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 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

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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(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 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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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

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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

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Clinical criteria for Familial Cancer Syndromes:

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› › ›

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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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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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Genetics of Non-Melanoma Skin Cancers and Associated Familial Syndromes

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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

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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 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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a

b

c

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

R. Kaufmann and M. Meissner

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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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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Systemic Chemotherapy of Non-Melanoma Skin Cancer

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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

10

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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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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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.

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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

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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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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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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

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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

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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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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,

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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

117

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-

119

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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Interleukin-2 for Nonmelanoma Skin Cancer

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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

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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

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

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

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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.

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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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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

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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

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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

215

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

217

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