Skin CancerRecognition and Management

Second Edition

Robert A. Schwartz, MD, MPH, FACP, FAADProfessor and Head, DermatologyProfessor of PathologyProfessor of MedicineProfessor of PediatricsProfessor of Preventive Medicine and Community HealthNew Jersey Medical SchoolNewark, New JerseyUSA

Skin Cancer

This book is dedicated to my wife, Camila KrysickaJanniger, MD, and our son, Edmund Jack Janniger,without whose support and encouragement thissecond edition would not have been possible.

Professor Robert A. Schwartz has been elected as an honorary member (MemberHonoris Causa) of the following international dermatology societies:Czech Dermatologic Society (Assocatio Medicorum Bohemicorum J.E. Purkyne,

Societas Dermatovenerologica Bohemica)Societa Italiana di Dermatologia medica e chirurgica e Malattie Sessualmente

TrasmesseAssociazione Dermatologi Ospedalieri ItalianiKorean Dermatological AssociationLatvian Association of Dermatology and Venereology (Latvijas Dematolovenerologu

Asociacija)Lithuanian Society of DermatovenereologyPolish Dermatologic Society (Societas Dermatologica Polona)Slovak Dermatovenereologic SocietySlovenian Association of Dermatology and VenereologyUkrainian Association of Dermatology and VenereologyYugoslav Association of Dermatology and Venereology

Skin CancerRecognition and Management

Second Edition

Robert A. Schwartz, MD, MPH, FACP, FAADProfessor and Head, DermatologyProfessor of PathologyProfessor of MedicineProfessor of PediatricsProfessor of Preventive Medicine and Community HealthNew Jersey Medical SchoolNewark, New JerseyUSA

C© 2008 by Blackwell PublishingBlackwell Publishing, Inc., 350 Main Street, Malden, Massachusetts 02148-5020, USABlackwell Publishing Ltd, 9600 Garsington Road, Oxford OX4 2DQ, UKBlackwell Publishing Asia Pty Ltd, 550 Swanston Street, Carlton, Victoria 3053, Australia

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First published 2008

1 2008

Library of Congress Cataloging-in-Publication Data

Skin cancer : recognition and management / [edited by] Robert Schwartz. – 2nd ed.p. ; cm.

Includes bibliographical references.ISBN 978-1-4051-5961-6 (alk. paper)

1. Skin–Cancer. I. Schwartz, Robert A., 1947–[DNLM: 1. Skin Neoplasms–diagnosis. 2. Skin Neoplasms–therapy. WR 500

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2007010197

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Contents

Contributors, vii

Preface, ix

1 Introduction, 1Robert A. Schwartz

2 Actinic keratosis, 5Robert A. Schwartz

3 Other premalignant cutaneous dysplasias, 16Robert A. Schwartz

4 Bowen’s disease, 33Robert A. Schwartz

5 Squamous cell carcinoma, 47Robert A. Schwartz

6 Keratoacanthoma, 66Robert A. Schwartz

7 Basal cell carcinoma, 87Robert A. Schwartz

8 Appendageal carcinomas and cutaneous sarcomas, 105Robert A. Schwartz

9 Kaposi’s sarcoma, 118Robert A. Schwartz

10 Dysplastic nevus and dysplastic nevus syndrome, 141Christopher J. Steen, Philip J. Cohen, and Robert A. Schwartz

11 Melanoma, 152Philip J. Cohen, Maja A. Hofmann, Wolfram Sterry, and Robert A. Schwartz

12 Dermoscopy for skin cancer, 200Giuseppe Micali, Francesco Lacarrubba, Beatrice Nardone, and Robert A. Schwartz

v

vi Contents

13 Merkel cell carcinoma, 220Mary S. Brady

14 Dermatitic precursors of mycosis fungoides, 227W. Clark Lambert and Robert A. Schwartz

15 Cutaneous lymphoma, leukemia, and related disorders, 238Gunter Burg, Werner Kempf, and Reinhard Dummer

16 Cutaneous metastatic disease, 267Robert A. Schwartz

17 Cutaneous markers of internal malignancy, 283Robert A. Schwartz

18 Early oral and oropharyngeal cancer diagnosis and management, 305Arthur Mashberg and Robert A. Schwartz

19 Histopathologic considerations in the management of skin cancer, 325Mark R. Wick

20 Historical survey: methods used to treat skin cancer, 350Sharyn A. Laughlin and Denis K. Dudley

21 Curettage and electrodesiccation, 367Sharyn A. Laughlin, Denis K. Dudley, and Robert A. Schwartz

22 Cryosurgery, 376Emanuel G. Kuflik

23 Excision of skin cancer, 385Daniel M. Siegel and Jeffrey I. Ellis

24 Local flap closure in the management of skin cancer, 403James W. Trimble and James R. Trimble

25 The role of skin grafts in the management of skin malignancies, 415James R. Trimble and James W. Trimble

26 Mohs micrographic surgery, 425David J. Goldberg and Eds Chua

27 Photodynamic therapy, 438David J. Goldberg and Eds Chua

28 Cutaneous cancer and radiotherapy, 449Thomas N. Helm, Klaus Helm, Kyu H. Shin, and Robert A. Schwartz

29 Local chemotherapy, 462Ulrich R. Hengge

30 Topical immunotherapy, 468Ulrich R. Hengge

31 Treatment of melanoma, 477Maja A. Hofmann, Wolfram Sterry, and Robert A. Schwartz

Index, 509

Contributors

Mary S. Brady, MDAssistant Professor, SurgeryJoan and Sanford I. Weill College

of Medicine of Cornell UniversityMemorial Sloan-Kettering Cancer CenterNew York, New York, USA

Gunter Burg, MDProfessor and Chairman EmeritusDermatologyUniversitat ZurichZurich, Switzerland

Eds Chua, MDVisiting Procedural Dermatology FellowSkin Laser and Surgery Specialists of

New York and New JerseyNew York, New York, USA

Philip J. Cohen, MDChief of DermatologyVA New Jersey Health Care SystemEast Orange, New Jersey, USA

Denis K. Dudley, MD, FRCS (C)Executive Director, LaserdermOttawa, Canada

Reinhard Dummer, MDProfessor of DermatologyUniversitat ZurichZurich, Switzerland

Jeffrey I. Ellis, MDDermatology, SUNY Downstate

School of MedicineDirector, Dermatologic Surgery

North Shore University Hospital andLong Island Jewish Medical Center

New Hyde Park, New York, USA

David J. Goldberg, MD, JDClinical Professor of DermatologyMt. Sinai School of MedicineClinical Professor of DermatologyNew Jersey Medical SchoolAdjunct Professor of LawFordham Law SchoolDirector, Skin Laser and Surgery Specialists of

New York and New JerseyNew York, New York, USA

Klaus Helm, MDProfessor of Dermatology and PathologyDirector, DermatopathologyPennsylvania State University

College of MedicineMilton S. Hershey Medical CenterHershey, Pennsylvania, USA

Thomas N. Helm, MDClinical Associate Professor of Dermatology and

PathologyState University of New York at BuffaloBuffalo, New York, USA

Ulrich R. Hengge, MDProfessor of DermatologyHeinrich-Heine-UniversityDusseldorf, Germany

Maja A. Hofmann, MDDepartment of Dermatology and AllergySkin Cancer Center

vii

viii Contributors

Charite - UniversitatsmedizinBerlin, Germany

Werner Kempf, MDLecturer and Consultant PhysicianDepartment of DermatologyUniversitat ZurichCo-DirectorKempf und PfaltzHistologische DiagnostikZurich, Switzerland

Emanuel G. Kuflik, MDClinical Professor of DermatologyNew Jersey Medical SchoolNewark, New Jersey, USA

Francesco Lacarrubba, MDAssistant Professor, DermatologyUniversity of CataniaCatania, Italy

W. Clark Lambert, MD, PhDProfessor and Associate Head, DermatologyProfessor of PathologyChief, DermatopathologyNew Jersey Medical SchoolNewark, New Jersey, USA

Sharyn A. Laughlin, MD, FRCS (C)Assistant Professor of DermatologyUniversity of Ottawa Faculty of MedicineOttawa, Ontario, Canada

Arthur Mashberg, DDSProfessor of Surgery, EmeritusNew Jersey Medical SchoolNewark, New Jersey, USA

Giuseppe Micali, MDProfessor and Chair, DermatologyUniversity of CataniaCatania, Italy

Beatrice Nardone, MDResident in DermatologyUniversity of CataniaCatania, Italy

Robert A. Schwartz, MD, MPH, FACP, FAADProfessor and Head, DermatologyProfessor of PathologyProfessor of MedicineProfessor of PediatricsProfessor of Preventive Medicine and

Community HealthNew Jersey Medical SchoolNewark, New Jersey, USA

Kyu H. Shin, MDProfessor of Radiation OncologyState University of New York at BuffaloDirector, CCS Oncology CenterBuffalo, New York, USA

Daniel M. Siegel, MD, MSClinical Professor of DermatologyDirector, Procedural Dermatology

FellowshipState University of New York Downstate

Medical CenterBrooklyn, New York, USA

Christopher J. Steen, MDStaff PhysicianDepartment of DermatologyNew Jersey Medical SchoolNewark, New Jersey, USA

Wolfram Sterry, MDProfessor and HeadDepartment of DermatologyUniversity of Medical Faculty ChariteBerlin, Germany

James R. Trimble, MDPrivate practiceJacksonville, Florida, USA

James W. Trimble, MDPrivate practiceJacksonville, Florida, USA

Mark R. Wick, MDProfessor and Associate Director,

Surgical PathologyUniversity of Virginia School of MedicineCharlottesville, Virginia, USA

Preface

The skin, uniquely positioned at the interfacebetween the human body and the external world,plays a multifaceted role in the expression of can-cer. Primary skin cancer is the most common cancerafflicting mankind and is rising in incidence, despitethe fact that it is often preventable. Besides primarycancer, the skin may show direct and indirect evi-dence of internal cancer, thus serving as a windowto the body for both laymen and physicians alike. Inaddition, the accessibility of the skin is useful for thestudy of carcinogenesis as well as cancer treatmentoptions.

I owe much of my interest in skin cancer toLeon Goldman, the father of dermatologic lasersurgery, and to Edmund Klein, the father ofmodern immunotherapy. I am also grateful toPeter J. Lynch for recruiting me as an early facultymember in the dermatology program he hadfounded at the University of Arizona. Their supportand guidance has proven invaluable in preparingme for academia, as I complete my 25th yearas professor and founding head of dermatologyat this the New Jersey Medical School. I amgrateful to Dr. Stewart Taylor, formerly Publisher,Medical Division, Blackwell Publishing in Oxford,United Kingdom, for encouraging and gainingapproval for this 2nd edition, and to his successor,Martin Sugden, working alongside Adam Gilbert(Development Editor), for facilitating its fruition.I thank my talented and loyal administrative staffperson, Mrs. Linda D. Hesselbirg. My dermatologistwife, Camila, and I are also thankful for the

encouragement of our mentor, Professor Stefa-nia Jabl�onska, and our distinguished colleagues,including in alphabetical order: Professors JulianAmbrus (Buffalo), Gerimanta Baleviciene (Vilnius),Eugeniusz Baran (Wrocl�aw), Jerzy Bowszyc(Poznan), Walter H. C. Burgdorf (Munich), StefanoCalvieri (Rome), Luiz G. Martins Castro (SaoPaolo), Olegas Ceburkov (Kaunas), Enrico Ceccol-ini (Bologna), Hong-Duo Chen (Shenyang), BozenaChodynicka (Bial�ystok), William P. Coleman III(New Orleans), Vincent A. De Leo (New York),Richard L. Dobson (Charleston), Peter M. Elias(San Francisco), Michael D. Fox (Mill Valley), PereGascon (Barcelona), Alberto Giannetti (Modena),Lawrence E. Gibson (Rochester), Harald Gollnick(Magdeburg), Vladimır Hegyi (Bratislava), JanaHercogova (Prague), Karl Holubar (Vienna), Chull-Wan Ihm (Chonju), Daniele Innocenzi (Rome),Aleksej Kansky (Ljubljana), Djordjije Karadaglic(Podgorica), Helmut Kerl (Graz), Neena Khanna(New Delhi), Uday Khopkar (Mumbai), CezaryKowalewski (Warsaw), Alicja Kurnatowska (L� odz),Piotr Kurnatowski (L� odz), Jonas Lelas (Vilnius),Jasna Lipozencic (Zagreb), Torello M. Lotti (Flo-rence), Sl�awomir Majewski (Warsaw), RomualdMaleszka (Szczecin), Jon G. Meine (Cleveland),Giuseppi Micali (Catania), Felix Milgrom (Buffalo),Halina Milgrom (Buffalo), Anastazy Omulecki(L� odz), Joseph L. Pace (Valletta), Lawrence C.Parish (Philadelphia), Zofia Piela (Rzeszow),Mario Pippione (Torin), Waldemar Placek (Byd-goszcz), Murlidhar Rajagopalan (Chennai), Jadwiga

ix

x Preface

Roszkiewicz (Gdansk), Andris Y. Rubins (Riga), Vin-cenzo Ruocco (Naples), Zbigniew Ruszczak (Berlin),Thomas Ruzicka (Munich), Stuart J. Salasche (Tuc-son), D.V. Siva Sankar (Westbury), Jean-HilaireSaurat (Geneva), Wojciech Silny (Poznan), JaySiwek (Washington DC), Georg Stingl (Vienna),Anna Sysa-Jedrzejowska (L� odz), Henryk Szarmach(Gdansk), Jacek C. Szepietowski (Wrocl�aw), JamesS. Taylor (Cleveland), Aurora Tedeschi (Catania),Wally J. Temple (Calgary), Kenneth J. Tomecki(Cleveland), Barbara Toruniowa (Lublin), TakuoTsuji (Nagoya), Skaidra Valiukevicıene (Kaunas),Frantisek Vosmık (Prague), and Alexander Za-jczenko (Lviv). Helping anchor Camila and me ona nonmedical front is our mother, Lusia Krysicka(a hero of the Warsaw Resurrection); 102-year-olduncle, Robert Upright, back home in San Francisco;and aunt Dolly Schwartz in Oakland, California.

We are fortunate in this work to have some of theworld’s foremost authorities in their areas of exper-tise as contributors, in alphabetical order: ProfessorsMary Sue Brady, Gunter Burg, David J. Goldberg,Ulrich R. Hengge, Emanuel G. Kuflik, W. ClarkLambert, Arthur Mashberg, Giuseppe Micali, DanielM. Siegel, Wolfram Sterry, and Mark R. Wick. I amalso blessed with the strong support and encour-agement of my colleagues at this New York Citymetropolitan area medical school (founded in 1954as Seton Hall College of Medicine; New Jersey Col-lege of Medicine 1965 to 1970; New Jersey MedicalSchool, since 1970).

I have been honored to serve in multiple roles atthe New Jersey Medical School, including as the firsttenured head of dermatology in the history of thestate of New Jersey, being able with Professors W.Clark Lambert, Roger H. Brodkin, Tamotsu Imaeda,and George Kihiczak to establish the first dermatol-ogy residency training program in New Jersey. Fromthis medical school faculty I also thank MichaelP. Bagley, Soly Baredes, Santiago A. Centurion,Stanley Cohen, Manuel A. Cruz, Hugh E. Evans,Lawrence P. Frohman, Bunyad Haider, George J.Hill, Robert L. Johnson, Mark Jordan, RajendraKapila, Julianne H. Kuflik, John Kwittken, Carroll

Moton Leevy, Ruy V. Lourenco, Judit Nyirady, JerryRothenberg, Christopher W. Scialis, Kenneth G.Swan, Isabelle Thomas, and Jeffrey M. Whitworth.Dermatology has become an important part of ouracademic community, allowing me to serve as Fac-ulty President, Alpha Omega Alpha National HonorMedical Society Chapter Councilor, and as SigmaXi Chapter President. I am gratified that one ofmy first dermatology residents, Philip J. Cohen, hascoauthored two chapters in this book as he con-tinues his thriving academic career after years withProfessor Stephen I. Katz at the National Institutesof Health, returning to his alma mater as chief ofdermatology at our New Jersey Veterans Admin-istrations Medical Center in East Orange. It is sat-isfying to have one of my loftiest chief residents,Christopher J. Steen, as a coauthor of a chapter. Iam appreciative of my talented current residents—Christopher J. Steen, Robyn D. Siperstein, LenisM. Gonzalez, George G. Kihiczak, Smeeta Sinha,Stephen J. Nervi, Justin Brown, Anjali K. Butani,Mordechai M. Tarlow, and Geover Fernandez—as well as our dermatopathology residents WenChen, Rajit Malliah, and Wanda M. Patterson—with particular thanks to Lenis Gonzalez, GeorgeG. Kihiczak, Sharon E. Hwang, and Wen Chen withregard to this book.

I am fortunate for many reasons. It is inspiringto have the friendship of Theodore Cardinal E.McCarrick, PhD. Munificent colleagues have fa-cilitated my election as an honorary member ofthe national dermatology societies of Italy, CzechRepublic, Korea, Poland, Slovenia, Slovakia, Latvia,Lithuania, Ukraine, and Yugoslavia. I am indebtedto Institute of Immunology and ExperimentalTherapeutics Director Jacek Szepietowski, rectorand the academic senate for the Academia MedicaWratislasiensis Medal, awarded in June 2007 by theUniversity Rector Magnificus, Medical University ofWrocl�aw (Breslau). Special thanks goes to ProfessorWiesl�aw Glinski, Chairman, Dermatology, MedicalUniversity of Warsaw, for his timely assistance andto Katie Greczylo for her superb efforts as projectmanager.

CHAPTER 1

IntroductionRobert A. Schwartz

Skin cancer, the most common cancer worldwide,has an incidence doubling every 15 to 20 years!The principle factor inducing most of the primaryskin cancers discussed in this book is ultravio-let light–induced carcinogenesis. However, as wewill stress, other parts of the electromagnetic spec-trum, such as x-rays and infrared rays (heat), mayalso be carcinogenic (Table 1.1). In addition, viraland chemical carcinogenesis may be very impor-tant. Details of ultraviolet light–induced carcinogen-esis are delineated within the respective chapterson basal cell carcinoma, squamous cell carcinoma,actinic keratosis, melanoma, and the deadliest ofall skin cancers: Merkel cell carcinoma [1]. Theincreased risks for five additional cancer types(prostate, breast, and colon cancers, non-Hodgkin’slymphoma, and multiple myeloma) in first-degreerelatives of melanoma cases suggest that individu-als with a family history of melanoma should strictlyadhere to recommended screenings for all cancers[2].

There are two major challenges in dealing withcancer, the first being prevention. The use of sun-screens has been emphasized and needs to bestressed. Actual skin protection chiefly depends onthe way sunscreens are used and the quantity ap-plied [3]. Skin cancer prevention is facilitated byexplicit labeling and free provision of sunscreen.Prevention should begin early in childhood [4].Proper young ladies and men should be seen withbonnets or hats and long sleeves, not photoag-ing themselves unnecessarily. Certainly, the struc-tural and functional changes of normal cutaneousaging include decreased growth of the epidermis,hair, and nails; delayed wound healing; and im-paired cutaneous immune responses. Photoaging,

however, is a different process [5]. Evidence sug-gests that topical retinoids not only may deceleratethe photoaging process but also are capable of re-pairing photoaged skin at both the clinical and bio-chemical levels and may prevent photoaging [6].In addition, topical retinoids could be beneficial inthe treatment of intrinsically aged skin. Antioxi-dants may also be employed, particularly in com-bination, to reduce and neutralize free radicals [7].Importantly, for every light-complexioned individ-ual (Fig. 1.1), protection from the premature andunsightly effects of sun exposure is mandatory (Ta-ble 1.2). As both melanocytic nevi and sunburn arerisk factors for the development of melanoma, weshould target fair-skinned transplant recipients withmelanocytic nevi for sun avoidance education [8].The goal should be the prevention of both photoag-ing and photocarcinogensis [9]. Risk assessment isa good idea [10].

A secondary challenge is detection, because mostcancers are curable if caught early. This pointis emphasized by the “developing epidemic ofmelanoma” in Hispanic men in California [11]. Astatistically significant 1.8% per year increase inincidence of invasive melanomas among Hispanicmales has been observed between 1988 and 2001.Among them, melanomas thicker than 1.5 mmat presentation increased at 11.6% per year. Thisincrease in melanoma in Hispanics, confined tothicker tumors with a poor prognosis, emphasizesthe need for both prevention and early detection.

The worldwide scourge of AIDS, beginning for usin Europe and America in the early 1980s, is an epi-demic that is not abating [12–16]. Kaposi’s sarcomahas been an intrinsic part of this epidemic, as de-lineated in the Kaposi’s sarcoma chapter. Since the

1

2 Chapter 1

Table 1.1 Electromagnetic spectrum

Type of Radiation Wavelength

Gamma rays, x-rays, Below 1 nm (10 angstroms)Grenz rays

Ultraviolet light (UV)UV “C” range 1–290 nm

UV B 290–320 nm(through ozone layer)

UV A 320–400 nm(through window glass)

Visible light 400–700 nm

Infrared radiation (heat) 700–1,000,000 nm

Radio waves 1,000,000 nm and above

first edition of this book was published, the etiologicagent of Kaposi’s sarcoma has been identified [17].Although the incidence of Kaposi’s sarcoma has de-clined dramatically in areas with access to highlyactive antiretroviral therapy, it remains the mostcommon AIDS-associated malignancy in the devel-oped world and is one of the most common malig-nancies in developing nations. Current treatmentoptions are ineffective, unavailable, or toxic to

Table 1.2 Preventing skin cancers and premature aging(photoaging)

Avoid sun exposureUse sunscreen preparations and cover body with clothingConsider topical retinoid use

many affected persons. A growing body of basic sci-ence, preclinical, and observational data suggeststhat antiviral medications may play an importantrole in the prevention and treatment of Kaposi’ssarcoma–associated herpesvirus, providing hope forthe future [18]. The skin may serve as an importantorgan for study in these patients and often manifeststhe first signs of AIDS.

Some cutaneous tumors remain an enigma. Agood example, one even better than melanoma, isperhaps the deadliest of all skin cancers—Merkelcell carcinoma—which appears to have tripled inincidence from 1986 to 2001 in the United Statesand Canada [1]. Often appearing as an asymp-tomatic nodule on sun-exposed skin, it may resem-ble a basal cell carcinoma, a common misdiagnosisboth clinically and histologically that may have fa-tal consequences. Its origin from the normal epider-mal Merkel cell remains controversial, because thisneoplasm originates in the dermis and only rarely

Fig. 1.1 The author’slight-complexioned 10-year-old son,Edmund, exhibiting evidence of skincancer prevention at a New Jerseybeach.

Introduction 3

Table 1.3 Cancers mimicking dermatitis

Erythroplasia of Queyrat and other sitesPaget’s disease of the breastExtramammary Paget’s diseaseInflammatory metastatic carcinomaBowen’s diseaseAmelanotic lentigo maligna melanomaScar carcinoma

demonstrates epidermal involvement. It may be de-rived from the haarscheibe or hair disc (touch cor-puscles), composed predominantly of Merkel cells.Advances in our understanding of it are moving for-ward [19].

Viral oncogenesis has taken large leaps aheadthrough exciting technologic advances that have al-lowed the typing of human papillomaviruses andhave linked them with a variety of skin cancers [20].In the chapters that follow, some of the probable as-sociations of human papillomavirus infections andcancer are discussed. Through the study of modeldiseases, such as epidermodysplasia verruciformisand xeroderma pigmentosum, much has been andwill continue to be learned about skin cancer. Thetopical application of the bacterial DNA repair en-zyme T4 endonuclease V to sun-damaged skin ofpatients with xeroderma pigmentosum has promisein lowering the rate of development of actinic ker-atoses and basal cell carcinoma [21,22].

As the chapters on recognition of skin cancernote, diagnosing skin cancers may at times be dif-ficult. It is amazing how often skin cancer maymimic dermatitis (eczema; Table 1.3). Conversely,worrisome skin tumors may represent benign cu-taneous processes or cutaneous infections, espe-cially in immunocompromised persons. The abilityto immunosuppress transplant recipients and theAIDS epidemic bring dermatology to the forefrontof medicine.

Modern molecular biology has led to muchprogress. There are important genetic changes con-tributing to the development of melanoma, basalcell carcinoma and squamous cell carcinoma, andother less common skin cancers [23]. Although ourunderstanding of oncogenes and tumor suppressor

genes involved in the development and progres-sion of skin tumors remains fragmentary, recentadvances have shown alterations affecting con-served signaling pathways that control cellular pro-liferation and viability. The BRAF oncogene is a goodexample [24,25]. There have been more than 30distinct BRAF mutations in melanomas described,varying in biological activity. Some may be predic-tive of clinically relevant tumor differences. BRAFsomatic mutations are often found in primary andmetastatic melanomas and melanocytic nevi. BRAF-mutant melanomas appear to be linked with hostphenotype, tumor location, and pigmentation, withthis somatic mutation sometimes associated with agermline one [26].

All of our modern advancements are of particularadvantage in studying patients with genetic cancersyndromes, such as the dysplastic nevus syndrome,the basal cell nevus syndrome, xeroderma pigmen-tosum, and the Muir-Torre syndrome—all of whichare also covered in the chapters to follow.

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24 Thomas NE. BRAF somatic mutations in malignant

melanoma and melanocytic naevi. Melanoma Res

2006;16:97–103.

25 Liu W, Kelly JW, Trivett M, et al. Distinct

clinical and pathological features are associated

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26 Landi MT, Bauer J, Pfeiffer RM, et al. MC1R germline

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ence 2006;313:521–2.

CHAPTER 2

Actinic keratosisRobert A. Schwartz

Actinic (or solar) keratoses (AKs) are common. Al-most all elderly light-complexioned people haveone or more of them. They represent a cutaneousdysplasia, akin to those of the uterine cervix, whichmay progress to full thickness in situ and then in-vasive squamous cell carcinoma (SCC). However,a good case can also be made that an AK is frominception an SCC [1,2]. There are approximately5.2 million visits annually in America for AKs, withan estimated cost of at least $920 million [3]. Theprevalence in the white population of northwestEngland in people over 40 years of age was 15.4%in men and 5.9% in women [4]. As the recre-ational habits of recent times have encouraged largeamounts of sun exposure, one identifies more andmore AKs on younger and younger people. Thesites on which one most commonly sees AKs arethe face (especially the forehead) and dorsal hands.Often the AK can better be palpated as a roughenedspot than visualized. AKs may gradually enlarge toform plaques, which may be skin colored, slightlyerythematous, or at times brownish or grayishyellow. The essentials of diagnosis are delineated inTable 2.1.

In the individual with AKs, one tends to also findobvious evidence of chronic solar exposure. Dilatedcapillaries may be evident around the nose. The skinmay appear thickened or yellowish and elastotic. Inregions with year-round solar exposure, one seesrelatively young people with these chronic degen-erative changes. I usually mention to my patientsthat our grandparents never deliberately exposedthemselves to chronic destructive sun exposure. Itis unfortunate that the tan, which was once equatedwith common laborers, remains fashionable.

The development of AK and SCC is likely an ex-ample of multistage carcinogenesis resulting from a

complex sequence of events initiated by exposureto ultraviolet (UV) light [5,6]. Initial damage takesplace in the DNA. Mutations in the tumor suppres-sor gene p53 are common in AK and SCC.

History

Although Dubreuilh is credited with describing thetypical AK in 1904 [7], it took another two decadesto separate it from seborrheic keratosis and verrucavulgaris in the medical literature. The careful workof Montgomery [8] and MacKee and Cipollaro [9]helped clarify any residual confusion in the UnitedStates, as did more recent work [10].

As it was easily linked with sun exposure, theterm solar keratosis became fashionable, followedmore recently by actinic keratosis, the preferred termtoday. The term senile keratosis, which has also beenemployed, is misleading, as its development appearsto be a function of sun exposure rather than ageper se.

Clinical features

The AK usually appears on sun-exposed areas inlight-complexioned people as a minute skin-coloredto yellowish-brown macule or papule, often witha dry adherent scale (Fig. 2.1). It may be consid-erably larger, up to several centimeters in diame-ter. It is characterized by a roughened quality onpalpation, which is often considerably more strik-ing than its visual qualities. The AK is often with-out symptoms. Sometimes a patient will notice amildly irritating quality to the AKs and on occa-sion gently rub them. If induration, erythema, orerosion is observed, the physician should suspect

5

6 Chapter 2

Table 2.1 The actinic keratosis: essentials of diagnosis

Roughened papule (often ill defined)Light-skinned individualSun-exposed siteSize: pinhead to 1 cmSkin colored or reddish, sometimes reddish brown or

yellowish blackEvidence of associated sun damage of skin

TelangiectasiasSolar elastosisFreckling

possible evolution into an SCC. Clinical parametersindicating AKs with an increased risk of malignancyhave been emphasized by the pneumonic IDRBEU: I(Induration/Inflammation), D (Diameter > 1 cm), R(Rapid Enlargement), B (Bleeding), E (Erythema),and U (Ulceration) [11]. Occasionally an AK ex-hibits proliferative characteristics both histologicallyand clinically, in which case it may be resistant tostandard therapies because of deep migration of ab-normal cells along hair follicles and sweat ducts. Thistype may have an increased risk of becoming an in-filtrative SCC and has been labeled a distinctive AKvariant: the proliferative AK [12].

One technique that can be employed to bet-ter visualize AKs is the application of topical

Table 2.2 Clinical types of actinic keratosis

Palpable papular AKHypertrophic AKActinic cheilitisSuperficial pigmented AKAtrophic AKLichenoid AKActinic conjunctivitis

5-fluorouracil (5-FU), which produces intenselesional inflammation 2 weeks later and often de-lineates otherwise unobserved early AKs. However,topical chemotherapy is best advised for the treat-ment rather than the diagnosis of AKs.

There are a number of types of AKs (Table 2.2).These variations and their differential diagnoses fol-low (Table 2.3). The subtleties of distinguishing thecommon AK from other entities, such as dissemi-nated superficial actinic porokeratosis, may requireclinical experience [13] (Fig. 2.2). The clinical di-agnosis of nonpigmented facial AK may be en-hanced by dermatoscopy, which may show a pe-culiar “strawberry” appearance [14].

The hypertrophic actinic keratosisThe AK may become hyperkeratotic. This phe-nomenon is often observed on the dorsal hands

Fig. 2.1 Roughened papules onbald scalp are better palpatedthan visualized. (Reprintedwith permission from SchwartzRA. Actinic keratoses. J AmAcad Dermatol1984;11(6):27A, 30A.)

Actinic keratosis 7

Table 2.3 Differential diagnosis of actinic keratosis

Discoid lupus erythematous (small papule)Salmon colored, atrophy, carpet-tackingThis photo-induced lesion may require biopsy to

distinguishSeborrheic keratosis

Under magnification, lesion shows pits and furrowsSolitary cutaneous papulonodule of coccidioidomycosis

History of travel to or residence in endemic areasDisseminated superficial actinic porokeratosis

Small keratotic ridge on border of each lesionLarge cell acanthoma

Slightly pigmented and keratotic 5–10 mm nondescriptplaque

and face. Sometimes the exophytic growth may beso impressive that a “cutaneous horn” is formed.This term is purely morphologic; however, theoverwhelming majority of cutaneous horns inlight-complexioned adults are actually exuberantlyprolific AKs. The full range of cutaneous horns is dis-cussed in a separate chapter. The trauma of chronicrubbing may produce the hyperkeratosis. A hyper-trophic AK may be so hyperkeratotic as to resem-ble the horn of an animal. This cutaneous horn,or cornu cutaneum, appears as a solid, dry, conicalprotuberance of variable coloration and angulation,

which varies in size from minute to huge. Most ap-pear 2 to 8 mm in diameter, projecting up to 3 cm(Fig. 2.3), as covered in Chapter 3.

The lichenoid actinic keratosisIn 1967, Hirsh and Marmelzat [15] employed theterm lichenoid actinic keratosis to describe five patientswith a specific localized skin lesion on sun-exposedareas. Each patient was a white woman with a singlelesion situated on the upper anterior chest. Clini-cally, the lesions resembled lichen planus, lichenoiddrug eruption, lichenoid polymorphous light erup-tion, lichenoid contact dermatitis, and lichen actini-cus. However, microscopically, the salient featureswere epidermal dysplasia and a lichenoid infiltrate.

Other descriptions, both preceding and since theabove account, called it solitary lichen planus-like keratosis [16], solitary lichen planus [17], andbenign lichenoid keratosis [18,19]. The histologicfeatures, however, are not those of AK, lackingevidence of cellular atypia or anaplasia. Melanocyticnevi with lichenoid regression may resemble abenign lichenoid keratosis histologically [20]. Theclinicopathologic spectrum of benign lichenoid ker-atosis is broad, encompassing several unrelated en-tities [21]. It has been proposed to classify lichenoidkeratosis into the following lichenoid entities: seb-orrheic keratosis, solar lentigo, AK, and idiopathic

Fig. 2.2 Roughened papule in solarexposure distribution disseminatedsuperficial actinic porokeratosis.

8 Chapter 2

Fig. 2.3 Hypertrophic AK on a nose; acutaneous horn.

lichen planus [22]. I have observed lichenoid AKs,as have James and colleagues [23]; it is my impres-sion that most solitary lichenoid keratoses are notlichenoid AKs. The James group noted pigmenta-tion in lichenoid AKs, the pigment being located inupper dermal macrophages.

Spreading pigmented actinic keratosesIn 1978, James, Wells, and Whimster [23] described10 patients with asymptomatic pigmented plaquesof the face between 1.5 and 4.0 cm in diameter. Al-though six had been diagnosed clinically as a lentigomaligna (Hutchinson’s freckle), all were microscop-ically found to be pigmented AKs. Most AKs exhibitlittle tendency for centrifugal growth over 1 cm.The surface of the spreading pigmented AK is vari-ably pigmented and either smooth, slightly warty, orscaly. Spreading pigmented AK and melanoma mayexhibit overlapping clinical features; dermoscopymay facilitate diagnosis [24]. Clinical features ofspreading pigmented AK may suggest seborrheickeratosis, senile lentigo, and melanocytic nevus aswell as early melanoma [25].

Their histology is similar to that of the typicalAK, although epidermal and melanophage pigmen-tation is more prominent. James and associates [23]found that melanocytes appeared normal in size,number, and morphology. The hyperpigmentationis the result of enhanced melanosome formation

and distribution and not a melanocyte–keratinocytemelanosome transfer block [26].

The evolution of the superficial pigmented AK isunknown, although one suspects the same behavioras with typical AKs. Whether they evolve into pig-mented Bowen’s disease is an unanswered questionat present.

Actinic cheilitisThe most important type of AK is that located onthe lip, the actinic cheilitis (AC). This incipient formof actinically induced SCC of the lower lip is of greatconcern, as SCC of the lip has a high malignant po-tential [27] (see “Lip Squamous Cell Carcinoma” inChapter 5). The AC invariably occurs on the lowerrather than the upper lip, because the carcinogenicagent is solar radiation. ACs are similar morphologi-cally to AKs on cutaneous surfaces, although a moreprominent atrophic quality may be noted on the lip(Fig. 2.4). One series divided AC into three clinicalforms: white nonulcerated lesions (29%), erosionsor ulcers of the lip (48%), and mixed white anderosive (23%) [28]. A recent study of 20 patientswith AC analyzed the entire lip vermilion searchingfor microscopic areas of progression; foci of inva-sive SCC were found in four (20%) of them [29].Patients with AC having poorly demarcated lesionsmay have severe histopathologic changes irregu-larly distributed along the vermilion. An intense

Actinic keratosis 9

Fig. 2.4 Roughened papule, lip, AK(actinic cheilitis).

inflammatory infiltrate was found to be predictiveof an adjacent invasive SCC [30]. In this study of70 cases of chronic AC, the p53 protein immunore-activity was not a marker of malignant transfor-mation. Differential diagnostic considerations arenoted in Table 2.4.

Actinic conjunctivitisUltraviolet light produces conjunctival alterationsclassified clinically as a pinguecula or pterygium. Itappears as a wedge-shaped opaque plaque near thelimbus. Actinic conjunctivitis may progress to SCCof the conjunctiva [31,32].

Histopathology

The AK is a cutaneous dysplasia of the epider-mis [2,10]. Thus, alterations of cellular polar-ity, dysplasia, and nuclear atypia are evident andcharacteristic. Epidermal cells appear abnormal, lessbasophilic than normal keratinocytes, and variable

Table 2.4 Differential diagnosis of actinic cheilitis

Necrotizing sialometaplasiaFactitial lip crustingLupus erythematosusCheilitis granulomatosis

in size and shape. Often one can observe a few nu-clei that are enlarged and contain prominent nucle-oli. Some cells may be multinucleated; others maydisplay mitotic figures. Individual cell keratiniza-tion is present sometimes. The overlying epidermisis slightly to markedly hyperkeratotic, with somestratum corneum appearing either loose or com-pact. Orthokeratotic hyperkeratosis and parakerato-sis may alternate, with the normal hyperkeratosisappearing above the adnexal structures. The acan-thosis is irregular; often small buds extend down-ward. Dyskeratosis may be prominent. Spaces in theepidermis with partially keratinized cells called corpsrounds and grains may be seen [8].

The dermis often shows basophilic degenerationwith a mild inflammatory infiltrate and edema ofthe upper dermis. Hair follicles, sebaceous glands,apocrine and eccrine sweat glands, and ducts appearunaltered.

Acantholytic changes were noted consistentlyin 18 of 402 cases of AK (4.4%) and involvedboth the epidermis and appendageal epithelia [33].Suprabasal clefting with acantholytic cells portendsno special clinical or prognostic distinction; how-ever, it is this type of AK that probably evolvesinto the so-called adenoid SCC [34]. The AK mayoccasionally show the changes of epidermolytic hy-perkeratosis along the entire epidermis (except ad-nexa) [35].

10 Chapter 2

Table 2.5 Histologic types of actinic keratoses

Typical (SCC grade 1/2)Bowenoid (full-thickness epidermal change)HypertrophicAcantholyticPigmentedLichenoidProliferative

Of the previously mentioned 402 skin biopsyspecimens, 49.7% were labeled atrophic-type AKs,38% were of the hypertrophic type, and 7.7% ofthe bowenoid type [33]. A breakdown of histologictypes of AKs is given in Table 2.5. When AKs extendto the biopsy specimen margins, about half recurwithin 3 years [36].

Although the AK is most closely linked with SCC,occasionally a basal cell carcinoma [37] and rarelya sebaceous carcinoma may arise on or from anAK [38].

Histologic differential diagnosis

The characteristic AK involves focal dysplasiasparing dermal appendages. Atypical vacuolatedcells may resemble mammary and extramammaryPaget’s disease [39]. However, the presence ofdesmosomes and keratinocyte dyskeratosis usuallyallows distinction.

At times, AKs may show hypergranulosis, at-rophy, and basal cell layer liquefactive degenera-tion, prompting confusion with lupus erythemato-sus, lichen planus, and other lichenoid eruptions.Columns of parakeratosis may resemble the coro-noid lamella of the porokeratoses and be difficultto distinguish from disseminated superficial actinicporokeratosis. Unusual findings occasionally occur,such as a primary cutaneous extraskeletal osteosar-coma under a previous electrodessicated actinic ker-atosis [40].

Prognosis

It is generally accepted that, except on the lip,AKs are of low-grade malignant potential [2]. Onestudy of 560 individuals from Wales found that

21% of AKs resolved spontaneously over a 12-month period and none progressed into SCC [41].An Australian analysis of 1140 aged 40 years andover found 616 (59.2%) with solar keratoses, 224(36.4%) of whom had spontaneous remission of atleast one of their solar keratoses within 1 year [42].A total of 485 lesions (25.9%) underwent sponta-neous remission out of the 1873 AKs evident atthe first examination of these 224 people. The in-cidence rate of SCC occurring in those with solarkeratoses was 0.24% for each solar keratosis evi-dent at the original examination. In up to 20% to25% of patients with AKs, one or more of the AKsdisplay evidence of SCC, either in situ or invasive[8]. Another analysis found 7.7% of AKs displayedbowenoid change [33]. Graham and Helwig [34]reviewed data on patients with AKs and found thatabout 13% showed actual change of SCC. Bendland Graham [43] studied the data from 156 patientswith 163 AKs having evidence of dermal invasion,which they labeled “solar keratosis with squamouscell carcinoma,” and found the metastatic potentialnonexistent or infinitesimally low.

Histologic evidence of a contiguous AK was foundin eight of 18 patients (44%) with SCC that hadmetastasized from skin [44]. If sampling errors areconsidered, this figure may be even higher. In-creased tumor thickness and depth of invasion werethe most consistent histologic features linked withthese metastasizing SCCs. Such SCCs may be locallyaggressive but do not commonly metastasize. Al-though some AKs may become clinically inappar-ent, possibly either because of immune rejection orsimply because their external surface unknowinglyhas been scraped off, an untreated AK represents apotentially curable fatal cancer.

Treatment

The therapeutic options for treating AKs are mul-tiple (Table 2.6). Treatment includes cryosurgery,curettage and excisional surgery, dermabrasion,chemical peels, laser resurfacing, 5-FU, imiquimod,diclofenac, and tretinoin [45]. I prefer liquid ni-trogen cryosurgery for individual AKs and 5-FUfor field therapy. Field cancerization is particularlyimportant with AC, as one must evaluate and, if

Actinic keratosis 11

Table 2.6 Therapeutic options for actinic keratoses

Liquid nitrogen cryosurgeryTopical 5-FUImiquimodDiclofenacCurettage and electrodessicationPhotodynamic therapyDermabrasionTopical retinoidsChemical peelT4 endonuclease V (T4N5) liposome lotionSystemic retinoids

need be, treat the entire lip vermilion, searchingfor microscopic areas of invasive SCC. Liquid nitro-gen cryotherapy has a cure rate approaching 100%[46,47]. Moreover, it and topical 5-FU can be em-ployed in combination. A 1-week course of topi-cal 0.5% fluorouracil before cryosurgery was sig-nificantly more effective in reducing AKs 6 monthsafter treatment than cryosurgery alone [48].

Topical 5-FU has been effectively used since itwas pioneered by Edmund Klein in the early 1960s[49–53]. It is an excellent option, particularly forAKs occurring on the face [54], but many patientsexperience considerable discomfort for weeks. Sev-eral formulations and concentrations of topical flu-orouracil are Food and Drug Administration ap-proved for the treatment of AK and AC, with themost commonly employed being the 5% and 0.5%creams [55]. They eradicate AKs, often with applica-tion site irritation, erythema, and burning. Compar-ative data suggest that the fluorouracil 0.5% creamis more cost-effective and may be safer, more tol-erable than, and as efficacious as fluorouracil 5%cream. I sometimes use a moderately potent topicalsteroid after the 5-FU to reduce irritation. In AKs ofthe forearms and hands, 5-FU alone has been rel-atively ineffective whereas the combination of 5%5-FU cream twice daily followed by nightly appli-cation of 0.05% tretinoin cream may be efficacious[56,57]. The efficacy and tolerability of 5% 5-FUcream and imiquimod cream were compared in 36patients with four or more AKs who were randomlyassigned to receive 5% 5-FU cream twice daily for2 to 4 weeks or 5% imiquimod cream twice weekly

for 16 weeks [58]. 5-FU was more effective thanimiquimod in exposing presumed subclinical AKs,reducing the final AK count (total AK count de-clined during the 24-week study by 94% vs. 66%),achieving complete clearance (incidence of 84% vs.24% by week 24), and achieving clearance rapidly.Tolerability was similar, although erythema was ini-tially significantly higher with 5-FU than with im-iquimod but resolved rapidly and was significantlylower than with imiquimod by week 16. This studyconcluded that 5% 5-FU remains the gold standardfield therapy for AKs.

Some favor imiquimod as having a higher effi-cacy than 5-FU for AK lesions located on the faceand scalp [59–62]. Local adverse events with im-iquimod in one study were erythema (27%), scab-bing or crusting (21%), flaking (9%), erosion (6%),edema (4%), and weeping (3%) [63]. Aphthousstomatitis may also become evident when using im-iquimod to treat AC [64]. Imiquimod 5% creamused three times weekly for 16 weeks is effectivein the treatment of AK [65]. It stimulates a cuta-neous immune response characterized by increasesin activated dendritic cells and CD4+ and CD8+ Tcells [66]. It also encourages keratinocytes to secretecytokines and chemokines, attracting inflammatorycells, resulting in immune cell–mediated destructionof AKs [62].

The relationship between a key mediator in theproinflammatory cascade, cyclooxygenase, and car-cinogenesis has provided a rationale for the useof topical nonsteroidal anti-inflammatory drugs forthe treatment of AK, with 3% diclofenac coming tothe forefront [61]. It has shown moderate efficacywith low morbidity in mild AKs. Treatment has beenwell tolerated; side effects were mainly pruritus, dryskin, and application site reactions. Assessing clini-cally meaningful end points in managing AKs withdiclofenac 3% gel may be challenging [67].

Other approaches are noteworthy. In areas ofwidespread involvement, such as the bald scalp, der-mabrasion may be a useful option and, moreover,may have a long-term prophylactic effect [68,69].Patients who have undergone both topical 5-FU anddermabrasion appear to find dermabrasion moretolerable [47]. Photodynamic therapy (PDT) is alsoan effective and safe treatment of nonhypertrophic

12 Chapter 2

Table 2.7 Dangers and opportunities posed by actinickeratoses

May evolve into metastatic SCCRare except on lip

Educate physician and patient about other skin-inducedcancersExamine entire skin surface, especially for melanomaReexamine every 6 months

Warn physician and patient about skin cancer preventionIn young patients, consider rare genetic syndrome:

xeroderma pigmentosumIf patient is immunocompromised, watch carefully for

other skin cancers and aggressive AKs

AKs of the scalp and face. PDT is good for multipleAKs and AC, without the adverse effects of 5-FUor imiquimod [70,71]. Blue light PDT is being ex-plored for treating AKs [72]. Blue light patch maybe a safe, effective, and alternative method for lightdelivery and topical aminolevulinic acid activationduring PDT [73]. Tretinoin cream, a topical retinoid,may moderate or reverse photoaging [74].

Topical or systemic retinoids may ultimatelyprove useful in the chemoprevention of AKs, butpreliminary evidence is contradictory [57,75]. Peo-ple with moderately severe AKs using daily vita-min A have experienced a 32% risk reduction incutaneous SCCs. The vitamin A doses of 50,000 and75,000 IU/day for 1 year have proven safe and ef-ficacious and have been recommended for futureskin cancer chemoprevention studies [76]. Intrale-sional α2-interferon has demonstrated efficacy ininducing complete regression of AKs but requiresmultiple injections and is less practical [77]. In pa-tients with xeroderma pigmentosum, T4 endonu-clease V (T4N5) liposome lotion applied for 1 yearreduced the rates of AK and skin cancer comparedwith placebo. Thus, T4 endonuclease V, an enzymethat repairs damaged bacterial DNA, apparently re-duces DNA damage and/or increases the rate of DNArepair in these patients [78].

An overview

Actinic keratosis tags the patient with a marker ofexcessive sun exposure. In selected model diseases,

Table 2.8 Curiosities about actinic keratoses

DNA repair deficiency in lymphocytes in patients with AKCutaneous vitamin A level may be low in AKDNA repair after UV light exposure in skin fibroblasts of

patients with AKs may be defectiveTopical retinoids appear to moderate or reduce skin

photoaging with elimination of dysplasia and atypia,but whether their use becomes popular remains to beseen

such as xeroderma pigmentosum and oculocuta-neous albinism, the solar limits are lower than forthe rest of the population. In recent years, it has be-come apparent that immunocompromised patientsshould also be considered at increased risk of AKswith progression to SCC. The dangers of AKs andopportunities posed by their detection are listed inTable 2.7.

Actinic keratosis also represents an opportunityas a model for carcinogenesis and cancer therapy. Itis not surprising that DNA repair deficiencies havebeen found in lymphocytes [79] and fibroblasts ofpatients with AKs. Other curious findings are listedin Table 2.8 [57,74,76,77,79–81].

Much of the challenge of AKs lies in preventionby public education [82]. Avoidance of sun expo-sure and the use of protective agents and garmentsif solar radiation is mandatory are difficult conceptsfor a public that craves deep tans. The use of sun-screens and sun blocks, such as zinc oxide ointment,is recommended.

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CHAPTER 3

Other premalignant cutaneousdysplasiasRobert A. Schwartz

Arsenical keratoses

Arsenic has been characterized as the number onetoxic environmental contaminant [1]. It is a hu-man carcinogen but not a potent mutagen, proba-bly acting by modifying DNA methylation patterns.Arsenical keratoses may disclose a cryptic exposureto arsenic many years earlier [2–4]. They usuallyappear on the palms and soles but may occur else-where as cornlike, hard, yellowish papulonodules,with a predisposition along sites of trauma and fric-tion. They may coalesce into verrucous plaques andmay evolve into full-thickness dysplasia or Bowen’sdisease (in situ squamous cell carcinoma [SCC]).

As Bowen’s disease, the eruption may be on sun-exposed or non–sun-exposed sites and may dis-play pigmentation. Whenever one sees Bowen’sdisease on a non–sun-exposed site, the carcino-gen is unlikely to be ultraviolet light. Accordingly,one should search for a history of previous ar-senic exposure years earlier. Arsenically inducedBowen’s disease may progress into metastatic inva-sive SCC. This point was amply illustrated by SirJonathan Hutchinson [5] when in 1887 he pre-sented to the Pathologic Society of London, withSir James Paget chairing the meeting, the propo-sition that arsenic can induce cancer. Hutchinsonpresented two patients, one an American physi-cian who had been treated with oral potassium ar-senite (Fowler’s solution) for psoriasis. Yet, evenwith its carcinogenicity known for so long, ar-senic exposure has continued medicinally, occupa-tionally, and environmentally [6,7]. Paradoxically,this carcinogen’s dramatic effect in the treatment

of acute promyelocytic leukemia has returned itto mainstream medicine. Interestingly, the triva-lent inorganic arsenic is the principal offender,whereas organic arsenical compounds, such as thosepreviously used against syphilis, are not carcino-genic. Nevertheless, the use of offending formsof arsenic in Asian pills and Chinese traditionalmedicine for asthma continues [8]. In addition,seafood such as kelp and clams may concentratearsenic [9,10]. Arsenic may appear in contami-nated well water from insecticides or from miningby-products [11,12]. Chromium-copper-arsenate–treated plywood has a toxic legacy [13].

The key is to catch arsenicism as early as possible,before the cutaneous and systemic stigmata presentserious problems. Arsenical keratoses and Bowen’sdisease will otherwise gradually extend, forming alarge erosion or ulceration that may be difficult totreat, even without metastases [14]. The first prob-lem is the diagnosis. Most patients referred to mewith a possible diagnosis of arsenical keratoses havethe relatively common autosomal dominant hyper-keratosis of the palms and soles, with small crater-like pits evident or easily produced when keratinousplugs are pulled [15] (Figs. 3.1 and 3.2). The plugsof arsenical keratoses, if removed, do not leave pits.

Other stigmata of chronic arsenicism include pig-mented changes in the skin, with hyperpigmentedpatches often displaying small areas of depigmen-tation resembling raindrops (Fig. 3.3). Such pig-mented patches tend to affect most commonly thenipples, axillae, groin, and other pressure points. Incontrast with the hyperpigmentation of Addison’sdisease, the oral mucosa tends to be spared with

16

Other premalignant cutaneous dysplasias 17

Fig. 3.1 Arsenical keratosis on the sole.

arsenicism. Other cutaneous signs of arsenicism in-clude Mees’ lines, transverse whitish narrow fin-gernail bands seen in both acute and chronic ar-senicism. These can be used to date the episodes ofexposure, with 30 to 40 days required for the lines tofirst appear above the lunulae of the fingernails. Inaddition, a diffuse alopecia of scalp, acrodermatitis,and thromboangiitis-like changes of the legs may beseen, with gangrene resulting. These destructive legchanges are called blackfoot disease.

Arsenicism is a systemic disease, with neuropa-thy often the hallmark [16]. One may see a

symmetrical polyneuropathy resembling Guillain-Barre syndrome or paresthesias, numbness, andpain on the soles of the feet. Hematologically,anemia and leukopenia may be accompanied bythrombocytopenia, with red blood cells displayinga “cloverleaf” nucleus. The patient may exhibit ametallic breath odor and may have diarrhea andmalabsorption as well as hepatic cirrhosis. Arsenicis also a myocardial toxin, producing electrocardio-graphic changes.

Although arsenic is known to predispose toBowen’s disease and SCC, there has been debateas to whether it may produce multiple superficial-type basal cell carcinomas (BCCs). There is nodoubt that arsenicism predisposes to cancer ofthe respiratory, gastrointestinal, and genitourinarytracts [17,18]. Long-term exposure to inorganicarsenic, mainly from drinking water, has beendocumented to induce cancers in lung, urinarybladder, kidney, liver, and skin in a dose–responserelationship. In addition, it is linked with liverangiosarcoma [19] and hepatoma [20]. Thus, ar-senical keratoses and bowenoid arsenical keratosesshould be viewed as representing arsenicism, acutaneous marker of internal malignancy. Thefeatures of chronic arsenicism are summarizedin Table 3.1. Table 3.2 lists some curiosities ofarsenicism.

Fig. 3.2 Autosomal dominantpunctate hyperkeratosis of the palmsand soles, to be distinguished fromarsenical keratoses. (Reprinted withpermission from Rubenstein et al.[15].)

18 Chapter 3

Fig. 3.3 Arsenical pigmentarychanges, showing hyperpigmentedpatches with “raindrop”hypopigmentation. Note the plaque ofBowen’s disease.

The chronology of the appearance of cutaneousand visceral findings in arsenicism is noteworthy.Arsenic does not remain in the tissues for the 10 to20 years required for arsenical keratoses to manifest.In one series, Bowen’s disease began within 10 yearsof exposure, invasive cutaneous SCC after 20 years,and lung cancer after 30 years [21].

PathologyArsenical keratoses show thick, compact paraker-atotic hyperkeratosis and other epidermal changescharacteristic of hypertrophic actinic keratoses [2].The histology is most reminiscent of hypertrophic

Table 3.1 Features of chronic arsenicism

Often cryptic exposureLong latent period, up to 50 yearsPunctate hyperkeratosis of palms and solesBowen’s disease on sun- and non–sun-exposed skinHyperpigmented patches, which may be mottled“Raindrop” hypopigmentationMees’ linesDiffuse alopeciaPeripheral neuropathyCancers of the respiratory, gastrointestinal, and

genitourinary tracts; hepatic angiosarcomaPeripheral circulatory disorders

actinic keratoses. The presence of numerous vac-uolated keratinocytes is suggestive of arsenical ker-atoses, but this is not a reliable criterion. Likewise,although basophilic degeneration of the dermis maybe absent, it also may be present with arsenical ker-atoses, regardless of anatomic location. Actinic andarsenical keratoses may spare adnexal epithelium,so there are no pathognomonic histologic findingsto separate arsenical keratoses or bowenoid arseni-cal keratoses from their solar equivalents. Arsenicmay induce abnormal differentiation in arsenicalkeratosis via the effects of integrin expression in ker-atinocytes [22].

Proving arsenic exposureEstablishing the arsenic exposure may be difficult.Analysis of body tissues, nails, and hair may be

Table 3.2 Curiosities about arsenic

Animal models for arsenic-induced carcinogenesis arelacking, yet in humans, arsenic is carcinogenic

Napoleon Bonaparte’s hair was exposed to considerablearsenic during 1816 in his exile at St. Helena

Trivalent inorganic arsenic is carcinogenic; organic arsenicmay not be