery excision BCC (primary) 1–2 3–10 BCC (recurrent) 4–10 >17 SCC (primary) 3–6 5–18 SCC (recurrent) 3–10 >23 Extramammary 8–26 33–60 Paget Merkel cell 8 13–39 carcinoma Microcystic 11 47 adnexal carcinoma Atypical 0–7 9–21 fibroxanthoma Malignant fibrous 9–43 44 histiocytoma Leiomyosarcoma 14 14–40

provides an assessment of up to 100% of surgical margins enabling removal of all tumour cells one should expect higher cancer clearance rates compared with standard bread-loaf sectioning, visualising less than 1% of the excised tumour margins. Among the epithelial skin cancer BCCs and SCCs are the most common subtypes accountable for about 95% of all NMSC tumours, whereas BCC outnumbers SCC by about 4:1. Among these tumours particularly those located on critical sites prone to high initial treatment failure or presenting as recurrences or with an unfavourable histological subtype will require a confirmation of complete surgical removal. In addition, there is a group of infrequent skin tumours including dermatofibrosarcoma protuberans, leiomyosarcoma, atypical fibroxanthoma, malignant fibrous histiocytoma, microcystic adnexal carcinomas, extramammary Paget’s disease or Merkel cell carcinoma, where MMS can be advantageous as compared to wide excision. Expected cure rates for relevant types of non-melanoma skin cancers are summarised in Table 7.1 and available data will be briefly discussed with emphasis on MMS.

7.2.1 BCCs and SCCs The 5-year recurrence rate of only 1–2% for primary BCCs and 3–6% for SCCs treated by micrographic

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Cure Rates Following Surgical Therapy – The Golden Standard

Table 7.2 Indications for micrographic surgery Large tumours (>2 cm in size) Recurrent tumours Tumours with aggressive histological growth pattern (e.g. morphea-like) Tumours with perineural infiltration Locations associated with high rates of recurrence (e.g. midface) Incompletely excised tumours Tumours with ill-defined borders (e.g. dermatofibrosarcoma protuberans) Tumours on irradiated skin

surgery, compared with those of 3–10% and 5–18% managed by simple surgical excisions provides convincing evidence for the effectiveness of MMS (Table 7.1) [6–8]. Also, for the managment of recurrent tumors, 5-year recurrence rates of 4–10% for BCCs and 3–10% for SCCs demonstrate superior results compared with the much greater recurrence rates of 17% and 23% for classical surgical excision (Table 7.1) [6, 9–11]. It is generally accepted that Mohs micrographic surgery should be limited especially to manage tumours with higher risk of recurrences (Table 7.2) because the procedure is usually much more time consuming than standard surgical excision and also requires the availability of a specially trained physician along with an endowed histological laboratory. On the other hand, it provides maximal cure rates, maximal preservation of uninvolved tissue and can thus be cost-effective at least in these critical subgroups of patients with tumours prone to recurrence. Such BCCs or SCCs at risk include larger lesions (>2 cm in size), recurrent tumours independent of their location (Fig. 7.1) or tumours with aggressive histological growth pattern (e.g. morpheatype, infiltrative or micronodular BCCs or poorly differentiated SCCs). Histological subtype is an important predictor for the likelihood of recurrence especially in BCCs. In particular, morphea-type BCC shows a distinct subclinical spread making conventional excision difficult [12–14]. Studies using MMS techniques have demonstrated morphea-type BCCs, excision with 3, 5 and 13–15-mm margins will achieve complete excision in 66%, 82% and greater 95% of cases, respectively. [15] Instead, in nodular well-defined BCCs smaller than 2 cm, 2-mm, 3-mm and 4–5-mm margins correspondingly result in complete excision in 75%, 85% and 98% of cases [16].

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Fig. 7.1 Micrographic surgery for a recurrent, deep-infiltrating BCC: (a) Clinical aspect of rather ill-defined cicatricial area of recurrence; (b) histology of a margin displaying a BCC with deep invasion of the Musculus orbicularis oris; (c) re-excision of distinct parts of medial and lateral margins (arrows) with residual tumour infiltrations after first step of micrographic surgery

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Moreover, certain anatomic areas of the head and neck are associated with higher recurrence rates. Especially the so-called H-Zone of the face including the nose, lips, periocular and periauricular region, ears, temple or the retroauricular sulcus, is an area with high recurrence rates when using standard surgical procedures as conventional excision, electrodesiccation and curettage or cryosurgery. With MMS, instead, the high recurrence rates in these areas can be significantly reduced. Malthora et al. could show, in a prospective series of 819 patients with periocular basal cell carcinomas, 5-year recurrence rates of 0% and 7.8% for primary and recurrent tumours, respectively, confirming micrographic surgery as the treatment of choice for periocular BCC [17]. Another high-risk area for BCC and SCC, the lip, was studied by Leibovitch et al. analysing the data of the Australian Mohs surgery database. In cases in which MMS was performed, the 5-year recurrence rate was only 3% in BCCs and no cases of recurrence occurred in SCCs or Bowen’s disease [18]. These data bolster the metaanalysis of Rowe et al. who found a 2.3% 5-year recurrence rate in 952 patients with SCC of the lip treated with MMS, compared with 10.5% for nonMohs modalities [19]. These data emphasise the importance of margin-controlled excision also for tumours of the lip. Carcinomas of the external ear are another therapeutic challenge. Already Mohs et al. could provide convincing data with 5-year recurrence rates being as low as 5.3% compared to 18.7% using conventional excisions [20]. Further studies confirmed better outcomes also for other high-risk anatomic areas using MMS. Incompletely excised tumours or those with illdefined clinical margins are another therapeutical challenge. Rates of incomplete excisions of BCCs range from 4% to 16.6% and have been associated with different recurrence rates from 26% to 67% with an estimated median interval to the recurrence of 18.5 months [21–24]. Therefore, in these cases re-excision with complete margin control is regarded as the final treatment of choice. Among the histological features, perineural invasion indicates higher tumour aggressiveness in both, BCC and SCC associated with an increased risk of recurrence and morbidity. Ratner et al. analysed 434 BCCs treated with Mohs surgery and detected perineural involvement in 6.7% of the cases [25]. The incidence in SCC is estimated to be between 2.5% and

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14%. Perineural invasion is regarded as an important factor for tumour extension, metastasis and spread to the central nervous system. Leibovitch et al. could demonstrate a significant subclinical extension of the tumours in 47.7% of perineural invasion cases in contrast to only 17.6% of those without perineural invasion [26]. Rowe et al. found that the local recurrence rate for 72 cases of SCC and perineural invasion treated with conventional excision was 47.2%, whereas no case of recurrence was noted in 17 cases treated with Mohs micrographc surgery [19]. The recent analysis of Leibowitch et al., concerning the perineural invasion in SCC, revealed a 5-year recurrence rate of 8% for patients with perineural invasion and treatment with MMS and therefore a much lower recurrence rate than with non-MMS treatment modalities [27]. Hence, this kind of tumour should also be excised with complete margin control and therefore micrographic surgery is again the treatment of choice. Further indications for Mohs micrographic surgery can be tumours associated with syndromes, in which patients develop a high number of tumours throughout their lifetime (e.g. xeroderma pigmentosum, basal cell nevus syndrome). It is also fundamental to use a treatment approach integrating a very high cure grade with a maximum of tissue preservation.

7.2.2 Extramammary Paget’s Disease Extramammary Pagets’s disease is an uncommon cutaneous adenocarcinoma believed to be derived from apocrine cells. The tumour mostly affects the genital skin and less frequently the axillar region. The clinical margins are very ill-defined and there is frequently an extensive subclinical spread. The surgical excision is up to now the standard procedure, though there were attempts to apply immunomodulators such as imiquimod to treat this disease with variable outcome (Fig. 7.2). On the other hand, conventional surgical procedures with wide local excision, vulvectomy etc., often lead to severe morbidity and are still associated with local recurrence rates of about 20–50% for wide excision and 33–60% for conventional surgical excision [28–31]. Interestingly, surgical margins of about 2 cm clear only 59% of the tumour, whereas a surgical margin of 5 cm from the visible tumour margins clears about 97% of the tumour [32].

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Cure Rates Following Surgical Therapy – The Golden Standard

a

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preponderance: 5-year recurrence rates range from 0% to 26% of the patients and compare, therefore, favourable to wide local excision with a recurrence rate of up to 60% [28, 33].

7.2.3 Merkel Cell Carcinoma

b

c

Fig. 7.2 Tremendous subclinical spread of extramammary Morbus Paget despite a seemingly successful treatment with Imiquimod: (a) Outcome after 4-month treatment with Imiquimod seven times a week. A histological re-exploration resulted in a persistent Morbus Paget, therefore surgical management by MMS was applied; (b) defect size after successful Mohs micrographic surgery; (c) closure by T-shaped advancement flap

The extraordinary high recurrence rates combined with the known tendency for distinct subclinical extension led to examine the use of MMS in dealing with extramammary Paget’s disease. The few studies available up to now provide at least evidence of its

Merkel cell carcinoma is an uncommon, aggressive neuroendocrine tumour of the skin. At present, the most used approach for the treatment of purely cutaneous stage I tumours is a wide local excision with an uninvolved margin of about 2–3 cm. Often this approach is accompanied by an adjuvant radiation and by sentinel lymph node biopsy. However, the local recurrence rates for this treatment range from 13% to 39% [34, 35]. Again, margin negative excision is a mainstay for the treatment of Merkel cell carcinoma as about two thirds of the patients who experience a local recurrence die of their tumour [34]. Nevertheless, there are only a few studies evaluating the potential advantage of MMS for the therapy of Merkel cell carcinoma. The retrospective study of O’Conner et al. compared the local recurrence in patients treated with MMS with those receiving wide local excision. Notably, the recurrence rate was 8.3% in subjects treated with MMS and 31.7% in patients treated with wide local excision [36]. In contrast to these results Senchenkov et al. did not see any differences concerning the local recurrence rate between Mohs surgery and wide local excision [37]. Thus, preliminary results of the various studies show that Mohs surgery might provide better results than wide local excision. However, at least in head and neck regions MMS should offer a superior approach for its increased preservation of normal surrounding tissue.

7.2.4 Dermatoﬁbrosarcoma Protuberans and Other Spindle Cell Tumours Dermatofibrosarcoma protuberans is a rare mesenchymal neoplasm that originates in the dermis. The histological tumour margins usually extend far beyond the clinical margins. Therefore, standard treatment has been a wide surgical excision with extended margins of at least 3 cm [38]. Local recurrence rate for conventional excision is about 30–50% and 20% for a wide

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(2–3 cm) local excision. Using MMS the recurrence rate of dermatofibrosarcoma protuberans drops to 2–6% [39]. Recent studies using Mohs micrographic surgery in these cases demonstrate that with a wide margin of 3 cm, 15.5% of tumours are inadequately excised, suggesting that the recommendation of a wide excision might not be sufficient [40]. On the other hand, Popov et al. could show that the histological tumour-free margins with an average size of 1.6 cm were enough for complete local control of dermatofibrosarcoma protuberans [41]. Therefore, MMS is the thoroughly proven treatment of choice for dermatofibrosarcoma protuberans. The experience in the treatment of other spindle cell tumours as in leiomyosarcoma, atypical fibroxanthoma or malignant fibrous histiocytoma is much more limited. First evidence demonstrates that MMS is at least as effective as wide local excision. Leiomyosarcoma is a quite rare tumour with a portion of about 7% of soft tissue sarcomas. Surgical treatment is historically performed with wide local excision and the recurrence rate is estimated to be between 30% and 45%. There is only one small study and a few case reports presenting a recurrence rate of 14% using Mohs micrographic surgery [42]. Therefore, there is only one evidence that MMS might provide a significant benefit in the therapy of leiomyosarcoma. Atypical fibroxanthoma represents a solitary tumour of the skin, which occurs mostly on sun-exposed areas in elderly people. As for the leiomyosarcoma the data concerning surgical treatment options are sparse. Recurrence rates for conventional surgery range from 9% to 21%, whereas Mohs micrographic surgery varies from 3% to 19% [43]. Leibovitch treated two cases by MMS without recurrency within 5 years [44]. Though atypical fibroxanthoma as a rule behaves benign, micrographic surgery intends at least to reduce the likelihood of local recurrence. The malignant fibrous histiocytoma (MFH) is the most aggressive of the fibrohistiocytic tumours with a high local recurrence rate and significant metastatic potential usually associated with a poorer prognosis. Sabesan et al. studied the recurrence rate of MFH in the head and neck region. They found a local recurrence in 86% after marginal resection, 66% after wide excision and 27% after radical resection with severe tissue loss [45]. A recent study using micrographic surgery in 31 cases of MFH demonstrated a 5-year recurrence rate of about 25%, which is far better than any

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wide conventional excision [46]. A study with 20 MFH tumours by Brown and Swanson presented a 3-year recurrence rate of no more than about 5% [47]. In contrast, only one smaller series analysed by Huether et al. displayed a 5-year recurrence rate of 43% [42]. Hence, there is now increasing evidence that Mohs micrographic surgery leads to a favourable outcome compared to conventional wide excision in malignant fibrous histiocytoma. Therefore, Mohs micrographic surgery might be recommended also for the treatment of these rarer tumour entities arising from cells within the dermal connective tissue, though data are still limited and further studies should address the value of MMS in the surgical management of the various spindle cell cancer subtypes.

7.3 Conclusions In the last decades, Mohs micrographic surgery has been well established as the ‘gold standard’ for the treatment of SCCs and BCCs as well as for certain uncommon cutaneous neoplasms. It combines a very high cure rate with a maximal preservation of normal tissue often leading to the maintenance of function and an ideal cosmetic result. Therefore, any alternative treatment option has to bear comparison with this ‘gold-standard’. Besides, its status as the highest standard of treatment and the increased use of Mohs micrographic surgery raises the question of its cost-effectiveness. Studies concerning this aspect provide evidence that a general use of MMS might not be cost-effective, even if there are fewer recurrences or the surgical management leads to smaller and easier-to-treat defects. Especially this seems to be the case for primary tumours and recurrent tumours in minor problematic regions [48–50]. In high-risk regions, aggressive histological subtypes, tumours with perineural or perivascular invasion, big or rare tumours such as the dermatofibrosarcoma protuberans, Leioymyosarcoma, etc., a probable lack of costeffectiveness is outweighed by the clinical advantages for the patient. Nevertheless, the vast majority of the prevailing smaller and more superficial primary tumours of unproblematic histology and in low-risk regions will stay rather as a target for simple surgical (conventional excision, curettage, electrodesiccation,

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Cure Rates Following Surgical Therapy – The Golden Standard

etc.) or non-surgical treatment options providing a cheaper but almost as effective therapy.

References 1. Kaufmann R. Surgery for tumours of the skin. In: Burg G Atlas of cancers of the skin. Philadelphia: Churchill Livingstone, 2000, pp. 230–42 2. Bennett, JH. On cancerous and cancroid growth. Sutherland and Knox, Edinburgh, 1849, p. 248 3. Mohs F. Chemosurgery, a microscopically controlled method of cancer excision. Arch Surg. 1941;42:279–95 4. Tromovitch TA, Stegman SJ. Microscopically controlled excision of skin tumors. Arch Dermatol. 1974;110:231–2 5. Moehrle M, Breuninger H, Röcken M. A confusing world: what to call histology of three-dimensional tumour margins? JEADV 2007;21:591–5 6. Garcia C, Holman J, Poletti E. Mohs surgery: commentaries and controversies. Int J Dermatol. 2005;44:893–905 7. Thissen MR, Neumann MH, Schouten LJ. A systematic review of treatment modalities for primary basal cell carcinomas. Arch Dermatol. 1999;135(10):1177–83 8. Nagore E, Grau C, Molinero J, Fortea JM. Positive margins in basal cell carcinoma: relationship to clinical features and recurrence risk. A retrospective study of 248 patients. J Eur Acad Dermatol Venereol. 2003;17(2):167–70 9. Dellon AL, DeSilva S, Connolly M, Ross A. Prediction of recurrence in incompletely excised basal cell carcinoma. Plast Reconstr Surg. 1985;75(6):860–71 10. Rowe DE, Carroll RJ, Day CL Jr. Mohs surgery is the treatment of choice for recurrent (previously treated) basal cell carcinoma. J Dermatol Surg Oncol. 1989;15(4):424–31 11. Wennberg AM, Larkö O, Stenquist B. Five-year results of Mohs’ micrographic surgery for aggressive facial basal cell carcinoma in Sweden. Acta Derm Venereol. 1999;79(5):370–2 12. Sexton M, Jones DB, Maloney ME. Histologic pattern analysis of basal cell carcinoma. Study of a series of 1039 consecutive neoplasms. J Am Acad Dermatol. 1990;23(6 Pt 1): 1118–26 13. Lang PG Jr, Maize JC. Histologic evolution of recurrent basal cell carcinoma and treatment implications. J Am Acad Dermatol. 1986;14(2 Pt 1):186–96 14. Salasche SJ, Amonette RA. Morpheaform basal-cell epitheliomas. A study of subclinical extensions in a series of 51 cases. J Dermatol Surg Oncol. May;1981;7(5):387–94 15. Breuninger H, Dietz K. Prediction of subclinical tumor infiltration in basal cell carcinoma. J Dermatol Surg Oncol. 1991;17(7):574–8 16. Wolf DJ, Zitelli JA. Surgical margins for basal cell carcinoma. Arch Dermatol. 1987;123(3):340–4 17. Malhotra R, Huilgol SC, Huynh NT, Selva D. The Australian Mohs database, part II: periocular basal cell carcinoma outcome at 5-year follow-up. Ophthalmology. 2004;111(4):631–6 18. Leibovitch I, Huilgol SC, Selva D, Paver R, Richards S. Cutaneous lip tumours treated with Mohs micrographic surgery: clinical features and surgical outcome. Br J Dermatol. 2005;153(6):1147–52

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19. Rowe DE, Carroll RJ, Day CL Jr. Prognostic factors for local recurrence, metastasis, and survival rates in squamous cell carcinoma of the skin, ear, and lip. Implications for treatment modality selection. J Am Acad Dermatol. 2001; 26(6):976–90 20. Mohs F, Larson P, Iriondo M. Micrographic surgery for the microscopically controlled excision of carcinoma of the external ear. J Am Acad Dermatol. 1988;19(4):729–37 21. Kumar P, Orton CI, McWilliam LJ, Watson S. Incidence of incomplete excision in surgically treated basal cell carcinoma: a retrospective clinical audit. Br J Plast Surg. 2000;53 (7):563–6 22. Sussman LA, Liggins DF. Incompletely excised basal cell carcinoma: a management dilemma? Aust N Z J Surg. 1996; 66(5):276–8 23. Richmond JD, Davie RM. The significance of incomplete excision in patients with basal cell carcinoma. Br J Plast Surg. 1987;40(1):63–7 24. Farhi D, Dupin N, Palangié A, Carlotti A, Avril MF. Incomplete excision of basal cell carcinoma: rate and associated factors among 362 consecutive cases. Dermatol Surg. 2007;33(10):1207–14 25. Ratner D, Lowe L, Johnson TM, Fader DJ. Perineural spread of basal cell carcinomas treated with Mohs micrographic surgery. Cancer. 2000;1;88(7):1605–13 26. Leibovitch I, Huilgol SC, Selva D, Richards S, Paver R. Basal cell carcinoma treated with Mohs surgery in Australia III. Perineural invasion. J Am Acad Dermatol. 2005;53(3):458–63 27. Leibovitch I, Huilgol SC, Selva D, Hill D, Richards S, Paver R. Cutaneous squamous cell carcinoma treated with Mohs micrographic surgery in Australia I. Experience over 10 years. J Am Acad Dermatol. 2005;53(2):253–60 28. Coldiron BM, Goldsmith BA, Robinson JK. Surgical treatment of extramammary Paget’s disease. A report of six cases and a reexamination of Mohs micrographic surgery compared with conventional surgical excision. Cancer. 1991;67(4):933–8 29. Zollo JD, Zeitouni NC. The Roswell Park Cancer Institute experience with extramammary Paget’s disease. Br J Dermatol. 2000;142(1):59–65 30. McCarter MD, Quan SH, Busam K, Paty PP, Wong D, Guillem JG. Long-term outcome of perianal Paget’s disease. Dis Colon Rectum. 2003;46(5):612–6 31. Sarmiento JM, Wolff BG, Burgart LJ, Frizelle FA, Ilstrup DM. Paget’s disease of the perianal region--an aggressive disease? Dis Colon Rectum. 1997;40(10):1187–94 32. Hendi A, Brodland DG, Zitelli JA. Extramammary Paget’s disease: surgical treatment with Mohs micrographic surgery. J Am Acad Dermatol. 2004;51(5):767–73 33. O’Connor WJ, Lim KK, Zalla MJ, Gagnot M, Otley CC, Nguyen TH, Roenigk RK. Comparison of Mohs micrographic surgery and wide excision for extramammary Paget’s disease. Dermatol Surg. 2003;29(7):723–7 34. Shaw JH, Rumball E. Merkel cell tumour: clinical behaviour and treatment. Br J Surg. 1991;78(2):138–42 35. Yiengpruksawan A, Coit DG, Thaler HT, Urmacher C, Knapper WK. Merkel cell carcinoma. Prognosis and management. Arch Surg. 1991;126(12):1514–9 36. O’Connor WJ, Roenigk RK, Brodland DG. Merkel cell carcinoma. Comparison of Mohs micrographic surgery and wide excision in eighty-six patients. Dermatol Surg. 1997;23(10):929–33

80 37. Senchenkov A, Barnes SA, Moran SL. Predictors of survival and recurrence in the surgical treatment of merkel cell carcinoma of the extremities. J Surg Oncol. 2007;95(3):229–34 38. Rutgers EJ, Kroon BB, Albus-Lutter CE, Gortzak E. Dermatofibrosarcoma protuberans: treatment and prognosis. Eur J Surg Oncol. 1992;18(3):241–8 39. Gloster HM Jr, Harris KR, Roenigk RK. A comparison between Mohs micrographic surgery and wide surgical excision for the treatment of dermatofibrosarcoma protuberans. J Am Acad Dermatol. 1996;35(1):82–7 40. Ratner D, Thomas CO, Johnson TM, Sondak VK, Hamilton TA, Nelson BR, Swanson NA, Garcia C, Clark RE, Grande DJ. Mohs micrographic surgery for the treatment of dermatofibrosarcoma protuberans. Results of a multiinstitutional series with an analysis of the extent of microscopic spread. J Am Acad Dermatol. 1997;37(4):600–13 41. Popov P, Böhling T, Asko-Seljavaara S, Tukiainen E. Microscopic margins and results of surgery for dermatofibrosarcoma protuberans. Plast Reconstr Surg. 2007;119(6): 1779–84 42. Huether MJ, Zitelli JA, Brodland DG. Mohs micrographic surgery for the treatment of spindle cell tumors of the skin. J Am Acad Dermatol. 2001;44(4):656–9 43. Fretzin DF, Helwig EB. Atypical fibroxanthoma of the skin. A clinicopathologic study of 140 cases. Cancer. 1973;31(6): 1541–52

R. Kaufmann and M. Meissner 44. Leibovitch I, Huilgol SC, Richards S, Paver R, Selva D. Scalp tumors treated with Mohs micrographic surgery: clinical features and surgical outcome. Dermatol Surg. 2006;32(11): 1369–74 45. Sabesan T, Xuexi W, Yongfa Q, Pingzhang T, Ilankovan V. Malignant fibrous histiocytoma: outcome of tumours in the head and neck compared with those in the trunk and extremities. Br J Oral Maxillofac Surg. 2006;44(3):209–12 46. Häfner HM, Moehrle M, Eder S, Trilling B, Röcken M, Breuninger H. 3D-Histological evaluation of surgery in dermatofibrosarcoma protuberans and malignant fibrous histiocytoma: differences in growth patterns and outcome. Eur J Surg Oncol. 2008;34(6):680–6 47. Brown MD, Swanson NA. Treatment of malignant fibrous histiocytoma and atypical fibrous xanthomas with micrographic surgery. J Dermatol Surg Oncol. 1989;15(12):1287–92 48. Essers BA, Dirksen CD, Nieman FH, Smeets NW, Krekels GA, Prins MH, Neumann HA. Cost-effectiveness of Mohs Micrographic Surgery vs Surgical Excision for Basal Cell Carcinoma of the Face. Arch Dermatol. 2006;142(2):187–94 49. Cook J, Zitelli JA. Mohs micrographic surgery: a cost analysis. J Am Acad Dermatol. 1998;39(5 Pt 1):698–703 50. Bialy TL, Whalen J, Veledar E, Lafreniere D, Spiro J, Chartier T, Chen SC. Mohs micrographic surgery vs traditional surgical excision: a cost comparison analysis. Arch Dermatol. 2004;140(6):736–42

8

Pharmacological Therapy: An Introduction Donald J. Miech

Key Point

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Pharmacological therapy has been most useful in earliest lesions of non-melanoma skin cancer. The actinic keratosis and squamous cell carcinoma in situ.

The medical options for treating non-melanoma skin cancer are quite limited due to the absorption and penetration of topical therapies. Accounting for one third of newly diagnosed cancers, skin cancer is the most common malignancy found in humans [1]. Of the broad categories of skin cancer, non-melanoma skin cancer far surpasses melanoma in frequency. Indeed non-melanoma skin cancer is more common than all other cancers combined. The incidence of non-melanoma skin cancer was estimated at 1.3 million in the USA in 2000 [2]. There is no estimate of the evolving malignant cutaneous neoplasm known as the actinic keratosis or more advanced lesion in the form of squamous cell carcinoma in situ. It is, however, the author’s experience that for every nonmelanoma skin cancer removed in clinic, at least 15–20 actinic keratoses are treated. Incidence will obviously vary with skin type and geographic locale. Actinic keratoses were described first by Dubreuilh [3] in 1898 at the Third International Congress of Dermatology. Actinic keratoses appear as macules or

D. J. Miech Marshfield Clinic, Marshfield, Wisconsin 54449 e-mail: [email protected]

slightly elevated papules in a vast array of colors from flesh-colored to red to pigmented. They range in size from a single millimeter to several centimeters. They are noted for occurring on skin exposed to solar radiation. The repetitive cycles of DNA damage resulting from chronic sun exposure can eventually result in a significant unrecoverable error. The DNA lesion most likely responsible for these neoplasms is the p53 mutation [4], although ras proto-oncogene too may play a significant role. The p53 mutation is present in 53% of acitinic keratoses and 69–90% of squamous cell carcinomas [5]. The number of actinic keratoses on a person will often reflect a balance between the development of new lesions and spontaneous resolution of existing ones. An Australian study shows an incidence rate as high as 48%, but spontaneous resolution is 26% [6]. The literature indicates that 60–99% of all squamous cell carcinomas arise from actinic keratoses, with an overall incidence of an actinic keratosis transforming into squamous cell carcinoma as 0.075–0.096%. With this data, the 10-year incidence rate for developing squamous cell carcinoma in a patient with an average actinic keratosis burden is 10.2% [7, 8]. Probably, the most commonly employed treatment for these irregular, scaly, and sometimes hyperkeratotic macules is liquid nitrogen applied to the lesions. However, some patients have so many lesions that the application of liquid nitrogen becomes difficult if not impossible. Furthermore, liquid nitrogen therapy as well as electrodesiccation of the skin almost always result in hypopigmentation of the treatment site, which might be cosmetically unacceptable to the patient. Pharmacological therapy may be one practical alternative to cryotherapy.

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References 1. Humphreys TR. Skin cancer: recognition and management. Clin Cornerstone. 2001;4:23–32 2. Nyugen TH, Ho DQ. Nonmelanoma skin cancer. Curr Treat Options Oncol. 2002;3:193–203 3. Dubreuilh W. Des hyperkeratosis circonscrites. In: Prigle JJ (ed) Third International Congress of Dermatology: official transactions. London: Waterlow, 1898, pp. 125–76 4. Ziegler A, Jonason AS, Leffel DJ, et al Sunburn and p53 in the onset of skin cancer. Nature. 1994;372:773–6

D. J. Miech 5. Nelson MA, Eiknspahr JG, Alberts DS, et al Analysis of p53 gene in human precancerous actinic keratosis lesions and squamous cell cancers. Cancer lett. 1994;85:23–9 6. Marks R, Foley P, Goodman G, et al Spontaneous remission of solar keratoses: the case for conservative management. Br J Dermatol. 1986;115:649–55 7. Marks R, Rennie G. Malignant transformation of solar keratoses to squamous cell carcinoma. Lancet. 1988;1:296–7 8. Dodson JM, DeSpain J, Hewett JE, et al Malignant potential of actinic keratoses and the controversy over treatment: a patient-oriented perspective. Arch Dermatol. 1991;127: 1029–31

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Systemic Chemotherapy of Non-Melanoma Skin Cancer Robert Gniadecki

Key Points

› › › › ›

Chemotherapy for non-melanoma skin cancer is rarely used since most tumors are curable in the early stage. There is limited experience with chemotherapy regimens including platinum compounds and taxanes. Overall response rate for metastatic squamous cell carcinoma is in the range of 25–75%. Epidermal growth factor receptor antagonists and bortezomib are emerging for the treatment of metastatic squamous cell carcinoma. Chemotherapeutic regimens can be used in adjuvant and neoadjuvant setting together with surgery or radiation.

Chemotherapy is defined as the treatment of disease with chemical agents that have a specific, toxic effect upon cancer cells and selectively destroy cancerous tissue. Chemotherapeutic agents can be used alone, but the efficacy of the treatment is often enhanced when the drugs are used in combination (combination chemotherapy). The ultimate goal of chemotherapy, a complete destruction of cancerous tissue, is not always achievable. However, in many instances, even the best available

R. Gniadecki University of Copenhagen, Department of Dermatology, Bispebjerg Hospital, Bispebjerg bake 23, 2400 Copenhagen, Denmark e-mail: [email protected]

chemotherapy does not provide complete, unsupported remissions, but rather partial remissions or stabilization of the disease. In these cases, chemotherapy can still be very useful as a palliative treatment providing symptomatic relief. Chemotherapy can also be employed in an adjuvant or neoadjuvant setting. In adjuvant chemotherapy, the drug is given to augment or stimulate some other form of treatment such as surgery or radiation therapy. Neoadjuvant chemotherapy is a preliminary cancer chemotherapy that precedes a necessary second modality of treatment, such as surgery or radiation.

9.1 Overview of Chemotherapeutic Drugs Most chemotherapy protocols for non-melanoma skin cancer (NMSC) employ combination chemotherapy. Many different regimens have been proposed and Table 9.1 summarizes the characteristics of the drugs that have been repetitively employed in NMSC chemotherapy.

9.2 Chemotherapy Regimens 9.2.1 Cisplatin Combination Regimens Cisplatin is the most constant ingredient of chemotherapy regimens used for NMSC. The central role of cisplatin stems from the positive experience with head and neck carcinomas, the biology and histogenesis of which resemble that of squamous cell carcinoma of the skin. Cisplatin-based combination therapies have been

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Table 9.1 Approved chemotherapeutic agents used in the treatment of NMSC Drug Usual dose Mechanism of action Cisplatin

Doxorubicin

Paclitaxel

50–100 mg/m2 i.v. once or 15–20 mg/m2 daily for 5 days, repeated every 3rd–4th week Depends on the combination chemotherapy protocol, usually approximately 50–75 mg/m2 100–175 mg/m2 i.v., repeated every third week

Bleomycin

5.000–15.000 IE/m2, usually in combination regimens

5-FU

10–15 mg/kg body weight once weekly

Capecitabine (Xeloda®)

1,250 mg/m2 bid for 14 days followed by a week break 400 mg/m2 followed by 250 mg/m2 weekly 100–150 mg daily

Cetuximab (Erbitux®) Erlotinib (Tarceva®)

Alkylation, DNA crosslinking, active mainly against actively cycling cells Anthracycline antibiotic. DNA intercalator and yopoisomerase II blocker Tubulin depolymerization blocker, formation of nonfunctional microtubules, active mainly against G2/M phase of actively cycling cells DNA strand scission by free radicals Causes DNA damage, active against mitotically active cells. Sensitizes cells to ionizing radiation Oral 5-FU prodrug, mechanism of action as 5-FU Anti-EGFR antibody EGFR tyrosine kinase inhibitor

widely used for the treatment of very large lesions or for metastatic NMSC. The most common combinations are with doxorubicin, paclitaxel, bleomycin, or 5-fluorouracil (5-FU). Cisplatin/doxorubicin combination therapy is, until now, the only regimen assessed in a prospective, clinical trial on 28 consecutive patients with advanced BCC and SCC [24]. These individuals were treated with 75 mg/m2 cisplatin and 50 mg/m2 doxorubicin i.v. every third week. The overall response was 68%, with 28% complete remissions. Toxicities were manageable. This regimen is particularly useful for the neoadjuvant therapy before surgery; but, in some cases, long-lasting unmaintained complete remissions can also be achieved. Moreover, there are numerous case reports documenting the effect of cisplatin/doxorubicin in NMSC [18, 23, 28, 32]. Another combination possibility is cisplatin and paclitaxel. In head and neck squamous cell carcinoma, cisplatin with docetaxel or paclitaxel produced the overall response of approximately 50%, unfortunately

Typical side effects Nausea, vomiting, nefrotoxicity, ototoxicity (especially over 50 mg/m2), neurotoxicity Cardiotoxicity (over cumulative dose of 550 mg/m2), bone marrow suppression, nausea, vomiting Bone marrow suppression, neuropathy (synergistic risk with cisplatin), alopecia

Flu-like symptoms, mucositis, lung fibrosis (especially over 250,000 IE/m2 cumulative dose) Nausea, vomiting, stomatitis, diarrhea, bone marrow suppression Diarrhea, nausea, vomiting, stomatitis, hand-and-foot syndrome, hepatotoxicity, jaundice Acneiform rash, paronychia, pyogenic granulomas, dyspnea Nausea, vomiting, stomatitis, anorexia, dyspnea, hepatotoxicity, acneiform rash, paronychia, pyogenic granulomas

with very few complete remissions [38]. Barcelo et al. [3] reported a successful treatment of two patients with advanced BCC. The first patient was a 60-year-old man who received 175 mg/m2 paclitaxel every third week, after six cycles of cisplatin and capecitabine. Partial response was seen after six cycles, and a complete response was achieved after 12 cycles. Tolerability was good with no grade 3–4 toxicities [13]. At 13th month after the first cycle of paclitaxel, the patient remained in a complete response. The second case was a 74-year-old Caucasian man with metastatic BCC who was treated with 75 mg/m2 cisplatin and 75 mg/m2 paclitaxel every third week. Partial response was achieved after five cycles, but the treatment was discontinued due to grade 2 neurotoxicity and intercurrent deep venous thrombosis with bilateral lung thromboembolism. Carneiro et al. [12] treated a 65-year-old male with metastatic BCC with carboplatin and paclitaxel (135 mg/m2) in cycles every 3 weeks. Partial remission was achieved after three cycles, but

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Systemic Chemotherapy of Non-Melanoma Skin Cancer

the patient developed pure red cell aplasia, which precluded more aggressive chemotherapy. Jefford et al. [27] achieved a palliative, partial response in a 62-yearold male with metastatic BCC with three courses of cisplatin (75 mg/m2) and paclitaxel (135 mg/m2) every 3 weeks. Paclitaxel can probably be substituted by docetaxel without loss of efficacy [9, 11]. A chemotherapy protocol known from urological oncology for penile squamous cell carcinoma comprises cisplatin, bleomycin, and methotrexate. This regimen has yielded objective responses in 25–72% of cases; however, complete responses are rarely observed [17, 33, 40]. This protocol is probably most efficient as a neoadjuvant therapy before surgery [6] and has also been widely used for head and neck cancer. A similar neoadjuvant regimen may also be effective for BCC. Denic [16] reported two patients with BCC who were treated before surgery with three cycles of cisplatin 20 mg/m2 and bleomycin 20 mg/day daily for four days repeated every third week. Both patients achieved partial remissions and underwent surgery. Further variations on the same theme are cisplatin/bleomycin/ 5-fluorouracil (PBF protocol, [4, 7, 15, 37]) and cisplatin/5-fluorouracil [20, 21, 29]. One of the possibilities of using cisplatin-based chemotherapy is an adjuvant therapy with radiation (radiochemotherapy). Cisplatin is an excellent radiosensitizer due to the inhibition of DNA repair. This property is further enhanced by paclitaxel that blocks G2/M phase of cell cycle. Radiochemotherapy with cisplatin/paclitaxel or cisplatin/fluorouracil is a useful approach in metastatic head and neck carcinomas achieving overall response rates of approximately 90% [1, 14]. Fujisawa et al. [21] used a similar radiochemotherapy approach comprising cisplatin/5-fluorouracil and conventional radiotherapy for advanced SCC of the skin. The results with their two patients were encouraging and open further venue to investigate the principle of chemoradiation regimens for metastatic SCC of the skin.

9.2.2 Paclitaxel or Docetaxel Monotherapy There is one report suggesting that taxanes are active against BCC not only in combination with cisplatin but also as monotherapy [19]. The patient was a 54-year-old man with multiple aggressive BCCs which developed in

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the context of the nevoid BCC syndrome. This patient had begun to develop multiple BCCs at the age of 13, and failed therapy with intravenous cisplatin. He was treated with a total of 19 cycles of i.v. paclitaxel at a dose of 175 mg/m2 given as an infusion over 3 h per treatment. Over the follow-up period of 16 months, most of the BCCs had completely healed and the remaining lesions diminished in size. Docetaxel has not been tried for BCC, but there is convincing evidence for efficacy in monotherapy for advanced head and neck squamous cell carcinoma, including the patients who failed cisplatin-based therapies [11]. Overall responses are in the range of 30% and neutropenia is the most important toxicity. In summary, paclitaxel or docetaxel in monotherapy may sometimes be effective for palliative treatment of metastatic BCC or SCC of the skin. Complete remissions are only rarely achieved, and this treatment is probably of value as a neoadjuvant regimen before surgery for the patients in whom cisplatin is contraindicated.

9.2.3 Capecitabine Capecitabine is an oral prodrug of 5-fluorouracil (reviewed in [43]). It is approved for the treatment of colorectal cancer in both the adjuvant and metastatic settings, but it has shown some efficacy in breast, prostate, renal cell, ovarian, and pancreatic cancers. The efficacy of capecitabine compares favorably with i.v. 5-FU/leucovorin. The most common dose-limiting adverse effects are hyperbilirubinemia and diarrhea. The idea of using capecitabine is appealing, since 5-FU is active in local therapy of precancerous conditions like actinic keratoses and shows efficacy against both BCC and SCC. Wollina et al. [44] used 950 mg/m2 capecitabine (slightly lower that recommended) in combination with standard, low-dose subcutaneous recombinant a-interferon (3 million units × 3 weekly) in cycles of 14 days interrupted by weekly breaks. Out of four included patients with advanced SCC one complete remission and two partial remissions were achieved. The treatment was well-tolerated. The author has experience (Gniadecki R and Jemec GB, 2007) with the use of intermittent, oral capecitabine monotherapy for immunosuppressed patients with extensive, multiple SCC. We use a dose of 1 g thrice daily in 3-week cycles repeated once a month. The side effects

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are very few, and partial, clinically significant responses are observed. However, we did not experience any complete responses in any of the four patients treated with this regimen.

9.3 Anti-Epidermal Growth Factor Receptor (EGFR) Strategies EGFR (HER-1) is indispensable for the development and survival of epidermal cells and is probably also involved in the pathogenesis of NMSC. The main downstream targets for the signaling pathways emanating from EGFR are mitogen-activated protein kinases ERK1/2 that directly stimulate mitotic activity of epidermal cells and kinase Akt which is indispensable for cell survival and metabolism. Inhibition of EGFR in vitro leads to cell death. Thus, EGFR is a promising target for therapeutic intervention in NMSC. EGFR tyrosine kinase activity seems to be increased in SCC, but it is unclear whether this receptor plays a role in BCC [22, 30, 35]. Enzymatic activity of EGFR seems to be normal in BCC [35], but subtle changes in receptor trafficking and dimerization with other HER receptors may take place [22, 30]. Several drugs interfering with EGFR signaling have recently emerged and have already shown promise in the treatment of head and neck carcinomas: inhibitory monoclonal antibodies (mouse chimeric cetuximab and panitumumab) and tyrosine kinase inhibitors: erlotinib (Tarceva®), and gefitinib (Iressa®). Cetuximab may be beneficial in advanced SCC. Bauman et al. [5] reported treatment of two patients of ages of 71 and 73 years with this antibody in monotherapy. The drug was well-tolerated and both patients achieved near complete responses after approximately 16 weeks of therapy. The authors chose to use maintenance treatment of 150–250 mg/m2 cetuximab. At present it is unknown whether anti-EGFR approach is efficacious in BCC. The author has experience with a single patient with multiple, infiltrating BCCs who was treated with erlotinib (Tarceva®) without any clinically significant effect (Fig 9.1. and Gniadecki R, unpublished [2008]). Probably, the future strategy will be combination therapies of anti-EGFR drugs with cisplatin. There are several prospective, controled trials showing promise of this approach in squamous cell carcinoma of the

R. Gniadecki

head and neck. Siu et al. [41] reported promising results of the combination regimen of erlotinib (100 mg p.o. daily) and cisplatin 75 mg/m2 i.v. every third week. Addition of cetuximab to cisplatin significantly improved response rate in patients with EGFR-positive head and neck carcinomas [10, 25], including those who failed on standard cisplatin-based regimens [2]. A second generation of EGFR tyrosine kinase inhibitors, such as EKB-569, HKI-272, and CI-1033 is now emerging [39]. Unlike the first generation of drugs (erlotinib, gefitinib) that compete with ATP in binding to the catalytic site in the EGFR kinase domain, newer drugs are capable of covalent, irreversible binding. The receptor specificity of the new tyrosine kinase blockers is broader and may also include such important receptors as vascular endothelial growth factor receptor (VEGFR) and other receptors from the EGFR family (HER-2, ErbB-4). Current development in the anti-EGFR strategies may lead to the discoveries of the compounds useful in the therapy of NMSC.

9.4 Experimental Agents 9.4.1 Bortezomib Bortezomib is a proteasome inhibitor. In some malignant cells, e.g., myeloma, upregulation of the proteasome leads to an increased destruction of the ubiquitinated inhibitor of nuclear factor kB (NFkB) and accumulation of NFkB which in turn leads to inhibition of apoptotic signals. Additionally, host antitumor immunity can be stimulated by proteasome inhibitors. Bortezomib inhibits cell growth in head and neck squamous carcinoma cell lines [31]. Bortezomib may be efficacious against cutaneous SCC, as demonstrated in a case report of Ramadan et al. [34].

9.4.2 Cyclopamine Cyclopamine is a natural substance found in false hellebore or corn lily. When ingested by sheep, it causes a developmental defect where lambs are born with a single eye such as the cyclops in Homer’s Odyssey. Cyclopamine has been found to be a potent stimulator of the patched gene. Since patched/smoothened/Sonic

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hedgehog pathway activation is responsible for the development of BCC, cyclopin is a possible therapeutic agent. Cyclopamine may be particularly useful for patients with nevoid BCC syndrome.

9.5 Role of Systemic Chemotherapy in Skin Cancer 9.5.1 Who Is the Candidate for Systemic Chemotherapy? The vast majority of patients with NMSC can be managed by local treatments without the need of systemic chemotherapy. However, there are situations where skin-directed therapies are no longer satisfactory. A minority of SCC (less that 5%), and very rare cases BCC may metastasize, mainly to local lymph nodes followed by the lung. In such cases local lymph node dissection and radiotherapy are treatments of choice, but chemotherapy must be considered in relapsing patients. Chemotherapy may also be considered as an adjuvant or neoadjuvant treatment in patients with metastatic disease, before surgery and radiotherapy (chemoradiotherapy). This approach may increase chances of cure, as already demonstrated for the squamous cell carcinoma of head and neck. There are situations where systemic chemotherapy can be contemplated even in the absence of metastases. These cases include patients with very extensive skin involvement, as sometimes seen in nevoid basal cell carcinoma syndrome (BCC) or in immunosuppressed patients (SCC) (Fig. 9.1). In these situations even partial responses are helpful and can provide a useful modality for disease control. Although not proven, such palliative chemotherapy may also retard, or even prevent, the development of distant metastases. This issue is relevant in patients with high-risk lesions, such as thick or recurrent tumors, localized on highrisk sites (dorsal hands, lip, ear, scalp, or penis), poorly differentiated tumors or those arising in areas of chronic ulceration. Locally advanced disease in an important anatomical region may also be an indication for chemotherapy. For instance, invasive tumors in the eye region may turn out to be impossible to eradicate by surgery or radiotherapy alone without the risk of severe mutilation. In high-risk SCC the cure is not

Fig. 9.1 Patient with nevoid basal cell carcinoma syndrome and an advanced basal cell carcinoma in the face who is a candidate for systemic chemotherapy. This patient has not responded to anti-EGFR agents (Tarceva®)

always possible with standard surgical and radiotherapeutic procedures and the estimated 5-year diseasefree survival rate is approximately 75% [42]. In all these cases it is justified to consider the neoadjuvant chemotherapy approach on an individual basis.

9.5.2 Which Chemotherapy? Several chemotherapy protocols have been tried in patients with advanced NMSC (see above and Table 9.2) but the number of treated patients has been relatively small and the efficacy of the treatment is difficult to assess. At present, no firm recommendations can be given as to which protocol has to be chosen as first-line treatment. Prospective clinical trials are difficult to perform due to a small number of eligible patients and because of many patients with disseminated NMSC are elderly with poor performance status precluding use of aggressive chemotherapy regimens. The treatment should thus be chosen on an individual basis, taking into account the risk of side effects and the potential benefit. Realistically, complete remissions cannot be expected in more than one-third of patients and there is a marginal, if any, effect on overall

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Table 9.2 Common systemic chemotherapy regimens for NMSC Regimen Remarks 2

Cisplatin 75 mg/m + Doxorubicin 50 mg/m2 i.v. every third week Cisplatin Paclitaxel 75–175 mg/m2 every third week Cisplatin 20 mg/m2 Bleomycin 20 mg/day Cisplatin 5-FU Capecitabine Cetuximab Cisplatin Erlotinib Cisplatin Cetuximab

Reference

Rather toxic regimen, limited use in elderly patients. Capable of producing unmaintained remissions Relatively toxic regimen, risk of neutropenia and neurotoxicity

[24]

Cycles repeated every third week. Can be used as neoadjuvant treatment before surgery Can also be combined with bleomycin Cisplatin/5-FU has been used as chemoradiotherapy for SCC No evidence for activity against BCC. Can be combined with interferon No evidence for activity against BCC No evidence for activity against BCC

[16]

No evidence for activity against BCC

[2, 10]

survival. Traditionally, cisplatin became a cornerstone component in combination chemotherapy, and can be combined with anthacyclin antibiotics, paclitaxel, or anti-EGFR agents. Capecitabin is an option for palliative treatment when low toxicity is of primary importance. An interesting treatment option is an adjuvant use of retinoids or biological response modifiers, such as interferons [8, 36, 44] together with chemotherapy. In experienced hands, retinoids and interferons are safe drugs free of significant toxicities and could be a valuable add-on modality in NMSC treatment. Systemic chemotherapy of advanced NMSC is still an area of unmet medical need. Current chemotherapeutic drugs, including cisplatin, Paclitaxel or 5-FU, target mainly mitotically active cancer cells. However, most neoplastic cells in BCC or SCC are mitotically quiescent and thus escape the cytotoxic activity of these drugs. The future treatment of NMSC must rely on newer anticancer compounds, such as EGFR tyrosine kinase blockers, which can induce cell death in quiescent cells and exhibit favorable side-effect profile.

9.6 Take Home Pearls • There is limited experience with chemotherapy for non-melanoma skin cancer; available evidence comes from case reports and studies on head and neck cancer. • Initial chemotherapy for squamous cell carcinoma should be based on cisplatin-containing regimen.

[38]

[21, 26] [44] [5] [41]

• There is no standard chemotherapy for basal cell carcinoma. • Efficacy of chemotherapy for metastatsic nonmelanoma skin cancer is limited and therefore chemotherapy should, if possible, be combined with other treatments such as surgical debulking, radiotherapy, or immunotherapy.

References 1. Adelstein DJ, Leblanc M. Does induction chemotherapy have a role in the management of locoregionally advanced squamous cell head and neck cancer? J Clin Oncol. 2006;24: 2624–8 2. Baselga J, Trigo JM, Bourhis J, Tortochaux J, CortésFunes H, Hitt R, Gascón P, Amellal N, Harstrick A, Eckardt A. Phase II multicenter study of the antiepidermal growth factor receptor monoclonal antibody cetuximab in combination with platinum-based chemotherapy in patients with platinum-refractory metastatic and/or recurrent squamous cell carcinoma of the head and neck. J Clin Oncol. 2005;23:5568–77 3. Barceló R, Viteri A, Muñoz A, Gil-Negrete A, Rubio I, López-Vivanco G. Paclitaxel for progressive basal cell carcinoma. J Am Acad Dermatol. 2006;54(2 Suppl):S50–2 4. Bason MM, Grant-Kels JM, Govil M. Metastatic basal cell carcinoma: response to chemotherapy. J Am Acad Dermatol. 1990;22(5 Pt 2):905–8 5. Bauman JE, Eaton KD, Martins RG. Treatment of recurrent squamous cell carcinoma of the skin with cetuximab. Arch Dermatol. 2007;143:889–92 6. Bermejo C, Busby JE, Spiess PE, Heller L, Pagliaro LC, Pettaway CA. Neoadjuvant chemotherapy followed by aggressive surgical consolidation for metastatic penile squamous cell carcinoma. J Urol. 2007;177:1335–8

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7. Boussen H, Cvitkovic E, Wendling JL, Azli N, Bachouchi M, Mahjoubi R, Kalifa C, Wibault P, Schwaab G, Armand JP. Chemotherapy of metastatic and/or recurrent undifferentiated nasopharyngeal carcinoma with cisplatin, bleomycin, and fluorouracil. J Clin Oncol. 1991;9:1675–81 8. Brewster AM, Lee JJ, Clayman GL, Clifford JL, Reyes MJ, Zhou X, Sabichi AL, Strom SS, Collins R, Meyers CA, Lippman SM. Randomized trial of adjuvant 13-cis-retinoic acid and interferon alfa for patients with aggressive skin squamous cell carcinoma. J Clin Oncol. 2007;25:1974–8 9. Buarque EJ. Chemotherapy with docetaxel and cisplatin for advanced and recurring basal cell carcinoma. Ann Oncol. 2004;15(Suppl 3):140 10. Burtness B, Goldwasser MA, Flood W, Mattar B, Forastiere AA; Eastern Cooperative Oncology Group. Phase III randomized trial of cisplatin plus placebo compared with cisplatin plus cetuximab in metastatic/recurrent head and neck cancer: an Eastern Cooperative Oncology Group study. J Clin Oncol. 2005;23:8646–54 11. Catimel G, Verweij J, Mattijssen V, Hanauske A, Piccart M, Wanders J, Franklin H, Le Bail N, Clavel M, Kaye SB. Docetaxel (Taxotere): an active drug for the treatment of patients with advanced squamous cell carcinoma of the head and neck. EORTC Early Clinical Trials Group. Ann Oncol. 1994;5:533–7 12. Carneiro BA, Watkin WG, Mehta UK, Brockstein BE. Metastatic basal cell carcinoma: complete response to chemotherapy and associated pure red cell aplasia. Cancer Invest. 2006;24:396–400 13. Chawla SP, Benjamin RS, Ayala AG, Carrasco CH, Hong WK, Martin RG. Advanced basal cell carcinoma and successful treatment with chemotherapy. J Surg Oncol. 1989;40:68–72 14. Chougule PB, Akhtar MS, Akerley W, Ready N, Safran H, McRae R, Nigri P, Bellino J, Koness J, Radie-Keane K, Wanebo H. Chemoradiotherapy for advanced inoperable head and neck cancer: A phase II study. Semin Radiat Oncol. 1999;9(2 Suppl 1):58–63 15. Cieplinski W. Combination chemotherapy for the treatment of metastatic basal cell carcinoma of the scrotum. A case report. Clin Oncol. 1984;10:267–72 16. Denic S. Preoperative treatment of advanced skin carcinoma with cisplatin and bleomycin. Am J Clin Oncol. 1999;22:32–4 17. Dexeus FH, Logothetis CJ, Sella A, Amato R, Kilbourn R, Fitz K. Combination chemotherapy with methotrexate, bleomycin and cisplatin for advanced squamous cell carcinoma of the male genital tract. J Urol. 1991;146:1284 18. Dickie GJ, Pratt GR. Basal cell carcinoma of the skin responding completely to chemotherapy. Arch Dermatol. 1988;124:494 19. El Sobky RA, Kallab AM, Dainer PM, Jillella AP, Lesher JL. Successful treatment of an intractable case of hereditary basal cell carcinoma syndrome with paclitaxel. Arch Dermatol. 2001;137:827–8 20. Forastiere AA, Metch B, Schuller DE, Ensley JF, Hutchins LF, Triozzi P, Kish JA, McClure S, VonFeldt E, Williamson SK. Randomized comparison of cisplatin plus fluorouracil and carboplatin plus fluorouracil versus methotrexate in advanced squamous-cell carcinoma of the head and neck: a Southwest Oncology Group study. J Clin Oncol. 1992;10:1245–51 21. Fujisawa Y, Umebayashi Y, Ichikawa E, Kawachi Y, Otsuka F. Chemoradiation using low-dose cisplatin and 5-fluorouracil in

89 locally advanced squamous cell carcinoma of the skin: a report of two cases. J Am Acad Dermatol. 2006;55(5 Suppl):S81–5 22. Groves RW, Allen MH, MacDonald DM. Abnormal expression of epidermal growth factor receptor in cutaneous epithelial tumours. J Cutan Pathol. 1992;19:66–72 23. Guthrie TH Jr, McElveen LJ, Porubsky ES, Harmon JD. Cisplatin and doxorubicin. An effective chemotherapy combination in the treatment of advanced basal cell and squamous carcinoma of the skin. Cancer. 1985;55:1629–32 24. Guthrie TH, Porubsky ES, Luxenburg MN, Shah KJ, Wurtz KL, Watson PR. Cisplatin-based chemotherapy in advanced basal and squamous cell carcinomas of the skin: results in 28 patients including 13 patients receiving multimodality therapy. J Clin Oncol. 1990;8:342–8 25. Herbst RS, Arquette M, Shin DM, Dicke K, Vokes EE, Azarnia N, Hong WK, Kies MS. Phase II multicenter study of the epidermal growth factor receptor antibody cetuximab and cisplatin for recurrent and refractory squamous cell carcinoma of the head and neck. J Clin Oncol. 2005;23:5578–87. 26. Jacobs C, Lyman G, Velez-García E, Sridhar KS, Knight W, Hochster H, Goodnough LT, Mortimer JE, Einhorn LH, Schacter L. A phase III randomized study comparing cisplatin and fluorouracil as single agents and in combination for advanced squamous cell carcinoma of the head and neck. J Clin Oncol. 1992;10:257–63 27. Jefford M, Kiffer JD, Somers G, Daniel FJ, Davis ID. Metastatic basal cell carcinoma: rapid symptomatic response to cisplatin and paclitaxel. ANZ J Surg. 2004;74:704–5 28. Kaufman D, Gralla R, Myskowski PL. Basal cell carcinoma: response to systemic chemotherapy for lung carcinoma. J Am Acad Dermatol. 1988;18(2 Pt 1):306–10 29. Khansur T, Kennedy A. Cisplatin and 5-fluorouracil for advanced locoregional and metastatic squamous cell carcinoma of the skin. Cancer. 1991;67:2030–2 30. Krähn G, Leiter U, Kaskel P, Udart M, Utikal J, Bezold G, Peter RU. Coexpression patterns of EGFR, HER2, HER3 and HER4 in non-melanoma skin cancer. Eur J Cancer. 2001;37:251–9 31. Lun M, Zhang PL, Pellitteri PK. Nuclear factor-kappaB pathway as a therapeutic target in head and neck squamous cell carcinoma: pharmaceutical and molecular validation in human cell lines using Velcade and siRNA/NF-kappaB. Ann Clin Lab Sci. 2005;35:251–58 32. Merimsky O, Neudorfer M, Spitzer E, Chaitchik S. Salvage cisplatin and adriamycin for advanced or recurrent basal or squamous cell carcinoma of the face. Anticancer Drugs. 1992; 3:481–4 33. Pizzocaro G, Piva L. Adjuvant and neoadjuvant vincristine, bleomycin, and methotrexate for inguinal metastases from squamous cell carcinoma of the penis. Acta Oncol. 1988;27: 823–4 34. Ramadan KM, McKenna KE, Morris TC. Clinical response of cutaneous squamous-cell carcinoma to bortezomib given for myeloma. Lancet Oncol. 2006;7:958–9 35. Rittié L, Kansra S, Stoll SW, Li Y, Gudjonsson JE, Shao Y, Michael LE, Fisher GJ, Johnson TM, Elder JT. Differential ErbB1 signaling in squamous cell versus basal cell carcinoma of the skin. Am J Pathol. 2007;170:2089–99 36. Saade M, Debahy NE, Houjeily S. Clinical remission of xeroderma pigmentosum-associated squamous cell carcinoma with isotretinoin and chemotherapy: case report. J Chemother. 1999;11:313–7

90 37. Sadek H, Azli N, Wendling JL. Treatment of advanced squamous cell carcinoma of the skin with cisplatin, 5-fluorouracil, and bleomycin. Cancer. 1990;66:1692–6 38. Schöffski P, Catimel G, Planting AS, Droz JP, Verweij J, Schrijvers D, Gras L, Schrijvers A, Wanders J, Hanauske AR. Docetaxel and cisplatin: an active regimen in patients with locally advanced, recurrent or metastatic squamous cell carcinoma of the head and neck. Results of a phase II study of the EORTC Early Clinical Studies Group. Ann Oncol. 1999; 10:119–22 39. Sequist LV. Second-generation epidermal growth factor receptor tyrosine kinase inhibitors in non-small cell lung cancer. Oncologist. 2007;12:325–30 40. Shammas FV, Ous S, Fossa SD. Cisplatin and 5-fluorouracil in advanced cancer of the penis. J Urol. 1992;147:630–2 41. Siu LL, Soulieres D, Chen EX, Pond GR, Chin SF, Francis P, Harvey L, Klein M, Zhang W, Dancey J, Eisenhauer EA, Winquist E; Princess Margaret Hospital Phase II Consortium;

R. Gniadecki National Cancer Institute of Canada Clinical Trials Group Study. Phase I/II trial of erlotinib and cisplatin in patients with recurrent or metastatic squamous cell carcinoma of the head and neck: a Princess Margaret Hospital phase II consortium and National Cancer Institute of Canada Clinical Trials Group Study. J Clin Oncol. 2007;25: 2178–83 42. Veness MJ, Morgan GJ, Palme CE, Gebski V. Surgery and adjuvant radiotherapy in patients with cutaneous head and neck squamous cell carcinoma metastatic to lymph nodes: combined treatment should be considered best practice. Laryngoscope. 2005;115:870–5 43. Walko CM, Lindley C. Capecitabine: a review. Clin Ther. 2005;27:23–44 44. Wollina U, Hansel G, Koch A, Köstler E. Oral capecitabine plus subcutaneous interferon alpha in advanced squamous cell carcinoma of the skin. J Cancer Res Clin Oncol. 2005; 131:300–4

Intralesional Agents to Manage Cutaneous Malignancy

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Whitney A. High

Key Points

› › ›

Only very limited clinical data exist on intralesional therapy A narrow range of drugs have been tried There is a need to establish protocols and trials in this area

• Difficulty in achieving tumor penetrance by the active agent • Systemic manifestations from the undesired diffusion of agents or metabolites • Difficulty in reliably assessing a cure without actual tissue sampling This chapter will discuss the use of intralesional agents as it pertains to basal cell carcinoma and squamous cell carcinoma.

10.1 Introduction As a concept, the intralesional treatment of keratinocyte skin cancer holds tremendous appeal. Such therapy, at least in theory, allows for dosing of powerful medicines directly into the tumor, preventing the untoward systemic manifestations of traditional chemotherapy. Similarly, an effective nonsurgical modality in the form of intralesional therapy would ameliorate, or at least significantly mollify, many of the attendant risks of traditional surgical techniques. Furthermore, intralesional treatment would afford a valuable therapeutic option for patients unfit for the physical and/or mental demands of surgery. Nevertheless, intralesional treatment of skin cancer has never achieved the same degree of success or adaptation as have other nonsurgical interventions, particularly topical medications such as imiquimod and 5-fluoruracil. The factors tempering enthusiasm for intralesional management include:

W. A. High Associate Professor, Departments of Dermatology and Pathology, University of Colorado Health Sciences Center, P.O. Box 6510, Mail Stop F703, Aurora, CO 80045–0510, USA e-mail: [email protected]

10.2 Basal Cell Carcinoma Basal cell carcinoma (BCC) is the most common cancer of mankind with substantially more than 1 million cases occurring annually in the United States alone [1]. In fact, BCC comprises >80% of all non-melanoma skin cancers diagnosed each year [2]. Intralesional therapy using 5-fluoruracil (5-FU), interferon (IFN), interleukin-2 (IL-2), bleomycin, aminolevulonic acid (ALA), and even candida antigen has been reported to treat BCC, each with a varying degree of success.

10.2.1 5-Fluoruracil 5-FU is an antimetabolite that exerts cytotoxic effect via the inhibition of thymidylate synthetase, a critical enzyme involved in the intracellular manufacture of thymidines used in DNA synthesis [3]. Additive effects of 5-FU treatment also include misincorporation into DNA, and some forms of RNA, with subsequent dysfunction [4, 5]. Cancerous and pre-cancerous cells, possessing higher rates of proliferation, are more

G. B. E. Jemec et al. (eds.), Non-Surgical Treatment of Keratinocyte Skin Cancer, DOI: 10.1007/978-3-540-79341-0_10, © Springer-Verlag Berlin Heidelberg 2010

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sensitive to the effects of the drug. 5-FU is available as a 2% and 5% solution. While the intralesional treatment of BCC with 5-FU has been reported for decades [6, 7], well-designed clinical trials evaluating the treatment are few in number. In 1997, Miller et al. investigated the efficacy of an intralesional gel comprising 5-FU (30 mg/ml) and epinephrine (0.1 mg/ml) in 122 patients with superficial and nodular BCC, employing six different dosing regimens [8]. Twelve weeks post-treatment, excision and histologic examination of the removed tissue demonstrated an overall treatment efficacy of 91%, with no significant statistical difference among the dosing regimens. However, no treatment group was exposed to intralesional 5-FU alone (without epinephrine), making it impossible to directly extrapolate this level of efficacy to treatments not employing this unique product. Side effects of the intralesional injection of 5-FU included stinging, burning, and pain at the site of injection. Erythema, edema, desquamation, and erosions have also been reported with this agent. In some series, ulceration was identified in 47% of cases, while hyperpigmentation occurred in 83% [8].

10.2.2 Bleomycin Bleomycin is an antibiotic compound produced by Streptomyces verticillatus. It exerts cytotoxic effects through scission of DNA and inhibition of repair by DNA ligase. It also yields secondary effects through sclerotic changes produced in endothelial cells. Normally, bleomycin is deactivated by aminopeptidase and bleomycin hydrolase, but these enzymes are absent from the skin, leading to higher concentrations of the drug in this tissue [9]. Bleomycin is directly cytotoxic to keratinocytes and eccrine epithelium [10]. In dermatology, intralesional bleomycin is used chiefly in the treatment of recalcitrant warts; but, it may also be employed for the intralesional treatment of BCC, typically in two different settings. Firstly, use of bleomycin has been described in electrochemotherapy (ECT) [21]. In ECT, the lesion is first anesthetized with 1% lidocaine with epinephrine, followed by an intralesional injection of 0.5–1.0 units of bleomycin. Approximately 10 min after injection, the tumor is exposed to electrical pulses using needle

W. A. High

electrodes. This technique, called electroporation, is thought to enhance the cellular penetration and cytotoxicity of the bleomycin. Using ECT on 20 patients with BCC, the authors reported a complete response in 53 of 54 tumors; 94% of which were cleared with a single treatment [11]. With a mean of 18 months follow-up, there were no recurrences. While ECT has not been widely adopted outside of the research setting, other investigators have reported on the use of intralesional bleomycin for BCC. Gyurova et al. reported use of seven intralesional injections of bleomycin (2 IU/ml administered every 48 h, diluted with equal parts of lidocaine 1%), into eight BCCs on the face of an 82-year-old woman [12]. The lesions ulcerated and re-epithelialized over the next 2 months. Systemic perturbations from the bleomycin were not observed. There was no recurrence with 2 years follow-up.

10.2.3 Aminolevulonic Acid Aminolevulonic acid (ALA) is often employed as a topical agent for photodynamic therapy (PDT) used in the treatment of superficial lesions, such as actinic keratoses and superficial forms of BCC. Use of topical PDT for other lesions, such as nodular BCC, has been limited due to concerns regarding penetration of the agent and/or light into tumors of greater thickness and depth. One study examined, in preliminary fashion, the concept of intralesional instillation of ALA [13], but at present this is not a viable treatment as better-established alternatives exist.

10.2.4 Candida In the mid-1970s, Holtermann et al. demonstrated that a delayed type hypersensivity response to Candida could result in regression of mycosis fungoides, adenocarcinoma of the breast, and BCC [14]. Building upon this concept, Aftergut et al. studied the intralesional treatment of nodular BCC with Candida antigen [15]. In a control group given sham injections no patient manifested complete clearance of the tumor, while in the Candida treatment group, 10 of 17 (56%) of patients had complete clearance. Nevertheless, the

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Intralesional Agents to Manage Cutaneous Malignancy

availability of much more efficacious intralesional alternatives renders this treatment impractical and illadvised in daily management.

10.3 Squamous Cell Carcinoma Squamous cell carcinoma (SCC) is the second most common form of non-melanoma skin cancer, with an estimated 250,000 cases occurring annually in the United States [16]. Invasive SCC, the topic considered herein, should be distinguished from intraepithelial processes, such as actinic keratosis and squamous cell carcinoma in situ, for which topical agents are employed. More difficult to distinguish, is the concept of keratoacanthoma. In brief, keratoacanathoma (KA) is distinguished clinically and histologically by abrupt onset of an exophytic and crateriform lesion derived from follicular epithelium. Originally KAs were thought to be a benign entity with a malignant appearance; however, over time, the distinctions separating KA from SCC blurred, and terms such as “keratocarcinoma” have been advocated by many authorities [17]. Indeed, many dermatologists and dermatopathologists consider KA to be simply a variant of SCC, and manage the condition as such. It is the practice in our region of the United States to classify keratoacanthomas as “squamous cell carcinoma, keratoacanthoma-type” and to manage them as a malignant process, albeit with an admittedly diminished risk for metastatic spread in comparison to other forms of invasive SCC. Because much of the early work on intralesional anti-neoplastic therapy arose from treatment of KAs with methotrexate, we will discuss this type of management alongside intralesional management of more classic forms of SCC.

10.3.1 5-Fluoruracil Intralesional 5-FU has been used to treat various invasive forms of SCC for decades. In 1962, Klein et al. first reported on the use of intralesional 5-FU to treat keratoacanthomas [18]. Two subsequent studies reported the use of intralesional 5-FU to treat a total of 55 keratoacanthomas occuring on the sun-exposed face, head, and extremities with a 96% cure rate after an average of

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three weekly injections of 0.2–0.6 ml of aqueous 5-FU (50 mg/ml) [19, 20]. Admittedly, the histological definition and interpretation of keratoacanthoma has evolved since these early reports, but in a single trial of a gel containing intralesional 5-FU and epinephrine for what was termed frank SCC, the authors noted a similar 96% cure rate for tumors of the face head, neck, trunk arms, or hands ranging from 0.24 cm to 7.5 cm in size [21]. These 23 patients received four to six injections of £1.0 ml of a combination of 30 mg/ml 5-FU and 0.1 mg/ml epinephrine. All patients reported a “good” to “excellent” surgical result without significant side effects. A more recent case of moderately differentiated SCC on the face of an African woman reported an excellent cosmetic result and biopsy-proven clearance after eight weekly injections of 5-FU, with doses ranging from 0.8 ml to 2.4 ml (total dose 12.8 ml, 50 mg/ml 5-FU) [22]. The authors suggested that intralesional 5-FU might provide an advantage for the treatment of invasive SCC involving cosmetically sensitive areas.

10.3.2 Methotrexate Methotrexate is a folic acid analog that binds irreversibly to the enzyme, dihydrofolate reductase, thereby blocking the synthesis of tetrahydrofolate, and ultimately inhibiting the formation of the purine nucleotide, thymidine [23]. This mechanism of action is potentially advantageous for the treatment of rapidly proliferating tumor cells. Methotrexate is available in 2 ml vials at a concentration of 25 mg/ml. Isolated case reports involving use of intralesional methotrexate for the treatment of keratoacanthomas date to the late 1960s and early 1970s. Recently, Annest et al. summarized the results of 38 keratoacanthomas treated with intralesional methotrexate since 1991 [24]. They discovered an observed cure rate of 92% using an average of 2.1 injections dosed an average of 18 days apart, with follow-up ranging from 1 month to 91 months. The average injection volume was 1.0 ml and this contained on average 17.6 mg/ml of methotrexate. Given the poorly cohesive nature of the neoplasms treated, the authors estimated that about 50% of the injection volume was lost when they performed the injection themselves (18 of the 38 cases).

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While the authors noted no adverse effects in the 18 patients they injected themselves, they did identify pancytopenia occurring in two cases for which a dose of 25 mg of methotrexate was utilized; but both of these patients suffered from hemodialysis-dependent renal failure, and methotrexate is renally excreted [25, 26]. The authors strongly recommended a baseline screen of renal function and a complete blood count (CBC), with a repeated blood count 1-week after injection. Annest et al. further noted a favorable cosmetic outcome, which they found akin to that of healing by second intention. Other touted advantages of intralesional methotrexate over intralesional 5-FU included: (1) the lack of need for local anesthesia with methotrexate injections, (2) the ability to use fewer doses spaced several weeks apart with methotrexate, and (3) the low cost of methotrexate (USD$2.00/2 ml vial).

10.3.3 Interferon Interferons (IFN) are glycoproteins produced by human cells that possess a broad spectrum of antiviral and immunomodulatory properties. Acting as cytokines, interferons result in the broad upregulation of genes involved in immune function [33]. For example, these compounds serve to stimulate macrophages and natural killer cells, augment lymphocyte-mediated cytotoxicity, and enhance expression of major histocompatability antigens [34]. With regard to the treatment of BCC, it is thought that interferons promote tumor regression through expression of Fas, a component of pro-apototic events [35]. Downregulation of IL-10 (an immunsuppressive cytokine), and anti-angiogenic effects may also contribute to the disruption to the mechanism of action [36, 37]. IFN-α is the form used in dermatology for intralesional therapy, and it is commercially available in two forms: IFN-α2a and IFN- α2b. In a pilot study examining interferon for the treatment of BCC, Greenway et al. injected IFN-α2b (1.5 × 106 IU) into the tumor three times per week for 3 weeks [38]. This dosing schedule continues to be the most widely employed, although some investigators have used doses of up to 3 × 106 IU injected three times per week. In the only double-blinded and placebo-controlled trial of IFN-α2b, the cure rate at 1 year was 81% [39]. Lee et al. summarized all the clinical series reporting use of IFN-α for BCC, and documented effi-

W. A. High

cacy ranging from 67% to 86% [40]. Typically, partial regression is first-apparent at 8 weeks, and most authorities recommend a 16-week period before reassessment of clinical and/or histological cure. In a recent examination, Tucker et al. reported a clinical cure in 95 of 98 nodular and superficial BCCs treated within 50 patients, with follow-up ranging from 9 months to 18.5 years. In a subset of 65 tumors with greater than 10 years of follow-up, the cure rate was reported to be 96%. All observed recurrences were on the face, and the authors speculated that large pore size in this highly sebaceous area may have led to extravasation of the interferon, and thereby, a lesser delivered dose. They attributed their overall success to a meticulous perilesional injection technique. Material injected into the soft and ulcerated portions of the tumor was avoided, and injectate lost to the surface was re-aspirated and reinjected, such that the full dose was delivered. Side effects of intralesional IFN-α treatment are dose dependent and include flu-like symptoms (fever, malaise, fatigue, chills, anorexia, headache, myalgias, and arthralgias). In one study, 82% of patients experienced at least one severe adverse reaction that interrupted daily activities [41]. In another study by Alpsoy et al., 4 of 45 patients experienced reversible leukopenia, and two patients experienced thrombocytopenia with elevated serum liver enzymes [42]. Typically, these side effects diminish upon repeated exposure and can be controlled with acetaminophen. Finally, evidence suggests that IFN-α is lkely not particularly appropriate for aggressive histologic subtypes of BCC (infiltrative, morpheaform, and desmoplastic tumors), unless the patient is simply not an acceptable candidate for more micrographically controlled surgery. Still, IFN-α has been employed successfully when candidates have been unable to tolerate the rigors of surgery, where tumors occurred over joints and scarring would impair function, and as a debulking procedure to lessen the complexity of a later surgical intervention [43].

10.3.4 Bleomycin Several case reports have detailed the use of bleomycin as an intralesional therapy for keratoacanthoma [29–31]. In the most recent report, a 2 cm keartoacanthoma upon the nasal ala was injected with aqueous bleomycin (1 mg/ml) diluted with an equal amount of 0.5%

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Intralesional Agents to Manage Cutaneous Malignancy

marcaine [32]. Using a tangential injection technique, a total of 0.4 ml of the solution was injected into the periphery of the lesion. The injection was repeated 1 week later. The lesion flattened completely 1 week after the second injection. With 18 months follow-up there was no recurrence and the aesthetic results were excellent. The only sequela was a small unpigmented depression.

10.6 Conclusion In sum, a variety of intralesional agents exist to treat common skin malignancies including basal cell carcinoma and squamous cell carcinoma. Cutaneous malignancy

Most widely employed intralesional agent(s) for managementa

Basal cell carcinoma

5-fluoruracil (5-FU) Interferon a Squamous cell carcinoma 5-fluoruracil (5-FU) Interferon a Methotrexate a While these agents represent commercially available agents with use widely reported in the literature, employment in cutaneous malignancy usually occurs “off label.”

Admittedly, intralesional management of cutaneous keratinocyte-derived malignancy has not been as widely integrated into clinical practice as have topical agents for superficial malignancies (such as use of imiquimod or topical 5-fluoruracil for superficial basal cell carcinoma). Still, this treatment modality still holds a place in the management of selected malignancies where surgical intervention is not appropriate, where intralesional therapy affords a possible cosmetic advantage, or where more significant consequences of systemic chemotherapy are to be avoided. Therefore, this modality is still worth studying by the dermatologist who endeavors to be an expert in dealing with cutaneous keratinocyte-derived malignancy.

References 1. American Cancer Society. Cancer facts and figures (online). Available from: http://www.cancer.org/downloads/ STT/2008CAFFfinalsecured.pdf. Last accessed: 9 Aug 2008

95 2. Rubin AI, Chen EH, Ratner D. Basal-cell carcinoma. N Engl J Med. 2005;353:2262–69 3. Longley DB, Harkin DP, Johnston PG. 5-fluorouracil: mechanisms of action and clinical strategies. Nature Rev Cancer. 2003;3:330–338 4. Schmittgen TD, Danenberg KD, Horikoshi T, Lenz HJ, Danenberg PV. Effect of 5-fluoro- and 5-bromouracil substitution on the translation of human thymidylate synthase mRNA. J Biol Chem. 1994;269:16269–75 5. Goette DK. Topical chemotherapy with 5-fluorouracil. A review. J Am Acad Dermatol. 1981;4:633–49 6. Kurtis B, Rosen T. Treatment of cutaneous neoplasms by intralesional injections of 5-fluorouracil (5-FU). J Dermatol Surg Oncol. 1980;6:122–7 7. Avant WH, Huff RC. Intradermal 5-fluorouracil in the treatment of basal cell cancer of the face. South Med J. 1976; 69:561–63 8. Miller BH, Shavin JS, Cognetta A, Taylor RJ, Salasche S, Korey A, Orenberg EK. Nonsurgical treatment of basal cell carcinomas with intralesional 5-fluorouracil/epinephrine injectable gel. J Am Acad Dermatol. 1997;36:72–7 9. Dorr RT, Fritz W (eds). Cancer chemotherapy handbook. New York: Elsevier, 1980, pp. 274–83 10. Templeton SF, Solomon AR, Swerlick RA. Intradermal bleomycin injections into normal human skin. Arch Dermatol. 1994;130:577–83 11. Glass LF, Jaroszeski M, Gilbert R, Reintgen DS, Heller R. Intralesional bleomycin-mediated electrochemotherapy in 20 patients with basal cell carcinoma. J Am Acad Dermatol. 1997;37:596–9 12. Gyurova MS, Stancheva MZ, Arnaudova MN, Yankova RK. Intralesional bleomycin as alternative therapy in the treatment of multiple basal cell carcinomas. Dermatol Online J. 2006;12:25 13. Cappugi P, Mavilia L, Campolmi P, Reali EF, Mori M, Rossi R. New proposal for the treatment of nodular basal cell carcinoma with intralesional 5-aminolevulinic acid. J Chemother. 2004;16:491–3 14. Holtermann OA, Papermaster B, Rosner D, Milgrom H, Klein E. Regression of cutaneous neoplasms following delayed-type hypersensitivity challenge reactions to microbial antigens or lymphokines. J Med. 1975;6:157–68 15. Aftergut K, Curry M, Cohen J. Candida antigen in the treatment of basal cell carcinoma. Dermatol Surg. 2005;31:16–8 16. Skin Cancer Foundation.Skin cancer facts. Available from: http://www.skincancer.org/content/view/317/78/. Last accessed: 10 Aug 2008 17. Schwartz RA. Keratoacanthaoma: a clinicopathologic engi ma. Dermatol Surg. 2004;30:326–33 18. Klein E, Helm F, Milgrom H, Stoll HL, Traenkle HL. Keratoacanthoma: local effect of 5-fluorouracil. Skin. 1962; 1:153–6 19. Odom RB, Goette DK. Treatment of keratoacanthomas with intralesional fluorouracil. Arch Dermatol. 1978;114:1779–83 20. Goette DK, Odom RB. Successful treatement of keratoacanthoma with intralesional fluorouracil. J Am Acad Dermatol. 1980;2:212–6 21. Kraus S, Miller BH, Swinehart JM, et al Intratumoral chemotherapy with fluororuracil/epinephrine injectable gel: a nonsurgical treatment of cutaneous squamous cell carcinoma. J Am Acad Dermatol. 1998;38:438–42

96 22. Morse LG, Kendrick C, Hooper D, Ward H, Parry E. Treatment of squamous cell carcinoma with intralesional 5-Fluorouracil. Dermatol Surg. 2003;29:1150–3 23. Olsen EA. The pharmacology of methotrexate. J Am Acad Dermatol. 1991;25:306–18 24. Annest NM, VanBeek MJ, Arpey CJ, Whitaker DC. Intralesional methotrexate treatment for keratoacanthoma tumors: a retrospective study and review of the literature. J Am Acad Dermatol. 2007;56:989–93 25. Goebeler M, Lurz C, Kolve-Goebeler ME, Brocker EB. Pancytopenia after treatment of keratoacanthoma by single lesional methotrexate infiltration. Arch Dermatol. 2001;137: 1104–5 26. Cohen PR, Schulze KE, Nelson BR. Pancytopenia after a single intradermal infiltration of methotrexate. J Drugs Dermatol. 2005;4:648–51 27. Wickramasinghe L, Hindson TC, Wacks H. Treatment of neoplastic skin lesions with intralesional interferon. J Am Acad Dermatol. 1989;20:71–4 28. Oh CK, Son HS, Lee JB, Jang HS, Kwon KS. Intralesional interferon alfa-2b treatment of keratoacanthomas. J Am Acad Dermatol. 2004;51:S177–80 29. Andreassi A, Pianigiani E, Taddeucci P, Lorenzini G, Fimiani M, Biagioli M. Guess what! Keratoacanthoma treated with intralesional bleomycin. Eur J Dermatol. 1999; 9:403–5 30. De la Torre C, Losada A, Cruces MJ. Keratoacanthoma centrifugum marginatum: treatment with intralesional bleomycin. J Am Acad Dermatol. 1997;37:1010–1 31. Sayama A, Tagami H. Treatment of keratoacanthoma with intralesional bleomycin. Br J Dermatol. 1983;109:449–52 32. Andreassi A, Pianigiani E, Taddeucci P, Lorenzini G, Fimiani M, Biagioli M. Guess what! Keratoacanthoma treated with intralesional bleomycin. Eur J Dermatol. 1999; 9:403–5

W. A. High 33. Liu KD, Gaffen SL, Goldsmith MA. JAK/STAT signaling by cytokine receptors. Curr Opin Immunol. 1998;10:271–8 34. Samuel CE. Antiviral actions of interferons. Clin Microbiol Rev. 2001;14:661–4 35. Buechner S, Wernli M, Bachmann F, Harr T, Erb P. Intralesional interferon in basal cell carcinoma: how does it work? Recent Results Cancer Res. 2002;160:246–50 36. Yamamura M, Modlin RL, Ohmen JD, Moh RL. Local expression of anti-inflammatory cytokines in cancer. J Clin Invest. 1993;91:1005–10 37. Sidky YA, Borden EC. Inhibition of antigenesis by interferons: effects on tumor and lymphocyte induced vascular responses. Cancer Res. 1987;47:5155–61 38. Greenway HT, Cornell RC, Tanner DJ, Peets E, Bordin GM, Nagi C. Treatment of basal cell carcinoma with intralesional interferon. J Am Acad Dermatol. 1986;15:437–43 39. Cornell RC, Greenway HT, Tucker SB, Edwards L, Ashworth S, Vance JC, Tanner DJ, Taylor EL, Smiles KA, Peets EA. Intralesional interferon therapy for basal cell carcinoma. J Am Acad Dermatol. 1990;23:694–700 40. Lee S, Selva D, Huilgol SC, Goldberg RA, Leibovitch I. Pharmacological treatments for basal cell carcinoma. Drugs. 2007;67:915–34 41. Edwards L, Tucker SB, Perednia D, Smiles KA, Taylor EL, Tanner DJ, Peets E. The effect of an intralesional sustainedrelease formulation of interferon alfa-2b on basal cell carcinomas. Arch Dermatol. 1990;126:1029–32 42. Alpsoy E, Yilmaz E, Bas¸aran E, Yazar S. Comparison of the effects of intralesional interferon alfa-2a, 2b and the combination of 2a and 2b in the treatment of basal cell carcinoma. J Dermatol. 1996;23:394–6 43. Stenquist B, Wennberg AM, Gisslen H, Larko O. Treatment of aggressive basal cell carcinoma with intralesional interferon: evaluation of efficacy by Mohs surgery. J Am Acad Dermatol. 1992;27:65–9

Topical Chemotherapy

11

Donald J. Miech

Key Points

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In this chapter, the author has attempted to show the relative efficacy of topical chemotherapies that have shown some success particularly in the treatment of actinic keratoses and intraepidermal carcinomas. One can conclude that none of the topical therapies is completely effective. Combinations of topical therapies such as chemical peel or topical retinoids can make some of these treatments more effective. Many studies are not without bias even when a double-blind approach is attempted, because of the inflammation and irritant response that can occur after applying these agents. Further studies with pulse therapies, peeling agents with the topical chemotherapies, and topical retinoids in combination with these forms of therapy are warranted, since the topical chemotherapies have a definite role in the treatment of precancerous or in situ forms of non-melanoma skin cancer.

D. J. Miech Marshfield Clinic, Marshfield, Wisconsin 54449, USA e-mail: [email protected]

The scope of this chapter is to consider the topical therapies that have been positively associated with superficial forms of non-melanoma skin cancer such as squamous cell carcinoma in situ and actinic keratoses. Superficial basal cell carcinoma has been found to be treated successfully with some of these treatments; however, more invasive forms of skin cancer should not be considered for treatment with topical therapy. To combat these very common lesions, a variety of other topical preparations have been investigated. Some of these include 5-flurouracil, the COX II inhibitor diclofenac, colchicine, and retinoids. Some of these products have been used in combination, and these will be discussed. Imiquimod and photodynamic therapies, although topical, will be discussed in other chapters.

11.1 5-Flurouracil 5-flurouracil was first synthesized by Heidelberger in 1957 [1]. It is a pyrimidine analog of thymine and has stearic properties so similar to uracil that it becomes incorporated in RNA and blocks synthesis of thymidilic acid and hence DNA by interfering with thymidilate synthetase [2]. 5-flurouracil also blocks uracil phosphatase and hence the utilization of preformed uracil [3]. Eaglestein et al. [4] confirmed that thymidilate synthesis is inhibited since tritiated thymidine and uridine were incorporated into DNA in normal skin and actinic keratoses prior to treatment and only tritiated thymidine was incorporated during the treatment. Falkinson and Smith [5] observed increased erythema in areas of sun-exposed “senile keratoses” in patients treated systemically with flurouracil. In 1965, Dillaha et al. [6] used 5-flurouracil topically in a 5% concentration to treat solar keratoses and reported

G. B. E. Jemec et al. (eds.), Non-Surgical Treatment of Keratinocyte Skin Cancer, DOI: 10.1007/978-3-540-79341-0_11, © Springer-Verlag Berlin Heidelberg 2010

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success, particularly when used on the face. The dorsum of the hand and arm was noted to be considerably more resistant to the therapy. Also, less responsive to this therapy were arsenical keratoses and lesions induced by X-irradiation. To enhance the effect of 5-flurouracil on the dorsum of hands and forearms, Robinson and Kligman [7] used topical retinoic acid (tretinoin). All of the patients with combined treatment for the forearms showed clearing. Two patients with keratotic lesions on the hands did not show response to the therapy. Sander et al. [8] used oral iso-tretinoin 20 mg twice daily with 5% 5-flurouracil in 27 patients with actinic keratoses. The actinic keratoses disappeared and the photodamaged skin improved in all of the patients of the study. The major side effect was erythema and discomfort on and surrounding the keratoses. If the patient was forewarned of this side effect, it was less of a problem. The erythema does not occur in normal skin but just on and around the lesion as shown in further studies by Dillaha [9]. An increased labeling index and histological abnormalities were found in clinically normal skin immediately surrounding actinic keratoses by Pearse and Marks [10]. This would support the author’s observation that many actinic keratoses seem to arise in the zone immediately surrounding the hypopigmentation induced by liquid nitrogen, if that modality is used. When Breza et al. [11] added 0.5% triamcinolone cream to the 5-flurouracil, the erythema was substantially reduced without appearing to reduce the efficacy. In addition to actinic keratoses 5-flurouracil has been reported to be successful in squamous cell carcinoma in situ (Bowen’s disease). Sturm [12] treated 41 cases of Bowen’s disease in his practice between 1965 and 1976 with 1–3% 5-flurouracil for up to 16 weeks (mean 9 weeks) with three recurrences. Generally if hair follicles were involved a longer treatment schedule was needed. Stoll et al. [13] treated five patients with multiple superficial basal cell carcinomas and concluded a cure rate of 80%. Of concern is the deceptive apparent healing of the superficial lesion with progression of the lesion deeply. Mohs et al. [14] reported 103 patients who had received 5-flurouracil topically with apparent success, but still had nodularity in scarred areas (many had been treated previously with cryosurgery, radiation, surgery or curettage, and electrodesiccation). They concluded that 5-flurouracil is quite effective for actinic keratoses and squamous cell carcinoma in situ, but should be avoided as an adjunct therapy for any other skin cancer.

D. J. Miech

A more recent formulation of 0.5% topical 5FU which is incorporated into a microsphere-based vehicle (microsponge) was shown by tritiated thymidine incorporation to have less flux (systemic absorption) than 5% 5FU cream and with a higher percentage of 5FU retained in the skin [15]. The clinical study of 21 patients showed greater efficacy in eradicating actinic keratoses and greater tolerability. The investigators admitted that the 0.5% cream still resulted in considerable irritation (similar to the 5% 5FU cream). However, patients indicated it was easier to apply and only had to be applied once daily. The study by Weiss et al. [16] showed the inflammatory response to be quite predictable with onset of redness beginning about 4–5 days after treatment was initiated and reached a plateau during the 3rd week of therapy even if the treatment was continued beyond that time. Because less of the 0.5% preparation is systemically absorbed and more is retained in the skin this cream may be the more preferable product to use. Another variation on the use of topical 5-FU is to combine it with chemical face peels particularly the alpha hydroxy agents. Griffin and Van Scott studied twelve patients with multiple actinic keratoses who were treated with either 5-flurouracil and pyruvic acid or pyruvic acid alone [17]. 60% pyruvic acid in ethanol was applied after 5–7 days of application of 5% 5-FU cream to one side of the face and only pyruvic acid was applied to the other side of the face. Their conclusion is that the combination of 5-flurouracil and pyruvic acid is an effective treatment for actinic keratosis and the combination shortens the 5-FU exposure and severe skin reaction that is seen with 3 weeks of 5-FU alone. Marrero and Katz [18] used another alpha hydroxy acid, glycolic acid, of 70% strength. They studied 18 patients with actinic keratoses who applied glycolic acid to one side of the face and glycolic acid and 5-FU in a pulse weekly dosage to the other side of the face. In a 6-month follow-up the combination treatment cleared 91.94% of the actinic keratoses, whereas the glycolic acid cleared only 19.67% of the actinic keratoses.

11.2 Diclofenac Diclofenac is a nonsteroidal, anti-inflammatory agent that is commercially available in a topical preparation of 2.5% hyaluronin gel. The mechanism of action in topical treatment of actinic keratosis is not clearly

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Topical Chemotherapy

understood. However, research suggests that there is a clinical inhibition of cyclooxygenase enzymes. This inhibition decreases the resulting products of arachidonic acid metabolism. Some of these products include control of overall immunosurveillance, inhibition of apoptosis and up-regulation of the invasive ability of tumor cells [19]. Several studies have been done with topical diclofenac gel to evaluate its overall efficacy. The earlier studies in 1997 both evaluated patients with twice daily application of 3% diclofenac for 180 days. McEwan and Smith concluded minimal benefit in 130 patients [20]. However, in this study a follow-up period was not allowed after the termination of treatment. On the other hand, Rivers and McLean [21] showed 22 of 27 patients with complete resolution of target lesions 1 month post treatment. More recent studies by Wolf [22] evaluated 120 patients with twice daily application for 3 months with 50% of patients achieving total clearance. A more recent multicenter study by Rivers et al. [23] of 195 patients showed significant benefit in the patients who received 3% diclofenac twice daily for 60 days, but patients who received the treatment for 30 days had less clearing. The most commonly reported side effects included pruritus, application-site reactions, dry skin, rash, and erythema. These were mainly classified as mild to moderate, and most resolved on their own. Interestingly, pruritus in the Rivers study [23] occurred less frequently (36% in the active treatment group versus 59% in the placebo group). This may be largely due to an antipruritic affect of diclofenac possibly secondary to its analgesic and anti-inflammatory properties.

11.3 Colchicine Colchicine is an alkaloid plant extract most commonly used for the treatment of gout. Colchicine has been known since antiquity but its first beneficial use was recorded in the sixth century for the management of sore joints and was first used by Baron von Storck of Vienna for treating gout in 1763 [24]. Colchicine is a pale yellow, water-soluble alkaloid (topical skin irritant) that darkens on exposure to light and converts into different photoisomers. It is extracted from corum and seeds of the meadow saffron, Colchicum autumnale (Liliaceae) and other colchicum species [25]. When absorbed colchicine penetrates rapidly into the cell and

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interferes with microtubule growth particularly in leukocytes, nerve cells, ciliated cells, and sperm [26]. Microtubule assembly is disrupted which limits the chemotactic and phagocytic activity of neutrophils. Colchicine also suppresses leukocyte function by increasing cellular cyclic adenosine monophosphate levels which inhibits lysosomal degranulation. This in turn results in release of prostaglandin E which further suppresses leukocyte function. Colchicine is also a potent mitotic inhibitor by arresting mitosis in metaphase. With the disruption of microtubule formation a selective destructive action on tumor cells then results. It was this action that was demonstrated by Marshall in 1968 in South Africa [27] which showed elimination of actinic keratoses with topical application of thiocolciran (N-desacetyothiocolchicine) 0.5% ointment and colcemid (demecolcine) 0.1% ointment. This had been suggested in work by Belisario in 1965 [28] who described selective destructive action on skin cancer and precancer (basal cell epithelioma, leukoplakia, solar keratoses, and intraepidermal carcinoma of Bowen and Queyrat). The products studied included 5-Flurouracil, podophyllin resin, vitamin K5, methotrexate, triaziquone and various isomers of colchicine used at a concentration of 0.1–1.0%. Colcemid is suggested to be 30 times less toxic to normal tissues and thiocolciran is thought to be even less toxic but have greater effect on mitoses in metaphase. Two more recent studies have been made with the use of topical colchicine. In 2000, Grimaitre et al. [29] applied 1% colchicine in a hydrophilic gel to the foreheads of 20 patients with actinic keratoses twice daily for 10 days in a double-blind approach. After a few days, the patients with colchicine were easily detectable and treatment was stopped with 30- and 60-day follow-up. Seven of ten patients showed no evidence of recurrence at 60-days follow-up. Systemic absorption was negligible, but the authors cautioned that only a small (2–3%) surface area was treated. The inflammatory reaction showed a particularly good result in those patients who developed a strong inflammatory response, which they described as a feeling of a sunburn. Akar et al. [30] compared safety and efficacy of twice daily application of 0.5% and 1.0% colchicine cream in 16 patients. Most were treated with a 10-day course with resulting lesion reduction of 77.7% and 73.9% for the 0.5% and 1.0% concentrations, respectively. Total target clearing occurred in seven of eight

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patients in the 0.5% group and six of eight patients in the 1.0% group. No systemic absorption was noted nor were there any systemic side effects. The authors suggested that comparison studies with the other topical agents are needed.

11.4 Retinoids Retinoids have demonstrated differentiation-inducing and some antiproliferative effects and have been reasonably effective in reducing the manifestations of photodamage. The first to use vitamin-A acid for the treatment of actinic keratoses was von Stuttgen in 1962 [31] who treated three patients. In 1975 Bollag and Ott [32] reported use of 0.1% tretinoin on the forearms and hands of several patients who experience greater than 50% reduction in actinic keratoses. Three patients treated with 0.3% tretinoin cream experienced similar levels of clearing. Kligman and Thorne [33] reported the results of a multicenter study on 1,265 patients who were treated twice daily with either 0.05% tretinoin, 0.1% tretinoin, or vehicle for up to 15 months. They concluded that the most effective treatment was 0.1% tretinoin cream applied twice daily (P < 0.001). The tretinoin-treated patients achieved an excellent response in 73% as compared with 40% in the vehicle patients. Another large study [34] showed that 0.05% tretinoin cream applied twice daily for 6–15 months reduced the number and size of actinic keratoses by about 50%. Alirezai et al. [34] used tretinoin cream 0.1% versus vehicle in a 100-patient double-blind, placebo-controlled, study and concluded that 66% achieved clearing of more than 30% of lesions compared to 45% in the placebo group. None of these results are terribly impressive, but the study by Bercovitch [35] and the somewhat comparable study by Robinson and Kligman [7] in which topical retinoids are used when applying topical 5-Flurouracil would demonstrate greater benefit particularly when used on the arms where 5-Flurouracil alone is not as effective.

References 1. Heidelberger C, Chaudhuri NK, Dannenberg P, et al Fluorinated pyrimidines: a new class of tumor-inhibiting compounds. Nature. 1957;179:663–6

D. J. Miech 2. Lindner A. Cytochemical effects of 5-flurouracil on sensitive and resistant Erlich-ascites tumor cells. Cancer Res. 1959;19:189–94 3. Skold O. Enzymatic ribosidation and ribotidation of 5-flurouracil by extracts of the Erlich-ascites tumor. Biochim Biophys Acta. 1958;29:651 4. Eaglestein WH, Weinstein GD, Frost P. Flurouracil: mechanism of action in human skin and actinic keratosesI. Effect on DNA synthesis in vivo. Arch Dermatol. 1970;101: 132–9 5. Falkson G, Schulz EJ. Skin changes in patients treated with 5-flurouracil. Br J Dermatol. 1962;74:229–36 6. Dillaha CJ, Jansen GT Honeycutt WM, et al Further studies with topical 5-flurouracil. Arch Dermatol. 1965;92:410–7 7. Robinson TA, Kligman AM. Treatment of solar keratoses of the extremities with retinoic acid and 5-flurouracil. Br J Dermatol. 1975;92:703–6 8. Sander CA, Pfeiffer C, Kligman AM, et al Chemotherapy for disseminated actinic keratosis with 5-flurouracil and isotretinoin. J Am Acad Dermatol. 1997;36:236–8 9. Dillaha CJ, Jansen GT, Honeycutt WM, et al Selective cytotoxic effect of topical 5-flurouracil. Arch Dermatol. 1963;88: 247–56 10. Pearse AD, Marks R. Actinic keratoses and the epidermis on which they arise. Br J Dermatol. 1977;96:45–50 11. Breza T, Taylor R, Eaglestein WH. Non inflammatory destruction of actinic keratoses by flurouracil. Arch Dermatol. 1976;112:1256–8 12. Sturm HM. Bowen’s disease and 5-flurouracil. J Am Acad Dermatol. 1979;1:513–22 13. Stoll HL, Klein E, Case RW. Tumors of the skin VIII. Effects of varying the concentration of locally administered 5-flurouracil on basal cell carcinoma. J of Investigative Dermatol. 1967;49:219–24 14. Mohs FE, Jones DL Bloom RF. Tendency of flurouracil to conceal deep foci of invasive basal cell carcinoma. Arch Dermatol. 1978;114:1021–2 15. Levy S, Furst K, Chern W. A comparison of the skin permeation of three topical 0.5% flurouracil formulations with that of the 5% formulation. Clin Ther. 2001;23:901–7 16. Loven K, Stein L, Furst K, et al Evaluation of the efficacy and tolerability of 0.5% flurouracil and 5% flurouracil cream applied to each side of the face in patients with actinic keratoses. Clin Ther. 2002;24:990–1000 17. Weiss J, Menter A, Hevia O, et al Effective treatment of actinic keratosis with 0.5% flurouracil cream for 1, 2, or 4 weeks. Cutis. 2002;70:22–9 18. Griffin TD, Van Scott EJ. Use of pyruvic acid in the treatment of actinic keratoses: a clinical and histopathologic study. Cutis. 1991;47:325–9 19. Marrero GM, Katz BE. The new fluor-hydroxy pulse peel. A combination of 5-flurouracil and glycolic acid. Dermatol Surg. 1998;24:973–8 20. Suobaramaiah K, Zakim D, Weksler BB, et al Inhibition of cyclooxygenase: a novel approach to cancer prevention. Proc Soc Exp Biol Med. 1997;216:201–10 21. McEwan LE, Smith JG. Topical diclofenac/hyaluronic acid gel in the treatment of solar keratoses. Australas J Dermatol. 1997;38:187–9 22. Rivers JK, McLean DI. An open study to assess the efficacy and safety of topical 3% diclofenac in a 2.5% hyaluronic acid gel for the treatment of actinic keratoses. Arch Dermatol. 1997;133:1239–42

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Topical Chemotherapy

23. Wolf JE Jr, Taylor JR, Tschen E, et al Topical 3.0% diclofenac in 2.5% hyaluronin gel in the treatment of actinic keratoses. Int J Dermatol. 2001;40:709–13 24. Rivers JK, Arlette J, Shear N, et al Topical treatment of actinic keratoses with 3.0% diclofenac in 2.5% hyaluronin gel. Br J Dermatol. 2002;146:94–100 25. Grimaitre M, Etienne A, Fathi M, et al Topical colchicine for actinic keratoses. Dermatology. 2000;200:346–8 26. Sullivan TP. Colchicine in dermatology. J Am Acad Dermatol. 1998;39:993–9 27. Ben-Chetrit E, Levy M. Colchicine: 1998 update. Semin Arthritis Rheum. 1998;28:48–59 28. Marshall B. Treatment of solar keratoses with topically applied cytostatic agents. Br J Dermatol. 1968;80:540–2 29. Belisario JC. Topical cystotatic therapy for cutaneous cancer and precancer. Arch Dermatol. 1965;92:293

101 30. Akar A, Bulent Tastan H, Erbil H, et al Efficacy and safety assessment of 0.5% and 1.0% colchicine cream in the treatment of actinic keratoses. J Dermatol Treat. 2001;12: 199–203 31. von Stuttgen G. Zur lokalbehandllung von keratosen mit vitamin-A sauté. Dermatologica. 1962;124:65 32. Kligman AL, Thorne EG. Topical therapy of actinic keratoses with tretinoin. In: Marks R (ed) Retinoids in cutaneous malignancy. Oxford: Blackwell, 1991, pp. 66–73 33. Thorne EG. Long-term clinical experience with a topical retinoid. Br J Dermatol. 1993;127(suppl):31–6 34. Alirezai M, Depuy P, Amblard P, et al Clinical evaluation of topical isotretinoin in the treatment of actinic keratoses. J Am Acad Dermatol. 1994;30:447–51 35. Bercovitch L. Topical chemotherapy of actinic keratoses of the upper extremity with tretinoin and 5-flurouracil: a doubleblind controlled study. Br J Dermatol. 1987;116(4): 549–52

Immunotherapy: An Introduction

12

Lajos Kemény

Key points

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The immune system recognizes and controls cancer cells. Both innate and the acquired immune pathways play an important role in skin cancer immunosurveillance. Decrease in cutaneous immunity induced by ultraviolet radiation, chemotherapeutic agents and other immunosuppressive factors result in loss of appropriate immune surveillance mechanisms and increase in skin cancer. Immunostimulatory agents have been proved to be effective for the treatment of skin cancer.

12.1 Cancer and the Immune System The concept that the immune system recognizes and controls cancer was first postulated over a century ago, and cancer immunity has continued to be vigorously investigated and experimentally tested. Increasing evidences support the involvement of both the innate and acquired immunities in controlling the tumor initiation, growth, and metastasis formation. Alterations in cutaneous immunity induced by ultraviolet radiation, chemotherapeutic agents, and other immunosuppressive factors result in loss of appropriate immune surveillance mechanisms, leading to nonrecognition of tumor antigens, thereby creating an environment favorable

L. Kemény Department of Dermatology and Allergology, University of Szeged, Hungary e-mail: [email protected]

for tumor growth. Immunomodulatory factors from tumor cells and/or surrounding stroma may also affect the behavior of established lesions and may direct their outcome toward either progression or regression.

12.2 NMSC and Immunosuppression Although non-melanoma skin cancers (NMCS) are multifactorial in etiology, the epidemiological studies indicate that the immune system plays an important role in the development of these malignancies (see Chapter 5). The primary evidence for immune surveillance in preventing skin cancer development is the considerable increase in NMSC on previously sun-exposed skin in transplant patients receiving chronic immune suppression to prevent organ rejection [1–3]. These immunosuppressed transplant patients are at a higher risk of developing both BCC and SCC than the general population. The ratio of SCC to BCC in transplant individuals is 4:1, whereas in the general population BCC is three to six times more frequent than SCC [4, 5]. These data suggest that SCC are more immunogenic than BCC, and the effective immune response directed against SCC tumor cells may lead to a partial control of these tumors in immunocompetent hosts. As transplant recipients are living longer, the risk of developing NMSC is also increasing. The degree of immunosuppression also influences the risk for NMCS, as heart transplant recipients receiving higher doses of immunosuppression are at a greater risk than renal transplant recipients [6]. The risk of SCC in organ transplant recipients might therefore be associated with the global immunosuppression rather than with a specific immunosuppressive drug [7].

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The role of the intact immune system in preventing cancer development is further strengthened by the fact that the incidence of cutaneous and extracutaneous malignancies increases in human immunodeficiency virus (HIV) patients [8, 9]. Highly active antiretroviral therapy induced reduction in the incidence and resulted in spontaneous regression of BCC in an HIV-positive patient supporting the critical role of immunomodulation in skin cancer susceptibility [10]. The role of the cutaneous immune system in the development of NMSC is also implicated by the observation that ultraviolet light, the main etiologic factor for BCC, has profound effects on both the local and systemic immune systems [11, 12]. Although the immune response to NMSC lesions is not adequate to clear the tumors, both the innate and the acquired immune pathways play an important role in skin cancer immunosurveillance. Cell-mediated immunity depends on direct interactions between T-lymphocytes and professional antigen-presenting cells, and this arm of the acquired immunity is critical for NMSC regression. Cytotoxic T-lymphocytes require the assistance of T helper cells. Both CD4+ T-lymphocytes (cytokine secreting cells) and the CD8+ T-lymphocytes (cytotoxic effector cells) are necessary for tumor regression in most tumor model systems, including skin cancer [13].

12.3 Immunostimulation for the Treatment of NMSC Since the cellular immune response plays a role in suppressing the development and growth of cancers, and also in the regression of established tumors, the use of immunostimulatory substances might be an excellent option to treat skin cancers. The first immunotherapeutic agent for the treatment of skin cancer was the potent skin sensitizer dinitrochlorobenzene (DNCB). This immunostimulatory agent resulted in the regression of BCC lesions after topical application. The regression of the tumors was dependent on successful sensitization and the development of allergic contact dermatitis [14]. Delayed-type reactions induced by microbial allergens also resulted in regression of sBCCs [15]. The aim of this type of therapy was to mobilize the T-cell-mediated immune response at the site of the NMSC lesions. The mechanism of action was probably

L. Kemény

due to the result of a local antitumor “bystander” effect of the cell-mediated immune response. The role of immunotherapy for NMSC was further strenghtened by the use of interferons. Interferons are naturally occurring glycoproteins that possess multiple biological effects including control of cell growth and differentiation, regulation of cell surface antigen expression, and modulation of humoral and cellular immune responses. Greenway et al. [16] reported first that eight out of eight BCC treated intralesionally three times a week for 3 weeks with 1.5 × 106 IU IFN-a2b per injection were clinically and histologically cured 2 months after completion of therapy. Although the effectiveness of intralesional IFN therapy in BCC has been established in a number of clinical trials, this therapeutic option involves frequent injections and can cause systemic side effects. In addition, there is still controversy regarding the duration and dosing of IFN-a (see Chapter 13). The use of other immunostimulatory cytokines, such as IL-2, has also been actively investigated in the treatment of various NMSC forms (see Chapter 14). As the immune response can play a role in the clearance of NMSC lesions, it is logical to predict that an effective treatment strategy for NMSC could be an agent that stimulates both the innate and the cell-mediated immune responses. An excellent candidate for this purpose was the topical immune response modifier imiquimod 5% cream that enhances both the innate and acquired immune responses, in particular, the cell-mediated immune pathways. Imiquimod has been approved for the treatment of external genital and perianal warts, actinic keratoses (AK), and superficial basal cell carcinoma (sBCC) in immunocompetent adults. There are some data on its efficacy in nodular BCC (nBCC) and in some other types of cutaneous malignancies. The mechanism of action of this immunostimulatory agent will be reviewed in Chapter 14.

12.4 Conclusion Since the cellular immune response has been shown to play an important role in suppressing the development and growth of cancers, a great number of pharmacological agents stimulating the immune system have been developed for the treatment of skin cancer. In the

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Immunotherapy: An Introduction

following chapters the most important immunostimulatory agents for the treatment of NMSC will be discussed.

References 1. Berg D, Otley CC. Skin cancer in organ transplant recipients: Epidemiology, pathogenesis, and management. J Am Acad Dermatol. 2002;47:1–17 2. Euvrard S, Kanitakis J, Claudy A. Skin cancers after organ transplantation. N Engl J Med. 2003;348:1681–91 3. Sheil AG, Disney AP, Mathew TG, et al Malignancy following renal transplantation. Transplant Proc. 1992;24:1946–7 4. Ondrus D, Pribylincova V, Breza J, et al The incidence of tumours in renal transplant recipients with long-term immunosuppressive therapy. Int Urol Nephrol. 1999;31:417–22 5. Barrett WL, First MR, Aron BS, et al Clinical course of malignancies in renal transplant recipients. Cancer. 1993;72: 2186–9 6. Euvrard S, Kanitakis J, Pouteil-Noble C. Comparative epidemiologic study of premalignant and malignant epithelial cutaneous lesions developing after kidney and heart transplantation. J Am Acad Dermatol. 1995;33:222–9 7. Fortina AB, Piaserico S, Caforio AL, et al Immunosuppressive level and other risk factors for basal cell carcinoma and squamous cell carcinoma in heart transplant recipients. Arch Dermatol. 2004;140:1079–85

105 8. Smith KJ, Skelton HG, Yeager J, et al Cutaneous neoplasms in a military population of HIV-1-positive patients. J Am Acad Dermatol. 1993;29:400–6 9. Rabkin CS, Janz S, Lash A, et al Monoclonal origin of multicentric Kaposi’s sarcoma lesions. N Engl J Med. 1997;336: 988–93 10. Chan SY, Madan V, Helbert M, et al Highly active antiretroviral therapy-induced regression of basal cell carcinomas in a patient with acquired immunodeficiency and Gorlin syndrome. Br J Dermatol. 2006;155:1079–80 11. Kondo S, Sauder DN. Keratinocyte-derived cytokines and UVB induced immunosuppression. J Dermatol. 1995;22: 888–93 12. Dytoc M, Sauder DN. Cutaneous carcinogenesis: cytokines and growth factors. In: Miller SJ, Maloney ME (eds) Cutaneous oncology: Pathophysiology, diagnosis, and management. Malden, MA: Blackwell Science, 1997, pp. 73–86 13. Halliday GM, Patel A, Hunt MJ, et al Spontaneous regression of human melanoma/nonmelanoma skin cancer: association with infiltrating CD4+ T cells. World J Surg. 1995;19: 352–8 14. Klein E. Immunotherapeutic approaches to skin cancer. Hosp Pract. 1976;11:107–16 15. Holtermann OA, Papermaster B, Rosner D, et al Regression of cutaneous neoplasms following delayed-type hypersensitivity challenge reactions to microbial antigens or lymphokines. J Med. 1975;6:157–68 16. Greenway HT, Cornell RC, Tanner DJ, et al Treatment of basal cell carcinoma with intralesional interferon. J Am Acad Dermatol. 1986;15:437–43

Intralesional Interferon in the Treatment of Basal Cell Carcinoma

13

Stanislaw Buechner

Key Points

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Interferons are a group of naturally occurring glycoproteins Interferons control cell growth and differentiation, regulation of cell surface antigen expression, and modulation of humoral and cellular immune responses 1.5×106 IU of IFN-a three times a week for 3 weeks appears to be the most effective in treating a BCC less than 2 cm in diameter Larger tumors need larger doses and longer time Additional Randomized Controlled Studies are necessary

evolved as a therapeutic alternative for superficial and nodular BCC [4]. Immune response modifiers such as interferon (IFN) and imiquimod have been shown to be effective in the treatment of BCC [5]. Interferons are a group of naturally occurring glycoproteins that possess multiple biological effects including control of cell growth and differentiation, regulation of cell surface antigen expression, and modulation of humoral and cellular immune responses [6]. Based on the cell of origin, four types of IFN are recognized, namely IFN-a, IFN-b, IFN-g, and IFN-t. IFN-a is produced mainly by leukocytes, IFN-b by fibroblasts and epithelial cells, IFN-g by lymphocytes, and IFN-t by trophoblasts. Although the effectiveness of intralesional IFN therapy in BCC has been established in a number of clinical trials, there is still a controversy regarding the duration and dosing of IFN-a.

13.1 Introduction 13.2 Clinical Studies Basal cell carcinoma (BCC) is by far the most common skin malignancy in the white human population worldwide accounting for about 80% of non-melanoma skin cancer [1, 2]. BCC is a slow-growing tumor and rarely metastasizes and does cause progressive local tissue destruction. The treatment goals focus on complete tumor removal and minimization of cosmetic and functional defects. Effective methods of treatment include excisional surgery, curettage and electrodesiccation, cryosurgery, radiotherapy, and Mohs micrographic surgery [3]. Recently, the photodynamic therapy has S. Buechner Professor of Dermatology, Blumenrain 20, 4059 Basel, Switzerland e-mail: [email protected]

Clinical trials have used several different dosages, intervals, and duration of treatment [7–16]. Various dosing schedules have been compared in order to determine the optimum dose and assess side effects and long-term results. Greenway et al. [17] first reported that eight out of eight BCC treated intralesionally three times a week for 3 weeks with 1.5×106 IU IFN-a2b per injection were clinically and histologically cured 2 months after completion of therapy. In another study, eight BCC with surface areas ranging from 2 to 35 cm were treated by intralesional injection of IFN-a2a. Most of the lesions were located in aesthetically important areas, including the eyelids, canthi, and cheek. The dose per injection varied from 1.5 × 106 to 6.0 × 106 IU, according to the size of the lesions. Injections were

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given three times a week. After 6–11 weeks of treatment using a total dose of IFN-a2a varying from 24 × 106 to 156 × 106 IU, all patients underwent complete clinical and histological remission [18]. Ten patients with BCC were treated with perilesional injections of IFN-a2b, three times a week for 3 weeks [19]. Eight patients received 1.5 × 106 IU per injection, whereas two patients with larger lesions were treated with 3.0 × 106 IU and 6.0 × 106 IU, respectively. Six treated lesions measuring less than 19 × 19 mm cleared completely. Two of the nonresponders had large BCCs with tumor diameters greater than 25 mm. Eleven BCCs injected intralesionally three times weekly for 3 weeks with a low dose (0.9 × 106 IU) of IFN-a2 failed to respond to the treatment [20]. In another study, 65 BCCs were treated with intralesional sustained-release protamine zinc chelate formulation of IFN-a2b (10 × 106 IU per injection) [21]. Only lesions ranging in size from 0.5 to 1.5 cm for nodular tumors or 2 cm for superficial lesions at their largest diameter were included. Patients were randomized to receive IFN-a2b either as a single dose of 10 × 106 IU or as one dose of 10 × 106 IU per week for 3 consecutive weeks. At the study week 16, the entire test lesion was excised. Histological examination of excisional biopsies confirmed elimination of tumor in 17 (52%) out of 33 patients treated with single injection, whereas 24 (80%) out of 30 patients treated with 3 weekly injections were histologically cured. Using a treatment regimen of 1.5 × 106 IU of IFN-a three times a week for 4–8 weeks in 140 patients with BCC, a complete remission was observed in 94 (67%) patients, a partial response in 33 (24%) patients, and no response in 13 (9%) patients [22]. In patients with complete clinical remission, no recurrences were observed during a follow-up period of 12–54 months. Effectiveness of IFN-a in the treatment of BCC was also confirmed by a multicenter placebo-controlled trial. A total of 172 patients with biopsy-proven noduloulcerative or superficial BCC were given IFN-a2b or placebo three times weekly for 3 weeks with a cumulative dosage of 13.5 × 106 IU. Examination of biopsy specimens for 16–20 weeks to determine treatment efficacy demonstrated cure of lesions in 86% of IFNtreated patients and in only 29% of placebo-treated patients. One year after initiation of therapy, 81% of IFN recipients and 20% of those given the placebo remained tumor-free [23]. In a long-term follow-up study of primary superficial and nodular BCCs treated with nine perilesional injections of 1.5 × 106 IU of

S. Buechner

IFN-a2b over 3–6 weeks of treatment, 95 (97%) of the 98 tumors were free of tumor at the final follow-up visit, with a mean follow-up period of 10.5 years [24]. Comparing various dosage regimens, 1.5 × 106 IU of IFN-a three times a week for 3 weeks appears to be the most effective in treating BCC less than 2 cm in diameter. Larger and more aggressive tumors probably need a higher total and/or individual dose and longer treatment periods of up to 12 weeks to achieve a cure. Evaluation of efficacy by Mohs surgery showed that only 27% of aggressive primary morpheaform or recurrent BCCs treated with a total dose of 13.5 × 106 IU IFN-a2b were tumor-free at surgery [25]. If lesions respond, they begin to regress 4–6 weeks after completion of therapy. However, maximum responses usually require 8–16 weeks. A 16-week posttreatment period is usually required for adequate assessment of IFN efficacy. The benefits of intralesional or perilesional IFN include minimal invasiveness and scarring. Lesions treated with IFN often show a transient inflammatory response that gradually decreases during the posttreatment period. The cosmetic outcome is generally very good. The treatment schedule with injections every other day for 3 weeks is the chief disadvantage of IFN treatment and is also time-consuming.

13.3 Patient Selection and Contraindications IFN treatment is an important alternative to surgery in patients with nodular or superficial BCC at critical anatomical sites where there is a need for preservation of function or more favorable cosmetic results. It may also be preferable to surgery in patients who are not candidates for surgical excision or who are not amenable to surgery (Figs. 13.1A, B and 13.2A, B). Intralesional IFN can be also used as a treatment of positive margins after surgical excision. In addition, adjuvant intralesional IFN therapy may be indicated for large or recurrent tumors in anatomical areas in which it is difficult to obtain clear surgical margins without cosmetic or functional loss. Contraindications are hypersensitivity to IFN or to any of its components, cardiac diseases including arrhythmias and congestive heart failure, depression, or other psychiatric disorders, leucopenia, and pregnancy (category C). It should also be avoided in

13 Intralesional Interferon in the Treatment of Basal Cell Carcinoma

a

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b

Fig. 13.1 A,B: Large basal cell carcinoma on the temple before treatment with intralesional IFN- a2b (a) and 3 years after therapy (b)

a

b

Fig. 13.2 Nodular basal cell carcinoma of the medial canthus before (a) and 7 years after intralesional therapy with IFN-a2b (b)

patients with a history of epilepsy and autoimmune chronic hepatitis and in patients on concomitant immunosuppressive therapy.

13.4 Dosing and Injection Technique The dosage of 1.5 × 106 IU IFN-a per injection three times a week for 3 weeks was found to be most effective in nodular or superficial BCC with a tumor area less than 2 cm2. For larger tumors a dosage of 0.5 × 106 IU IFN-a per cm2 tumor area three times a week for a total of 9–12 injections is recommended. Nonpreserved lyophilized IFN-a is mixed with supplied diluent such that the concentration of reconstituted IFN is 3.0 × 106 IU/ml. Using intralesional and perilesional injection technique, 0.5 ml of solution (1.5 × 106 IU) is injected at each treatment session (Fig. 13.3). It is recommended

Fig. 13.3 Perilesional injection technique

that patients take acetaminophen, paracetamol, or ibuprofen for flu symptoms 1 h before the office visit and 3 h later.

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13.5 Side Effects Adverse reactions to IFN are, for the most part, limited to influenza-like symptoms and consist of mild fever, chills, headache, arthralgias, and myalgias. The severity of adverse reactions is directly related to the dosage of IFN. When giving larger doses of IFN, one must consider the fact that adverse reactions usually increase and influenza-like symptoms can become severe. The symptoms start 2–4 h postinjection and may last for 4–8 h. They usually decrease during the course of treatment with repeated doses. With treatment given late in the day the vast majority of the side effects occur during the evening and night hours. These symptoms respond to acetaminophen, paracetamol, or ibuprofen. Amongst the patients treated with intralesional IFN, adverse reactions of any degree of severity were noted in 30–70% of patients. About 15% of the patients receiving IFN-a at a dosage of 1.5 × 106 IU per injection showed decreases in the total white blood cell count. Local reactions at the injection site are minimal and manifest as erythema, pruritus, and burning sensation.

13.6 Mechanism of Action The rationale for the use of IFNs for treatment of BCC rests primarily on their ability to control cell growth and differentiation. Accumulating evidence indicates that IFNs act indirectly on tumor cells by inducing a variety of immune responses [6]. The observation of a considerable increase in the number of CD4+ T cells infiltrating the dermis and surrounding the BCC nests after intralesional IFN-a therapy has been interpreted to indicate that this T cell subset is involved in triggering the immune response against tumor cells [10, 26]. IFN-a promotes a shift toward secretion of Th1-type cytokines such as IFN-g and IL-2 facilitating cellular immunity, and enhancement of HLA class I and class II expression [27, 28]. Induction of apoptosis is the major mechanism by which cytolytic CD4+ and CD8+ T cell subsets kill target cells, including tumor cells. CD4+ cytotoxic T cells preferentially induce apoptosis in their target cells via CD9–CD95 ligand (CD95L) interaction [29]. CD95, also termed Fas or APO-1, is a cell surface transmembrane receptor of the tumor necrosis factor receptor superfamily and is expressed

S. Buechner

on a variety of cell types [30]. CD95 expression has been found on the membrane of basal and suprabasal keratinocytes in normal human epidermis whereas BCC tumor cells express low to undetectable levels of CD95 [31–33]. CD95L is expressed on activated T cells, BCC, and squamous cell carcinoma tumor cells [30, 31, 34]. CD95L is also expressed on the basal cells of the normal human epidermis. Using terminal deoxynucleotidyl transferasemediated dUDP nick-end labeling (TUNEL) technique, no apoptotic cells are found in BCCs. In contrast, numerous single apoptotic cells are present within the tumor masses in patients with BCC treated with intralesional injections of IFN-a [30, 31]. IFN-treated BCCs show a dense dermal infiltrate of CD4+ T-cells surrounding the tumor nests. However, only few T cells are found within the tumor nodules. Immunohistochemistry shows that BCC cells of untreated patients do not express CD95, but are strongly CD95L positive. BCC cells make use of the CD95L to escape from a local immune response by averting the attack from activated CD95+/ CD4+ T cells. Upon treatment with IFN-a the BCC cells express not only CD95L but also CD95, and regress by committing suicide or fratricide through apoptosis induction via CD95–CD95L interaction [30, 31]. The CD95L of BCC cells is functional because CD95+ target cells incubated on BCC cryosections become apoptotic and lyse. It has been shown recently that IFN-a induces CD95 expression and apoptosis in sonic hedgehog pathway-activated BCC cells through interference with mitogen-activated Erk-regulating kinase (Mek) [35].

References 1. Diepgen T, Mahler V. The epidemiology of skin cancer. Br J Dermatol. 2002;146:1–6 2. Lear W, Dahlke E, Murray CA. Basal cell carcinoma: review of epidemiology, pathogenesis, and associated risk factors. J Cutan Med Surg. 2007;11:19–30 3. Ceilley RI, Del Rosso JQ. Current modalities and new advances in the treatment of basal cell carcinoma. Int J Dermatol. 2006;45:489–98 4. Braathen LR, Szeimies RM, Basset-Seguin N, Bissonnette R, Foley P, Pariser D, Roelandts R, Wennberg AM, Morton CA. Guidelines on the use of photodynamic therapy for nonmelanoma skin cancer: an international consensus. International Society for Photodynamic Therapy in Dermatology, 2005. J Am Acad Dermatol. 2007;56:125–43

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Intralesional Interferon in the Treatment of Basal Cell Carcinoma

5. Bath-Hextall FJ, Perkins W, Bong J, Williams HC. Interventions for basal cell carcinoma of the skin. Cochrane Database Syst Rev. 2007;CD003412 6. Berman B, De Araujo T, Lebwohl M. Immunomodulators. In: Bolognia J, Jorizzo JL, Rapini RP (eds) Dermatology., London: Elsevier Science, 2003, Vol. 2, pp. 2033–53 7. Alpsoy E, Yilmaz E, Basaran E, Yazar S. Comparison of the effects of intralesional interferon alfa-2a, 2b and the combination of 2a and 2b in the treatment of basal cell carcinoma. J Dermatol. 1996;23:394–6 8. Boneschi V, Brambilla L, Chiappino G, Mozzanica N, Finzi AF. Intralesional alpha 2b recombinant interferon for basal cell carcinomas. Int J Dermatol. 1991;30:220–4 9. Bostanci S, Kocyigit P, Alp A, Erdem C, Gurgey E. Treatment of basal cell carcinoma located in the head and neck region with intralesional interferon alpha-2a: Evaluation of longterm follow-up results. Clin Drug Investig. 2005;25:661–7 10. Buechner SA. Intralesional interferon alfa-2b in the treatment of basal cell carcinoma. Immunohistochemical study on cellular immune reaction leading to tumor regression. J Am Acad Dermatol. 1991;24:731–4 11. DiLorenzo PA, Goodman N, Lansville F, Markel W. Regional and intralesional treatment of invasive basal cell carcinoma with interferon alfa-n2b. J Am Acad Dermatol. 1994;31: 109–11 12. Epstein E. Intralesional interferon therapy for basal cell carcinoma. J Am Acad Dermatol. 1992;26:142–3 13. Georgouras K. Treatment of basal cell carcinoma with intralesional interferon. Australas J Dermatol. 1994;35:47 14. Healsmith MF, Berth-Jones J, Fletcher A, Graham-Brown RA. Treatment of basal cell carcinoma with intralesional interferon alpha-2b. J R Soc Med. 1991;84:524–6 15. Ikic D, Padovan I, Pipic N, Knezevic M, Djakovic N, Rode B, Kosutic I, Belicza M. Basal cell carcinoma treated with interferon. Int J Dermatol. 1991;30:734–7 16. Kim KH, Yavel RM, Gross VL, Brody N. Intralesional interferon alpha-2b in the treatment of basal cell carcinoma and squamous cell carcinoma: revisited. Dermatol Surg. 2004;30: 116–20 17. Greenway HT, Cornell RC, Tanner DJ, Peets E, Bordin GM, Nagi C. Treatment of basal cell carcinoma with intralesional interferon. J Am Acad Dermatol. 1986;15:437–43 18. Grob JJ, Collet AM, Munoz MH, Bonerandi JJ. Treatment of large basal-cell carcinomas with intralesional interferonalpha-2a. Lancet. 1988;1:878–9 19. Thestrup-Pedersen K, Jacobsen IE, Frentz G. Intralesional interferon-alpha 2b treatment of basal cell carcinoma. Acta Derm Venereol. 1990;70:512–4 20. Wickramasinghe L, Hindson TC, Wacks H. Treatment of neoplastic skin lesions with intralesional interferon. J Am Acad Dermatol. 1989;20:71–4 21. Edwards L, Tucker SB, Perednia D, Smiles KA, Taylor EL, Tanner DJ, Peets E. The effect of an intralesional sustained-

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release formulation of interferon alfa-2b on basal cell carcinomas. Arch Dermatol. 1990;126:1029–32 22. Chimenti S, Peris K, Di Cristofaro S, Fargnoli MC, Torlone G. Use of recombinant interferon alfa-2b in the treatment of basal cell carcinoma. Dermatology. 1995;190:214–7 23. Cornell RC, Greenway HT, Tucker SB, Edwards L, Ashworth S, Vance JC, Tanner DJ, Taylor EL, Smiles KA, Peets EA. Intralesional interferon therapy for basal cell carcinoma. J Am Acad Dermatol. 1990;23:694–700 24. Tucker SB, Polasek JW, Perri AJ, Goldsmith EA. Long-term follow-up of basal cell carcinomas treated with perilesional interferon alfa 2b as monotherapy. J Am Acad Dermatol. 2006;54:1033–8 25. Stenquist B, Wennberg AM, Gisslen H, Larko O. Treatment of aggressive basal cell carcinoma with intralesional interferon: evaluation of efficacy by Mohs surgery. J Am Acad Dermatol. 1992;27:65–9 26. Mozzanica N, Cattaneo A, Boneschi V, Brambilla L, Melotti E, Finzi AF. Immunohistological evaluation of basal cell carcinoma immunoinfiltrate during intralesional treatment with alpha 2-interferon. Arch Dermatol Res. 1990;282:311–7 27. Kooy AJ, Prens EP, Van Heukelum A, Vuzevski VD, Van Joost T, Tank B. Interferon-gamma-induced ICAM-1 and CD40 expression, complete lack of HLA-DR and CD80 (B7.1), and inconsistent HLA-ABC expression in basal cell carcinoma: a possible role for interleukin-10? J Pathol. 1999; 187:351–7 28. Stadler R. Interferons in dermatology. Present-day standard. Dermatol Clin. 1998;16:377–98 29. Ashkenazi A, Dixit VM. Death receptors: signaling and modulation. Science. 1998;281:1305–8 30. Wehrli P, Viard I, Bullani R, Tschopp J, French LE. Death receptors in cutaneous biology and disease. J Invest Dermatol. 2000;115:141–8 31. Buechner SA, Wernli M, Harr T, Hahn S, Itin P, Erb P. Regression of basal cell carcinoma by intralesional interferon-alpha treatment is mediated by CD95 (Apo-1/Fas)CD95 ligand-induced suicide. J Clin Invest. 1997;100: 2691–6 32. Lee SH, Jang JJ, Lee JY, Kim SY, Park WS, Shin MS, Dong SM, Na EY, Kim KM, Kim CS, Kim SH, Yoo NJ. Fas ligand is expressed in normal skin and in some cutaneous malignancies. Br J Dermatol. 1998;139:186–91 33. Filipowicz E, Adegboyega P, Sanchez RL, Gatalica Z. Expression of CD95 (Fas) in sun-exposed human skin and cutaneous carcinomas. Cancer. 2002;94:814–9 34. Erb P, Ji J, Wernli M, Kump E, Glaser A, Buchner SA. Role of apoptosis in basal cell and squamous cell carcinoma formation. Immunol Lett. 2005;100:68–72 35. Li C, Chi S, He N, Zhang X, Guicherit O, Wagner R, Tyring S, Xie J. IFNalpha induces Fas expression and apoptosis in hedgehog pathway activated BCC cells through inhibiting Ras-Erk signaling. Oncogene. 2004;23:1608–17

Interleukin-2 for Nonmelanoma Skin Cancer

14

Arpad Farkas

Key Points

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›

› ›

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Surgery is the most frequent approach to treat Non-melanoma skin cancer (NMSC), but newer noninvasive treatment options such as immunotherapy with intralesional or perilesional interleukin-2 (IL-2) have already proven efficacy. Intratumoral local IL-2 therapy leads to higher IL-2 concentrations at the tumor site and has fewer systemic side-effects compared to systemic IL-2 treatment. Local IL-2 treatment of the primary malignant lesion may result in regression of both the primary tumor and metastases. Immune-modulating agents such as IL-2 may be used in instances when other methods are difficult to perform or where cosmetic results are important. Additionally IL-2 may be a candidate for a combination therapy with standard and experimental NMSC treatment options.

A. Farkas CLINIC DUFOUR 31, Dufourstrasse 31, 8008 Zürich, Switzerland e-mail: [email protected]

14.1 Introduction Nonmelanoma skin cancer (NMSC) belongs to the most frequent cancer types; the two most common forms are basal cell carcinoma (BCC) and squamous cell carcinoma (SCC), accounting for more than 95% of NMSC cases [1]. Other less common NMSC types include certain sarcomas such as Kaposi sarcoma (KS), cutaneous lymphoma (CL), skin appendageal tumors, and Merkel cell carcinoma. The mortality rate of BCC and SCC is low, but they are locally invasive, and SCC can metastasize. Some of the rare types of NMSCs may run a relatively benign course for a long time (e.g., CLs) and could also be very aggressive (e.g., skin appendageal cancers and cutaneous sarcomas). The most widely used therapeutic modality for common NMSCs is simple surgical excision. Other therapies for localized disease include Mohs micrographic surgery, cryotherapy, curettage, cautery/electrodesiccation, CO2 laser ablation, irradiation, photodynamic therapy, and local cytostatics [2, 3]; however, the recurrence rate after conventional treatments can reach 20% [4, 5]. The role of the immune status in the progression of NMSC is highlighted by the increased incidence of skin cancer in immunosuppressed [6–8] and in human immunodeficiency virus (HIV)-positive patients [9, 10]. NMSC lesions may regress partially as a result of a spontaneous antitumor immune response. For example, up to 50% of BCCs show a partial regression at some time, and it is thought that both innate and acquired immune pathways are responsible for this phenomenon [11–13]. In actively regressing BCCs, the number of T cells has been five times higher as compared to nonregressing lesions [14]. Until now,

G. B. E. Jemec et al. (eds.), Non-Surgical Treatment of Keratinocyte Skin Cancer, DOI: 10.1007/978-3-540-79341-0_14, © Springer-Verlag Berlin Heidelberg 2010

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several tumor antigens have been identified in NMSCs; one of them, mutated p53, can be found in more than 90% of SCCs and in most BCCs [15]. Many of these antigens could be recognized by CD8+ T lymphocytes, which require the assistance of CD4+ T cells. In regressing BCC lesions, CD4+ T lymphocytes produce increased levels of interferon (IFN)-gamma, tumor necrosis factor-alpha, and interleukin (IL)-2, therefore, contributing to tumor destruction [16]. On the other hand, NMSC lesions often produce IL-10, which leads to the depletion of activated antigen presenting cells in the skin and to the downregulation of costimulatory molecules such as CD80 and CD86 on their surface [17–19]. As the immune response can play a role in the clearance of NMSC lesions, in recent years, different immunotherapy forms have become effective treatment strategies.

14.2 Locally Applied IL-2 Immunotherapy for NMSC The use of dinitrochlorobenzene, a topical chemotherapeutic agent for the treatment of BCC, highlighted the possible role of immunotherapy in the treatment of

Fig. 14.1 The principal responders of IL-2 IL-2 is mainly produced by activated CD4+ T lymphocytes; its major action is on T lymphocytes, NK cells, B lymphocytes, and monocytes. IL-2 induces cell proliferation, differentiation, mediates self-tolerance and promotes cell lysis and/or apoptosis. It induces the production of cytokines, cytolytic molecules, and immunoglobulins.

A. Farkas

NMSCs. The regression of BCC lesions after dinitrochlorobenzene treatment depends on the development of hypersensitivity [20] or delayed-type immune reactions induced by microbial allergens and cytokines [21], which may mobilize T-cell-mediated immune responses against the malignant lesion. Later, cytokines such as intralesional and perilesional IFN-alpha and topical IFN-alpha inducers such as imiquimod and IL-2 have been actively investigated in the treatment of various NMSC forms. IL-2 is mainly produced by activated CD4 + T lymphocytes and exerts its antitumoral effect by boosting the immune system rather than having a direct cytotoxic effect on tumor cells. IL-2 is capable of regulating the development and the functions of CD4+ , CD8+ , suppressor, and regulatory T lymphocytes (Treg). IL-2 augments the activity of natural killer cells, neutrophils, or macrophages. It stimulates the growth and differentiation of B lymphocytes and may promote dendritic cell differentiation from monocytes [22–24]. Thus, it seems that IL-2 plays an important role in the augmentation of cytotoxic activity against tumor cells. The principal responders of IL-2 are shown in Fig. 14.1. IL-2 can decrease blood vasculature [25, 26] and has been shown to trigger the vascular leakage system, resulting in endothelial cell damage [27] and in tumor

After Karolina Olejniczak and Aldona Kasprzak (Med Sci Monit, 2008; 14(10): RA179-189) Abbreviations: Th - T helper; Tc - cytotoxic; Ts - T suppressor, Treg - T regulatory lymphocytes; NK - natural killer; TNF-α tumor necrosis factor-alpha; IFN-γ - interferon-gamma; GMCSF – granulocyte macrophage-colony stimulating factor.

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Interleukin-2 for Nonmelanoma Skin Cancer

Fig. 14.2 Mechanism of local IL-2 IL-2 decreases vasculature and has been shown to trigger the vascular leakage system, resulting in endothelial cell damage and tumor necrosis. The release of tumor-associated antigens leads to the development of an immune reaction. After Willem Den Otter et al. (Cancer Immunol Immunother. 2008 Jul; 57(7):931-50). The cartoon in the original article was drawn by Anne-Marie Keegstra.

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necrosis. Then, the release of tumor-associated antigens leads to the development of an immune reaction (Fig. 14.2). During IL-2-induced vascular leakage, Fas ligand, perforin, CD4+, and CD8+ T cells were required for endothelial cell damage [27]. Both CD4+ [28] and CD8+ T cells [29, 30] can target and destroy endothelial cells directly. Furthermore, activated CD8+ T cells, secrete cytokines, such as IFN-gamma, which can result in the destruction of blood vessels [31]. IL-2 also seems to be responsible for controlling autoreactive T-cell activity as a result of its role in activation-induced cell death as well as in the maintenance of Tregs [32, 33]. IL-2 has been used in a wide range of tumor immunotherapy approaches and is currently approved for the treatment of renal cell carcinoma and metastatic melanoma. It was shown recently that the number of Tregs is increased in the circulation of patients with melanoma and renal cancer receiving high-dose IL-2 [34], and decreased in responding patients [35]; differences have been also observed in the number of IL-2-responsive cells in the circulation versus the tumor microenvironment. In early studies, IL-2 was systemically administered, but adverse effects were significant. The most frequent side effects included fever, chills, diffuse erythema, pruritus, hypotension, edema, renal insufficiency, hematological alterations, psychiatric disorders, cardiopulmonary toxicity [36–38] and vascular leakage syndrome [39, 40]. Therefore, IL-2 has been applied directly into, or around, solid tumors with promising results and with fewer side effects [41, 42]. Locally applied IL-2 has been evaluated in the treatment of various cutaneous tumors including melanoma, BCC, SCC, Bowen’s disease, metastatic eccrine poroma, angiosarcomas, and CL. Table 14.1 summarizes the most important clinical studies performed until now in NMSCs. Mihara and colleagues have treated a histologically diagnosed BCC lesion with intratumoral recombinant IL-2 (rIL-2) once daily at a dose of 1,000 Units for 13 consecutive days. The day after the last injection a biopsy was performed, which showed an inflammatory infiltrate and the tumor was replaced by nearly normal epidermal cells. However, when the specimen was excised a month later a recurrence of BCC could be detected histologically [43]. The same group has injected a histologically proven Bowen’s disease with rIL-2 once daily at a dose of 1,000 Units for 10 consecutive days. Posttreatment histological analysis showed an inflammatory infiltrate without any signs of Bowen’s disease.

rIL-2 PEG-IL-2

rIL-2 Adenovirus-IL-2 (TG1024) rIL-2 and rIFN-α-2b

IL-2 in CCM** or rIFN-α rIL-2

rIL-2

rIL-2 rIL-2

1/1

8/12

1/3

1/5

1/3 (A, B, C)*

20/20

1/multiple

5/multiple

1/5

22/multiple

Bowens’s disease

BCC

Nevoid basal cell syndrome

Metastatic SCC

Metastatic eccrine poroma

HIV-negative KS

HIV-negative KS

HIV-positive KS

CTCL

MF, SS

s.c.

p.t

s.c.

i.t.

p.t i.t.

p.t

i.t.

i.t

p.t

i.t.

i.t.

Route

11 x 106 IU

2 x 102 IU

0.4 x 106 IU/m2 to 1.2 x 106 IU/m2

3.5 x 105 IU

5 x 104 IU IFN-α (12 pts) or IFN-α + IL-2 in CCM** (8pts)

A/ 4.5 x 106 IU rIL-2 B/ 0.75 x 106 IU IFN-α-2b C/ combination (A+B)

3 x 1011 virus particles

NS

3 x 103 − 12 x 105 IU

1 x 103 IU

1 x 103 IU

Dose

4 days weekly for 6 weeks then 2 weeks off (1 cycle)

6 x every other days

daily for 90 days

1 x a week for 6 months

2 x a week for 4−6 weeks

1 x daily for 2 weeks for IL-2

3 x with 2 week intervals

5 days

1 to 4 weekly

1 x daily for 10 days

1 x daily for 13 days

Schedule

4 PR 18 PD

4 CR 1 PR

3 SD 2 PD

CR

CR

CR

MTTF 5 months range: 3–9

After 13 months

After 1, 2 and 17 months

None within 13 months

NS

NS

NS

NS

NS 1 CR 3 PD 1 SD

NS

After 1 month

After 1 month

Relapse

8 CR 1 SD 3 PR

CR

CR

Response

constitutional, gastrointestinal, hematologic toxicities (e.g. lymphopenia)

NS

local reaction, flu-like symptoms, diarrhea, hyperkalemia thrombocytopenia

None

None

subfebrile temperature, local inflammation, pain

injection site disorders, fever, asthenia

local pain, fever, flu-like symptoms

local pain, swelling, erythema, flu-like symptoms

NS

NS

Adverse events

Querfeld et al. [53]

Nagatani et al. [52]

Bernstein et al. [50]

Shibagaki et al. [49]

Ghyka et al. [48]

Dummer et al. [47]

Dummer et al. [46]

Urosevic et al. [45]

Kaplan et al. [44]

Mihara et al. [43]

Mihara et al. [43]

Reference

BCC – basal cell carcinoma; SCC – squamous cell carcinoma; HIV – human immunodeficiency virus; KS – Kaposi sarcoma; CTCL – cutaneous T-cell lymphoma; MF – mycosis fungoides; SS – Sezary syndrome; rIL-2 – recombinant human interleukin-2; PEG-IL-2 – polyethylene glycol interleukin-2; rIFN-a – recombinant interferon alpha; CCM – concentrated conditioned medium; i.t. – intratumoral; p.t. – peritumoral; s.c. – subcutaneous; pts – patients; CR – complete response; PR – partial response; SD – stable disease; PD – progressing disease; NS – not stated; MTTF – mean time to failure. * One subcutaneous metastasis was treated perilesionally with 4.5 million Unit IL-2 (A), another with 0.75 million Unit rIFN-α-2b (B), and the third with both cytokines (C). ** Lymphocytes were stimulated in vitro and the supernatant was used as a concentrated conditioned medium (CCM), which contained IL-2 and IFN-γ (10–50 IU/ml).

rIL-2

1/1

BCC

Treatment

Patients/ lesions

Tumor type

Table 14.1 The most important clinical studies performed until now in NMSCs

116 A. Farkas

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Interleukin-2 for Nonmelanoma Skin Cancer

However, the specimen again showed bowenoid changes 1 month later when it was radically excised [43]. Kaplan et al. treated 12 BCCs in eight patients perilesionally with polyethylene glycol (PEG)-IL-2. Complete response (CR) was observed in eight of 12 treated tumors, partial response in three out of 12 treated tumors, and stable disease (SD) with no improvement in one tumor. In 10 of 12 injected sites pain, swelling, and erythema was observed, resolving within a week. One patient developed systemic symptoms, such as fever, fatigue, and headache [44]. Urosevic and colleagues have successfully treated multiple BCCs in a patient with nevoid basal cell syndrome by daily intralesional injections of 0.5 ml rIL-2 divided on three lesions for 5 days. They observed some side effects such as fever, flu-like symptoms and local pain at the injection site [45]. Lately Dummer et al. conducted a phase I/II openlabel, dose-escalating study with repeated intratumoral injections of an adenovirus-IL-2 construct (TG1024) in patients with advanced solid tumors and melanoma. One patient with metastatic SCC of the skin was enrolled. Five lesions were treated with 3 × 1011 virus particles. Each tumor received a total of three injections with 2-week intervals. Three lesions progressed, one was stable and one showed a CR. Median plasma IL-2 levels measured at 24 h after injection showed significant increases, paralleling the dose/regimen intensification. Adverse events were mild to moderate such as injection site disorders, fever, and asthenia [46]. IL-2 was also evaluated in rare types of NMSCs. An experimental treatment using IL-2 and IFN-alpha for metastatic eccrine poroma was performed by Dummer and coworkers. One subcutaneous metastasis was treated perilesionally with 4.5 million Units IL-2, another with 0.75 million Units recombinant IFNalpha-2b, and the third with both cytokines. After 2 weeks, the lesions treated with IL-2 showed hemorrhagic necrosis but the IFN-alpha treated nodule was unaffected. One month later, this resistant lesion was treated with both cytokines for a 2-week period that induced a complete clinical disappearance. Only moderate side effects were observed such as subfebrile temperature, local inflammation, and pain [47]. Ghyka et al. treated HIV-negative KS patients with intra- and peritumoral injections of IFN-alpha (12 cases) or, alternatively, with IFN-alpha and IL-2 (eight cases). In each patient, one tumor received 50,000 Units IFNalpha alone or alternatively associated with IL-2 twice a

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week for 4–6 weeks. IL-2 was obtained by in vitro stimulation of lymphocytes. The supernatant was used as a concentrated conditioned medium (CCM), which also contained IFN-gamma (10–50 IU/ml). The treated nodules were cured in all the investigated cases; IL-2 in combination with IFN-alpha induced a more rapid involution of cutaneous lesions than IFN-alpha monotherapy [48]. Later, a clinical trial with human rIL-2 for the treatment of classic KS was performed by Shibagaki and colleagues. Weekly intralesional doses of 3.5 × 105 Units of rIL-2 were injected into the skin lesions. The lesions began to regress after the tenth injection (3 months). A biopsy specimen revealed a marked decrease in the number of tumor cells with moderate inflammatory infiltration. After the 26th injection, which was equivalent to a total dose of 9.1 × 106 Units of rIL-2, a CR of all measurable lesions was observed. A beneficial effect on distant uninjected lesions was also noted, suggesting a systemic effect. There have been no recurrences of the resolved lesions within 13 months after discontinuation of therapy. No local or general adverse effects or laboratory abnormalities were noted during treatment [49]. Bernstein and his group treated five HIV-associated KS patients with 17 courses of IL-2 therapy at doses ranging from 0.4 × 106 Units/m2/day to 1.2 × 106 Units/m2/day. Two of the five patients developed new KS lesions during their first IL-2 course. All the other three patients completed at least one course, having SD. Two of them had later progressive disease and one remained in SD for 17 months. The most common side effects were mild flu-like symptoms, local reaction at the injection site, thrombocytopenia, transient hyperkalemia, and brief episodes of diarrhea [50]. Another report also exists for the treatment of HIVrelated KS with the use of rIL-2 suggesting that prolonged low-dose subcutaneous administration of this cytokine is nontoxic and has the potential to improve the immunodeficient hosts’ immune response to infectious pathogens that require IFN-gamma for clearance [51]. The first case report for the treatment of cutaneous T-cell lymphoma (CTCL) with local rIL-2 injection was performed by Nagatani and colleagues. After six injections, four nodules out of five disappeared and the remaining nodule was diminished in size. A biopsy specimen from the diminished nodule showed infiltration lymphocytes, histiocytes, and plasma cells in the dermis without atypical cells and without large hyperconvoluted lymphocytes. The patient maintained CR

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for a period of 13 months. He then noticed a recurrence which was cleared with chemotherapy [52]. Recently, Querfeld et al. conducted a phase II trial with subcutaneous injections of rIL-2 in 22 heavily pretreated CTCL patients. Only a modest response rate (18%) was observed. The most frequent toxicities included constitutional symptoms, gastrointestinal symptoms, and hematologic toxicities. One patient developed grade four lymphopenia. Treatment was discontinued in two patients after grade three constitutional symptoms. Based on their experience rIL-2 is mostly ineffective in patients with advanced and heavily pretreated CTCL patients. Whether rIL-2 has the potential to cure untreated early stage CTCL cases needs to be clarified in larger trials [53].

14.3 Perspectives Systemic high-dose IL-2 treatment has many side effects and can induce a generalized vascular leakage syndrome [39, 54], which strongly limits the potential use of this therapeutic modality. It is clear that local IL-2 therapy requires smaller doses, therefore fewer complications are expected. Locally applied IL-2 leads to much higher IL-2 concentrations at the site of the tumor and to much lower concentrations elsewhere in the body. Although local IL-2 can be applied with therapeutic efficiency both intratumorally and peritumorally, lately it was proven in a lymphoma model that intratumoral IL-2 therapy is more effective than peritumoral therapy [55]. On the other hand, local application of free IL-2 can still have notable side effects such as pain, swelling, erythema, skin-necroses, and sometimes fatigue or flu-like symptoms. Systemic side effects are often seen if several lesions are treated at the same time and if the total dose reaches a certain amount. Because of the very short half-life of free IL-2 repeated injections are needed. Different preparations might be helpful to overcome this problem. Some attempts have been made to perform changes in IL-2 structure including covalent attachment to PEG to provide a longer half-life and reduced immunogenicity [44]. Another approach is the use of ReGel, which is an aqueous polymer. Pharmacokinetic studies after peritumoral ReGel/IL-2 injection in mice demonstrated a significant reduction in tumor growth and improved survival. Untreated lesions also responded, suggesting systemic activation of antitumor immunity [56].

A. Farkas

Approaches using viral vectors expressing IL-2 have shown a potential therapeutical benefit in humans. TG1024, which has been successfully used in the treatment of metastasized SCC, is a suspension of recombinant nonpropagative, nonintegrating adenoviral particles carrying a gene encoding for the human IL-2 [46]. The ALVAC viral vector system uses a recombinant canarypox virus engineered with genes of interest such as IL-2. In the treatment of melanoma the ALVAC IL-2 system has been successfully tested [57]. Nonviral intratumoral gene transfer, using a plasmid containing the human IL-2 gene complexed with cationic lipid mixture (Leuvectin) also showed promising results in patients with metastatic melanoma [58]. Electroporation-assisted intralesional delivery of IL-2 plasmid was evaluated in animals and is currently being investigated in a phase I clinical trial in humans [59]. It seems that viral and nonviral plasmid IL-2 gene transfer can generate and sustain high rates of local cytokine production; therefore this could be a future therapeutic option for NMSCs and needs further evaluation. Standard tumor treatment involves the combination of various therapeutic modalities. In different tumors combined therapy of locally applied IL-2 and surgery, radiotherapy, or chemotherapy may lead to a synergistic therapeutic effect [60]. Combining cytokines may also lead to an effective tumor regression as it was seen in metastatic eccrin poroma or in HIVnegative KS, when IFN-alpha and IL-2 were used together. The toll-like receptor agonist immunmodulator imiquimod alone is often enough to elicit a response in NMSC lesions such as in BCCs. The addition of intralesional IL-2 may increase the response rates, as it was shown in melanoma patients; therefore, local IL-2 treatment can be a valuable addition to standard, and to recently developed, immunotherapeutic treatment options [61]. Local IL-2 treatment of the primary malignant lesion may result in regression of both the primary tumor and metastases in the draining regional lymph nodes [62]; this was proven by the durable complete responses of melanoma metastases in the lung after combined chemotherapy and IL-2 [63]. This systemic therapeutic effect might be an additional advantage of local IL-2 treatment in metastatic disease. IL-2 is capable of breaking tolerance [64, 65], which is mediated through the activation of intratumoral dendritic cells [66] and through local Tregs. This local tregs mediated tolerance reversal could be the connection between local IL-2 effects and systemic immunity. Stimulation of systemic

14

Interleukin-2 for Nonmelanoma Skin Cancer

immunity by local IL-2 therapy is also suggested by cytokine data in treated human patients. After local IL-2 therapy proinflammatory cytokines (e.g., IFN-gamma) are increased. In contrast, anti-inflammatory cytokines (e.g., IL-10) are increased after systemic IL-2 therapy [67]. These data also highlight the important differences between local and systemic IL-2 therapy. All the different standard treatment forms for NMSCs are effective, but are often associated with pain, scarring, and may be sometimes cosmetically deforming. Additional treatment options are desired in problematic situations related to tumor histologic type, size, number, and location. Local immunmodulation including the use of different IL-2 forms may represent one of the future treatment options for NMSCs. As a topical alternative to surgery, local IL-2 treatment may be particularly useful for the older, infirm, anticoagulated, or otherwise inoperable patients. In addition, different standard and immunological therapies may be combined with IL-2. Further clinical trials with larger numbers of patients are needed to confirm the role of topical IL-2 in the treatment of NMSCs.

Take Home Pearls • IL-2 is capable of regulating the development and functions of T cells, natural killer cells, B cells and dendritic cells, thus plays an important role in the augmentation of antitumoral activity of these cell types. • IL-2 induces endothelial cell damage and tumor necrosis. The release of tumor-associated antigens leads to the development of an anti-tumoral immune response. • Intratumoral IL-2 therapy is more effective than peritumoral treatment. • Intratumoral IL-2 therapy seems to have many advantages such as (1) high local IL-2 concentrations and (2) fewer side effects compared to systemic treatment. • The most important local side effects are pain, swelling, erythema, skin-necroses. Systemic side effects are sometimes fatigue and flu-like symptoms. • Free IL-2 has a short half-life, therefore some attempts have been made to overcome this problem such as (1) covalent attachment to polyethylene glycol polymers, (2) using viral vectors, (3) nonvi-

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ral plasmid IL-2 gene transfer and (4) electroporation-assisted delivery. • The treatment of the primary tumor with local IL-2 may contribute to the regression of metastatic disease. • Local IL-2 therapy may be useful for treating superficial variants of NMSC in older, infirm, anticoagulated, or otherwise inoperable patients. • In the future local IL-2 may be combined with other standard and experimental therapies for the treatment of NMSC. Acknowledgements The author would like to thank Andrea Gyimesi for her help in preparing this manuscript.

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42. Fiszer-Maliszewska L, Den Otter W, Mordarski M. Effect of local interleukin-2 treatment on spontaneous tumours of different immunogenic strength. Cancer Immunol Immunother. 1999;47:307–14 43. Mihara M, Nakayama H, Nakamura K, Morimura T, Hagari Y, Shimao S: Histologic-changes in superficial basal-cell epithelioma and Bowens disease by intralesional injection of recombinant Interleukin-2 – recombinant Interleukin-2 may induce redifferentiation of malignant-tumor cells invivo. Arch Dermatol. 1990;126:1107 44. Kaplan B, Moy RL. Effect of perilesional injections of PEGinterleukin-2 on basal cell carcinoma. Dermatol Surg. 2000; 26:1037–40 45. Urosevic M, Dummer R. Immunotherapy for nonmelanoma skin cancer – does it have a future? Cancer. 2002;94:477–85 46. Dummer R, Rochlitz C, Velu T, Acres B, Limacher JM, Bleuzen P, Lacoste G, Slos P, Romero P, Urosevic M. Intralesional adenovirus-mediated interleukin-2 gene transfer for advanced solid cancers and melanoma. Mol Ther 2008;16:985–94 47. Dummer R, Becker JC, Boser B, Hartmann AA, Burg G. Successful therapy of metastatic eccrine poroma using perilesional interferon-alfa and Interleukin-2. Arch Dermatol. 1992;128:1127–8 48. Ghyka G, Alecu M, Halalau F, Coman G: Intralesional human leukocyte interferon treatment alone or associated with IL-2 in non-AIDS related Kaposi’s sarcoma. J Dermatol 1992;19:35–9 49. Shibagaki R, Kishimoto S, Takenaka H, Yasuno H. Recombinant interleukin 2 monotherapy for classic Kaposi sarcoma. Arch Dermatol. 1998;134:1193–6 50. Bernstein ZP, Porter MM, Gould M, Lipman B, Bluman EM, Stewart CC, Hewitt RG, Fyfe G, Poiesz B, Caligiuri MA. Prolonged administration of low-dose Interleukin-2 in human immunodeficiency virus-associated malignancy results in selective expansion of innate immune effectors without significant clinical toxicity. Blood. 1995;86: 3287–94 51. Khatri VP, Fehniger TA, Baiocchi RA, Yu F, Shah MH, Schiller DS, Gould M, Gazzinelli RT, Bernstein ZP, Caligiuri MA. Ultra low dose interleukin-2 therapy promotes a type 1 cytokine profile in vivo in patients with AIDS and AIDSassociated malignancies. J Clin Invest. 1998;101:1373–8 52. Nagatani T, Kin ST, Baba N, Miyamoto H, Nakajima H, Katoh Y. A case of cutaneous T-cell lymphoma treated with recombinant Interleukin-2 (Ril-2). Acta Derm-Venereol. 1988;68:504–8 53. Querfeld C, Rosen ST, Guitart J, Rademaker A, Foss F, Gupta R, Kuzel TM. Phase II trial of subcutaneous injections of human recombinant interleukin-2 for the treatment of mycosis fungoides and Sezary syndrome. J Am Acad Dermatol. 2007;56:580–3 54. Rosenstein M, Ettinghausen SE, Rosenberg SA. Extravasation of intravascular fluid mediated by the systemic administration

121 of recombinant Interleukin-2. J Immunol. 1986;137: 1735–42 55. Jacobs JJ, Sparendam D, Den Otter W. Local interleukin 2 therapy is most effective against cancer when injected intratumourally. Cancer Immunol Immunother. 2005;54:647–54 56. Samlowski WE, McGregor JR, Jurek M, Baudys M, Zentner GM, Fowers KD. ReGel (R) polymer-based delivery of interleukin-2 as a cancer treatment. J Immunother. 2006; 29:524–35 57. Hofbauer GFL, Baur T, Bonnet MC, Tartour E, Burg G, Berinstein NL, Dummer R. Clinical phase I intratumoral administration of two recombinant ALVAC canarypox viruses expressing human granulocyte-macrophage colony-stimulating factor or interleukin-2: the transgene determines the composition of the inflammatory infiltrate. Melanoma Res. 2008; 18:104–11 58. Galanis E, Hersh EM, Stopeck AT, Gonzalez R, Burch P, Spier C, Akporiaye ET, Rinehart JJ, Edmonson J, Sobol RE, Forscher C, Sondak VK, Lewis BD, Unger EC, O’Driscoll M, Selk L, Rubin J. Immunotherapy of advanced malignancy by direct gene transfer of an interleukin-2 DNA/ DMRIE/DOPE lipid complex: phase I/II experience. J Clin Oncol. 1999;17:3313–23 59. Horton HM, Lalor PA, Rolland AP. IL-2 plasmid electroporation: from preclinical studies to phase I clinical trial. Methods Mol Biol. 2008;423:361–72 60. Den Otter W, Jacobs JJL, Battermann JJ, Hordijk GJ, Krastev Z, Moiseeva EV, Stewart RJE, Ziekman PGPM, Koten JW. Local therapy of cancer with free IL-2. Cancer Immunol Immunother. 2008;57:931–50 61. Green DS, Bodman-Smith MD, Dalgleish AG, Fischer MD. Phase I/II study of topical imiquimod and intralesional interleukin-2 in the treatment of accessible metastases in malignant melanoma. Br J Dermatol. 2007;156:337–45 62. Van Es RJJ, Baselmans AHC, Koten JW, Van Dijk JE, Koole R, Den Otter W. Perilesional IL-2 treatment of a VX2 headand-neck cancer model can induce a systemic anti-tumour activity. Anticancer Res. 2000;20:4163–70 63. Enk AH, Nashan D, Rubben A, Knop J. High dose inhalation interleukin-2 therapy for lung metastases in patients with malignant melanoma. Cancer. 2000;88:2042–6 64. Bendiksen S, Rekvig OP. Interleukin-2, but not interleukin-15, is required to terminate experimentally induced clonal T-cell anergy. Scand J Immunol. 2004;60:64–73 65. Margolin KA. Interleukin-2 in the treatment of renal cancer. Semin Oncol. 2000;27:194–203 66. Kubo T, Hatton RD, Oliver J, Liu XF, Elson CO, Weaver CT. Regulatory T cell suppression and anergy are differentially regulated by proinflammatory cytokines produced by TLRactivated dendritic cells. J Immunol. 2004;173: 7249–58 67. Tomova R, Pomakov J, Jacobs JJL, Adjarov D, Popova S, Altankova I, Den Otter W, Krastev Z. Changes in cytokine profile during local IL-2 therapy in cancer patients. Anticancer Res. 2006;26:2037–47

Topical Imiquimod

15

Lajos Kemény

Key Points

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Imiquimod belongs to the family of synthetic small nucleotid-like molecules of imidazoquinolinamines. It is an immune response modifier (IRM) with potent antiviral and antitumoral effects that are mediated through Toll-like receptor (TLR)7 (and 8) signaling. Imiquimod targets predominantly TLR7 expressing plasmacytoid dendritic cells (pDC) and Langerhans cells, with secondary recruitment and activation of other inflammatory cells. Activation of TLR7 results therefore in the stimulation of both the innate and acquired immune responses, in particular, cell-mediated immune pathways. Topical imiquimod cream 5% (Aldara™, 3M) has been found to be effective for the treatment of external genital and perianal warts, actinic keratoses (AK), and superficial basal cell carcinoma (sBCC) in immunocompetent adults. There are some data on its efficacy in nodular BCC (nBCC) and in some other skin cancers.

15.1 Introduction The immune system plays an important role in the pathogenesis of nonmelanoma skin cancer (NMSC). Immunosuppressed patients, such as organ-transplant recipients, have a greater incidence of squamous cell carcinomas (SCC); their preinvasive form, actinic keratoses (AK); basal cell carcinomas (BCC); and other skin tumors [7, 12, 43]. Since the cellular immune response plays a role in suppressing the development and growth of cancers, it is not too outrageous that an immune response modifier such as imiquimod could be used to treat cancers. Topical imiquimod cream 5% (Aldara™, 3M) is a topical immune response modifier (IRM) that enhances both the innate and acquired immune responses, in particular, the cell-mediated immune pathways (Fig. 15.1). Imiquimod has been approved for the treatment of external genital and perianal warts, actinic keratoses (AK), and superficial basal cell carcinoma (sBCC) in immunocompetent adults. There are some data on its efficacy in nodular BCC (nBCC) and in some other types of cutaneous malignancies. In this chapter, the current experience and possible future development of imiquimod for the treatment of NMSC are reviewed.

15.2 Mechanism of Action L. Kemény Department of Dermatology and Allergology, University of Szeged, Hungary e-mail: [email protected]

Imiquimod belongs to the family of synthetic small nucleotid-like molecules of imidazoquinolinamines. It is an immune response modifier (IRM) with potent antiviral and antitumoral effects.

G. B. E. Jemec et al. (eds.), Non-Surgical Treatment of Keratinocyte Skin Cancer, DOI: 10.1007/978-3-540-79341-0_15, © Springer-Verlag Berlin Heidelberg 2010

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Fig. 15.1 Effects of imiquimod on the innate and acquired immunity

Imiquimod exerts its biologic activity primarily by ligation of Toll-like receptor (TLR)7 and, to a lesser extent, TLR8, both of which have been identified as natural receptors for single-stranded RNA [3, 11, 19]. Cell stimulation via TLR7 and TLR8 leads to downstream activation of nuclear factor (NF)-kB and other transcription factors [4, 29]. Consequently, several genes-encoding mediators and effector molecules of the innate as well as the adaptive immune response, such as IFN-a, IL-1, -6, -8, -10, -12, TNF-a, and IFN-g, are transcribed [6, 33, 45]. Because of the prominent expression of TLR7 on plasmacytoid DCs (pDCs) [22] imiquimod targets predominantly TLR7 expressing plasmacytoid dendritic cells (pDC), with secondary recruitment and activation of other inflammatory cells. Local application of imiquimod leads to the activation of antigen presenting Langerhans cells, which migrate to regional lymph nodes, where they activate cytotoxic T lymphocytes and natural killer cells [35]. Other mechanisms explaining the antitumor activity of imiquimod include the reversal of CD4+ regulatory T-cell function [38], a TLR-independent

immunostimulatory action via adenosine receptor signaling [41], and indirect, via IFN-a [40]. In addition, imiquimod has also been shown to exert direct proapoptotic effects on tumor cells by upregulating the receptors required in the p53 apoptotic pathway [31]. As pathological angiogenesis occurs in skin cancers, the antiangiogenic activity of imiquimod might also play a role in its therapeutic activity [26] (Fig. 15.2). Treatment of BCC patients with topical imiquimod, sizable numbers of both myeloid dendritic cells (mDCs), and pDCs were detected within the inflammatory infiltrate suggesting that mDCs and pDCs are directly involved in the imiquimod-induced destruction of BCC lesions [47].

15.3 Pharmacokinetics Imiquimod is applied topically to the affected areas and its clinical effects are primarily localized to the skin. Systemic absorption is minimal (for a review

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NH2 N

N

N Immunologic effect

Inhibition of angiogenesis imiquimod ∗Upregulation of angiogenesis inhibitors ∗Down-regulation of pro-angiogenic factors

Antiaging

∗Decrease in sun-damaged melanocytes ∗Restoration of epidermal thickness ∗Less hyperkeratosis ∗More ordered proliferation ∗Improved epidermal skin barrier

Apoptosis induction

Upregulation: (Th1 cytokines) IL-1α,IL-1β, IFN-α, IL-6, IL-8, IL-10, IL 12, TNF α, GM-CSF Downregulation: (Th2 cytokines) IL-4, IL-5

∗Induction of caspases ∗Bcl-2 dependent cytochrome c translocation ∗Downregulation of antiapoptotic genes (hurpin, HAX-1)

Fig. 15.2 Mechanism of action of topical imiquimod treatment

see [57]). After daily application of imiquimod 5% cream to 20 healthy volunteers, serum imiquimod concentrations were 62 and 87 pg/ml after 2 days in two individuals, 52–99 pg/ml after 3 days in five individuals, and 58 pg/ml 2 days after the seventh application in one individual, whereas in the remaining individuals it was below the detection limit of 50 pg/ml. When imiquimod was applied three times per week for 16 weeks in 58 patients with AK, the mean peak serum levels at the end of week 16 were very low, measuring approximately 0.1–3.5 ng/ml depending on whether one packet (12.5 mg) or up to six packets (75 mg) were used. Peak serum concentrations were reached in 9–12 h, and the steady-state serum concentrations were reached after 2 weeks. Serum concentrations of imiquimod metabolites were also low and transient [18]. Systemically absorbed imiquimod is excreted in urine and feces. The half-life of topically applied imiquimod is approximately 26 h with urinary recovery of less than 0.6% [57].

15.4 Therapeutic Efﬁcacy 15.4.1 Imiquimod for the Treatment of AK Actinic keratosis (AK; solar keratosis or squamous cell carcinoma in situ), is a localized area of dysplasia with malignant potential and regarded as a strong predictor of a subsequent squamous cell carcinoma [1, 30]. AKs can occur as some single lesion or affect a complete field like the forehead or the back of the hand (“field cancerization”) [9]. Approximately 10% (6–16%) of AK-patients and about 40% of immunosuppressed patients develop an invasive SCC [16, 51]. Organtransplanted patients have a 250-fold higher risk to develop AKs and a 100-fold higher risk to develop invasive SCCs [51, 55]. It is impossible to predict the point at which an individual AK lesion will evolve into invasive SCC, so most clinicians advocate the treatment of all AK lesions [25].

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Table 15.1 Imiquimod 5% cream in the treatment of actinic keratoses (AK): Summary of randomized, double-blind, placebocontrolled trials in which patients applied study cream two or three times weekly Trial Treatment duration Number of Response P Value (weeks) patients Stockfleth et al. [50]

3×/week for maximum of 12 weeks 3×/week for 8 weeks

T cc: 84% P cc: 0% Persaud et al. [39] 22 T: Mean reduction of 3.9 lesions P: Mean reduction of 0.5 lesions Szeimes et al. [52] 3×/week for 16 weeks 286 T cc: 57.1%; pc:72.1% P cc: 2.3%; pc: 4.3% Lebwohl et al. [25] 2×/week for 16 weeks 436 T cc: 45.1%; pc: 59.1% P cc: 3.2%; pc: 11.8% Korman et al. [23] 3×/week for 16 weeks 492 T cc: 48%, pc: 64% P cc: 7.2%; pc: 13.6% Alomar et al. [5] 3×/week for 4 or 8 weeks 259 T cc: 55% P cc: 2.3% Jorizzo et al. [21] 3×/week for 4 or 8 weeks 146 T cc: 53.7%; pc: 61% Abbreviations: T: treatment group, P: placebo group, cc: complete clearing, pc: partial clearing (> or = 75% reduction in baseline lesions).

Imiquimod is an effective and safe treatment in patients with AKs. Table 15.1 reviews clinical studies of AKs treated with imiquimod 5% cream. Stockfleth et al. performed a randomized, doubleblind, vehicle-controlled study with 5% imiquimod cream or vehicle to AK lesions three times per week for a maximum of 12 weeks or until lesions had resolved [50]. In the event of an adverse reaction, application of imiquimod was reduced to one or two times per week. Of 52 patients screened, 36 men and women with AK confirmed by histological diagnosis were enrolled. Lesions treated with 5% imiquimod cream were clinically cleared in 21 (84%) of 25 patients and partially cleared in 2 (8%). Clearance was histologically confirmed 2 weeks after the last application of imiquimod in all patients clinically diagnosed as lesion-free. Only 10% of patients treated with imiquimod were clinically diagnosed with recurrence 1 year after treatment. No reduction in the size or number of AK lesions was observed in vehicle-treated patients. Adverse effects reported by patients treated with imiquimod included erythema, edema, induration, vesicles, erosion, ulceration, excoriation, and scabbing. However, imiquimod was well-tolerated since all patients completed the 12-week treatment. These results suggested that imiquimod is effective and safe in patients with AKs. Recurrence rate was found to be 10% within 1-year follow-up period and 20% within 2-years follow-up period [49].

52

<0.001 <0.05

<0.001 <0.001 <0.001 <0.001 <0.001

In another small study 22 patients with AK lesions were treated with imiquimod 5% cream, initially at three times per week for 8 weeks, or until total clearance of lesions [39]. Patients applied imiquimod to lesions on one side of the body and vehicle cream to the other side. A total of 17 patients who completed treatment were evaluated for number of lesions and adverse reactions before treatment and at weeks 2, 4, 6, and 8 after initiation of treatment. AK lesions were also assessed 4 and 8 weeks after treatment. A significant reduction in the average number of lesions per patient was observed for patients treated with imiquimod. The most frequent reactions to treatment were erythema, itching, and scabbing; however, all adverse events were mild to moderate. Szeimies et al. performed a randomized, doubleblind, parallel group, vehicle-controlled study to evaluate the efficacy of imiquimod 5% cream compared with vehicle in the treatment of AK lesions on the face and balding scalp including pretreatment and posttreatment biopsy specimens [52]. A total of 286 patients at 18 centers in six European countries with histologically confirmed AK were randomized to either imiquimod 5% cream or vehicle cream. Study cream was applied once per day, 3 days per week, for 16 weeks. Clearance of AK lesions was clinically and histologically assessed at an 8-week posttreatment visit. The complete clearance rate for the imiquimod

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Topical Imiquimod

group was 57.1% versus 2.2% for the vehicle group. The partial clearance rate (> or = 75% reduction in baseline lesions) for the imiquimod group was 72.1% versus 4.3% for the vehicle group (P < 0.001). The most common side effects were erythema, scabbing/ crusting, and erosions/ulceration. Two phase III, randomized, double-blind, vehiclecontrolled studies evaluated the efficacy of imiquimod 5% cream compared with vehicle in the treatment of AK lesions on the face and balding scalp [25]. A total of 436 participants at 24 centers in the United States and Canada were randomized to receive either imiquimod 5% or vehicle cream. Study cream was applied one time per day, 2 days per week for 16 weeks. Clearance of AK lesions was clinically assessed at an 8-week posttreatment visit. The complete clearance rate was 45.1% for the imiquimod group and 3.2% for the vehicle group. The partial (> or = 75%) clearance rate was 59.1% for the imiquimod group and 11.8% for the vehicle group. The median percent reduction in AK lesions was 83.3% for the imiquimod group and 0% for the vehicle group. Local skin reactions were common. Severe erythema was reported by 17.7% of participants who received imiquimod and 2.3% of participants who received vehicle. These results suggested that imiquimod 5% cream used two times per week for 16 weeks is an effective and well-tolerated treatment for AK. Korman et al. evaluated the efficacy and safety of 5% imiquimod cream compared to the vehicle in the treatment of actinic keratosis (AK) in two phase III randomized, double-blind, parallel-group, vehicle-controlled studies [23]; 492 patients, with four to eight AK lesions in a 25-cm2 treatment area on the face or the balding scalp were randomized in 26 ambulatory care offices. Patients applied 5% imiquimod or vehicle cream to the treatment area once daily, three times per week, for 16 weeks, followed by an 8-week posttreatment period. Complete and partial clearance rates for imiquimod-treated patients (48.3% and 64.0%, respectively) were clinically and statistically significantly higher than for vehicle-treated patients (7.2% and 13.6%, respectively). The median percentage reduction of baseline lesions was 86.6% for the imiquimod-treated group and 14.3% for the vehicle-treated group. To evaluate imiquimod versus vehicle applied three times a week for 4 weeks in one or two courses of treatment for AK, 22 study center enrolled a total of 259 patients in a clinical study [5]. Patients applied the study drug for 4 weeks, entered a 4-week rest period

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and if they did not have complete clearance, they then entered a second course of treatment. Patients in the imiquimod group had an overall complete clearance rate of 55% versus a rate of 2.3% for the vehicle group. There was a high rate of agreement between the clinical assessment and histological findings with respect to AK lesion clearance. These results showed that a 4-week course of treatment with three times weekly dosing of imiquimod 5% cream, with a repeated course of treatment for those patients who fail to clear after the first course of treatment, was a safe and effective treatment for AK. The overall complete clearance rate (complete clearance after either course 1 or course 2) was comparable to the 16-week treatment regimen, while decreasing drug exposure to the patient and decreasing the overall treatment time. A shorter dosing regimen of imiquimod for the treatment of AK may be effective, with long-term clinical benefits. Therefore, imiquimod in one or two shorter courses of treatment was evaluated [21]. Patients with AK lesions on the head applied imiquimod or vehicle cream three times per week for 4 weeks (course 1). Patients with remaining lesions received another course of treatment. Complete and partial clearance rates were evaluated after course 1, after course 2 (overall), and 1 year later. Complete clearance rates were 26.8% (course 1) and 53.7% (overall). Partial clearance rates were 36.6% (course 1) and 61.0% (overall). Imiquimod three times perweek in one or two courses of treatment appeared, therefore, to be effective for the treatment of AK on the head, providing long-term clinical benefits. A meta-analysis based on a total of 1,293 patients with AK treated with imiquimod 5% cream revealed a complete clearance in an average of 50% of patients [17]. These data clearly show that imiquimod represents an effective therapeutic alternative for topical treatment of AK. Imiquimod 5% cream has recently also been shown to be a safe and effective treatment for AK in solid organ-transplant recipients while no impairment of graft function or graft rejection has been observed [54]. These results suggest that topical administration of imiquimod 5% cream might represent a useful and safe therapeutic approach even in immunosuppressed individuals. This finding appears important considering the significantly higher incidence of AK and its increased rate of progression to SCC in immunosuppressed patients.

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The United States Food and Drug Administration (FDA) and the Australian Therapeutic Goods Administration (TGA) approved imiquimod for the treatment of AK, whereas label for the indication of AK through the EMEA is in process.

15.4.2 Imiquimod for the Treatment of BCC Basal cell carcinoma (BCC) is considered the most common skin cancer in white adults. The annual incidence of BCC in Europe is estimated between 40 and 140 cases per 100,000, and has been rising markedly over the last 20 years, coming to represent a significant burden on health care systems. Incidence rates increase with age and most patients present after age 60. The majority of BCCs are low-risk tumors. The most common pattern is the nodular form of BCC (nBCC), which accounts for 45–60% of cases. Clinically these appear as translucent, light-colored, pearly papules with telangiectasia, especially on the face, ears, and neck. The superficial subtype of BCC (sBCC) accounts for approximately 15–35% of BCCs, and presents clinically as red, scaly, frequently multiple macules or plaques, primarily on the trunk or the extremities. Highrisk BCCs include infiltrative, morpheaform (sclerosing), ulcerated, and micronodular subtypes, which tend to infiltrate more diffusely such that subsequent recurrence is more common. The nodular subtype, especially, may become pigmented. It can resemble a seborrhoeic keratosis, and occasionally malignant melanoma has to be considered in the differential diagnosis. BCCs develop from stem cells of the basal layer of the epidermis as a result of DNA damage from intermittent exposure to sunlight. Continuing exposure to ultraviolet B radiation further impairs immune defences and over time immune surveillance breaks down so clinical disease becomes apparent. BCC occurs more frequently in immunosuppressed patients, also suggesting the role of the immune system in the development of BCC [7, 12, 43]. As BCC responds to interferon therapy [24], and imiquimod is an interferon inducer, it seemed reasonable to investigate whether imiquimod was effective for the treatment of BCC (Table 15.1). In 2004, imiquimod 5% cream was approved by the Food and Drug Administration for the treatment of superficial basal cell carcinoma (sBCC) and may offer

L. Kemény

the advantage to avoid surgery in patients who refuse it or to provide a more practical treatment. The first randomized, double-blind pilot trial to evaluate the efficacy and safety of imiquimod 5% cream was performed on 35 patients with BCC (87% sBCCs, 17% nBCCs) [8]. In this clinical study 24 patients received imiquimod 5% cream in one of five dosing regimens for up to 16 weeks and 11 received vehicle cream. Six weeks after treatment, an excisional biopsy of the target site was performed. BCC cleared in all 15 patients (100%) dosed twice daily, once daily, and three times weekly; in three of five (60%) patients dosed twice weekly; two of four (50%) dosed once weekly; and in 1 of 11 (9%) treated with vehicle. A multicenter, randomized, open-label dose-response trial of imiquimod 5% cream in the treatment of primary sBCC was performed by Marks and colleagues [28]. Ninety-nine patients were randomized to 6 weeks’ application of imiquimod in one of four treatment regimens: twice every day, once every day, twice daily three times per week, once daily three times per week. Intention-to-treat analysis revealed 100% histologic clearance in the twice-daily regimen, 87.9% clearance in the once every day regimen, 73.3% clearance in the twice-daily three times per week regimen, and 69.7% clearance in the once-daily three times per week regimen [28]. In a second multicenter double-blind, vehiclecontrolled study, 128 patients with sBCC were randomized to 12 weeks of imiquimod twice daily, once daily, five times per week and three times per week. Complete response rates varied from 100% in the b.i.d. group to 51.7% in the three times per week group [15]. The treatment of nBCC using imiquimod was also assessed with or without occlusion using 6- and 12-week protocols [44, 48]. Once daily dosing produced the highest clearance rates with 71% and 76% of cancers showing clearance in the 6- and 12-week studies, respectively. The data suggested that imiquimod 5% cream was affective and safe for the treatment of BCC. Occlusion did not have a clinically significant effect on the treatment of either sBCC or nBCC, and the 6-week treatment protocol was as effective as a 12-week long regimen. Geisse and colleagues [14] evaluated the efficacy and safety of imiquimod 5% cream compared with vehicle for treating BCC Subjects with one sBCC were dosed with imiquimod or vehicle cream once daily

15

Topical Imiquimod

five or seven times per week for 6 weeks in two randomized, double-blind, vehicle-controlled studies. The lesion site was clinically examined 12 weeks posttreatment and then excised for histological evaluation. Composite clearance rates (combined clinical and histological assessments) for the five and seven times per week imiquimod groups were 75% and 73%, respectively. Histological clearance rates for the five and seven times per week imiquimod groups were 82% and 79%, respectively. The difference in clearance rates between the two imiquimod dosing groups was not significant, therefore the five times per week regimen was recommended for the treatment of BCC. A recent study was designed to compare the safety and efficacy of two cycled dosing regimens of imiquimod 5% cream for treatment of sBCC. Patients were randomized to receive one of two treatment regimens: 8 weeks of treatment with once-daily dosing for alternate weeks (R1) and 5 weeks of once-daily dosing with a 1-week interval in the middle of the course (R2). Treatment of 32 patients revealed an initial clearance rate of 64% at week 19 for R1 and 81% for R2. However, clearance rates at week 52 were significantly different: 43% for R1 and 88% for R2. These results suggested that 5 weeks of 5% imiquimod cream once daily with a 1-week interval was more effective but as well tolerated as the 8-week alternate week regimen for sBCC [13]. Combination of imiquimod therapy with curettage or curettage and electrodissecation in patients with nBCC result in a better clearance rate, and has been suggested as an effective alternative therapeutic approach in single cases, where surgical therapy is hardly feasible due to the localization of the lesion, age or morbidity of the patient [34, 46, 58]. Currently, imiquimod 5% cream is approved in the United States, Europe, and Australia to treat superficial basal cell carcinoma, using a regimen of once daily, five times per week for 6 weeks.

15.4.3 Off-Label Use of Imiquimod for the Treatment of Other Skin Malignancies Imiquimod has demonstrated promise in off-label use for other types of NMSC including Bowen’s disease, a type of SCC in situ that presents as a slow growing, well-demarcated erythematous plaque. In one study of

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16 patients with Bowen’s disease located on the legs and shoulder, a 93% clearance rate was achieved [27]. Two studies report the successful treatment of in situ SCC lesions on the penis using imiquimod. The treatment regimen used in the first study involved 11 days of therapy repeated in two cycles, while imiquimod was given three times a week for 12 weeks in the second study. No clinical recurrence at 18 months after therapy was noted [37, 42].

15.5 Adverse Effects Although treatment with imiquimod cream is associated with adverse events, particularly local skin reactions, such as erythema, edema, induration, erosion, scaling, crusting, pruritus, and burning sensations, this could be deemed important in arriving at the optimal efficacy. Better clearance was seen in subjects with the most severe adverse events [10, 49], found that better clearance occurred in subjects with larger increases in AK lesions during initial therapy, and [23] found that both an increase in the number of lesions and intensity of local skin reaction was associated with better clearance rates. From the clinical point of view, it appears, therefore, that a patient’s local reaction correlates with the treatment success rate. The incidence of distant reactions, i.e., at sites other than the site of application, is low. Distant reactions include erythema, fatigue, myalgia, arthralgia, as well as lymphadenopathy.

15.6 Conclusion and New Innovative TLR Agonist Compounds In summary, numerous studies have shown the safety and efficacy of topical imiquimod 5% cream for the treatment of AK and sBCC. The efficacy of imiquimod in AK (Table 15.2) and BCC (Table 15.2) is similar or even better than that of other topical treatments and results in lower recurrences [32, 36]. Topical, noninvasive, patient-administered modalities continue to expand our options for treating a variety of skin conditions including skin cancers. Less patient discomfort, favorable cosmetic outcome, and documented efficacy against BCCs make imiquimod an attractive treatment choice. In addition, patients

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Table 15.2 Efficacy of topical imiquimod 5% in patients with superficial basal cell carcinoma (sBCC) and nodular (nBCC) lesions Trial Treatment duration Frequency of applications Number of patients Response (%) (weeks) Beutner et al. [8] sBCC and nBCC

16

Marks et al. [28] sBCC

6

Geisse et al. [15]

12

sBCC Shumack et al. [44] nBCC

6

12

Sterry et al. [48] sBCC

6

nBCC

6

Geisse et al. [14]

6

2×/day; 1×/day; 3×/week 2×/week 1×/week 2×/day 1×/day BID 3×/week QD 3×/week 2×/day 1×/day 5×/week 3×/week 2×/day 1×/day BID 3×/week QD 3×/week 2×/day 1×/day QD 3×/week QD 5×/week 3×/week 3×/week (occlusion) 2×/week 2×/week (occlusion) 3×/week 3×/week (occlusion) 2×/week 2×/week (occlusion) 5×/week 7×/week

who are poor surgical candidates (i.e., patients who are elderly, anticoagulated or who have implanted cardiac pacemakers) would benefit from this noninvasive, selfadministered topical therapy. In addition, its usefulness as an adjunct to surgical modalities, such as curettage or surgical excision, allows us to combine immunological-based treatment with surgical intervention. Resiquimod belongs to the imidazoquinoline, closely related to imiquimod. Resiquimod binds to TLR7 and TLR8, and similarly to that of imiquimod, it activates dendritic cells and macrophages to secrete INF-α, IL-12, and TNFα, leading to a Th1-cell-mediated immune response [2, 53, 56]. Resiquimod has been shown to be a more potent cytokine inducer than imiquimod [53]. A great number of other compounds related to imiquimod have been identified as TLR7 agonists R-850

35

99

128

99

92

93

90

369

100 60 50 100 88 73 70 100 87 81 52 No data 71 42 59 75 76 60 70 76 87 50 43 50 65 57 50 82 79

(Sotirimod), R-851, and R-852A are in clinical trials for the treatment of AK and early cervical HPV infections [20]. Another compound 3M-854 binds both TLR7 and TLR8, and has shown activity against asthma, allergic rhinitis and cancer [36]. These TLR agonists have shown promising results in preclinical studies, but efficacy and safety should be proven in future clinical studies.

References 1. Ackerman AB. Solar keratosis is squamous cell carcinoma. Arch Dermatol. 2003;139:1216–17 2. Ahonen CL, Gibson SJ, Smith RM, et al Dendritic cell maturation and subsequent enhanced T-cell stimulation induced with the novel synthetic immune response modifier R-848. Cell Immunol. 1999;197:62–72

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3. Akira S, Hemmi H. Recognition of pathogen-associated molecular patterns by TLR family. Immunol Lett. 2003;85: 85–95 4. Akira S, Takeda K. Toll-like receptor signalling. Nat Rev Immunol. 2004;4:499–511 5. Alomar A, Bichel J, McRae S. Vehicle-controlled, randomized, double-blind study to assess safety and efficacy of imiquimod 5% cream applied once daily 3 days per week in one or two courses of treatment of actinic keratoses on the head. Br J Dermatol. 2007;157:133–41 6. Barnetson RS, Satchell A, Zhuang L, et al Imiquimod induced regression of clinically diagnosed superficial basal cell carcinoma is associated with early infiltration by CD4 T cells and dendritic cells. Clin Exp Dermatol. 2004;29:639–43 7. Berg D, Otley CC. Skin cancer in organ transplant recipients: epidemiology, pathogenesis, and management. J Am Acad Dermatol. 2002;47:1–17 8. Beutner KR, Geisse JK, Helman D, et al Therapeutic response of basal cell carcinoma to the immune response modifier imiquimod 5% cream. J Am Acad Dermatol. 1999; 41:1002–7 9. Braakhuis BJ, Tabor MP, Kummer JA, et al A genetic explanation of Slaughter’s concept of field cancerization: evidence and clinical implications. Cancer Res. 2003;63:1727–30 10. Chen K, Yap LM, Marks R, et al Short-course therapy with imiquimod 5% cream for solar keratoses: a randomized controlled trial. Australas J Dermatol. 2003;44:250–5 11. Diebold SS, Kaisho T, Hemmi H, et al Innate antiviral responses by means of TLR7-mediated recognition of single-stranded RNA. Science. 2004;303:1529–31 12. Euvrard S, Kanitakis J, Claudy A. Skin cancers after organ transplantation. N Engl J Med. 2003;348:1681–91 13. Ezughah FI, Affleck AG, Evans A, et al Confirmation of histological clearance of superficial basal cell carcinoma with multiple serial sectioning and Mohs’ micrographic surgery following treatment with imiquimod 5% cream. J Dermatolog Treat. 2008;19:156–8 14. Geisse J, Caro I, Lindholm J, et al Imiquimod 5% cream for the treatment of superficial basal cell carcinoma: results from two phase III, randomized, vehicle-controlled studies. J Am Acad Dermatol. 2004;50:722–33 15. Geisse JK, Rich P, Pandya A, et al Imiquimod 5% cream for the treatment of superficial basal cell carcinoma: a doubleblind, randomized, vehicle-controlled study. J Am Acad Dermatol. 2002;47:390–8 16. Glogau RG. The risk of progression to invasive disease. J Am Acad Dermatol. 2000;42:23–4 17. Hadley G, Derry S, Moore RA. Imiquimod for actinic keratosis: systematic review and meta-analysis. J Invest Dermatol. 2006;126:1251–5 18. Harrison LI, Skinner SL, Marbury TC, et al Pharmacokinetics and safety of imiquimod 5% cream in the treatment of actinic keratoses of the face, scalp, or hands and arms. Arch Dermatol Res. 2004;296:6–11 19. Heil F, Hemmi H, Hochrein H, et al Species-specific recognition of single-stranded RNA via toll-like receptor 7 and 8. Science. 2004;303:1526–9 20. Inglefield JR, Dumitru CD, Alkan SS, et al TLR7 agonist 852A inhibition of tumor cell proliferation is dependent on plasmacytoid dendritic cells and type I IFN. J Interferon Cytokine Res. 2008;28:253–63

131 21. Jorizzo J, Dinehart S, Matheson R, et al Vehicle-controlled, double-blind, randomized study of imiquimod 5% cream applied 3 days per week in one or two courses of treatment for actinic keratoses on the head. J Am Acad Dermatol. 2007;57:265–8 22. Kadowaki N, Ho S, Antonenko S, et al Subsets of human dendritic cell precursors express different toll-like receptors and respond to different microbial antigens. J Exp Med. 2001;194:863–9 23. Korman N, Moy R, Ling M, et al Dosing with 5% imiquimod cream 3 times per week for the treatment of actinic keratosis: results of two phase 3, randomized, double-blind, parallel-group, vehicle-controlled trials. Arch Dermatol. 2005;141:467–73 24. Kowalzick L, Rogozinski T, Wimheuer R, et al Intralesional recombinant interferon beta-1a in the treatment of basal cell carcinoma: results of an open-label multicentre study. Eur J Dermatol. 2002;12:558–61 25. Lebwohl M, Dinehart S, Whiting D, et al Imiquimod 5% cream for the treatment of actinic keratosis: results from two phase III, randomized, double-blind, parallel group, vehiclecontrolled trials. J Am Acad Dermatol. 2004;50:714–21 26. Li VW, Li WW, Talcott KE, et al Imiquimod as an antiangiogenic agent. J Drugs Dermatol. 2005;4:708–17 27. Mackenzie-Wood A, Kossard S, de Launey J, et al Imiquimod 5% cream in the treatment of Bowen’s disease. J Am Acad Dermatol. 2001;44:462–70 28. Marks R, Gebauer K, Shumack S, et al Imiquimod 5% cream in the treatment of superficial basal cell carcinoma: results of a multicenter 6-week dose-response trial. J Am Acad Dermatol. 2001;44:807–13 29. Medzhitov R, Preston-Hurlburt P, Janeway CA, Jr. A human homologue of the Drosophila Toll protein signals activation of adaptive immunity. Nature. 1997;388:394–7 30. Memon AA, Tomenson JA, Bothwell J, et al Prevalence of solar damage and actinic keratosis in a Merseyside population. Br J Dermatol. 2000;142:1154–9 31. Meyer T, Nindl I, Schmook T, et al Induction of apoptosis by Toll-like receptor-7 agonist in tissue cultures. Br J Dermatol. 2003;149(Suppl 66):9–14 32. Meyer T, Stockfleth E. Clinical investigations of Toll-like receptor agonists. Expert Opin Investig Drugs. 2008;17:1051–65 33. Michalopoulos P, Yawalkar N, Bronnimann M, et al Characterization of the cellular infiltrate during successful topical treatment of lentigo maligna with imiquimod. Br J Dermatol. 2004;151:903–6 34. Neville JA, Williford PM, Jorizzo JL. Pilot study using topical imiquimod 5% cream in the treatment of nodular basal cell carcinoma after initial treatment with curettage. J Drugs Dermatol. 2007;6:910–4 35. Newman MD, Weinberg JM. Topical therapy in the treatment of actinic keratosis and basal cell carcinoma. Cutis. 2007;79:18–28 36. Novak N, Yu CF, Bieber T, et al Toll-like receptor 7 agonists and skin. Drug News Perspect. 2008;21:158–65 37. Orengo I, Rosen T, Guill CK. Treatment of squamous cell carcinoma in situ of the penis with 5% imiquimod cream: a case report. J Am Acad Dermatol. 2002;47:S225–8 38. Peng G, Guo Z, Kiniwa Y, et al Toll-like receptor 8-mediated reversal of CD4 + regulatory T cell function. Science. 2005; 309:1380–4

132 39. Persaud AN, Shamuelova E, Sherer D, et al Clinical effect of imiquimod 5% cream in the treatment of actinic keratosis. J Am Acad Dermatol. 2002;47:553–6 40. Schon M, Bong AB, Drewniok C, et al Tumor-selective induction of apoptosis and the small-molecule immune response modifier imiquimod. J Natl Cancer Inst. 2003;95: 1138–49 41. Schon MP, Schon M, Klotz KN. The small antitumoral immune response modifier imiquimod interacts with adenosine receptor signaling in a. J Invest Dermatol. 2006;126: 1338–47 42. Schroeder TL, Sengelmann RD. Squamous cell carcinoma in situ of the penis successfully treated with imiquimod 5% cream. J Am Acad Dermatol. 2002;46:545–8 43. Sheil AG, Disney AP, Mathew TG, et al Malignancy following renal transplantation. Transplant Proc. 1992;24:1946–7 44. Shumack S, Robinson J, Kossard S, et al Efficacy of topical 5% imiquimod cream for the treatment of nodular basal cell carcinoma: comparison of dosing regimens. Arch Dermatol. 2002;138:1165–71 45. Smith KJ, Hamza S, Skelton H. Topical imidazoquinoline therapy of cutaneous squamous cell carcinoma polarizes lymphoid and monocyte/macrophage populations to a Th1 and M1 cytokine pattern. Clin Exp Dermatol. 2004;29: 505–12 46. Spencer JM. Pilot study of imiquimod 5% cream as adjunctive therapy to curettage and electrodesiccation for nodular basal cell carcinoma. Dermatol Surg. 2006;32:63–9. 47. Stary G, Bangert C, Tauber M, et al Tumoricidal activity of TLR7/8-activated inflammatory dendritic cells. J Exp Med. 2007;204:1441–51 48. Sterry W, Ruzicka T, Herrera E, et al Imiquimod 5% cream for the treatment of superficial and nodular basal cell carcinoma: randomized studies comparing low-frequency dosing with and without occlusion. Br J Dermatol. 2002;147: 1227–36 49. Stockfleth E, Christophers E, Benninghoff B, et al Low incidence of new actinic keratoses after topical 5% imiquimod cream treatment: a long-term follow-up study. Arch Dermatol. 2004;140:1542

L. Kemény 50. Stockfleth E, Meyer T, Benninghoff B, et al A randomized, double-blind, vehicle-controlled study to assess 5% imiquimod cream for the treatment of multiple actinic keratoses. Arch Dermatol. 2002;138:1498–502 51. Stockfleth E, Ulrich C, Meyer T, et al Epithelial malignancies in organ transplant patients: clinical presentation and new methods of treatment. Recent Results Cancer Res. 2002;160:251–8 52. Szeimies RM, Gerritsen MJ, Gupta G, et al Imiquimod 5% cream for the treatment of actinic keratosis: results from a phase III, randomized, double-blind, vehicle-controlled, clinical trial with histology. J Am Acad Dermatol. 2004; 51:547–55 53. Tomai MA, Gibson SJ, Imbertson LM, et al Immunomodulating and antiviral activities of the imidazoquinoline S-28463. Antiviral Res. 1995;28:253–64 54. Ulrich C, Bichel J, Euvrard S, et al Topical immunomodulation under systemic immunosuppression: results of a multicentre, randomized, placebo-controlled safety and efficacy study of imiquimod 5% cream for the treatment of actinic keratoses in kidney, heart, and liver transplant patients. Br J Dermatol. 2007;157(Suppl 2):25–31 55. Ulrich C, Christophers E, Sterry W, et al Skin diseases in organ transplant patients. Hautarzt. 2002;53:524–33 56. Wagner TL, Ahonen CL, Couture AM, et al Modulation of TH1 and TH2 cytokine production with the immune response modifiers, R-848 and imiquimod. Cell Immunol. 1999;191: 10–9 57. Wagstaff AJ, Perry CM. Topical imiquimod: a review of its use in the management of anogenital warts, actinic keratoses, basal cell carcinoma and other skin lesions. Drugs. 2007;67:2187–210 58. Wu JK, Oh C, Strutton G, et al An open-label, pilot study examining the efficacy of curettage followed by imiquimod 5% cream for the treatment of primary nodular basal cell carcinoma. Australas J Dermatol. 2006;47:46–8

16

Photodynamic Therapy Gregor B. E. Jemec

Key Points

› › › ›

Photodynamic therapy was invented around 1900. PDT requires the interaction between a photosenitizer, oxygen, and light. Several photosensitizers are being developed. The most commonly used photosensitizer for NMSC is aminolevulenic acid.

or secondary skin tumors (both BCC and SCC) were studied, and of these only two were resistant to PDT. Since then a number of studies have reported beneficial effects of PDT in skin cancer, esophageal and nonsmall-cell lung cancer, bladder cancer, as well as several other non-neoplastic diseases. The treatment is now routinely being used for both superficial skin cancer and actinic keratoses.

16.1 Photodynamic Therapy The concept of photodynamic therapy (PDT) was developed more than 100 years ago in Germany by the medical student Oscar Raab and Professor Herman von Tappeiner in Munich, studying the effects of acridine and light on malaria-causing protozoa [1]. In the space of a few years the idea was developed and logical conclusions about the mechanisms drawn, which have since proved to be accurate. In the first therapeutic application of the new method, von Tappeiner and Jesionek used a combination of topical eosin and white light to treat skin tumors [2]. The method was then only slowly developed until the late 1970s when a resurgence of interest was noted following the paper by Dougherty reporting a large series of patients treated with PDT [3]. Twenty-five patients with 113 primary

Light

Photosensitizer

G. B. E. Jemac Department of Dermatology, Roskilde Hospital, Health Sciences faculty, University of Copenhagen, Denmark e-mail: [email protected]

The key components of PDT are photosensitizer, light, and tissue oxygen. The principle is that a substance (the photosensitizer) is preferentially absorbed in the cells of the diseased tissue, activated by illumination

Fig. 16.1 Described effects of PDT in cells

G. B. E. Jemec et al. (eds.), Non-Surgical Treatment of Keratinocyte Skin Cancer, DOI: 10.1007/978-3-540-79341-0_16, © Springer-Verlag Berlin Heidelberg 2010

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with visible light, and subsequently a phototoxic effect is exerted on the cells through the development of singlet oxygen (see Fig. 16.1). The mechanism of action of PDT is, however, still not fully understood, possibly because many different processes occur in parallel [4, 5]. It was initially shown to have effects at cellular and vascular levels [6, 7]. In the cell, several structures are disrupted by PDT, including the plasma membrane, mitochondria, nuclei, and lysosomes [8, 9]. PDT causes both an apoptotic response in cells as well as direct cytotoxicity within the tumor microenvironment [10, 11]. In addition the vasculature supply is targeted. This influence on the vasculature is thought to be a crucial part of the antitumoral effects of PDT as both the normal function and patency of the vessels are disrupted leading to necrosis [9, 12]. The treatment therefore appears to be able to induce both apoptosis and necrosis at the same time. Additional subcellular and immunological effects apparently also occur and are being studied. In addition to the proapoptotic and pronecrotic mechanisms, data indicate that PDT may also act as a biological response modifier [13, 14]. PDT sets off an inflammatory process activating a range of inflammatory mediators and chemoattractants. The acute inflammatory response and possible generation of tumor-specific immunity may play a role in the effects of PDT [5, 6, 15–18]. To complicate matter, further evidence suggests that PDT may suppress some parts of the immune system while it stimulates others. These immunological effects are speculated to lead to some of the possible longer-term effects of the

Table 16.1 Some photosensitizers Type Aminolevulinic acid Benzoporphyrin derivative monoacid ring A Phthalocyanines N-aspartyl chlorin e6 Texaphyrins Ethyl etiopurpurin Meso-tetra(hydroxyphenyl)porphyrins

treatment. The effects of PDT therefore appear to be more complex than a simple phototoxic reaction in cells accumulating a photosensitizer.

16.2 Perspectives The options for improvement of PDT are the three core components of the method: photosensitizer, the oxygen supply, and the light, and each of them is being studied. The common commercially available photosensitizers are mostly forms of aminolevulenic acid, which is usually applied either as a cream under occlusion, or as a premedicated patch. New photosensitizers are being developed not only for the treatment of NMSC but also for other indications such as antimicrobial or antiinflammatory therapy (see Table 16.1). Photosensitizers with a high specificity and sensitivity are the aim. The attempts to influence the oxygenation of the tissue currently involve more simple general measures such as warming the tissue, although a more refined or technology-intensive approach cannot be ruled out in the future [19, 20]. Finally, the most common illumination is currently by continuous simple blue or red light (see Fig. 16.2). Several changes in the illumination schedule are, however, being studied, ranging from laser or intense pulsed light through intermittent exposure and highintensity light, to prolonged exposure to natural sunlight. The increased routine use of PDT is likely to stimulate continued development in the field.

Indication

Status

Skin and mucosal cancers Age-related macular degeneration

Routine use Routine use

Bladder cancer Endobronchial tumors Areteriosclerotic plaques, breast cancer, age-related macular degeneration Cutaneous metastatic malignancies Head and neck cancers

Experimental Experimental Experimental Experimental Without regulatory approval

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Fig. 16.2 Illumination with visible red light. Blue light or broad spectrum light can be used as well

References 1. Raab O. Uber die Wirkung fluoreszierender Stoffe auf Infusorien. Z Biol. 1900;39:524–46 2. Von Tappeiner H, Jesionek A. Therapeutische Versuche mit fluoreszierenden Stoffen. Muench Med Wochenschr. 1903; 47:2042–4 3. Dougherty TJ. Photoradiation therapy for the treatment of malignant tumours. Cancer Res. 1978;36:2628–35 4. Dougherty TJ, Gomer CJ, Henderson BW, Jori G, Kessel D, Korbelik M, Moan J, Peng Q. Photodynamic therapy. J Natl Cancer Inst. 1998;90:889–905 5. Henderson BW, Dougherty TJ. How does photodynamic therapy work? Photochem Photobiol. 1992;55:145–57

135 6. Henderson BW, Dougherty TJ, Malone PB. Studies on the mechanism of tumor destruction by photoradiation therapy. In: Doiron DR, Gomer CJ (eds) Porphyrin localization and treatment of tumors. New York: A. R. Liss, 1984, pp. 301–14 7. Star WM, Marijnissen HP, van den Berg-Blok AE, Versteeg JA, Franken KA, Reinhold HS. Destruction of rat mammary tumor and normal tissue microcirculation by hematoporphyrin derivative photoradiation observed in vivo in sandwich observation chambers. Cancer Res. 1986;46:2532–40 8. Peng Q, Moan J, Nesland JM. Correlation of subcellular and intratumoral photosensitizer localization with ultrastructural features after photodynamic therapy. Ultrastruct Pathol. 1996; 20:109–29 9. Kessel D, Luo Y. Mitochondrial photodamage and PDTinduced apoptosis. J Photochem Photobiol B Biol. 1998;42: 89–95 10. Agarwal ML, Clay ME, Harvey EJ, Evans HH, Antunez AR, Oleinick NL. Photodynamic therapy induces rapid cell death by apoptosis in L5178Y mouse lymphoma cells. Cancer Res. 1991;51:5993–6 11. Moor AC. Signaling pathways in cell death and survival after photodynamic therapy. J Photochem Photobiol B Biol. 2000;57:1–13 12. Reed MW, Wieman TJ, Schuschke DA, Tseng MT, Miller FN. A comparison of the effects of photodynamic therapy on normal and tumor blood vessels in the rat microcirculation. Radiat Res. 1989;119:542–52 13. Hryhorenko EA, Oseroff AR, Morgan J, Rittenhouse-Diakun K. Antigen specific and nonspecific modulation of the immune response by aminolevulinic acid based photodynamic therapy. Immunopharmacology. 1998 Nov;40(3):231–40 14. Oseroff A. PDT as a cytotoxic agent and biological response modifier: Implications for cancer prevention and treatment in immunosuppressed and immunocompetent patients. J Invest Dermatol. 2006 Mar;126(3):542–4 15. Fingar VH. Vascular effects of photodynamic therapy. J Clin Laser Med Surg. 1996;14:323–8 16. Korbelik M. Induction of tumor immunity by photodynamic therapy. J Clin Laser Med Surg. 1996;14:329–34 17. Korbelik M, Cecic I. Contribution of myeloid and lymphoid host cells to the curative outcome of mouse sarcoma treatment by photodynamic therapy. Cancer Lett. 1999;137:91–8 18. MacDonald IJ, Dougherty TJ. Basic principles of photodynamic therapy. J Porphyrin Phthalocyanines. 2001;5:105–29 19. Woodhams JH, Macrobert AJ, Bown SG. The role of oxygen monitoring during photodynamic therapy and its potential for treatment dosimetry. Photochem Photobiol Sci. 2007;6: 1246–56 20. van den Akker JT, Boot K, Vernon DI, Brown SB, Groenendijk L, van Rhoon GC, Sterenborg HJ. Effect of elevating the skin temperature during topical ALA application on in vitro ALA penetration through mouse skin and in vivo PpIX production in human skin. Photochem Photobiol Sci. 2004;3:263–7

Critical Evidence-Based Review of Current Experience and Possible Future Developments of Topical PDT

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Olle Larkö and Ann-Marie Wennberg

Key Points

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Most suitable for superficial basal cell carcinoma Extremely well-suited for multiple actinic keratoses and squamous cell carcinoma in situ (Bowen’s disease) When treating multiple actinic keratoses the cosmetic results after PDT seem to be better than after conventional therapy PDT may also be used to treat other skin diseases The most common side effect is pain during and after treatment

17.1 Introduction Recently, many treatment methods have become available for superficial skin cancer and premalignant lesions. This applies mainly to dermatology. One of these new treatment modalities is photodynamic therapy (PDT). Internationally, many authors have earlier shown good results with this treatment method for skin cancer of non-melanoma type (NMSC) [1]. The method has been used for many years in Scandinavia. Since approximately 5 years it is a well-established clinical treatment method in most dermatological practices. There are mainly three forms of malignant tumours in the skin. These are malignant melanoma, basal cell O. Larkö () Department of Dermatolgy, Sahlgrenska Academy at Gothenburg University, Sahlgrenska University Hospital, 413 45 Gothenburg, Sweden e-mail: [email protected]

carcinoma, and squamous cell carcinoma with its precursors actinic keratosis and squamous cell carcinoma in situ. Malignant melanoma shall always be treated surgically and photodynamic therapy is no treatment option for this type of skin cancer. Basal cell carcinoma can be divided into three major forms depending on the growth pattern. The most common type is nodular basal cell carcinoma (NBCC). This is a well-delineated lesion and is most common in the face. Superficial basal cell carcinoma (SBCC) occurs mainly on the trunk and has a superficial growth pattern. Clinically, it may be hard to distinguish from guttate psoriasis. The third type of basal cell carcinoma is more uncommon and is of the so-called morphea type. It grows in an infiltrative and aggressive way and is most common in the face. Transitions between the different forms often occur. Photodynamic therapy is mainly suitable for superficial basal cell carcinoma but prepared nodular basal cell carcinoma can also come into question [1]. Squamous cell carcinoma can present itself in many ways. The prognosis and rate of growth is dependent on the histological differentiation and the localisation of the tumour. The precursor is actinic keratosis and is very common. The incidence in Sweden is unknown but has been estimated to be 50,000. Some of these can eventually progress into squamous cell carcinoma [2]. Photodynamic therapy is extremely well-suited for multiple actinic keratoses [3] and squamous cell carcinoma in situ (Bowen’s disease (BD)) [4]. The incidence of skin cancer is increasing rapidly every year since many years [5]. One of the etiological factors is regarded to be changing sun habits during recent decades. Solar exposure for a long time and repeated acute sunburns are established risk factors for the development of different forms of skin cancer [6]. This is especially true for persons with a lighter skin complexion (skin type I-II).

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Individuals on immunosuppression are a new and steadily increasing group of patients due to the fact that solid-organ transplantations increase in our society [7]. Depending on the latitude and the exposure of sun these patients suffer to different degrees from multiple NMSC [8]. Organ transplant recipients (OTR) show an increased risk of cancerous, mainly SCCs, and precancerous, mainly AKs and to some extent also BCCs. Their frequency increases with time after transplantation. These patients often suffer from a large amount of AKs that more often than in a normal population develop into SCCs. The SCCs are also of a more aggressive type than normal. An increasing number of patients seek care with a sun-damaged skin and skin tumours. They have to be dealt with in an effective and safe manner. Also, the costs to society must be kept to a minimum. The patients demand effective treatments with minimal scarring. Photodynamic therapy is a method, which has become a new promising complement to already established treatments for non-melanoma skin cancer and precursors in OTR [9].

17.2 Mechanism of Action Photodynamic therapy involves the topical application of delta-aminolevulinic acid (ALA) or the methyl form (MAL). When applied, MAL and ALA are converted into photoactive porphyrins in the tumour tissue. After approximately 3 h, the treated area is illuminated with visible light, most commonly red light but in some instances blue light [10]. Demonstrates the normal heme cycle in the cells. When delta-aminolevulinic acid is applied over the skin tumour excess amounts of protoporphyrin IX (Pp IX) are formed. Pp IX is extremely photosensitizing. The reason for the accumulation of Pp IX in tumours is not entirely known, but it is probably due to a defective skin barrier over the tumour. Using microdialysis, it has been demonstrated that there is a relatively rapid transport of ALA and MAL from the skin surface [11]. However, it seems that the penetration depth is less than 1 mm. For the patient, the treatment is very convenient as it only involves application of ALA or MAL followed 3 h later by less than 10 min of illumination. ALA or MAL themselves are not photodynamically active but are converted via the enzyme systems of the

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body to Pp IX. Also, the conversion of PpIX to heme is reduced in tumour tissue. Hence, an accumulation of Pp IX occurs. In recent years, ALA methyl ester (MAL) has been introduced and Sweden was the first country to approve the use of MAL in clinical practice.

17.3 Procedure When treating a superficial skin tumour, a light curettage is performed. During this procedure crusts and scales are removed without causing any bleeding. Thereafter, a cream containing ALA or MAL is applied over the treatment area, which is then covered with a plastic film occluding the area for approximately 3 h. During this time span, the tumour cells build up a sufficient amount of Pp IX and the area may be illuminated. Before illumination the plastic film is removed and the cream surplus is wiped off [12]. The Pp IX molecules are excited by the light into a higher energy triplet state. The energy is then transferred to oxygen and singlet oxygen and free radicals are formed. The main part of this reaction occurs in the mitochondrias and singlet oxygen damages the cell membranes. Figure 17.1 demonstrates how curettage, application of the substance, and illumination are performed. Some new photosensitizing derivatives are under development. This is especially interesting concerning macular degeneration in the eyes and diagnosis and treatment of urinary bladder cancer [13, 14].

17.4 Light Sources Different light sources can be used for photodynamic therapy. Both lasers and incoherent light sources work [15]. However, it is important that the emitted light matches the Pp IX absorption curve. The wavelengths of light chosen are based upon the absorption spectrum of porphyrins. The best absorption is seen around the largest peak, the so-called Soret band at 405 nm (blue light), but here the penetration depth in tissue is seldom sufficient. There is also a lower peak at 650 nm, the Q band (red light), and here the penetration of light through the skin is much better. Therefore, red light around 630 nm is often used although this is not the absorption maximum for porphyrines.

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Fig. 17.1 Preparation of skin lesion before PDT

Also, blue and green light are used but the efficacy seems to be inferior to red light [16]. Recently, light sources of the LED type have come into use. These are small efficient lamps making a treatment smoother [17].

17.5 Tumour Indications At present, photodynamic therapy is mainly used for widespread actinic keratosis, squamous cell carcinoma in situ and superficial forms of basal cell carcinoma.

17.6 Actinic Keratosis Widespread actinic keratoses are well-suited for treatment with photodynamic therapy. One such example is widespread lesions of the scalp. Organ transplant

recipients receiving immunosuppressive therapy have a more than 100-fold increased risk of contracting actinic keratosis and squamous cell carcinoma compared to the general population [18]. This group of patients is well-suited for treatment with PDT. Solitary actinic keratoses are usually still treated with cryotherapy with good clinical results. Comparative studies between photodynamic therapy with MAL and cryotherapy have been conducted for actinic keratosis. In a study where 699 lesions were treated, the clearance rate was equal in both treatment groups [19]. However, the cosmetic result was much better after photodynamic therapy and the patients preferred this therapy over cryotherapy. In a similar study of 204 patients the healing rate for photodynamic therapy and MAL PDT was 91% versus 68% for cryotherapy and 30% for placebo treatment [20]. In studies where PDT has been compared to 5-fluorouracil (5-FU) the two treatment modalities have been of comparative efficacy [21].

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For actinic keratosis, one treatment is usually sufficient with photodynamic therapy. For more hyperkeratotic actinic keratosis, still two treatments are recommended 1 week apart [22]. Thus, photodynamic therapy is at least as good as traditional treatment for actinic keratosis. The cosmetic results seem to be better.

17.7 Squamos Cell Carcinoma In Situ (Morbus Bowen) Also, squamous cell carcinoma in situ (Bowen) is well-suited for PDT. Even in this case comparative trials with conventional therapy modalities have been done. In a recent study with 1 year follow-up time, PDT proved to be more effective than both crytotherapy (80% versus 67%) and 5-FU (80% versus 69%) [23]. For squamous cell carcinoma in situ, two treatments 1 week apart is advocated. Consequently, photodynamic therapy seems to be at least as good as traditional methods for squamous cell carcinoma in situ and the cosmetic outcome usually better.

17.8 Basal Cell Carcinoma For basal cell carcinoma, so far it seems like PDT is most suitable for superficial basal cell carcinomas. Results from several studies clearly demonstrate that superficial basal cell carcinomas can be excellently treated with PDT. Even in this case, the cosmetic results seem to be better than for conventional methods [24]. In a comparative 5-year study for the treatment of superficial basal cell carcinomas with PDT and cryotherapy respectively, the efficacy of the two treatments was comparable, but again, the cosmetic result was superior for photodynamic therapy [25]. A recent study on organ transplant recipients demonstrates that PDT seems to be much more efficient than 5-FU for actinic keratosis in this group. In a study where PDT was compared to surgery for nodular basal cell carcinomas, the cosmetic result was significantly better in the PDT group. However, the number of recurrences seems to be slightly higher after 2 years [26]. In nodular basal cell carcinomas, surgery

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or cryosurgery is advocated as the first line of therapy. In a few selected cases, PDT may be performed. For PDT of basal cell carcinomas, two treatments 1 week apart are recommended.

17.9 Non-Tumour Indications Good results have recently been reported with PDT for acne [27, 28]. The mechanism of action is not quite clear but it is probably the sebum producing cells in the sebaceous gland that accumulate ALA or MAL. This is then converted to Pp IX. Subsequent illumination with red light selectively destroys the sebocytes. It seems that the sebum production can be reduced for almost half a year with a few PDT treatments. Also, PDT has been tried for psoriasis as this is a disease with rapidly produced proliferating tissue. So far, the results have varied. Limited success has been achieved for local lesions of cutaneous T-cell lymphoma [29]. Also, hand and foot warts have been successfully treated with PDT and effect is at least better than placebo [30]. Photodynamic therapy has been tried in selected cases of other skin diseases such as necrobiosis lipoidica, cutaneous sarcoidosis, localised scleroderma, lichen sclerosus et atroficus, etc. In these diseases there are usually only case reports and it is yet too early to draw any conclusions about the efficacy of methods in these conditions.

17.10 Acute Side Effects The most common side effect is pain during and after treatment. There are big variations between individuals and the level of pain is hard to foresee. As it appears, the treated area size is an important factor concerning the severity of pain. Also, the localisation is important. Illumination of the scalp is often more painful than the trunk [31]. The pain can be reduced by using local anaesthetics, pre-medication, etc., but it is most common to use an ordinary fan or cooling water sprayed topically. An erythema and a slight oedema locally are often seen directly after treatment. Erosions and crusts are formed the following days and the entire area is

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Critical Evidence-Based Review of Current Experience and Possible Future Developments of Topical PDT

usually healed within 1–2 weeks. However, ulceration is rare. Pigmentary changes can occur. When performing topical photodynamic therapy no general photosensitivity has been reported. This is common after i.v.treatment with porphyrins. A protective dressing is recommended over the treated area for 2 days after treatment to reduce the risk of photosensitisation.

17.11 Chronic Side Effects These are rare. On the contrary, the cosmetic result is usually very good after treatment. Surgery gives rise to various degrees of scars and cryotherapy often gives rise to pigmentary changes. As it appears, there is no long-term carcinogenic effect of photodynamic therapy [32]. However, longterm data in a large clinical material are lacking.

17.12 Diagnostics Diffusely growing or morphea-type basal cell carcinomas in the face can sometimes be hard to delineate. They are often situated centrally in the face and grow in an octopus-like pattern. The whole tumour may be hard to visualise. This often results in repeated surgery due to tumours that are not excised radically. Such tumours should be treated with microscopically controlled surgery, i.e. Mohs’ micrographic surgery. Fluorescence diagnostics may be used experimentally to facilitate radical surgery. ALA is applied over the tumour area in exactly the same way as during treatment, although no curettage occurs. Pp IX is accumulated in the tumour cells and gives rise to a strong fluorescence when irradiated with UVA and blue light. This fluorescence can be used for the demarcation of a tumour hard to delineate with the naked eye. Also, the tissue itself has an auto-fluorescence and this is lower over tumour tissue. By using the quotient: induced fluorescence/auto-fluorescence, better tumour delineation may be achieved [33]. The method is still under development but in the future it may be possible that fluorescence diagnostics may be a useful complement when treating diffusely delineated tumours.

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17.13 Future Development Photodynamic therapy with topical applied ALA or MAL is an effective treatment for widespread actinic keratosis, squamous cell carcinoma in situ and superficial basal cell carcinoma. The cosmetic result is often superior to other therapeutic modalities and is a major advantage with the method. Also, there is no atrophy from photodynamic therapy. There is a very low risk of keloids. Photodynamic therapy is to be preferred on the lower legs where other methods are less advantageous.

References 1. Braathen LR, Szeimies RM, Basset-Seguin N, Bissonnette R, Foley P, Pariser D, Roelandts R, Wennberg AM, Morton CA. International society for photodynamic therapy in dermatology. Guidelines on the use of photodynamic therapy for nonmelanoma skin cancer: an international consensus. International Society for Photodynamic Therapy in Dermatology, 2005. J Am Acad Dermatol. 2007 Jan;56(1): 125–43 2. Glogau RG. The risk of progression to invasive disease. J Am Acad Dermatol. 2000 Jan;42(1 Pt 2):23–4 3. Pariser DM, Lowe NJ, Stewart DM, Jarratt MT, Lucky AW, Pariser RJ, Yamauchi PS. Photodynamic therapy with topical methyl aminolevulinate for actinic keratosis: results of a prospective randomized multicenter trial. J Am Acad Dermatol. 2003 Feb;48(2):227–32 4. Cox NH, Eedy DJ, Morton CA. Therapy guidelines and audit subcommittee, British Association of Dermatologists. Guidelines for management of Bowen’s disease: 2006 update. Br J Dermatol. 2007 Jan;156(1):11–21 5. Tarstedt M, Larkö O, Molin L, Wennberg AM. Increasing number of skin cancer cases – also among the younger. Lakartidningen. 2005 June 27–July 10;102(26–27):1972–5 6. Dal H, Boldemann C, Lindelöf B. Trends during a half century in relative squamous cell carcinoma distribution by body site in the Swedish population: support for accumulated sun exposure as the main risk factor. J Dermatol. 2008 Feb;35(2):55–62 7. Bordea C, Wojnarowska F, Millard PR, Doll H, Welsh K, Morris PJ. Skin cancers in renal-transplant recipients occur more frequently than previously recognized in a temperate climate. Transplantation. 2004 Feb 27;77(4):574–9 8. Ramsay HM, Fryer AA, Hawley CM, Smith AG, Harden PN. Non-melanoma skin cancer risk in the Queensland renal transplant population. Br J Dermatol. 2002 Nov;147(5): 950–6 9. Piaserico S, Belloni Fortina A, Rigotti P, Rossi B, Baldan N, Alaibac M, Marchini F. Topical photodynamic therapy of actinic keratosis in renal transplant recipients. Transplant Proc. 2007 Jul-Aug;39(6):1847–50

142 10. Touma D, Yaar M, Whitehead S, Konnikov N, Gilchrest BA. A trial of short incubation, broad-area photodynamic therapy for facial actinic keratoses and diffuse photodamage. Arch Dermatol. 2004 Jan;140(1):33–40 11. Sandberg C, Halldin CB, Ericson MB, Larkö O, Krogstad AL, Wennberg AM. Bioavailability of aminolaevulinic acid and methylaminolaevulinate in basal cell carcinomas: a perfusion study using microdialysis in vivo. Br J Dermatol. 2008 Nov;159(5):1170–6 12. Morton CA. Methyl aminolevulinate (Metvix) photodynamic therapy – practical pearls. J Dermatolog Treat. 2003; 14(Suppl 3):23–6 13. Brown GC, Brown MM, Brown HC, Kindermann S, Sharma S. A value-based medicine comparison of interventions for subfoveal neovascular macular degeneration. Ophthalmology. 2007 June;114(6):1170–8. Epub 2007 Feb 23 14. Berger AP, Steiner H, Stenzl A, Akkad T, Bartsch G, Holtl L. Photodynamic therapy with intravesical instillation of 5-aminolevulinic acid for patients with recurrent superficial bladder cancer: a single-center study. Urology. 2003 Feb;61(2): 338–41 15. Alexiades-Armenakas M. Laser-mediated photodynamic therapy. Clin Dermatol. 2006 Jan-Feb;24(1):16–25 16. Morton CA, Whitehurst C, Moore JV, MacKie RM. Comparison of red and green light in the treatment of Bowen’s disease by photodynamic therapy. Br J Dermatol. 2000 Oct;143(4):767–72 17. Babilas P, Kohl E, Maisch T, Bäcker H, Gross B, Branzan AL, Bäumler W, Landthaler M, Karrer S, Szeimies RM. In vitro and in vivo comparison of two different light sources for topical photodynamic therapy. Br J Dermatol. 2006 Apr;154(4):712–8 18. Adami J, Gäbel H, Lindelöf B, Ekström K, Rydh B, Glimelius B, et al Cancer risk following organ transplantation: a nationwide cohort study in Sweden. Br J Cancer 2003;89:1221–7 19. Szeimies RM, Karrer S, Radakovic-Fijan S, Tanew A, Calzavara-Pinton PG, Zane C, et al Photodynamic therapy using topical methyl 5-aminolevulinate commpared with cryotherapy for actinic keratosis: a randomized prospective study. J Am Acade Dermatol. 2002;47:258–62 20. Freeman M, Vinciullo C, Francis D, Spelman L, Ngyuen R, Fergin P, et al A comparison of photodynamic therapy using topical methylaminolevulinate (Metvix) with single cycle cryotherapy in patients with actinic keratosis: a prospective randomised study. J Dermatolog Treat. 2003;14:99–106 21. Kurwa HA, Yong-Yee SA, Seed PT, Markey AC, Barlow RJ. A randomized paired comparison of photodynamic therapy and topical 5-fluorouracil in the treatment of actinic keratosis. J Am Acad Dermatol. 1999;41:414–8 22. Tarstedt M, Rosdahl I, Berne B, Svanberg K, Wennberg AM. A randomized multicenter study to compare two treatment regimens of topical methylaminolevulinate (Metvix-PDT) in actinic keratosis of the face and scalp. Acta Derm Venereol. 2005;85:424–8

O. Larkö and A.-M. Wennberg 23. Morton C, Horn M, Leman J, Tack B, Bedane C, Tjioe M, et al Comparison of topical methylaminolevulinate photodynamic therapy with cryotherap or fluorouracil for treatment of squamous cell carcinoma in situ:Results of amulticenter randomized trial. Arch Dermatol. 2006;142:729–35 24. Horn M, Wulf P, Wulf HC, Warloe T, Fritsch C, Rhodes LE, et al Topical methylaminolaevulinate photodynamic therapy in patients with basal cell carcinoma prone to complications and poor cosmetic outcome with conventional treatment. Br J Dermatol. 2003;149:1242–9 25. Basset-Seguin N, Ibbotson SH, Emtestam L, Tarstedt M, Morton C, Maroti M, Calzavara-Pinton P, Varma S, Roelandts R, Wolf P. Topical methyl aminolaevulinate photodynamic therapy versus cryotherapy for superficial basal cell carcinoma: a 5 year randomized trial. Eur J Dermatol. 2008 Sep-Oct;18(5):547–53 26. Rhodes LE, de Rie M, Enström Y, Groves R, Morken T, Goulden V, Wong GA, Grob JJ, Varma S, Wolf P. Photodynamic therapy using topical methyl aminolevulinate vs surgery for nodular basal cell carcinoma: results of a multicenter randomized prospective trial. Arch Dermatol. 2004 Jan;140(1):17–23 27. Hörfelt C, Funk J, Frohm-Nilsson M, Wiegleb Edström D, Wennberg AM. Topical methyl aminolaevulinate photodynamic therapy for treatment of facial acne vulgaris: results of a randomized, controlled study. Br J Dermatol. 2006 Sep; 155(3):608–13 28. Hörfelt C, Stenquist B, Larkö O, Faergemann J, Wennberg AM. Photodynamic therapy for acne vulgaris: a pilot study of the dose-response and mechanism of action. Acta Derm Venereol. 2007;87(4):325–9 29. Edström DW, Porwit A, Ros AM. Photodynamic therapy with topical 5-aminolevulinic acid for mycosis fungoides: clinical and histological response. Acta Derm Venereol. 2001 June-July;81(3):184–8 30. Stender IM, Na R, Fogh H, Gluud C, Wulf HC. Photodynamic therapy with 5-aminolaevulinic acid or placebo for recalcitrant foot and hand warts: randomised double-blind trial. Lancet. 2000 Mar 18;355(9208):963–6 31. Sandberg C, Stenquist B, Rosdahl I, Ros AM, Synnerstad I, Karlsson M, Gudmundson F, Ericson MB, Larkö O, Wennberg AM. Important factors for pain during photodynamic therapy for actinic keratosis. Acta Derm Venereol. 2006;86(5):404–8 32. Morton CA, Brown SB, Collins S, Ibbotson S, Jenkinson H, Kurwa H, Langmack K, McKenna K, Moseley H, Pearse AD, Stringer M, Taylor DK, Wong G, Rhodes LE. Guidelines for topical photodynamic therapy: report of a workshop of the British Photodermatology Group. Br J Dermatol. 2002; 146:552–67 33. Ericson MB, Uhre J, Strandeberg C, Stenquist B, Larkö O, Wennberg AM, Rosén A. Bispectral fluorescence imaging combined with texture analysis and linear discrimination for correlation with histopathologic extent of basal cell carcinoma. J Biomed Opt. 2005 May-June;10(3):034009

Electrochemotherapy in Treatment of Cutaneous Tumors

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Gregor Sersa

Keywords Electroporation • electrochemotherapy • bleomycin • cisplatin • cutaneous tumors

Key Points

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Electroporation is a physical method for delivery of various molecules, such as chemotherapeutic drugs and plasmid DNA into the cells by transiently increasing permeability of the cell membrane using application of controlled external field to the cells. Electrochemotherapy is anticancer treatment that utilizes electroporation of cells to increase chemotherapeutic drug uptake, specifically at the site where electric pulses are applied. Suitable chemotherapeutic drugs for electrochemotherapy are those with hampered transport through the plasma membrane, such as bleomycin and cisplatin. Preclinical studies have demonstrated good antitumor effectiveness of electrochemotherapy with bleomycin and cisplatin, given either intravenously or intratumorally, on different tumor and animal models. Besides antitumor effectiveness, minimal toxicity and safety of the procedure were demonstrated.

G. Sersa Department of Experimental Oncology, Institute of Oncology Ljubljana, Zaloska 2, 1000, Ljubljana, Slovenia e-mail: [email protected]

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Clinical studies using electrochemotherapy for treatment of cutaneous and subcutaneous tumors of different histology have demonstrated pronounced antitumor effectiveness with ~85% objective responses of the treated tumors. Electrochemotherapy is a new, clinically acknowledged method for the treatment of cutaneous and subcutaneous tumor nodules. The advantage of this therapy is its high effectiveness on tumors of different histology, simple application, minimal side effects, and the possibility of effective repetitive treatment.

18.1 Introduction To increase therapeutic index, several drug delivery systems for tumor targeting are under investigation in cancer treatment. Among several approaches, tissue electroporation, a physical approach, is extensively studied [22]. Electroporation is a method that uses electric pulses to induce an electrically mediated reorganization of cell membrane. When the cell is exposed to an external electric field, for instance when electric pulses are applied to the tissue, the induced transmembrane potential is generated across the cell

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membrane. If the induced transmembrane potential is sufficiently high, structural changes, so-called electropores, leading to increased membrane permeability are induced. Although the exact mechanisms operating on the molecular level and the various structures have not been fully elucidated, a flow of molecules was demonstrated through areas of membranes in regions where the highest absolute value of the induced transmembrane potential was observed after exposure of cells to electric pulses. Under controlled conditions using square wave electric pulses of suitable duration and amplitude, the increase in permeability of the plasma membrane is transient with resealing of the cell membrane within a few minutes after application of electric pulses and preservation of the cell viability [19]. Electroporation can be performed on cells in vitro, or in vivo on different organs and tumors, also across the skin. Electroporation is performed by suitable electric pulse generator that generates electric pulses, which are delivered to cells or tissue by electrodes that can have different geometry (shape). Transient increase in permeability of cell membrane allows exogenous molecules to enter the cells. These molecules can be chemotherapeutic drugs with hampered transport through the plasma membrane, naked DNA, RNA, enzymes, or dyes [22, 24]. Electroporationbased cancer treatment approaches are currently undergoing intensive investigation in the field of drug therapy and gene therapy. The first clinically applicable biomedical application in treatment of cancer was electrochemotherapy, which in the last 15 years has evolved into clinically verified treatment approach for treatment of cutaneous and subcutaneous tumor nodules [4, 20, 31, 34]. Electrochemotherapy is defined as a local treatment which, via cell membrane permeabilizing electric pulses, potentiates the cytotoxicity of nonpermeant or poorly permeant anticancer drugs with high intrinsic cytotoxicity at the site of electric pulse application. Electrochemotherapy is currently successfully used in human and veterinary oncology [9, 31, 32]. Another promising development in electroporation-based therapies is electrogene therapy (gene electrotransfer), that has already been tested in veterinary and human medicine in order to induce either the expression of cytokine to boost the immune response or to obtain a high level of antigen expression to trigger the immune response needed for DNA vaccine [1, 7, 8, 17].

G. Sersa

18.2 Mechanisms of Action of Electrochemotherapy Preclinical studies on electrochemotherapy demonstrated good antitumor effectiveness with two chemotherapeutic drugs, bleomycin and cisplatin, although several other chemotherapeutic drugs were tested. The prerequisite for the drug to be effective in combination with electroporation is that they are hydrophilic or lack transport systems in the membrane, since electroporation can facilitate the drug transport through the plasma membrane only for poor or nonpermeant molecules [22, 32]. Based on demonstration that bleomycin cytotoxicity was increased up to several 1,000-fold, and cisplatin up to 70-fold by electroporation, electrochemotherapy with these two drugs has been successfully tested in several experimental tumors in mice, rats, and hamsters. The drugs were injected either intratumorally or intravenously and the electric pulses were applied to the tumors within a few minutes thereafter (eight electric pulses; amplitude over distance 1,300 V/cm, duration 100 µs; frequency 1 Hz). The drug dosage that was used was so low that it had no antitumor effectiveness without electroporation of tumors and, consequently, no systemic toxicity. Furthermore, the application of electric pulses to the tumors had no antitumor effectiveness and no systemic side effects. Local side effects were contractions of the muscles underlying the treated area, but muscle contractions and associated pain were present only during the application of electric pulses. Therefore, besides very good antitumor effectiveness, minimal toxicity and safety of the procedure were demonstrated [22, 32]. Mechanisms involved in antitumor effectiveness of electrochemotherapy were also elucidated. Briefly, they can be summarized as: • Electroporation is the principal mechanism involved in antitumor effectiveness of electrochemotherapy. In the tumor the cells that are electropermeabilized, drug is accumulated and the cells undergo cell death either by necrosis or apoptosis [2, 6]. • Vascular lock in the area that is exposed to electric pulses is due to the effect of electric pulses on the vessels in the tumors that causes abrogation of tumor blood flow. The immediate decrease in tumor blood flow is up to 80%, and provides for several hours’ prolonged action of the drug by its entrapment in the electroporated tissue [29]. The blood flow restores

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in the tumors within 24 h, whereas in normal tissue the restoration is much faster, within several hours [11, 29]. • Vascular disrupting action of electrochemotherapy provides additional mechanism that contributes to antitumor effectiveness of electrochemotherapy. Electroporation of tumors affects not only tumor cells but also other stromal cells in the tumor, like endothelial cells, enabling drug uptake also into these cells. Therefore, within 24 h they also undergo cell death, which induces abrogation of blood flow in tumor vessels. A consequence of that is a cascade of tumor cell death that surrounds capillaries in the tumor due to prolonged lack of oxygen and nutrients supply [33]. • Immune response that is induced by antigen shedding from tumor cells undergoing cell death is another mechanism involved in antitumor effectiveness of electrochemotherapy. It was demonstrated that for high curability of tumors by electrochemotherapy active immune system is required. Namely, in immunosuppressed mice good antitumor effectiveness of electrochemotherapy can be obtained, but without tumor cures. Whereas in immunocompetent mice, therapy results in high percentage (80%) of tumor cures [27]. Furthermore, adjuvant immunotherapy to electrochemotherapy was shown to increase response rate of the treated tumors [22].

sions. Regardless of the protocol and equipment used, all clinical studies reported almost the same treatment effectiveness, with very little variability in the results. An objective response rate of ~85% (~74% complete response rate) was achieved for electrochemotherapytreated tumor nodules, regardless of tumor histology and drug or route of administration used. The clinical experience gained by these clinical studies can be summarized in some basic principles that have to be followed during the treatment procedure to obtain good antitumor effectiveness of electrochemotherapy. The prerequisite is to obtain high enough drug concentration and its homogeneous distribution in the tumor, as well as adequate electric field distribution in the tissue. Therefore, special attention has to be given to the drug and its route of administration, electrical parameters for specific type of electrodes, type of electrodes for specific clinical condition (depending on size and shape of the tumor) and application of electric pulses by the electrodes to cover the whole tumor area (Fig. 18.1). Recently, standard operating procedures (SOP) using an electric pulse generator Cliniporator™ (IGEA, s.r.l. Carpi, Modena, Italy), have been published [23].

Based on preclinical data that demonstrated antitumor effectiveness of electrochemotherapy and elucidation of underlying mechanisms, it was very soon tested in clinical trials.

18.3 How to Perform the Treatment? Several clinical studies using electrochemotherapy in treatment of cutaneous and subcutaneous tumors of different histologies have been performed so far (reviewed in [31]). Different electric pulse generators, different types of electrodes, and also different routes of drug administration were used in different protocols. It has to be stressed that the treated tumors were of different histologies, that single or multiple nodules were treated, that the size of the nodules varied considerably (from several millimeters to several centimeters in diameter) and that tumor nodules were treated in one or in several consecutive electrochemotherapy ses-

Fig. 18.1 Principle of electrochemotherapy. Nonpermeant or poorly permeant anticancer drug with intracellular target (bleomycin or cisplatin) is injected either systemically or intratumorally. Application of adequate electric pulses by electrodes causes an increase in membrane permeability, which allows for the entrance of anticancer drug into the cells to exert its cytotoxic action

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18.3.1 Drug Selection

18.3.4 Selection of the Electrodes

Clinical data have demonstrated that the choice of the drug (bleomycin or cisplatin) for electrochemotherapy is not based on tumor histology. Response of the tumors is equally good to either of the drugs, as long as the treatment is performed adequately. Tumor nodules can be treated by electrochemotherapy with intravenous or intratumoral injection of bleomycin and by electrochemotherapy with cisplatin given intratumorally. Intratumoral drug injection is more suitable for treatment of single or few tumor nodules, whereas intravenous bleomycin injection is recommended for treatment of multiple tumor nodules [16, 18, 23].

Although there are several different types of electrodes available on the market [25], in principle two different types of electrodes exist: plate electrodes and needle electrodes. Plate electrodes are used for the treatment of skin or superficial lesions and are placed on the skin (Fig. 18.1). The depth of penetration of the effective electric field is rather small, and it depends on the distance between the electrodes - the greater the distance, the deeper the penetration of the electric field into the tissue, given that a larger voltage needs to be applied between both electrodes. Needle electrodes are of two kinds: needles are positioned either in two parallel rows or in a circular (hexagonal) array. They are more appropriate for treatment of thicker and deeper-seeded tumors. In contrast to plate electrodes, needle electrodes must be inserted throughout the tumor tissue up to the deep tumor border [19]. Regardless of the type of electrode, whether plate or needle, the electric field is the highest around the electrodes and between the electrodes, but drops off very rapidly outside the electrode array. Thus, if the tumor is larger than the distance between the electrodes, the entire tumor can be efficiently treated by moving and placing electrodes adjacently, for each consecutive electric pulse application [19].

18.3.2 Timing and Drug Dosage The key issue in electrochemotherapy is to assure that the drug is present in the tumor when electric pulses are applied. When bleomycin is delivered intravenously, electric pulses need to be delivered to the tumor during the pharmacokinetic peak, which was reported to be between 8 and 28 min in humans [10]; for intratumoral application the pulses need to be delivered from 1 to 10 min after bleomycin or cisplatin injection [6, 14]. The recommended dose for bleomycin intravenous bolus injection is 15,000 IU/m2, while for intratumoral injection the recommended dose for bleomycin is approximately 500 IU/cm3 and for cisplatin approximately 1 mg/cm3, depending on the tumor volume [23].

18.3.3 Electric Pulse Parameters Good antitumor effectiveness of electrochemotherapy can be achieved when most of the cells in tumor are permeabilized. Therefore, the cells must be exposed to sufficiently high electric field to permeabilize the cells in the tissue. This depends on the electric field distribution in the tissue which is controlled by the geometry of the electrodes and the cells in tissue [19]. In most reported cases eight rectangular electric pulses of pulse amplitude 1,300 V/cm, 100 µs duration, at 1 Hz, or more recently, 5 kHz repetition frequency, were delivered by plate electrodes; for needle electrodes electric field can be lower [18, 31].

18.4 Clinical Results The first clinical study published in 1991 was on recurrent head and neck squamous cell carcinoma treated by electrochemotherapy with bleomycin performed at the Institut Gustave Roussy [20]. Later on, several studies reported on good antitumor effectiveness of electrochemotherapy on other tumor types; malignant melanoma, basal cell carcinoma, and skin metastases of mammary, ovarian, Kaposi’s sarcoma, hypernephroma, and chondrosarcoma [3, 5, 14, 21, 30]. Lately, results of electrochemotherapy in a prospective, nonrandomized, multi-institutional study were published demonstrating good treatment response of tumors regardless of the tumor type, drug used, route of administration, and type of electrodes used [18]. An objective response rate of 85%, of these 74% were complete responses, was achieved by electrochemotherapy. The results of this study are comparable to other studies [34]. Altogether, approximately 300 patients were included

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and 1,200 tumor nodules were treated in the clinical studies published so far [34]. The predominant tumor types treated by electrochemotherapy in the reported clinical studies are skin metastases on melanoma and basal cell carcinoma. Lately, electrochemotherapy has become the clinically acknowledged method for the treatment of cutaneous and subcutaneous tumor nodules in several cancer centers in Italy, Spain, France, and Slovenia. In these centers electrochemotherapy is performed on a regular basis and in the last 2 years additional 350 patients with approximately 1,300 tumor nodules were treated.

to 99% [4, 15, 18]. Electrochemotherapy is predominantly used in treatment of unresectable and in-transit melanoma metastases, located either on the limbs or on the trunk. Several other treatment approaches are available for treatment of progressive melanoma, radiotherapy, carbon dioxide laser ablation, intralesional therapies with Bacillus Calmette-Guerin (BCG), IL-2, tumor necrosis factor alpha (TNF-a), systemic chemotherapy, or regional therapies with isolated limb perfusion or isolated limb infusion [26]. All of these approaches, including electrochemotherapy, are of clinical value because they provide good local tumor control. Electrochemotherapy with bleomycin or cisplatin offers simple and effective treatment for solitary or multiple tumor nodules (Fig. 18.2). The response of the treated nodules is long-lasting, reported up to 8 years complete remission [36]. Single or multiple tumor nodules can be treated. In our study, 224 small tumor nodules were successfully treated on the limb in

18.4.1 Malignant Melanoma Electrochemotherapy is an effective treatment of melanoma nodules with objective response rate from 78%

Fig. 18.2 Response of melanoma tumor nodule to electrochemotherapy with cisplatin given intratumorally. After the treatment, the scab formed is exfoliated within few weeks.

Complete response of the treated nodule is visible. In the treated area pigmentation remained

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Only few studies have been published so far on treatment of non-melanoma skin tumors using electrochemotherapy. In contrast to melanoma tumor nodules that were predominantly metastatic nodules, in the studies on treatment of basal cell carcinoma the tumors were predominantly primary tumors. The treatment was performed by plate or needle electrodes using bleomycin given either intravenously or intratumorally and using cisplatin given intratumorally (Fig. 18.3) [13, 28]. The representative study was performed in Tampa, Florida in 1998; a total of 65 basal cell carcinoma

primary tumors were treated in 20 patients. Effectiveness of electrochemotherapy versus treatment of nodules with intratumoral injection of bleomycin alone, or electric pulses alone, or no treatment was compared [15]. The results clearly demonstrated that electrochemotherapy was effective since 94% of the treated nodules disappeared within 1 month and did not recur during the 12-weeks observation period and were designated complete response. Treatment with bleomycin alone and application of electric pulses to the tumors did not affect tumor growth and the tumors progressed. Furthermore, it was demonstrated that re-treatment by electrochemotherapy of the tumors that had partial response after the first treatment, resulted in a complete response. Based on this study, it was suggested that electrochemotherapy is an ideal application of electrochemotherapy for treatment of basal cell carcinoma. Its advantage over surgery is reduction of scarring, tissue sparing, and maintenance of tissue functionality. The other advantage is that this approach can be used on areas that are damaged by the sun, such as ears, lips, and nose [16]. Since the reports in the 1990s that were so encouraging, no current studies on basal cell carcinoma have been published. The reason for that is not known, we can speculate that this treatment approach by electrochemotherapy is not known enough, and therefore it needs promotion also in the area of dermatology.

Fig. 18.3 Response of basal cell carcinoma to electrochemotherapy treatment (ECT) with cisplatin (CDDP) given intratumorally in comparison to treatment with cisplatin alone. Visible

is better response to treatment with electrochemotherapy in comparison to cisplatin only, from 3 to 7 weeks after the treatment

four treatment sessions in a patient with unresectable cutaneous metastases [37]. Electrochemotherapy can also be successfully used as cytoreductive treatment before surgical resection with the intent of organ-sparing treatment. It has been used in such a setting in management of residual primary anorectal melanoma that was partially excised as thrombosed hemorrhoid before sphincter-saving treatment [35]. Of special importance is that electrochemotherapy can be used in treatment of hemorrhaging and ulcerated cutaneous melanoma nodules [12]. The treatment is also successful for treatment of nodules in previously irradiated or surgically intervened areas [18].

18.4.2 Basal Cell Carcinoma

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18.5 Conclusion (Take Home Pearls) Electrochemotherapy is currently used for treatment of cutaneous and subcutaneous tumors, either primary, as is the case of basal cell carcinoma, or progressive disease such as treatment of metastatic skin nodules of melanoma. Since the treatment has already gained clinical recognition and is in clinical practice, we can expect its broader use in the future. Electroporation-based treatment is advancing also in the field of gene therapy, where the first clinical trials were reported. This fastexpanding field may also find applications in dermatology in the treatment of non-melanoma skin cancer. Acknowledgements The author gratefully acknowledges financial support from the state budget of the Slovenian Research Agency and the European Commission’s ESOPE project (QLK2002–02003), funded under the 5th Framework Program

References 1. Andre F, Mir LM. DNA electrotransfer: its principles and an updated review of its therapeutic applications. Gene Ther. 2004;11(Suppl 1):S33–42 2. Belehradek J Jr, Orlowski S, Ramirez LH, Pron G, Poddevin B, Mir LM. Electropermeabilization of cells and tissues assessed by the quantitative and qualitative electroloading of bleomycin. Biochim Biophys Acta. 1994;1190:155–63 3. Bloom DC, Goldfarb PM. The role of intratumour therapy with electroporation and bleomycin in the management of advanced squamous cell carcinoma of the head and neck. Eur J Surg Oncol. 2005;31:1029–35 4. Byrne CM, Thompson JF, Johnston H, Hersey P, Quinn MJ, Hughes M, McCarthy WH. Treatment of metastatic melanoma using electroporation therapy with bleomycin (electrochemotherapy). Melanoma Res. 2005;15:45–51 5. Byrne CM, Thompson JF. Role of electrochemotherapy in the treatment of metastatic melanoma and other metastatic and primary skin tumors. Expert Rev Anticancer Ther. 2006;6:671–8 6. Cemazar M, Milacic R, Miklavcic D, Dolzan V, Sersa G. Intratumoral cisplatin administration in electrochemotherapy: antitumor effectiveness, sequence dependence and platinum content. Anticancer Drugs. 1998;9:525–30 7. Cemazar M, Golzio M, Sersa G, Rols MP, Teissie J. Electrically-assisted nucleic acids delivery to tissues in vivo: where do we stand? Curr Pharm Des. 2006;12:3817–25 8. Cemazar M, Sersa G. Electrotransfer of therapeutic molecules into tissues. Curr Opin Mol Ther. 2007;9:554–62 9. Cemazar M, Tamzali Y, Sersa G, Tozon N, Mir LM, Miklavcic D, Lowe R, Teissie T. Electrochemotherapy in veterinary oncology. J Vet Int Med. 2008;22:826–31

149 10. Domenge C, Orlowski S, Luboinski B, De Baere T, Belehradek J Jr, Mir LM. Antitumor electrochemotherapy: new advances in the clinical protocol. Cancer. 1996;77:956–63 11. Gehl J, Skovsgaard T, Mir LM. Vascular reactions to in vivo electroporation: characterization and consequences for drug and gene delivery. Biochim Biophys Acta. 2002; 1569:51–8 12. Gehl J, Geertsen PF. Palliation of haemorrhaging and ulcerated cutaneous tumours using electrochemotherapy. EJC Suppl. 2006;4:35–7 13. Heller R, Jaroszeski MJ, Glass LF, Messina JL, Rapaport DP, DeConti R, Fenske NA, Gilbert RA, Mir LM, Reintgen DS. Phase I/II trial for treatment of cutaneous and subcutaneous tumors using electrochemotherapy. Cancer. 1996; 77:964–71 14. Heller R, Jaroszeski M, Perrott R, Messina J, Gilbert R. Effective treatment of B16 melanoma by direct delivery of bleomycin using electrochemotherapy. Melanoma Res. 1997;7:10–8 15. Heller R, Jaroszeski MJ, Reintgen DS, Puleo CA, DeConti RC, Gilbert RA, Glaas LF. Treatment of cutaneous and subcutaneous tumors with electrochemotherapy using intralesional bleomycin. Cancer. 1998;83:148–57 16. Heller R, Gilbert R, Jaroszeski MJ. Clinical applications of electrochemotherapy. Adv Drug Deliver Rev. 1999;35:119–29 17. Heller LC, Heller R. In vivo electroporation for gene therapy. Hum Gene Ther. 2006;17:890–7 18. Marty M, Sersa G, Garbay JR, Gehl J, Collins CG, Snoj M, Billard V, Geertsen PF, Larkin JO, Miklavcic D, Pavlovic I, Paulin-Kosir SM, Cemazar M, Morsli N, Soden DM, Rudolf Z, Robert C, O’Sullivan GC, Mir LM. Electrochemotherapy – an easy, highly effective and safe treatment of cutaneous and subcutaneous metastases: results of ESOPE (European Standard Operating Procedures of Electrochemotherapy) study. EJC Suppl. 2006;4:3–13 19. Miklavcic D, Corovic S, Pucihar G, Pavselj N. Importance of tumour coverage by sufficiently high local electric field for effective electrochemotherapy. EJC Suppl. 2006;4: 45–51 20. Mir LM, Belehradek M, Domenge C, Orlowski S, Poddevin B, Belehradek J, Schwaab G, Luboinski B, Paoletti C. Electrochemotherapy, a new antitumor treatment: first clinical trial. C R Acad Sci III. 1991;313:613–8 21. Mir LM, Glass LF, Sersa G, Teissie J, Domenge C, Miklavcic D, Jaroszeski MJ, Orlowski S, Reintgen DS, Rudolf Z, Belehradek M, Gilbert R, Rols MP, Belehradek J Jr, Bachaud JM, DeConti R, Stabuc B, Cemazar M, Coninx P, Heller R. Effective treatment of cutaneous and subcutaneous malignant tumours by electrochemotherapy. Br J Cancer. 1998;77:2336–42 22. Mir LM. Bases and rationale of the electrochemotherapy. EJC Suppl. 2006;4:38–44 23. Mir LM, Gehl J, Sersa G, Collins CG, Garbay JR, Billard V, Geertsen P, Rudolf Z, O’Sullivan GC, Marty. Standard operating procedures of the electrochemotherapy: instructions for the use of bleomycin or cisplatin administered either systemically or locally and electric pulses delivered by the CliniporatorTM by means of invasive or non-invasive electrodes. EJC Suppl. 2006;4:14–25 24. Neumann E, Schaefer-Ridder M, Wang Y, Hofschneider PH. Gene transfer into mouse lyoma cells by electroporation in high electric fields. EMBO J. 1982;1:841–5

150 25. Puc M, Corovic S, Flisar K, Petkovsek M, Nastran J, Miklavcic D. Techniques of signal generation required for electropermeabilization: survey of electropermeabilization devices. Bioelectrochem. 2004;64:113–24 26. Sarnaik AA, Zager JS, Sondak VK. Multidisciplinary management of special melanoma situations: oligometastatic disease and bulky nodal sites. Curr Oncol Rep. 2007; 9:417–27 27. Sersa G, Miklavcic D, Cemazar M, Belehradek J Jr, Jarm T, Mir LM. Electrochemotherapy with CDDP on LPB sarcoma: comparison of the anti-tumor effectiveness in immunocompetent and immunodeficient mice. Bioelectroch Bioener. 1997;43:279–83 28. Sersa G, Stabuc B, Cemazar M, Jancar B, Miklavcic D, Rudolf Z. Electrochemotherapy with cisplatin: Potentiation of local cisplatin antitumor effectiveness by application of electric pulses in cancer patients. Eur J Cancer. 1998; 34:1213–8 29. Sersa G, Cemazar M, Parkins CS, Chaplin DJ. Tumour blood flow changes induced by application of electric pulses. Eur J Cancer. 1999;35:672–7 30. Sersa G, Stabuc B, Cemazar M, Miklavcic D, Rudolf Z. Electrochemotherapy with cisplatin: clinical experience in malignant melanoma patients. Clin Cancer Res. 2000;6:863–7

G. Sersa 31. Sersa G. The state-of-the-art of electrochemotherapy before the ESOPE study: advantages and clinical uses. EJC Suppl. 2006;4:52–9 32. Sersa G, Cemazar M, Miklavcic D, Rudolf Z. Electrochemotherapy of tumours. Radiol Oncol. 2006;40:163–74 33. Sersa G, Jarm T, Kotnik T, Coer A, Podkrajsek M, Sentjurc M, Miklavcic D, Kadivec M, Kranjc S, Secerov A, Cemazar M. Vascular disrupting action of electroporation and electrochemotherapy with bleomycin in murine sarcoma. Brit J Cancer. 2008;98:388–98 34. Sersa G, Miklavcic D, Cemazar M, Rudolf Z, Pucihar G, Snoj M. Electrochemotherapy in treatment of tumours. EJSO. 2008;34:232–40 35. Snoj M, Rudolf Z, Cemazar M, Jancar B, Sersa G. Successful sphincter-saving treatment of anorectal malignant melanoma with electrochemotherapy, local excision and adjuvant brachytherapy. AntiCancer Drugs. 2005; 16:345–8 36. Snoj M, Rudolf Z, Paulin-Kosir S, Cemazar M, Snoj R, Sersa G. Long lasting complete response in melanoma treated by electrochemotherapy. EJC Suppl. 2006;4: 26–8 37. Snoj M, Cemazar M, Slekovec Kolar B, Sersa G. Effective treatment of multiple unresectable skin melanoma metastases by electrochemotherapy: case report. Croat Med J. 2007;48:391–5

Radiotherapy: At a Glance

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Renato Panizzon

Key Points

› › › ›

Radiotherapy is, besides surgery, still the mainstay treatment in the management of different types of skin cancer. Grenz-ray treatment should be preferred for skin lesions up to 1 mm thickness. To give the best information to the patient, the dermatologist should know the advantages and disadvantages of radiotherapy. The ideal patient for radiotherapy is over 60 years old with a medium-sized tumor in the face.

Curative radiotherapy is achieved in BCC, SCC, disseminated actinic keratoses, Bowen’s disease, Merkel cell tumor, lentigo maligna, and lentigo maligna melanoma. Palliative radiotherapy is known in Kaposi’s sarcoma, lymphomas, melanomas (other types) and cutaneous metastases. Soon after the discovery of X-rays by Röntgen in 1895, the therapeutic potential of radiation was recognized. The first time a patient was treated for a squamous cell carcinoma of the nose was in 1900. Thereafter, radiation therapy was used empirically for a host of conditions, both benign and malignant. In many situations, in which no effective therapeutic alternatives existed, radiation therapy may have been one of the few treatment options available.

R. Panizzon Department of Dermatology, CHUV Lausanne, Switzerland e-mail: [email protected]

This was true until the 1950s. Thereafter, radiation treatment declined for two major reasons: One reason was the awareness of the deleterious effects of radiation, including the potential for the induction of malignancy. In addition, advances in surgical techniques and the development of effective medical therapies such as corticosteroids and antibiotics provided effective alternatives to the use of ionizing radiation. The other reason was the progression of dermato-surgical procedures and therefore a decline in the use of radiotherapy accompanied by the increase of insurance contributions. Finally, less and less training possibilities in university departments resulted in a lack of knowledge in the subject. Nonetheless, dermatologists should retain primary expertise in the indication and treatment with X-rays for skin diseases [1–4]. Dermatologists, often in collaboration with radiation oncologists, can assist the patient and referring physician in selecting the treatment regimen with the highest therapeutic ratio for a particular individual. In many cases, the morbidity of radiation is low when compared to the morbidity or even mortality associated with alternative therapies, or with the complications associated with progressive or recurrent disease.

19.1 Radiation Therapy of Malignant Skin Diseases/Tumors Carcinomas of the skin are the most accessible cancers, the diagnosis is readily made and the limits of the lesion are usually easy to define. No single treatment method is best for all cancers of the skin. If the sole criterion of success is eradication of the lesion, surgery and radiotherapy yield similar results. Most cutaneous cancers are sufficiently sensitive to radiation to be

G. B. E. Jemec et al. (eds.), Non-Surgical Treatment of Keratinocyte Skin Cancer, DOI: 10.1007/978-3-540-79341-0_19, © Springer-Verlag Berlin Heidelberg 2010

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eradicated by doses that are well-tolerated by the surrounding normal tissue. If appropriate principles are followed and precautions are taken, X-irradiation is a safe and effective method of therapy [1, 9]. Our discussion is deliberately limited to radiotherapy of cutaneous cancers of moderate size that can be effectively treated with Grenz rays, soft or superficial X-rays, or contact therapy units. Larger and more complicated skin cancers should be referred to Mohs surgeons and/ or radiation oncologists for treatment with higher kilovoltage or megavoltage techniques, or for implants with radioactive isotopes. When treating skin cancer, the advantages of softor superficial X-ray therapy are • Performable on an outpatient basis • Painless • Usable for physically or psychologically handicapped patients (also patients over 90 years old [7]) • Usable in patients in whom there exists a contraindication for a surgical intervention • Healthy tissue or organs can be protected • Usually a wide margin of normal-appearing skin (wider than in surgical excisions, i.e., over 5 mm) • Atraumatic intervention However, there also are disadvantages to radiation therapy about which the patient should be informed: • The treatment has to be given in several sessions • If the patient has already received full tumor doses in a radiation field, this particular field cannot be irradiated a second time • Radiation treatment is followed by alopecia (except if treated by Grenz rays) • Chronic radiation dermatitis tends to be accentuated with time [8]

R. Panizzon

19.1.2 What Are the Best Areas to Be Treated by Radiation Therapy? The real superiority of irradiation over excision lies in its greater preservation of uninvolved tissue. In certain anatomic regions this may pose a problem for the surgeon but not for the radiotherapist who can easily adjust the size of the field to the required area of treatment. Therefore, radiation is often the treatment of choice in areas where tissue cannot be readily sacrificed for cosmetic and/or functional reasons. There is general agreement that ionizing radiation is often preferable to other methods of treatment for cutaneous tumors of the following areas [1]: • • • • • • • •

Eyelids Medial or lateral canthi of the eyes Nose Ears Lips Nasolabial folds Preauricular areas Larger tumors of the cheek

On the other hand, the skin of the trunk and extremities has a greater tendency to develop radiation sequelae, particularly telangiectasias and changes in pigmentation [14]. Before radiation therapy of a lesion is begun, the diagnosis must be confirmed by biopsy.

19.1.3 Why Biopsy? The histologic examination determines

19.1.1 What Is the Ideal Indication for Radiotherapy?

• • • • •

The type of the tumor The radiosensitivity of the tumor The exact extension of the tumor The depth of the tumor The exclusion of an error

Radiotherapy is particularly valuable for medium-sized tumors of 1–4 cm in diameter on the face of elderly people, because smaller tumors are mostly treated by surgery and larger lesions are mostly treated either by Mohs surgery or by a combination of surgery and radiation (megavoltage) treatment.

Concerning the radiosensitivity of skin tumors, four categories are distinguishable: (1) Highly indicated and unique advantage: Kaposi’s sarcoma, mycosis fungoides, and other lymphomas of the skin. (2) Good indication: basal cell and squamous cell carcinomas, keratoacanthoma, Bowen’s disease, Queyrat’s erythroplasia, Merkel cell carcinoma, lentigo maligna, and lentigo maligna

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Radiotherapy: At a Glance

melanoma. (3) Sometimes indicated: angiosarcoma, melanoma (other types) (4) Rarely indicated: fibrosarcoma, carcinomas of the scrotum, soles, and palms. We also distinguish between curative radiotherapy in tumors such as basal cell carcinomas; squamous cell carcinomas; keratoacanthomas; precancerous lesions melanomas of the lentigo maligna type, and Merkel cell carcinoma, and palliative radiation therapy in tumors such Kaposi’s sarcoma, most lymphomas, melanomas (other types) and metastases. The contraindications for radiotherapy with soft X-rays include: Tumors penetrating into cartilage or bone Intraoral tumors Tumors penetrating into the nostrils Tumors in scars of osteomyelitis, burns, chronic leg ulcers, or in chronic radiodermatitis • No retreatment of previously irradiated skin carcinomas • Genodermatoses that are prone to neoplasms such as basal cell nevus syndrome or xeroderma pigmentosum • • • •

19.1.4 Which Radiation Quality? Since the work done in England, Germany, and the United States, and with the introduction of the beryllium-windowed X-ray units, as a rule of thumb, radiation qualities with a half-value depth (HVD = D1/2) corresponding to the depth of the tumor have been proposed. Most of the radiation will then be absorbed in the pathologic tissue and the possibility of undesirable radiation effects to underlying uninvolved tissue will be markedly reduced. The depth of the tumor can either be reasonably estimated by inspection and palpation or by an exact histopathologic description of the tumor depth, preferably by an experienced dermatopathologist. Several studies show that 50% of all basal cell and squamous cell cancers infiltrate to a depth of only 2 mm or less, and 75% of such tumors infiltrate to a depth of 5 mm or less [1]. With Grenz and superficial X-ray machines, the kilovoltage is in a fixed combination with filters in order to avoid filter mistakes and thus application of faulty dosages. These X-ray machines have a kilovoltage between 10 and 50 kV, sometimes up to 100 or even 150 kV. With

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filter combinations, a HVD (= D1/2) from 1mm to 20 mm can be reached. For dermatologic purposes, it is rarely necessary to irradiate tumors thicker than 20 mm.

19.1.5 Why Fractionated Doses? Fractionation of radiation dosage is based on the assumptions that tissues recover at different rates from the effects of radiation and that tumor tissue recovers more slowly than normal tissue. When a given dose of radiation is divided into several increments and delivered over a period of several days, the biological effect is usually less pronounced than that of the same radiation administered in a single dose. This lesser damage with fractionation appears to be related to cell recovery between increments and to the capabilities of recovering cells to adapt to radiation-induced alterations of the surrounding tissues. Small tumors and radiation fields support higher single doses than do large tumors with large irradiation fields that have to be irradiated with smaller single doses. In addition, in large irradiation fields, we have to consider an additional backscatter factor. Much work has been done in an attempt to define optimum time-dose-volume relationships for carcinomas of the skin. There is no consensus as to the total dose needed to eradicate a cutaneous cancer and when to terminate radiotherapy. Different authors have recommended different dosages [1]. The tendency is to use standardized schedules. It is still worthwhile to observe the patient’s reaction during radiation therapy and to look for an exudative or erosive reaction in the irradiated margin. When larger individual doses are administered, the recommended total dose is usually smaller than in cases where smaller individual doses were used.

19.2 Disseminated Actinic Keratoses Usually, there is agreement that small actinic keratoses are best treated by surgical excision or other equivalent methods. The problem arises in extensive and disseminated actinic keratoses as, for example, on the scalp. Here, again, there are possibilities with topical treatments such as 5-fluorouracil, imiquimod, or Diclofenac cream, but usually recurrence rates are higher or appear

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sooner than after treatment with radiotherapy. Because these lesions are intraepidermal and often in an atrophic epidermis, the ideal treatment is with Grenz rays [5]. The treatment consists of six sessions of 6 Gy twice weekly applied on one or several divided fields [15]. At the end of the treatment, an erythema or an exudative reaction will occur. If there is marked pruritus, topical glucocorticoid creams may be of help to the patient. One month after the end of treatment, the erythema nearly disappears. The patient has to be told to continue sun protection with a hat and application of a sunscreen. Rarely it is necessary to perform a second treatment years later.

19.3 Bowen’s Disease/Queyrat’s Erythroplasia This carcinoma in situ is treated in a similar fashion to actinic keratosis, but histopathologically, these lesions are thicker. Even in elderly patients, it is possible to apply Grenz rays with a D1/2 of 1 mm [5]. If the lesions are more infiltrated, soft X-rays with a quality of 20 kV or more are necessary. The dose schedule can be adapted. Again fractions of single doses of 6 Gy up to total dose around 40 Gy may be used. Single doses with soft X-rays would be 4 Gy. Exudative reactions have to be expected a little earlier in the genitoanal area. Treatment results are excellent [15].

Fig. 19.1 Left: Extensive lentigo maligna on the left cheek of a 76-year-old woman before and right 2 years after Grenz-ray treatment (ten times 10 Gy (100 Gy), twice per week)

R. Panizzon

19.4 Lentigo Maligna This is another precancerous lesion that is an excellent indication for radiation treatment. This treatment modality is not well known because it is thought that it is not curative. Recent reports show that treatment results are at least as good as surgical procedures [16–18]. As mentioned earlier, the inclusion of a wide enough margin is not a problem for the radiation therapist; consequently, large lentigo malignas are an excellent indication for radiotherapy. The classical treatment schedule is named after Miescher who proposed 5–6 doses of 20 Gy Grenz rays for medium-sized lesions (around 2.5 cm in diameter). For larger lesions we prefer to apply 10–12 doses of 10 Gy Grenz rays [5, 11, 12]. The epidermis in the elderly is atrophic, and with a HVD of 1 mm we reach even atypical melanocytes in the hair follicles! One has to be aware that there may be nonpigmented, areas in or around lentigo maligna [10]. Figure 19.1 shows a Grenz-ray treatment result.

19.5 Basal Cell Carcinoma, Squamous Cell Carcinoma, Keratoacanthoma These tumors represent the classical indications for radiotherapy with soft X-rays or superficial X-rays, because most of these tumors are well-circumscribed and rarely larger than 2.5 cm. In addition, 75% of these

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Radiotherapy: At a Glance

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a

b

Fig. 19.2 (a) Basal cell carcinoma on the left outer canthus of a 67-year-old woman before and (b) 6 months after soft X-ray treatment (30 kV) (12 times 4 Gy (48 Gy), twice per week)

tumors are less than 5 mm thick. Some treatment centers use the same treatment schedules for basal cell carcinomas (BCCs) and squamous cell carcinomas (SCCs), although one could imagine that SCC should be treated with a higher total dose, because it represents a more aggressive tumor [1]. Elderly patients prefer not to come every day for the treatment sessions. Therefore, medium-sized lesions can be treated with, for example, a 4-Gy single dose in three fractions per week. There is even the possibility of applying a higher single dose, for example, 6–8 Gy per fraction once or twice a week, to small lesions that cannot be excised. We agree that large lesions, (larger than 4 cm) are best treated with daily fractions of 2 or 3 Gy. Figure 19.2 shows the results of treating a BCC as described here. We want to stress the importance of knowing the histopathology of BCC and SCC for the outcome of the treatment. A large study has shown that if the histopathology shows a sclerosing (sclerodermiform or scirrhous) type rather than a nodular type of BCC or a poorly differentiated SCC, the recurrence rate rises immediately [15]. Consequently, the sclerosing histologic type is not well-suited for treatment with soft X-rays. There are two possibilities: (1) if the patient is operable, Mohs surgery is the preferred method, or (2) if surgery is contraindicated, megavoltage therapy should be chosen. For keratoacanthomas the same dose schedule is used as for SCCs [13]. Carcinomas of the skin appendages and carcinomas penetrating into cartilage or bone, localized in the mucous membranes, or arising in chronic scars, are not an indication for soft X-ray therapy.

Radiation treatment is possible for BCCs, SCCs, or keratoacanthomas that were not completely excised or were incompletely treated by electrodesiccation or cryotherapy. The techniques are the same as for primary tumors. The functional and the cosmetic results after irradiation of such treated tumors are usually satisfactory [1].

19.6 Melanoma of the Lentigo Maligna Type Since the time of Miescher, it has been well known that not only lentigo malignas (LMs), but also lentigo maligna melanomas (LMMs) respond well to radiation treatment [16–18]. In contrast to lentigo malignas, LMMs penetrate into the dermal tissues. As a result, Grenz-ray treatment is not recommended; instead, soft or superficial X-rays, that is, radiation qualities of at least 20 kV or more are recommended. We want to stress that LM and LMM are not to be considered radioresistant; instead, they may be tumors with a reduced radiosensitivity for the following reasons [14]: • • • •

High percentage of nonproliferating cells High percentage of hypoxic cells High probability of potentially lethal repair Subpopulations of cells with different radiosensitivity in the “shoulder” region of the survival curve • Synthesis of the prostaglandins (radioprotectors) in the tumor cells • Melanin is a scavenger of “radicals”

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Therefore, higher doses per fractions are recommended, mostly situated around 6 Gy per fraction. Our results from treatment of 64 patients show a similar outcome for radiation treatment as for surgical treatment, with a cure rate of approximately 90% [38]. This rate is seen for both LM and LMM, especially for large lesions on the face of elderly patients, which lets these patients avoid major surgical procedures and scarring. From the cosmetic and functional point of view, the outcome is excellent.

19.7 Paget’s Disease Paget’s disease of the nipple shows mostly an underlying carcinoma. In extramammary Paget’s disease, seldom is an underlying carcinoma found. In these situations, we are dealing with a superficial lesion and thus Grenz rays can be used. The dose schedule is similar to that used for Bowen’s disease.

R. Panizzon

B-cell lymphomas or localized CD30+ lymphomas where radiotherapy is curative, the radiation treatment for lymphomas is palliative. Total doses in the range of 20–30 Gy are commonly used and offer excellent palliation. Doses in this range may result in a relapse rate of up to 30%. Single doses of 2 Gy, either daily or three times per week, seem to offer the best local control. Because of the possible need for the subsequent treatment in adjacent areas, it is important to document the treated areas with photographs, accurate drawings, and, if feasible, tattooing of the corners of the fields with India ink. In most patients, the lesions will not clear during or at the completion of irradiation and it may take up to 6–8 weeks for complete response (Fig. 19.3). For individual skin lesions, energies may range from orthovoltage to electron beam. The depth of infiltration defines the energy of the beam required. Larger, bulkier lesions, such as deep ulcers or lymph nodes, may be treated by either Cobalt or 4–6 MeV photons.

19.8 Merkel Cell Tumor

19.10 Kaposi’s Sarcoma

Merkel cell tumor is a rare primary skin tumor and occurs most frequently in the seventh and eighth decades. Tumors occur with greatest frequency in the head and neck region (50%). They are characterized by a high rate of local recurrence after surgical excision (25–60%) and by frequent involvement of regional lymph nodes (45–79%); distant metastatic failure is common (22–48%) [15]. Several series have shown promising results when radiation therapy is added to the initial surgical management. At the M.D. Anderson Cancer Center 83% of patients showed disease control when they were treated with surgery and radiation therapy for palpable neck disease. Total doses of 50 Gy at conventional fractionation appear adequate for the treatment of subclinical disease, but when microscopic or gross residual disease exists, boosting the total doses to 60–70 Gy is indicated [16].

NON-AIDS-ASSOCIATED KAPOSI’s sarcoma Local irradiation of Kaposi’s sarcoma (KS) includes the lesion plus a normal tissue border of approximately 1–2 cm. Thin, cutaneous lesions can be effectively treated either by superficial X-ray therapy (e.g., 20–150 kV) or relatively low-energy electron beams (e.g., 4–6 MeV). Thick nodules are best treated by electron beams that encompass the entire lesion homogeneously but spare underlying normal tissues. Lesions on the eyelids are treated most easily by superficial X-rays with protective shields over the optic lens [15, 25]. Based on the available evidence, both local therapy and elective regional therapy are effective techniques for the treatment of classical KS. The literature supports the use of a wide range of doses and fractionation patterns. As long as a sufficient dose is delivered (e.g., 20–30 Gy in ten fractions or, for small lesions, 8 Gy in one fraction), a salutary outcome is likely [20].

19.9 Cutaneous Lymphomas In general, the lesions of cutaneous lymphomas, that is, T-cell or B-cell lymphomas, are very radiosensitive [6, 17, 18, 19]. With the exception of certain circumscribed

AIDS-ASSOCIATED KAPOSI’s sarcoma Usually, the same dose schedules are used and no difference is evident, although it may take 3–4 months for the tumors to resolve. Radiation-induced edema of the feet or face as well as symptomatic mucositis, are more severe in patients with AIDS than in other patients [20].

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Radiotherapy: At a Glance

Fig. 19.3 (a) Mycosis fungoides in a 75-year-old man before and (b) 3 months after soft X-ray treatment (40 kV) (six times 2 Gy (12 Gy), three times per week)

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a

Radiation therapy may be reserved for specific indications such as pain, ulceration, bleeding, functional impairment (e.g., on the legs), or improvement of the appearance of cosmetically disfiguring lesions (e.g., the eyelids). In the case of palliative radiation therapy for AIDS-associated Kaposi’s sarcoma: • Sufficient dose should be delivered to accomplish the desired goal and maintain that state for as long as possible. • The treatment should be delivered as rapidly as possible. • Distressing side effects should not be induced by the treatment.

19.11 Other Skin Tumors Other possible indications for radiation therapy include [5]: • Angiosarcoma • Leukemic infiltrates of the skin (e.g., infiltrations of chronic myelogenous leukemia, or chronic lymphatic leukemia) • Metastatic nodules of melanoma, breast carcinoma, or other primary tumors.

b

References 1. Goldschmidt H. Treatment planning. In: Goldschmidt H, Panizzon RG (eds) Modern dermatologic radiation therapy. New York: Springer, 1991, pp. 49–63 2. Goldschmidt H. Chronic radiation effects and radiation protection. In: Goldschmidt H, Panizzon RG (eds) Modern dermatologic radiation therapy. New York: Springer, 1991, pp. 37–48 3. Goldschmidt H. FDA recommendations on radiotherapy of benign diseases. J Dermatol Surg Oncol. 1978;4:619 4. Lindelöf B, Eklund G. Incidence of malignant skin tumors in 14,140 patients after grenz ray treatment for benign skin disorders. Arch Dermatol. 1986;122:1391 5. Lindelöf B. Grenz ray therapy. In: Goldschmidt H, Panizzon RG (eds) Modern dermatologic radiation therapy. New York: Springer, 1991, pp. 155–9 6. Holloway KB et al Therapeutic alternatives in cutaneous T-cell lymphoma. J Am Acad Dermatol. 1992;27:367 7. Mitsuhashi N et al Cancer in patients aged 90 years or older: radiation therapy. Radiology. 1999;211:829 8. Panizzon RG, Goldschmidt H. Radiation reactions and sequels. In: Goldschmidt H, Panizzon RG (eds) Modern dermatologic radiation therapy. New York: Springer, 1991, pp. 25–36 9. Panizzon RG. Radiotherapie des précancéroses et tumeurs malignes de la peau. Med Hyg. 1998;56:461 10. Gaspar ZS, Dawber RP. Treatment of lentigo maligna. Australas J Dermatol. 1997;38:1 11. Panizzon RG. Radiotherapy of lentigo maligna and lentigo maligna melanoma. Skin Cancer. 1999;14:203 12. Schmid-Wndtner MH et al Fractionated radiotherapy of lentigo maligna and lentigo maligna melanoma in 64 patients. J Am Acad Dermatol. 2000;43:477

158 13. Caccialanza M, Sopelama N. Radiation therapy of keratoacanthomas: results in 55 patients. Int J Radiat Oncol Biol Phys. 1988;16:475 14. Panizzon RG. Radiation therapy of melanomas. In: Goldschmidt H, Panizzon RG (eds) Modern dermatologic radiation therapy. New York: Springer, 1991, pp. 133–7 15. Pilotti S et al Clinicopathologic correlations of cutaneous neuroendocrine Merkel cell carcinoma. J Clin Oncol. 1988; 6:1863 16. Wegmuller EA Jr et al Merkel cell carcinoma of the ear. Head Neck. 1991;13:68 17. Bekkenk MW et al Treatment of multifocal primary cutaneous B-cell lymphoma: a clinical follow-up study of 29 patients. J Clin Oncol. 1999;17:2471

R. Panizzon 18. Micaily B, Vonderheid EC. Cutaneous T-cell lymphoma. In: Perez CA, Brady LW (eds) Principles and practice of radiation oncology. Philadelphia, PA: Lippincott-Raven, 1997, pp. 763 19. Goldschmidt H. Radiation therapy of other cutaneous tumors. In: Goldschmidt H, Panizzon RG (eds) Modern dermatologic radiation therapy. New York: Springer, 1991, pp. 123–31 20. Cooper JS. Classic and acquired immunodeficiency syndrome (AIDS)- related Kaposi’s sarcoma. In: Perez CA, Brady LW (eds) Principles and practice of radiation oncology. Philadelphia, PA: Lippincott-Raven, 1997, pp. 745

Prevention and Adjuvant Therapy

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Veronique del Marmol and Gregor B. E. Jemec

Key Points

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UV radiation is the main environmental risk factor for the induction of non-melanoma skin cancer (NMSC). The mechanisms underlying the development of NMSC are sufficiently clear to allow preventive treatment. Primary prevention is related to reduction of UV exposure. Basal cell carcinoma is related to sunburns during childhood. Prevention of this type of skin cancer is thus related to avoidance of aggressive sun exposure at this age. Squamous cell carcinoma is related to chronic sun exposure. Prevention of squamous cell carcinoma is related to avoidance of sun exposure associated with outdoor activities such as outdoor work and sports. Immunosuppressed patients are particularly at risk of NMSC if they are exposed to UV. A specific primary and secondary prevention should be focused for them. There is a high risk of de novo NMSC following treatment of NMSC. NMSC is most often the result of field cancerisation, indicating that metachronous lesions are present.

V. del Marmol () Professor – Université Libre de Bruxelles, Hopital Erasme, Service de Dermatologie, 808, route de Lennik, 1070 Bruxelles – Belgium e-mail: [email protected]

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The same mechanisms may prove useful as adjuvant therapy. Treatment schedules should include not only evidence-based targeted treatments of tumours, but also preventive and adjuvant measures.

The skin is not only our largest organ, but also the exposed barrier to our surroundings and as such its cells are constantly exposed to a carcinogenic selection pressure, much like animal populations in their natural environment are subject to a selection pressure by changes in living conditions or predator populations. For the cells of the epidermis, this selection pressure, however, does not select the fittest in a Darwinian sense, but selects the ugliest in a biological sense: autonomous cancer cells. As has been described in the introductory chapters of this book, this process is synchronous and multifocal, while progression from transformed cell to clusters of cells and to clinical tumours occurs metachronously due not only to the nature of the mutations induced, but to the local and temporal variation of immune surveillance, HPV load, etc. In practical terms this means that field cancerisation leads to metachronous tumours, and that the initial diagnosis of NMSC often is not the end of a diagnostic and therapeutic process, but the beginning of a long process of treatment and prevention combined. NMSC is best viewed not in the traditional paradigm of a disease occurring as single curable event, but more within the paradigm of a chronic recurrent disease, recurrent for the patient either after therapy, or preferably because new tumours arise. This gives sense to the preventive interventions introduced in this chapter.

G. B. E. Jemec et al. (eds.), Non-Surgical Treatment of Keratinocyte Skin Cancer, DOI: 10.1007/978-3-540-79341-0_20, © Springer-Verlag Berlin Heidelberg 2010

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Preventive measures may be primary, altogether preventing the disease from occurring. In an NMSC context the avoidance of UVR is such a measure. Most often, physicians, however, deal with secondary prevention, or the prevention of disease progression. Here the disease is established, is being treated – and treatment encompasses the prevention of disease progression. In a NMSC context this is most easily understood as early diagnosis and treatment, as described in the earlier chapters. Finally, tertiary prevention exists, dealing with the prevention of complications that are the result of a given disease. One form of prevention does not exclude another.

20.1 Primary Prevention Primary prevention is often either the responsibility of the individual patient or of the society in general. The dermatologists’ role is limited to advising either of the parties and providing the relevant data. In the context of NMSC, UVR is both an initiator and promoter. The pattern of sun exposure appears to play a selective role for different types of skin cancer, with cumulative sun exposure most closely associated with particularly squamous cell carcinoma whilst intermittent sun exposure may be more relevant for basal cell carcinoma and melanoma. The best exemption involving a physician directly could be the use of vaccines, but currently there are no vaccines against NMSC, even if HPV may play a role in the pathogenesis of some tumours.

20.2 Sun Exposure Sun exposure is a difficult variable to measure. One type of sun exposure is incidental sun exposure which occurs as a part of normal life; another type is the recreational sun exposure which occurs when people actively pursue hobbies such as sailing or skiing and thereby expose themselves to the sun. A third type of sun exposure is occupational sun exposure which occurs in outdoor occupations. Finally, an increasingly important type of sun exposure in Western societies is intentional sun exposure taken by artificial (sunbeds) or natural sunlight exposure. These different types of sun exposure therefore lead to different approaches for skin cancer prevention.

V. del Marmol and G. B. E. Jemec

20.3 Primary Prevention Behaviour Successful skin cancer prevention should include strategies for changing several different behaviours in relation to sun exposure, clothing, seeking shade and using sunscreens. Behaviour in the sun shows considerable national and cultural differences, for example, the contrast between the shade-seeking locals and sun-seeking tourists around the Mediterranean Sea. In addition latitude, climate and geography, religious factors and skin type also play a role. Assessment of sun-related behaviour typically involves self-reporting, parental reports and direct observation of behaviour [1]. Most studies rely on selfreport of habitual sun protection practice although there is no gold standard questionnaire [2, 3], but direct observation is known to be the most effective approach to assess wearing hats, shirts and sunglasses. Like other topical therapies, the accurate evaluation of sunscreen use is very challenging and needs more objective methods. Monitoring sunburn prevalence with population-based surveys also allows an estimate of compliance regarding sun protection behaviours, but is uncertain as well. A report on sunburn prevalence among US adults from the Behavioural Risk Factor Surveillance System Surveys failed to show a decrease in sunburn prevalence over time with 31.8% in 1999 compared to 33.7% in 2004 [4]. The total level of information does not appear to cause obvious changes in individual sun behaviour – yet? [5].

20.4 Primary Prevention Targets: Location, Age, Period, Environment Different targets and interventions can be used. These include childcare centres, primary schools, secondary schools, recreational or tourism settings, occupational settings and health care settings. Two sites of intervention appeared effective: primary schools and tourism sites [1, 6], where sun-protective behaviour such as wearing protective clothing including long sleeves or hats was encouraged. Children and young people are ideal targets for prevention, as it has been estimated that 80% of a person’s lifetime exposure to UVR occurs before 21 years of age [7]. Recently it has also been shown that sun protection education for young children

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has a good cost – benefit ratio, cost-effectiveness perspective and that even a small behavioural change may result in a significant reduction in later skin cancer incidence and mortality [8]. Furthermore, lifestyle habits are often established during childhood, particularly before adolescence [9]. Health education is furthermore most likely to succeed if it is supported by strategies in the school environment, particularly primary schools [10, 11]. Finally, the period during which the education programme is scheduled has to be adapted to time of year, as observations suggest that it is most useful immediately before the summer break [12]. In children any exposure in the sun is likely to be unintentional thus in sunny climates, preventive efforts can reasonable be extended to the planning of the physical surroundings of children, i.e. the provision of shady play areas. Special attention should however be given to teenagers as their sun exposure usually becomes intentional. Most studies indicate that intentional tanning peaks are in late adolescence [12, 13, 16, 17]. Similarly, wearing protective clothing, a wide-brimmed hat, or staying in the shade are infrequent behaviour among teenagers. The need for special attention to this age group is supported by the observation that interventions performed in secondary schools and colleges do not appear to be as effective in decreasing sunburns or improving sun-protective behaviours as that of younger children [11]. Just as is the case with adults, information does not appear to be enough. A study showed that adolescents with a family history of skin cancer were not more likely to use sunscreens than other teenagers [7]. It would appear that for teenagers, the attractiveness of a tan is the major motivation for frequent intentional exposure. The tan may have become an aesthetic imperative. Consequently, the educational strategies that stress photo-ageing and threaten the aesthetic imperative may be more effective [13]. Recreational and tourism setting is another good setting for sun-protection education among adults and children. These interventions include at least one of the elements listed in Table 20.1. Interventions in a recreational or tourism setting appear more effective for adults than children, but the evidence is weak. Several reports however demonstrate evidence of effectiveness of focusing on children’s protective behaviours, including sunscreen use and sun-protective behaviours [8, 9]. Primary prevention of NMSC is therefore primarily done by the individual through UVR avoidance; both physically avoiding situations with a high risk of UVR

161 Table 20.1 Recreational sun exposure interventions 1. Providing information to children and adults (i.e. through leaflets and posters and small media education or both) 2. Activities intended to change the knowledge, attitudes, beliefs or intentions of children and adults 3. Additional activities to influence the behaviour of children and adults such as modelling, demonstration or roleplaying 4. Environmental or policy approaches including provision of sunscreen or shade or scheduling of outdoor activities to avoid hours of peak sunlight

exposure, as well as chemically using sunscreens as discussed in Chapter 21. It is obvious that limiting sun exposure has to be carefully adapted and tailored to various parts of the world as one primary prevention programme will certainly not fit all and may even be detrimental. The evidence in favour of primary prevention is however such that no case of NMSC should be treated without being informed of appropriate UVR reduction measures. A group where the primary prevention is particularly sensible is the organ transplant recipient (OTR) where a remarkably high rate of NMSC is observed. The risk factors amendable to preventive measure are the same as for non-organ transplant patients, but in OTR NMSC appears associated with human papilloma virus infections (HPV) [14, 15]. Our current knowledge about the role of HPV in NMSC is however insufficient to allow very strong recommendations. On mucosal surfaces their role is sufficiently clear to have promoted the introduction of a HPV vaccine to prevent long-term development of neoplasms. At the moment, it is unclear if the specificity of HPV vaccines prevents them from having an effect on the development of NMSC; or if the high-risk subgroups such as organ transplant patients where the role of HPV in NMSC is best established, may derive a benefit from the use of the available vaccines. Finally, societal development has meant that the use of a number of known carcinogens encountered in an occupational setting, have been restricted and regulated to provide better protection of the individual. The avoidance of known initiators, such as, for example, industrial exposure to bitumens and tars, cosmetic exposure to tars, as well as iatrogenic or industrial exposure to arsenic offer another possibility of NMSC primary prevention [20–26]. BCC and precursors of SCC (Bowen’s disease and arsenical keratoss) are induced by arsenic. Arsenic has been used previously as a dermatological treatment for psoriasis but is also

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an abundant element which is ubiquitous in soil and is in water wells in Taiwan, Argentina, Sweden and other regions where mining and smelting is prevalent [23]. It is also present in some form of traditional Indian medicine and in illegally produced alcoholic beverages [24, 25]. It is also used in the agricultural industry. The distribution of lesions caused by arsenic exposure is not limited to parts of the body that have been exposed to sun or X-rays. A scattering of neoplasms throughout the body is observed with the preferential formation of arsenical keratoses of the palm. It takes an estimated average of 17.8 years from initial exposure to arsenic to developing cancer [23, 26].

20.5 Secondary Prevention Skin cancers are amenable to secondary prevention as these tumours are usually visible on the skin surface and can be detected at an early curable stage. Secondary prevention has the aim of encouraging people or health care providers to recognise skin changes and seek early diagnosis and treatment, as well as improving effective diagnosis. Once the damage is done to the skin, secondary prevention is aimed at limiting its effects through minimising new cancers. Secondary prevention takes place where an increased risk is recognised, either in predisposed patients (see Table 20.2) or predisposed, i.e. usually severely sun-damaged skin. One major risk factor for the development of a NMSC is a previous diagnosis of NMSC. A meta-analysis reviewing 17 studies showed that people with fewer than three previous NMSCs, the risk of developing another NMSC within the following 3 years is 38%. In people with three to nine previous NMSCs this risk raises to 93%. One study found that individuals with more than Table 20.2 Target groups for secondary prevention Individuals with a precursor lesion (KA or Bowen’s disease) Individuals with a previous NMSC Lowered immunity (organ transplant recipient) Xeroderma pigmentosum Albinism Trauma and burns Basal cell naevus sundrome Exposure to arsenic Recessive dystrophic epidermolysis bullosa (RDEB) Previous PUVA treatment Parkinson disease

V. del Marmol and G. B. E. Jemec

nine prior NMSCs develop a new NMSC within 2 years [27]. In addition, any treatment of NMSC comes with a recurrence rate, even if the gold standard of surgical excision is used. People who have had organ transplants (OTRs) have a three- to fourfold increase risk of developing any cancer over the general population. The risk of developing NMSC has been estimated up to 500 times than the general population, depending on the previous solar exposition [28]. The incidence in immunosuppressed patients is generally increased up to tenfold, but even this dramatic finding is overshadowed by the more ominous 50- to 100-fold specific increase in SCC [29]. As with the normal population tumour development is more likely with increased ultraviolet exposure, advancing age and fair skin. A cumulative risk of over 40% by 20 years post-transplant is reported in temperate climates, rising to more than 80% in Australia [29]. Increased vigilance is not only needed in OTR and other immunosuppressed patients, but also where patients have been exposed iatrogenically to treatments known to induce or promote NMSC as an unwanted side effect. It is long recognised that previous treatment with PUVA (psoralen and UVA) constitutes a risk factor increasing the risk of developing SCC more than 100-fold within 10 years of stopping treatment [31]. Early detection of NMSC also plays a role in specific diseases, where NMSC is a part of a syndrome. Major increased risk of NMSC is associated with syndromes such as xeroderma pigmentosum, Gorlin’s syndrome or a recessive dystrophic epidermolysis bullosa as reviewed in Chapter 4. The physician therefore has a more prominent role in secondary prevention. This can happen with intensifying the screening in patients who are particularly at risk but also by the educational role that he can take. Compared to the general practitioner, the dermatologist is particularly well adapted to detect NMSC but also counselling [32]. However, even dermatologists often find it difficult to provide adequate screening in the time allotted and not enough attention given to skin cancer recommendations [33]. There is therefore a need to widen the range of those involved. This implies a need for specific education of general practitioners and nurses [34, 35]. The ultimate extension of individual screening programmes is, of course, the empowerment of patients themselves. Improving the examination practice should be coupled with an appropriate education of patients. Skin self-examination (SSE) may reduce mortality and morbidity of NMSC and an annual

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skin examination by physician and monthly SSE by patients are mutually reinforcing and promote early detection [36–38]. For additional preventive measures a number of treatment strategies are available, including both the use of dietary interventions such as antioxidants found in green tea, as well as specific pharmacological interventions. A Cochrane review of the interventions for preventing non-melanoma skin cancers in high-risk groups was recently published [39]. The use of antioxidants and retinoids are discussed in Chapters 22 and 23, while a number of other options are hovering on the horizon. These include the enzymes Difluoromethylornithine (DFMO) and T4 endonuclease V; polyphenolic antioxidants in green tea and grape seeds; Silymarin found in milk thistle; phytoestrogen Genistein and the spice Curcurmin. The role of dietary fats has also been debated and conflicting results presented. Although secondary prevention takes place in a skin already under the influence of carcinogens the effects may be difficult to assess in randomised controlled trials. The problem of randomised controlled trial is primarily the lag time between the intervention and the outcome. Preliminary studies are therefore often done in small groups of patients suffering from genetic predispositions such as xeroderma pigmentosum, where the rate of de novo NMSC development is such as to make any preventive effects obvious in a comparatively short time. The question of how these observations, made in very special patients are extended to the greater population of NMSC patients is unknown. If the underlying mechanisms are clear, as in, for example, xeroderma pigmentosum, this obviously strengthens the validity of the observation but does not necessarily constitute proof. Many of the substances used in secondary prevention, however, appear to have a low risk of unwanted side effects or toxicity. They are furthermore readily available, and some level of recommendation for these substances therefore appears warranted.

20.6 Tertiary Prevention Tertiary prevention and adjuvant therapy this involves extra intervention after treatment to reduce the risk of reoccurrence or further development of the disease NMSC patients demonstrated disease specific

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behaviour modification by selectively improving their sun habits but showed non significant improvement in other health behaviour [40]. Tertiary prevention is aimed at minimising the complications of a disease and return the patient to good health and minimise risk of recurrence, and therefore involves the appropriate choice of therapy. This is entirely within the realm of the treating physician, and involves the judicious use of the techniques described in this book, as well as careful and appropriate surgery. Tertiary prevention usually is also taken to involve some level of rehabilitation, which for visible skin diseases invariable involves assessment of a cosmetic aspect of the disease. Dermatologists are often keen to use combination therapy to achieve a synergistic therapeutic effect. The combined use of retinoids and UV-therapy in, for example, psoriasis is one well-known example, which may lead to a faster resolution of lesions than monotherapy. Cases have suggested that the combination of imiquimod treatment with retinoids may be an efficient form of therapy, have been published [41]. Combining classical surgery, with established forms of secondary prevention may however also show synergistic effects if the preventive efforts have an influence on the immunity of the patients. No specific randomised studies are available, but it is suggested, that combination of, for example, surgery and imiquimod, may beneficially affect the prognosis of specific tumours in the future.

20.7 Media Awareness in Prevention The ability to raise media awareness is a strong element of any prevention campaign. Non-melanoma skin cancer awareness and prevention behaviours already vary significantly among countries. In countries like Australia, with a high prevalence of BCC and AK, greater levels of awareness and knowledge concerning NMSC exist [36]. Improving population-specific knowledge and prevention behaviours facilitates the development and assessment of public health campaigns [36]. Patients’ personal responsibility should be promoted [42] and the performance of regular skin self-examinations should be encouraged. Interestingly, a good validity of the self-reported skin screening has been pointed out [37, 38]. Patient empowerment is, however, a venture into areas less well known by most

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physicians as new techniques are required. To improve this type of knowledge different elements of communication can be used, interventions and events including health fairs, mass media campaigns and distribution of educational materials [43]. However, even when a degree of mastery has been achieved over such techniques many of the established preventive measures remain suboptimal. The media is certainly a powerful tool for cancer prevention and education, if not always a very sharp one. A content analysis of news coverage of skin cancer prevention and detection between 1979 and 2003 showed that during those years the media paid little attention to skin cancer and the stories that were published were lacking in important educational information [44]. The analysis furthermore showed that 70% of skin cancer stories were reports of new research or celebrity experiences with skin cancer. Two important conclusions were drawn: Researchers must make themselves available to the news media and enlisting celebrities to provide specific prevention messages may be particularly useful. The use of celebrity spokespersons that can influence public behaviour substantially as has been shown recently in a Euromelanoma campaign where a former prime minister successfully offered his image to mobilise men above 50 years [45]. A manual published by the American public health association provides detailed strategies for media efficacy efforts [46]. Patients’ information-seeking behaviour may be changing as a result of the development in information technology. Even if the NMSC mostly affects the elderly rather than young people, a web-based access to information can also be a rewarding tool for promoting preventive information. Although physicians are ranked as the primary source of information for the majority of patients it has been reported that more than half of patients with cancer do not receive adequate information from their physicians about their disease. Thus it is not surprising that many seek other sources of information, such as the worldwide web. However, because the Internet can be a source of inaccurate, inappropriate or misleading information that may cause anxiety, health care professionals should direct patients and their families to appropriate websites. This in turn requires the physicians either to provide Internet information, or scan the available sites for the most appropriate information sources.

V. del Marmol and G. B. E. Jemec

20.8 Perspectives A focus on preventive measures and possible adjuvant therapies for NMSC appears to be a natural development in the treatment of these tumours. In addition to sunscreens, several other regimens need to be tested for their effect as adjuvant therapy. The routine use of combination therapy, combining medical treatments or medical treatment with, for example, PDT should be studied in randomised controlled trials. Similarly the combination of surgery and adjuvant medical therapy warrants further studies. It is to be expected that over time protocols for standard combination therapy may evolve which will further improve the results of treatment. Finally, the dermatological community needs to embrace the new communication technologies and empower patients to actively participate in the prevention and treatment of their disease through direct education.

Infobox Sun protection behaviours are mainly described in three main categories: Seeking shade Covering up (wearing hats and protective clothing) Sunscreen use

References 1. Glanz K, Halpern A, Sarayia M. Behavorial and community interventions to prevent skin cancer. Arch Dermatol. 2006; 142:356–60 2. Turrisi R Hillhouse J, Heavin S, Robinson J, Adam M, Berry J. Examination of the short term efficacy of a parent-based intervention to prevent skin cancer. J Behav Med. 2004; 27:393–412 3. Pagoto S, McChargue D, Fuqua RW. Effects of a multicomponent intervention on motivation and sun protection among Midwestern beachgoers. Health Psychol. 2003;22:429–33 4. Sarayia M, Balluz L. Sunburn prevalence among adultsUnited States, 1999, 2003 and 2004, MMWR – CDC 2007; 56:524–8 available at www.cdc.gov/mmwr 5. Jemec GBE. Primary prevention of malignant melanoma – to know may not be enough. J Am Acad Derm. 1993;28: 799–800

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6. Sarayia M, Glanz K, Briss P, Nichols P, White C, Das D. Preventing skin cancer: findings of the task force on community preventive services on reducing exposure to ultraviolet light, MMWR. Oct 17, 2003;52 (RR15):1–12 7. Banks BA, Silverman RA, Schwartz RH, Tunnessen WW. Attitudes of teenagers towards sun exposure and sunscreen use. Pediatrics. 1992;89:40–2 8. Kyle JW, Hammitt, JK, Lim HW, Geller A, Hall Jordan L, Maibach EW, De Fabo E, Wagner MC. Economic evaluation of the US environmental protection agency’s Sunwise program: sun protection education of young children. Pediatrics. 2008; 121:1074–84 9. Iammarino NK, Weinberg AD. Cancer prevention in the schools. J Sch Health. 1985;55:86–95 10. Denman S. Health promoting school in England, a way forward in development. J public Health Med. 1999;21: 215–20 11. Sarayia M, Glanz K, Briss P, White C, Das D, Smith J, Tannor B, Hutchinson A, Wilson K, Gandhi N, Lee N, Rimer B, Coates R, Kerner J, Buffler P, Rochester P. Interventions to prevent skin cancer by reducing exposure to ultraviolet radiation: a systematic review. Am J Prev Med. 2004;27: 422–66 12. Hewitt M, Denman S, Hayes L, Pearson J. Wallbanks C: evaluation of “sun-safe”: a health education resource for primary schools. Heatlh Educ Res. 2001;16:623–33 13. Boldeman C, Bränström R, Dal, H, Kristjansson S, Rodvall Y, Jansson B, Ullén H. Tanning habits and sunburns in a Swedish population age 13–50 years. Eur J Cancer. 2001; 37:2441–8 14. Nindl I, Rosl F. Molecular concept of viruses infections causing skin cancer in organ transplant recipients. Am J Transplant. 2008;8:2199–204 15. Karagas M, Nelson H, Sehr P, Waterboer T, STukel T, Andrew A, Green A, Bouwes Barwick J, Perry A, Spencer Rees J, Mott L, Pawlita M. Human papillomavirus infection and incidence of squamous cell and basal cell carcinomas of the skin. JNCI. 2006;98:389–95 16. Davis KJ, Cokkinides VE, Weinstock MA, O’Connell MC, Wingo PA. Summer sunburn and sun exposure among US youths ages 11 to 18: national prevalence and associated factors. Pediatrics. 2002;110:27–35 17. Vail-Smith K, Felts WM. Sunbathing: college students’ knowledge, attitudes and perception of risks. J Am Coll Health. 1993;42:21–6 18. Mahler HI, Kulik JA, Correa A, Gibbons FX, Gerrard M. Effects of UV photographs, photoaging information and use of sunless tanning lotion on sun protection behaviours. Arch Derm. 2005;141:373–80 19. Mitropoulos P, Norman R. Occupational nonsolar risk factors of squamous cell carcinoma of the skin: a populationbased case-controlled study. Dermatol Online J. 2005;11:5 20. Voelter-Mahlknecht S, Scheriau R, Zwahr G, Koch B, Escobar Pinzon LC, Drexler H, Letzel S. Skin tumors among employees of a tar refinery: the current data and their implications. Int Arch Occup Environ Health. 2007;80:485–95 21. Lei U, Masmas TN, Frentz G. Occupational non-melanoma skin cancer. Acta Derm Venereol. 2001;81:415–7 22. Partanen T, Boffetta P. Cancer risk in asphalt workers and roofers: review and meta-analysis of epidemiologic studies. Am J Ind Med. 1994;26:721–40

165 23. Neubauer O. Arsenical cancer: a review. British Journal of Cancer. 1947;1:192–251 24. Hughes GS, Davis L. Variegate porphyria and heavy poisoning from ingestion of “moonshine”. Southern Med J. 1983;76:1027–29 25. Treleaven J, Meller S, Farmer P, Birchall D, Goldman J, Piller G. Arsenic and ayurveda. Leuk Lymphoma. 1993;10: 343–5 26. Schwartz RA. Arsenic and the skin. Int J Dermatol. 1997; 36:241–50 27. Marcil I. Stern R Risk of developing a subsequent non melanoma skin cancer in patients with a history of non melanoma skin cancer: a critical review of the literature and meta analysis. Arch Derm. 2000;136:1524–30 28. Hartevelt MM, Bavinck JN, Kootte AM, Vermeer BJ, Vandenbroucke JP. Incidence of skin cancer after renal transplantation in the Netherlands. Transplantation. 1990;49: 506–9 29. Lindelof B, SigurgeirssoB, Gabel H, Stern RS. Incidence in skin cancer in 5356 patients following organ transplantation. Br J Dermatol. 2000;143:513–9 30. Bordea C, Wojnarowska F, Millard PR, Doll H, Welsh K, Morris PJ. Skin cancers in renal transplant recipients occur more frequently than previously recognized in a temperate climate. Tranplantation. 2004;77:574–9 31. Stern RS, Liebman EJ, Vakewa L. Oral psoralen and ultraviolet A light (PUVA) treatment of psoriasis and persistent risk of non-melanoma skin cancer. J Nat Cancer Inst. 1998; 90:1728–84 32. Helfand M, Mahon SM, Eden KB, Frame PS, Orleans CT. Screening for skin cancer. Am J Prev Med. 2001; 20(3S): 47–58 33. Federman D, Kravetz J, Kirsner R. Skin cancer screening by dermatologists: prevalence and barriers. J Am Acad Derm. 2002;46:710–4 34. Mikkilineni R, Weinstock MA, Goldstein MG, Dube CE, Rossi JS. The impact of the basic skin cancer triage curriculum on providers’ skills, confidence, and knowledge in skin cancer control. Prev Med. 2002;34:144–52 35. Olivera SA, Altman JF, Christos PJ, Halpern AC. Use of nonphysician health care providers for skin cancer screening in the primary care setting. Prev Med. 2002;34:374–9 36. Halpern A, Kopp L. Awareness, knowledge and attitudes to non melanoma skin cancer and actinic keratosis among the general public. Int J dermatology. 2005;44:107–11 37. Robinson J, Fisher S, Turrisi R. Predictors of skin self examination performance. Cancer. 2002;95:135–46 38. Aitken JF, Janda M, Elwood M, Ring I, Lowe J, Firman D. Validity of self reported skin screening histories. Am J Epidemiol. 2004;159:1098–105 39. Bath-Hextall FJ, Leonardi-Bee J, Somchand N, Webster AC, Delitt J, Perkins W. Interventions for preventing non melanoma skin cancers in high risk groups (review). Cochrane data base systematic reviews, 2007, Issue 4 °CD005414DOI: 10.1002/14651858.CD005414.pub2 40. Rhee JS, Davis-Malesevich M, Logan BR, Neuburg M, Burzynski M, Nattinger AB. Behavior modification and risk perception in patients with nonmelanoma skin cancer. WMJ. 2008;107:62–8 41. Ingves C, Jemec GBE. Combined imiquimod and acitretin for non-surgical treatment of basal cell carcinoma. Scand J Plast Reconstr Surg. 2003;37:293–5

166 42. Rhodes AR. A Public education and cancer of the skin: what do people need to know about melanoma and non melanoma skin cancer? Cancer. 1995;75:613–36 43. Stone EG, Morton SC. Hulscher ME et al Interventions that increase use of adult immunization and cancer screening services: a Meta analysis. Ann Intern Med. 2002;136:641–51 44. Stryker E, Solky B, Emmons KA. content analysis of news coverage of skin cancer prevention and detection, 1979 to 2003. Arch Derm. 2005;141:491–6

V. del Marmol and G. B. E. Jemec 45. Del Marmol V, de Vries E, Roseeuw D, Pirard C, van der Endt J, Trakatelli M, Maselis T. A Prime minister managed to attract elderly men in a Belgian Euromelanoma campaign. Eur J Cancer. 2009 Jun;45(9):1532–4 46. Media advocacy Manual APHA. American Public Health Association. Washington DC: American public Health association, 2000

21

Sunscreens Hans Christian Wulf

Key Points

› › › ›

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The biological efficacy (erythema action) of the radiation is dependent on wavelength. The unit SED (standard erythema dose) is a direct measure of the erythema action of radiation. The skin by itself absorbs UV radiation depending on the thickness of stratum corneum and the degree of pigmentation. When testing SPF of a sunscreen in humans 2 mg/cm2 is applied, in real life much less sunscreen is used 0.5 mg/cm2. It has been suggested that the protection is reduced exponentially when a thinner layer is used. The number of sunburn cells, cutaneous DNA damage, conversion of urocanic acid, and immunosuppression are diminished by sunscreen use. Human studies have indicated that the number of actinic keratoses as well as squamous cell carcinomas can be reduced if sunscreens are used regularly.

21.1 Introduction The need for sun protection has increased considerably along with longer vacations, shorter working hours, and wealth in the society. This has resulted in travels to sunny destinations, sometimes several times a year, also in winter when the natural sun protection of the skin is low. The interest in sun protection seems to have been already prevalent during World War I and especially World War II when red veterinary petrolatum (red vet pet) and salicylates were used [40]. The first commercial available sunscreen was developed in 1928 and was used by the military during World War II [34, 40]. In 1935, Eugene Scheuller produced benzyl salicylate (Ambre Solaire) that gave good protection against erythema [40]. We had to reach the 1970th before the use of sunscreens became popular on holidays and on the beach, to avoid burning and scaling. Since then, sunscreens have developed further, not only to avoid sunburn by absorbing UVB, but also to protect against UVA, primarily to minimize wrinkle formation. Protection against skin cancer was assumed because of UVB absorption. At the same time, focus has also been on long-term safety with emphasis on stability, carcinogenesis, and hormone-disturbing properties.

21.2 Sunlight

H. C. Wulf Bispebjerg Hospital, University of Copenhagen, Department of Dermatol, D42, Bispebjerg Bakke 23 DK-2400 Copenhagen NV, Denmark e-mail: [email protected]

The spectral distribution of sunlight is dependent on the time of day, time of year, and the geographical location. In all places, the shortest wavelengths are found when the sun is in its highest position in the sky. However, even at the equator, the wavelengths at ground levels are longer than 295 nm. The biological

G. B. E. Jemec et al. (eds.), Non-Surgical Treatment of Keratinocyte Skin Cancer, DOI: 10.1007/978-3-540-79341-0_21, © Springer-Verlag Berlin Heidelberg 2010

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a

H. C. Wulf Erythema potential

Sun intensity (log)

10 1

-5 Summer

CIE

-6

Winter

0.1

-7

0.01

-8

0.001

-9

0.0001

b

100

280

300

CIE x SUN

320

340

360

380

-10 400

360

380

400

22. July

80 14. April

60 40 20

15. Dec.

effect of sunlight increases with higher sun altitude and on high reflective surfaces, such as snow and water [25]. The biological efficacy (erythema action) of the radiation is dependent on wavelength (Fig. 21.1a). When the spectral power distribution of sunlight is multiplied by the erythema action spectrum (Fig. 21.1a), it results in a curve showing which wavelengths are the most erythemogenic in human skin (Fig. 21.1b). The unit SED (standard erythema dose) is a direct measure of the erythema action of radiation and is thus very usable when assessing risk of erythema and for practical reasons, also the risk of skin cancer [11, 43]. Typical numbers of SED received per day at a given time of the year is seen in Table 21.1. Very few SEDs are present in sunlight in winter and early mornings and evenings (Fig. 21.2).

0 280

300

320

340

Wavelength (nm)

Fig. 21.1 (a) The spectral power distribution of sunlight in summer and winter together with the erythema action spectrum (CIE). (b) Multiplication of CIE with the sun spectrum shows which wavelengths in sunlight cause erythema at different times of the year. It is seen that UVB (300–320) is most efficient in causing erythema and protection against UVB is consequently of greatest importance

Fig. 21.2 Bell-shaped distributions of erythema active radiation (SED) over the year and on clear sky days in January, April, and June in Denmark

Table 21.1 Daily average standard eyrthema dose, SED (range), received by Danes on the beach in Denmark and in southern Europe in spring, summer, and autumn Summer Spring/autumn Denmark average (range) Southern Europe average (range)

5 (0–28) 10 (0–54)

3 (0–10) 5 (2–23)

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Table 21.2 Primarily UVB absorbing organic filters allowed in sunscreens [28] Chemical substance Max. concentration PABA derivatives 4-Aminobenzoic acid 2-Ethylhexyl 4-dimethylaminobenzoate Ethoxylated ethyl 4-benzoic acid 2,4,6-Trianilino-(p-carbo-2'ethylhexyl-1'-oxy)-1,3,5-triazine Cinnamates Ethylhexyl methoxycinnamate 2-Ethoxyethyl p-methoxycinnamate Isopentenyl-4-methoxycinnamate Salicylates 2-Ethylhexyl salicylate Homomethyl salicylate Triethanolamine salicylate

5%, 15% 8% 10% 5%

7.5–10% 3–6% 10% 5% 10–15% 12%

Camphors Benzylidene camphor sulfonic acid Polymer of N-[(2 and 4)-[(2-oxoborn3-ylidene) methyl]

6% 6%

Benzyl acrylamide N,N,N-Trimethyl-4-(2-oxoborn-3ylidenemethyl) anilinium

6%

Methyl sulphate 3-(4’-Methylbenzylidene)-d-1 camphor 3-Benzylidene camphor Others 2-ethylhexyl-2-cyano-3,3 diphenylacrylate 2-Phenylbenzimidazole-5-sulfonic acid

4% 2% 10% 4–8%

Protection against the short wavelengths (Fig. 21.1) is most important. It means that UVB-protection is essential, and UVA may also contribute with about 10% of the erythema effect. UVA-protection therefore may also be of importance (Tables 21.2–21.4). The skin itself absorbs UV depending on thickness of stratum corneum and the degree of pigmentation [46]. The most sensitive in a group of very sun-sensitive red-haired people may only tolerate 1 SED before getting erythema of the skin, whereas a completely black person may tolerate about 20 times more before erythema occurs [44]. A white, north-European population tolerates about 3–5 SEDs depending on the time of year [27]. Comparing the data in Table 21.1 with the natural protection of the skin allows us to estimate the need for individual photoprotection (Table 21.5).

Table 21.3 Primarily UVA-absorbing organic filters allowed in sunscreens [28] Chemical substance Max. concentration Benzophenones Benzophenone 2-Hydroxy-4-methoxybenzophenone5-sulfonic acid 2-Hydroxy-4-methoxybenzophenone5-sulfonic sodium salt Dioxybenzone (Benzophenone-8) Others Methyl anthranilate 1-(4-tert-butylphenyl)-3(4-methoxyphenyl)propane-1,3-dione 2,2’-Methylene-bis-6-(2Hbenzotriazol-2yl)-4-(tetramethylbutyl)-1,1,3,3-phenol Phenol,2-(2H-benzotriazol-2-yl)-4methyl-6[2-methyl [1,3,3, 3-tetramethyl-1-[(trimethylsilyl) oxy]disiloxanyl]propyl 2,2’-(1,4-Phenylene)bis-(1-H-benzimidazole-4,6-disulfonic acid, monosodium salt Terephthalylidene dicamphor sulfonic acid 4,4-((6-(((1,1-dimethylethyl)amino) carbonyl)phenyl)amino) 1,3,5-triazine-2,4-diyl)diimino) bis-,bis(2-ethylhexyl)ester) Dimethico-diethylbenzalmalonate (1,3,5)-Triazine-2,4-bis((4-(2-ethylhexyloxy)-2-hydroxy) phenyl)-6(4-methoxyphenyl)

3.6–10% 5–10% 5–10% 3% 5% 3–5% 10%

3–15%

10%

10% 10%

10% 10%

Table 21.4 Inorganic broadband filters allowed in sunscreens. These are normally micronized and coded with silicium or aluminium oxides [12] Chemical substance Max. concentration Titanium dioxide Zink oxide

25% 25%

21.3 UV-Absorbers Chemical products that absorb ultraviolet radiation may be usable in sunscreen products. However, the European Community (EC), the FDA (Food and Drug Administration, USA), and Australians have accepted a selected number of chemicals that can be used in up to a certain concentration in sunscreens (Table 21.2–21.4) [1, 28].

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Table 21.5 The SPF needed to avoid erythema for persons with the highest sun exposure (max. SED/day) and for the average person (A) in the summer in Denmark or in the Mediterranean area in spring/autumn and (B) summer. The SPF depends on the SED that would give erythema of the skin of Danes with different skin sensibility to UV (skin types) A Skin type SED to Exposure max. SPF to erythema SED/day in avoid DK and the sunburn Mediterranean Very sensitive Normal sensitive Less sensitive Average (*) B Skin type

2 5

30 30

15 6

10 5

30 5

3 1

SED to erythema

Exposure max. SED/day Mediterranean

SPF to avoid sunburn

Very sensitive 2 54 27 Normal 5 54 11 sensitive Less sensitive 10 54 5 Average (*) 5 10 2 The average (*) indicates the SPF needed to avoid sunburn when an average person is exposed as the average Dane. SPF 1 equals no sunscreen.

These substances absorb predominantly UVB or in the UVA range, and a mixture of chemicals is normally needed to obtain high SPF (sun protection factor) and broad-spectrum photoprotection. A new regulation has been adopted by the EC. From 2008, the protection in the UVA range must at least be one third of the protection in the UVB range [14]. Chemicals and concentrations, in which they may be used in the sunscreens, are listed in Tables 21.2, 21.3, and 21.4 for the ones that have been approved by one of the three mentioned organizations. The so-called organic substances absorb UV-radiation and transfer the energy to heat. Inorganic substances may also be used (Table 21.4). They have a broad-spectrum reflectance and scattering and some degree of absorption [12]. UVB photoprotection is enhanced by micronization of the particles to sizes smaller than 100 nm. Micronization of zinkoxid and titanium dioxide also diminishes the white color of the substances when on the skin. These substances have previously mainly been recommended for children, as they have been considered not to be absorbed in normal intact skin [10, 26].

Inorganic agents may also protect to some extent against visible light and may thus be useful in certain photodermatoses such as solar urticaria. Even the micronized particles gives some whitening of the skin because of the higher reflective index.

21.4 Sun Protection Factor (SPF) The recommended amount of sunscreen used when testing the SPF is 2 mg/cm2 skin area [8, 16]. Testing must take place in individuals with light skin types and up to 20 persons are used in the test situation. The in vivo tests are performed according to the Food and Drug Administration (FDA) and the European Cosmetic Toiletry and Perfumery Association (Colipa). Every person is exposed to different doses of ultraviolet radiation to elicit erythema (MED) on protected and unprotected skins. The SPF is calculated as the ratio of the UV (solar) dose that elicits just perceptible erythema on the sun-protected skin divided by the dose required to produce the same degree of erythema on unprotected skin. The SPF is normally given on the containers and for consumers ease at the same time as “low protection” SPF 6–10, “medium protection” SPF 10–25, “high protection” SPF 30–50, and “very high protection” SPF 50 + [14] (Table 21.6).

21.5 SPF Stability Sunscreens must be photochemically stable in sunlight, which has not always been the case [36]. Sunscreens should preferably also be resistant to perspiration and swimming. In the USA, a “water resistant” sunscreen should be labeled with the SPF value Table 21.6 Labeled SPF related to real SPF if reduced amount of sunscreens is applied and assuming an exponential function [15] Category 2 mg/cm2 0.5 mg/cm2 mg/cm2 labeled applied applied SPF Low protection Medium protection High protection Very high protection

6, 10 15, 20, 25 30, 50 81

2.5, 3 4, 4.5, 5 5.5, 7 9

1.6, 1.8 2, 2.1, 2.2 2.3, 2.6 3

21 Sunscreens

found after two times 20 min in a bathtub with an intermittent pause of 20 min with air-drying. A “very water resistant” sunscreen should be labeled with SPF found after four times 20 min in a bathtub again with pauses of air-drying. In the EU the labeled SPF can only fall by less than 50%, when exposed to the mentioned regimens, to be called “water resistant” or “extra water resistant” [1]. Several organic compounds have been shown to be degraded by sunlight and effort is given to increase stability by the formulation of the base crème. There are also problems associated with the stability of the SPF after the sunscreen has been applied on the skin. There are several reasons for a decrease in SPF such as dressing at an early stage after application, perspiration, and swimming. Therefore, WHO has recommended that sunscreens should be reapplied every 2 h [42]. However, recently it has been shown that about 60% of the SPF is still present in the skin, both for organic and inorganic compounds, after 4 h with a T-shirt in, with physical activity in a hot environment, and bathing. About 40% of the SPF was still present after 8 h under these conditions and without any reapplication [5]. Unpublished data also indicate some SPF loss due to absorption and time on the skin before clothing. Since the end of the time course of 8 h will coincide with the daily decrease in sun activity, 40% of the original SPF may be sufficient in northern Europe, at that time of day (Fig. 21.2) [5].

21.6 Amount of Sunscreens Applied When testing SPF of a sunscreen in humans 2 mg/cm2 is applied, and the SPF number given on the bottles are thus obtained under this circumstance [17]. However, in real life much less sunscreen is used and the number on the bottles can thus only be taken as a way to compare different brands. In real life the amount of sunscreen used may be 1/3 or less. In a Danish beach study, it was found that children, women, and men, using their own sunscreen on the beach, only applied about 0.5 mg/cm2. Thus, they got much lower protection than expected from the labels on the bottles [2, 3]. It has been suggested that the protection is reduced exponentially so that use of 0.5 mg/cm2, corresponding to one fourth of the amount in the test situation, would result in the fourth root of the original SPF. That means that SPF 16 would only protect as SPF 2 when used in

171

that small amount [15]. It also indicates, as seen from Table 21.6, that too small an amount of the sunscreen cannot be compensated by increasing the SPF, as even a very high SPF (i.e., >60) will end up giving less than a SPF of three when applying 0.5 mg/cm2. Sunscreens should thus be used more liberally than in most reallife situations [47]. There has also been indication of a linear SPF decrease with decreasing amount [4]. However, the span in amount used was smaller, making it difficult to show the exponential function, which becomes clearly evident with a larger span in sunscreen amount.

21.7 Biological Effect of Sunscreens When testing the SPF, erythema is used as the endpoint, and it is therefore clearly proven that sunscreens are able to protect against UV-induced erythema. It is much more difficult to prove that sunscreens also protect against photoageing and photocarcinogenesis. In controlled animal studies it has been established that sunscreens protect against wrinkling and photocarcinogenesis [45], which also should be expected since UVB is absorbed, and less UVB is therefore available for DNA damage and collagen and elastic fiber crosslinking and aggregation [46]. In human studies they have also been shown to reduce the severity of solar elastasis [6] and cutaneous photodamage [48]. From a theoretical point of view a carcinogenic effect of the organic sunscreens themselves has been proposed but in animal studies tumors are not provoked or at least heavily overshadowed by the beneficial effect of the protection against ultraviolet radiation. Inorganic sunscreens have generally been considered to be inactive but may in fact cause oxidation and damage DNA [12]. Few human studies have indicated that the number of actinic keratoses as well as squamous cell carcinomas can be reduced if sunscreens are used regularly [9, 19, 30, 39, 41]. There has been no published data indicating a direct beneficial effect in preventing malignant melanomas by sunscreens. On the other hand, a 3-year randomized controlled trial of sunscreen use in children showed a 30–40% reduction in new nevi compared to individuals that used vehicle only [18]. This indicates that sunscreens may have a

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protective role in connection with malignant melanoma as the number of melanocytic nevi is a strong predictor of risk of subsequent cutaneous malignant melanomas. It is also known that the number of sunburn cells, cutaneous DNA damage, conversion of urocanic acid, and immunosuppression is diminished by sunscreen use. It is also demonstrated that UV immunosupression resulting in herpes labialis can be prevented by sunscreen use [30]. A main problem is, however, the unsystematic use of sunscreens and it has been shown that sunscreens are only used for a few weeks per year and mostly in situations when people know that they are going to expose themselves to higher amounts of sunlight [38]. On the beach, only 50% of men and about two thirds of women use sunscreens [35]. So even in situations with high risk, quite a number of persons will be unprotected. This makes it very complex to make studies that will show a clear-cut connection between sunscreen use and biological endpoints caused by uncontrollable environmental exposure and developing over many years.

21.8 Sunscreen and Vitamin-D It has been shown that sunscreen SPF 15, applied to different body areas, reduced vitamin-D formation in the skin in an area-dependent manner, when the persons subsequently were exposed to UVB. Total coverage totally blocked vitamin D formation in this experimental setting [29]. However, people using sunscreens now and then (the real-life situation) have not had any lowering in vitamin-D levels in plasma. This was shown in a study of 381 volunteers from Boston including sun habits and sunscreen use [20]. This again indicates that systematic use of sunscreens hardly occurs in real life. As sunscreen users may be more sun-exposed than non-sunscreen users [38], they can even be expected to have higher vitamin D. This was also found to be the case in a study of older adults by Kligman et al. [24]. Low vitamin-D has been related to cutaneous malignant melanoma, and it may therefore be of relevance to avoid sunscreens at time of year with borderline vitamin-D provoking wavelengths, such as October to April in Scandinavia. It may therefore be advisable to avoid sunscreens in cosmetics in this part of the year.

H. C. Wulf

21.9 Skin Penetration Full-body application of sunscreens for up to 5 days has not shown accumulation in the body, but clearly detectable amounts of sunscreens in the blood with maximum about 3–4 h after the first application and the parent compound could also be found in urine. This has especially been found for Benzophenone-3 (BP-3), OctylMethoxycinnamate(OMC),and3-(4-Methylbenzylidene) camphor (4-MBC), products that are suspected of being endocrine-disrupting compounds [21]. It has also been questioned, whether the inorganic compounds consisting of micronized particles, being less than 100 nm, can be absorbed through normal skin. Special emphasis has been on skin conditions with impaired stratum corneum such as in eczema and other diseases leaving defective stratum corneum. In normal skin, absorption is not considered to be relevant [10].

21.10 Endocrine-Disrupting Effect The BP-3, 4-MBC, and OMC have been investigated in animal studies for their endocrine-disrupting effect. After oral administration there has been breast cancer cell proliferation and increased uterine weight in immature Long-Evans rats. Increased uterine weight was also found after dermal application. These findings suggested estrogenic and anti-androgenic activity of sunscreens [13, 32, 33]. An examination of humans exposed to the mentioned sunscreens daily for 5 days did not result in changes in the levels of FSH, LH, SHBG, testosterone, or inhibin B, neither a few hours after an application nor after 5 days of full-body treatments [23]. Likewise, TBG, FT-4, FT-3, T-4, and T-3 were unaffected and in the human situation no influence on the hypothalamic-pituitary-gonodalaxis could be found [22], although these substances could clearly be found in the bloodstream [21].

21.11 Allergy and Photoallergy Allergy to sunscreen ingredients is not uncommon, but considering that most of the population is exposed to sunscreens regularly, allergy is rather infrequent.

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Table 21.7 Median (IQR) doses in SED per day in different locations and with and without use of a sunscreen. Risk days are days off-work and going to the beach and/or with bare shoulders.The sunscreens used were labeled SPF 10 (average), resulting in a protection factor of 7.9/5.3 = 1.5 [36] No sunscreen Sunscreen All days Risk days Non-risk days Risk days Non-sunburn days Sunburn days

1.0 (0.6–1.4)

2.3 (1.3–3.9) 5.3 (3.2–7.5)

Photoallergy (allergy only if the test sites are exposed to UVA) to sunscreen ingredients is the most common photoallergy. It may be hidden if the test product absorbs UVA. Sometimes the patients feel that it is the sun that causes the trouble and do not realize that it is the sunscreen that is causing the eczema. When the ingredient causing the trouble is identified, all products containing this ingredient must be avoided [7].

1.9 (0.9–3.6)

4.7 (3.1–8.1) 7.9 (4.3–12.5)

made the participants tolerate 2.6 SED more and the SPF labeled 10 gave a real-life SPF of 7.9/5.3 = 1.5 (Table 21.7). This is very close to the predicted SPF 1.8 by the exponential model (Table 21.6). A SPF of about 2 seems to be needed to avoid a sunburn corresponding to a labeled SPF of 16 (Table 21.6) and unchanged behavior (use of 0.5 mg/cm2). In cases when higher SPF than 3 is needed to avoid a sunburn, as shown by Table 21.5, this cannot be achieved by a higher SPF, as shown in Table 21.6. This can only be obtained by using a proper sunscreen layer.

21.12 SPF Level in Photoprotection Squamous cell carcinomas and to some extent basal cell carcinomas are a result of the cumulative UV-dose received during life. Protection will therefore be best if the UV-dose is reduced as much as possible. WHO recommends at least SPF 15 and even better, SPF 30 [42]. For malignant melanoma and partly basal cell carcinoma, sunburns, especially in childhood, are an important factor for the development of these tumors. The question is therefore, what SPF is necessary to avoid sunburns under different circumstances. The SPF will depend on the geographical location, time of year, the sensibility of the skin (skin type), and individual behavior. Table 21.5 shows the combination of such circumstances, when the most extreme exposure is considered (maximum daily dose for anyone) and the average dose for a group of persons. The SPF needed to avoid sunburn is 3–27 for the extreme sunworshipper, and no sunscreen or SPF 2 for the average Dane with average sun exposure in summer in Denmark or in spring/autumn in southern Europe. Table 21.7 can confirm these numbers. It shows the measured SED received under different circumstances and with or without sunscreen use. 5.3 SED gave sunburn when no sunscreen was used and 7.9 SED when sunscreen (average labeled SPF 10) was used. Assuming the same degree of sunburn, the sunscreen

21.13 Other Protective Measures It is still important to remember that sun protection can be obtained by clothing, indoor siesta, and outdoor activities in shade, especially important when traveling to sunny areas [28].

References 1. Antoniou C, Kosmadaki MG, Stratigos AJ, Katsambas AD. Sunscreens – what’s important to know. JEADV. 2008;22: 1110–9 2. Autier P, Boniol M, Severi G, Doré JF. Quantty of sunscreen used by European students. Br J Dermatol. 2001;144:288–91 3. Bech-Thomsen N, Wulf HC. Sunbathers’ applicaton of sunscreen is probably inadequate to obtain the sun protection factor assigned to the preparation. Photodermatol Photoimmunol Photomed. 1992/1993;9:242–4 4. Bimczok R, Gers-Barlag H, Mundt C, Klette E, Bielfeldt S, Rudolph T, Pflucker F, Heinrich U, Tronnier H, Johncock W, Klebon B, Westenfelder H, Flosser-Muller H, Jenni K, Kockott D, Lademann J, Herzog B, Rohr M. Influence of applied quantity of sunscreen products on the sun protection factor – a multicenter study organized by the DGK Task Force Sun Protection. Skin Pharmacol Physiol. 2007;20: 57–64 5. Bodekær M, Faurschou A-S, Philipsen PA, Wulf HC. Sun protection factor persistence during a day with physical

174 activity and bathing. Photodermatol Photoimmunol Photomed. 2008;24:296–300 6. Boyd AS, Naylor M, Camerson GS, Pearse AD, Gaskell SA, Nelder KH. The effects of chronic sunscreen use on the histologic changes of dermatoheliosis. J Am Acad Dermatol. 1995;33:941–6 7. Bryden AM, Moseley H, Ibotson SH, Chowdhury MM, Beck MH, Bourke J, et al 2006. Photopatch testing of 1155 patients: results of the U.K. multicentre photopatch study group. Br J Dermatol. 2006;155(4):737–47 8. CTFA-SA, COLIPA, JCIA: International sun protection factor (SPF) test method. 2003 9. Darlington S, Williams G, Neale R, Frost C, Green A. A randomized controlled trial to assess sunscreen application and beta carotene supplementation in the prevention of solar keratoses. Arch Dermatol. 2003;139:451–5 10. Derry JE, McLean WM, Freeman JB. At study of the percutaneous absorption from topically applied zinc oxide ointment. JPEN J Parenter Enteral Nutr. 1983;7:131–5 11. Diffey BL, Jansén CT, Urbach F, Wulf HC. The standard erythema dose. A new photobiological concept. Am Soc Photobiol Newslet. 1997;26(2):6–7 12. Dunford R, Slinaro A, Cai L, Serpone N, Horikoshi S, Hidaka H, Knowland J. Chemical oxidation and DNA damage catalysed by inorganic sunscreen ingredients. Federation Eup Biochem Soc. 1997;418:87–90 13. Durrer S, Maerkel K, Schlumpf M, Lichtensteiger W. Estrogen target gene regulation and coactivator expression in rat uterus after developmental exposure to the ultraviolet filter 4-methylbensylidene camphor. Endocrinology. 2005; 146(5):2130–9 14. EC, Commission Recommendation of 22 September 2006. On the efficacy of sunscreen products and the claims made relating thereto. Text with EEA relevance. Official Journal of the European Union 2006;L265:39–43 15. Faurschou A, Wulf HC. The relation between sun protection factor and amount of sunscreen applied in vivo. Br J Dermatol. 2007;156:716–9 16. FDA, Department of Health and Human Services Food and Drug Administation, USA, Sunscreen drug products for overthe-counter use: proposed safety, effectiveness and labelling conditons, Fed Reg. 1978 N-0038 RIN 0910-AF43. 17. FDA, U.S. Food and Drug Administration, Department of Health and Human Services FDA.Sunscreen drug products for over-the-counter human use. http://www.regulations.gov 2007 18. Gallagher RP, Rivers JK, Lee TK, Bajdik CD, McLean DI, Coldman AJ. Broad-spectrum sunscreen use and the development of new nevi in white children: a randomized controlled trial. JAMA. 2000;283:2955–60 19. Green A, Williams G, Neale R, Heart V, Leslie D, Parson P, Marks GC, Gaffney P, Battistutta D, Frost C, Lang C, Russel A. Daily sunscreen application and betacarotene supplementation in prevention of basal-cell and squamous-cell carcinomas of the skin: a randomized controlled trial. Lancet. 1999;354:723–9. Erratum in Lancet 1999;354:1038 20. Harris SS, Dawson-Hughes B. Reduced sun exposure does not explain the inverse association of 25-hydroxyvitamin D with body fat in older adults. J Clin Endocrin Metab. 2007; 92:3155–7

H. C. Wulf 21. Janjua NR, Kongshoj B, Andersson AM, Wulf HC. Sunscreen in human plasma and urine after repeated whole-body topical application. Eup Acad Dermatol Venereol. 2008;22(4):456–61 22. Janjua NR, Kongshoj B, Petersen JH, Wulf HC. Sunscreen and thyroid function. Br J Deratol. 2007;156:1080–2 23. Janjua NR, Mogensen B, Anderson AM, Holm J, Henriksen M, Skakkebæk NE, Wulf HC. Systemic absorption of the sunscreens benzophenone-3, octyl-methoxycinnamate and 3-(4-methylenzylidene) camphor after whole body topical application and reproductive hormone levels in humans. J Invest Dermatol. 2004;123(1):57–61 24. Kligman EW, Watkins A, Johnson K, Kronland R. The impact of lifestyle factors on serum 25-hydroxy vitamin D levels in older adults: a preliminary study. Fam Pract Res J. 1989;9:11–9 25. Kromann N, Wulf HC, Eriksen P, Brodthagen H. Relative ultraviolet spectral intensity of direct solar radiation, sky radiation and surface reflection. Photodermatol. 1986;3: 73–82 26. Lademann J, Weigmann H-J, Rickmeyer C, Barthelmes H, Schaefer H, Mueller G, Sterry W. Penetration of titanium dioxide microparticles in a sunscreen formulation into the horny layer and the follicular orifice. Skin Pharmacol Appl Skin Physiol. 1999;12:247–56 27. Lock-Andersen J, Wulf HC. Seasonal variation of skin pigmentation. Acta Derm Venereol. 1997;77:219–21 28. Lautenschlager S, Wulf HC, Pittelkow MR. Photoprotection. Lancet. 2007;370:528–37 29. Matsuoka LY, Wortsman J, Hollis BW. Use of topical sunscreen for the evaluation of regional synthesis of vitamin D3. J Am Acad Dermatol. 1990;22:772–5 30. Naylor MF, Boyd A, Smith DW, Cameron GS, Hubbard D, Neldner KH. High SPF sunscreens in the suppression of actinic neoplasia. Arch Dermatol. 1995;131:170–5 31. Rooney JF, Bryson Y, Mannix ML, Dillon M, Wohlenberg CR, Banks S, Wallington CJ, Notkins AL, Straus SE. Prevention of ultraviolet-light-induced herpes laialis by sunscreen. Lancet. 1991;338:1419–22 32. Schlumpf M, Schmid P, Durrer S, Conscience M, Maerkel K, Henseler M, Gruetter M, Herzog I, Reolon S, Ceccatalli R, Faass O, Stutz E, Jarry H, Wuttke W, Lichtensteiger W. Endocrine activity and developmental toxicity of cosmetic UV – filters – an update. Toxicology. 2004;205:113–22 33. Schmutzler C, Hamann I, Hofmann PJ, Konvacs G, Stemmler L, Mentrup B, Schomburg L, Ambrugger P, Grunters A, Seidlove-Wuttke D, Jarry H, Wuttke W, Kohrle J. Endocrine active compounds affect thyrotropin and thyroid hormone levels in serum as well as endpoints of thyroid hormone action in liver, heart and kidney. Toxicology. 2004;205: 95–102 34. Shaath NA. Evolution of modern sunscreen chemicals. In: Lowe NJ, Shaath NA (eds) Sunscreens: development, evaluation and regulatory aspects. New York: Marcel Dekker, 1990, pp. 3–35 35. Stender I-M, Lock-Anderson J, Wulf HC. Sun exposure and sunscreen use among sunbathers in Denmark. Acta Derm Venereol. 1996;76:31–3 36. Tarras-Wahlberg N, Stenhagen G, Larkö O, Rosén A, Wenneberg A-M, Wennerström O. Changes in ultraviolet absorption of sunscreens after ultraviolet irradiation. J Invest Dermatol. 1999;113:547–53

21 Sunscreens 37. Thieden E, Philipsen PA, Heydenreich J, Wulf HC. UV radiation exposure related to age, sex, occupation, and sun behavior based on time-stamped personal dosimeter readings. Arch Dermatol. 2004;140:197–203 38. Thieden E, Philipsen PA, Sandby-Moeller J, Wulf HC. Sunscreen use related to UV exposure, age, sex and occupation based on personal dosimeter readings and sun-exposure behavior diaries. Arch Dermatol. 2005;141:967–73 39. Thompson SC, Jolley D, Marks R. Reduction of solar keratoses by regular sunscreen use. N Engl J Med. 1993; 329: 1147–51 40. Urbach F. The historical aspects of sunscreens. J Photochem Photobiol B. 2001;64(2):99–104 41. Van der Pols JC, Williams G, Paneya N, Logan V, Green AC. Prolonged prevention of squamous cell carcinoma of the skin by regular sunscreen use. Cancer Epidemiol Biomarkers Prev. 2006;15:2546–8 42. World Health Organisation. Sun protection message for tourists. Available at: www.who.int/uv/publications/en/tourists. Accessed 8 January 2007

175 43. Wulf HC, Lock-Andersen J. Standard erythema dose. Skin Res Technol. 1996;4:192 44. Wulf HC, Lock-Andersen J. Measurement of constitutive skin phototypes. In: Altmeyer et al (eds) Skin cancer and UV radiation. Berlin/Heidelberg, Germany: Springer, 1997, pp. 169–80 45. Wulf HC, Poulsen T, Brodthagen H, Hou-Jensen K. Sunscreens for delay of ultraviolet induction of skin tumors. J Am Acad Dermatol. 1982;7:194–202 46. Wulf HC, Sandby-Moeller J, Kabayasi T, Cniadecki R. Skin aging and natural photoprotection. Micron. 2004;35(3): 185–91 47. Wulf HC, Stender I-M, Lock-Andersen J. Sunscreens used at the beach do not protect against erythema: a new definition of SPF is proposed. Photodermatol Photoimmunol Photomed. 1997;13:129–32 48. Young AR, Orchard GE, Harrison GI, Klock JL. The detrimental effects of daily sub-erythemal exposure on human skin in vivo can be prevented by a daily-care broad-spectrum sunscreen. J Invest Dermatol. 2007;127:975–8

Skin Cancer: Antioxidants and Diet

22

Daniela Göppner and Harald Gollnick

Key Points

›

›

› › ›

Antioxidants are molecules that prevent or reduce the damage of other substances caused by oxygen and its intermediates, the so-called reactive oxygen species (oxidative stress). The protection provided by an antioxidant thus depends not only on its concentration and its reactivity toward a particular ROS (reactive oxygen species) but also on the status of antioxidants with which it interacts. Systemic retinoids may play a role in the regulation of NMSC, Kaposi’s sarcoma, and cutaneous lymphoma. Some dietary antioxidants such as carotenoids and vitamin C reduce solar erythema, although their role in the control of NMSC is less clear. Dietary vitamin D and E have not been conclusively shown to have a beneficial effect in the prevention of NMSC.

22.1 Introduction Due to a widely believed link between diet and cancer incidence supplementary intake of antioxidants has a long-lasting tradition in healthy individuals as well as cancer patients. Cheap, non-prescription, and ostensibly well-tolerated antioxidants are taken on a regular basis

H. Gollnick () Department of Dermatology und Venerology, Otto-von-Guericke-University Magdeburg Leipziger Straße 44, 39120 Magdeburg, Germany e-mail: [email protected]

by an estimated 50–80% of all adults. Despite a plethora of epidemiological studies that described the protective effects of vitamins [39, 83] on some cancers, the mode of action of these dietary micronutrients is complex and yet far from being fully understood. Countering the conventional wisdom that although vitamins may not really help, they cannot hurt, a lately increasing body of research however questioned the safety of microconsituents as a means of prevention or improving outcome in healthy individuals and cancer patients likewise [6, 83]. A highdose, medically unsupervised intake is at the center of criticism as it might exert pro-oxidative effects and allow clonal expansion and tumor promotion by protecting initiated cells from oxidant toxicity and apoptosis [15]. In contrast to many other cancer fields, dermato-oncology profits by a long-lasting, controlled, and trial-approved experience in the use of antioxidants, mainly vitamin A derivates, not as an additional dietary supplement, but as a disease-specific medication for restricted indications and limited duration in skin cancer. Its advantage lies not only in the fairly well-established understanding of how ultraviolet (UV) radiation, the primary cause of cutaneous malignancies, elicits epidermal carcinogenesis and immunosuppression but also how this DNA damage is counteracted by vitamin-derived pharmaceuticals. Of particular interest for the skin is the unique topical applicability of these drugs, which allows a localized treatment and a limitation of possible side effects.

22.2 Antioxidants and the Oxidative Challenge Antioxidants are molecules that prevent or reduce the damage of other substances caused by oxygen and its intermediates, the so-called reactive oxygen species

G. B. E. Jemec et al. (eds.), Non-Surgical Treatment of Keratinocyte Skin Cancer, DOI: 10.1007/978-3-540-79341-0_22, © Springer-Verlag Berlin Heidelberg 2010

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(oxidative stress). They include a complex network of intracellular enzymes and metabolites such as superoxide dismutase (SOD), catalase, various peroxidases, and endogenous products, e.g., uric acid, as much as extracellular organic compounds, the so-called vitamins that must be supplied exogenously. Trace elements such as selenium or zinc, commonly referred to as further antioxidative nutrients, play a specific role; hence, they do not have any antioxidant function themselves but are instead required for the proper activity of some antioxidant enzymes. Classified in hydrophilic and hydrophobic antioxidants, the former in terms of vitamin A, D, E, and K react with oxidants in the cell cytoplasm while the latter in terms of vitamin C and vitamin B-complex protect the cell membranes from lipid peroxidation. The challenge however is not to have an entire removal of oxidants by the antioxidants, but to keep them at an optimized level, given that reactive oxygen species (ROS) do have useful functions in cells [63]. Of essential importance is therefore the interaction between these different antioxidants with various metabolites and enzyme systems having synergistic and interdependent effects on one another. The protection provided by an antioxidant thus depends not only on its concentrations and its reactivity toward a particular ROS but also on the

Fig. 22.1 Photocarcinogenesis

D. Göppner and H. Gollnick

status of antioxidants with which it interacts, making an excess supplementary intake, especially in cancer, questionable [79].

22.3 Photocarcinogenesis and UV-Induced Immune Suppression It is well-established that the primary cause of skin cancer is chronic exposure to ultraviolet (UV) radiation found in sunlight or in other UV sources of artificial suntanning. Its deleterious effects are a complex interplay of different types of DNA damage, counteracting repairing enzymes, and a versatile induction of cutaneous immune suppression. Each specific UV wavelength thereby causes not only a specific damage to the genome but also induces a specific repair mechanism and thus a specific alteration of the immune system. With UVC predominantly absorbed by the stratospheric ozone layer, the mid-wave mutagen component UVB and long-wave UVA – although the effects of the latter are less pronounced – trigger the initial, yet central, role of DNA damage and repair in the process of photocarcinogenesis (Fig. 22.1). Studies

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Skin Cancer: Antioxidants and Diet

of immune-suppressed transplant recipients and patients with biopsy-proven skin cancer have confirmed that in particular the UVB-induced immune suppression abets the development of skin cancer in several ways [21, 43]. The induction of DNA photoproducts such as cis-urocanic and reactive oxygen intermediates by UVB compromises the antigen presentation of Langerhans cells, leads to a depletion of Langerhans cells in the skin, inhibits the expression of ICAM-1 and thereby the T-cell/Langerhans cell clustering, induces T regulatory cells (T reg), and releases immunosuppressive cytokines such as interleukin (IL)1, IL-10, and TNF-a [1]. Of potential significance appears to be the fact that a number of tumors, including melanoma and non-melanoma skin cancer, produce IL-10 that may be one of the mechanisms of how these tumors escape the immunologic control [40].

22.4 Chemopreventive Efﬁcacy of Dietary Antioxidants in Skin Cancer The increased incidence of skin cancer as the most common cancer in human beings has brought much attention to the process by which these tumors develop and how they can be prevented. Due to numerous studies that demonstrated the role of ROS in cutaneous carcinogenesis and immune suppression [7, 67], the focus is on the oral as much as on the topical use of dietary and pharmalogic agents of possible chemopreventive and therapeutic potency to inhibit or reverse the development of cancer. Of the large number of antioxidants as well as non-antioxidants studied to date, vitamin A and its derivates are so far the only compounds proven to be chemopreventive in skin carcinogenesis (Table 22.1).

22.4.1 Vitamin A and the Retinoids The term “retinoids” comprises natural as well as synthetic derivatives of vitamin A (retinol) with retinoic acid as its natural product derived physiologically through the two-step oxidative process of dietary retinol (retinol –> retinal –> retinoic acid). They exert their complex molecular effects through two different nuclear receptors, the retinoic acid receptor RAR and

179 Table 22.1 Overview of current chemopreventive agents Antioxidants Non-antioxidants Vitamin A and retinoids Carotenoids: beta carotene and lycopene Vitamin E Vitamin C Polyphenolic antioxidants: Green tea Polyphenolic antioxidants: Grape seeds Silymarin Genistein Trace elements Selenium Zinc

Difluoromethylornithine (DFMO) T4 endonuclease V

Nonsteroidal anti-inflammatory drugs Curcurmin

the retinoid X receptor RXR. Each of them can further be divided into three subtypes (a, b, g), whose combination to homo- and heterodimeres, as well as tissuespecific expression enhance a diversity of biologic functions. Due to gene expression and gene inhibition, and particularly interaction with other ligand-dependent transcription factors of the steroid-thyroid hormone superfamily, they catalyse a wide-ranging spectrum of pleiotropic and sometimes opposing reactions of immunomodulation, cell growth, cell differentiation, and cell death (apoptosis). Significant insights in the last two decades about the configuration of the retinoid receptors and their signaling pathways not only allowed a better understanding of their multimodal characteristics, but enabled the development of a new generation of synthetic retinoid (RAR) and rexinoid (RXR) agonists and antigonists whose efficacy is highly defined and selective (Fig. 22.2). The reduction of these complex biological interactions to a small number of factors relevant for the chemoprevention makes retinoids a class of medication that holds high promise for antitumor therapy. So far, their chemopreventive potency against carcinogeneses, though not understood in every detail, relies on three different mechanisms in terms of inhibition of proliferation, stimulation of differentiation, and induction of apoptosis [31]. Teratogenicity is the major drawback of retinoids. Therefore, its oral and systemic application is strictly

180

D. Göppner and H. Gollnick

Retinol

RAMBAs

R 115866 R 116010

1. Generation non-aromatic

Tretinoin - topical - systemic

Isotretinoin - topical - systemic

2. Generation monoaromatic

Etretinat - systemic

Acitretin - systemic

Motretinid - topical

3. Generation polyaromatic

Arotinoids - systemic

Adapalene - topical

Tazaroten - topical

4. Generation selektiv RAR/RXR

Bexarotene - topical

Alitretinoin - systemic

Tamibaroten - topical

5. Generation atypical

Fenretinid/ (4-HPR) - topical

Liarozole

CD 437 / AHPN Acne / Psoriasis / Ichthyosis / Eczema Lymphoma / BCC / SCC / AK no Indication

Fig. 22.2 Retinoid-Generations [31]

contraindicated during pregnancy and lactation, and the use of contraceptives in women of childbearing age is mandatory. All other possible dose-related side effects, e.g., hypertriglyceridemia or hypothyroidism, demand a close medical supervision and are fully reversible after cessation.

22.4.2 Non-Melanoma Skin Cancer According to current understanding the development of actinic keratosis and its progression to squamous cell carcinoma (SCC) are a multifactored issue. Several pathogenic defects are involved, e.g., the mutation of tumor suppressor gene p53 and p16 or the alterations of the extrinsic CD95/TRAIL-induced apoptosis, which are key elements of the effect of retinoids [11]. Moreover, it has been proven that the epidermal expression of retinoid receptors decreases during the

transformation of healthy skin into actinic keratosis up to the point of invasive squamous cell carcinoma. A reduction of the retinoid receptors, and also a UV-induced vitamin A deficiency, therefore, appear to be important for cutaneous carcinogenesis [44, 84]. Several clinical trials have been conducted on retinoids as chemopreventive agents for non-melanoma skin tumors. These studies have involved oral administration of retinoids (isotretinoin, etretinate, acitretin) in the chemoprevention of new cutaneous cancer, in particular, squamous cell carcinoma (SCC) and basal cell carcinomas (BCC). Two larger studies in patients who had several epithelial tumors in their histories, demonstrated a significant reduction for moderate-risk patients in developing a first new SCC in the retinol relative to the placebo group. There was, however, no effect for BCC and for high-risk patients [57]. In another study by Tangrea et al. with isotretinoin 10 mg/day for 3 years, there was also no difference in occurrence of BCCs between the treated and the

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Skin Cancer: Antioxidants and Diet

placebo groups. Yet, acitretin given to renal transplant recipients showed a significant decrease in the occurrence of SCC and BCC [5, 50]. In addition, these studies showed that the chemopreventive effect can be sustained over a 4-year period. Moreover, the side effects were mostly tolerable and treated successfully without having to discontinue retinoid therapy. Together these studies showed that retinoids are effective chemopreventive agents that disrupt nonmelanoma skin tumor carcinogenesis. Depending on the dosage, side effects have to be closely monitored. However, there seems to be contradicting evidence for the inhibition and treatment of BCCs. A more detailed understanding of their molecular pathogenesis and its interaction with retinoids, e.g., in the form of the Tazaroten-induced gene 3, will achieve a more specific effect of vitamin-A derivates [18]. Recently published data by So et al. are promising [71].

22.4.3 Malignant Melanoma, Lentigo Maligna, and Dysplastic Nevi Up to now, currently available retinoids are seen as ineffective for the treatment of malignant melanoma. Despite several studies in vitro with retinol, retinylaldehyd, and b-trans-retinylaldehyd that described a reduction of tumor growth, the results ranged from a 60–70% inhibition to a twofold stimulation of tumor progression [45, 46, 54]. Only RAR g-selective derivates resulted in an antiproliferative effect [68]. Retinoids applied as chemotherapy in malignant melanoma patients clinical stage I-IIIb obtained partial remission rates of 30% but did not prolong the recurrence-free or overall survival [72, 24, 53]. In summary, the heterogeneity of the published results regarding melanoma and its precursors, e.g., lentigo maligna, requires a more detailed molecular knowledge of its pathogenesis [77, 64, 37].

22.4.4 Kaposi Sarcoma The first ever applied rexinoid alitretinoin (9-cis RA, Panretin®) was officially FDA-approved, for topical treatment of HIV-related Kaposi sarcoma, in 2002 [80]. Irrespective of their HAART-therapy, 35% of 268 patients had a significant reduction of their tumor load.

181

Side effects were minor. The oral use of 45 mg/m2/day tretinoin over a 12-week interval did not achieve better results [66].

22.4.5 Cutaneous T-Cell Lymphoma Even though the pathogenesis of cutaneous T-cell lymphoma (CTCL) is not fully understood, the evidence is becoming substantial that as a consequence of genomic aberrations essential apoptotic genes in T cells are inhibited [82]. As crucial elements of regular cell proliferation and the complex apoptotic signaling pathway, in particular, rexinoids, retinoid-derived synthetic compounds that exclusively bind to retinoid X receptor (RXR), are in the focus of therapeutic interests. Already in 2000, bexarotene (LGD-1069) was officially approved for oral, later for topical third-line treatment in patients with CTCL in Europe. Already in several phase-I trials bexarotene showed lower dose-dependent toxicity regarding hypertriglyceridemia and hypothyroidism than its arotinoid precursor. Triglyceride and thyroid levels returned to baseline following treatment cessation [22, 65, 56]. Two phase II/III multicenter, open-labeled trials involving 58 patients with early-stage mycosis fungoides and 94 patients with late-stage CTCL achieved response rates depending on the dosage of up to 67% and 55% respectively [19, 20]. In addition, baxoretene became an ideal candidate for joint use with phototherapy, photopheresis, radiotherapy, or other biological immune response modifiers such as interferone making it an indispensable molecule in preventing the progression of refractory CTCL [25, 73].

22.4.6 Carotenoids Dietary carotenoids, mainly b-carotene, are widely used supplements as oral and topical sun protectants. As one of the most effective naturally occurring antioxidants, they scavenge ROS and interact with peroxyl radicals, thus inhibiting lipid peroxidation in synergism with a-tocopherol [10, 17, 62, 76]. Once proven to decrease with UV radiation in plasma and skin [8], several studies with high dietary intake have demonstrated a clear protective effect with a significant decrease of UV-induced erythema [32, 42, 49], especially in combination with

182

vitamin E [2, 56, 75]. Yet an oral dose of 180 mg/d of b-carotene for an interval of 10 weeks showed only a slight increase in the erythema dose [49]. In subjects given 50 mg/day for 5 years or even 12 years, however, no skin cancer chemopreventive benefit was achieved [26, 35]. And Garmyn et al. found no protective effects of b-carotene given for 23 days at a dosage of 90 mg/ day, although plasma and skin concentrations were higher than control values [30]. The inconsistency of duration and/or dosage of the supplementation probably might explain the diverging results as claimed by Stahl et al. [74], who therefore argue for a prolonged and dietary exceeding dosage [75]. Yet there is strong evidence that b-carotene metabolism and storage depends on skin types and is significantly decreased in smokers [33]. Lycopene, zeaxanthin, and lutein, three open-chain unsaturated carotenoids that lack pro-vitamin-A activity, might become however subject to closer investigation, as these so-called xantophyllic carotenoids already showed dose-dependent reduction of photoinjury and control of epidermal tumor markers when applied topically [23].

22.4.7 Vitamin C Not synthesized in humans and therefore necessary to be provided by diet or pharmacological means, ascorbic acid (vitamin C) is in vivo required for the proper function of several hydroxylases and monooxygenases. As a reducing water-soluble agent it also neutralizes ROS such as superoxid anion radical, hydrogen peroxide, hypochlorite, hydroxyl radical, peroxyl radical, and singlet oxygen and prevents lipid peroxidation [59, 61, 69]. Although it appears to predominantly have an antioxidant action in the body similar to vitamin E, it can also act as a pro-oxidant [14]. Due to its known pivotal interaction in the regeneration of oxidized vitamin E, mainly combined studies undertaken so far showed, when orally applied, a significant decrease of erythema in volunteers exposed to solar-simulated UV radiation [27].

D. Göppner and H. Gollnick

levels. Synthesized under UVB irradiation it is stored in the skin and released into circulation in a complex with vitamin-D-binding protein. Its role in cancer prevention is however still unclear. While the positive association between UV exposure, non-melanoma skin cancer and an elevated serum calcidiol is apparent, a lately growing body of scientific literature indicates an inverse correlation of vitamin D with internal cancer incidence and morality [25, 34]. Calcitriol furthermore convincingly induces cell cycle arrest and apoptosis in cancer cells [47]. Yet, a link between UVB-induced skin cancer and vitamin D seems possible; vitamin-D treatment failed efficacy in non-melanoma skin cancer until now [9, 70].

22.4.9 Vitamin E Especially as a-tocopherol, its most important lipidsoluble molecule, vitamin E, preserves the stability of biological membranes as a chain-breaking antioxidant and as such the skin-barrier function by protecting against lipid peroxidation [41, 58]. It is also shown to scavenge superoxid anion radical, perhydroxyl radical, and hydroxyl radical [28]. These reactions produce oxidized a-tocopheroxyl radicals that can be recycled back to the active reduced form through other antioxidants, such as vitamin C, retinol or ubiquinol (Fig. 22.3). Most specifically, vitamin C plays a pivotal role in the subsequent regeneration of a-tocopherol in vivo, hence staying oxidized, vitamin E can act as a pro-oxidant that persists long enough to penetrate deeper into tissues, to increase even the rate of lipid peroxidation and to damage lipoproteins [3]. Probably, as a consequence of eight different existing forms of vitamin E however, whose roles, importance, and therefore distinctive effects are presently unclear [16, 52, 78, 86], the results from clinical trials with oral vitamin E as far as chemoprevention is concerned are LOO*

Vitamin E

Vitamin C*

NADH

LOOH

Vitamin E

Vitamin C

NAD*

22.4.8 Vitamin D Vitamin D regulates calcium and phosphorus absorption and deposition as well as serum alkaline phophatase

Fig. 22.3 Pathways of chain-breaking actions of vitamin E and its subsequent regeneration

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Skin Cancer: Antioxidants and Diet

contradicting. While studies with single high dose or combined application with beta carotene demonstrated no significant protective effects [75, 81], others, mainly in combination with further antioxidants, clearly showed a pharmacological prevention of UV-induced reactions such as chronic skin damage, erythema, and sunburn cell formation [36, 60]. Not only is there hardly any proven significant association between dietary intake and tumor inhibition up to now [29, 51], but worse, recent publications suggest even an increasing risk of skin tumors. Heinen et al. [38], for example, showed that depending on the dosage a medium vitamin-E intake doubled and a high intake even tripled the risk of developing basal cell carcinoma.

22.5 Others In addition to xantophyllic carotenoids, an overabundance of possible chemopreventive agents are currently under investigation, ranging from difluoromethylornithine (DFMO) and T4 endonuclease V, two enzymes, nonsteroidal anti-inflammatory drugs, polyphenolic antioxidants in green tea and grape seeds, a component of milk thistle called silymarin, phytoestrogen genistein and the spice curcurmin (Table 22.1). With the exception of DFMO and T4 endonuclease V so far only preliminary trials on mice or on a few patients proceeded. Two phase-I studies with DFMO already established however a potential starting dose for further phase-II investigations [12, 13]. Side effects were limited to urinary infections, nausea, and vomiting [12]. Equally promising results were already achieved in several trials with T4 endonuclease, a bacterial enzyme that proved to accelerate the UVB-induced repair of cyclobutane pyrmidine dimers (CPDs). Topically applied in 30 XP patients for a year resulted in a reduced rate of BCCs and actinic keratosis with no side effects whatsoever [85]. Trials investigating nonsteroidal anti-inflammatory drugs are not yet really conclusive [4].

22.6 Conclusion Whether antioxidant supplements are beneficial or harmful is still an open question. Recent alarming news suggests that dietary supplementation with vitamins

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and trace element antioxidants may not only be not beneficial, worse, they may even induce cancer. Neither are their complex synergistic and interdependent effects on one another, nor their necessary concentration to provide the protection needed in cancer patients or healthy individuals understood. Considering the fact further that not the entire removal but an optimized balance of oxidants might be the challenge, an excess supplementary intake is definitely unwise. So even in dermato-oncology with the advantage of long-term experience with at least two micronutrients, vitamin A and carotenoids, they still need to be viewed as medication. This certainly entails an appropriate, diseaserelated application and control of possible side effects under careful medical supervision. Given the imperfect knowledge, the only safe option especially for cancer patients currently is to recommend the daily intake of a balanced combination of natural antioxidants through a diet high in fruits and vegetables.

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184 11. Brash D, Ziegler A, Jonason A, et al Sunlight and sunburn in human skin cancer: p53, apoptosis, and tumor promotion. J Invest Dermatol Symp Proc. 1996;1:136–42 12. Carbone P, Pirsch J, Thomas J, et al Phase I chemoprevention study of difluoromethylornithine in subjects with organ transplants. Cancer Epidemiol Biomarkers Prev. 2001;10:657–61 13. Carbone P, Douglas J, Larson P, et al Phase I chemoprevention study of piroxicam and alpha-difluoromethylornithine. Cancer Epidemiol Biomarkers Prev. 1998;7:907–12 14. Carr A, Frei B. Does vitamin C act as a pro-oxidant under physiological conditions? FASEB J. 1999;13(9):1007–24 15. Cerrutti P. Oxy-radicals and cancer. Lancet. 1994;344:862–3 16. Clarke M, Ward N, Wu J, et al Supplementation with mixed tocopherols increases serum and blood cell gamma-tocopherol but does not alter biomarkers of platelet activation in subjects with type 2 diabetes. Am J Clin Nutr. 2006;83:95–102 17. Conn P, Scharlach W, Truscott T. The singlet oxygen carotenoid interaction. J Photochem Photobiol B. 1991;11:41–7 18. Duvic M, Helekar B, Schulze C, et al Expression of a retinoid-inducible tumor suppressor, tazarotene-inducible gene 3 is decreased in psoriasis and skin cancer. Clin Cancer Res. 2000;6:3249–59 19. Duvic M, Hymes K, Heald P, et al Bexarotene is effective and safe for treatment of refractory advanced-stage cutaneous T-cell lymphoma: multinational phase II-III trail results. J Clin Oncol. 2001;19:2456–71 20. Duvic M, Martin A, Kim Y, et al Phase 2 and 3 clinical trial of oral bexarotene (Targretin capsules) for the treatment of refractory persistent early-stage cutaneous T-cell lymphoma. Arch Dermatol. 2001;137:581–93 21. Euvard S, Kanitakis J, Claudy A. Skin cancer after organ tranplantation. N Engl J Med. 2003;348:1681–91 22. Farol L, Hymes K. Bexarotene: aclinical rewiev. Expert Rev Anticancer Ther. 2004;4(2):180–8 23. Fazekas Z, Gao D, Saladi R, Lu Y, et al Protective effects of lycopene against ultraviolet B-induced photodamage. Nutr. Cancer 2003;47(2):181–187 24. Fierlbeck G, Schreiner T, Rassner G. Combination of highly purified human leukocyte interferon alpha and 13-cis-retinoic acid for the treatment of metastatic melanoma. Cancer Immunol. Immunother. 1995;40(3):157–164 25. Freedman D, Looker A, Chang S. Prospective study of serum vitamin D and cancer mortality in the United States. J Natl Cancer Inst. 2007;99(21):1594–602 26. Frieling U, Schaumberg D, Kupper T, et al A randomized, 12-year primary prevention trial of beta carotene supplementation for nonmelanoma skin cancer in the Physicians’ Health Study. Arch Dermatol. 2000;136:179–84 27. Fuchs J, kern H. Modulation of UV-light induced skin inflammation by D-alpha tocopherol and L-ascorbic acid: a clinical study using solar simulated radiations. Free Radic Biol Med. 1998;25:16–12 28. Fukuzawa K, Gebicki J. Oxidation of alpha-tocopherol in micelles and liposomes by the hydroxyl, perhydroxyl, and superoxide free radical. Arch Biochem Biophys. 1983;226: 242 29. Fung T, Spiegelman D, Egan K. Vitamin and carotenoid intake and risk of squamous cell carcinoma of the skin. Int J Cancer. 2003;103:110–5 30. Garmyn M, Ribaya-Mercado J, Russel R, et al Effect of beta-carotene supplementation on the human sunburn reaction. Exp Dermatol. 1995;4:101–11

D. Göppner and H. Gollnick 31. Gollnick H, Göppner D. In Szeimies Antitumorale Therapie. Topisch applizierte antitumorale Medikamente - Retinoide. Thieme Verlag, Stuttgart (2009, in press) 32. Gollnick H, Hopfenmüller W Hemmes C, et al Systemic beta carotene plus topical UV-screen are an optimal protection against harmful effects of natural UV-sunlight: results of the Berlin-Eilah study. Eur J Dermatol. 1996;6:200–5 33. Gollnick H, Siebenwirth C. B-carotene plasma levels and content in oral mucosal epithelium is skin type associated. Skin Pharmacol Appl Skin Physiol. 2002;15:360–6 34. Grant W. A meta-analysis of second cancers after a diagnosis of non-melanoma skin cancer: additional evidence that solar ultraviolet-B irradiance reduces the risk of internal cancers. J Sterod Biochem Mol. 2007;103:668–74 35. Greenberg E, Baron J, Stukel T, et al A clinical trail of betacarotene to prevent basal-cell and squamous cell cancers of skin. N Engl J Med. 1990;323:789–95 36. Greul AK, Grundmann JU, Heinrich F, et al Photoprotection of UV-irradiated human skin: an antioxidative combination of vitamin E and C, carotenoids, selenium and proanthocyanidins. Skin Pharmacol Appl Skin Physiol. 2002;15:307–15 37. Halpern A, Schuchter L, Elder D, et al Effects of topical tretinoin on dysplastic nevi. J Clin Oncol. 1994;12(5):1028–1035 38. Heinen M, Hughes M, Ibiebele T, et al Intake of antioxidant nutrients and the risk of skin cancer. Eur J Cancer. 2007;43: 2707–16 39. IARC. IARC handbooks of cancer prevention. Fruit and vegetables. IARC Press, Iyon, 2003 40. Kim J, Modlin R, Moy R, et al IL-10 production in cutaneous basal and squamous cell carcinomas. A mechanism for evading the local T cell immune response. J Immunol. 1995;155: 2240–7 41. Krol E, Kramer-Strickland K, Liebler D. Photoprotective actions of topically applied vitamin E. Drug Metab Rev. 2000;32:413 42. Lee J, Jiang S, Levine N, et al Carotenoid supplementation reduces erythema in human skin after simulated solar radiation exposure. Proc Soc Exp Biol Med. 2000;223:170–4 43. Lindelof B, Sigurgeirsson B, Gabel H, et al Incidence of skin cancer in 5356 patients following organ transplantation. Br J Dermatol. 2000;143:513–9 44. Lippmann S, Kalvakolanu D, Lotan R. Retinoids and interferons in non-melanoma skin cancer. J Investig Dermatol Symp Proc. 1996;1:219–22 45. Lotan R, Hendrix M, Lippmann S. Retinoids in the management of melanoma. In R. Marks: Retinoids in cutaneous malignancy. Blackwell, Oxfort, U.K., 1991;133–149 46. Lotan R. Different susceptibilities of human melanoma and breast carcinoma cell lines to retinoic acid-induced growth inhibition. Cancer Res. 1979;30:1014–9 47. Malloy P, Feldman D. Inactivation of Human Vitmain D Receptor by Caspase-3. Endocrinology. 2008; Epub ahead of print. 48. Malloy P, Feldman D. Inactivation of the human vitamin D receptor by caspase-3. Endocrinology. 2009;150(2):679–686 49. Matther-Roth M, Pathak M, Parish J, et al A clinical trial of the effect of oral beta-carotene on the response of human skin to solar radiation. J Invest Dermatol. 1972;58:349–53 50. McKenna D, and Murphy G. Skin cancer chemoprophylaxis in renal transplant recipients: 5 years of experience using low-dose acitretin. Br J Dermatol. 1999;140(4):656–660

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51. Mc Naughton S, Marks G, Gaffney G, et al Antioxidants and basal cell carcinoma of the skin: a nested case-control study. Cancer Causes Control. 2005;16:609–18 52. McVean M, Lieber D. Prevention of DNA photodamage by vitamin E compounds and sunscreen: roles of ultraviolet absorbance and cellular uptake. Mol Carcinog. 1999;24: 69–76 53 Meyskens F, Liu Jr, Tuthill R, et al Randomized trial of vitamin A versus observation as adjuvant therapy in high-risk primary malignant melanoma: a Southwest Oncology Group study. J Clin Oncol. 1994;12(10):2060–2065 54. Meyskens F, Salmon S. Inhibition of human melanoma colony formation by retinoids. Cancer Res. 1979;39:4055–7 55. Michaelis S, Cozzio A, Kempf W, et al Combination of bexarotene and psoralen-UVA therapy in patients with Mycosis fungoides. Dermatol 2004;209(1):72–4 56. Miller V, Benedetti F, Rigas J, et al Initial clinical trail of a selective retinoid X receptor ligand, LGD1069. J Clin Oncol. 1997;15:790–795 57. Moon T, Levine N, Cartmel B, et al Retinoids in prevention of skin cancer. Cancer Lett. 1997;114(1–2):203–205 58. Nabi Z. Bioconversion of vitmain E acetate in human skin. Oxidants and antioxidants in cutaneous biology. In: Thiele J, Elsner P (eds) Current problems in dermatology. Basel, Switzerland: Karger, 2001, p. 175 59. Nakamura T, Pinnell S, Darr D, et al Vitmai C abrogates the deleterious effects of UVB radiation on cutaneous immunity by a mechanism that does not depend on TNF-a. J Invest Dermatol. 1997;109:20–4 60. Packer L, Valacchi G. Antioxidants and the response of skin to oxidative stress: vitamin E as a key indicator. Skin Pharmacol Appl Skin Physiol. 2002;282:15 61. Padayatta S, Katz A, Wang Y, et al Vitmain C as an antioxidant: evaluation of its role in disease prevention. J Am Coll Nutr. 2003;22(1):18–35 62. Palozza O, Krinsky N. b-Carotene and b-tocopherol are synergistic antioxidants. Arch Biochem Biophys. 1992;297:184–7 63. Rhee S. Cell signaling. H202, a necessary evil for cell signaling. Science. 2006;312:1882–3 64. Rivers J, McCarthy W. No effect of topical tretinoin on lentigo maligna. Arch Dermatol. 1991;127(1):129 65. Rizvi N, Marshall J, Dahut W, et al A Phase I study of LGD1069 in adults with advanced cancer. Clin Can Res. 1999;5:1658–1664 66. Saiag P, Pavlovic M, Clerici T. Treatment of early AIDSrelated Kaposi’s sarcoma with oral all-trans-retinoic acid: results of a sequential non-randomized phase II trial. Kaposi’s Sarcoma ANRS Study Group. Agence Nationale de Recherches sur le SIDA. AIDS. 1999;12:2169–76 67. Sander C, Chang H, Elsner P, et al Role of oxidative stress and the antioxidant network in cutaneous carcinogenesis. Int J Dermatol. 2004;43:326–35 68. Schadendorf D, Worm M, Jurgovsky K, et al Effects of various synthetic retinoids on proliferation and immunphenotype of human melanoma cells in vitro. Recent Results Cancer Res. 1995;139:1801.03.1993 69. Sies H, Stahl W. Vitamins E and C, beta-carotene, and other carotenoids as antioxidants. Am J Clin Nutr. 1995;62: 1315–20 70. Smit J, Cox S, Blokx W, et al Actinic keratosis in renal transplant recipients do not improve with calcipotriol cream and

185 all-tran retinoic acid cream as monotherapies or in combination during a 6-week treatment period..Br J Dermatol. 2002:147:816–8 71. So P, Fujimoto M, Epstein E. Pharmacologic retinoid signaling and physiologic retinoic acid receptor signaling inhibit basal cell carcinoma tumorigenesis. Mol Cancer Ther. 2008; 7:1275–84 72. Sondak V, Liu P, Flaherty L, et al A phase II evaluation of all-trans-retinoic acid plus interferon alfa-2a in stage IV melanoma: a Southwest Oncology Group study. Cancer J Sci Am. 1999;5(1):41–47 73. Stadler R, Otte H, Luger T, et al Prospective randomized multicenter clinical trial on the use of interferon -2a plus acitretin versus interferon-2a plus PUVA in patients with cutaneous T-cell lymphoma stages I and II. Blood. 1998;92(10):3578–3581 74. Stahl E et al Carotenoids and carotenoids plus vitamin E protect against ultraviolet light-induced erythema in tumors. Am J Clin Nutr. 2007;71:797–8 75. Stahl W, Heinrich U, Jungmann H, et al Carotenoids and carotenoids plus Vitamin E protect against ultraviolet light-induced erythema in humans. Am J Clin Nutr. 2000;71:795–8 76. Stahl W, Nicolai S, Briviba K, et al Biological activities of natural and synthetic carotenoids: induction of gap junctional communication and singlet oxygen quenching. Carcinogenesis. 1997;18:89–92 77. Stam-Posthuma J, Vink J, Cessie S, le et al Effect of topical tretinoin under occlusion on atypical naevi. Melanoma Res. 1998;8(6):539–548 78. Treloar V. Chemoprevention and vitmain E. J Am Acad Dermatol. 2007;57:903 79. Vertuani S, Angusti A, Manfredini S. The antioxidants and pro-antioxidants network: an overview. Curr Pharm Des. 2004;10 (14):1677–94 80. Walmsley S, Northfelt D, Melosky B, et al Treatment of AIDS-related cutaneous Kaposi’s sarcoma with topical alitretinoin (9-cis-retinoic acid) gel. J Acquir Immune Defic Syndr. 1999;22:235–46 81. Wernighaus K, Meydani M., Bhawan J. et al Evaluation of the protective effect of oral vitamin E supplementation. Arch Dermatol 1994; 130: 1257–61 82. Whittaker S. Biological insights into the pathogenesis of cutaneous T-cell lymphomas (CTCL). Semin Oncol. 2006; 33(1 Suppl 3):S3–S6 83. World Cancer Research Fund/American Insitute of Cancer Research. Food, nutrition and the prevention of cancer: a global perspective. WCRF/AICR 2007, Washington 84. Xu X, Wong W Goldberg L, et al Progressive decreases in nuclear retinoid receptors during skin carcinogenesis. Cancer Res. 2001; 61: 4306–10 85. Yarosh D, Klein J, O’Connor A, et al Effect of topically applied T4 endonuclease V in liposomes on skin cancer in xeroderma pigmentosum: a randomized study. Xeroderma Pigmentosum Study Group. Lancet. 2001;357:926–9 86. Yoshida E, Watanabe T, Takata T, et al Topical application of a novel, hydrophilic gamma-tocopherol derivate reduces photo-inflammation in mice skin. J Invest Dermatol. 2006; 126:1633–40

Retinoids in the Management of Non-Melanoma Skin Cancer

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Mohamed Badawy Abdel-Naser and Christos C. Zouboulis

Key Points

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Retinoids (vitamin-A metabolites and analogues) are effective in chemoprevention and chemosuppression of non-melanoma skin cancer but of no or limited efficacy as the chemotherapeutics of preexisting tumors. The main mechanisms of action are the activation of nuclear retinoid receptors, transrepression of activation protein-1 complex, growth arrest, and induction of apoptosis and differentiation. Retinoids administered systemically are associated with several adverse effects and, therefore, are mainly indicated for patients with significant current or future morbidity or mortality risk from non-melanoma skin cancer. The most accepted indications include xeroderma pigmentosum, nevoid basal cell carcinoma syndrome, immunosuppressed organ transplant recipients, and patients actively developing many new skin cancers regardless of the underlying etiology. Oral retinoid administration as a chemopreventive and chemosuppressive treatment must be continued indefinitely because discontinuation is likely to be followed by a relapse in tumor development.

C. C. Zouboulis () Departments of Dermatology, Venereology, Allergology and Immunology, Dessau Medical Center, Auenweg 38, 06847 Dessau, Germany e-mail: [email protected]

The incidence of non-melanoma skin cancer has steadily increased in recent years. This is attributed to the ultraviolet (UV) damage, hence, providing explanation for higher incidence among fair-skinned populations. Furthermore, patients with genetic diseases, such as nevoid basal cell carcinoma syndrome and xeroderma pigmentosum, and immunosuppressed organ transplant recipients are at increased risk of developing not only multiple but also metastatic and aggressive skin tumors [3, 15]. The most often applied therapies of skin tumors include curettage and electrodesiccation, surgical excision, cryotherapy [40] radiation, and lasers (Er:YAG, CO2); however, recurrences as well as scarring and cosmetically disfiguring outcomes of several of these treatments occasionally occur. Mohs micrographic surgery offers more secure therapeutic outcome but the procedure is expensive and timeconsuming and therefore is indicated for patients with risk of disfigurement or functional impairment [27]. Other therapeutic modalities include photodynamic therapy, topical treatment with 5-fluorouracil and topical application of diclofenac or imiquimod cream. However, surgical interventions do not secure a complete tumor targeting and both surgical and topical therapies do not prevent subsequent tumor development [35]. In humans, the process of carcinogenesis begins when the DNA is damaged, which then leads to a cascade of events resulting in the development of a tumor. Besides UV light, other etiological factors for non-melanoma skin cancer are chemical carcinogens such as arsenic or coal tar and ionizing radiation. The role of sunlight in the development of skin cancer has been recently elucidated. UV radiation can induce mutations in several genes involved in the initiation, promotion, and progression of non-melanoma skin cancer. UVB radiation (290–320 nm) primarily induces

G. B. E. Jemec et al. (eds.), Non-Surgical Treatment of Keratinocyte Skin Cancer, DOI: 10.1007/978-3-540-79341-0_23, © Springer-Verlag Berlin Heidelberg 2010

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cyclobutane-type pyrimidine dimers and pyrimidine pyrimidone photoproducts. Mutations arise as a result of the false repair of these products. UV radiation can also induce other types of DNA lesions, such as cytosine photohydrates, purine photoproducts, and singlestrand breaks in the DNA. On the other hand, UVA radiation (320–400 nm) can cause DNA damage indirectly by producing reactive oxygen species (ROS) such as singlet oxygen, superoxide anion, and hydrogen peroxide via endogenous photosensitizers. These highly reactive, short-lived molecules produce singlestrand breaks, DNA-protein cross-links, and altered bases in DNA. Transformation of keratinocytes occurs when the cell cycling control is lost. Several tumorsuppressor genes are involved in photocarcinogenesis, including p53 and PTCH genes. UV radiation disturbs the genetic pathway governed by these molecules [25]. Because of the well-recognized role of UV light in carcinogenesis, potent and effective sunscreens are mandatory. Moreover, additional measures are required for a subset of patients who are highly susceptible to the development of non-melanoma skin cancer. Systemic retinoids emerge as effective chemopreventive and chemosuppressive agents, a modality that is lacking in most conventional methods. Chemoprevention decreases the number of new tumors, whereas chemosuppression reduces the risk of recurrence or disease progression. Retinoids regulate a wide variety of essential biological processes, such as vertebrate embryonic morphogenesis and organogenesis, cell growth arrest, differentiation and apoptosis, immune response and homeostasis, as well as their disorders. In addition, retinoids have shown antitumor activity in models of carcinogenesis including skin cancer.

23.1 Retinoids 23.1.1 Historical Background and Retinoid Classiﬁcation The existence of vitamin A was recognized when the clinical features of hypervitaminosis A were first detected in the early 1900s among Antarctic explorers following consumption of polar bear liver. In 1931,

M. B. Abdel-Naser and C. C. Zouboulis

vitamin A in the form of retinoic acid was purified from liver oil. At almost the same time the relationship between vitamin A and cancer was suggested based on the observation of hypovitaminosis A in rats suffering from gastric cancer and epithelial changes suggestive of malignancy. These epithelial changes were in the form of squamous metaplasia, abnormal cornification, desquamation, and stratification that were fully reversed by vitamin A and other retinoids [38]. Accordingly, the development of various synthetic retinoids in the 1960s through the 1980s was accompanied with hope for novel and effective treatment of malignancies. Animal and human studies showed that high doses with intractable and severe side effects are required for chemosuppression and that retinoids have a limited efficacy in treating existing non-melanoma skin cancer. Thus, the use of retinoids as chemotherapeutic agents in human cancers has gone from a zenith in the 1990s to something of a nadir nowadays. Currently, retinoids are only effective in chemoprevention and chemosuppression of non-melanoma skin cancer [28]. The term “retinoids” includes all natural and synthetic compounds that have vitamin A activity. Vitamin A exists in three main forms, namely alcohol (retinol), aldehyde (retinal), and acid (retinoic acid). The therapeutic use of these natural compounds requires high doses that are unsafe and are accompanied by unacceptable and often intolerable side effects. Modification of the vitamin A molecule resulted in several synthetic vitamin A analogues that are more effective and with a safer therapeutic index. Currently, there are three generations of synthetic retinoids [39]: 1. The first generation (nonaromatic) retinoids include retinol, tretinoin (all-trans-retinoic acid or tRA), isotretinoin (13-cis-retinoic acid), and alitretinoin (9-cis-retinoic acid or 9cRA). Because of its inacceptable systemic toxicity, tretinoin is used only as a topical formulation. 2. The second generation (monoaromatic) retinoids include etretinate and its active metabolite acitretin. The use of etretinate has been discontinued in several countries, e.g., in the USA, and is replaced by acitretin which has a shorter half-life. 3. The third generation (polyaromatic) retinoids also known as arotinoids include tazarotene, bexarotene, and adapalene. Bexarotene is the only orally used compound [28].

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Retinoids in the Management of Non-Melanoma Skin Cancer

23.2 Mechanism of Action of Retinoids in Chemoprevention and Tumor Progression Animal studies revealed that skin carcinogenesis is a complex process involving mainly three steps, namely initiation, promotion, and progression. Initiation is induced by a carcinogen, such as topical 7, 12-dimethylbenz[a]anthracene, whereby normal cells are converted to premalignant ones. On the other hand, promotion occurs by repeated application of a tumor promoter, such as 12–0-tetradecanoylphorbol 13-acetate to the initiated skin. Promotion results in clonal proliferation of cells to form benign premalignant tumors known as papillomas. The final step is progression in which premalignant lesions convert to malignant squamous cells [7]. It has been shown that retinoids inhibit the promotion and progression steps of carcinogenesis, mechanisms that provide an explanation for their chemosuppressive and chemopreventive effects [5]. Most of the biological effects of retinoids are mediated by two classes of nuclear receptors, namely retinoic acid receptors (RARs) and retinoid X receptors (RXRs), both of which are members of the steroid hormone receptor superfamily. Each receptor has three subtypes (a, b, and g) and each subtype has different isoforms. In humans, mRNA for RAR and RXR are not uniformly expressed in different tissues and organs, a fact that may provide explanation for the variable pharmacologic effects of retinoids. In general, RAR-b and RXR-g are not expressed in skin (Table 23.1) [23]. Changes in the expression of these receptors have been considered to cause neoplasia and malignant transformation in human cells [34].

In addition, retinoids play a central role in tumor stroma production and thus in the control of tumor progression and invasion through their ability to regulate the expression of matrix metalloproteinases, transforming growth factor-b, and cell cycle regulator proteins, such as cyclin-dependent kinase I, p16 or p21 [1, 13].

23.3 Indications of Retinoids in Treatment of Non-Melanoma Skin Cancer There is a large body of literature on clinical and preclinical studies using natural retinoids and related compounds either as a monotherapy or in combination therapies for the prevention and the treatment of cancer [30]. Animal studies demonstrated that topical and systemic retinoids have a very weak and unsatisfactory effect as chemotherapeutics in treatment of existing malignant tumors but are effective as chemopreventive agents in premalignant lesions of the skin. Retinoids are used primarily in the chemoprevention and chemosuppression of certain skin tumors. Possible indications are listed in Table 23.2. Because of the several and often severe adverse effects [31] specific indications in which the benefits outweigh the risks including the overall expenses are suggested (Table 23.3).

23.4 Premalignant Cutaneous Diseases Patients with actinic keratoses [26], arsenic keratoses [6], and Bowen’s disease benefit from retinoid therapy. Keratoacanthoma and bowenoid papulosis

Table 23.1 Nature and distribution of retinoid receptors Receptor Subtype Chromosomal Natural ligand location RARs

RXRs

RARa RARb RARg RXRa RXRb RXRg

17q21.1 3p24 12q13 9q34.3 6p21.3 1q22-q23

189

tRA and 9cRA tRA and 9cRA tRA and 9cRA 9cRA 9cRA 9cRA

Major isoform

Distribution

a1 and a2 b1, b2, b3 and b4 g1 and g2 a1 and a2 b1 and b2 g1 and g2

Most tissues Neural tissue Skin Liver, kidney, spleen, skin All tissues Muscle, brain

190 Table 23.2 General indications of systemic retinoids as chemopreventive and chemosuppressive Chemopreventive agents Premalignant lesions Actinic keratoses Arsen-induced keratoses Bowen’s disease Bowenoid papulosis Syndromes and other conditions with increased risk of cutaneous malignancy Basal cell naevus syndrome Xeroderma pigmentosum Epidermal dysplasia and epidermodysplasia verruciformis Immunosuppressed organ and bone marrow transplant recipients Cutaneous malignancies Multiple basal cell carcinoma Multiple verrucous carcinomas (carcinoma cuniculatum) Squamous cell carcinoma (high risk > 20% risk of metastases) Mycosis fungoides

Table 23.3 Specific indications including specific patient populations who have a considerably increased risk for non-melanoma skin cancer • Solid organ transplant recipients with a non-melanoma skin cancer • Patients with xeroderma pigmentosum • Patients with basal cell naevus syndrome (Gorlin–Goltz syndrome) • Chronically immunosuppressed patients with a nonmelanoma skin cancer • Patients under long-term psoralene/ultraviolet A (PUVA) treatment with a non-melanoma skin cancer • Patients with radiation-induced non-melanoma skin cancer • Patients with non-Hodgkin’s lymphoma or chronic lymphocytic leukemia with a non-melanoma skin cancer • Patients with Bazex’s syndrome • Patients with Rombo syndrome • Human immunodeficiency virus-positive patients with multiple non-melanoma skin cancer lesions • Patients with epidermodysplasia verruciformis Source: [31].

also respond to retinoids. Patients with widespread conditions that are unresponsive to other basic therapeutic modalities are the proper candidates for retinoid therapy, which often needs to be sustained indefinitely to maintain clinical improvement.

M. B. Abdel-Naser and C. C. Zouboulis

23.5 Syndromes with Increased Risk of Cutaneous Malignancy Successful retinoid therapy has been reported in patients with basal cell naevus syndrome, xeroderma pigmentosum, widespread epidermal dysplasia [33], and epidermodysplasia verruciformis. High doses of isotretinoin usually 2 mg/kg/day or higher in chemoprevention of basal cell naevus syndrome and xeroderma pigmentosum have been recommended, whereas significant adverse effects are inevitable. Basal cell naevus syndrome or Gorlin-Goltz syndrome is a rare autosomal dominant disorder characterized by palmoplantar pits, odontogenic horn cysts of the jaw, and multiple basal cell carcinomas that may begin at an early age. Mutations in the human homolog of the Drosophila PATCHED-1 (i) gene have been demonstrated in some families with basal cell naevus syndrome. Xeroderma pigmentosum is a rare, autosomal recessive genetic disorder with impaired ability to repair ultraviolet radiation-induced DNA damage. These patients may develop skin cancer as early as at 2 years of age and on average develop their first skin cancer before the age of 10. They continue to develop skin cancers at a frequency of more than 1,000 times that of the general population [17]. Abnormalities in this pathway have also been associated with sporadic basal cell carcinoma [14]. Bazex’s and Rombo syndromes are other very rare autosomal dominant diseases known to present with multiple basal cell carcinomas at an early age. In addition, Bezex’s syndrome includes hypotrichosis, follicular atrophoderma of extremities, and localized or generalized hypohidrosis. Rombo syndrome is characterized by vermiculate atrophoderma causing grainy skin texture, trichoepitheliomas and acral cyanosis. Several studies demonstrated significant reduction of new malignant tumors when patients with these syndromes were maintained on oral isotretinoin given at a dosage of 2 mg/kg/day. Treatment has to be sustained indefinitely as discontinuation was followed by rebound in skin cancer frequency [12, 16].

23.6 Malignant Cutaneous Diseases Marked reduction in the formation of new basal cell carcinomas with isotretinoin with a maintenance dose of 1.5 mg/kg/day has been demonstrated [21].

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Retinoids in the Management of Non-Melanoma Skin Cancer

Cutaneous verrucous carcinoma is a rare variant of low-grade squamous cell carcinoma. It often appears as a single, slow-growing, painful, nonhealing exophytic mass or plaque with a verrucous or ulcerated surface of skin and genitalia. It usually shows a striking similarity to intractable plantar warts. Treatment with acitretin given at a dosage of 35–50 mg/day was reported to be successful in the multiple and inoperable lesions [18, 24]. Acitretin has also been used to prevent recurrence of multiple squamous cell carinomas arising following long-term treatment with psoralene/ultraviolet A and cyclosporine A combination therapy, thus providing a dual benefit for psoriasis and non-melanoma skin cancer [37]. Mycosis fungoides in early stage, i.e., in patch and plaque stages, is mainly treated by psoralene/ultraviolet A in combination with retinoids and/or interferon alfa in order to improve response rates. Retinoids may reduce the total number of psoralene/ultraviolet A sessions, whereas both isotretinoin and etretinate have been shown to be efficient in the treatment of mycosis fungoides. A clinical response was detected in 44% of patients. The initial dose is 1 mg/kg/day and may be increased up to 3 g/day if tolerated. Retinoids may be effective in stage IB (T2) and III patients and palliative in stage IVA. Bexarotene (Targretin™), a synthetic third-generation oral retinoid (“rexinoid”), that is bound preferentially by RXR induces apoptosis in a number of tumor cell lines. It has been approved for treatment of cutaneous T-cell lymphoma [8]. A 45% response rate was reported in regimens of 300 mg/m2/ day. Combination therapy with either psoralene/ultraviolet A or extracorporal photophoresis is also reported to enhance the response [36].

23.7 Organ Transplantation The development of skin cancer in organ transplant recipients is the result of a complex interplay between exposure to ultraviolet radiation, human papillomavirus infection, and genetic predisposition. Oral retinoids have some effect in reducing the number of hyperkeratotic skin lesions and in the prevention of skin cancer in organ transplant recipients [19]. Based on case reports, survey studies, and randomized controlled studies, the chemopreventive and chemosuppressive role of acitretin has

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Table 23.4 Indications for use of oral retinoids in organ transplant recipients [15] Strong 1. Five or more low-risk squamous cell carcinomas yearly with or without extensive actinic keratoses 2. Two or more high-risk squamous cell carcinomas yearly with or without extensive actinic keratoses 3. In transit, nodal, or systemic squamous cell carcinoma Moderate 1. Extensive actinic keratoses without squamous cell carcinoma 2. One to five low-risk squamous cell carcinomas yearly with extensive actinic keratoses 3. Two to five low-risk squamous cell carcinomas yearly without extensive actinic keratoses 4. One high-risk squamous cell carcinoma yearly with or without extensive actinic keratoses

been confirmed and indications of its use have been outlined (see Table 23.4) [15].

23.8 Selection of Patients for Retinoid Chemoprevention and Chemosuppression Patients who may benefit from retinoid chemoprevention and chemosuppression are those reported in Tables 23.2, 23.3, and 23.4.

23.9 Selection of Retinoids 23.9.1 Retinoids as Monotherapy Most published studies on non-melanoma skin cancer chemoprevention used isotretinoin, etretinate, acitretin, and bexarotene. Due to its shorter half-life, isotretinoin has been used primarily in xeroderma pigmentosum and basal cell naevus syndrome and is the drug of choice for similar indications for women of childbearing potential. On the other hand, acitretin and its predecessor etretinate have been used in organ transplantation recipient individuals and generally in older populations. Bexarotene has been approved by the Food and Drug Administration for use in cutaneous T-cell lymphoma patients.

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23.9.2 Retinoids in Combination Therapies 1. Mucocutaneous: The most common mucocutaneThe combined use of two or more agents is often advantageous since it permits lower drug dosages, thereby decreasing the overall toxicity and also providing the potential for synergistic effects between agents. Attempts of enhancing the chemopreventive and chemosuppressive effects of systemic retinoids revealed inconsistent results. In vitro studies showed a synergistic antitumor activity of isotretinoin and several cytokines. Also, preliminary clinical data demonstrated high response rates in patients treated with a combination of interferon alfa and isotretinoin [22]. Similarly, a randomized phase II study using a combination of interleukin-2 and isotretinoin as a maintenance therapy reported clinical improvement of progression-free survival and overall survival in patients with metastatic colorectal cancer [32]. On the other hand, results of a phase III trial did not show any benefits from the use of isotretinoin plus interferon alfa as an adjuvant therapy of aggressive skin squamous cell carcinoma as patients continued to develop new lesions while they were on treatment [2]. In most of these studies the number of patients was small and, therefore, larger studies are needed to confirm the benefits of combining retinoids with cytokines with known antitumor activities in the management of non-melanoma skin cancer.

23.10 Adverse Events of Systemic Retinoid Chemoprevention In general, most of the adverse effects are dosedependent and reversible upon discontinuation of the retinoid therapy (Table 23.5) [29].

ous adverse events are cheilitis occurring in more than 95% of the patients and dry skin with increased fragility in 80%. Retinoid dermatitis can mimic pityriasis rosea, rosacea, mycosis fungoides, and eczema craquelé and may proceed to erythroderma. 2. Neuro-ocular: Ocular side effects are more common with isotretinoin. Blepharoconjunctivitis may occur in 20–50% of the patients, which may be superadded by Staphylococcus aureus infection. Photophobia, blurred vision and ocular discomfort are infrequent. Corneal erosions leading to corneal opacities and impaired night vision may occur but they slowly resolve following discontinuation of retinoids. Most ocular changes are due to decreased tear formation and its lipid content. Regular use of artificial tears and antistaphylococcal antibiotics for superadded infection usually alleviate the symptoms. Irreversible eye dryness, abnormal night vision and cataract may rarely occur. Pseudotumor cerebri (benign intracranial hypertension) is the most important neurologic side effect. It is manifested by headache accompanied with nausea, vomiting, and visual changes due to papilliedema. Half of the reported cases were taking tetracycline or minocycline concomitantly. Although depression, irritability, and suicidal intentions have been reported, a causal relationship has not been demonstrated [9, 11]. 3. Gastrointestinal: Nausea, diarrhea, abdominal pain and hepatotoxicity are characteristic gastrointestinal side effects of retinoids. 4. Musculoskeletal: DISH-like hyperostosis, lesions mimicking seronegative spondyloarthropathy, arthralgia, myopathy, muscular damage and musculoskeletal pain can occur under retinoids.

Table 23.5 Adverse effects of retinoid chemoprevention therapy Side effects Findings Mucocutaneous

Cheilitis (90%), mucocutaneous xerosis (30%), nose-bleeding (15%), mild hair loss, augmented skin fragility, palmoplantar desquamation (80%) Ocular Keratitis, corneal ulceration, blurred vision, decreased vision, photophobia, decreased dark adaptation, papilledema, corneal opacities, and retinal dysfunction Gastrointestinal Nausea, diarrhea, abdominal pain, hepatotoxicity Rheumatological DISH-like hyperostosis (30%), lesions mimicking seronegative spondyloarthropathy, musculoskeletal pain and arthralgia, muscular damage with myopathy and vasculitis Neuromuscular Headache, fatigue, lethargy, myopathy, pseudotumor cerebri, depression, irritability, psychosis Laboratory abnormalities Hypertriglyceridemia (50%), hypercholestinemia (30%), decrease in HDL, increase in LDL, mild transaminase increase (20–30%) Teratogenicity Congenital defects including CNS abnormalities, ear, eye and craniofacial abnormalities, cardiovascular abnormalities, bone and thymus abnormalities

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Retinoids in the Management of Non-Melanoma Skin Cancer

5. Metabolic: Increased serum lipids (hypertriglyceridemia > hypercholestinemia) with decreased HDL and increased LDL as well as mild transaminase increase are characteristic metabolic side effects of retinoids. Teratogenicity is the most important side effect of retinoid therapy. Unlike other adverse events, teratogenicity is dose-independent. The most common congenital defects caused by retinoids are those in the central nervous system (hydrocephalus, cranial nerve abnormalities), craniofacial anomalies (anotia, microtia, absent external auditory canal), cardiac abnormalities (septal defects, aortic arch abnormalities) and thymus abnormalities (aplasia, hypoplasia). These defects are also known collectively as retinoic acid embryopathy [20]. The USA package insert recomTable 23.6 Retinoid monitoring guidelines Baseline • Pregnancy test in serum (in women of childbearing potential) • Complete blood count • Liver function tests: AST (SGOT), ALT (SGPT), alkaline phosphatase and bilirubin • Lipid profile during fasting (triglycerides, cholersterol and high density lipoprotein) • Renal function tests (blood urea, creatinine) • Urinalysis • Other routine chemistry (optional) Follow-up • Clinical evaluation monthly for first 4–6 months, then every 3 months At 2 weeks • Liver function tests • Triglyceride and cholesterol levels (fastinga) Monthly for the first 4–6 months, then every 3 months • Complete blood count • Liver function tests • Triglyceride and cholesterol levels (fastinga) • Renal function test, urinalysisb Periodically as indicated by the clinical history and symptoms • Pregnancy test in serum • X-ray of significantly symptomatic joints with long-term therapy • Yearly X-ray of ankle or thoracic spine (optional) More frequent surveillance is needed if laboratory values are abnormal a Lipids should be drawn after ³12-h fasting and 36-h abstinence from ethanol. b Renal function tests and urinalysis are infrequently altered by retinoids; consider performing them every other time a laboratory evaluation is done.

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mends two negative pregnancy tests to be obtained before starting treatment and monthly while on treatment. It also recommends the use of two forms of effective contraception for 1 month before starting isotretinoin, continuing through treatment and for at least 1 month after discontinuation of drug use. Acitretin has the same advisory as isotretinoin with the additional recommendation of using two forms of effective contraception for 3 years after cessation of treatment. Ethanol avoidance is also recommended as it can lead to conversion of acitretin to etretinate which has a much longer half life. A new risk-management program called iPLEDGE was implemented in the USA as mandatory in March 2006 [10]. Retinoid monitoring guidelines (Table 23.6) and management of retinoid side effects (Table 23.7) [31] are well-defined and allow a better individual control of retinoid treatment.

23.11 Take Home Message • Retinoids are not a substitute of the conventional therapy of non-melanoma skin cancer; they are only adjuvant. • Systemic retinoids are of proven efficacy in chemoprevention and chemosuppression of non-melanoma skin cancer but consideration of cost and risk–benefit ratio is critical in making decision of their use. • The dosage of systemic retinoids should be individualized for specific patients and preferably given in a gradual dose escalation to an effective dose. • The goal of chemoprevention is not complete inhibition of new non-melanoma skin cancer formation as it often requires high and often intolerable doses. • Isotretinoin is the drug of choice for women of childbearing potential and is commonly used in xeroderma pigmentosum and basal cell naevus syndrome, whereas acitretin is used for patients with organ transplants, psoriasis, and severe actinic damage. • Retinoid treatment in association with sun protection and early diagnosis and management of nonmelanoma skin cancer may lead to decreased number of new skin cancers. • The use of oral retinoids is associated with a number of cumbersome adverse events and it is important for physicians and patients to work together to develop a working skin cancer management plan [4].

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Table 23.7 Management of adverse effects of retinoids for chemoprevention (in organ transplant recipients, active management of hyperlipidemia is mandatory due to the high rate of atherosclerotic disease in this population. Other uncommon adverse events are managed on a case-by-case basis) [31] Adverse Effect Management options Comments Hypercholesterinemia

Hypertriglyceridemia

Increased liver function tests

Arthralgia/myalgia Mucocutaneous

Atorvastatin (10 mg daily, increased to a maximum of 80 mg daily, based on response maximum of 80 mg daily, based on response) or other lipid-reducing agent Gemfibrozil, 600 mg twice daily

Liver function tests = 1–3 × normal levels: decrease dose by 50% and recheck in 2 weeks; stop use of ethanol and acetaminophen. Liver function tests > 3 × normal: discontinue use and recheck every 2 weeks until resolved; consider reintroduction at 25% dose Decrease dose by 25% until resolved Aggressive application of emollients to skin twice daily; vitamin B-containing ointment to lips 5–10/day; petrolatum inside nose each evening; moisturizing soaps or soapless cleansers; tepid showers/baths; artificial tears to eyes as needed and Lacri-Lubez ointment to eyes each evening; avoid wearing contact lenses; decrease dose by 25% for severe involvement

References 1. Ayer DE, Lawrence QA, Eisenman RN. Mad-Max transcriptional repression is mediated by ternary complex formation with mammalian homologs of yeast repressor Sin3. Cell. 1995;80:767–76 2. Brewster AM, Lee JJ, Clayman GL, Clifford JL, Reyes MJ, Zhou X, Sabichi AL, Strom SS, Collins R, Meyers CA, Lippman SM. Randomized trial of adjuvant 13-cis-retinoic acid and interferon alfa for patients with aggressive skin squamous cell carcinoma. J Clin Oncol. 2007;25:1974–8 3. Campbell RM, Digiovanna JJ. Skin cancer chemoprevention with systemic retinoids: an adjunct in the management of selected high-risk patients. Dermatol Ther. 2006;19:306–14 4. Cheepala SB, Syed Z, Trutschl M, Cvek U, Clifford JL. Retinoids and skin: microarrays shed new light on chemopreventive action of all-trans retinoic acid. Mol Carcinogen. 2007;46:634–9

Decrease dietary fat intake; increase exercise; liver function tests every 3 months (same as with retinoids); creatine kinase at baseline and monthly for 3 months, at dose changes, and then every 3 months; combination with gemfibrozil is generally avoided because of risk of rhabdomyolysis Decrease dietary fat intake; increase exercise; combination with atorvastatin is generally avoided because of risk of rhabdomyolysis; decrease retinoid dose by 50% if triglycerides > 5.64 mmol/l; discontinue retinoid if triglycerides > 9.03 mmol/l; may reinitiate use of retinoids after medical therapy of hypertriglyceridemia is maximized Minimize use of ethanol and acetaminophen; avoid concomitant use of methotrexate; consider hepatology consultation if liver function tests > 3 × normal; use caution with patients with preexisting liver disease

Preventive measures should be used from beginning of retinoid therapy

5. Chen L-C, De Luca LM. Retinoid effects on skin cancer. In: Mukhtar H (ed) Skin cancer: mechanisms and human relevance. Boca Raton, FL: CRC Press, 1994, pp. 401–24 6. Coburn PR, Cream JJ, Glaser M. Arsenical keratosesresponse to etretinate and electron beam therapy. Br J Dermatol. 1983;109(suppl 24):72 7. DiGiovanni J. Multistage carcinogenesis in mouse skin. Pharmacol Ther. 1992;54:63–128 8. Duvic M, Hymes K, Heald P, Breneman D, Martin AG, Myskowski P, Crowley C, Yocum RC; Bexarotene Worldwide Study Group. Bexarotene is effective and safe for treatment of refractory, advanced-stage cutaneous T-cell lymphoma: multinational phase II-III trial results. J Clin Oncol. 2001;19:2456–71 9. Enders SJ, Enders JM. Isotretinoin and psychiatric illness in adolescents and young adults. Ann Pharmacother. 2003;37: 1124–7 10. Food and drug administration. iPLEDGE Update 2006. http://www.fda.gov/cder/drug/infopage/accutan/iPLEDGE update

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11. Gold JA, Schupack JL, Nemel MA. Ocular side effects of retinoids. Int J Dermatol. 1989;28:218–25 12. Goldberg LH, Hsu SH, Alcalay J. Effectiveness of isotretinoin in preventing the appearance of basal cell carcinomas in basal cell nevus syndrome. J Am Acad Dermatol. 1989;21: 144–5 13. Hassig CA, Fleischer TC, Billin AN, Schreiber SL, Ayer DE. Histone deacetylase activity is required for full transcriptional repression by mSin3A. Cell. 1997;89:341–7 14. Kimonis VE, Goldstein AM, Pastakia B, Yang ML, Kase R, DiGiovanna JJ, Bale AE, Bale SJ. Clinical manifestations in 105 persons with nevoid basal cell carcinoma syndrome. Am J Med Genet. 1997;69:299–308 15. Kovach BT, Murphy G, Otley CC, Shumack S, Ulrich C, Stasko T. Oral retinoids for chemoprevention of skin cancers in organ transplant recipients: results of a survey. Transplant Proc. 2006;38:1366–8 16. Kraemer KH, DiGiovanna JJ, Moshell AN, Tarone RE, Peck GL. Prevention of skin cancer in xeroderma pigmentosum with the use of oral isotretinoin. N Engl J Med. 1988;318: 1633–7 17. Kraemer KH, Lee MM, Scotto J. DNA repair protects against cutaneous and internal neoplasia: evidence from xeroderma pigmentosum. Carcinogenesis. 1984;5:511–4 18. Kuan Y-Z, Hsu H-S, Kuo T-T, Huang Y-H, Ho H-C. Multiple verrucous carcinomas treated with acitretin. J Am Acad Dermatol. 2007;56:s29–32 19. Kuijken I, Bouwes Bavinck JN. Skin cancer risk associated with immunosuppressive therapy in organ transplant recipients: epidemiology and proposed mechanisms. BioDrugs. 2000;14:319–29 20. Lammer EJ, Chen DT, Hoar RM, Agnish ND, Benke PJ, Braun JT, Curry CJ, Fernhoff PM, Grix AW Jr, Lott IT, et al Retinoic acid embryopathy. N Eng J Med. 1985;313: 837–41 21. Lippman SM, Kesseler JF, Meyskens FL Jr. Retinoids as preventive and therapeutic anticancer agents (Part II). Cancer Treat Resp. 1987;21:493–515 22. Lippman SM, Parkinson DR, Itri LM, Weber RS, Schantz SP, Ota DM, Schusterman MA, Krakoff IH, Gutterman JU, Hong WK. 13-cis-retinoic acid and interferon alpha-2a: effective combination therapy for advanced squamous cell carcinoma of the skin. J Natl Cancer Inst. 1992;84: 235–41 23. Mangelsdorf DJ, Thummel C, Beato M, Herrlich P, Schutz G, Umesono K, Blumberg B, Kastner P, Mark M, Chambon P, Evans R. The nuclear receptor superfamily: the second decade. Cell. 1995;83:835–9 24. Mehta RK, Rytina E, Sterling JC. Treatment of verrucous carcinoma of vulva with acitretin. Br J Dermatol. 2000;142: 1195–8

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25. Melnikova VO, Ananthaswamy NH. Cellular and molecular events leading to the development of skin cancer. Mut Res. 2005;571;91–106 26. Moriatry M, Dunn J, Darragh A, Lambe R, Brick I. Etretinate in treatment actinic keratosis: A double blind cross over study. Lancet. 1982;8268:364–5 27. Nexville JA, Welch E, Leffell DJ. Management of nonmelanoma skin cancer in 2007. Oncology. 2007;4:462–9 28. Nguyen EH, Wolverton SE. Systemic retinoids. In: Wolverton SE, Wilkin JK (eds) Systemic drugs for skin diseases. Philadelphia, PA: WB Saunders, 2000, pp. 269–310 29. Orfanos CE, Zouboulis CC, Almond-Roesler B, Geilen CC. Current use and future potential role of retinoids in dermatology. Drugs. 1997;53:358–88 30. Ortiz MA, Bayon Y, Lopez-Hernandez FJ, Piedrafita FJ. Retinoids in combination therapies for the treatment of cancer: mechanisms and perspectives. Drug Resist Updat. 2002;5:162–75 31. Otley CC, Stasko T, Tope WD, Lebwohl M. Chemoprevention of nonmelanoma skin cancer with systemic retinoids: practical dosing and management of adverse effects. Dermatol Surg. 2006;32:562–8 32. Recchia F, Saggio G, Cesta A, Candeloro G, Di Blasio A, Amiconi G, Lombardo M, Nuzzo A, Lalli A, Alesse E, Necozione S, Rea S. Phase II study of interleukin-2 and 13-cisretinoic acid as maintenance therapy in metastatic colorectal cancer. Cancer Immunol Immunother. 2007;56: 699–708 33. Shuttleworth D, Marks R, Griffin PJ, Salaman JR. Treatment of cutaneous neoplasia with etretinate in renal transplant recipients. Q J Med. 1988;68:717–25 34. Soprano DR, Qin P, Soprano KJ. Retinoic acid receptors and cancers. Annu Rev Nutr. 2004;24:201–21 35. Sziemies RM, Karrer S. Towards a more specific therapy: targeting nonmelanoma skin cancer cells. Br J Dermatol. 2006;145:16–21 36. Talpur R, Ward S, Apisanthanarax N, Breur-Mcham J, Duvic M. Optimizing bexrotene therapy for cutaneous T-cell lymphoma. J Am Acad Dermatol. 2002;47:627–88 37. Van de Kerkhof PC, de Rooij MJ. Multiple squamous cell carcinomas in a psoriatic patient following high-dose photochemotherapy and cyclosporine treatment: response to long term acitretin maintenance. Br J Dermatol. 1997;136:275–8 38. Wolbach SB, Howe PR. Tissue changes following deprivation of fat soluble vitamin A. J Exp Med. 1925;47:753–77 39. Zouboulis CC, Orfanos CE. Retinoids. In: Millikan LE (ed) Drug therapy in dermatology. New York/Basel, Switzerland: Marcel Dekker, 2000, pp. 171–233 40. Zouboulis CC. Kryochirurgie. In: Szeimies R-M, Hauschild A, Garbe C, Kaufmann R, Landthaler M (eds) Tumoren der Haut. Grundlagen - Diagnostik - Therapie. Stuttgart, Germany: Thieme (2009, in press)

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PDT for Cancer Prevention C. A. Morton

Key Points

› › › ›

PDT has a great potential as a preventive agent for NMSC. Immunocompromised patients at increased risk of skin cancer could gain the most from regular prophylactic PDT. A preventive program for OTR patients commenced before multiple neoplasia develop may greatly benefit this group. Additional long-term studies with reliable clinically relevant outcomes are needed.

Can PDT prevent skin cancer, and if so, is there a practical protocol that could be employed to reduce the cancer burden for high-risk patients? PDT practitioners are certainly aware of the high efficacy of topical PDT for actinic keratoses (AK), in situ squamous cell carcinoma (SCC), Bowen’s disease (BD), and superficial and thin nodular basal cell carcinomas (BCC). In patients with multiple lesions, with histories of rapid development of new lesions, there is a clinical impression of delay in new lesion development where photosensitizer has been applied to the area of light illumination (“field-PDT”). The concept of field cancerization has been reexplored in view of the emergence of area therapies such as PDT that might delay/prevent cancer development.

C. A. Morton Department of Dermatology, Stirling Royal Infirmary, Livilands, Stirling, Scotland, FK8 2AU, UK e-mail: [email protected]

The relative contribution of primary prevention of de novo lesions and treatment of preclinical lesions requires careful consideration in deciding upon the mechanism for the observed reduction in the expected new skin cancers. In this chapter, the current evidence for the delay/prevention of skin cancer by PDT is explored.

24.1 Current Evidence: In Vivo Studies Repeated topical and systemic ALA-PDT has been shown to delay the appearance of ultraviolet (UV)induced skin cancer in mice. Because of the difficulty in prospective human studies in cancer prevention over a short time frame, the immunocompetent hairless mouse model has been studied by several research teams. The hairless mouse develops skin tumors within 2–4 months of daily UV exposure, developing AKs, which later develop into invasive squamous cell carcinomas (SCC). In an early experiment, Stender et al. [1], (Table 24.1) demonstrated that topical ALA-PDT delayed photo-induced carcinogenesis in hairless mice. A total of 140 mice were divided into seven groups: solar-UV exposure, UV+ cream base and visible light once in a week, UV and PDT once in a week, UV and PDT once in every second week, UV and PDT in every fourth week, PDT once in a week, or no treatment. The time to first and to second tumor was significantly longer in the PDT-treated mice than in mice only exposed to UV and UV/cream base and visible light. However, significantly, more PDTtreated mice were withdrawn because of the development of large tumors. The reason for this was unclear although it is reassuring that subsequent studies have failed to replicate this observation.

G. B. E. Jemec et al. (eds.), Non-Surgical Treatment of Keratinocyte Skin Cancer, DOI: 10.1007/978-3-540-79341-0_24, © Springer-Verlag Berlin Heidelberg 2010

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Table 24.1 In vivo mouse studies on skin cancer prevention following PDT Study Type of PDT Treatment protocol Stender et al. [1]

Topical ALA

Daily UV + Weekly, bi-weekly or monthly PDT. Assessed time to first and second tumor Sharfaei et al. [2] Systemic ALA UV 6 days/week + weekly PDT up to 24 weeks Liu et al. [3] Topical ALA UV 5 days/week + weekly PDT Sharfaei et al. [4] Topical MAL UV 5 days/week + weekly PDT for 26 weeks Caty et al. [7] Topical MAL UV 5 days/week + weekly PDT for 20 weeks Bissonnette et al. [6] Topical ALA PDT weekly for 10 months, observation for 12 months a Observation of excess large tumors not observed with any subsequent study.

Sharfaei et al. [2] studied the potential for weekly systemic suberythemogenic ALA-PDT to prevent the appearance of UV-induced tumors in hairless mice. The tumor-free survival was significantly longer for mice exposed to daily UV and weekly PDT (ALA delivered via intra-peritoneal injection) as compared with the control groups. Neither the mortality nor the incidence of large skin tumors was higher in the PDT group. Liu et al. [3] compared the ability of topical and systemic ALA-PDT to delay the appearance of UV-induced skin cancer in hairless mice. Tumorfree survival was compared for mice exposed to UV (5 days/week) and treated weekly with PDT with mice exposed only to UV radiation. Weekly topical or systemic ALA-PDT was able to delay the induction of skin tumors. In this study, a delay in both AK and SCC was observed and the delay was evident whether or not PDT was started concurrent with or at the end of UV exposure. Sharfaei et al. [4] also studied the effect of weekly PDT using topical application of methyl aminolaevulinate (MAL), the current most widely licensed topical photosensitizing agent for PDT, on the induction of skin tumors in UV-exposed mice. The group of mice receiving PDT developed far fewer large tumors after 26 weeks of UV exposure, with only one tumor in the UV/PDT group, compared with 14 in the UV-only group. In mice treated on one side with MAL, and the other side only with vehicle, the tumor delay was only observed on the MAL-PDT side, suggesting a local rather than systemic effect. If PDT as a preventive therapy is to become an established therapy, there is a need to confirm that the

Type of lesions delayed/prevented Delayed development of AK (but more SCC observed)a AK and SCC AK and SCC AK and SCC BCC No tumors induced by repeated PDT

very act of delivering repeated treatments with PDT does not risk promoting cancer development, noting that there is evidence for pro-oxidant and genotoxic potential as well as antioxidant and antimutagenic properties of ALA-PDT [5]. Bissonnette et al. [6] therefore assessed the carcinogenic potential of multiple PDT sessions on hairless mice. The mice received weekly treatments with either ALA alone, blue light alone or ALA-PDT using blue light, for a total of 10 months, followed by an additional 2-month observation. No skin tumors were noted to be induced in all the treatment groups, supporting the view that repeated PDT using visible light appears to be safe, in contrast to the well-established carcinogenic potential of UV light. More recently, from this group, Caty et al. [7] described a study of the ability of multiple large surface MAL-PDT treatments to prevent BCC, using the PTCH heterozygous mouse as a model. These mice develop microscopic BCCs when chronically exposed to ultraviolet light. Mice were exposed either to UV 5 days/week alone, or plus weekly MAL-PDT for 20 weeks. Eight weeks later, 19 BCC were found in 9 out of 20 mice exposed to UV only whereas there were no BCC in 15 mice additionally exposed to PDT.

24.2 Evidence for Cancer Prevention: Clinical Studies Topical PDT is effective in treating precancerous lesions in organ transplant recipients (OTR) suggesting the potential of this modality in reducing the development

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Table 24.2 Comparison of parameters for clinical studies of cancer prevention in OTR Study Wulf et al. [12] Wennberg et al. [13] Type of PDT Lesion preparation Light Time since transplant (years) Sites treated Protocol

Primary outcome

MAL Yes Red 16 (4–32) Face, hand Single treatment – standard dosimetry for AK/BCC Delayed occurrence of AK, no new BCC nor SCC

MAL Yes Red 16 (3–34) Face, scalp, trunk, or extremities PDT day 1 + 8, then 3, 9, and 15 months – standard dosimetry for AK/BCC Reduced AKs – significant at 3 and 15 months

of invasive skin cancer. Dragieva et al. [8, 9] demonstrated clearance of AK and Bowen’s disease following topical PDT in two studies of OTR patients. Clinical response rates for OTR (n = 20) and immunocompetent (n = 20) individuals were compared in an open prospective trial of PDT (ALA application for 5 h, illumination with a noncoherent light source: 600–730 nm, 75 J/cm2, 80 mW/cm2) for AK and BD [8]. Clinical response in both groups was similar at 4 weeks, at 86% and 94% respectively. However, by 48 weeks the response rate in the OTR patients had reduced to 48% compared to 72% in the immunocompetent patients. The reduced effectiveness of topical PDT in OTR patients compared to immunocompetent individuals lends support to the importance of the role of immune response factors in its mechanism of action. Although a disappointing observation, this suggests that PDT protocols require to be optimized in OTR patients to maximize its cytotoxic mechanism of action. The same group reported in a randomized controlled trial, clearance of AK in 13 of 17 OTR at 16 weeks in areas treated by MAL-PDT (3 h application, illumination with noncoherent light: 600–730 nm, 75 J/cm2, 80 mW/cm2) [9]. Schleier et al. reported complete remission of 24 tumors (75%) in five OTR patients with 32 facial tumors (21 BCC, 8 AK, 1 keratoacanthoma and 2 SCC), following PDT (ALA application for 3–5 h, illumination with a 635 nm diode laser, 120 J/cm2, 0.1 W/cm2) [10]. Two tumors, both of the SCC lesions, were refractory to PDT. Is there evidence to suggest that topical PDT is superior to other therapies in the OTR patient group? Perrett et al. [11] compared MAL-PDT (cream application 3 h, red LED light source: 633 ± 15 nm, 75 J/ cm2, 80 mW/cm2) with topical 5-fluorouracil cream in the treatment of post-transplant epidermal dysplasia. This

De Graaf et al. [14] ALA No Blue 22 (7–34) Forearm and hand non-formulary ALA, one or two treatments (0 and 6 months) using a non-licenced protocol No decrease in observed SCC over 2-year follow-up

small intra-patient comparison in eight patients, revealed that PDT (two treatments 7 days apart) was more effective and cosmetically acceptable than 5-FU (applied twice daily for 3 weeks) at 6-month follow-up, the former clearing 8/9 lesion areas, compared with only 1/9 areas treated by the latter (lesional area reduction: PDT 100%, 5-FU: 79%). These studies demonstrate that PDT can clear premalignant lesions, with the presumption that this might reduce the pool of lesions available to transform into invasive, potentially fatal, squamous cell carcinoma. Another study approach has been to prophylactically treat areas of skin in patients at high risk of skin cancer, with PDT, and prospectively observe for delays/prevention of anticipated new lesions (Table 24.2). Wulf et al. [12] performed an open intra-patient randomized pilot study of 27 renal transplant patients with AK and other skin lesions. Two contra-lateral areas each with at least two AKs and up to ten lesions (AK, BCC, warts) received either topical MAL-PDT, using a standard protocol (3 h cream application, then noncoherent red light 570–670 nm, light dose 75 J/cm2) or no treatment. Patients studied had received immunosuppressive therapy for a mean period of 16 years (4–32 years) and had a median age at transplantation of 41–44 years. The mean time to the occurrence of the first new lesion was significantly longer in treated than control areas (9.6 vs 6.8 months). Over 12 months, 62% (16/26) of treated areas were free from new lesions compared with 35% (9/26) in control areas, suggesting a preventive effect of PDT in this high-risk patient group. Most new lesions were AK, with no new SCC or BCC observed. The absolute number of new lesions was three times higher in the control than treated areas at 12 months. Only one PDT treatment

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a

C. A. Morton

b

Fig. 24.1 Extensive AK on the forehead (a) before and (b) 5 years following topical ALA-PDT

was applied, so that lesion response was not optimal, with 56% of the original AK lesions clear at 4 months and 37% of warts. Further delay/prevention, as well as improved efficacy towards clinically obvious lesions would be expected with additional PDT treatments during this 12-month period. Wennberg et al. [13] performed a multi-centre intrapatient comparison study in OTR patients, to date presented, but not published, comparing the occurrence of new lesions (AK, BCC, SCC, and warts) in symmetrical areas receiving either MAL-PDT or no treatment. Patients had received immunosuppressive therapy for at least 3 years, and required to have at least two AK and no more than ten lesions in each of two symmetrical contralateral areas, each measuring 5 × 10 cm. MAL-PDT was performed using the standard licensed protocol (cream for 3 h, red LED light: 630 nm, 37 J/ cm2) with two treatments 1 week apart at baseline, then single treatments after 3, 9, and 15 months, with subsequent lesion-specific therapy only at 21 and 27 months, if required. On the control side, lesion-specific therapies were performed at baseline and then at the investigators discretion at review appointments. At each time-point, more AK lesions were observed in the control area compared with the PDT treated sites, significant at 3 and 15, but not at 27 months. For patients transplanted within 15 years from recruitment, the protective effect of PDT appeared to be greatest, with 33% fewer AK on the treated sides, compared with 15% for the patient group transplanted over 15 years. This study suggests that prospective

PDT treatments can significantly reduce AK development, especially for patients with shorter time since transplantation. The results suggest that additional treatments might have maintained the significant improvement to the final time-point at 27 months and those protocols for preventive PDT still need refinement. Evidence of prevention of BCC/SCC awaits full study publication (Fig. 24.1). De Graaf et al. [14], however, published a study indicating that topical PDT does not prevent SCC in OTR patients. In this randomized controlled trial of 40 patients, 23 patients received only a single PDT treatment (nonformulary ALA preparation applied for 4 h, noncoherent blue light: 400–450 nm, 5.5–6 J/cm2) whilst the remaining patients received treatments at baseline and 6 months. Reviews were performed 3 monthly over 2 years. No significant difference in the occurrence of new SCC was observed between the treated and control limbs (15 SCC in 9 PDT-treated limbs, 10 SCC in nine control arms) and no difference was noted between those patients receiving a single versus repeat PDT treatments. Full results were available in only 33 patients (five nonskin cancer deaths and two losses to follow-up). The number of keratotic lesions in the arms randomized to PDT did, however, contain a mean of 4.5 more lesions than the control limbs. PDT led to a less pronounced further increase in these lesions at 9 and 12 months. The differences in these studies are highlighted in Table 24.2. The patients studied by de Graaf et al. [14] had received immunosuppression for an overall longer

24

PDT for Cancer Prevention

period than patients in the other two trials, with the suspicion that preventive treatment here might simply have been “too little, too late” in this study. PDT delivered using more superficial wavelengths than red are known to not achieve the same level of success in PDT for lesions beyond AK, with green light significantly inferior to red light in one study of squamous cell carcinoma in situ [15]. The relevance of the use of ALA rather than MAL in this study is not known, with mice studies suggesting the photosensitizers can achieve a similar effect. The absence of lesion preparation and the lack of overall decrease in keratotic lesions, unlike the other studies, suggest that the PDT treatments were not as effective as in the other two clinical studies. Nevertheless, it remains a concern that, to date, the prevention of SCC using PDT has not been conclusively demonstrated. Conventional thinking suggests that OTR patients are vulnerable to SCC with histological features of aggressive potential. However, Harwood et al. [16] failed to demonstrate more aggressive pathology in a large retrospective case-control series of OTR recipients where 160 transplant tumors were compared with 165 immunocompetent tumors. Reported differences in overall prognosis may therefore reflect greater tumor burden, suggesting that regular reviews of such patients possibly combined with proactive early preventive therapy such as PDT might reduce risks in this patient group. A few authors have made specific comment about the sustained clearance, and absence of new lesions, following PDT. Itkin and Gilchrest [17] reported the successful treatment of two patients with naevoid basal cell carcinoma syndrome (NBCCS) by ALA-PDT, with no new lesions in PDT-treated sites during 8 months of follow-up. Oseroff et al. [18] reported multiple large area ALA-PDT treatments for three further children with NBCCS with clearance rates of 82–93% achieved. During follow-up of 2–6 years, there was no evidence of new BCC on treated sites, a remarkable achievement given the many hundreds of small lesions originally treated. This concurs with my own experience of PDT over 12 years, where large area treatments with PDT in “heart-sink” patients presenting with multiple non-melanoma cancers and precursor lesions can achieve a sustained improvement with the impression of slowed rate of development of new lesions. This is manifest in the clinic by patients’ initial intensive attendance for treatment of all visible lesions

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over 6 months or more, often at monthly intervals, then follow-up treatments at 6-monthly intervals, where a few individual new lesions might require treatment.

24.3 Preventive PDT: Mechanism of Action The opportunity for skin cancer prevention via treatment of the area around existing tumors has seen considerable recent interest following conformation of cancer-associated genetic alterations in tumor-adjacent macroscopically normal tissue [19]. There is evidence that the majority if not all head-and-neck squamous cell carcinomas develop within a contiguous field of pre-neoplastic cells [20]. The development of an expanding pre-neoplastic field appears to be a critical step in epithelial carcinogenesis and is likely to be of particular importance for patients with altered immunesurveillance, including OTR. Wide area therapies, including PDT may therefore provide the opportunity for treatment both of clinically visible disease, and adjacent subclinical lesions. How is PDT delivering its effect? PDT might act either at the stage of initiation, between normal and mutated cells, via prevention of promotion between mutated cells and precancerous lesions, or via some effect on the progression to invasive cancer. Topical PDT is considered to achieve its principal effect via site-localized generation of reactive oxygen species formed by the transfer to molecular oxygen of energy captured by the light excitation of photosensitizing drugs. Topical PDT may cause selective destruction of keratinocytes-bearing mutated p53 induced by UV exposure. The use of field PDT, applying photosensitizer to the entire “at risk” surface rather than to individual lesions followed by illumination of the entire site, may induce phototoxic reactions in nonvisible sites, achieving “prevention” via the effective treatment of subclinical lesions. PDT also induces an associated host response, inducing both innate and adaptive host immune responses [21]. The relative contribution to response of this biological response modifier function remains unclear, and is reduced in immunosuppressed patients, explaining the observed reduction in efficacy of PDT in OTR patients described above [8]. The curative ability of PDT has been shown to be severely

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compromised if tumors are growing in immunodeficient hosts, as demonstrated in several mouse model experiments [22]. The immunocompetent hairless mice model fails to clarify the relative contributions of destruction of subclinical lesions versus induction of antitumor responses. The reduced efficacy is, as expected, not limited to PDT, with a trial of imiquimod in OTR patients achieving only a 36% response rate for AK and a 50% improvement in atypia after 16 weeks of treatment [23]. To the benefit of PDT, it is more than a biologic response modifier, and protocols that optimize the direct cell kill by PDT require study in this patient group. Lesion preparation, adequate interval of photosensitizer application and ensuring adequate light delivery, with repeat treatments at intervals of probably 6–12 months are likely to be required. PDT still needs to be compared to alternative potential therapies as a preventive therapy. Nevertheless, PDT offers the opportunity for treatment of large areas of susceptible skin, is noninvasive, with no reports of treatment-induced infections, and with reassuring experience, to date, over its long-term safety. Given the prevalence of cutaneous lesions in OTR patients, episodic large area PDT is likely to achieve, both, treatment of visible and subclinical lesions, as well as possible primary prevention. This contrasts, for example, with surgery for specific lesions including thin nodular BCC, followed by topical 5-fluorouracil or imiquimod, where the latter therapies would be unlikely to clear both the lesions and provide an area-wide protective effect. Topical PDT offers the advantages of being devoid of systemic adverse effects, without potential for interaction with immunosuppressive therapies. Moreover, a high-quality cosmetic outcome is widely reported in the literature following topical PDT, with reported benefits in reversing certain aspects of photo-ageing. Hence, its use on clinically normal skin should not create concern.

24.4 Conclusion There exists a great potential for PDT as a preventive agent for skin cancer although confirmation is required of its ability to prevent SCC in high-risk patients. Further studies to define a practical, viable as well as clinically effective protocol are necessary. Although

C. A. Morton

immunocompetent patients might respond best, it is immunocompromised patients at increased risk of skin cancer that could gain the most from regular prophylactic PDT. There remains no evidence to suggest PDT might prevent melanoma, but considerable in vivo and clinical research to suggest its efficacy in NMSC. OTR patients are a particular group that stands to benefit, with well-reported incremental risk of NMSC with duration of immunosuppressive therapy. A preventive program commenced before multiple neoplasia develop could greatly benefit this group. Other “at risk” patient groups, including those with NBCCS and xeroderma pigmentosum (XP), might benefit but specific studies are required. However, XP patients are very vulnerable to skin cancer and careful study of risks and benefits will be required in this group.

References 1. Stender IM, Beck-Thomsen N, Poulsen T, et al Photodynamic therapy with topical delta-aminolevulinic acid delays UV photocarcinogenesis in hairless mice. Photochem Photobiol. 1997;66:493–6 2. Sharfaei S, Viau G, Lui H, et al Systemic photodynamic therapy with aminlaevulinic acid delays the appearance of ultraviolet-induced skin tumours in mice. Br J Dermatol. 2001;144:1207–14 3. Liu Y, Viau G, Bissonnette R. Multiple large-surface photodynamic therapy sessions with topical or systemic aminolevulinic acid and blue light in UV-exposed hairless mice. J Cutan Med Surg. 2004;8:131–9 4. Sharfaei S, Juzenas P, Moan J, Bissonnette R. Weekly topical application of methyl aminolevulinate followed by light exposure delays the appearance of UV-induced skin tumours in mice. Arch Dermatol Res. 2002;294:237–42 5. Fuchs J, Weber S, Kaufmann R. Genotoxic potential of porphyrin type photosensitizers with particular emphasis on 5-aminolevulinic acid: implications for clinical photodynamic therapy. Free Rad Biol Med. 2000;28:537–48 6. Bissonette R, Bergeron A, Lui Y. Large surface photodynamic therapy with aminolaevulinic acid treatment of actinic keratoses and beyond. J Drugs Dermatol. 2004;3:S26–31 7. Caty V, Liu Y, Viau G, Bissonnette R. Multiple large surface photodynamic therapy sessions with topical methylaminolaevulinate in PTCH heterozygous mice. Br J Dermatol. 2006;154:740–2 8. Dragieva G, Hafner J, Dummer R, et al Topical photodynamic therapy in the treatment of actinic keratoses and Bowen’s disease in transplant recipients. Transplantation. 2004;77:115–21 9. Dragieva G, Prinz BM, Hafner J, et al A randomised controlled clinical trial of topical photodynamic therapy with methyl aminolaevulinate in the treatment of actinic keratoses in transplant recipients. Br J Dermatol. 2004;151:196–200

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10. Schleier P, Hyckel P, Berndt A, et al Photodynamic therapy of virus-associated epithelial tumours of the face in organ transplant recipients. J Cancer Res Clin Oncol. 2004;130: 279–84 11. Perrett CM, McGregor JM, Warwick J, et al Treatment of post-transplant premalignant skin disease: a randomized intrapatient comparative study of 5-fluorouracil and topical photodynamic therapy. Br J Dermatol. 2007;156:320–8 12. Wulf HC, Pavel S, Stender I, Bakker-Wensveen CAHB. Topical photodynamic therapy for prevention of new skin lesions in renal transplant recipients. Acta Derm Venereol. 2006;86:25–8 13. Wennberg AM, Stenquist B, Stockfleth et al Photodynamic therapy with methyl aminolevulinate for prevention of new skin lesions in transplant recipients: a randomized study. Transplantation 2008;86:423–9 14. De Graaf YGL, Kennedy C, Wolterbeek R, et al Photodynamic therapy does not prevent cutaneous squamous-cell carcinoma in organ-transplant recipients: results of a randomizedcontrolled trial. J Invest Dermatol. 2006;126:569–74 15. Morton CA, Whitehurst C, Moore JV, MacKie RM. Comparison of red and green light in the treatment of Bowen’s disease by photodynamic therapy. Br J Dermatol. 2000;143: 767–72 16. Harwood CA, Proby CM, McGregor JM, et al Clinicopathologic features of skin cancer in organ transplant recipients: a retrospective case-control series. J Am Acad Dermatol. 2006;54:290–300

203 17. Itkin A, Gilchrest B. Delta-aminolaevulinic acid and blue light photodynamic therapy for the treatment of multiple basal call carcinomas in two patients with naevoid basal cell carcinoma syndrome. Dermatol Surg. 2004;30:1054–61 18. Oseroff AR, Shieh S, Frawley NP, et al Treatment of diffuse basal cell carcinomas and basaloid follicular hamartomas in naevoid basal cell carcinoma syndrome by wide-area 5-aminolaevulinic acid photodynamic therapy. Arch Dermatol. 2005;141:60–7 19. Braakhuis BJM, Tabor MP, Kummer JA, et al A genetic explanation of Slaughters concept of field cancerization: evidence and clinical implications. Cancer Res. 2003;63:1727–30 20. Braakhuis BJM, Brakenhoff RH, Leemans CR. Second field tumours: a new opportunity for cancer prevention? Oncologist. 2005;10:493–500 21. Oseroff A. PDT as a cytotoxic agent and biological response modifier: implications for cancer prevention and treatment in immunosuppressed and immunocompetent patients. J Invest Dermatol. 2006;126:542–4 22. Korbelik M, Dougherty GJ. Photodynamic therapy-mediated immune response against subcutaneous mouse tumors. Cancer Res. 1999;59:1941–6 23. Brown VL, Atkins CL, Ghali L, et al Safety and efficacy of 5% imiquimod cream for the treatment of skin dysplasia in high-risk renal transplant recipients: randomized doubleblind, placebo-controlled trial. Arch Dermatol. 2005;141: 985–93

Dermabrasion, Laser Resurfacing, and Photorejuvenation for Prevention of Non-Melanoma Skin Cancer

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Annesoﬁe Faurschou and Merete Hædersdal

Key Points

›

›

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Rejuvenation procedures comprise ablative techniques (dermabrasion, laser resurfacing) and non-ablative photorejuvenation techniques (intense pulsed light, visible and near-infrared lasers). Rejuvenation procedures are not established for the prevention of non-melanoma skin cancer but have been suggested to serve this purpose by eliminating malignant skin cells. In murine studies, dermabrasion, laser resurfacing, and treatment with intense pulsed light do not prevent or delay formation of squamous cell carcinoma. Currently available human evidence does not support a role for ablative skin resurfacing in prevention of non-melanoma skin cancer but well-designed randomized clinical trials are needed. The lack of effect is presumably due to the cancer stem cells residing deep in the hair follicles. No human studies have addressed the effect of non-ablative photorejuvenation on skin carcinogenesis.

A. Faurschou () Department of Dermatology, University of Copenhagen, Bispebjerg Hospital, Bispebjerg Bakke 23, 2400 Copenhagen NV, Denmark e-mail: [email protected]

Photodamaged skin is a result of long-term cumulative UV exposure. The skin presents with dyspigmentation, teleangiectasias, coarse skin texture, and wrinkles. Often, actinic keratoses (AK) and non-melanoma skin cancer (NMSC) are found as well. Rejuvenation procedures of photodamaged skin are performed increasingly in order to meet the quest for physical beauty and to reverse the visual signs of aging, especially of the facial skin. Rejuvenation procedures include ablative techniques with dermabrasion and laser resurfacing as well as non-ablative photorejuvenation with intense pulsed light (IPL) and lasers operating in the visible and near-infrared parts of the electromagnetic spectrum. The non-ablative procedures are more preservative and less effective and are also associated with less postoperative downtime and fewer side effects as compared with the ablative techniques. The first procedure employed to rejuvenate the skin was dermabrasion. Dermabrasion is based on mechanical removal of the top layers of the skin creating an upper to mid-dermal wound. Most often, small motorized handheld dermabraders are used with end-pieces such as wire brushes, diamond fraises, serrated wheels, and high rotation speeds to sand-off the skin. Following dermabrasion, new epidermis is regenerated within few weeks [13]. Since the introduction of lasers, laser resurfacing has been widely implemented as an ablative technique for facial skin rejuvenation due to the precise control of tissue ablation and tissue coagulation with favorable cosmetic results. The two laser types most often used for skin resurfacing are the carbon dioxide (CO2) laser at 10,600 nm and the erbium:YAG (Er:YAG) laser at 2,940 nm, now being available in the newer fractionated modes, which influence the skin with vertical zones. These wavelengths are highly absorbed

G. B. E. Jemec et al. (eds.), Non-Surgical Treatment of Keratinocyte Skin Cancer, DOI: 10.1007/978-3-540-79341-0_25, © Springer-Verlag Berlin Heidelberg 2010

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by intracellular water, creating rapid heating with vaporization and coagulation of epidermal and superficial dermal tissues where the depth of tissue damage depends on fluence and number of passes used. The CO2 laser induces a deeper tissue reaction than the Er:YAG laser due to more pronounced thermal coagulation and is thus considered a more efficient treatment modality [26]. Biopsy specimens of sun-damaged skin have shown reversal of actinic damage in the epidermis, an increase in sub-epidermal fibroplasias, and a decrease in solar elastosis of the superficial papillary dermis after laser resurfacing [31]. Non-ablative treatment of photodamaged skin can be categorized into three different general modalities: vascular lasers (e.g., pulsed dye lasers (PDL, 585, 595 nm), KTP laser (532 nm)), intense pulsed light systems (IPL, 500–1,200 nm), and mid-infrared lasers (Nd:YAG 1,064 and 1,320 nm, diode laser 1,450 nm, erbium:glass 1,540 nm). The vascular lasers and the IPL systems are used to target microvessels and pigment of the skin while the near-infrared lasers target dermal intracellular water. The ensuing thermal injury to the papillary and upper reticular dermis leads to fibroblast activation with synthesis of new collagen and extracellular matrix without epidermal damage [20]. It is debatable whether dermabrasion, laser resurfacing, and photorejuvenation may be preventive for a subsequent development of NMSC. Theoretically, precancerous lesions, superficial basal cell carcinoma (BCC) or squamous cell carcinoma (SCC) should be removed with the ablative procedures. Non-ablative procedures might serve as a new way of achieving prophylaxis for NMSC by rejuvenating the skin and destroying potential cancer stem cells of the hair follicle. The aim of this chapter is to evaluate basic knowledge and to present clinical evidence for the prevention of NMSC by dermabrasion, laser resurfacing, and non-ablative photorejuvenation.

A. Faurschou and M. Hædersdal

25.1.1 The Target Cells of Skin Carcinogenesis Stem cells are attractive targets for carcinogenesis due to their long-lived nature that makes them susceptible for accumulating mutations, and their capacity for selfrenewal necessary for cancer development. Prevailing evidence indicates that multipotent skin stem cells reside in the bulge area of the hair follicle [3, 6, 29]. The bulge stem cells are activated in response to wounding to proliferate and regenerate the epidermis whereas an independent population of cells with stem-cell characteristics form epidermal proliferative units (EPU) responsible for homeostasis of the epidermis [17, 21]. Several studies support that stem cells of the hair follicle and the interfollicular epidermis are potential target cells for skin carcinogenesis [8, 12, 27, 39, 40]. Experimental data however strongly suggest that it is the cells residing in the hair follicle that are most important for malignant transformation of skin tumors. Thus, when a mutant H-ras oncogene capable of initiating skin carcinogenesis is introduced into suprabasal layers in transgenic mice, benign papillomas arise that rarely progress [1, 32, 38]. In contrast, a spontaneous conversion to SCC and spindle cell carcinoma frequently occurs if the putative stem cells in the hair follicle are targeted [4]. In support of this, a significant reduction of papilloma development is seen if the interfollicular epidermis is removed in carcinogeninitiated skin leaving the hair follicles intact [24] whereas the development of SCC is unaffected [10, 24]. Also, a recent study showed a loss of tumor-forming capacity in mice depleted of CD43, a marker of the hair follicle bulge keratinocytes [36]. Taken together, this indicates that initiated cells of the hair follicle are responsible for development of the majority of skin tumors with malignant potential. Prophylaxtic treatments for NMSC should eradicate these cells.

25.1.2 Dermabrasion, Laser Resurfacing, and Non-Ablative Photorejuvenation for the The effect of dermabrasion, laser resurfacing, and nonPrevention of NMSC in Mice ablative skin rejuvenation for prevention of non25.1 Murine Models

melanoma skin cancer is crucially dependent on the elimination of potentially malignant cells. The target cells of skin carcinogenesis therefore need to be considered.

The question as to whether different ablative and nonablative procedures serve as prophylaxis for NMSC has been addressed in a few murine studies.

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Dermabrasion, Laser Resurfacing, and Photorejuvenation for Prevention of Non-Melanoma Skin Cancer

Morris et al. showed that dermabrasion was ineffective for preventing NMSC in mice [24]. Carcinogenesis was initiated by daily topical treatment with 7,12-dimethylbenz(alpha) anthracene (DMBA) for 1 week followed by dermabrasion with removal of the entire epidermis leaving the hair follicles intact. Tumor promotion was conducted with 12-O-tetradecanoylphorbol-13-acetate (TPA) twice weekly starting 4 weeks after dermabrasion and continued for 20 weeks. Carcinoma responses did not vary significantly between abraded and non-abraded groups of mice. The lack of effect of skin ablation for NMSC prophylaxis was further substantiated by a study of CO2 laser resurfacing in hairless mice [15]. This study showed that UV-induced carcinogenesis was not prevented or delayed by this procedure. Simulated solar irradiations were administered for 7 weeks before removal of the epidermis by CO2 laser. After treatment the mice were irradiated for further 23 weeks. The mice that underwent this treatment developed tumors as quickly as mice that were exposed to simulated solar irradiations in a similar manner but did not undergo laser resurfacing. The laser treatment did not by itself promote carcinogenesis. Hedelund et al. addressed the effect of non-ablative photorejuvenation for prevention of skin carcinogenesis in a study using IPL (530–750 nm) [16]. Hairless mice that have rudimentary hair follicles were exposed to simulated solar irradiation for 11 weeks before three IPL treatments at 2-weeks interval. After treatment the mice were irradiated for further 26 weeks. Skin tumors developed in UV-exposed mice regardless of IPL treatments. Considering the present evidence it is both conceivable and likely that dermabrasion, laser resurfacing, and non-ablative photorejuvenation in mice do not prevent or delay skin cancer formation.

25.2 Human Studies The clinical studies included in this chapter were identified from searching PubMed, EMBASE, and Cochrane central register using the search terms: Skin cancer, skin neoplasms, prophylaxis, prevention, dermabrasion, resurfacing, photorejuvenation, laser, and intense pulsed light (IPL). The reference lists of the studies identified were examined for further studies. We included only English-language articles.

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The literature mainly comprises small, uncontrolled studies with short follow-up times and case reports. The primary outcome of most studies is clearance and recurrence rate of actinic keratoses. Our focus is on dermabrasion, skin resurfacing, and skin rejuvenation for the prophylaxis of NMSC but only one randomized clinical trial (RCT) directly addresses the effect of skin resurfacing in this regard. Since most squamous cell carcinomas arise in actinic keratoses [7], we include studies describing prevention of AK as an indirect measure for prevention of NMSC. No human studies have yet been performed that investigate the efficacy of non-ablative procedures for prophylaxis of actinic keratoses or NMSC. Details of the identified controlled studies are given in Table 25.1.

25.2.1 Laser Resurfacing One RCT including 34 patients examined resurfacing for non-melanoma skin cancer prophylaxis, and one RCT with 55 patients evaluated the efficacy of laser resurfacing on the recurrence rate of AK [11, 14].

25.2.1.1 Controlled Clinical Trials Hantash et al. conducted a randomized clinical trial comparing the effect of CO2 laser resurfacing, chemical peeling with 30% trichloroacetic acid (TCA), and topical 5% 5-fluorouracil (FU-5) for the prevention of NMSC [14]. Twenty-seven patients with a history of actinic keratoses and/or NMSC were randomized to one of the three treatment arms. The incidence of NMSC was assessed for a minimum of 2 years after treatment. Following laser resurfacing, three patients in the laser group developed BCC after 14, 31, and 39 months, respectively. One SCC in situ occurred in the TCA group after 3 and 5 months, and one patient had 5 SCCs in the FU group after 18, 28, and 32 months. Five patients who declined studyrelated treatment were used as untreated controls. The control group had 24 new NMSC. The main problem with the study is a potential bias in the control group because patients were not randomized into this group. Moreover, small numbers of participants constituted each group. However, noteworthy is that new NMSC developed in all patient groups within 3–39 months following treatment.

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Table 25.1 Characteristics of identified controlled trials Study Study Randomization method Interventions design allocation concealment blinded response evaluation follow-up Hantash et al.

RCT

Randomization unclear, inadequate randomization into untreated control group Allocation concealment unclear Unblinded on-site clinical evaluation Follow-up: Minimum 24 M

Subjects no., dropouts, age treatment site treatment purpose skin type

(i) CO2 laser (N = 8) (ii) 30% trichloroacetic acid peel (TCA) (N = 10) (iii) 5% fluorouracil cream (5-FU) twice daily for 3 weeks (N = 9) (iiii) sham treatment (N = 7)

Major results

N = 34 patients included, 29 completed Tx, 25 completed 24-month follow-up. ITT was done Age: Mean 71.7 years Treatment site: face Treatment purpose: NMSC prophylaxis Skin type I–III

No significant difference in cancer incidence (total number of new NMSC in treatment area divided by total number of patient years followed in each group) between the three active interventions Significant difference in cancer incidence between each treatment group (laser: 0.15; TCA: 0.04; 5-FU: 0.21) and sham treatment (1.57) Ostertag RCT Randomization: (i) Er:YAG laser N = 55 patients included, After 12 M, the laser group et al. Computer-generated combined with 52 completed had significantly less sequence CO2 laser (N = 28) 12-month follow-up. clinical recurrences than the Allocation conceal(ii) 5% fluorouracil ITT was not done 5-FU group (40.7% vs. ment: Adequate cream (5-FU) Age: Mean 72 years 80.8%) Unblinded on-site twice daily for 4 (range 52–85 years) After 3 M, histologic proven clinical and weeks (N = 27) Treatment site: scalp recurrence occurred histopathological and face significantly more seldom in evaluation Treatment purpose: AK the laser group (14%) than Follow-up: 12 M treatment in the 5-FU group (48%). Skin type I-III One SCC was found in each group after treatment RCT = randomized clinical trial; NMSC = non-melanoma skin cancer; AK = actinic keratoses; ITT = intention to treat; Tx = treatment; Adequate allocation concealment keeps clinicians and participants unaware of upcoming assignments.

Ostertag et al. conducted a RCT of 55 patients comparing Er:YAG plus CO2 laser resurfacing with topical 5-FU. The primary outcome was the proportion of patients with recurrence of AK according to clinical evaluation within 1 year after treatment. Next to clinical evaluation, AK on the scalp and/or the face were investigated histologically before and 3 months after treatment. There were significantly fewer recurrences in the laser group compared to the 5-FU group (40.7% versus 80.8%, p = 0.003). Histologically proven recurrences also occurred less frequently in the laser group than in the 5-FU group (14% versus 48%). One squamous cell carcinoma appeared after treatment in each group [31].

25.2.1.2 Uncontrolled Clinical Trials/Case Reports and Retrospective Studies Fulton et al. treated 35 patients with CO2 laser resurfacing. Three patients developed actinic keratoses and two patients had BCC within 12 months after treatment [11]. Another uncontrolled clinical study by Trimas et al.

included 14 patients with AK and SCC. Following skin resurfacing with CO2 laser, all patients remained free of malignant or precancerous lesions during a follow-up of 6–24 months [37]. Laser resurfacing was further evaluated as treatment for AK in two case series involving a total 11 patients. Three months after Er:YAG laser treatment, all patients had between 86–96% reduction in clinically visible AK in one case series [19] while another reported a clearance rate of 100% after 13.5 months [9]. In addition to this, a few case reports address laser resurfacing for the prevention of NMSC. Two patients treated with CO2 laser resurfacing developed NMSC 6 months after treatment [35]. Two other patients undergoing this procedure remained free of cancers in the treated areas for 33 and 52 months, respectively while developing new NMSC in untreated areas [22]. Pianigiani et al. reported three patients that were treated with Er:YAG laser and, as a new approach, had epidermis reconstructed with autologous epidermal sheets expanded in vitro from healthy cells obtained from unexposed areas of the body [33]. After 2 years no recurrences were observed.

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Dermabrasion, Laser Resurfacing, and Photorejuvenation for Prevention of Non-Melanoma Skin Cancer

Finally, the efficacy of laser resurfacing in the treatment of AK has been further investigated through retrospective studies. Ostertag et al. conducted a retrospective study of 25 patients that underwent laser resurfacing with CO2 and/or Er:YAG laser for widespread AK with a mean follow-up of 39 months (7–70 months). After a mean time of 23 months following treatment, 56% of patients had recurrences and three patients developed NMSC in the treatment areas [30]. Iyer et al. carried out a retrospective study of 24 patients who presented with AK and underwent resurfacing with CO2 laser (eight patients), Er:YAG laser (one patient), or a combination of both (15 patients). A total of 87.5% of the patients was lesion-free at 1 year and 58.3% remained lesion-free after 2 years. BCC was diagnosed in two patients (8%) at 7 and 12 months after laser treatment respectively and one SCC was found at the inner canthus after 14 months [18]. Sherry et al. performed a retrospective chart analysis of 31 patients who had CO2 laser resurfacing for AK. A total of 42% of the patients had recurrent AK within 6–51 months after treatment [34].

25.2.2 Dermabrasion No controlled clinical trials were obtained addressing the efficacy of dermabrasion for skin cancer prophylaxis. In an uncontrolled prospective clinical trial, Benedetto et al. described dermabrasion to be effective in reducing the necessity for continued treatment of premalignant and malignant lesions in 12 patients with diffuse AK [2]. Coleman et al. conducted a retrospective study of 23 patients with actinic AK. A total of 96% of the patients remained free of AK at 1 year, 83% at 2 year, 64% at 3 years, and 54% at 5 years. During the fourth year after treatment, three patients developed BCCs in the treatment areas [5]. In a case report, dermabrasion was effective treatment of widespread superficial multifocal BCC of the scalp with development of no new malignant skin lesions for approximately 4 years [23]. Nelson et al. reported one patient with xeroderma pigmentosum who continued to develop multiple BCCs after other treatment. Following dermabrasion only one BCC developed in treated skin [25]. Similarly, Ocampo et al. treated one patient with xeroderma

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pigmentosum with dermabrasion and no additional treatment was needed for 4 month after which new AK developed [28].

25.3 Conclusion Despite the wide use of dermabrasion, laser resurfacing, and non-ablative photorejuvenation, only few prospective, controlled clinical studies have estimated the efficacy of these treatment procedures as prophylaxis for new premalignant and malignant skin lesions. Theoretically, potentially malignant cells should be removed with ablative procedures. However, in most of the studies dealing with this matter new AK and NMSC developed in the treatment areas within months after treatment. This suggests that atypical cells were not completely eradicated but were located deep in the follicular epithelium and continued to grow postoperatively. Studies in mice support this notion as removal of epidermis does not prevent or delay development of skin cancer in carcinogen-initiated skin. The murine model points to the hair follicle stem cells as the source of a population of latent neoplastic cells with high malignant potential necessary for development of the majority of malignant skin tumors. This contradicts the general belief that resurfacing of the skin may serve as prophylaxis for NMSC. If the observations in mice prove to be true for humans, it may indicate that other treatment options will be needed for complete removal and prevention of skin malignancies. Since differences between murine and human skin exists and the literature is lacking well-designed RCTs, further studies are however clearly needed to decipher the complexity of tumor origin in human skin and determine the effectiveness of dermabrasion, skin resurfacing, and photorejuvenation for prevention of NMSC.

25.4 Take Home Pearls • Current evidence from murine and human studies does not substantiate a role for dermabrasion, laser resurfacing, and photorejuvenation in preventing development of non-melanoma skin cancer. • Well-designed randomized clinical trials are needed to clarify whether ablative and non-ablative rejuvenation procedures may serve as prophylactic treatment of non-melanoma skin cancer.

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References 1. Bailleul B, Surani MA, White S, et al Skin yyperkeratosis and papilloma formation in transgenic mice expressing a ras oncogene from a suprabasal keratin promoter. Cell. 1990;62: 697–708 2. Benedetto AV, Griffin TD, Benedetto EA, et al Dermabrasion – therapy and prophylaxis of the photoaged face. J Am Acad Dermatol. 1992:439–47 3. Blanpain C, Lowry WE, Geoghegan A, et al Self-renewal, multipotency, and the existence of two cell populations within an epithelial stem cell niche. Cell. 2004;118:635–48 4. Brown K, Strathdee D, Bryson S, et al The malignant capacity of skin tumours induced by expression of a mutant H-ras transgene depends on the cell type targeted. Curr Biol. 1998;8:516–24 5. Coleman WP, Yarborough JM, Mandy SH. Dermabrasion for prophylaxis and treatment of actinic keratoses. Dermatol Surg. 1996;22:17–21 6. Cotsarelis G, Sun TT, Lavker RM. Label-retaining cells reside in the bulge area of pilosebaceous unit – implications for follicular stem-cells, hair cycle, and skin carcinogenesis. Cell. 1990;61:1329–37 7. Czarnecki D, Meehan CJ, Bruce F, et al The majority of cutaneous squamous cell carcinomas arise in actinic keratoses. J Cut Med Surg. 2002;6:207–9 8. de Gruijl FR, Rebel H. Early events in UV carcinogenesis – DNA damage, target cells and mutant p53 foci. Photochem Photobiol. 2008;84:382–7 9. Drnovsek-Olup B, Vedlin B. Use of Er:YAG laser for benign skin disorders. Lasers Surg Med. 1997;21:13–9 10. Faurschou A, Haedersdal M, Poulsen T, et al Squamous cell carcinoma induced by ultraviolet radiation originates from cells of the hair follicle in mice. Exp Dermatol. 2007;16:485–9 11. Fulton JE, Rahimi AD, Helton P, et al Disappointing results following resurfacing of facial skin with CO2 lasers for prophylaxis of keratoses and cancers. Dermatol Surg. 1999;25: 729–32 12. Gerdes MJ, Yuspa SH. The contribution of epidermal stem cells to skin cancer. Stem Cell Rev. 2005;1:225–31 13. Gold MH. Dermabrasion in dermatology. Am J Clin Dermatol. 2003;4:467–71 14. Hantash BM, Stewart DB, Cooper ZA, et al Facial resurfacing for nonmelanoma skin cancer prophylaxis. Arch Dermatol. 2006;142:976–82 15. Hedelund L, Haedersdal M, Egekvist H, et al CO2 laser resurfacing and photocarcinogenesis: an experimental study. Lasers Surg Med. 2004;35:58–61 16. Hedelund L, Lerche C, Wulf HC, et al Intense pulsed light and UV exposure: carcinogenesis and side effects. An experimental animal study. Lasers Surg Med. 2006;21:198–201 17. Ito M, Liu YP, Yang ZX, et al Stem cells in the hair follicle bulge contribute to wound repair but not to homeostasis of the epidermis. Nature Med. 2005;11:1351–4 18. Iyer S, Friedli A, Bowes L, et al Full face laser resurfacing: therapy and prophylaxis for actinic keratoses and non-melanoma skin cancer. Lasers Surg Med. 2004;34:114–9 19. Jiang SB, Levine VJ, Nehal KS, et al Er: YAG laser for the treatment of actinic keratoses. Dermatol Surg. 2000;26:437–40 20. Jørgensen GF, Hedelund L, Hædersdal M. Long-pulsed dye laser versus intense pulsed light for photodamaged skin. A randomized split-face trial with blinded response evaluation. Lasers Surg Med. 2008;40:293–9

A. Faurschou and M. Hædersdal 21. Lavker RM, Sun TT. Epidermal stem cells: properties, markers, and location. Proc Natl Acad Sci USA. 2000;97:13473–5 22. Massey RA, Eliezri YD. A case report of laser resurfacing as a skin cancer prophylaxis. Dermatol Surg. 1999;25:513–6 23. Melandri D, Carruthers A. Widespread basal-cell carcinoma of the scalp treated by Dermabrasion. J Am Acad Dermatol. 1992;26:270–1 24. Morris RJ, Tryson KA, Qu KQ. Evidence that the epidermal targets of carcinogen action are found in the interfollicular epidermis or infundibulum as well as in the hair follicles. Cancer Res. 2000;60:226–9 25. Nelson BR, Fader DJ, Gillard M, et al The role of Dermabrasion and chemical peels in the treatment of patients with xeroderma-pigmentosum. J Am Acad Dermatol. 1995;32:623–6 26. Newman JB, Lord JL, Ash K, et al Variable pulse erbium: YAG laser skin resurfacing of perioral rhytides and side-byside comparison with carbon dioxide laser. Lasers Surg Med. 2000;26:208–14 27. Nijhof JGW, van Pelt C, Mulder AA, et al Epidermal stem and progenitor cells in murine epidermis accumulate UV damage despite NER proficiency. Carcinogenesis. 2007;28: 792–800 28. OcampoCandiani J, SilvaSiwady G, FernandezGutierrez L, et al Dermabrasion in xeroderma pigmentosum. Dermatol Surg. 1996;22:575–7 29. Oshima H, Rochat A, Kedzia C, et al Morphogenesis and renewal of hair follicles from adult multipotent stem cells. Cell. 2001;104:233–45 30. Ostertag JU, Quaedvlieg PJF, Neumann MHAM, et al Recurrence rates and long-term follow-up after laser resurfacing as a treatment for widespread actinic keratoses in the face and on the scalp. Dermatol Surg. 2006;32:261–7 31. Ostertag JU, Quaedvlieg PJF, van der Geer S, et al A clinical comparison and long-term follow-up of topical 5-fluorouracil versus laser resurfacing in the treatment of widespread actinic keratoses. Lasers Surg Med. 2006;38:731–49 32. Pazzaglia S, Mancuso M, Primerano B, et al Analysis of c-Ha-ras gene mutations in skin tumors induced in carcinogenesis-susceptible and carcinogenesis-resistant mice by different two-stage protocols or tumor promoter alone. Mol Carcinog. 2001;30:111–8 33. Pianigiani E, Di Simplicio FC, Ierardi F, et al A new surgical approach for the treatment of severe epithelial skin sun-induced damage. J Eur Acad Dermatol Venereol. 2003;17: 680–3 34. Sherry SD, Miles BA, Finn RA. Long-term efficacy of carbon dioxide laser resurfacing for facial actinic keratosis. J Oral Maxillofac Surg. 2007;65:1135–9 35. Stratigos A, Tahan S, Dover JS. Rapid development of nonmelanoma skin cancer after CO2 laser resurfacing. Arch Dermatol. 2002;138:696–7 36. Trempus CS, Morris RJ, Ehinger M, et al CD34 expression by hair follicle stem cells is required for skin tumor development in mice. Cancer Res. 2007;67:4173–81 37. Trimas SJ, Ellis DAF, Metz RD. The carbon dioxide laser – an alternative for the treatment of actinically damaged skin. Dermatol Surg. 1997;23:885–9 38. Quintanilla M, Brown K, Ramsden M, et al CarcinogenSpecific Mutation and Amplification of Ha-Ras During Mouse Skin Carcinogenesis. Nature. 1986;322:78–80 39. Van Duuren BL, Sivak A, Katz C, et al Inhibition of tumor induction in two-stage carcinogenesis on mouse skin. Cancer Res. 1969;29:947–52 40. Yuspa SH, Dlugosz AA, Cheng, et al Role of oncogenes and tumor-suppressor genes in multistage carcinogenesis. J Invest Dermatol. 1994;103:S90–5

26

To Cut or Not, That Is the Question Barbara Jemec and Gregor B. E. Jemec

Key Points

› › › › ›

Primum non noccere Some methods are operator-dependant An overall risk assessment aids the choice Individualised treatments often include different therapeutic regimes Adjuvant therapy may reduce the risk of recurrence

the method of surgical excision not only provides a proven method of obtaining accurate pathological diagnosis but also sets the reference for the cure of non-melanotic skin cancers. With the continued development of new methods of accurate diagnosis and treatments, the treatment of choice may however diversify to routinely include some of the methods mentioned in this book.

26.1 ‘The Objective of the Exercise’ Box 26.1 If in doubt, cut it out Old surgical saying

Box 26.2 The most important tool for the surgeon is the brain What we do today is based on the available methods of securing knowledge; as our methods evolve so does our practice. Traditionally, dermatology is heavily dominated by a morphological approach to disease definition and classification; hence, histopathology has received attention and prominence in the diagnosis. Currently, the gold standard for diagnosis is therefore the histopathology of biopsies; so,

B. Jemec () Department of Plastic Surgery, Chelsea and Westminster Hospital, London, U.K. e-mail: [email protected]

The primary objective of any therapeutic intervention is always patient cure. The potential malignancy of any tumour depends on both its locally destructive nature and the metastatic and fatal potential. The choice of treatment however depends on a number of unique variables such as expected cure rate, available treatments, patient factors, etc. The most important decision to be made for the choice of treatment is whether the lesion is malignant or benign. Usually, this decision is reached after the examination of a biopsy: If the lesion is small and easily excisable, the excisional biopsy is preferred. This confers advantages in the way of offering an immediate potential cure, usually acceptable cosmesis and low cost in reducing the number of patient visits. The incisional biopsy is reserved for larger lesions, which are not amenable for simple excision and direct closure. As a rule, incisional biopsies for pigmented lesions are warranted only for areas representing an identifiable localised colour change within a larger lesion, such as in lentigo or giant congenital naevi, to avoid a false negative result. After obtaining an accurate diagnosis, subsequent ablative treatment, which does not yield

G. B. E. Jemec et al. (eds.), Non-Surgical Treatment of Keratinocyte Skin Cancer, DOI: 10.1007/978-3-540-79341-0_26, © Springer-Verlag Berlin Heidelberg 2010

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material suitable for histopathological examination, can be considered. It is also paramount that the invasive potential, such as seeding in the biopsy track of soft tissue sarcomas, does not change with incisional surgical biopsies. For NMSC, the incisional biopsy appears fraught with fewer problems, and often necessary due to the field cancerization, which provides a number of similar tumours often involving large areas. Although generally safe, i.e. low-risk tumours situated in a low risk area, for example, large BCC on the back, may be amenable to serial excisions or non-surgical therapy in frail patients, multiple biopsies in areas or field cancerization cause scarring and inconvenience to patients which they may prefer to avoid. Non-invasive methods to secure an accurate diagnosis in vivo, such as optical measurements of biochemical markers are currently being pursued by a number of researchers. If they provide a satisfactory sensitivity and specificity, this crucial information would allow the full range of therapeutic options to be considered in all cases. At present, the gold standard however remains histopathological examination, though this still has less than 100% sensitivity and specificity, suggesting room for further improvement. One source of false negative results may be a biopsy taken from an inappropriate area of the tumour, and one possible scenario is therefore the introduction of a non-invasive in vivo diagnostic aid to help identify the most appropriate site for biopsies to be taken. At present, non-invasive methods of diagnosis, such as in vivo confocal microscopy, have an impressive reported sensitivity and specificity, but the practical use is restricted not only by the availability of the technology, but also by a very limited view of depth (0.8 mm), limiting its use to superficial lesions. In contrast, for example, spectrometry incorporates information from a greater depth albeit at a lower specificity. It is envisaged that the scope and accuracy of non-invasive means of diagnosis will continuously improve.

26.2 Recurrence Risk and Invasive Potential The occurrence and ease with which recurrences can be detected matters in both human and monetary costs. Furthermore, the consequences of a recurrence must be taken into consideration, should it change (or as it changes) prognosis.

B. Jemec and G. B. E. Jemec

The primary treatment modality must not preclude the detection of recurrence or induce any later malignant changes (radiotherapy) or change the invasive potential of the treated tumour. Some tumours, which primarily have been removed with an adequate excision margin, will not generally recur, for instance nodular BCCs, and if they recur it does not appear to affect the long-term prognosis. It therefore seems sensible to combine the diagnosis and cure in one for these lesions. In contrast, Merkel cell tumour may recur years after presumed curative resection and as such adversely affect the survival. It may be speculated that in this case it is advantageous to the patient if excisions are combined with adjuvant treatment, although a discussion of this falls outside the scope of this book. In syndromes or conditions which feature numerous tumours, the paucity of normal skin often prevents a purely surgical solution and necessitates other treatment methods. A repetitive non-ablative treatment is therefore acceptable as a means of local, albeit temporary, control. The importance of predictable and reproducible control is of course paramount. Non-invasive methods may be able to accurately pinpoint malignant changes, rather than guessing at optimal biopsy sites, both when used to scan larger areas as well as looking for possible recurrences.

26.3 Field Cancerization You can only specifically target something you can see with physical means, such as surgery. In contrast, nonsurgical modes of therapy rely on their ability to seek out and destroy cancerous cells without the need for an operator-limited identification of the precise target. NMSC is often the result of general exposure to carcinogens, such as UV irradiation affecting large areas of the skin. The identification of a cancerous cells combined with the treatment of same, is the ideal combination, especially in field cancerization, which therefore becomes a strong indication for field or non-surgical therapy.

26.4 Location Location plays a vital role in the choice of the mode of treatment; because of the characteristics of both the lesions and the treatment.

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To Cut or Not, That Is the Question

Lesions with a low invasive potential on the face situated in the cleavage lines more readily invade and therefore require a more aggressive and definitive treatment, than if situated elsewhere. Potential impairment of function can occur with major surgical excisions of lesions close to the eyes and mouth, where tissues with special function such as tear and salivary glands are at risk and diminution of aperture is undesirable. Lesions which are situated within specialised skin such as on the palm or any hair-bearing areas are better replaced by same skin than just ablated, or even better, treated by removing only the cancerous cells and leaving the normal tissues intact. Finally, the mechanical access to the lesion itself may pose specific problems, such as, for instance, the ear canal which presents problems with detection, surveillance and treatment.

26.5 General Health In deciding the final mode of treatment, the patient’s general health and life expectancy is very important. It is important to preserve the patient’s social acceptability and presentable potential. Non-ablative conservative means of controlling any negative impact from fungating tumours, including the smell must be sought. Should the general health preclude any major surgery, a non-invasive option, though it may not always be curative, is to be preferred. Non-surgical methods play a role here, although it would appear at present that their main advantage lies in tackling early lesions, rather than late complications.

26.6 Cosmesis The patient often asks whether the removal of the lesion will produce a scar and McGrouther et al. [1] showed that scarring occurs on the hip skin when the wound is 0.56 + /−0.03 mm, or 33.1% of normal hip-skin thickness. It may be fair to extrapolate this to other areas of skin, though the deltoid and décolletage region are more prone to produce hypertrophic or even keloid scarring. Similarly, the incidence of keloids differs among races, the Afro-Caribbeans and Kelts being more prone to developing keloids. The question as to whether a procedure will produce scarring therefore

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depends on the depth of the wounding of the skin, whether this is by surgical or non-surgical means. If one is not able to preserve normal skin architecture with non-surgical treatment methods, it is better to hide the scars respecting aesthetic units in the face, if the curative ablation of the lesion involves the whole thickness of the skin, favouring surgical excision and replacement of like (skin) with like (skin). Such procedures often require the assistance of especially trained surgeons.

26.7 Combined Treatment It is well established in many fields of medicine that monotherapy is not always sufficient. In dermatology, combination treatments are well established in inflammatory diseases such as for example psoriasis, where the use of UV irradiation simultaneously with retinoids appears to have a synergistic therapeutic effect. Similarly, concurrent therapies may form an appropriate overall strategy in the treatment of many NMSC. One of the most obvious areas for combined treatment is in areas subject to field cancerization, i.e. areas with multiple tumours of varying size and level. In these cases the judicious combined use of non-surgical treatment and excisional surgery is not only advisable but necessary as well. The non-surgical therapies can help identify the tumours that require excision by clearing more superficial or pre-malignant lesions, while at the same time treating the majority of skin changes in a time-efficient and cosmetically advantageous way. Similarly, tumours may benefit from surgical debulking before for example systemic therapy in advanced cases. In either scenario the individualised treatment plan encourages the combined use of the full range of available therapies to provide optimum therapy for the patient.

26.8 Adjuvant Therapies The concept of a disease often determines the treatment plans. If diseases are seen as unique and curable events, one type of therapy is often advocated, while chronic recurrent disease invokes a different paradigm. NMSC is generally seen as a single curable event, and hence excised. In reality, the diagnosis of NMSC more

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Table 26.1 General considerations Absolute indications Relative indications

Excision

Non-surgical therapy

• • • • • •

• • • • • • •

Risk < advantage to the patient High-risk tumours Follow-up not available Immediate need for reconstruction Service available One tumour

often follows a chronic course, with either multiple de novo tumours, precursor lesions or even recurrences arising over time. By viewing the whole patient as having chronic recurrent disease, rather than individual tumours only, it becomes obvious that adjuvant therapy is of benefit to the patients. This is most often given as advice on UV protection, but more active adjuvant therapy is possible through the use of topical and dietary interventions. Particularly in high-risk groups such as organ-transplant recipient patients such adjuvant therapy may be speculated to play a significant role in achieving overall control of the disease.

26.9 Follow-Up The risk of a secondary primary NMSC is high, and the more NMSC tumors the patient has the higher the risk. In addition the recurrence rates differ between the different treatments. Photodynamic therapy cure rates and especially cosmetic outcomes are good, but more long term follow up data are needed. Surgery and to a somewhat lesser extent radiotherapy, still appear to be the most effective treatments, with surgery showing the lowest failure rates [2]. The possibility of adequate follow-up therefore also influences the choice of therapy. If there is no opportunity for follow-up, this mandates more aggressive therapy, while good follow-up allows closer inspection and less aggressive therapy.

Risk < advantage to the patient The patient rejects surgery Low-risk tumour Low-risk area Cosmesis paramount No surgical service available Multiple tumours and their precursors

guided by the patient’s best interests. In some cases this may therefore be surgery, whilst in others some of the newer non-surgical techniques are preferable. Where NMSC arises as a single event, for example, a nodular BCC on the arm, targeted destruction or excision is clearly the best option for the patient. Where NMSC appears as a part of a chronic recurrent disease, for example, multiple and varied lesions in an area of field cancerization developed over a long period of time, surgery is only part of the solution of the problem, and surgical monotherapy clearly not the best option for the patient as a whole. Single tumours may need surgery, but the whole patient needs more. Individualised treatment is always preferable, and there is little doubt that a multidimensional approach to therapy is of benefit to the patient. Treatment must be tailor-made and often has to encompass traditional, newer and adjuvant therapies in order to solve the medical problems in the best possible way. There is no doubt that several of these methods need additional confirmatory studies to bring them into routine clinical use, but the best physicians are characterised not only by their knowledge and experience, but also by their general understanding of the subject matter and the broadest possible range of therapeutic options to choose from. The individual health problems are potentially innumerable, and so are the possible solutions.

References 26.10 When to Cut and When Not to A number of principal decisions need to be made when choosing among the therapeutic options for NMSC (see Table 26.1). The choice of method must always be

1. Dunkin CS, Pleat JM, Gillespie PH, Tyler MP, Roberts AH, McGrouther DA. Scarring occurs at a critical depth of skin injury: precise measurement in a graduated dermal scratch in human volunteers. Plast Reconstr Surg. 2007;119: 1722–32 2. Bath-Hextall FJ, Perkins W, Bong J, Williams HC. Interventions for basal cell carcinoma of the skin. Cochrane Database Syst Rev. 2007 Jan 24;(1):CD003412

Index

A Acquired Immunodeficiency Syndrome (AIDS), 43, 156–157 ALA (delta-aminolevulenic acid), 92, 133, 138–141, 197–201 Antioxidants, 163, 177–183 Apoptosis, 2–4, 25–28, 110, 125, 179–180, 188, 191 Arsenic, 2, 45–47, 161, 162, 187, 189 B Basal cell nevus syndrome, 29–31, 76, 153 Bazex syndrome, 34 Bleomycin, 84, 85, 91, 92, 94–95, 144, 146–148 Bortezomib, 86

C Capecitabine, 6, 84–86 Carotenoids, 46, 181–183 Cell cycle, 10, 26–28, 42, 85, 182, 189 Cetuximab, 86 Chemotherapy intralesional, 91–95, 104, 107–110, 114 systemic, 83–88, 95, 147 topical, 97–100 Cisplatin, 83–86, 88, 144–148 Clonal expansion, 3, 177 Colchicine, 97, 99–100 Cosmesis, 211, 213 Cutaneous lymphomas, 156 Cyclooxygenase (COX)-2, 13, 99 Cyclopamine, 86–87 Cytology, 52, 54

D Delta-aminolevulenic acid (ALA), see ALA Deoxyribonucleic acid (DNA) damage, 2, 3, 5, 27, 33, 40, 81, 128, 171, 172, 177, 178, 188 repair, 1–4, 20, 27, 32, 40, 42, 85, 188, 190 Dermabrasion, 205–209 Dermatofibrosarcoma protuberans, 74, 77–78 Dermoscopy, 5, 58–59, 62, 66 Diagnosis, 4, 11–12, 19, 20, 21, 33, 51–67, 126, 128, 138, 151, 152, 159, 160, 162, 193, 211–213

Diclofenac, 6, 97–99, 153, 187 Diet, 42, 46, 47, 177–183 Doxorubicin, 84

E E-cadherin, 13 Electrical impedance, 66 Electrochemotherapy, 92, 143–149 Electroporation, 92, 118, 143–145, 149 Environment, 20, 39–47, 103, 115, 134, 159–162, 171 Epidemiology, 4, 15–22 Epidermal growth factor receptor (EGFR), 86–88 Epidermolysis verruciformis, 162 Eumelanin, 3 Extramammary Paget's disease, 76–77, 156

F Familiar cancer syndromes (FCS), 26–27 Field cancerization, 1–6, 9–11, 212 5-Fluorouracil (5-FU), 3–6, 30, 84, 85, 88, 91–95, 97–100, 139, 140, 153, 187, 199, 202, 207, 208

G Genes mismatch repair gene (MMR), 34 oncogenes, 2, 25, 26, 28, 43 patched gene, 1, 4, 30, 86 RAS, 28, 81, 206 tumor suppressor genes, 25–27, 188 Genetics, 25–35 Gorlin’s syndrome, 1, 6, 29

H Histopathology, 54–56, 61–64, 67, 155, 211 Human immunodeficiency virus (HIV), 43, 104, 113, 116–119, 181 Human papilloma virus, 2, 3, 11, 20, 21, 35, 40–44, 46, 130, 159–161 Hypermethylation, 10, 12, 13

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216 I Imaging techniques computed tomography (CT), 11, 66–67 confocal microscopy (CM), 11, 51, 62–63, 67, 212 fluorescence spectroscopy, 64–65 magnetic resonance imaging (MRI), 11, 57, 66, 67 multiphoton imaging microscopy (MPMI), 51, 62, 65 near infrared (NIR) spectroscopy, 64 optical coherence tomography (OCT), 11, 51, 56, 57, 59–62, 67 positron emission tomography (PET), 11, 66–67 spectrophotometric intracutanous analysis (SIA), 65–66 terahertz pulsed imaging (TPI), 66 ultrasonography, 56–58, 66 Imiquimod, 5, 6, 30, 63, 76, 77, 91, 95, 97, 104, 107, 114, 118, 123–130, 153 Immune system acquired, 103, 104, 113, 123, 124 innate, 103, 104, 113, 123, 124, 201 Immunostimulation, 104 Immunosuppression acquired immunodeficiency syndrome (AIDS), 43, 156–157 iatrogenic, 42–43 Immunotherapy, 88, 103–105, 114–118, 145 Incidence, 2, 4, 10, 15–19, 21, 22, 30, 39, 40, 42–44, 81, 104, 113, 123, 127–129, 137, 162, 177, 179, 182, 187, 198, 213 Interferon (IFN) adjuvant, 108 intralesional, 6, 94, 107–110, 114 Interleukin-2 (IL-2), 91, 113–119, 192 Ionizing radiation, 151, 152, 187

K Kaposi's sarcoma (KS), 6, 113, 116, 146, 152, 153, 156–157, 181

L Laser resurfacing, 205–209 Light sources, 138–139 Loss of heterozygosity (LOH), 26, 35

M Merkel cell carcinoma, 74, 77, 113, 151–153 Methotrexate, 85, 93–94, 99 Mohs's micrographic surgery (MMS), 62, 73, 74, 76, 78, 113, 141, 187 Mortality, 15, 19–22, 31, 43, 51, 113, 151, 161, 162, 198 Muir-Torre syndrome (MTS), 32–34 Mutation CDKN2A, 28–29 patched (PTC), 30, 31, 190 RAS, 28 TP53, 27–28

Index N Necrosis, 5, 56, 110, 114, 115, 117, 119, 134, 144, 147 Nucleotide excision repair (NER), 32 O Oncogenes, 2, 25, 26, 28, 43 Organ transplant recipient (OTR), 1–3, 6, 19, 42–44, 103, 123, 127, 138–140, 161, 187, 191, 194, 198, 214

P Paclitaxel, 84, 85, 88 Paget's disease, 74, 76–77, 156 Phaeomelanin, 3 Photoallergy, 172–173 Photocarcinogenesis, 171, 178–179, 188 Photodynamic therapy (PDT), 6, 30, 73, 92, 97, 107, 113, 133–135, 137–141, 187, 214 Photoprotection, 4, 6, 169, 173 Photorejuvenation, 205–209 Photosensitizer, 3, 6, 31, 133–134, 138, 141, 188, 197, 198, 201, 202 Phototherapy photochemotherapy (PUVA), 1, 10, 42–47, 162 ultraviolet B, 44, 128, 169 Polycyclic aromatic hydrocarbons (PAH), 45 Porokeratosis disseminated superficial actinic, 2 mibelli, 3 Prevention primary, 160–162 secondary, 162–163 tertiary, 163 Prognosis, 15, 19–20, 22, 51, 67, 78, 137, 163, 201, 212

R Radiochemotherapy, 85 Radiotherapy, 44 Raman spectroscopy, 64 Retinoid acid receptors (RARs), 189 Retinoids, 6, 88, 97, 100, 163, 179–181, 187–194, 213 Retinoid X receptors (RXRs), 179, 181, 189, 191 Rombo syndrome, 34, 190

S Skin type, 1–3, 40, 64, 81, 137, 160, 170, 173, 182 Sonic Hedgehog, 30, 31, 110 Sunburn cell, 172, 183 Sun exposure, 1, 4, 18, 20, 39–45, 81, 160, 161, 170, 173 Sunlight, 16, 18, 39, 40, 44, 128, 160, 167–169, 171, 172, 178, 187 Sunscreen, 4, 6, 154, 160, 161, 164, 167–173, 188

Index

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T Toll-like receptor (TLR), 5, 118, 124, 129–130 Tyrosine kinase inhibitor erlotinib, 86 gefinitib, 86

V Vitamin A, 100, 177–183, 187, 188 C, 178, 182 D, 21, 172, 182 E, 46, 182–183

U Ultraviolet (UV) radiation, 1, 3, 5, 26, 29, 39–41, 46, 103, 169, 171, 190, 191

X Xeroderma pigmentosum, 1, 2, 6, 26, 30–33, 40, 76, 153, 162, 163, 187, 190, 191, 202, 209