Archives of Dermatology

ARCHIVES OF DERMATOLOGY SEPTEMBER 2007 VOLUME 143, NUMBER 9 ARCHIVES A CENTURY AGO Some Further Observations on the Treatment of Pigmented Hairy Naevi With Liquid Air; Three Additional Case Reports. 1108 THE CUTTING EDGE Infliximab as a Therapy for Idiopathic Hypereosinophilic Syndrome Josephine A. Taverna, MD; Adam Lerner, MD; Lynne Goldberg, MD; Stephen Werth, MD; Marie-France Demierre, MD, FRCPC 1110 PAGES 1093-1234 Primary Cutaneous Diffuse Large B-Cell Lymphoma, Leg Type: Clinicopathologic Features and Prognostic Analysis in 60 Cases Florent Grange, MD, PhD; Marie Beylot-Barry, MD, PhD; Phillipe Courville, MD; Eve Maubec, MD; Martine Bagot, MD, PhD; Béatrice Vergier, MD, PhD; Pierre Souteyrand, MD; Laurent Machet, MD, PhD; Sophie Dalac, MD; Eric Esteve, MD; Isabelle Templier, MD; Emmanuel Delaporte, MD; Marie-Françoise Avril, MD; Caroline Robert, MD, PhD; Stephane Dalle, MD; Liliane Laroche, MD, PhD; Michele Delaunay, MD; Pascal Joly, MD, PhD; Janine Wechsler, MD; Tony Petrella, MD 1144 STUDIES OBSERVATIONS Clinical Severity of Psoriasis in Last 20 Years of PUVA Study Tamar Nijsten, MD, PhD; Caspar W. N. Looman, PhD; Robert S. Stern, MD 1113 Clinical, Biochemical, and Genetic Study of 11 Patients With Erythropoietic Protoporphyria Including One With Homozygous Disease Carmen Herrero, MD, PhD; Jordi To-Figueras, PhD; Celia Badenas, PhD; Manuel Méndez, PhD; Patricia Serrano, MD; Rafael Enrı́quez-Salamanca, MD, PhD; Mario Lecha, MD, PhD 1125 Five-Year Follow-up of a Randomized, 1131 Prospective Trial of Topical Methyl Aminolevulinate Photodynamic Therapy vs Surgery for Nodular Basal Cell Carcinoma Lesley E. Rhodes, MD, FRCP; Menno A. de Rie, MD; Ragna Leifsdottir, MD; Raymond C. Yu, MD, FRCP; Ingeborg Bachmann, MD; Victoria Goulden, MD, FRCP; Gavin A. E. Wong, MRCP; Marie-Aleth Richard, MD; Alex Anstey, MD, FRCP; Peter Wolf, MD Effect of Cold Air Cooling on the Incidence of Postinflammatory Hyperpigmentation After Q-Switched Nd:YAG Laser Treatment of Acquired Bilateral Nevus of Ota–like Macules Woraphong Manuskiatti, MD; Sasima Eimpunth, MD; Rungsima Wanitphakdeedecha, MD 1139 Familial Acanthosis Nigricans Due to K650T FGFR3 Mutation David R. Berk, MD; Elaine B. Spector, PhD; Susan J. Bayliss, MD 1153 Eczematoid Graft-vs-Host Disease: A Novel Form of Chronic Cutaneous Graft-vs-Host Disease and Its Response to Psoralen–UV-A Therapy Daniel Creamer, MD; Claire L. Martyn-Simmons, MRCP(England); Genevieve Osborne, MRCP(England); Michelle Kenyon, MSc; Jon R. Salisbury, MD; Stephen Devereux, MD; Antonio Pagliuca, MD; Aloysius Y. Ho, MD; Ghulam J. Mufti, MD; Anthony W. P. du Vivier, MD 1157 Epidermolysis Bullosa Nevus: An Exception to the Clinical and Dermoscopic Criteria for Melanoma Sarah H. Cash, MD; Tara T. Dever, MD; Patrice Hyde, MD; Jason B. Lee, MD 1164 Herpes Gestationis in a Mother and Newborn: 1168 Immunoclinical Perspectives Based on a Weekly Follow-up of the Enzyme-Linked Immunosorbent Assay Index of a Bullous Pemphigoid Antigen Noncollagenous Domain Yumi Aoyama, MD; Kanako Asai, MD; Kana Hioki, MD; Michinori Funato, MD; Naomi Kondo, MD; Yasuo Kitajima, MD (REPRINTED) ARCH DERMATOL/ VOL 143 (NO. 9), SEP 2007 1097 WWW.ARCHDERMATOL.COM ARCHIVES OF DERMATOLOGY EVIDENCE-BASED DERMATOLOGY: STUDY Balancing the Benefits and Risks of Drug Treatment: A Stated-Preference, Discrete Choice Experiment With Patients With Psoriasis Elizabeth M. Seston, PhD; Darren M. Ashcroft, PhD; Christopher E. M. Griffiths, MD, FRCP 1175 Diffuse Nodules in a Woman With Renal Failure Erin B. Lesesky, MD; Michelle T. Pelle, MD; Terence C. O’Grady, MD 1201 Tender Nodules on the Palms and Soles Lisa Esler-Brauer, MD; Ilene Rothman, MD 1201 CORRESPONDENCE: RESEARCH LETTERS EVIDENCE-BASED DERMATOLOGY: RESEARCH COMMENTARY Use of Antibiotic Ointment After Clean Cutaneous Surgery Michael Bigby, MD 1209 1180 A Novel Missense Mutation in the CYLD Gene in a Spanish Family With Multiple Familial Trichoepithelioma Agustı́n España, MD; Fermin Garcı́a-Amigot, PhD; Leyre Aguado, MD; Jesús Garcı́a-Foncillas, MD 1210 1185 A Novel PTPN11 Gene Mutation in a Patient With LEOPARD Syndrome Aurélie Du-Thanh, MD; Hélène Cave, PharmD, PhD; Didier Bessis, MD; Carine Puso, MD; Jean-Jacques Guilhou, MD; Olivier Dereure, MD, PhD EDITORIAL Evidence-Based Dermatology Section Welcomes a New Feature: Critically Appraised Topic Michael Bigby, MD EVIDENCE-BASED DERMATOLOGY: CRITICALLY APPRAISED TOPIC What Is the Chance of a Normal Pregnancy in a Woman Whose Fetus Has Been Exposed to Isotretinoin? Michael J. Sladden, MAE, MRCP(UK); Karen E. Harman, MD, MRCP CORRESPONDENCE: COMMENTS AND OPINIONS 1187 ON THE HORIZON Accessible Evidence-Based Medicine: Critically Appraised Topics David A. Barzilai, MD, PhD; Martin A. Weinstock, MD, PhD 1189 EDITORIALS Long-term Treatment for Severe Psoriasis: We’re Halfway There, With a Long Way to Go Joel M. Gelfand, MD, MSCE 1191 Dermatology and the Human Genome: An Epidemiologic Approach Marta Gwinn, MD, MPH; Muin J. Khoury, MD, PhD 1194 OFF-CENTER FOLD Hyperpigmented Keratotic Nodules Ser Ling Chua, MRCP; Kusum Kulkarni, MRCPath; Eric Saihan, FRCP 1201 Verrucous Papules and Plaques in a Pediatric Patient Mercedes E. Gonzalez, MD; Fiona P. Blanco, MD; Maria C. Garzon, MD 1201 Sponsorship of Graduate Medical Education: One Successful Model William D. James, MD 1211 Narrowband UV-B Phototherapy for Extragenital Lichen Sclerosus Alexander Kreuter, MD; Thilo Gambichler, MD 1213 Exclusively Benign Dermoscopic Pattern in a Patient With Acral Melanoma Ralph P. Braun, MD; Olivier Gaide, MD; Andreas M. Skaria, MD; Alfred W. Kopf, MD; Jean-Hilaire Saurat, MD; Ashfaq A. Marghoob, MD 1213 In Reply Toshiaki Saida, MD, PhD 1215 Evidence Insufficient to Recommend Melanoma Surveillance Following Phototherapy for Jaundice Thomas B. Newman, MD, MPH; M. Jeffrey Maisels, MB BCh 1216 In Reply Vincent Descamps, MD, PhD 1216 Allergic Contact Dermatitis: Another Adverse Effect of Over-the-counter Topical Hydrocortisone Kalman L. Watsky, MD; Erin M. Warshaw, MD, MS 1217 In Reply William H. Eaglstein, MD; Scott M. Ravis 1217 (REPRINTED) ARCH DERMATOL/ VOL 143 (NO. 9), SEP 2007 1099 WWW.ARCHDERMATOL.COM ARCHIVES OF DERMATOLOGY CORRESPONDENCE: VIGNETTES SKINSIGHT Successful Treatment of Pityriasis Versicolor With 5-Aminolevulinic Acid Photodynamic Therapy Young Jin Kim, MD; You Chan Kim, MD, PhD 1218 Leukemia Cutis: A Presenting Sign in Acute Promyelocytic Leukemia Tania R. Markowski, BA; Donna Bilu Martin, MD; Grace F. Kao, MD; Linda Lutz, MD; April Deng, MD, PhD; Anthony A. Gaspari, MD 1220 Necrolytic Migratory Erythema: The Outermost Marker for Glucagonoma Syndrome Mary L. Gantcheva, MD, PhD; Valentina K. Broshtilova, MD; Adriana I. Lalova, MD, PhD 1221 Lymphomatoid Granulomatosis Induced by Imatinib-Treatment Amir S. Yazdi, MD; Gisela Metzler, MD; Susanne Weyrauch, MD; Mark Berneburg, MD; Michael Bitzer, MD; Hans-Konrad Müller-Hermelink, MD; Martin Röcken, MD 1222 Focal Acne During Topical Tacrolimus Therapy for Vitiligo Lucio Bakos, MD, PhD; Renato Marchiori Bakos, MD, MSc 1223 Pneumocystis carinii Pneumonia in Infant Treated With Oral Steroids for Hemangioma Mandi L. Maronn, MD; Timothy Corden, MD; Beth A. Drolet, MD 1224 Clinical and Dermoscopic Features of Agminated Blue Nevus Maria A. Pizzichetta, MD; H. Peter Soyer, MD; Cesare Massone, MD; Lorenzo Cerroni, MD 1225 Subungual Exostosis Marı́a Elena Sánchez-Castellanos, MD; Cecilia Sandoval-Tress, MD; Patricia Ramı́rez-Bárcena, MD 1234 CORRECTION Error in Byline in: Breaking Strength of Barbed Polypropylene Sutures: Rater-Blinded, Controlled Comparison With Nonbarbed Sutures of Various Calibers Rashid [M.] Rashid, MD, PhD; Mark Sartori, BS; Lucile E. White, MD; Mark T. Villa, MD; Simon S. Yoo, MD; Murad Alam, MD, MSCI 1186 REGULAR DEPARTMENTS This Month in Archives of Dermatology 1107 Online CME Article 1113 Archives Feature 1121 Call for Papers 1136 Announcement 1162 Archives Web Quiz Winner 1182 Classified Advertising 1229 Journal Advertiser Index 1232 Contact Information 1233 Information for authors and readers and the subject and author indexes are available on our Web site: http://www.archdermatol.com. (REPRINTED) ARCH DERMATOL/ VOL 143 (NO. 9), SEP 2007 1100 WWW.ARCHDERMATOL.COM ARCHIVES OF DERMATOLOGY Mission Statement: The Archives of Dermatology publishes information concerning the skin, its diseases, and their treatment. Its mission is to explicate the structure and function of the skin and its diseases and the art of using this information to deliver optimal medical and surgical care to the patient. We attempt to enhance the understanding of cutaneous pathophysiology and improve the clinician’s ability to diagnose and treat skin disorders. This journal has a particular interest in publishing clinical and laboratory studies that reveal new information pertinent to the interests and needs of the medical dermatologist, dermatologic surgeon, and all those concerned with state-of-the-art care of cutaneous disease. We believe that knowledge derived from well-designed clinical trials and studies of cost-effectiveness are especially important for improving the practice of dermatology. Studies that increase the understanding of the outcome of treatment or the means by which the burden of dermatologic disease can be measured and reduced to promote the health of patients with skin disease will receive special priority. The Archives regularly publishes reports on clinical investigations, editorials, and reviews. It also features reports and discussions on clinicopathologic correlations; clinical disorders of unique didactic value; pharmacologic, medical and surgical therapeutics; and ethical, moral, socioeconomic, and political issues. Editor: June K. Robinson, MD Chicago, Illinois Associate Editor: Jeffrey P. Callen, MD Louisville, Kentucky Editorial Assistant: Mark D. Matthews Chicago, Illinois Editorial Office: Archives of Dermatology 132 E Delaware Pl #5806 Chicago, IL 60611 Telephone (312) 943-7759; Fax (312) 943-7752 e-mail: archdermatol@jama-archives.org Section Editors Archives a Century Ago: Mark Bernhardt, MD Ft Lauderdale, Florida The Cutting Edge: George J. Hruza, MD St Louis, Missouri Assistant Section Editors: Michael P. Heffernan, MD Dayton, Ohio Christie Ammirati, MD Hershey, Pennsylvania Evidence-Based Dermatology: Michael Bigby, MD Boston, Massachusetts Assistant Section Editors: Damiano Abeni, MD, MPH Rome, Italy Rosamaria Corona, DSc, MD Rome, Italy Urbà González, MD, PhD Barcelona, Spain Abrar A. Qureshi, MD, MPH Boston, Massachusetts Hywel Williams, MSc, PhD, FRCP Nottingham, England Feature Editor: Michael J. Sladden, MAE, MRCP(UK) Launceston, Tasmania Off-Center Fold: Michael E. Ming, MD, MSCE Philadelphia, Pennsylvania Assistant Section Editors: Carrie Ann R. Cusack, MD Philadelphia, Pennsylvania Senait W. Dyson, MD Irvine, California Jacqueline M. Junkins-Hopkins, MD Philadelphia, Pennsylvania Vincent Liu, MD Iowa City, Iowa Karla S. Rosenman, MD New York, New York On the Horizon: Gary S. Wood, MD Madison, Wisconsin Assistant Section Editors: Craig A. Elmets, MD Birmingham, Alabama Molly A. Hinshaw, MD Madison, Wisconsin Jay C. Klemme, MD, MPH Wooster, Ohio Mark R. Pittelkow, MD Rochester, Minnesota Martin A. Weinstock, MD, PhD Providence, Rhode Island David T. Woodley, MD Los Angeles, California Publication Staff Offices: 515 N State St, Chicago, IL 60610 Catherine D. DeAngelis, MD, MPH Editor in Chief Scientific Publications & Multimedia Applications Cheryl Iverson: Managing Editor Editorial Processing Department Department Director: Paula Glitman Manuscript Editing Manager: Lauren B. Fischer Senior Manuscript Editors: Dee Egger, John McFadden, Donald S. Smith Manuscript Editor: Karen L. Boyd Freelance Manuscript Editing Manager: Diane L. Cannon Freelance Manuscript Editing Coordinators: Cheryl Tobey Davidow, Vickey Golden, Connie Manno Freelance Copy Editors and Copyreaders: Catherine A. Alden, Lisa M. Cluver, Mary Coerver-Connolly, Allison Esposito, GeorgeMary Gardner, Robin Husayko, Laura King, Mary A. Kingzette, Nicole C. Netter, Beena Rao, Caroline Woods Editorial Systems Managers: Paul Frank, Monica Mungle Systems Programmer/Internet Specialist: J.D. Neff Editorial Assistant: Wanda Hill Scientific Publications & Multimedia Applications Executive Assistant to the Editor: Marla A. Hall Scientific Online Resources Web Editor: Ashish C. Bhatia, MD Naperville, Illinois CME Editor: Andrew D. Samel, MD Attleboro, Massachusetts skINsight: James M. Grichnik, MD, PhD Durham, North Carolina This Month: Robin L. Travers, MD Boston, Massachusetts Editorial Board Murad Alam, MD Chicago, Illinois Ashish C. Bhatia, MD Naperville, Illinois Michael Bigby, MD Boston, Massachusetts Mary-Margaret Chren, MD San Francisco, California Robert P. Dellavalle, MD, PhD, MSPH Denver, Colorado Alan B. Fleischer, Jr, MD Winston-Salem, North Carolina James M. Grichnik, MD, PhD Durham, North Carolina Thomas D. Horn, MD Little Rock, Arkansas George J. Hruza, MD St Louis, Missouri Moise L. Levy, MD Houston, Texas Michael E. Ming, MD, MSCE Philadelphia, Pennsylvania Ronald L. Moy, MD Los Angeles, California Anthony E. Oro, MD, PhD Stanford, California Darrell S. Rigel, MD New York, New York Lawrence A. Schachner, MD Miami, Florida Kathryn Schwarzenberger, MD Burlington, Vermont Maria L. Chanco Turner, MD Bethesda, Maryland Gary S. Wood, MD Madison, Wisconsin Surgical Advisory Board Murad Alam, MD, Chairman Chicago, Illinois Leslie Baumann, MD Miami, Florida Jeffrey S. Dover, MD, FRCP Boston, Massachusetts Scott W. Fosko, MD St Louis, Missouri Dee Anna Glaser, MD St Louis, Missouri Glenn D. Goldman, MD Burlington, Vermont Seth L. Matarasso, MD San Francisco, California International Advisory Committee Alvaro E. Acosta, MD Bogota, Colombia Jan Nico Bouwes Bavinck, MD Leiden, the Netherlands Reuven Bergman, MD Haifa, Israel Francisco G. Bravo, MD Lima, Peru Lorenzo Cerroni, MD Graz, Austria Yahya Dowlati, MD, PhD Tehran, Iran Reinhard Dummer, MD Zurich, Switzerland James Ferguson, MD Dundee, Scotland Miguel Ruben Guarda, MD Santiago, Chile John L. M. Hawk, MD London, England Jana Hercogova, MD Prague, Czech Republic Chung-Hong Hu, MD, FACP Taipei, Taiwan Abdul-Ghani M. Kibbi, FACP, MD Beirut, Lebanon Andreas D. Katsambas, MD Athens, Greece Steven Kossard, MD Sydney, Australia Margarita M. Larralde, MD Buenos Aires, Argentina Sungnack Lee, MD Suwon, Korea Thomas A. Luger, MD Munster, Germany Gillian Murphy, MD Dublin, Ireland Oumeish Y. Oumeish, MD Amman, Jordan Fezal Ozdemir, MD Izmir, Turkey Jaime Piquero-Martin, MD Caracas, Venezuela Niwat Polnikorn, MD, FRCP(T) Bangkok, Thailand Marcia Ramos-e-Silva, MD, PhD Rio de Janeiro, Brazil Jean E. Revuz, MD Creteil, France Luis Requena, MD Madrid, Spain Hiroshi Shimizu, MD Sapporo, Japan Mohsen Soliman, MD Cairo, Egypt T. Thirumoorthy, MD Singapore Antonella Tosti, MD Bologna, Italy Hans Christian Wulf, MD Copenhagen, Denmark Wen-Yuan Zhu, MD Nanjing, China Periodic Publishing & Business Staff Senior VP & Publisher: Robert A. Musacchio, PhD Publishing Operations Advertising Sales & Marketing Division Director: Vanessa Hayden Directors: Karen Adams-Taylor, Sue Sherrill Division Director: Jeffery J. Bonistalli Manager: Kathy Russell Staff: Mirna Monal Sales Representatives: Peter G. 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Zarkadas Director: Margaret Winker, MD Electronic Media Department Director: Michelle Kurzynski Associate Web Editors: Christopher Hastings, Peter Kim Web Administrative Assistant: Reuben Rios All articles published, including editorials, letters, and book reviews, represent the opinions of the authors and do not reflect the policy of the American Medical Association, the Editorial Board, or the institution with which the author is affiliated, unless this is clearly specified. Copyright 2007 by the American Medical Association. All rights reserved. Reproduction without permission is prohibited. (REPRINTED) ARCH DERMATOL/ VOL 143 (NO. 9), SEP 2007 1104 Managers: David Antos, Karen Branham, Suzanne J. Bukovsky, Debbie Camp, Susan Chiara, Diane Darnell, Susana Eloy de Vitale, Karl Elvin, Mary Ellen Johnston, Michael McGraw, Chris Meyer, Phil O’Leary, Ryan Patella, Susan Price, Stacy Tucker AMA Executives Michael D. Maves, MD, MBA Executive Vice President, Chief Executive Officer Bernard L. Hengesbaugh Chief Operating Officer Robert A. Musacchio, PhD Senior Vice President, Publishing & Business Services WWW.ARCHDERMATOL.COM THIS MONTH IN ARCHIVES OF DERMATOLOGY SECTION EDITOR: ROBIN L. TRAVERS, MD Effect of Cold Air Cooling on the Incidence of PIH After Q-Switched Nd:YAG Laser Treatment of Acquired Bilateral Nevus of Ota–like Macules P ostinflammatory hyperpigmentation (PIH) is very likely the most common adverse effect of laser treatment in dark-skinned individuals. Treatment of PIH is difficult, thus emphasizing the need for prevention strategies. Acquired bilateral nevus of Ota–like macules (ABNOMs) are clinically characterized by bluebrown macules on periocular and nasal skin, and Q-switched lasers represent an excellent therapeutic modality. In this randomized, controlled, split-face study, Manuskiatti et al sought to evaluate the benefit of epidermal cooling on reducing the occurrence of PIH after Q-switched Nd:YAG laser treatment of ABNOMs. Unexpectedly, cold air cooling was associated with an increased risk of PIH after laser treatment, through an unknown mechanism. See page 1139 Herpes Gestationis in a Mother and Newborn H erpes gestationis (HG) is a rare, autoimmune, bullous disease that affects women in the second or third trimester of pregnancy. Immunologically, HG is characterized by linear deposition of C3 with or without associated IgG at the basement membrane zone on direct immunofluorescence and by the presence of serum antibodies directed against the 180-kDa bullous pemphigoid antigen (BP180). In this case report, Aoyama et al describe a mother and neonate with cutaneous manifestations of HG. The BP180 enzymelinked immunosorbent assay indexes were observed in both patients and clearly demonstrated that the vesicular lesions in the neonate were caused by transplacental passage of pathogenic BP180 antibodies. See page 1168 Eczematoid Graft-vs-Host Disease G raft-vs-host disease (GVHD) is a multisystem disease initiated by allogeneic T lymphocytes that recognize foreign tissue antigens in the host. In the chronic form, GVHD demonstrates cutaneous manifestations that may be classified as lichenoid or sclerodermatous in nature. In this case series of patients who developed cutaneous GVHD after hematopoietic stem cell transplantation, Creamer et al identified a novel, distinct B A group of 10 who were characterizedbypersistent,widespread, chronic eczematous dermatitis. Histopathologically, these eczematous features strikingly coexisted with changes of GVHD. The factors provoking the expression of an eczematous phenotype in these patients remain unclear. See page 1157 Clinical, Biochemical, and Genetic Study of 11 Patients With Erythropoietic Protoporphyria Including One With Homozygous Disease E rythropoietic protoporphyria (EPP) is an inherited disorder of porphyrin metabolism caused by a partial deficiency of the ferrochelatase gene (FECH). Clinical expression of the disease commonly results from the coinheritance of a null FECH mutation plus a wild-type low-expressed allele, which further reduces ferrochelatase activity to below a critical threshold of about 35%. The low-expression allele IVS3-48C is relatively common among European populations, such that overt EPP is typically inherited in such a way that it resembles an autosomal dominant disease with low clinical penetrance. In this case series, Herrero et al confirm the common view that clinically overt EPP is most typically associated with inheritance of the low-expression IVS3-48C allele in trans to a severe FECH mutation. One rare homozygous mutation was identified in a patient showing early signs of liver involvement. See page 1125 Balancing the Benefits and Risks of Drug Treatment P soriasis is a common, chronic, inflammatory, hyperproliferative skin disease. Therapeutic options for psoriasis vary widely in terms of efficacy and toxic effects. In this discrete choice experiment, Seston et al explore the extent to which different attributes of a treatment affect a patient’s choice of therapy and the hierarchical importance of these attributes. Most respondents were willing to trade among different attributes of a treatment to achieve an improvement in their psoriasis with minimal adverse effects. For example, patients indicated that they would wait longer for therapy to work if the chance of a severe adverse effect could be reduced. Long-term risks (such as skin cancer or liver damage) were prioritized over short-term risks (such as skin irritation). Only one-quarter of the sample patients were unwilling to trade among attributes and always chose the therapy with a particular level of their chosen attribute, most often no risk of skin cancer. See page 1175 (REPRINTED) ARCH DERMATOL/ VOL 143 (NO. 9), SEP 2007 1107 WWW.ARCHDERMATOL.COM ARCHIVES A CENTURY AGO SECTION EDITOR: MARK BERNHARDT, MD THE JOURNAL OF CUTANEOUS DISEASES VOL. XXV. SEPTEMBER, 1907. NO. 9. SOME FURTHER OBSERVATIONS ON THE TREATMENT OF PIGMENTED HAIRY NAEVI WITH LIQUID AIR; THREE ADDITIONAL CASE REPORTS. By WILLIAM B. TRIMBLE, M. D. Everyone is more or less familiar with this new remedial agent, yet it may be well to quote here some of its physical characteristics. Liquid air is the common air we breathe, very much reduced in temperature. It liquefies at 312º F. below zero. We can readily understand how cold it must be when we are told that it is about 400º colder than the ordinary atmospheric air. J Cutan Dis. September 1907;25(9);409-413. The bridge at midnight trembles, The country doctor rambles, Bankers’ nieces seek perfection, Expecting all the gifts that wise men bring. The wind howls like a hammer, The night blows cold . . . Love Minus Zero/No Limit Bob Dylan, 1965 Temperature, °C ⫹116 0 Occurrence At this temperature, Hell’s lakes of sulfuric brimstone freeze over Temperature of water when Dr John Gorrie created the first artificial ice (Apalachicola, Florida, July 14, 1850) a −2 Coldest temperature recorded in West Palm Beach, Florida (January 19, 1977) −4 to −20 Temperature of ethyl chloride spray, depending on delivery system −20 to −30 Your tongue sticks to a metal pole, stupid! −39 Temperature at which the bulb of mercury in a thermometer (aka, the witch’s tit) freezes −57 Temperature of over-the-counter wart treatment −70 Coldest temperature recorded in contiguous 48 states (Rogers Pass, Montana, January 20, 1954) −75 Exposed skin freezes within 30 seconds −78 Surface temperature of a block of dry ice −89 Coldest air temperature recorded on earth (Vostok, Antarctica, July 21, 1983) −196 Temperature of liquid nitrogen in which Ted Williams’ head is preserved −230 Average surface temperature on the dark side of the moon −235 Lowest temperature in our solar system (Neptune’s moon Triton) −271 Temperature of intergalactic deep space −272.000000083 Bose-Einstein condensate first formed (Boulder, Colorado, June 5, 1995) −273 Absolute zero (Sorry, Bob. That is the limit.) a Bernhardt M. Selections: Morbus Maculosus Werlhofu. Arch Dermatol. 1992;128(9):1298. (REPRINTED) ARCH DERMATOL/ VOL 143 (NO. 9), SEP 2007 1108 WWW.ARCHDERMATOL.COM THE CUTTING EDGE SECTION EDITOR: GEORGE J. HRUZA, MD; ASSISTANT SECTION EDITORS: MICHAEL P. HEFFERNAN, MD; CHRISTIE AMMIRATI, MD Infliximab as a Therapy for Idiopathic Hypereosinophilic Syndrome Josephine A. Taverna, MD; Adam Lerner, MD; Lynne Goldberg, MD; Stephen Werth, MD; Marie-France Demierre, MD, FRCPC; Boston University School of Medicine (Drs Taverna, Lerner, Goldberg, and Demierre) and Tufts University School of Medicine (Dr Werth), Boston, Massachusetts The Cutting Edge: Challenges in Medical and Surgical Therapeutics REPORT OF A CASE A 77-year-old woman from Guyana presented with a 3-year history of a generalized, pruritic eruption associated with chronic chills, fatigue, generalized malaise, and a 14-kg weight loss over a 9-month period (Figure 1). Her medical history was significant for hypertension and diabetes, and her medications included glucophage, atenolol, and lisinopril. She had no personal or family history of atopy. Her physical examination findings were remarkable for exfoliative erythroderma and keratoderma associated with generalized lymphadenopathy (Figure 1). Complete blood cell counts were normal except for a persistently elevated absolute eosinophil count (1500-3000/ µL) for more than 8 months. Positron emission tomographic scans detected enhanced fludeoxyglucose F 18 uptake bilaterally in the supraclavicular, axillary (largest node measuring 2.5 cm), and inguinal nodes (largest node measuring 2 cm). A left inguinal lymph node biopsy specimen revealed dermatopathic lymphadenitis and no evidence of a lymphoproliferative disorder. Histopathologic examination of a skin sample revealed parakeratosis, hypogranulosis, psoriasiform epidermal hyperplasia, mild spongiosis, a mild superficial perivascular lymphocytic infiltrate with occasional plasma cells and A rare eosinophils, and numerous melanophages. Flow cytometry and skin and bone marrow biopsy specimens revealed no evidence of a clonal T- or B-cell population on immunophenotyping or molecular genetic analysis, and FIP1L1-PDGFRA gene fusion was not detected. Extensive studies were performed to rule out infectious, allergic, vasculitic, rheumatic, and malignant causes of eosinophilia. A transthoracic echocardiogram, which was obtained to rule out heart failure or mural thrombus in the setting of chronic hypereosinophilia, demonstrated no abnormalities. THERAPEUTIC CHALLENGE The pruritic eruption was initially thought to be caused by the use of a newly prescribed medication (lisinopril). Unfortunately, erythroderma and keratoderma persisted long after therapy with the angiotensinconverting enzyme inhibitor was discontinued. In the following 3 years, the patient was treated unsuccessfully with a variety of therapeutic modalities, including systemic corticosteroids, psoralen–UV-A, isotretinoin, bexarotene, and extracorporeal photopheresis. Two years after her initial presentation, the patient required inpatient hospitalization for intense pruritus and failure to thrive, and B Figure 1. Exfoliative erythroderma (A) and keratoderma (B) before treatment with infliximab. (REPRINTED) ARCH DERMATOL/ VOL 143 (NO. 9), SEP 2007 1110 WWW.ARCHDERMATOL.COM the decision was made to initiate treatment targeting Tcell activation. After 3 monthly cycles of denileukin diftitox infusions (18 µg/kg/d) in combination with oral bexarotene, there was no improvement in erythroderma or pruritus. A 1-month course of oral imatinib mesylate therapy (400 mg/d) was not helpful. A trial of chemotherapy with 2 cycles of fludarabine–mitoxantrone– dexamethasone (fludarabine phosphate, 25 mg/m2 days 1-3; mitoxantrone, 10 mg/m2 day 1; and dexamethasone, 20 mg/d days 1-5), resulted in a transient decrease in the patient’s absolute eosinophil count but no clinical improvement. An effective treatment was needed to ameliorate her skin lesions and severe pruritus. SOLUTION Intravenous infusions of infliximab (5 mg/kg) were followed by a sharp decrease in the peripheral blood eosinophil count to 700/µL (Figure 2), with complete resolution of erythroderma, keratoderma, and pruritus after 3 monthly cycles of therapy (Figure 3). For maintenance, the patient received 5 additional monthly cycles of infliximab that were well tolerated, without reported adverse effects or evidence of recurrent disease. Infliximab therapy was subsequently discontinued, and the pa3500 Series 1 Eosinophils, µL 3000 2500 2000 1500 1000 500 0 Feb 2005 Apr 2005 Jun 2005 Aug 2005 Oct 2005 Dec 2005 Feb 2006 Apr 2006 Jun 2006 Month Figure 2. Eosinophil count in a patient with idiopathic hypereosinophilic syndrome. Infliximab therapy was initiated in late November 2005, with a sharp decrease in absolute eosinophil counts. Normalization of eosinophil count was achieved after 3 monthly doses of infliximab, and the effect was maintained after 7 monthly doses. A tient’s skin remained clear at the 1-month follow-up visit. Her debilitating skin condition, which was associated with hypereosinophilia, had responded quickly and dramatically to infliximab therapy alone, resulting in improved sleep and functional status. COMMENT Hypereosinophilic syndrome (HES) is a heterogeneous group of conditions that are characterized by blood hypereosinophilia and end-organ dysfunction due to eosinophilic infiltration and toxic mediator release.1-3 Endorgan damage commonly affects the skin, heart, lungs, and nervous system. Idiopathic HES (IHES), which is a diagnosis of exclusion, is defined as blood eosinophilia exceeding an eosinophil count of 1500/µL for more than 6 consecutive months, of unknown etiology, with evidence of end-organ damage.1-3 The distinctions between myeloid and lymphoid lineages of IHES are based on differences in molecular pathogenesis, clinical presentation, complications, and prognosis and are necessary to guide patient treatment.4 Lymphocytic HES (l-IHES) is characterized by a nonmalignant expansion of a T-cell population that produces eosinophilopoetic cytokines (ie, interleukin 5). It carries a good prognosis, with prolonged survival, and may respond to glucocorticoid therapy or to treatment with human monoclonal anti– interleukin 5 antibody.4,5 Cutaneous lesions are common in l-HES and vary from pruritic erythematous macules, papules, plaques, or nodules to urticaria and angioedema.4 Myeloproliferative HES (m-IHES) is characterized by clonally derived eosinophils, carries a poor prognosis, and may respond to imatinib mesylate (a tyrosine kinase inhibitor) therapy, particularly in the presence of FIP1L1-PDGFRA gene fusion.4,6 If left untreated, patients with m-IHES can undergo a rapidly fatal course owing to congestive heart failure or to the development of acute leukemic disease.4 Other therapies for m-IHES reported in the literature include hydroxyurea, interferon alfa,7 cyclosporine, and allogenic stem cell transplantation.8 Based on the results of clinical and molecular analysis, our patient had l-IHES: she presented with cutaneous end-organ damage in the absence of heart inB Figure 3. Full response to infliximab following 7 monthly infusions, with complete resolution of erythroderma (A) and keratoderma (B). (REPRINTED) ARCH DERMATOL/ VOL 143 (NO. 9), SEP 2007 1111 WWW.ARCHDERMATOL.COM volvement, failed to improve with imatinib mesylate therapy, and did not harbor the FIP1L1-PDGFRA fusion gene. We report the first case (to our knowledge) of l-IHES that was responsive to infliximab therapy. Infliximab is a chimeric, human-mouse antibody for tumor necrosis factor (TNF) ␣ that has been shown to be effective in the treatment of Crohn disease, rheumatoid arthritis, severe psoriasis (ie, recalcitrant erythrodermic psoriasis),9-11 and pityriasis rubra pilaris.12 Tumor necrosis factor ␣ is a proinflammatory cytokine that contributes to lymphocyte and eosinophil recruitment by upregulating vascular cell adhesion molecule 1 (VCAM-1), endothelial leukocyte adhesion molecule 1 (ELAM-1), and intercellular adhesion molecule 1 (ICAM-1) on activated endothelial cells.13-15 The precise mechanism by which infliximab therapy could induce remission in an erythrodermic patient with HES is not fully understood but could be the result of inhibition of TNF-␣–induced eosinophildependent recruitment, toxic effects, and leukocyte infiltration. It has been proposed that through a positive feedback loop of TNF interacting with TNF receptors on keratinocytes, “secondary” keratinocyte cytokines are released, including ICAM-1.16 Also, Costa et al17 have shown that blood eosinophils isolated from hypereosinophilic patients can also represent a potential source of TNF-␣. By blocking TNF-␣ expression from primary sources in the skin, TNF-␣ inhibitors could break the cycle of cytokine feedback by down-regulating VCAM-1, ICAM-1, and ELAM-1 expressions on dermal endothelial cells, thereby preventing eosinophils from homing to skin and subsequent toxic mediator release. Several adverse effects of infliximab therapy have been reported. In a recent meta-analysis, Bongartz et al18 showed an increased risk of serious infection and a dosedependent increased risk of malignancy in patients with rheumatoid arthritis treated with anti–TNF antibody therapy. For this reason, the decision to initiate TNF-␣ therapy requires careful thought, and patients must be monitored closely during treatment. In our patient, the clinical response resulted in significantly improved functioning and symptom relief. The efficacy of a treatment suggested by a single report may serve to provide clues about the pathogenesis of the disease but will need to be subjected to further study before the treatment is widely used. Accepted for Publication: September 28, 2006. Correspondence: Marie-France Demierre, MD, FRCPC, Boston University School of Medicine, Skin Oncology Program, Boston Medical Center, 720 Harrison Ave, DOB801A, Boston, MA 02118 (mariefrance.demierre @bmc.org). Author Contributions: Dr Demierre had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study Concept and Design: Taverna, Lerner, and Demierre. Acquisition of Data: Taverna, Lerner, Werth, and Demierre. Analysis and Interpretation of Data: Taverna, Lerner, Goldberg, and Demierre. Drafting of the Manuscript: Taverna. Critical Revision of the Manuscript for Important Intellectual Content: Taverna, Lerner, Goldberg, Werth, and Demierre. Obtained funding: Demierre. Administrative, Technical, and Material Support: Taverna, Goldberg, and Demierre. Study Supervision: Taverna, Goldberg, Werth, and Demierre. Financial Disclosure: Dr Demierre has acted as a speaker for Schering, Ligand, Therakos, Merck, and Gloucester; has received research support from Ligand, Therakos, Merck, Gloucester, Genmab, Curagen, and Novartis; has been a consultant for Ligand and Novartis; and has served on the advisory board of Gloucester. Previous Presentation: This work was presented as a case series at the Annual Fall meeting of the Massachusetts Academy of Dermatology; September 17, 2006; Newport, Rhode Island. Additional Contributions: We thank Robert E. Tigelaar, MD, for thoughtful discussions and Swarne Adikari for technical photographic assistance. REFERENCES 1. Chusid MJ, Dale DC, West BC, Wolff SM. The hypereosinophilic syndrome: analysis of fourteen cases with review of the literature. Medicine (Baltimore). 1975; 54(1):1-27. 2. Brito-Babapulle F. The eosinophilias, including the idiopathic hypereosinophilic syndrome. Br J Haematol. 2003;121(2):203-223. 3. Tefferi A. Blood eosinophilias: a new paradigm in disease classification, diagnosis, and treatment. Mayo Clin Proc. 2005;80(1):75-83. 4. Roufosse F, Cogan E, Goldman M. Recent advances in pathogenesis and management of hypereosinophilic syndromes. Allergy. 2004;59(7):673-689. 5. Sutton SA, Ass’ad AH, Rothenberg ME. Anti–IL-5 and hypereosinophilic syndromes. Clin Immunol. 2005;115(1):51-60. 6. Cools J, DeAngelo DJ, Gotlib J, et al. A tyrosine kinase created by fusion of the PDGFRA and FIP1L1 genes as a therapeutic target of imatinib in idiopathic hypereosinophilic syndrome. N Engl J Med. 2003;348(13):1201-1214. 7. Yoon TY, Ahn GB, Chang SH. Complete remission of hypereosinophilic syndrome after interferon-alpha therapy: report of a case and literature review. J Dermatol. 2000;27(2):110-115. 8. Ueno NT, Anagnostopoulos A, Rondon G, et al. Successful non-myeloablative allogeneic transplantation for treatment of idiopathic hypereosinophilic syndrome. Br J Haematol. 2002;119(1):131-134. 9. Fiehn C, Andrassy K. Case number 29: hitting three with one strike: rapid improvement of psoriatic arthritis, psoriatic erythroderma, and secondary renal amyloidosis by treatment with infliximab (Remicade). Ann Rheum Dis. 2004;63 (3):232. 10. O’Quinn RP, Miller JL. The effectiveness of tumor necrosis factor alpha antibody (infliximab) in treating recalcitrant psoriasis: a report of two cases. Arch Dermatol. 2002;138(5):644-648. 11. Winterfield LS, Menter A, Gordon K, Gottlieb A. Psoriasis treatment: current and emerging directed therapies. Ann Rheum Dis. 2005;64(suppl 2):ii87-ii92. 12. Liao WC, Mutasim DF. Infliximab for the treatment of adult-onset pityriasis rubra pilaris. Arch Dermatol. 2005;141(4):423-425. 13. Bochner BS, Luscinskas FW, Gimbrone MA, Newman W. Adhesion of human basophils, eosinophils and neutrophils to interleukin 1–activated human vascular endothelial cells: contributions of endothelial cell adhesion molecules. J Exp Med. 1991;173(6):1553-1557. 14. Kyan-Aung U, Haskard DO, Poston RN, Thornhill MH, Lee TH. Endothelial leukocyte adhesion molecule-1 and intercellular adhesion molecule-1 mediate the adhesion of eosinophils to endothelial cells in vitro and are expressed by endothelium in allergic cutaneous inflammation in vivo. J Immunol. 1991;146(2): 521-528. 15. Weller PF, Rand TH, Goelz SE, Chi-Rosso G, Lobb RR. Human eosinophil adherence to vascular endothelium mediated by binding to vascular cell adhesion molecule 1 and endothelial leukocyte adhesion molecule 1. Proc Natl Acad Sci U S A. 1991;88(16):7430-7433. 16. Williams IR, Kupper TS. Immunity at the surface: homeostatic mechanisms of the skin immune system. Life Sci. 1996;58(18):1485-1507. 17. Costa JJ, Matossian K, Resnick MB, et al. Human eosinophils can express the cytokines tumor necrosis factor alpha and macrophage inflammatory protein-1 alpha. J Clin Invest. 1993;91(6):2673-2684. 18. Bongartz T, Sutton AJ, Sweeting MJ, Buchan I, Matteson EL, Montori V. AntiTNF antibody therapy in rheumatoid arthritis and the risk of serious infections and malignancies: systematic review and meta-analysis of rare harmful effects in randomized controlled trials. JAMA. 2006;295(19):2275-2285. (REPRINTED) ARCH DERMATOL/ VOL 143 (NO. 9), SEP 2007 1112 WWW.ARCHDERMATOL.COM STUDY Clinical Severity of Psoriasis in Last 20 Years of PUVA Study Tamar Nijsten, MD, PhD; Caspar W. N. Looman, PhD; Robert S. Stern, MD Objective: To assess the severity of psoriasis over time. Design: We analyzed the results of structured dermatologic examinations administered over a 20-year period beginning 10 years after study enrollment. Setting: The PUVA [psoralen–UV-A] Follow-up Study, which is a prospective cohort study. Patients: The analyses were restricted to 815 patients (83.2% of those eligible) who underwent at least 2 of 4 possible examinations between 1985 and 2005. Main Outcome Measure: A 4-point physician global assessment (PGA). Results: The distribution of the PGA levels in the study group did not change significantly over time, except that in 2005 more patients had no psoriasis compared with P patients who underwent examinations in the previous study years (9.6% vs ⬍ 5.1%, P ⬍ .03). The PGA level changed more than 1 level between examinations in only 14% of patients. Multistate Markov models estimated that patients had a likelihood of about 80% to remain at the same PGA level 1 year later. After 10 years, this likelihood varied between 19% and 53%, depending on the PGA level. Except for patients who were clear of disease at baseline, on average patients had about 1 year without psoriasis over 20 years. On average, individuals with moderate to severe disease remained at these levels for 11 or more years. Conclusion: Three decades after a large and diverse group of patients sought a cure for their psoriasis, consistent control of their psoriasis often had not been achieved. Arch Dermatol. 2007;143(9):1113-1121 SORIASIS IS A COMMON chronic skin condition that affects about 2% of the people in the United States. 1 Although it is widely accepted that psoriasis waxes and wanes and varies substantially in severity among patients, the severity of psoriasis over a long CME available online at www.archdermatol.com Author Affiliations: Departments of Dermatology (Dr Nijsten) and Public Health (Dr Looman), Erasmus Medical Center, Rotterdam, the Netherlands; and Department of Dermatology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts (Dr Stern). period in a single person or group has not been well documented. In the 1960s and 1970s, several cross-sectional studies based on self-reports and without clearly defined outcomes estimated that 40% of patients with psoriasis had experienced a “complete remission” at least once in their lifetime.2-4 In clinical trials with a maximum of 16 weeks of follow-up, the mean relative change of the psoriasis area and severity index ranged from −20% to 50% among almost 500 placebo-treated patients.5 A recent study using the General Practice Research Database found that the prevalence of psoriasis, as reported as an independent diagnosis, declined in pa- (REPRINTED) ARCH DERMATOL/ VOL 143 (NO. 9), SEP 2007 1113 tients older than 70 years, suggesting that psoriasis may go into remission in elderly patients.6 The severity of psoriasis in a given individual at any point reflects both endogenous (underlying disease activity) and exogenous factors, including treatment. The short- to intermediate-term effects of therapies on disease severity have been examined in hundreds of clinical trials, but they are unlikely to be representative of the psoriasis severity over a long period among individuals who have this disease for an average of 40 or more years. Also, persons entering clinical trials are likely to have worse psoriasis than their usual state. Patients who are receiving active treatment are likely to have less disease, and there is a discrepancy between the efficacy of treatments observed in clinical trials and their effectiveness in daily life. For editorial comment see page 1191 The PUVA [psoralen–UV-A] Follow-up Study is a long-term prospective cohort safety study, which has included WWW.ARCHDERMATOL.COM Annual clinical examinations likely to be related to seeking care Patients receiving PUVA therapy, %∗ 89 1975 Start 92 64 51 42 37 1977-1982 Periodical clinical examinations likely not to be related to seeking care 15 19 5 1986 1991 2001 3 2005 Start PUVA approval Figure 1. Time line of the clinical examinations for the entire PUVA [psoralen–UV-A] Follow-up Study and for the study period. Asterisk indicates the percentage of patients who received 10 or more PUVA treatments for that year. study-sponsored structured dermatologic examinations, including an assessment of psoriasis severity using a physician global assessment (PGA) scale administered over nearly 30 years.7 In contrast to earlier examinations in the first study decade, by 1985 the timing of these examinations was not coordinated with therapeutic decisions and/or disease status. Therefore, the results of the last 4 examinations were used in this study. The primary objective of the present study was to analyze change of psoriasis severity among participants in a prospective cohort study over the last 2 decades. METHODS THE PUVA FOLLOW-UP STUDY The PUVA Follow-up Study is a long-term safety and efficacy study that has prospectively studied 1380 patients with moderate to severe psoriasis who were first treated with PUVA in 1975 and 1976 at 16 university centers in the United States. In 1977, a total of 1380 of 1450 patients who participated in the original trial enrolled in the PUVA Follow-up Study. By 2005, 22 cycles of follow-up interviews and 9 cycles of physical examinations had been completed. The Declaration of Helsinki protocols were followed, and at time of enrollment all patients provided written informed consent. A more detailed description of this cohort study has been published previously.8,9 GLOBAL PSORIASIS SEVERITY During 5 periods of the cohort study, from entry (1975-1976) to 1983, members were invited to come to a participating center for an in-person follow-up interview (which assessed treatment exposures and health-related outcomes since last interview) and a structured dermatologic examination, both of which were performed annually by a local investigator (Figure 1). These examinations were very likely to coincide with medical care. By 1985, a coordinating center conducted telephone interviews, with the exception of 1 center, which interviewed its own patients. At the time of the telephone interview in designated years, the interviewer helped to arrange the patient’s clinical examination, which, when possible, was performed at a participating center or, alternatively, at the patient’s current dermatology department and was performed relatively independently of clinical status or care. Also, by 1985, PUVA use had decreased substantially (Figure 1). In this report, the dermatologic examinations analyzed were performed during 4 periods (1985-1986, 1990-1991, 2000-2001, and 2003-2005). The study provided instructions and standardized forms to all examining physicians for scoring several clinical cutaneous signs. Each clinical examination included a 4-point assessment of PGA (clear, mild, moderate, and severe). STUDY POPULATION Cohort members were included in this analysis if they had undergone 2 or more PGA assessments between 1985 and 2005. To be eligible, patients must have undergone a second examination after 1985; therefore, they had to have received follow-up at least until 1991. In 1991, a total of 979 patients were still participating in the study, 341 had died, 37 were unavailable for follow-up, and 23 had withdrawn from the study (Figure 1). A comparison of the 979 cohort members who were followed up in 1991 and the 815 patients who were eligible to enter this study demonstrated that the study patients were significantly more likely to be male (66.6% vs 61.7%, P =.03), but men and women were of comparable age (mean [SD], 56.7 [12.9] years vs 55.9 [15.9] years, P=.16). Up to 1986, the cumulative exposures to PUVA, UV-B, and methotrexate were comparable between the study patients and those not included (mean [SD], 188.5 [137.6] PUVA treatments vs 203.3 [163.1] PUVA treatments, P = .12; 248.6 [351.1] UV-B treatments vs 288.5 [458.5] UV-B treatments, P=.31; and 15.6 [31.2] months of methotrexate therapy vs 17.4 [32.9] months of methotrexate therapy, P=.27, respectively). At time of the enrolment in the PUVA study, the 815 study patients were significantly younger and more likely to be female than the other 565 cohort members (mean age, 41.5 years vs 47.1 years [P ⬍ .001] and 64.2% women vs 56.4% women [P = .005], respectively). At time of the first PGA assessment (1977, N = 1192), study participants were significantly more likely to have more moderate to severe disease compared with the remaining patients (18.9% vs 32.9% [P⬍ .001], respectively). STATISTICAL ANALYSIS We used the ␹2 test to determine the statistical significance of difference in the distribution of categorical variables and the t test for continuous variables. For paired comparisons, the Wilcoxon signed rank test and the McNemar test were used as appropriate. To test for statistical differences between multiple (REPRINTED) ARCH DERMATOL/ VOL 143 (NO. 9), SEP 2007 1114 WWW.ARCHDERMATOL.COM Interviewed Died Lost Withdrew 1400 1200 No. of Patients 1000 800 600 400 200 0 1975 1978 1981 1984 1987 1990 1993 1996 1999 2002 Study Year Figure 2. Of 1380 cohort members, the number of patients who were interviewed and the cumulative number of patients who died, who were unavailable for follow-up (Lost), and who withdrew from the study each year. groups, 2-way analysis of variance or the Kruskal-Wallis test was used as appropriate. To assess the intraindividual variability of the PGA scorings, we calculated turnover tables for all intervals and pooled them. We applied multistate Markov modeling, which describes the process in which an individual moves through a series of states in continuous time.10 The multivariate statistical modeling package for the statistical program R was used to estimate a transition intensity matrix (hazard matrix: hazard ratios with 95% confidence intervals [CIs] [data not shown]), which were subsequently transformed to proportions (without 95% CIs because of software limitations).11 First, multistate Markov modeling was used to estimate the transit rates between levels of PGA after 1, 5, and 10 years. We chose a model that allowed changes only to subsequent PGA stages but used a likelihood ratio test to compare it with a model that allowed all possible changes. Second, Markov models estimated the length of stay of the total study period (20 years) in each of the PGA levels stratified by the patients’ PGA level at baseline in 1986. To study the effect of aging and disease duration on the 4-point PGA, we compared the distribution of these variables across the PGA levels at each clinical examination. Also, a multivariate ordered logistic regression model, which is a type of logistic regression model with an ordinal-depending variable that has more than 2 categories, was used to calculate adjusted odds ratios (ORs) and 95% CIs. For the 4 analyses, collinearity was absent and the proportional odds assumption was tested using a likelihood ratio test and a Brant test, the results of which were nonsignificant (P ⬎.05). About three-quarters of the cohort members who were followed up participated in the clinical examinations (Table 1). Of the 979 patients, 815 (82.3%) underwent 2 or more clinical examinations between 1985 and 2005. The majority of 815 study participants were middleaged male patients who had psoriasis for more than 25 years (Table 1). The age at onset of psoriasis ranged from 0 to 68 years (mean [SD] age, 19.0 [17.8] years). Graphically, no bimodal distribution was detected. A little fewer than 50% of the patients had PGA scores of moderate to severe psoriasis at 1 or more of the examinations. The distribution of PGA levels remained stable over a period of 20 years, except that a larger percentage of patients were reported clear of psoriasis at the 2005 examination compared with the prior examinations (9.6% vs 4.5%, 3.9%, and 5.1%, respectively; P⬍.03). However, the percentage of patients with none to mild and moderate to severe psoriasis was comparable at the different examinations (56.8% vs 52.1%, 52.6%, and 55.0%, respectively; P ⬎.13). RESULTS DISTRIBUTION THE COHORT OVER TIME In 1986, 1991, 2001, and 2005, the total number of clinically examined patients was 889, 979, 580, and 424, respectively. Of the patients who were followed up after 1991, 92.2% of the 884 patients who underwent 1 examination between 1985 and 2005 underwent a second examination. Of the study patients who were followed up in 2005, 8.8% underwent 2, 30.5% underwent 3, and 60.8% underwent 4 examinations. The likelihood that a Figure 2 demonstrates that of the patients who were actively followed up in each year of the PUVA study, the overwhelming majority were interviewed, and that the number of participants who were unavailable for follow-up or withdrew from the study was very small. Death of the cohort members was the primary reason for the decreasing number of participants between 1975 and 2005. CHARACTERISTICS OF STUDY POPULATION (REPRINTED) ARCH DERMATOL/ VOL 143 (NO. 9), SEP 2007 1115 WWW.ARCHDERMATOL.COM Table 1. Characteristics of Patients With Psoriasis Who Underwent 2 or More Clinical Examinations Examination (Year) Characteristics 1 (1985-1986) 2 (1990-1991) 3 (2000-2001) 4 (2004-2005) 865 (73.7) b 333 (38.1) 54.0 (13.9) 32.6 (13.6) 743 (74.1) b 280 (37.4) 56.1 (13.0) 34.9 (12.8) 571 (78.3) b 221 (38.1) 59.9 (12.6) 41.6 (12.2) 400 (76.0) b 151 (37.8) 63.7 (13.5) 45.0 (13.0) 40 (4.5) 404 (45.4) 308 (34.6) 121 (13.6) 29 (3.8) 340 (44.7) 270 (35.5) 109 (14.3) 29 (4.8) 289 (47.8) 193 (31.9) 63 (10.4) 38 (9.5) c 188 (47.0) 127 (31.8) 47 (11.8) Participants, No. (%) a Women, No. (%) Age, mean (SD), y Duration of disease, mean (SD), y Physician global assessment of psoriasis, No. (%) Clear Mild Moderate Severe a Of the patients who underwent at least 2 examinations (n = 815). b Percentage of patients who were followed up during that period. c Statistically significant (P ⬍ .02) on ␹² test. None 1 Level 2 Level 3 Level 100 Patients, % 80 had severe disease in 1991, about 25% remained at this level in 2001 and 2005, and between 65% to 85% had at least moderate disease at subsequent examinations. About 90% of 602 patients with mild and moderate psoriasis in 1986 remained within 1 PGA level at the subsequent examinations. About 70% of patients with no or mild disease in 1986 had these same levels of psoriasis severity at subsequent examinations. PAIRED COMPARISONS 60 40 20 0 2 (n = 308) 3 (n = 266) 4 (n = 241) No. of Clinical Examinations The median change in PGA score between the 4 examination periods was 0 (25th percentiles of 0.0 and −1.0 and 75th percentiles of 0.0 and 1.0). Paired analyses between the 4 assessments showed no significant difference in PGA levels of patients (P⬎.06). After categorizing the PGA levels of patients with none to mild and moderate to severe psoriasis, paired analyses showed no statistical significant differences between periods (P ⬎.33). INTRAINDIVIDUAL VARIABILITY Figure 3. Maximum level of change in physician global assessment score for the maximum number of clinical examinations. second examination was reported increased significantly for each year a patient was followed up after the first examinations between 1985 and 2005 (OR, 1.31; 95% CI, 1.27-1.36). A total of 2378 examinations were included in this study (mean, 3 examinations per patient). The mode of PGA level was mild (48.0%). Of the 815 patients, 290 (35.6%) had the exact same PGA score, and 50.3% had a maximum difference of 1 level; 13.3%, of 2 levels; and 0.9%, of 3 levels (ie, had an examination reporting clear psoriasis and an examination reporting severe psoriasis) at examinations in which they participated. The difference between the 2 broad severity categories (none or mild vs moderate or severe psoriasis) changed in more than half of the participants (52.3%). Although the variance increased significantly (P⬍ .001) with the maximum number of observations (Figure 3), the majority of patients remained within 1 level of their baseline assessment in 1986 (Figure 4). Of the 94 patients who had severe disease in 1986, almost half still Patients’ probability of having the same global psoriasis severity 1 year later is about 80% but decreases at 5- and 10-year intervals (Table 2). Of patients with mild to moderate disease, about 85% were likely to still have the same level of disease after 10 years. It was estimated that almost half the patients with moderate disease will have mild disease after 10 years. About a third of patients with severe psoriasis are likely to have mild or moderate disease 10 years later, and almost a quarter of those with no psoriasis will have moderate disease. Table 3 provides the results of our statistical model that predicts the expected duration in years of the total 20-year study period for individual time in each PGA level according to their baseline level (the sum of the years in the rows equals 20 years). Patients with no psoriasis in 1986 were likely to have about 5 years with no disease and 5 years with moderate to severe disease over a subsequent 20-year period. Patients who had mild psoriasis in 1985 would remain in that PGA level for an average of 12 of 20 subsequent years and be clear for 1 year. Pa- (REPRINTED) ARCH DERMATOL/ VOL 143 (NO. 9), SEP 2007 1116 WWW.ARCHDERMATOL.COM B 100 80 80 60 60 Patients, % Patients, % A 100 40 20 40 20 0 0 1 1991 2 2001 3 2005 1 1991 Clinical Examination, y 3 2005 Clinical Examination, y No change Worse 1 level Improved 3 levels Worse 2 levels Improved 2 levels Worse 3 levels Improved 1 level C No change D 100 100 80 80 60 60 Patients, % Patients, % 2 2001 40 20 40 20 0 00 1 1991 2 2001 3 2005 1 1991 Clinical Examination, y 2 2001 3 2005 Clinical Examination, y Figure 4. The distribution of change of 4-point physician global assessment (PGA) for subsequent clinical examinations stratified by PGA level at 1986 examination. A, No psoriasis (n=33). B, Mild psoriasis (n=347). C, Moderate psoriasis (n = 255). D, Severe psoriasis (n = 94). tients with moderate psoriasis in 1986 were expected to have moderate or severe disease in 11 of 20 subsequent years. Those with severe disease at the initial examination would average 6 years of mild, moderate, and severe psoriasis and should be clear of psoriasis for only half a year over 2 decades. EFFECT OF AGING A comparison of patients’ age and disease duration at the time of examination between the 4 PGA levels showed no statistical significant differences in any of the examination periods (P⬎.18). After adjustment for sex in a multivariate proportional logistic regression model, age and disease duration were not significantly associated with level of PGA in 1986, 1991, 2001, or 2005 (eg, age in 2005, adjusted OR, 0.98 [95% CI, 0.96-1.02]; and duration of disease in 2005, adjusted OR, 1.00 [95% CI, 0.981.03]). SENSITIVITY ANALYSES To study whether patients with active or persistent disease were more likely to accept an invitation for a studysponsored clinical examination, several sensitivity analyses were performed. The demographic and disease characteristics of the patients who underwent all examinations during follow-up (72.2% of the study population) were comparable to those of the patients who missed intermediate examinations (data not shown). Restricting the analysis to the 241 participants who underwent all 4 examinations did not change the results substantially (data not shown). We compared the PGA levels of patients who were examined only in 1986 with those of (REPRINTED) ARCH DERMATOL/ VOL 143 (NO. 9), SEP 2007 1117 WWW.ARCHDERMATOL.COM Table 2. The Transit Rate Between Levels of Physician Global Assessment of Psoriasis at Consecutive Examinations After 1, 5, and 10 Years a Psoriasis, y None 1 5 10 Mild 1 5 10 Moderate 1 5 10 Severe 1 5 10 a Multistate None Mild Moderate Severe 0.82 0.40 0.19 0.17 0.47 0.53 0.01 0.12 0.23 0.00 0.02 0.05 0.02 0.06 0.07 0.88 0.63 0.53 0.10 0.26 0.30 0.00 0.05 0.09 0.00 0.02 0.05 0.15 0.39 0.46 0.78 0.44 0.36 0.07 0.15 0.14 0.00 0.01 0.03 0.02 0.15 0.37 0.19 0.78 0.39 0.79 0.15 0.22 Markov modeling (see “Methods” section). Table 3. Of the Total of 20 Years, the Expected Number of Years That Patients Will Spend in Each of the Levels of the Physician Global Assessment (PGA) Stratified by PGA of Psoriasis in 1986 a PGA of Psoriasis in 1986 None Mild Moderate Severe None Mild Moderate Severe 5.79 1.23 0.78 0.55 9.28 11.80 8.15 6.22 3.90 5.42 8.44 7.04 1.03 1.55 2.63 6.18 a Multistate Markov modeling (see “Methods” section). patients who were assessed in both 1986 and 1991. The same comparison was performed for examinations in 1991 and 2001. There were no significant differences in the distribution of the PGA levels of the patients with 1 vs 2 observations, except that patients who underwent only 1 examination were significantly more likely to have severe psoriasis than were those who underwent 2 examinations (11.9% vs 3.1%, P ⬍ .001). When we fitted a Markov model with all transitions possible (ie, also from PGA levels 1 to 4), the likelihood ratio test comparing this model with the presented model showed no significant difference (df=6, P = .41). COMMENT Nearly all data concerning the variability in clinical psoriasis severity over time come from a few cross-sectional studies using self-reported psoriasis severity in time or from clinical trials with follow-up measured in weeks rather than years or decades. The PUVA Follow-up Study cohort is unique. Patients have been followed up for nearly 30 years from enrollment in a clinical trial irrespective of their use of PUVA or any other therapy. In the first 5 years of the study, many patients still relied on PUVA and the study protocol linked interviews and study-sponsored dermatologic examinations. By the mid-1980s, use of PUVA had decreased significantly.9 Also beginning in 1985, the timing of interviews and study-sponsored dermatologic examinations were no longer closely linked to each other or to patients seeking care for their psoriasis. As a result, the structured dermatologic examinations performed from 1985 to 2005 provide a unique assessment of the distribution of psoriasis over time in a group of patients who joined this cohort nearly a decade earlier and of the variability in individuals’ physician-assessed psoriasis severity over a 20year period. To quantify the variation of the patients’ disease severity over these 20 years, we used new statistical techniques to estimate transition rates and the expected number of years that patients would be at the different PGA levels depending on their baseline assessment. PSORIASIS SEVERITY IN TIME Based on nearly 2400 structured dermatologic examinations, the distribution of psoriasis severity within this group assessed by dermatologists changed little for the PUVA cohort as a whole over a 20-year period. Only about 25% of individual study participants had more than 1 PGA level change (with up to 3 levels possible) in multiple examinations. Paired comparisons demonstrated no significant differences between patients’ PGA levels over time. Moreover, transition rate analysis estimated that patients had about an 80% chance to have the same level of psoriasis severity after 1 year, but these rates decreased after 5 and 10 years, especially for the 2 extreme PGA levels. At least 50% of patients with moderate to severe disease are likely to still be at this level 10 years later, but patients with severe psoriasis will have mild to moderate disease in at least two-thirds of the follow-up years. Therefore, at least in this heterogeneous population cared for by many dermatologists, including many with a special interest in psoriasis, the likelihood that the extent of disease will change more than 1 PGA level over 1 year and over 10 years is relatively small, and fewer than 5% will have no psoriasis. As expected, patients who had no psoriasis at baseline, which may reflect the natural course of their disease or may be attributable to therapy, have the best chance of having no or mild disease in the future. Although treatment exposure and PGA examination results were not linked in this study, overall treatment use has been substantial in this cohort. For example, from study entry to 1984, cohort members had used twice as many PUVA as UV-B treatments, but after 1984, UV-B was used 3 times as often (between 1985 and 2005, the cohort used more than 200 000 UV-B treatments). Despite substantial therapy use over time, only 9.0% and 2.3% of the 815 study participants were clear of disease at 1 or 2 examinations and only 5 (1.0%) of the 507 patients who underwent 3 or more clinical examinations were clear at 3 examinations, which may be a spontaneous outcome or attributable to therapy. These low proportions of clearance contrast with those observed in an older prospective study of an isolated population followed up for a median interval of 1 year as well as those of a study that noted that 75% of patients reported a com- (REPRINTED) ARCH DERMATOL/ VOL 143 (NO. 9), SEP 2007 1118 WWW.ARCHDERMATOL.COM plete remission of their disease and that 2% of men and 8% of women had no signs of the disease for at least 5 years.2-4 Both of these studies relied on patient reports rather than on examination and included a much higher percentage of persons with mild psoriasis than did the PUVA Follow-up Study. EFFICACY VS EFFECTIVENESS The study findings confirm the discrepancy between the efficacy of treatments observed in clinical trials and our success in controlling psoriasis over the long term. In the original PUVA trial, 88% of the patients achieved clearance at completion of the study,12 but 1 years or more thereafter, including at time points close to the introduction of cyclosporine and the biologics, 55% or fewer of those patients were described as having no or mild psoriasis. This difference of 30% may suggest that clearing psoriasis over the short term is quite feasible but that it is much more difficult to substantially reduce psoriasis over the long term, which may be attributable to other issues such as care setting (clinical trials vs real life), access and availability, safety, convenience, satisfaction, and costs.13-15 Although our study was unable to differentiate which of these issues or what other factors may be the root cause, our findings indicate that those patients who sought a cure for their psoriasis 30 years ago and temporarily achieved good control of their disease have suffered from substantial disease over the long term. Psoriasis severity reported at the first 5 examinations after the introduction of PUVA (1976-1982), which were excluded from the analyses, was significantly less than that at later examinations. In the years in which the first 5 examinations were performed, the use of PUVA was significantly greater than in the years before the examinations that were performed between 1985 and 2005 (Figure 1). However, this level of control diminished in association with the decline of PUVA use after it became widely accepted to be carcinogenic in the 1980s.16 At least in our cohort, the introduction of new treatments from 1985 to 1998 (ie, vitamin D derivatives, retinoids, and cyclosporine) did not seem to have substantially affected the severity of the patients’ psoriasis. However, the distribution of PGA levels of 400 patients with psoriasis who were examined in 2005 showed that a significantly larger percentage (9.6% vs ⬍5.1%) of patients were rated clear compared with the patients at prior examinations. Fewer than one-fourth of those who were clear in 2005 had ever used biologics, but the availability of biologics and the publicity about psoriasis treatments may have stimulated more patients to seek care again. Therefore, these recent data, as well as our cohorts’ experience from 1977 to 1982, are compatible with the hypothesis that more intensive therapy, both new and old, is able to reduce psoriasis, at least for short periods. EFFECT OF AGING A medical claims–based study that used prevalence estimates that were based on general physicians’ record- ing diagnoses and assessing the distribution of severity among different groups suggested that psoriasis may go into remission in the elderly.6 Our logistic regression model, which was based on a prospective study of a defined cohort, indicates that psoriasis severity does not decrease substantially with age. Also, our study could not confirm that the extent of psoriasis depends on the duration of disease (ie, age at onset) but indicates that it may depend on family history.17-19 STRENGTHS AND LIMITATIONS To our knowledge, this is the first prospective study that has used standardized structured dermatologic examination to assess psoriasis severity longitudinally over 2 decades at 4 time points that were not substantially related to treatment use. This is a long-term ecologic study of a cohort with psoriasis. As such, it has several advantages and disadvantages. Although we documented patient treatments through nearly annual telephone interviews with members of the cohort, the timing of dermatologic examination was not coordinated with therapy or therapeutic decisions but rather was arranged to suit the patient’s convenience. Therefore, we cannot link the use of specific treatments with specific disease states. Instead, we present a unique perspective of physician-assessed severity in a cohort of patients who were periodically examined over a 20-year period. A true “natural history” study of a chronic disease such as psoriasis would need to withhold treatment from the affected individuals. Such a study would be both impractical and unethical, particularly in a cohort such as ours. Enrollment in a clinical trial may be associated with worsening of a disease, with subsequent observed decreased severity a reflection of “regression to the mean” rather than a true change in the “usual” disease severity. Since we used examination 1, which was administered nearly a decade after enrollment, as our baseline, this potential ascertainment bias is unlikely to have substantially influenced our results. However, this phenomenon may in part explain the relatively large proportion of patients with mild disease. Although cohort members with persistent or active psoriasis may have been more likely than those with less or inactive disease to accept the invitation for a clinical examination, the number of patients who were unavailable for follow-up or who withdrew from the cohort study was small. Although several sensitivity analyses also suggest that this potential selection bias has not substantially affected our results, study patients had more severe psoriasis in 1977 than cohort members who were not included in this study. Despite the fact that patients were invited randomly in a follow-up cycle, the probability may have been greater that the participating patients who attended the examination were more likely than nonparticipating patients to be seeking medical care, including therapeutic and nontherapeutic interventions. However, this association is not likely to be different among the 4 assessments, suggesting a nondifferential effect. The study findings are not generalizable to all patients with psoriasis, because this cohort included patients who sought experimental therapy 30 years ago at tertiary referral centers. At the (REPRINTED) ARCH DERMATOL/ VOL 143 (NO. 9), SEP 2007 1119 WWW.ARCHDERMATOL.COM time of patients’ enrollment in the PUVA study, nearly a decade before the first examinations included in these analyses were performed, the patients had sufficiently severe and/or treatment-resistant psoriasis that both patients and their treating dermatologists at 16 centers, which were selected for their expertise in the treatment of psoriasis, deemed them appropriate candidates for a then-experimental therapy, which included the systemic administration of drug. We believe that our results are likely to be representative of the course of psoriasis severity among patients with moderate to severe psoriasis who at least initially had access to care at a leading dermatologic center. Although mortality may be associated with clinical psoriasis severity (owing to increased incidence of comorbidities),20 it is not likely to be associated with the degree of disease fluctuations, which is the objective of this study. The Markov model was used to create the transition tables. As a statistical model, it is based on several assumptions. The results of these kinds of analyses should be interpreted with some caution and applied cautiously in advising individual patients. However, a sensitivity analysis with altered assumptions confirmed the findings of the presented model. Because of software limitations, we were unable to calculate 95% CIs for the transition rates. However, the 95% CIs were estimated for the transition intensities (hazard matrix), which is in an intermediate step in the process of the transition rate calculation, and were reasonably narrow (data not shown). We believe that a 4-point PGA scale, which was assessed by dermatologists who were trained at investigators’ meetings and through instructions, as part of a structured dermatologic examination, is likely to be a reliable and valid measurement in the assessment of psoriasis. However, the PGA was not strictly defined and did not include parameters such as percentage of body surface area affected and/or plaque characteristics but is widely used and has “face” validity.21-23 Although a global assessment may be relatively insensitive for measuring small changes over time, we believe it should be sensitive to clinically meaningful changes, which are the focus of this study. In addition to the intraobserver variability of the PGA, interobserver variability may also have affected our results, because different investigators may have assessed some patients over time. The extent to which observer bias affects the PGA in psoriasis is not well documented.22 In conclusion, even with substantial use of psoriasis therapies after 1984, including more than an average of 170 UV-B treatments, 50 PUVA treatments, and a year of methotrexate therapy, our cohort was assessed by dermatologists as having moderate or severe psoriasis at nearly half of almost 2400 examinations performed over a 20-year period. Although at some times the disease may improve or worsen, most individuals in our cohort had similar extents of psoriasis at subsequent examinations. Three decades after this large diverse group of patients sought a cure for their psoriasis, they have not achieved consistent control of their disase. Additional prospective longitudinal studies that assess the (natural) course of psoriasis and its determinants are warranted. Accepted for Publication: February 25, 2007. Correspondence: Robert S. Stern, MD, Department of Dermatology, Beth Israel Deaconess Medical Center, 330 Brookline Ave, Boston, MA 02215 (rstern@bidmc.harvard .edu). Author Contributions: Dr Stern is the principal investigator of the PUVA Follow-up Study. Study concept and design: Nijsten and Stern. Acquisition of data: Stern. Analysis and interpretation of data: Nijsten, Looman, and Stern. Drafting of the manuscript: Nijsten. Critical revision of the manuscript for important intellectual content: Nijsten, Looman, and Stern. Statistical analysis: Nijsten and Looman. Obtained funding: Stern. Administrative, technical, and material support: Nijsten and Stern. Study supervision: Stern. Financial Disclosure: None reported. Funding/Support:This study was funded in part by Public Health Service contract N01-AR-0-2246 from the National Health Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Department of Health and Human Services. Additional Contributions: We thank the patients and principal investigators of the multicenter PUVA Follow-up Study for their participation; M. Cosmos and S. Paquette for collecting and managing data for this project; D. Spiegelman for input on data analysis; and Christopher Jackson, PhD, Imperial College, London, England, for providing access to Markov modeling software. The following institutions and investigators have participated in the recruitment and follow-up of patients in this study: Stanford University School of Medicine, Stanford, California (E. Bauer and E. Abel); University of California at San Francisco (J. H. Epstein and J. Koo); Baylor College of Medicine, Houston, Texas (J. Wolf); Washington Hospital Center, Washington, DC (T. P. Nigra); University of Michigan Medical School, Ann Arbor (T. F. Anderson); Columbia University College of Physicians and Surgeons, New York, New York (J. Prystowsky and M. J. Stiller); Mayo Graduate School of Medicine, Rochester, Minnesota (M. McEvoy); University of Miami Medical School, Miami, Florida (J. R. Taylor); Mt Sinai Medical Center, Miami Beach, Florida (N. Zaias); Temple University School of Medicine, Philadelphia, Pennsylvania (F. Urbach); Beth Israel Deaconess Medical Center, Boston, Massachusetts (R. S. Stern); Dartmouth Medical School, Hanover, New Hampshire (R. D. Baughman); Yale University of Medicine, New Haven, Connecticut (I. M. Braverman); Duke University Medical Center, Durham, North Carolina (J. Murray); University of Pennsylvania Hospitals, Phildelphia (V. P. Werth); and Massachusetts General Hospital, Boston (T. B. Fitzpatrick [deceased], J. Parrish, C. Taylor, and A. J. Sober). REFERENCES 1. Stern RS, Nijsten T, Feldman SR, Margolis DJ, Rolstad T. Psoriasis is common, carries a substantial burden even when not extensive, and is associated with widespread treatment dissatisfaction. J Investig Dermatol Symp Proc. 2004;9(2): 136-139. 2. Farber EM, Bright RD, Nall ML. Psoriasis: a questionnaire survey of 2,144 patients. Arch Dermatol. 1968;98(3):248-259. (REPRINTED) ARCH DERMATOL/ VOL 143 (NO. 9), SEP 2007 1120 WWW.ARCHDERMATOL.COM 3. Farber EM, Nall ML. The natural history of psoriasis in 5,600 patients. Dermatologica. 1974;148(1):1-18. 4. Molin L. Psoriasis: a study of the course and degree of severity, joint involvement, socio-medical conditions, general morbidity and influences of selection factors among previously hospitalized psoriatics. Acta Derm Venereol Suppl (Stockh). 1973;53:1-125. 5. Spuls PI, Witkamp L, Bossuyt PM, Bos JD. The course of chronic plaque-type psoriasis in placebo groups of randomized controlled studies. Arch Dermatol. 2004;140(3):338-344. 6. Gelfand JM, Weinstein R, Porter SB, Neimann AL, Berlin JA, Margolis DJ. Prevalence and treatment of psoriasis in the United Kingdom: a population-based study. Arch Dermatol. 2005;141(12):1537-1541. 7. Stern RS, Laird N, Melski J, Parrish JA, Fitzpatrick TB, Bleich HL. Cutaneous squamous-cell carcinoma in patients treated with PUVA. N Engl J Med. 1984;310 (18):1156-1161. 8. Stern RS, Thibodeau LA, Kleinerman RA, Parrish JA, Fitzpatrick TB. Risk of cutaneous carcinoma in patients treated with oral methoxsalen photochemotherapy for psoriasis. N Engl J Med. 1979;300(15):809-8138. 9. Stern RS, Laird N, Melski J, Parrish JA, Fitzpatrick TB, Bleich HL. Cutaneous squamous-cell carcinoma in patients treated with PUVA. N Engl J Med. 1984;310 (18):1156-1161. 10. Gladman DD, Farewell VT. Progression in psoriatic arthritis: role of time-varying clinical indicators. J Rheumatol. 1999;26(11):2409-2413. 11. The R project for statistical computing. http://www.r-project.org/. Accessed September 10, 2006. 12. Melski JW, Tanenbaum L, Parrish JA, Fitzpatrick TB, Bleich HL. Oral methoxsalen photochemotherapy for the treatment of psoriasis: a cooperative clinical trial. J Invest Dermatol. 1977;68(6):328-335. 13. Krueger G, Koo J, Lebwohl M, Menter A, Stern RS, Rolstad T. The impact of psoriasis on quality of life: results of a 1998 National Psoriasis Foundation patientmembership survey. Arch Dermatol. 2001;137(3):280-284. 14. Zaghloul SS, Goodfield MJ. Objective assessment of compliance with psoriasis treatment. Arch Dermatol. 2004;140(4):408-414. 15. Nijsten T, Margolis DJ, Feldman SR, Rolstad T, Stern RS. Traditional systemic treatments have not fully met the needs of psoriasis patients: results from a national survey. J Am Acad Dermatol. 2005;52(3, pt 1):434-444. 16. Housman TS, Rohrback JM, Fleischer AB Jr, Feldman SR. Phototherapy utilization for psoriasis is declining in the United States. J Am Acad Dermatol. 2002; 46(4):557-559. 17. Melski JW, Stern RS. The separation of susceptibility to psoriasis from age at onset. J Invest Dermatol. 1981;77(6):474-477. 18. Gudjonsson JE, Karason A, Runarsdottir EH, et al. Distinct clinical differences between HLA-Cw*0602 positive and negative psoriasis patients—an analysis of 1019 HLA-C– and HLA-B–typed patients. J Invest Dermatol. 2006;126(4):740745. 19. Henseler T, Christophers E. Psoriasis of early and late onset: characterization of two types of psoriasis vulgaris. J Am Acad Dermatol. 1985;13(3):450-456. 20. Gelfand JM, Neimann AL, Shin DB, Wang X, Margolis DJ, Troxel AB. Risk of myocardial infarction in patients with psoriasis. JAMA. 2006;296(14):1735-1741. 21. Naldi L, Svensson A, Diepgen T, et al. Randomized clinical trials for psoriasis 1977-2000: the EDEN survey. J Invest Dermatol. 2003;120(5):738-741. 22. Ashcroft DM, Wan Po AL, Williams HC, Griffiths CE. Clinical measures of disease severity and outcome in psoriasis: a critical appraisal of their quality. Br J Dermatol. 1999;141(2):185-191. 23. Feldman SR, Krueger GG. Psoriasis assessment tools in clinical trials. Ann Rheum Dis. 2005;64:ii65-ii68. ARCHIVES Feature Free color publication if color illustrations enhance the didactic value of the article. (REPRINTED) ARCH DERMATOL/ VOL 143 (NO. 9), SEP 2007 1121 WWW.ARCHDERMATOL.COM STUDY Clinical, Biochemical, and Genetic Study of 11 Patients With Erythropoietic Protoporphyria Including One With Homozygous Disease Carmen Herrero, MD, PhD; Jordi To-Figueras, PhD; Celia Badenas, PhD; Manuel Méndez, PhD; Patricia Serrano, MD; Rafael Enrı́quez-Salamanca, MD, PhD; Mario Lecha, MD, PhD Objective: To study the mutations in the ferrochelatase gene (FECH) and the phenotypic expression of erythropoietic protoporphyria (EPP) in a group of Spanish patients. Design: Case series. Setting: University-based hospital. Patients: Eleven unrelated patients with EPP and 19 asymptomatic relatives from 10 families. Main Outcomes Measures: Measurement of protoporphyrin concentration in red blood cells and feces by fluorometry and chromatography. Analysis of the mutations of the FECH gene by single-strand conformation analysis. Expression of mutations in Escherichia coli. Results: FECH gene mutations were found in all 11 patients. Ten were heterozygous and carried the IVS3-48C low-expression allele. Three novel mutations were found: IVS4⫹1delG, 347-351delC, and 130_147dupl 18. One patient did not present the IVS3-48C polymorphism and was found to harbor a novel A185T missense mutation in both alleles. The familial study confirmed a recessive mode of inheritance of the disease. The A185T mutation showed a residual activity 4% of normal when expressed in E coli. This patient presented cutaneous photosensitivity similar to the heterozygous cases, but a higher protoporphyrin accumulation in erythrocytes, microcytic anemia, and early signs of liver engagement. FECH mutations were found in 10 healthy relatives, none of whom carried the low-expression allele. The frequency of the IVS3-48C allele among 180 nonporphyric Spanish individuals was 5.2%. Conclusions: These findings confirm, among a group of Spanish patients, that most cases of EPP result from the coinheritance of IVS3-48C and a mutation in the FECH gene, and also document the existence of patients with mutations in homozygosity that may present a more severe form of the disease. Arch Dermatol. 2007;143(9):1125-1129 E Author Affiliations: Departments of Dermatology (Drs Herrero, Serrano, and Lecha) and Biochemistry and Molecular Genetics (Drs To-Figueras and Badenas), Hospital Clinic of Barcelona, University of Barcelona, IDIBAPS (Institut d’Investigacions Biomèdiques August Pi i Sunyer), Barcelona, Spain; and Centro de Investigación, Hospital 12 de Octubre, Madrid, Spain (Drs Méndez and Enrı́quez-Salamanca). RYTHROPOIETIC PROTOPORphyria (EPP) (Mendelian Inheritance in Man 177000) is an inherited disorder of porphyrin metabolism caused by a partial deficiency of ferrochelatase (FECH) (European Community 4.99.1.1), which catalyzes the insertion of iron into protoporphyrin IX to form heme. Patients with EPP accumulate free protoporphyrin mainly in erythropoietic tissues, but the metabolite may also reach the skin, absorb light at certain wavelengths, and generate free radicals, resulting in phototoxic cell injury. Most patients with EPP develop solely photosensitivity commencing in childhood, but in some cases liver complications also appear. The strong hydrophobic nature of the molecule does not allow renal clearance but only bile secretion. Therefore, massive hepatic accumulation of protoporphyrin in the liver may cause cholestasis and liver dam- (REPRINTED) ARCH DERMATOL/ VOL 143 (NO. 9), SEP 2007 1125 age in a minority of patients with EPP. Hepatic involvement may vary in severity, ranging from abnormalities in 20% of the cases to cirrhosis and liver failure in less than 5%.1-3 Blood disorders such as mild anemia with hypochromia and microcytosis may also be detected in 20% to 50% of these patients.2,4,5 See also pages 1153, 1194, and 1209 The FECH gene is assigned to chromosome 18q21.3 (GenBank No. D00726), with more than 110 different mutations having been described in EPP families to date.6 Individuals who are heterozygous for these mutations remain asymptomatic, despite having FECH activity reduced by about 50%. Clinical expression of the disease in most cases results from WWW.ARCHDERMATOL.COM the coinheritance of a null FECH allele plus a wild-type low-expressed allele, which further reduces FECH activity to below a critical threshold of about 35%.7 In a haplotype segregation analysis,8 it was found that the lowexpression allele is the C variant of an intronic singlenucleotide polymorphism (SNP) IVS3-48T/C in intron 3 of the FECH gene. Because the IVS3-48C allele is relatively common among European populations,6 overt EPP is normally inherited in such a way that it resembles an autosomal dominant disease with low clinical penetrance. Erythropoietic protoporphyria is rarely inherited as an autosomal recessive disease with true mutations in both alleles.9-12 In some areas of southern Europe, the prevalence of EPP and the genetic defects underlying the disease are not sufficiently elucidated. Therefore, we investigated the mutations in the FECH gene and the phenotypic expression of the disease in a series of Spanish patients with EPP. The molecular, biochemical, and clinical study included a rare case of recessive EPP. amplification are available from the authors. All polymerase chain reaction (PCR) analyses were carried out using the PCR Master Mix (Promega Corporation, Madison, Wisconsin) following the manufacturer’s instructions. The following PCR conditions were applied: initial denaturizing step (5 minutes at 95°C), 35 cycles (1 minute at 95°C, 1 minute at 57°C, and 1 minute at 72°C), followed by final extension (10 minutes at 72°C) and maintenance at 4°C until single-strand conformational polymorphism or sequencing studies were carried out. Part of intron 3 was sequenced in all samples to test for the IVS348T/C polymorphism. Single-strand conformation analysis was used to detect mutations. Three microliters of denatured PCR product was combined with loading buffer and loaded into GeneGel Excel 12.5 acrylamide gels (Amersham Biosciences, Uppsala, Sweden) and run following the manufacturer’s instructions. The different migrations were silver stained.19 DNA samples with abnormal migrations were sequenced. The PCR products were purified using the GFX PCR DNA and gel band purification kit (Amersham Biosciences) and automatically sequenced using the BigDye Terminator v3.1 Cycle Sequencing Kit (Applied Biosystems, Foster City, California) and an ABI3100 automatic sequencer (Applied Biosystems). METHODS PROKARYOTIC EXPRESSION OF MUTANT FECH PATIENTS We studied 11 unrelated patients (6 female and 5 male, with a mean age of 12.8 years [range, 4-26 years]) who attended the Department of Dermatology of the Hospital Clinic of Barcelona (Barcelona, Spain) for photosensitivity and suspicion of porphyria. The diagnosis of EPP was established initially by clinical and biochemical criteria and was later confirmed by DNA analysis of mutations in the FECH gene. A complete hematological and biochemical profile and specific liver function tests were performed in every case. In addition, 19 asymptomatic relatives from 8 families were also included in the genetic study. The study was conducted in accordance with the Declaration of Helsinki principles and was approved by the hospital ethics committee of the Hospital Clinic of Barcelona. Written consent was obtained from all patients. PORPHYRIN DETERMINATION Protoporphyrin concentration in erythrocytes was determined fluorometrically after solvent partition according to the method described elsewhere.13-15 Protoporphyrin in feces was extracted according to Lockwood et al16 and was analyzed by high-performance liquid chromatography according to Lim and Peters.17 Porphyrins in urine were analyzed by standard methods of high-performance liquid chromatography.17 LYMPHOCYTE FECH ENZYME ASSAY FECH activity in lymphocytes was determined by incubating a homogenate with zinc and mesoporphyrin and measuring zincmesoporphyrin formation by fluorometry according essentially to the method of Rossi et al,18 as modified by Gouya el al.6 FECH activity was expressed as nanomoles of zinc-mesoporphyrin formed per hour per milligram of protein at 37°C. DNA ANALYSIS We analyzed exons 1 to 11 of the FECH gene and the associated splice donor and acceptor sites. The primers used for exon Mature ferrochelatase was expressed in Escherichia coli strain JM109 (Promega Corporation) using the expression vector pKK223-3 (Pharmacia Biotech Inc, Piscataway, New Jersey). The wild-type human ferrochelatase complementary DNA (cDNA) was synthesized by PCR excluding the region encoding the mitochondrial leader sequence and including a new ATG start site of translation, and cloned into the EcoRI-HindIII sites of pKK223-3. This construct was designated pKK-FECH-wt. To generate the mutant construct pKK-FECH-A185T, a fragment of FECH cDNA, containing the A185T mutation was generated by PCR site-directed mutagenes20 using the pKKFECH-wt plasmid as templated. Then, the PCR product was digested with the restriction endonucleases MfeI and CveI (New England Biolabs, Beverly, Massachusetts) and the MfeI-CveI fragment was ligated as a cassette into the corresponding sites in pKKFECH-wt, and transformed in E coli strain JM109. The integrity of each expression construct was checked by automated sequencing. The primers are available from the authors. Bacterial clones, each of them containing one of the plasmids pKK223-3, pKK-FECH-wt, or pKK-FECH-A185T, were grown to log phase and were induced with 5mM isopropylthiogalactoside for 3 hours. Then, cells were harvested by centrifugation and washed twice in phosphate-buffered saline. The pellets were resuspended in 250 µL of lysis buffer (100mM Tris hydrochloride, pH 7.6; 0.1% Triton-X 100) and sonicated on ice. After centrifugation, ferrochelatase activity was measured in the supernatant using protoporphyrin IX and zinc sulfate as substrates, according to the method described by Camadro and Labbe.21 RESULTS CLINICAL CHARACTERISTICS The main clinical and biochemical outcomes of the patients with EPP are given in the Table. All presented acute cutaneous photosensitivity, with the symptoms beginning in early childhood in most cases. Only 3 cases presented with chronic skin thickening over the knuckles. Microcytic anemia was present in 4 cases. Liver func- (REPRINTED) ARCH DERMATOL/ VOL 143 (NO. 9), SEP 2007 1126 WWW.ARCHDERMATOL.COM Table. Major Clinical and Biochemical Features and FECH Genotypes in 11 Patients With EPP Patient No./ Sex/Age at First Symptoms, y 1/F/4 2/F/2 3/M/1 4/M/1 5/F/6 6/M/3 7/F/8 8/M/2 9/M/2 10/F/1 11/F/6 Hemoglobin, 12-17 g/dL MCV, 80-100 fL Liver Dysfunction Erythrocyte PP ⬍1.5 µmol/L Fecal PP ⬍100 nmol/g of Dried Feces FECH Mutation IVS3-48C/T SNP 11.5 11.1 13.7 13.4 12.0 12.6 11.8 12.3 12.5 11.7 12.4 73 75 80 79 87 75 79 83 81 76 79 Yes a No No No No No No No No No No 32 12 11 10 13 18 17 11 5 10 7 1066 ND 90 715 114 327 115 ND ND ND 186 A185T/A185T 757del5 IVS4 ⫹ 1delG 347-351delC 757del5 130_147dupl18 I186T H386P 843delC R115X P334L T/T C/T C/T C/T C/T C/T C/C C/T C/T C/T C/T Abbreviations: EPP, erythropoietic protoporphyria; MCV, medium corpuscular volume; ND, not done; PP, protoporphyrin; SNP, single-nucleotide polymorphism. SI conversion factor: To convert the hemoglobin to grams per liter, multiply by 10. aminotransferase, alanine aminotransferase, and ␥-glutamyltransferase levels greater than 40 U/L (to convert to microkatals per liter, multiply by 0.0167). a Aspartate tion test results were persistently normal in 10 cases, most with a long clinical follow-up (mean, 8.6 years; range 1-26 years). Only 1 case showed alterations in the liver function test results. The main characteristics of this patient are described in the “Report of a Case” subsection. MUTATIONS IN THE FECH GENE Ten different mutations in the FECH gene were found, thereby confirming the molecular heterogeneity of EPP (Table). Four novel mutations were found: 553G⬎A in exon 5 (A185T); IVS4⫹1delG and 347-351delC, both in exon 4; and 130_147dupl 18 in exon 1. The A185T mutation was homozygous, while the other mutations were heterozygous. Only the already described 575del5 mutation was present in 2 patients. Patients 7, 8, 9, and 10 (I186T, H386P, 843delC, and R115X, respectively) were previously studied by Gouya et al,22 but the status of the SNP of the allele trans to mutant allele was not determined in that study. All patients, except patient 1 who was homozygous for IVS348T/T, were heterozygous for IVS3-48C/T. PROKARYOTIC EXPRESSION OF GENE MUTATION The A185T mutation was expressed in E coli. FECH specific activity was determined in 4 independent experiments. The residual activity was calculated from the value of the normal FECH construct (pKK-FECH-wt) and was 4% of normal activity. FAMILIAL AND POPULATION ANALYSES Molecular analysis of 19 asymptomatic relatives from patients 1 through 6 and 8 through 10 were performed. This allowed the identification of 10 relatives who were carriers of heterozygous mutations. Inspection of the intron 3 SNP showed that none harbored the IVS3-48C allele. All of these relatives had normal values of protoporphyrin in blood. Analysis of 180 nonporphyric unrelated Spanish individuals showed that the IVS348C allele was present in 10.5% (allele frequency, 5.2 %). REPORT OF A CASE Patient 1 was a 15-year-old girl with microcytic anemia since she was 4 months old and photosensitive dermatitis since she was 4 years old. When she was 10 years old, alterations in liver function had been detected, with the persistence of microcytic anemia. She presented an itchy erythema and edema on the hands and face after sun exposure. On examination, pitted and linear scars on the nose, cheeks, and forehead and mild skin thickening over the knuckles were observed. There was no family history of photosensitivity and no apparent familial consanguinity. Results from porphyrin analyses included the following: erythrocyte protoporphyrin level, 32 µmol/L (reference value, ⬍ 1.5 µmol/L; ⬎90% free protoporphyrin); and fecal protoporphyrin level, 1066 nmol/g of dried feces (reference value, ⬍100 nmol/g), which allowed for the diagnosis of EPP. The excretion of coproporphyrins in urine was normal. Results from biochemical analysis included the following: aspartate transaminase level, 52 U/L (reference value, ⬍40 U/L), alanine aminotransferase level, 109 U/L (reference value, ⬍40 U/L), and ␥-glutamyltransferase level, 57 U/L (reference value, ⬍40 U/L) (to convert to microkatals per liter, multiply by 0.0167); hemoglobin level, 11.5 g/dL (reference range, 12.0-17.0 g/dL) (to convert to grams per liter, multiply by 10); median corpuscular volume, 73 fL (reference range, 80100 fL); median corpuscular hemoglobin concentration, 22.7 pg (26.7-33.3 pg); serum iron level, 59 µg/dL (reference range, 50-150 µg/dL) (to convert to micromoles per liter, multiply by 0.179); ferritin level, 28 ng/mL (reference range, 15-200 ng/mL) (to convert to picomoles per liter, multiply by 2.247); and soluble transferrin receptor level, −0.089 mg/dL (reference range, 0.083-0.176 mg/dL) (to convert to micromoles per liter, multiply by 0.0123). The appearance of the liver on echography was normal. A hepatic biopsy revealed normal liver (REPRINTED) ARCH DERMATOL/ VOL 143 (NO. 9), SEP 2007 1127 WWW.ARCHDERMATOL.COM architecture and the presence of brown material without birefringence at polarized light. Hemoglobin electrophoresis demonstrated normal percentages of hemoglobin A2 and F, and findings from DNA analysis excluded the thalassemia trait. Bone marrow examination showed normal percentages of the hematopoietic cell lineages with dysplasia signs in the erythroid cells. The bone marrow karyotype was 46,XX[20]. Findings from a molecular study of the DNA showed that this patient was apparently homozygous for a novel A185T missense mutation and homozygous for the T variant of the IVS3-48C/T polymorphism. The residual activity of the mutant FECH in E coli was 4% of normal activity. The FECH activity in peripheral lymphocytes was 0.4 nmol of zinc-mesoporphyrin per hour per milligram of protein at 37°C (reference value, mean±SD, 4.5±1). Two years later, the erythrocyte protoporphyrin level had increased to 77 µmol/L (fecal protoporphyrin level, 1221 nmol/g of dried feces). Familial investigation showed that both parents and a sister were heterozygous for the A185T mutation, and none harbored the low-expression IVS3-48C allele, thus confirming recessive EPP. All were asymptomatic and had an erythrocyte protoporphyrin concentration of less than 1.5 µmol/L. COMMENT We present the clinical, biochemical, and molecular characteristics of 11 cases of EPP and 19 asymptomatic relatives from 10 Spanish families. Among the series of patients with EPP, 1 had homozygous disease. Recessive inheritance of EPP, with patients presenting mutations in both alleles is rare. Only 13 cases (12 families) have been reported to date,6,9-12 most being compound heterozygotes. To our knowledge, the patient who was homozygous for an A185T mutation is the second case of true homozygous EPP, with the same mutation in both alleles confirmed by molecular analysis.12 The A185T mutation is located within the ␤3-strand of the enzyme and may produce a significant structural alteration owing to the replacement of a hydrophobic amino acid by a polar amino acid. Although the alanine residue at this position is not invariant among different species, it is conserved in mammals, yeast, and some prokaryotic species.23,24 Expression of the A185T allele revealed a low but still detectable residual activity of 4% in a crude bacterial extract. These data indicate that the mutation produces important structural and/or functional consequences in the FECH enzyme but is not completely deleterious. It has been suggested that recessive EPP forms may have a higher risk of liver failure than the more usual dominant forms.10 According to published reports, severe liver disease has been observed in 4 of 13 patients with recessive EPP detected to date.6,10,12 This is a high proportion, taking into account that liver failure appears in only in less than 5% of patients with EPP dominant forms.6,25 The determinants of liver injury in EPP are not well understood because genetic factors may modulate the accumulation of protoporphyrin in the liver.26 It is likely, however, that the amount of residual FECH activity in cells12,25 may play a key role in determining the course of the disease. Most of the missense mutations found in heterozygous EPP cases show a drastic reduction or even undetectable activity when expressed in prokaryotes.27-29 In contrast, in a report of recessive EPP, all the mutations retained a FECH residual activity ranging from 12% to 50% when expressed in E coli.12 This is in accordance with the general view that homozygous cases of porphyria must retain a substantial residual enzyme activity to be compatible with life. The A185T mutation, however, showed only 4% of the normal activity in E coli, thus suggesting a severe impairment in functionality. Consequently, even if this homozygous patient is free of cholestasis signs and the liver markers remain stable to date, the progression of the disease should be considered of risk and advocates close clinical follow-up. Except for the recessive case, all the other patients in our study showed mutations in heterozygosity within the FECH gene. Some of the new mutations can also cause severe impairment in enzyme activity. The c.351delC mutation is a single C deletion from a stretch of 5 C that causes a frameshift and introduces a premature termination codon of translation in exon 4. As a consequence, we can predict the rapid degradation of the mutant transcript due to nonsense-mediated messenger RNA decay.30,31 The c.130_147dupl 18 mutation does not result in a frameshift, but its location within the mitochondrial leader sequence could result in a defective targeting to mitochondria or a deficient processing of the polypeptide. The novel splicing defect IVS4⫹1delG affects the consensus donor splice site of intron 4.32 Unfortunately, RNA from this patient was not available for analysis. Nonetheless, this mutation probably results in exon 4 skipping, as was observed in a previously reported mutation (IVS4⫹ 1G⬎C) in this donor site.27 All heterozygous cases presented the low-expression IVS3-48C allele, thereby confirming the common view that clinically overt EPP is associated with inheritance of this allele in trans to a severe FECH mutation.6,12,33,34 The study of the relatives yielded additional confirmation of the importance of this polymorphism in EPP, since all asymptomatic carriers had the IVS3-48T/T genotype. Familial investigation of patient 1 showed that several relatives harbored the A185T mutation, but none had the IVS3-48C allele. Therefore, the phenotype of a hypothetical carrier of the A185T mutation with the lowexpression allele in trans remains unknown. In conclusion, among our series of Spanish patients with EPP, we have found 10 cases with coinheritance of 1 FECH gene mutation with IVS3-48C and 1 rare case with a severe homozygous mutation with very low residual activity. This patient presented a cutaneous photosensitivity similar to the heterozygous cases but had a higher protoporphyrin accumulation, pronounced microcytic anemia, and early signs of liver involvement. These findings emphasize the need for further research on the genotypicphenotypic relationships in porphyria. Accepted for Publication: January 26, 2007. Correspondence: Jordi To-Figueras, PhD, Department (REPRINTED) ARCH DERMATOL/ VOL 143 (NO. 9), SEP 2007 1128 WWW.ARCHDERMATOL.COM of Biochemistry and Molecular Genetics, Villarroel 170, Hospital Clinic Barcelona, 08036 Barcelona, Spain (JTO @clinic.ub.es). Author Contributions: Drs To-Figueras and Carmen Herrero had full access to all the data and take full responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Herrero, ToFigueras, Méndez, Enrı́quez-Salamanca, and Lecha. Acquisition of data: Herrero, To-Figueras, Badenas, Méndez, and Serrano. Analysis and interpretation of data: Herrero, To-Figueras, and Méndez. Drafting of the manuscript: Herrero, To-Figueras, Méndez, and Serrano. Critical revision of the manuscript for important intellectual content: Badenas, Enrı́quez-Salamanca, and Lecha. Obtained funding: Herrero and To-Figueras. Administrative, technical, and material support: Badenas. Study supervision: Méndez, Enrı́quez-Salamanca, and Lecha. Financial Disclosure: None reported. Funding/Support: This study was supported in part by grants from “Fondo de Investigación Sanitaria” (03/ 0489) and “Fundación Mutua Madrileña.” Both are nonprofit organizations that supported the Universitybased research as a contribution to health progress. Role of the Sponsors: The sponsors did not participate in the conduction of the study; collection, management, analysis, interpretation of the data; or preparation, review, or approval of the manuscript. Additional Contributions: We appreciate the participation of the family members in this study. M. Bruguera, MD, provided help in the control of hepatic disease, J. M, Mascaró, MD, collaborated in the recruitment of patients, and M. Sala provided technical assistance. REFERENCES 1. Nordmann Y. Erythropoietic protoporphyria and hepatic complications. J Hepatol. 1992;16(1-2):4-6. 2. Todd DJ. Erythropoietic protoporphyria. Br J Dermatol. 1994;131(6):751-766. 3. Meerman L. Erythropoietic protoporphyria: an overview with emphasis on the liver. Scand J Gastroenterol Suppl. 2000;(232):79-85. 4. DeLeo VA, Poh-Fitzpatrick M, Mathews-Roth M, Harber LC. Erythropoietic protoporphyria: 10 years experience. Am J Med. 1976;60(1):8-22. 5. Thunell S, Harper P, Brun A. Porphyrins, porphyrin metabolism and porphyrias, IV: pathophysiology of erythyropoietic protoporphyria—diagnosis, care and monitoring of the patient. Scand J Clin Lab Invest. 2000;60(7):581-604. 6. Gouya L, Martin-Schmitt C, Robreau AM, et al. Contribution of a common singlenucleotide polymorphism to the genetic predisposition for erythropoietic protoporphyria. Am J Hum Genet. 2006;78(1):2-14. 7. Gouya L, Puy H, Lamoril J, et al. Inheritance in erythropoietic protoporphyria: a common wild-type ferrochelatase allelic variant with low expresión accounts for clinical manifestation. Blood. 1999;93(6):2105-2110. 8. Gouya L, Puy H, Robreau AM, et al. The penetrance of dominant erythropoietic protoporphyria is modulated by expression of wildtype FECH. Nat Genet. 2002; 30(1):27-28. 9. Lamoril J, Boulechfar S, Verneuil H, Grandchamp B, Nordmann Y, Deybach J-Ch. Human erythropoietic protoporphyria: two point mutations in the ferrochelatase gene. Biochem Biophys Res Commun. 1991;181(2):594-599. 10. Sarkany RP, Alexander GJ, Cox TM. Recessive inheritance of erythropoietic protoporphyria with liver failure. Lancet. 1994;343(8910):1394-1396. 11. Poh-Fitzpatrick MB, Wang X, Anderson KE, Bloomer JR, Bolwell B, Lichtin AE. Erythropoietic protoporphyria: altered phenotype after bone marrow transplantation for myelogenous leukemia in a patient heteroallelic for ferrochelatase gene mutations. J Am Acad Dermatol. 2002;46(6):861-866. 12. Whatley SD, Mason NG, Khan M, et al. Autosomal recessive erythropoietic protoporphyria in the United Kingdom: prevalence and relationship to liver disease. J Med Genet. 2004;41(8):e105. 13. Piomelli S. Free erythrocyte porphyrin in the detection of undue absorption of lead and iron deficiency. Clin Chem. 1977;23(2, pt 1):264-269. 14. Blake D, Poulos V, Rossi R. Diagnosis of porphyria—recommended methods for peripheral laboratories. Clin Biochem Rev. 1992;13(suppl 1):S1-S24. 15. Deacon AC, Elder GH. ACP Best Practice No 165: front line tests for the investigation of suspected porphyria. J Clin Pathol. 2001;54(7):500-507. 16. Lockwood WH, Poulos V, Rossi E, Curnow DH. Rapid procedure for fecal porphyrin assay. Clin Chem. 1985;31(7):1163-1167. 17. Lim CK, Peters TJ. Urine and faecal porphyrin profiles by reversed-phase highperformance liquid chromatography in the porphyrias Clin Chim Acta. 1984; 139(1):55-63. 18. Rossi E, Costin KA, Garcia-Webb P. Ferrochelatase activity in human lymphocytes, as quantified by a new high-performance liquid-chromatographic method. Clin Chem. 1988;34(12):2481-2485. 19. Badenas C, Torra R, Lucero L, Milà M, Estivill X, Darnell A. Mutational analysis within the 3⬘ region of the PKD1 gene. Kidney Int. 1999;55(4):1225-1233. 20. Cormack B. Mutagenesis by the polymerase chain reaction. In: Ausubel FM, Brent R, Kingston RE, et al, eds. Current Protocols in Molecular Biology. New York, NY: Wiley & Sons, Inc; 1991:8.5.1-8.5.9. 21. Camadro JM, Labbe P. Purification and properties of ferrochelatase from yeast Saccharomyces cerevisiae: evidence for a precursor from of the protein. J Biol Chem. 1988;263(24):11675-11682. 22. Gouya L, Schneider-Yin X, Rüfenacht U, et al. Mutations in the ferrochelatase gene of four Spanish patients with erythropoietic protoporphyria. J Invest Dermatol. 1998;111(3):406-409. 23. Dailey HA, Sellers VM, Dailey TA. Mammalian ferrochelatase: expression and characterization of normal and two human protoporphyric ferrochelatases. J Biol Chem. 1994;269(1):390-395. 24. Dailey TA, Dailey HA. Identification of [2Fe-2S] clusters in microbial ferrochelatases. J Bacteriol. 2002;184(9):2460-2464. 25. Chen FP, Risheg H, Liu Y, Bloomer J. Ferrochelatase gene mutations in erythropoietic protoporphyria: focus on liver disease. Cell Mol Biol (Noisy-le-grand). 2002;48(1):83-89. 26. Abitbol M, Bernex F, Puy H, et al. A mouse model provides evidence that genetic background modulates anemia and liver injury in erythropoietic protoporphyria. Am J Physiol Gastrointest Liver Physiol. 2005;288(6):G1208-G1216. 27. Rüfenacht UB, Gouya L, Scheneider-Yin X, et al. Systematic analysis of molecular defects in the ferrochelatase gene from patients with erythropoietic protoporphyria. Am J Hum Genet. 1998;62(6):1341-1352. 28. Schneider-Yin X, Gouya L, Dorsey M, Rufenacht U, Deybach J-C, Ferreira GC. Mutations in the iron-sulfur cluster ligands of the human ferrochelatase gene lead to erythropoietic protoporphyria. Blood. 2000;96(4):1545-1549. 29. Rüfenacht UB, Gregor A, Gouya L, Tarcznska-Nosal S, Schneider-Yin X, Deybach J-C. New missense mutation in the human ferrochelatase gene in a family with erythropoietic protoporphyria: functional studies and correlation of genotype and phenotype. Clin Chem. 2001;47(6):1112-1113. 30. Maquat LE. Defects in RNA splicing and the consequence of shortened translational reading frames. Am J Hum Genet. 1996;59(2):279-286. 31. Hentze MW, Kulozik AE. A perfect message: RNA surveillance and nonsensemediated decay. Cell. 1999;96(3):307-310. 32. Shapiro MB, Senepathy P. RNA splice junctions of different classes of eukaryotes: sequence statistics and functional implications in gene expression. Nucleic Acids Res. 1987;15(17):7155-7174. 33. Risheg H, Fu-Ping Ch, Bloomer JR. Genotypic determinants of phenotype in North American patients with erythropoietic protoporphyria. Mol Genet Metab. 2003; 80(1-2):196-206. 34. Wiman A, Flodeurs Y, Harper P. Novel mutations and phenotypic effect of the splice site modulator IVS3-48C in nine Swedish families with erythropoietic protoporphyria. J Hum Genet. 2003;48(2):70-76. (REPRINTED) ARCH DERMATOL/ VOL 143 (NO. 9), SEP 2007 1129 WWW.ARCHDERMATOL.COM STUDY Five-Year Follow-up of a Randomized, Prospective Trial of Topical Methyl Aminolevulinate Photodynamic Therapy vs Surgery for Nodular Basal Cell Carcinoma Lesley E. Rhodes, MD, FRCP; Menno A. de Rie, MD; Ragna Leifsdottir, MD; Raymond C. Yu, MD, FRCP; Ingeborg Bachmann, MD; Victoria Goulden, MD, FRCP; Gavin A. E. Wong, MRCP; Marie-Aleth Richard, MD; Alex Anstey, MD, FRCP; Peter Wolf, MD Objective: To compare 5-year lesion recurrence rates in primary nodular basal cell carcinoma treated with topical methyl aminolevulinate photodynamic therapy (PDT) or simple excision surgery. Design: Prospective, randomized, multicenter study. Setting: University hospital dermatology departments. Patients: A total of 97 patients, 50 with 53 lesions treated with methyl aminolevulinate PDT and 47 with 52 lesions treated by excision surgery, were included in the per protocol analysis. Of the lesions treated with methyl aminolevulinate PDT and surgery, 49 and 52, respectively, showed complete clinical response at 3 months after treatment and were observed for long-term outcome evaluation. Interventions: Topical methyl aminolevulinate cream, 160 mg/g, applied for 3 hours before illumination (75 J/cm2 of red light at 570 to 670 nm) on 2 or 4 occasions (12 [23%] of 53 lesions); or excision surgery. Main Outcome Measures: Histologically confirmed lesion recurrence, sustained lesion complete response rate T Author Affiliations are listed at the end of this article. (time-to-event analysis), and investigator assessment of cosmetic outcome, 5 years after the last treatment. Results: At 5 years, recurrence was documented in 7 (14%) of 49 lesions (95% confidence interval [CI], 6%27%) treated with methyl aminolevulinate PDT vs 2 (4%) of 52 lesions (95% CI, 1%-13%) treated with excision surgery (P = .09). Estimated sustained lesion complete response rates were 76% (95% CI, 59%-87%) and 96% (95% CI, 84%-99%), respectively (P=.01). More patients treated with methyl aminolevulinate PDT than surgery had an excellent or good cosmetic outcome: 27 (87%) of 31 patients (95% CI, 70%-96%) vs 19 (54%) of 35 patients (95% CI, 37%-71%) (P=.007). Conclusions: Long-term follow-up indicates superior efficacy of surgery to methyl aminolevulinate PDT in nodular basal cell carcinoma. However, methyl aminolevulinate PDT is also an effective treatment for this indication and exhibits a more favorable cosmetic outcome. Arch Dermatol. 2007;143(9):1131-1136 OPICAL PHOTODYNAMIC therapy (PDT) is an attractive modality for the treatment of basal cell carcinoma (BCC), based on its generally favorable efficacy and adverse effect profile and its excellent cosmetic outcome. Moreover, because PDT is a noninvasive procedure causing minimal damage to surrounding tissue, it offers advantages over excision surgery, particularly for the treatment of lesions in cosmetically sensitive areas, such as the face.1-3 However, long-term follow-up data of controlled clinical trials of topical PDT vs excision surgery (regarded as the treatment of choice for nodular BCC)4,5 are lacking. We performed a prospective, randomized, multicenter study of simple excision surgery vs topical PDT, using methyl ami- (REPRINTED) ARCH DERMATOL/ VOL 143 (NO. 9), SEP 2007 1131 nolevulinate, a drug showing highly selective uptake by malignant cells,6 in the treatment of primary nodular BCC. Initial data covering a 2-year follow-up demonstrated that methyl aminolevulinate PDT was an effective treatment for nodular BCC. Clearance rates of 93% (vs 100% for excision surgery) were seen after 3 months and 85% (vs 98% for excision surgery) after 12 months, with no significant difference between treatment groups. Methyl aminolevulinate PDT also gave a significant superior cosmetic outcome compared with excision surgery at 3, 12, and 24 months.7 At 24 months, 5 lesions that initially cleared with methyl aminolevulinate PDT had recurred, compared with 1 after surgery. The potential for lesion recurrence following PDT is an issue of clinical concern, particularly in the treatment of deeper WWW.ARCHDERMATOL.COM 101 Patients randomized and treated 52 In the methyl aminolevulinate PDT group (ITT population) 49 In the surgery group (ITT population) 2 Not included 1 Protocol violation 1 Discontinued because of an adverse event 2 Not included 1 Discontinued because of an adverse event 1 Withdrew consent 50 Patients in the PP population 47 Patients in the PP population 19 Not included 10 Experienced treatment failure (all lesions) 6 Discontinued because of an adverse event 1 Withdrew consent 2 Were lost to follow-up 12 Not included 2 Experienced treatment failure (all lesions) 4 Discontinued because of an adverse event 4 Withdrew consent 2 Were lost to follow-up 31 Patients completed the 5-y follow-up 35 Patients completed the 5-y follow-up Figure 1. Disposition of patients 5 years after the last treatment. The protocol violation in the methyl aminolevulinate group was also a treatment failure (all lesions). ITT indicates intention-to-treat; PDT, photodynamic therapy; and PP, per protocol. (nodular) BCC. Nearly two-thirds of all recurrent BCC lesions appear in the first 3 years after treatment, with 18% appearing between 5 and 10 years posttreatment.8 We therefore performed a 5-year follow-up to examine the sustained complete lesion response and recurrence rate over time for methyl aminolevulinate PDT vs excision surgery in patients with nodular BCC. METHODS European university hospital dermatology departments participated in a prospective, randomized study of methyl aminolevulinate PDT vs simple excision surgery in patients with nodular BCC. The study design and procedures have been detailed in a prior report.7 Patients aged at least 18 years with previously untreated primary nodular BCC, suitable for simple excision surgery, were enrolled from the clinics of participating centers. The diagnosis of nodular BCC was confirmed by histological examination. Patients with more than 10 eligible lesions; lesions in the midface region, orbital areas, and ears; lesions with a longest diameter of less than 6 mm or more than 15 mm (face or scalp), more than 20 mm (extremities or neck), or more than 30 mm (trunk); and pigmented or morpheaform BCCs were excluded. Patients were enrolled from October 26, 1999, to August 29, 2000, and were followed up until October 12, 2005. All patients gave written informed consent before enrollment. The study was performed in accordance with the Declaration of Helsinki, with ethical approval obtained from the local ethics committee of each of the participating centers. Eligible patients were randomized to treatment with PDT using methyl aminolevulinate cream, 160 mg/g (Metvix; PhotoCure ASA, Oslo, Norway, and Galderma, Sophia Antipolis, France), or excision surgery.7 In the PDT group, lesion surface preparation was performed in a standardized manner between centers, before application of methyl aminolevulinate cream. Surface scale or crust was gently removed with a curette or scalpel blade, without anesthesia, insufficient to cause pain or bleeding. An occlusive and light-shielding dressing was applied, and after 3 hours, the area was illuminated with noncoherent red light (wavelength, 570670 nm; total fluence, 75 J/cm2; and fluence rate, 50-200 mW/ cm2). Patients in the PDT group were treated with either 1 or 2 PDT cycles, each composed of 2 PDT sessions, with an interval of 1 week between sessions. Simple elliptical excision surgery with at least 5-mm margins was performed once under local anesthesia in accordance with the usual practice of the center. Patients with a complete response at 3 months after the last treatment (ie, complete disappearance of the lesion as evaluated on clinical inspection by the same investigator [M.A.R., V.G., G.A.E.W., or P.W.]) were followed up at yearly intervals for 5 years after the last treatment. Any clinically suspected recurrence was confirmed by histological examination. Investigatorassessed cosmetic outcome was judged yearly for up to 5 years in all patients with a complete response in all lesions, using a 4-point scale7 as follows: (1) excellent: no scarring, atrophy, or induration and slight or no redness or change in pigmentation compared with adjacent skin; (2) good: no scarring, atrophy, or induration and moderate redness or increase in pigmentation compared with adjacent skin; (3) fair: slight to moderate occurrence of scarring, atrophy, or induration; and (4) poor: extensive occurrence of scarring, atrophy, or induration. Details of adverse events, including local phototoxicity reactions reported up to 3 months after last treatment, have been provided.7 During the 5-year follow-up, any adverse events that led to discontinuation were documented. The primary statistical analysis was based on the per protocol (PP) population, including all eligible patients who completed surgery or the first PDT treatment cycle and had a response assessment at 3 months or who completed the second PDT treatment cycle and received treatment in accordance with the study procedures. In addition, an intention-to-treat analysis was performed. The analysis populations (intention-totreat and PP groups) were almost identical and gave similar results in all aspects. Two patients in each treatment group (4 of 101) were excluded from the PP population. The present study therefore focuses on the population of primary interest (ie, the PP population). Analyses were performed independently (PAREXEL International GmbH, Berlin, Germany) using SAS statistical software (SAS Institute Inc, Cary, North Carolina). Of primary interest during long-term follow-up was the histologically confirmed lesion recurrence rate. Lesion recurrence rates were the proportion of recurrent lesions, of all lesions that (REPRINTED) ARCH DERMATOL/ VOL 143 (NO. 9), SEP 2007 1132 WWW.ARCHDERMATOL.COM Table 1. Baseline Characteristics of Lesions in the PP Population a Methyl Aminolevulinate PDT Group (n = 53) Surgery Group (n = 52) 21 (40) 27 (51) 5 (9) 32 (62) 15 (29) 5 (10) 29 (55) 19 (36) 2 (4) 34 (65) 14 (27) 3 (6) Lesion location Face or scalp Trunk or neck Extremities Longest lesion diameter, mm b ⱕ 10 ⬎ 10 and ⬍20 ⱖ 20 Abbreviations: PDT, photodynamic therapy; PP, per protocol. a Data are given as number (percentage) of lesions for each group. Percentages may not total 100 because of rounding or because of missing data. b Data are missing for 3 patients in the methyl aminolevulinate PDT group and 1 in the surgery group. had a clinical complete response 3 months after treatment. They were presented with 95% confidence intervals (CIs), and the treatment difference was tested with the Fisher exact test. A time-to-event approach was used to estimate lesion complete response rates over time, using all available information and keeping the original sample size and randomization scheme. The event of interest was failure, defined as nonresponse at 3 months after the last treatment or recurrence at the follow-up intervals of 1, 2, 3, 4, or 5 years. Censoring occurred when a patient with a lesion in complete response discontinued for reasons other than treatment failure. Discontinuations or recurrences were only recorded at the yearly follow-up. Thus, the exact time when the event occurred was unknown. Furthermore, some patients had more than 1 lesion. The lesions formed clusters within these patients and therefore could no longer be regarded as independent observations. The interval censoring and the lesion clusters made the data unsuitable for standard procedures, such as the Kaplan-Meier or the life-table approach. Instead, a complementary log-log model suggested by Guo and Lin9 was used. In a first step, a logistic regression using the complementary log-log link function was run with standard software (PROC LOGISTIC; SAS Institute Inc). In a second step, the standard errors of the estimates were adjusted for the dependencies in the data caused by the lesion clusters, as described using computer software (IML; SAS Institute Inc). Recurrence rates could not be derived from the time-toevent model because the failure rates were a combination of nonresponse rates at 3 months after the last treatment and recurrence rates during later follow-ups. The proportions of patients categorized with excellent or good overall cosmetic outcome were summarized with 2-sided 95% CIs. The treatment difference was tested with the Fisher exact test using the categories of excellent or good vs fair or poor. RESULTS Of 103 randomized patients, 101 were treated in the study, 52 with methyl aminolevulinate PDT and 49 with surgery. The PP population comprised 97 patients, 50 with 53 lesions treated with methyl aminolevulinate PDT and 47 with 52 lesions treated with excision surgery (Figure 1). Four patients were excluded from the PP population, 1 in the methyl aminolevulinate PDT group with a major protocol violation (received a light dose less Lesion CR Rate (Complementary Log-Log Model) Characteristic 100 75 50 25 Surgery group Methyl aminolevulinate PDT group 0 12 24 36 48 60 Time, mo Figure 2. Lesion complete response (CR) over time (time-to-event analysis) for the per protocol population. PDT indicates photodynamic therapy. than that stipulated) and 3 for whom response at 3 months could not be assessed (in the surgery group, 1 died and 1 withdrew consent; and in the methyl aminolevulinate PDT group, 1 discontinued the study prematurely because of treatment-related pain). Forty-nine lesions in 46 patients treated with methyl aminolevulinate PDT and 52 lesions in 47 patients treated with excision surgery showed complete lesion response at 3 months and were included in the long-term follow-up. Sixty-six patients, 31 treated with methyl aminolevulinate PDT and 35 treated with surgery, completed the 5-year follow-up evaluation with at least 1 lesion in complete response. Twelve patients, 10 treated with methyl aminolevulinate PDT and 2 treated with surgery, discontinued the study before the 5-year follow-up evaluation, with treatment failure in all lesions (Figure 1). Only 4 patients (2 in each treatment group) were truly lost to follow-up during the 5-year period. Eight patients (4 in each group) died during the follow-up, and 2 discontinued because of intercurrent disease. The baseline characteristics of the 2 groups were similar.7 The mean (range) age was 69 (40-95) years in the methyl aminolevulinate PDT group and 67 (38-82) years in the surgery group; there were 32 men and 20 women in the methyl aminolevulinate PDT group and 29 men and 20 women in the surgery group. Most patients in each group had 1 lesion (94% [47 of 50 patients] in the methyl aminolevulinate PDT group and 89% [42 of 47 patients] in the surgery group). In each group, most lesions were less than 20 mm in diameter and were located on the face or scalp or trunk or neck (Table 1). However, the distribution of these lesions differed between the 2 groups. In the surgery group, there were more lesions on the face or scalp than on the trunk or neck, whereas in the methyl aminolevulinate PDT group, the distribution of lesions to these areas was similar (Table 1). Most lesions in the methyl aminolevulinate PDT group were treated with 1 PDT cycle (41 of 53 lesions [77%]). LESION RESPONSE AND RECURRENCE A time-to-event analysis of lesion response over time showed that excision surgery was more favorable than methyl aminolevulinate PDT (Figure 2). At 5 years af- (REPRINTED) ARCH DERMATOL/ VOL 143 (NO. 9), SEP 2007 1133 WWW.ARCHDERMATOL.COM Table 2. Lesion Complete Response and Recurrence Rates in the Per Protocol Population Interval After Last Treatment, y Variable 1 Missing, No. (%) Lesion recurrence (n = 49) No. of lesions Proportion (95% CI) of lesions, % Lesion size, mm d ⱕ 10 ⬎ 10 and ⬍20 Missing, No. (%) Lesion recurrence (n = 52) No. of lesions Proportion (95% CI) of lesions, % Lesion size, mm d ⱕ 10 ⬎ 10 and ⬍20 2 3 Methyl Aminolevulinate PDT Group a,b 2 (4) 9 (18) 9 (18) 4 5 10 (20) 10 (20) 2 4 (1-14) 5 10 (3-22) 7 14 (6-27) 7 14 (6-27) 7 14 (6-27) c 1 1 4 1 5 2 5 2 5 2 7 (13) 10 (19) 11 (21) 1 (2) Surgery Group b,e 3 (6) 0 0 (0-100) 0 0 (0-100) 1 2 (0-10) 2 4 (1-13) 2 4 (1-13) c 0 0 0 0 0 1 0 2 0 2 Abbreviations: CI, confidence interval; PDT, photodynamic therapy. a Complete response at 3 months occurred in 49 of 53 lesions (92%) (95% confidence interval, 82%-98%). b P = .12 for the treatment difference at 3 months in lesion response rate. c P = .09 for the treatment difference at 5 years in lesion recurrence rate. d There were no 20-mm or larger lesions in either group. e Complete response at 3 months occurred in 52 of 52 lesions (100%) (95% confidence interval, 93%-100%). A B Figure 3. The appearance of the nodular basal cell carcinoma in a study participant in the photodynamic therapy group (a 72-year-old woman) at baseline (A) and at 5 years, showing an excellent cosmetic outcome and complete lesion response (B). In A and B, the inset shows a close-up. ter last treatment, the sustained lesion complete response rate, estimated by the complementary log-log model, was 76% (95% CI, 59%-87%) for methyl aminolevulinate PDT compared with 96% (95% CI, 84%99%) for excision surgery in the PP population (P =.01). Lesion recurrence was documented in 14% of lesions with complete response after 3 months treated with methyl aminolevulinate PDT, compared with 4% of lesions treated with excision surgery (P =.09) (Table 2). The methyl aminolevulinate PDT group recurrences included 5 of 40 lesions given 1 treatment cycle and 2 of 9 lesions given 2 treatment cycles. No recurrences in the methyl aminolevulinate PDT group were observed from 3 to 5 years, and only 1 lesion treated with excision surgery recurred (REPRINTED) ARCH DERMATOL/ VOL 143 (NO. 9), SEP 2007 1134 WWW.ARCHDERMATOL.COM within this period. In the methyl aminolevulinate PDT group, there was no evidence that lesion recurrence was higher in larger lesions because recurrence was documented in 5 lesions with a maximum diameter of up to 10 mm and in 2 lesions with a diameter between 11 and 20 mm (Table 2). Recurrence rates at 5 years were identical in the intention-to-treat population. COSMETIC OUTCOME In the PP population, outcome at 3 months rated as excellent or good was found in 36 of 44 patients (82%) (95% CI, 67%-92%) in the methyl aminolevulinate PDT group vs 15 of 45 patients (33%) (95% CI, 20%-49%) in the surgery group (P⬍.001). The overall cosmetic outcome 5 years after last treatment was also superior with methyl aminolevulinate PDT compared with excision surgery. At final assessment, outcome as rated by the investigators [L.E.R., M.A.R., R.L., R.C.Y., I.B., V.G., M.-A.R., A.A., and P.W.]was good or excellent in 27 of 31 patients (87%) (95% CI, 70%-96%) treated with methyl aminolevulinate PDT compared with 19 of 35 patients (54%) (95% CI, 37%71%) treated with excision surgery (P=.007) (Figure 3). COMMENT Findings from this long-term follow-up study add to evidence supporting a role for methyl aminolevulinate PDT in the treatment of primary nodular BCC. The cumulative 5-year lesion recurrence rate with methyl aminolevulinate PDT was 14% compared with 4% for excision surgery, the latter being consistent with the published low rate for this modality.8,10,11 We anticipate that we have captured all relevant events and that a longer than 5-year follow-up would be unlikely to yield further recurrences because only 2 recurrent lesions were observed in the methyl aminolevulinate PDT group and 1 in the surgical group between 2 and 3 years’ follow-up. There were no recurrent lesions observed in the methyl aminolevulinate PDT group and only 1 in the surgical group from 3 to 5 years’ follow-up. While the sustained lesion complete response rate at 5 years was statistically superior with excision surgery compared with methyl aminolevulinate PDT (96% vs 76%; P=.01), lesions treated with methyl aminolevulinate PDT showed a substantially better cosmetic outcome at 5 years, as assessed by the investigator, than those treated with surgery (P = .007). Thus, the results of our study indicate that, whereas simple excision surgery will generally remain the treatment of choice for nodular BCC amenable to this intervention, methyl aminolevulinate PDT is also an effective treatment. There are a number of instances (eg, when there are multiple lesions; when there are lesions in sites such as the lower leg, where there is poor healing; and when there are patients undergoing anticoagulation) in which excision can be challenging. Moreover, methyl aminolevulinate PDT may be more suitable for the treatment of lesions in cosmetically sensitive areas, such as the face (involving approximately 50% of lesions in the present study), where optimal cosmetic outcome is an important clinical consideration. Systematic reviews4,5,8,11 of treatment modalities for BCC highlight the lack of published long-term follow-up data from controlled clinical trials and advocate evaluation of 5-year lesion recurrence rates as a primary outcome in clinical studies. The lack of long-term data from randomized PDT studies has been a particular concern among dermatologists.12 To our knowledge, we present the first randomized study to report cumulative 5-year recurrence rates in nodular BCC comparing topical PDT with the standard treatment of excision surgery. We conclude that the moderately low 5-year lesion recurrence rate with methyl aminolevulinate PDT documented in this study, together with the favorable long-term cosmetic outcome, supports a clinical role for this modality in the treatment of nodular BCC, particularly when avoidance of scarring is a priority. Accepted for Publication: April 4, 2007. Author Affiliations: Photobiology Unit, Departments of Dermatology, University of Manchester and Salford Royal Foundation Hospital, Manchester (Dr Rhodes), University College Hospital, London (Dr Yu), Leeds General Infirmary, Leeds (Dr Goulden), and Royal Liverpool University Hospital, Liverpool (Dr Wong), England; Academic Medical Centre, Amsterdam, the Netherlands (Dr de Rie); Norra Älvsborgs Länssjukhus, Trollhättan, Sweden (Dr Leifsdottir); Haukeland Hospital, Bergen, Norway (Dr Bachmann); Hôpital Sainte-Marguerite, Marseille, France (Dr Richard); University Hospital of Wales, Cardiff (Dr Anstey); and Medical University Graz, Graz, Austria (Dr Wolf). Correspondence: Lesley E. Rhodes, MD, FRCP, Photobiology Unit, Department of Dermatology, University of Manchester, Salford Royal Foundation Hospital, Manchester M6 8HD, England (lesley.e.rhodes@manchester.ac .uk). Author Contributions: Dr Rhodes had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Rhodes, de Rie, Goulden, and Wong. Acquisition of data: Rhodes, de Rie, Leifsdottir, Yu, Bachmann, Goulden, Wong, Richard, Anstey, and Wolf. Analysis and interpretation of data: Rhodes, de Rie, Yu, Anstey, and Wolf. Drafting of the manuscript: Rhodes, Yu, and Richard. Critical revision of the manuscript for important intellectual content: Rhodes, de Rie, Leifsdottir, Yu, Bachmann, Goulden, Wong, Richard, Anstey, and Wolf. Statistical analysis: Rhodes. Obtained funding: Rhodes. Administrative, technical, and material support: Rhodes, de Rie, Yu, Richard, Anstey, and Wolf. Study supervision: Rhodes, Yu, and Wolf. Financial Disclosure: None reported. Funding/Support: This study received financial support from Photocure ASA. Role of the Sponsor: Photocure ASA assisted in the design and conduct of the study, performed the data collection, and assisted in the preparation of the manuscript. Additional Contributions: Parexel GmbH, Berlin, Germany, performed the data analysis. (REPRINTED) ARCH DERMATOL/ VOL 143 (NO. 9), SEP 2007 1135 WWW.ARCHDERMATOL.COM REFERENCES 7. 1. Horn M, Wolf P, Wulf HC, et al. Topical methyl aminolaevulinate photodynamic therapy in patients with basal cell carcinoma prone to complications and poor cosmetic outcome with conventional treatment. Br J Dermatol. 2003;149(6): 1242-1249. 2. Vinciullo C, Elliott T, Francis D, et al. Photodynamic therapy with topical methyl aminolaevulinate for “difficult-to-treat” basal cell carcinoma. Br J Dermatol. 2005; 152(4):765-772. 3. Szeimies RM, Morton CA, Sidoroff A, Braathen LR. Photodynamic therapy for non-melanoma skin cancer. Acta Derm Venereol. 2005;85(6):483-490. 4. Thissen MRTM, Neumann MHA, Schouten LJ. A systematic review of treatment modalities for primary basal cell carcinomas. Arch Dermatol. 1999;135(10): 1177-1183. 5. Telfer NR, Colver GB, Bowers PW. Guidelines for the management of basal cell carcinoma. Br J Dermatol. 1999;141(3):415-423. 6. Angell-Petersen E, Sørensen R, Warloe T, et al. Porphyrin formation in actinic 8. 9. 10. 11. 12. keratosis and basal cell carcinoma after topical application of methyl 5-aminolevulinate. J Invest Dermatol. 2006;126(2):265-271. Rhodes LE, de Rie M, Enström Y, et al. Photodynamic therapy using topical methyl aminolevulinate vs surgery for nodular basal cell carcinoma: results of multicenter randomized prospective trial. Arch Dermatol. 2004;140(1):17-23. Rowe DE, Carroll RJ, Day CL. Long-term recurrence rates in previously untreated (primary) basal cell carcinoma: implications for patient follow-up. J Dermatol Surg Oncol. 1989;15(3):315-328. Guo SW, Lin DY. Regression analysis of multivariate grouped survival data. Biometrics. 1994;50(3):632-639. Silverman MK, Kopf AW, Bart RS, Grin CM, Levenstein MS. Recurrence rates of treated basal cell carcinomas, part 3: surgical excision. J Dermatol Surg Oncol. 1992;18(6):471-476. Bath-Hextall F, Bong J, Perkins W, Williams H. Interventions for basal cell carcinoma of the skin: systematic review. BMJ. 2004;329(7468):705-709. Morton CA, Brown SB, Collins S, et al. Guidelines for topical photodynamic therapy: report of a workshop of the British Photodermatology Group. Br J Dermatol. 2002; 146(4):552-567. Call for Papers Genetics and Genomic Manuscripts In March 2008, the JAMA and Archives family of journals will publish manuscripts in a theme issue devoted to practical applications of genetics and genomics that are currently clinically important or may become clinically relevant in the near future. We invite authors to submit manuscripts reporting the results of original research, especially clinical trials; systematic reviews including metaanalyses; special communications; and commentaries. Evidence-based articles will be given priority. Topics of particular interest include genetic diagnosis, including prenatal tests, and genetic testing, especially for illnesses for which presymptomatic intervention such as prevention of disease or increased surveillance for disease can be expected to change the patient’s quality of life. Other presymptomatic interventions may include pharmacogenomics, gene therapy, evolutionary medicine such as genotypes with proven adaptive responses to emerging infections, genetic counseling, and ethical issues that dermatologists will need to consider as the role of genetics and presymptomatic interventions expands. Manuscripts received by October 15, 2007, will have the best chance for consideration for this theme issue. All manuscripts will undergo our usual rigorous editorial review process.Authorsareencouragedtoconsultthe ArchivesInstructions for Authors at http://www.archdermatol.com for guidelines on preparing and submitting manuscripts. June K. Robinson, MD Editor Jeffery P. Callen, MD Associate Editor (REPRINTED) ARCH DERMATOL/ VOL 143 (NO. 9), SEP 2007 1136 WWW.ARCHDERMATOL.COM STUDY Effect of Cold Air Cooling on the Incidence of Postinflammatory Hyperpigmentation After Q-Switched Nd:YAG Laser Treatment of Acquired Bilateral Nevus of Ota–like Macules Woraphong Manuskiatti, MD; Sasima Eimpunth, MD; Rungsima Wanitphakdeedecha, MD Objective: To investigate the effect of cold air cooling on the incidence of postinflammatory hyperpigmentation (PIH) after laser treatment in Asian patients. a spectrometer, and it was subjectively assessed by 2 nontreating physicians before treatment and once weekly for 4 weeks. Design: Randomized, controlled, split-face study. Results: Of the 21 patients who completed the study, Setting: Skin laser center of a university hospital. Patients: Twenty-three Thai women with acquired bilateral nevus of Ota–like macules. Interventions: Patients were treated using a 1064-nm Q-switched Nd:YAG laser at an average fluence of 7.0 J/cm2 using a 3-mm spot size. The same laser fluence was used on both sides of the face in individual patients. One randomly selected face side of each patient was cooled using a cold air cooling device during and 30 seconds before and after laser irradiation, and the other side was irradiated without cooling. 13 (62%) and 5 (24%) developed PIH on the cooled and uncooled sides, respectively. One patient (5%) had PIH on both the cooled and uncooled sides, and 2 (10%) did not experience PIH. The cooled sides were significantly more likely to become hyperpigmented after laser irradiation than the uncooled sides (relative risk, 2.6; 95% confidence interval, 1.13-6.00; P=.03). The clinical evaluation corresponded to the spectrometer reading. Conclusion: Epidermal cooling with cold air is associated with an increased risk of PIH after Q-switched Nd: YAG laser treatment. Trial Registration: clinicaltrials.gov Identifier: NCT00287001 Main Outcome Measures: Occurrence of PIH was objectively evaluated by measuring the melanin index using P Author Affiliations: Department of Dermatology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand. Arch Dermatol. 2007;143(9):1139-1143 OSTINFLAMMATORY HYPERPIG- mentation (PIH) is a frequently encountered problem and represents the sequelae of various cutaneous disorders and therapeutic interventions. The pathogenesis of PIH includes an increase in melanin production and an abnormal distribution of this pigment. After trauma or cutaneous inflammation, melanocytes can react with increased or decreased production of melanin, reflected clinically as hyperpigmentation or hypopigmentation.1 Postinflammatory hyperpigmentation is probably the most common adverse effect of laser treatments in dark-skinned individuals.2,3 Treatment of PIH is difficult because there are few, if any, therapeutic options that are consistently successful. Little is known about whether PIH can be prevented or minimized.4,5 Acquired bilateral nevus of Ota–like macules (ABNOMs), or Hori nevus, is clini- (REPRINTED) ARCH DERMATOL/ VOL 143 (NO. 9), SEP 2007 1139 cally characterized by blue-brown macules occurring bilaterally on the forehead, temples, eyelids, malar areas, nasal alae, and nasal root. Unlike the nevus of Ota, these pigmented lesions usually appear in the fourth or fifth decade of life in women (only rarely in men) and are not observed in the conjunctiva or mucous membranes of the mouth or nose.6,7 Histologically, active melanin-synthesizing dermal melanocytes are dispersed in the papillary and middle portions of the dermis.8 Q-switched lasers have been used successfully as a treatment modality.9-11 However, the incidence of transient PIH after laser treatment is as much as 50% to 73%.2 Skin cooling has been used to protect the epidermis in a variety of laser dermatologic procedures, including leg vein treatment, hair removal, and port-wine stain removal. The use of epidermal cooling during laser treatment decreases procedureassociated pain, allows safer treatment of WWW.ARCHDERMATOL.COM A B Figure 1. The left side of the face before laser treatment with cold air cooling (A) and the right side of the face before laser treatment without cooling (B). darker-skinned individuals, and allows the use of higher fluences.12-14 Studies to determine the benefit of epidermal cooling on the prevention of PIH after laser treatment are limited. Epidermal cooling is thought to reduce the nonspecific thermal injury caused by the laser pulses and consequently to minimize the incidence of PIH. The present study was performed to address the advantage of epidermal cooling on reducing the occurrence of PIH after laser treatment of ABNOMs. However, we found that epidermal cooling with cold air was associated with an increased risk of PIH after Qswitched Nd:YAG laser treatment. An unexpected finding was a clinically and statistically significant darkening of the cooled side compared with the uncooled side. METHODS Twenty-three Thai women with ABNOMs (Hori nevus) were enrolled in the study. The patients were randomized as to which side of the face would be treated with Q-switched Nd:YAG laser and a cold air cooling device vs Q-switched Nd:YAG laser alone by using a table of uniform random digits. The study protocol and informed consent documents were submitted and approved by the Ethics Committee on Research Involving Human Subjects, Faculty of Medicine Siriraj Hospital, Mahidol University. Written informed consent was obtained from each patient before enrollment. PATIENT CHARACTERISTICS The mean age of the patients was 43 years (range, 27-72 years). Their skin types were III (17/23) and IV (6/23). Patients who were pregnant or lactating, who were taking birth control pills or undergoing hormone therapy, or who participated in major outdoor activities were excluded. Patients who used bleaching agents, such as hydroquinone preparation, and those who received chemical peels, laser treatment, or intense pulsed light treatment before enrollment were also excluded. TREATMENT Lidocaine, 2.5%, and prilocaine, 2.5%, cream (a eutectic mixture of local anesthetic) (AstraZeneca LP, Wilmington, Delaware) was applied to the lesions 1 hour before treatment, and a dressing (Tegaderm; 3M, St Paul, Minnesota) was used to occlude the area. Each patient received 1 Q-switched Nd:YAG laser treatment. The uncooled side of the patient’s face was always treated first, followed by the side with cold air cooling. The clinical end point was defined as the point of immediate whitening without bleeding and tissue splatter. The same fluence setting was used on both sides. COOLING TECHNIQUE A commercially available cold air cooling device (CRIOjet AIR Mini; CRIO Medizintechnik GmbH, Birkenfeld, Germany) was used at a cooling level of 4 for all treatments. This instrument works with a compressor system similar to those in refrigerators and uses ambient air to generate a permanent stream of cold air with a flow of 500 to 1000 L /min and temperatures as low as −30°C, depending on the cooling delivery system and the desired cooling level (range, 1-9). The nozzle-to–cooled surface distance was 5 cm (as suggested by the manufacturer). Relative humidity was 60%, and room temperature was approximately 25°C. The nozzle was held with a rotating motion during the treatment. The cooled side was always cooled during and 30 seconds before and after laser irradiation. The skin surface temperature, measured using an infrared thermometer (MiniTemp MT4; Raytek Corp, Santa Cruz, California) during the treatment, was 4°C to 5°C. Postoperatively, antibacterial mupirocin ointment (Bactroban Ointment; SmithKline Beecham Pharmaceuticals, Philadelphia, Pennsylvania) was applied to the treated area. Patients were instructed to cleanse the treated sites gently with tap water and to reapply the mupirocin ointment 4 times a day until all crusting had subsided. After crusting completely healed, all the patients were instructed to wear a broad spectrum sunscreen with a sun protection factor of 40 and were also asked to avoid sun exposure, which could cause hyperpigmentation. CLINICAL EVALUATION Masked assessment of the occurrence of PIH in all the patients was made by 2 expert dermatologists from the digital photographs taken before treatment (baseline) and 1, 2, 3, 4, and 12 weeks after laser treatment. Photographs were taken using a digital camera (D70s; Nikon Corporation, Tokyo, Japan) equipped with a 60-mm lens (Nikkor; Nikon Corporation) and Canfield TwinFlash (Canfield Scientific Inc, Fairfield, New Jersey). All the photographs were taken in raw format with identical conditions (REPRINTED) ARCH DERMATOL/ VOL 143 (NO. 9), SEP 2007 1140 WWW.ARCHDERMATOL.COM A B Figure 2. The left (cooled) (A) and right (uncooled) (B) sides of the face 1 week after treatment. and camera settings. Standardized views (face front and 45° oblique) were used. The liquid crystal display monitor was calibrated for precise on-screen displays using a colorimeter (Spyder2; Colorvision Inc, Lawrenceville, New Jersey). Clinical observations for cutaneous changes (specifically, erythema, urticaria, blistering, dyspigmentation, and scarring) were conducted at 1-hour and 1-week intervals after cold air exposure. Observable skin changes were graded on the following scale: 0, absent; 1, minimal (light pink; barely perceptible skin elevation; whitening of skin; no evident blister); 2, mild (light red/pink; slight skin elevation; skin wrinkling; no wellformed blister); 3, moderate (red; clearly visible urticaria; flaccid blisters); and 4, severe (very red; pronounced urticaria; tense blisters). Clinical evaluation for the improvement in lesional pigmentation was subjectively graded at baseline and week 12 using a quartile grading scale as follows: poor, less than 25%; fair, 25% to 50%; good, 51% to 75%; and excellent, more than 75% improvement. COLOR READING The designated lesions of pigmented macules on both sides of the face were marked on every patient and mapped with a translucent sheet at the first visit to ensure consistency of location. The degree of lesion lightening was defined as the percentage of darkness reduction compared with baseline. The degree of pigmentation was assessed using a handheld reflectance spectrometer (DermaSpectrometer; Cortex Technology, Hadsund, Denmark). By emitting red light at 655 nm and measuring the absorption coefficients in the skin, the instrument provides a readout of a melanin index (M-index) based on the absorption characteristics of the skin pigmentation. During measurements, the device was placed perpendicularly on the skin; blanching was minimized by applying light pressure. The value used was the average of 3 measurements at each site at each assessment. A higher M-index value indicates increased saturation toward darkness. STATISTICAL ANALYSIS Two-tailed paired t test analyses using statistical software (SPSS version 14; SPSS Inc, Chicago, Illinois) were performed to compare mean M-index values for each treatment technique and at baseline vs the 12-week follow-up visit. Relative risk was calculated using statistical software (Epi Info version 3.3.2; Centers for Disease Control and Prevention, Atlanta, Georgia). P ⬍ .05 was considered statistically significant. RESULTS Of the 23 patients, 21 completed all the follow-up visits. Two patients were withdrawn from the study because they did not attend scheduled visits. Acute erythema was noted in 18 of 21 patients (86%), 1⫹ erythema was observed in 16 of 21 patients (76%), and 2⫹ erythema was present in 2 of 21 patients (10%). One hour after treatment, the redness disappeared in 12 of 18 patients (67%) who developed erythema. In all the patients, the erythema resolved in 24 hours. One patient each with skin types III and IV developed 1⫹ urticaria. All urticaria resolved by the day 1 follow-up visit. No blistering was observed in any patients. The crusting healed completely within 1 and 2 weeks of treatment in 17 of 21 patients (81%) and 4 of 21 patients (19%), respectively. No difference in crusting resolution rates was observed between the cooled and uncooled sides. No patients developed hypopigmentation or scarring. All the patients noted significant pain reduction on the cooled side during laser treatment. No postoperative analgesic treatment was required beyond the application of mupirocin ointment and ice compresses. As judged by the 2 expert dermatologists, of the 21 patients who completed the study, 13 (62%) developed PIH on the cooled side, and 5 (24%) had PIH on the uncooled side (Figures 1, 2, 3, and 4). One patient (5%) had PIH on both the cooled and uncooled sides, and 2 (10%) did not experience PIH. The cooled sides were 3 times more likely than the uncooled sides to develop PIH after laser treatment (relative risk, 2.6; 95% confidence interval, 1.13-6.00; P=.03). The onset of PIH was at week 1, 2, 3, and 4 in 5% (1/21), 62% (13/21), 14% (3/21), and 10% (2/21) of the patients, respectively. The PIH was completely resolved 12 weeks after laser treatment in all the patients except 1 with skin type IV, who developed PIH on the cooled side. All the patients showed less than 25% overall lightening of the pigmented macules at week 12. No difference in clinical improvement was observed regarding the cooling used on 1 side during treatment. At baseline, there was no significant difference in the M-index values of the (REPRINTED) ARCH DERMATOL/ VOL 143 (NO. 9), SEP 2007 1141 WWW.ARCHDERMATOL.COM A B Figure 3. The left (cooled) (A) and right (uncooled) (B) sides of the face 2 weeks after treatment. Note the postinflammatory hyperpigmentation of the lesions on the left (cooled) side of the face. A B Figure 4. The left (cooled) (A) and right (uncooled) (B) sides of the face 12 weeks after treatment. Note the disappearance of the postinflammatory hyperpigmentation on the left (cooled) side of the face. cooled and uncooled sides (P = .17). At week 12, there was also no significant difference in the M-index values of the lesions on the cooled (P=.07) and uncooled (P=.55) sides compared with baseline. The M-index value of all areas considered to have PIH was significantly increased compared with the baseline value (P =.03). COMMENT Postinflammatory hyperpigmentation is one of the most common adverse effects in dark-skinned patients after laser treatment. It is not life threatening, but PIH may cause substantial psychological problems. The incidence of transient PIH after carbon dioxide laser resurfacing is approximately 37% in patients with all skin types15 and nearly 70% in those with skin type IV or higher.16 Hori nevus or ABNOMs is a common pigmentary disorder in Asian individuals. Q-switched lasers provide favorable treatment responses, but transient PIH after laser irradiation affects as much as 50% to 73% of patients and can last for many months.11,17 Postinflammatory hyperpigmentation takes a long time to dissipate. The treatment of PIH is difficult and time-consuming, often lasting many months to achieve the desired results, which causes frustration in patients and physicians.1,2 Thus, various attempts to reduce the occurrence of PIH after skin laser surgery have included sun avoidance, use of preoperative and postoperative treatment regimens, and techniques for epidermal protection. Current commercial cooling methods and devices include passive cooling with aqueous gel, active cooling with water or refrigerated air, and dynamic active cooling with cryogen spray. Lowering the temperature of the skin’s surface is a method of selectively controlling the depth at which heat is produced in the skin by lasers or pulsed light sources. Cooling of the epidermis can prevent its temperature elevation from exceeding the threshold for thermal injury.12 Minimizing the nonspecific thermal injury to the skin surface caused by the laser pulses may therefore lower the incidence of PIH. A previous study18 of a freeze injury in normal human skin showed that a brief (5-second) freezing of liquid nitrogen caused hypopigmentation, with a periph- (REPRINTED) ARCH DERMATOL/ VOL 143 (NO. 9), SEP 2007 1142 WWW.ARCHDERMATOL.COM eral rim of hyperpigmentation in all frozen lesions. Similarly, a recent study by Datrice et al19 also found that transient hyperpigmentation occurred after cryogen spray cooling exposure in individuals with skin type III or higher, and all hyperpigmentation was resolved by 8 weeks without medical intervention. In trying to address the possible causes of this occurrence, we tested the effect of the cold air cooling in 2 patients with untreated ABNOMs (not in the present study). The same cooling techniques were performed without laser irradiation on 1 side of the face of each patient. The patients were followed up every week for 4 weeks. However, none of the patients developed PIH on the cold air– exposed side. Thus, it is unlikely that cold air exposure alone is the mechanism causing PIH. However, some inflammatory triggers from the laser irradiation may underlie the increased incidence of PIH in the present study. The underlying mechanisms and the variability individuals show for developing hyperpigmentation or hypopigmentation are not well understood. An inherited individual chromatic tendency based on “strong” or “weak” melanocytes and their tendency to respond to trauma or inflammation with either hyperpigmentation or hypopigmentation has been postulated.1 In addition, keratinocytes probably play an active role in the regulation of melanogenesis and can stimulate melanocytes to become dendritic and transfer melanosomes.20 We therefore hypothesize that the laser-irradiated melanocyte or keratinocyte may be more hyperactive to stimuli such as cold temperature. In conclusion, the mechanism by which cold air cooling is associated with an increased risk of PIH after laser treatment is unknown. It is possible that the mechanism was a melanocyte’s or keratinocyte’s responses to the laser pulses together with cold air exposure. Future studies should address the question of whether the other methods of epidermal cooling are associated with an increase risk of PIH. Of particular interest is the mechanism that underlies the cause of hyperpigmentation after cold air cooling. Accepted for Publication: March 6, 2007. Correspondence: Woraphong Manuskiatti, MD, Department of Dermatology, Faculty of Medicine, Siriraj Hospital, Mahidol University, 2 Pran-nok Rd, Bangkok 10700, Thailand (siwmn@mahidol.ac.th). Authors Contributions: Study concept and design: Manuskiatti and Wanitphakdeedecha. Acquisition of data: Manuskiatti and Eimpunth. Analysis and interpretation of data: Manuskiatti. Drafting of the manuscript: Manuskiatti and Eimpunth. Critical revision of the manuscript for important intellectual content: Wanitphakdeedecha. Statistical analysis: Manuskiatti and Wanitphakdeedecha. Administrative, technical, and material support: Eimpunth. Study supervision: Manuskiatti. Financial Disclosure: None reported. Previous Presentation: This study was presented at the Annual Meeting of the American Society for Dermatologic Surgery; October 29, 2006; Palm Desert, California. REFERENCES 1. Ruiz-Maldonado R, Orozco-Covarrubias ML. Postinflammatory hypopigmentation and hyperpigmentation. Semin Cutan Med Surg. 1997;16(1):36-43. 2. Chan HH, Alam M, Kono T, Dover JS. Clinical application of lasers in Asians. Dermatol Surg. 2002;28(7):556-563. 3. Manuskiatti W, Goldman MP. Use of lasers on Asian skin. In: Goldman MP, ed. Cutaneous and Cosmetic Laser Surgery. Philadelphia, PA: Mosby Elsevier; 2006: 349-374. 4. Grimes P, Nordlund JJ, Pandya AG, Taylor S, Rendon M, Ortonne JP. Increasing our understanding of pigmentary disorders. J Am Acad Dermatol. 2006; 54(5)(suppl 2):S255-S261. 5. Pandya AG, Guevara IL. Disorders of hyperpigmentation. Dermatol Clin. 2000;18 (1):91-98, ix. 6. Ee HL, Wong HC, Goh CL, Ang P. Characteristics of Hori naevus: a prospective analysis. Br J Dermatol. 2006;154(1):50-53. 7. Hori Y, Kawashima M, Oohara K, Kukita A. Acquired, bilateral nevus of Ota–like macules. J Am Acad Dermatol. 1984;10(6):961-964. 8. Hori Y, Takayama O. Circumscribed dermal melanoses: classification and histologic features. Dermatol Clin. 1988;6(2):315-326. 9. Lam AY, Wong DS, Lam LK, Ho WS, Chan HH. A retrospective study on the efficacy and complications of Q-switched alexandrite laser in the treatment of acquired bilateral nevus of Ota–like macules. Dermatol Surg. 2001;27(11):937-942. 10. Manuskiatti W, Sivayathorn A, Leelaudomlipi P, Fitzpatrick RE. Treatment of acquired bilateral nevus of Ota–like macules (Hori’s nevus) using a combination of scanned carbon dioxide laser followed by Q-switched ruby laser. J Am Acad Dermatol. 2003;48(4):584-591. 11. Polnikorn N, Tanrattanakorn S, Goldberg DJ. Treatment of Hori’s nevus with the Q-switched Nd:YAG laser. Dermatol Surg. 2000;26(5):477-480. 12. Nelson JS, Majaron B, Kelly KM. Active skin cooling in conjunction with laser dermatologic surgery. Semin Cutan Med Surg. 2000;19(4):253-266. 13. Raulin C, Greve B, Hammes S. Cold air in laser therapy: first experiences with a new cooling system. Lasers Surg Med. 2000;27(5):404-410. 14. Zenzie HH, Altshuler GB, Smirnov MZ, Anderson RR. Evaluation of cooling methods for laser dermatology. Lasers Surg Med. 2000;26(2):130-144. 15. Nanni CA, Alster TS. Complications of carbon dioxide laser resurfacing: an evaluation of 500 patients. Dermatol Surg. 1998;24(3):315-320. 16. Sriprachya-anunt S, Marchell NL, Fitzpatrick RE, Goldman MP, Rostan EF. Facial resurfacing in patients with Fitzpatrick skin type IV. Lasers Surg Med. 2002; 30(2):86-92. 17. Kunachak S, Leelaudomlipi P, Sirikulchayanonta V. Q-switched ruby laser therapy of acquired bilateral nevus of Ota–like macules. Dermatol Surg. 1999;25(12): 938-941. 18. Burge SM, Bristol M, Millard PR, Dawber RP. Pigment changes in human skin after cryotherapy. Cryobiology. 1986;23(5):422-432. 19. Datrice N, Ramirez-San-Juan J, Zhang R, et al. Cutaneous effects of cryogen spray cooling on in vivo human skin. Dermatol Surg. 2006;32(8):1007-1012. 20. Minwalla L, Zhao Y, Le Poole IC, Wickett RR, Boissy RE. Keratinocytes play a role in regulating distribution patterns of recipient melanosomes in vitro. J Invest Dermatol. 2001;117(2):341-347. (REPRINTED) ARCH DERMATOL/ VOL 143 (NO. 9), SEP 2007 1143 WWW.ARCHDERMATOL.COM STUDY Primary Cutaneous Diffuse Large B-Cell Lymphoma, Leg Type Clinicopathologic Features and Prognostic Analysis in 60 Cases Florent Grange, MD, PhD; Marie Beylot-Barry, MD, PhD; Phillipe Courville, MD; Eve Maubec, MD; Martine Bagot, MD, PhD; Béatrice Vergier, MD, PhD; Pierre Souteyrand, MD; Laurent Machet, MD, PhD; Sophie Dalac, MD; Eric Esteve, MD; Isabelle Templier, MD; Emmanuel Delaporte, MD; Marie-Françoise Avril, MD; Caroline Robert, MD, PhD; Stephane Dalle, MD; Liliane Laroche, MD, PhD; Michele Delaunay, MD; Pascal Joly, MD, PhD; Janine Wechsler, MD; Tony Petrella, MD Objectives: To describe clinicopathologic features and to identify prognostic factors in a large series of primary cutaneous diffuse large B-cell lymphoma, leg type (PCLBCL LT), as defined in the recent World Health Organization– European Organization for Research and Treatment of Cancer classification of cutaneous lymphomas. Design: Retrospective multicenter study from the French Study Group on Cutaneous Lymphomas. Setting: Nineteen departments of dermatology in 10 regions of France. Patients: Sixty patients with a PCLBCL LT included in the registry of the French Study Group on Cutaneous Lymphomas. Main Outcome Measures: Age, sex, outcome, therapy, B symptoms, cutaneous extent, number of lesions, location (leg vs nonleg), serum lactate dehydrogenase level, and MUM-1 and Bcl-2 expression were recorded. Diseasespecific survival was used as the main end point. Prognostic factors were identified using a Cox proportional hazards model. I Author Affiliations are listed at the end of this article. Results: Primary cutaneous diffuse large B-cell lymphoma, leg type is characterized by a predilection for the leg (72%), a high proportion of Bcl-2 expression (85%), an advanced age at onset (mean age, 76 years), and frequent relapses and extracutaneous dissemination. The overall 5-year disease-specific survival rate was 41%. Location on the leg and multiple skin lesions were predictive of death in multivariate analysis. Although no variable related to therapy was significantly associated with survival, patients recently treated with combinations of anthracycline-containing chemotherapies and rituximab had a more favorable shortterm outcome. Conclusions: Primary cutaneous diffuse large B-cell lymphoma, leg type is a distinct entity with a poor prognosis, particularly in patients with multiple tumors on the legs. Despite the advanced age of many patients, the prognosis could be improved with combinations of anthracycline-containing chemotherapies and rituximab. Arch Dermatol. 2007;143(9):1144-1150 2005, A NEW WORLD HEALTH Organization–European Organization for Research and Treatment of Cancer (WHO-EORTC) classification of cutaneous lymphomas was proposed1 and was widely accepted2,3 as an important consensual advance for the characterization and management of cutaneous lymphomas. In this classification, primary cutaneous B-cell lymphomas (PCBCLs) were divided into the following 3 main groups: primary cutaneous marginal zone B-cell lymphoma, primary cutaneous follicle center cell lymphoma, and primary cutaneous diffuse large B-cell lymphoma, leg type (PCLBCL LT). Whereas the first 2 groups had been identified long before and studied in numerous N (REPRINTED) ARCH DERMATOL/ VOL 143 (NO. 9), SEP 2007 1144 large reports,4-10 the third group was newly defined and had not yet been characterized by large multicenter studies. Since the report of the WHO-EORTC classification, 2 studies11,12 have included information about 40 and 51 cases of PCLBCL LT as subgroup analyses of larger series of PCBCLs of different subtypes. However, no large studies specifically dedicated to PCLBCL LT have been published to date, to our knowledge. In addition, although PCLBCL LT is known to have a more aggressive clinical behavior than other groups of PCBCLs,1,11,12 we are aware of only 1 study11 that has attempted to identify prognostic factors in these patients. In this study, we analyzed the outcome, therapy, prognostic factors, clinical characteristics, and WWW.ARCHDERMATOL.COM immunohistologic features in a large series of patients with PCLBCL LT. METHODS PATIENT SELECTION A retrospective review of PCBCLs included in the registry of the French Study Group on Cutaneous Lymphomas between January 1, 1988, and March 31, 2006, was carried out. Patients with PCLBCL LT according to the WHO-EORTC classification1 were selected for analysis after clinicopathologic review. Primary cutaneous B-cell lymphomas were defined as Bcell lymphomas manifesting on the skin without evidence of extracutaneous disease. Among PCBCLs, PCLBCL LT was defined histologically as cases with a predominance or confluent sheets of centroblasts and immunoblasts, irrespective of the location of skin lesions and Bcl-2 protein expression. There were no recorded patients with associated chronic lymphocytic leukemia or Richter syndrome. To avoid selection biases, events occurring after diagnosis were not used as exclusion criteria. In particular, patients unable to receive any treatment because of their poor general condition, those who developed extracutaneous dissemination within 6 months after diagnosis, and those who died soon thereafter were included in the study. HISTOLOGIC AND IMMUNOHISTOCHEMICAL REVIEW All cases were reviewed by a panel of 3 of us (B.V., J.W., and T.P.) who were blinded to the clinical data to confirm the inclusion criteria based on the predominance (ⱖ80%) of centroblasts (large cells with round or oval nuclei and several small nucleoli generally sticking to the nucleus membrane) and immunoblasts (large cells with round nuclei and ⱖ1 large central nucleoli). Cases showing a large proportion of large centrocytic cells (cleaved cells) were excluded. For each case, hematoxylin-eosin stains and CD20- and CD3-immunostained slides from formalin-fixed and paraffinembedded biopsy specimens were required. In all cases, tumor cells expressed CD20 and were negative for CD3. The cases that did not correspond to the morphological and phenotypical criteria of centroblastic or immunoblastic B-cell lymphomas were excluded. Unstained sections or paraffin blocks were subsequently collected from each center to perform Bcl-2 and MUM-1 immunostainings. The analysis was performed in the same laboratory (that of T.P.) at the same time to avoid techniquedependent variability using an automated system (BenchMark; Ventana Medical System, Illkich, France). We used reactive lymph node specimens as positive and negative controls. The following monoclonal antibodies were used for the study: clone 124 for Bcl-2 protein and clone mum1p for MUM-1 protein (Dako Company, Globstrup, Denmark). After consensus among reviewers, an estimated quantification of the proportion of neoplastic large cells that showed unequivocal Bcl-2 and MUM-1 positivity was given, ranging from 0% to 100%. As in previous studies, Bcl-2 expression was considered positive when this proportion exceeded 50%. MUM-1 expression was categorized as positive (ⱖ50% positive tumor cells), intermediate (30%-49% positive tumor cells), or negative (⬍30% positive tumor cells). CLINICAL AND FOLLOW-UP DATA All medical records were reviewed. The following clinical characteristics were recorded at diagnosis and were evaluated for prognostic value: age, sex, B symptoms, number of skin lesions, duration of skin lesions before diagnosis, serum lactate dehydrogenase level, anatomical site (arm, leg, head and neck, anterior aspect of the trunk, or posterior aspect of the trunk), and cutaneous extent (namely, “localized” when 1 or multiple skin lesions were restricted to 1 anatomical site and “disseminated” when several anatomical sites were involved). Follow-up data were recorded until April 1, 2006, including initial and subsequent therapies, achievement of a complete response, cutaneous relapse, extracutaneous progression of the disease, final status, and date and cause of death. Causes of death were ascertained in most cases by physician members of the French Study Group on Cutaneous Lymphomas who followed up patients and in other cases by questioning their general practitioners. Follow-up ranged from 0.3 to 155 months (mean follow-up, 32 months). Fifty-two patients (86.7%) were followed up until death, until the end point, or for longer than 5 years, whereas 8 patients (13.3%) were lost to follow-up after less than 5 years (range, 17-49 months). STATISTICAL ANALYSIS Disease-specific survival duration was calculated from diagnosis to the date of disease-related death or censoring. Patients whose deaths were unrelated to lymphoma were considered censored. Prognostic factors were identified by disease-specific survival univariate and multivariate analyses using a Cox proportional hazards model.13 Factors significant at the 0.2 level in univariate analysis were included in stepwise regression multivariate analyses. Comparisons between subgroups of patients according to factors of prognostic value were performed using ␹2 test or Fisher exact test for categorical variables and t test or Mann-Whitney test for continuous variables. The KaplanMeier method was used to estimate lymphoma-specific survival and to construct corresponding survival curves.14 Survival rates were compared separately for each category of prognostic variable identified by the Cox proportional hazards model using the Mantel-Cox test. RESULTS BASELINE CLINICAL AND HISTOLOGIC CHARACTERISTICS AND FOLLOW-UP DATA Sixty patients met the inclusion criteria. Thirty-two had been included in a previous study.15 All patients had negative staging investigations at diagnosis, including physical examination (100% of cases), routine laboratory test results (100%), bone marrow cytologic or histologic features (90%), chest radiography or thoracic computed tomography (100%), abdominal ultrasonographic tomography or abdominal computed tomography (100%), and lymph node histologic features in patients with clinically enlarged lymph node (13%). The main characteristics of patients at diagnosis and the follow-up data are summarized in Table 1. The femalemale sex ratio was 1.6. Patient age ranged from 44 to 96 years (mean age, 76 years; median age, 77 years). The performance status was 0 (fully active), 1 (ambulatory), 2 (bedridden ⬍50% of the time), 3 (bedridden ⱖ50% of the time), and 4 (completely bedridden) in 12, 13, 4, 4, and 2 patients, respectively, and was unavailable for 25 patients. Fifty-four patients had cutaneous nodules or tumors, 3 patients had deeply infiltrated plaques, 2 patients had large subcutaneous tumors, and 1 patient had a leg ulcer. Twenty (REPRINTED) ARCH DERMATOL/ VOL 143 (NO. 9), SEP 2007 1145 WWW.ARCHDERMATOL.COM Table 1. Main Findings at Diagnosis and Follow-up Data and According to Location of Skin Tumors a Variable Total No. of cases Age, y Mean (range) ⬎ 75 Sex Male Female No. of lesions 1 ⬎1 Extent Localized Disseminated Serum lactate dehydrogenase level Normal High Immunohistochemistry c Bcl-2 positive, No. of patients/total No. of patients MUM-1 positive, No. of patients/total No. of patients Complete response Yes No Relapse d No Yes Extracutaneous progression No Yes, nodal only Yes, visceral with or without nodal Status Alive, disease free Alive with disease Died of lymphoma Died, other cause Disease-specific survival rate, % 3y 5y Leg Nonleg 60 43 17 76 (44-96) 35 (58.3) 78 (44-92) 30 (69.8) 72 (49-96) 5 (29.4) 23 (38.3) 37 (61.7) 15 (34.9) 28 (65.1) 8 (47.1) 9 (52.9) 20 (33.3) 40 (66.7) 8 (18.6) 35 (81.4) 12 (70.6) 5 (29.4) 48 (80.0) 12 (20.0) 32 (74.4) 11 (25.6) 16 (94.1) 1 (5.9) 54 (90.0) 6 (10.0) 38 (88.4) 5 (11.6) 16 (94.1) 1 (5.9) 51/60 (85.0) 23/41 (56.1) 39/43 (90.7) 18/29 (62.1) 12/17 (70.6) 5/12 (41.7) 41 (68.3) 19 (31.7) 27 (62.8) 16 (37.2) 14 (82.4) 3 (17.6) 15 (36.6) 26 (63.4) 8 (29.6) 19 (70.4) 7 (50.0) 7 (50.0) 34 (56.7) 9 (15.0) 17 (28.3) 23 (53.5) 6 (14.0) 14 (32.6) 11 (64.7) 3 (17.6) 3 (17.6) 16 4 31 9 5 (11.6) 4 (9.3) 27 (62.8) 7 (16.3) 11 (64.7) 0 4 (23.5) 2 (11.8) 43 26 77 77 P Value b .03 .004 .4 ⬍.001 .15 .6 a Data are given as number (percentage) unless otherwise indicated. b Leg vs nonleg primary cutaneous diffuse large B-cell lymphoma, leg .1 .3 .2 .13 .3 .001 (26.7) (6.7) (51.7) (15.0) .002 53 41 type. For 5-year survival rates, P values were calculated from a comparison of survival curves. c Not available in all patients. d Considered only in 41 patients who achieved a complete response. patients (33.3%) had 1 lesion, 19 patients (31.7%) had 2 to 5 lesions, and 21 (35.0%) had more than 5 lesions. Eight patients (13.3%) had lesions on the trunk, 9 patients (15.0%) had lesions on the arm, 11 patients (18.3%) had lesions on the head, and 43 patients (71.7%) had lesions on the leg (in 5 of these 43 patients, lesions were located both on the leg and at other anatomical sites). Using the previous EORTC classification,16 all 43 of these cases would have been classified by most authors as PCLBCL of the leg, whereas 17 cases without leg lesions (28.3%) would have been classified as primary cutaneous follicle center cell lymphoma. In the present study, these 17 cases are referred to as nonleg PCLBCL LT, as defined in the WHO-EORTC classification.1 Seven patients (11.7%) had a high serum lactate dehydrogenase level, 6 patients (10.0%) had B symptoms, and 2 patients (3.3%) had both conditions. Bcl-2 staining was positive in 51 patients (85.0%). MUM-1 staining was scored as positive, intermediate, and negative in 23 (56.1%), 5 (12.2%), and 13 (31.7%) of 41 patients, respectively, and was unavailable in 19 patients. Table 2 summarizes first-line and subsequent therapies administered in our 60 patients. First-line therapy was most often radiation therapy (38.3%) or variable combinations of systemic chemotherapies (49.9%) with or without rituximab. In addition, 17 patients (28.3%) received second-line or third-line therapies. Overall, 39 patients (65.0%) were treated with polychemotherapies as first-line or subsequent therapies during the course of the disease (data not shown). These included 9 patients (15.0%) who received polychemotherapies only without anthracycline, 18 patients (30.0%) who received anthracycline-containing chemotherapies without rituximab, and 12 patients (20.0%) who received various combinations of anthracycline-containing chemotherapies and rituximab. No statistically significant difference with respect to therapies administered was observed between patients with leg vs nonleg PCLBCL LT. (REPRINTED) ARCH DERMATOL/ VOL 143 (NO. 9), SEP 2007 1146 WWW.ARCHDERMATOL.COM Table 2. Summary of Therapiesa Therapy First-line Therapies (n = 60) Subsequent Therapies (n = 17) 23 (38.3) b 1 (1.7) 8 (13.3) c 11 (18.3) d 11 (18.3) 6 (10.0) e 3 2 5 7 1 Radiation therapy Single-agent chemotherapy Polychemotherapies without anthracycline Anthracycline-containing chemotherapies without rituximab Various combinations of anthracycline-containing chemotherapies and rituximab Other a Data are given as number (percentage). b Associated with single-agent chemotherapy in 1 patient. c Associated with radiation therapy in 1 patient. d Associated with radiation therapy in 3 patients. e Consisted of surgery in 3 patients, oral corticosteroid use in 1 patient, and no therapy in 2 patients. Table 3. Results From the Multivariate Analysis Result Location of skin lesions Nonleg Leg No. of lesions Single Multiple P = .003 Nonleg (n = 17) 0.75 P Value Survival Relative Risk (95% Confidence Interval) 1.00 .02 1 [Reference] 3.3 (1.1-10.0) 0.50 Leg (n = 43) 0.25 .05 1 [Reference] 2.3 (1.0-5.4) Among 41 patients (68.3%) who achieved at any time a complete response, 26 (63.4%) experienced 1 or several relapses. Of 60 patients, 26 (43.3%) developed extracutaneous disease. The mean time until extracutaneous dissemination was 20 months. The dissemination was restricted to the lymph nodes in 9 patients. The remaining 17 patients had visceral progression associated with lymph node involvement (6 patients) or without (11 patients). The central nervous system was the most frequent site of visceral dissemination (7 patients). Other sites included the bones (2 patients), kidney (2 patients), liver (1 patient), spleen (1 patient), testis (1 patient), pancreas (1 patient), breast (1 patient), pelvis (1 patient), and brachial plexus (1 patient). Thirty-one patients (51.7%) died of lymphoma, and 9 patients (15.0%) died of unrelated disease. Of 31 diseasespecific deaths, 24 (77.4%) followed extracutaneous progression of the disease. Eight other deaths were considered disease-related despite the absence of obvious extracutaneous involvement. These included patients who developed fatal sepsis after chemotherapy and those who died of secondary infection, major cutaneous tumor bulk and ulceration, or major worsening of their general condition. The 3-year and 5-year disease-specific survival rates were 53% and 41%, respectively. PROGNOSTIC FACTORS In univariate analysis, disease-related death was statistically significantly associated with location on the leg (P=.003), disseminated distribution (P=.04), and the presence of multiple skin lesions at diagnosis (P = .004). Pa- 0 0 12 24 36 48 60 72 84 Months Figure. Kaplan-Meier lymphoma-specific survival curves according to location of skin lesions. tients older than 75 years had a slightly poorer prognosis (P=.06). Sex, B symptoms, Bcl-2 expression, MUM-1 expression, performance status, serum lactate dehydrogenase level, duration of lesions before diagnosis, and variables related to therapy had no effect on survival. Multivariate analysis of lymphoma-specific survival using all candidate variables identified location on the leg (P=.02) and multiple skin lesions (P=.05) as independent factors associated with a poorer prognosis (Table 3). Similar results were observed when age was forced in the model. CHARACTERISTICS OF PATIENTS AND OUTCOMES IN DIFFERENT PROGNOSTIC GROUPS Because the topographic subtype (leg vs nonleg) was the strongest prognostic factor, the main features at diagnosis and the follow-up data were subsequently analyzed according to the location of skin lesions (Table 1). Patients with the leg subtype were older and had more numerous skin lesions at diagnosis than patients with nonleg PCLBCL LT; they showed a tendency for less frequent response to therapy and more frequent relapses and visceral progressions. The 3-year disease-specific survival rates were 43% in the leg subtype group and 77% in the nonleg subtype group (P=.002). Kaplan-Meier lymphomaspecific survival curves according to the location of skin lesions are shown in the Figure. The number of skin lesions at diagnosis also was a major distinctive factor for predicting survival in the entire (REPRINTED) ARCH DERMATOL/ VOL 143 (NO. 9), SEP 2007 1147 WWW.ARCHDERMATOL.COM series, with 3-year disease-specific survival rates of 39% in patients with multiple skin lesions vs 77% in those with a single lesion (P = .004). The number of lesions was related to the topographic subtype (Table 1). Only 8 of 43 patients (18.6%) in the leg subtype group had a single lesion at diagnosis. In this subgroup, the 3-year survival rate was 78% compared with 32% in 35 patients with multiple lesions involving 1 or both legs. No difference in survival was observed between Bcl-2–positive cases (3year survival, 54%) and Bcl-2–negative cases (3-year survival, 43%) in the entire series (P = .8). ROLE OF THERAPY Although no variable related to therapy was statistically significantly associated with survival in this retrospective study, we further analyzed patients who received at any time various combinations of anthracyclinecontaining chemotherapies and rituximab (12 patients) and compared them with those who received other therapies only (48 patients). These 2 groups did not differ by age, location, or number of skin lesions. They strongly differed by period of inclusion because rituximab was never used before 2002 and was used only rarely before 2004. Therefore, no long-term (ⱖ3 year) survival comparison was available at the end point. The 2-year survival rate differed between the 2 groups (group receiving various combinations of anthracycline-containing chemotherapies and rituximab, 81%; group receiving other therapies, 59%) without reaching a statistically significant difference (P = .3). However, the short-term outcome was more favorable in patients treated with various combinations of anthracycline-containing chemotherapies and rituximab. Among these 12 patients, all but 1 (91.6%) achieved a complete response (compared with 62% in the group receiving other therapies) (P=.05), and 10 of 11 patients had no relapse. At the end point, 9 of these patients were alive with a mean follow-up of 19 months (8 patients without disease and 1 patient with disease), 2 patients had died of lymphoma (1 patient of septicemia after chemotherapy and 1 patient of brain involvement), and 1 patient had died of unrelated disease. A similar comparative analysis between patients treated with anthracycline-containing chemotherapies without rituximab and other patients failed to disclose any difference in outcomes. COMMENT We report herein the largest study of PCLBCL LT, to our knowledge, and provide new data on its clinicopathologic features and prognostic factors. In addition, we provide preliminary results comparing outcomes in patients treated with classic vs new therapeutic regimens. Most PCBCLs, including almost all small-cell lymphomas and a large proportion of large-cell lymphomas, have an indolent clinical course.4-6,9,16-18 However, a subset of PCBCLs with a predominance of large cells comprises aggressive lymphomas. This finding led researchers to look for discriminating prognostic factors within this heterogeneous group of primary cutaneous large B-cell lymphomas. Small case series first identified the location on the leg as a criterion of aggressiveness.4,19 In further multicenter studies, round-cell morphological features20 (ie, the predominance of large cells with round nuclei over large cells with cleaved nuclei) and Bcl-2 protein expression15 were identified as additional adverse prognostic factors. In the WHO-EORTC classification,1 the term primary cutaneous diffuse large B-cell lymphoma, leg type was introduced beside primary cutaneous follicle center cell lymphoma and primary cutaneous marginal zone B-cell lymphoma to designate PCBCLs with a predominance of large cells and a less favorable prognosis. Primary cutaneous diffuse large B-cell lymphoma, leg type was primarily defined on the basis of morphological features by the presence of confluent sheets of large cells with round nuclei (ie, centroblasts and immunoblasts). Primary cutaneous diffuse large B-cell lymphoma with a predominance of large cleaved cells and fewer centroblasts was classified within the group of primary cutaneous follicle center cell lymphoma. In addition, it was specified that PCLBCL LT arises on the leg in most (but not all) cases and demonstrates strong Bcl-2 expression.1 The role of Bcl-2 expression for classifying these lymphomas remained unclear. In further studies, some authors excluded rare Bcl-2–negative cases from the group of PCLBCL LT and included them in the heterogeneous group termed large B-cell lymphoma, other,11 whereas other authors (as we do in the present study) included all cases with characteristic roundcell morphological features within the group of PCLBCL LT, irrespective of Bcl-2 expression.12 Using these criteria, we found that PCLBCL LT is characterized by a poor prognosis, a high proportion of Bcl-2 expression (85%), an advanced age at onset (median age, 77 years), and a frequent location on the leg (72% in 43 cases, including 5 cases with lesions on the leg and at other sites). The 3-year and 5-year disease-specific survival rates in the entire group were 53% and 41%, respectively. Survival rates in the present study (Table 1) were lower than those in previous reports. The Italian study Group for Cutaneous Lymphomas12 recently reported a 5-year survival rate of 73% in 51 patients with PCLBCL LT, including 6 patients without leg lesions. Kodama et al11 reported a 5-year survival rate of 61.7% in 40 Austrian patients with Bcl-2–positive PCLBCL LT, 32 of whom had disease on the leg. Such differences in survival may result from variations in management and therapy or from differences in baseline characteristics of patients resulting from various selection biases. Although patients included in the Austrian study did not differ in age from our patients, those included in the Italian series were younger (median age, 70 years). In addition, only patients who had 6 months of follow-up without extracutaneous dissemination were included in the Italian series. In our study, patients were included on the basis of negative initial staging, irrespective of further outcome. Some older patients had multiple and bulky tumors on the legs, could receive only palliative care, and died early after diagnosis. These patients were not excluded from the study and affected the survival rate in the entire series. We identified location on the leg as the main negative prognostic factor. Patients with leg tumors had a (REPRINTED) ARCH DERMATOL/ VOL 143 (NO. 9), SEP 2007 1148 WWW.ARCHDERMATOL.COM 3-year disease-specific survival rate of 43%, compared with 77% in patients with nonleg PCLBCL LT. This result confirms and extends previous reports of the aggressiveness of primary cutaneous large B-cell lymphoma of the leg, as defined in the previous EORTC classification.16,19,20 However, the prognosis of nonleg PCLBCL LT (Figure) seems poorer than that of primary cutaneous follicle center lymphoma or primary cutaneous marginal zone B-cell lymphoma, which are characterized by 5-year survival rates of 95% to 100%.1,8 Therefore, it seems preferable to classify these lymphomas on a morphological basis within the group of PCLBCL LT, as proposed in the recent WHO-EORTC classification,1 rather than in the group of primary cutaneous follicle center cell lymphoma, as in the previous EORTC classification.16 The second negative prognostic factor in our study was the presence of multiple skin lesions. Although the number of skin lesions had no prognostic value in the Austrian series,11 2 previous studies15,20 on aggressive PCBCLs identified multiple skin lesions as an important adverse prognostic factor. This is in accord with earlier studies9,21,22 of different types of cutaneous or noncutaneous lymphomas that underlined the prognostic value of variables related to tumor burden. In the present study, the 3-year disease-specific survival rate was 39% in patients with multiple skin lesions vs 77% in patients with only 1 lesion (P=.004). Most patients with leg involvement had multiple tumors. However, those with only 1 tumor on a leg had a favorable prognosis. Whether these patients may be first treated with less aggressive procedures such as radiation therapy alone remains questionable. In the present study, PCLBCL LT showed intermediate or positive staining for MUM-1 protein in most cases and consistently expressed Bcl-2 protein. This finding confirms that the expression of MUM-1 and Bcl-2 characterizes not only primary cutaneous large B-cell lymphomas of the leg, as previously demonstrated,23-25 but also PCLBCL LT defined on a morphological basis. Bcl-2 expression was almost universal in cases located on the leg and was observed in most nonleg cases (Table 1). Overall, only 9 of 60 cases had negative Bcl-2 staining. Bcl-2–negative PCLBCL LT is rare and has been poorly characterized to date. Kodama et al11 described 9 cases using the term large B-cell lymphoma, other. Four cases were located outside of the leg. No difference in survival was observed between these 9 patients (5-year survival, 50%) and 40 patients with typical Bcl-2–positive PCLBCL LT (5-year survival, 61.7%). We found similar results, with 3-year survival rates of 43% in Bcl-2–negative patients vs 54% in Bcl-2– positive patients (P=.8). Although these results need to be confirmed in larger series, it seems suitable to include all of these cases within the group of PCLBCL LT as defined morphologically by confluent sheets of large round B-cells, irrespective of Bcl-2 staining. Primary cutaneous diffuse large B-cell lymphoma, leg type is an aggressive lymphoma that requires effective therapies. This seems to be a difficult challenge in view of the advanced age of many patients. Historically, some of these patients received only palliative care, radiation therapy, or nonaggressive chemotherapies. However, the report of the effectiveness of various combinations of anthracycline-containing chemotherapies and rituximab in older patients with noncutaneous diffuse large B-cell lymphomas22 led to changes in the French practices regarding the cutaneous counterparts of these lymphomas. The rationale for this attitude was enhanced by the demonstration that rituximab was able to overcome Bcl-2– associated resistance to chemotherapy,26,27 which coincided with findings that most PCLBCL LT strongly expressed Bcl-2.15,23 In the present study, 12 patients who received various combinations of anthracyclinecontaining chemotherapies and rituximab were retrospectively compared with 48 patients who received other treatments. Although the follow-up was insufficient to objectively determine a statistically significant difference in survival, more favorable short-term outcomes were observed with various combinations of anthracyclinecontaining chemotherapies and rituximab. While awaiting appropriate controlled trials to confirm these observations, we recommend that patients with PCLBCL LT should be treated as often as possible with age-adapted various combinations of anthracycline-containing chemotherapies and rituximab, particularly in patients with multiple skin tumors. Accepted for Publication: February 25, 2007. Author Affiliations: Department of Dermatology, Hôpital Robert Debré, Reims (Dr Grange); Departments of Dermatology (Dr Beylot-Barry) and Pathology (Dr Vergier), Hôpital du Haut Lévêque, Pessac; Departments of Dermatology (Dr Courville) and Pathology (Dr Joly), Hôpital Charles Nicolle, Rouen; Department of Dermatology, Hôpital Bichat (Dr Maubec), and Department of Dermatology, Hôpital Tarnier (Dr Avril), Paris; Departments of Dermatology (Dr Bagot) and Pathology (Dr Wechsler), Hôpital Henri-Mondor, Créteil; Department of Dermatology, Hôtel Dieu, Clermont-Ferrand (Dr Souteyrand); Department of Dermatology, Hôpital Trousseau, Tours (Dr Machet); Department of Dermatology (Dr Dalac) and Centre de Pathologie and Department of Pathology (Dr Petrella), Hôpital du Bocage, Dijon; Department of Dermatology, Hôpital Porte Madeleine, Orléans (Dr Esteve); Department of Dermatology, Hôpital Michallon, Grenoble (Dr Templier); Department of Dermatology, Hôpital Claude Huriez, Lille (Dr Delaporte); Department of Dermatology, Institut Gustave Roussy, Villejuif (Drs Avril and Robert); Department of Dermatology, Hôpital de l’Hôtel-Dieu, Lyon (Dr Dalle); Department of Dermatology, Hôpital Avicenne, Bobigny (Dr Laroche); and Department of Dermatology and Cancerology, Hôpital Pellegrin, Bordeaux (Dr Delaunay); France. Correspondence: Florent Grange, MD, PhD, Department of Dermatology, Hôpital Robert Debré, Avenue du Général Koenig, Reims 51100, France (fgrange@chu-reims.fr). Author Contributions: Study concept and design: Grange. Acquisition of data: Grange, Beylot-Barry, Courville, Maubec, Bagot, Vergier, Souteyrand, Machet, Dalac, Esteve, Templier, Delaporte, Avril, Robert, Dalle, Laroche, Delaunay, Joly, Wechsler, and Petrella. Analysis and interpretation of data: Grange and Petrella. Drafting of the manuscript: Grange and Petrella. Critical revision of the manuscript for important intellectual content: BeylotBarry, Courville, Maubec, Bagot, Vergier, Souteyrand, Machet, Dalac, Esteve, Templier, Delaporte, Avril, Robert, (REPRINTED) ARCH DERMATOL/ VOL 143 (NO. 9), SEP 2007 1149 WWW.ARCHDERMATOL.COM Dalle, Laroche, Delaunay, Joly, and Wechsler. Statistical analysis: Grange. Study supervision: Grange and Petrella. Financial Disclosure: None reported. 13. 14. 15. REFERENCES 16. 1. Willemze R, Jaffe ES, Burg G, et al. WHO-EORTC classification for cutaneous lymphomas [published online ahead of print February 3, 2005]. Blood. 2005; 105(10):3768-3785. 2. Burg G, Kempf W, Cozzio A, et al. WHO/EORTC classification of cutaneous lymphomas 2005: histological and molecular aspects. J Cutan Pathol. 2005;32 (10):647-674. 3. Slater DN. The new World Health Organization–European Organization for Research and Treatment of Cancer classification for cutaneous lymphomas: a practical marriage of two giants. Br J Dermatol. 2005;153(5):874-880. 4. Willemze R, Meijer CJLM, Scheffer E, et al. Diffuse large cell lymphomas of follicle center cell origin presenting in the skin: a clinicopathologic and immunologic study of 16 patients. Am J Pathol. 1987;126(2):325-333. 5. Santucci M, Pimpinelli N, Arganini L. Primary cutaneous B-cell lymphoma: a unique type of low-grade lymphoma: clinicopathologic and immunologic study of 83 cases. Cancer. 1991;67(9):2311-2326. 6. Pimpinelli N, Santucci M, Mori M, Vallecchi C, Giannotti B. Primary cutaneous B-cell lymphoma: a clinically homogeneous entity? J Am Acad Dermatol. 1997; 37(6):1012-1016. 7. Rijlaarsdam JU, van der Putte SC, Berti E, et al. Cutaneous immunocytomas: a clinicopathologic study of 26 cases. Histopathology. 1993;23(2):117-125. 8. Hoefnagel JJ, Vermeer MH, Jansen PM, et al. Primary cutaneous marginal zone B-cell lymphoma: clinical and therapeutic features in 50 cases. Arch Dermatol. 2005;141(9):1139-1145. 9. Grange F, Hedelin G, Joly P, et al; The French Study Group on Cutaneous Lymphomas. Prognostic factors in primary cutaneous lymphomas other than mycosis fungoides and the Sézary syndrome. Blood. 1999;93(11):3637-3642. 10. Fink-Puches R, Zenahlik P, Bäck B, et al. Primary cutaneous lymphomas: applicability of current classification schemes (European Organization for Research and Treatment of Cancer, World Health Organization) based on clinicopathologic features observed in a large group of patients. Blood. 2002;99(3): 800-805. 11. Kodama K, Massone C, Chott A, Smolle J, Kerl H, Cerroni L. Primary cutaneous large B-cell lymphomas: clinicopathologic features, classification, and prognostic factors in a large series of patients. Blood. 2005;106(7):2491-2497. 12. Zinzani PL, Quaglino P, Pimpinelli N, et al; Italian Study Group for Cutaneous Lymphomas. Prognostic factors in primary cutaneous B-cell lymphoma: the Ital- 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. (REPRINTED) ARCH DERMATOL/ VOL 143 (NO. 9), SEP 2007 1150 ian Study Group for Cutaneous Lymphomas [published online ahead of print February 21, 2006]. J Clin Oncol. 2006;24(9):1376-1382. Cox DR. Regression models and life tables. J R Stat Soc B. 1972;34:187-202. Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc. 1958;53:157-181. Grange F, Petrella T, Beylot-Barry M, et al. Bcl-2 protein expression is the strongest independent prognostic factor of survival in primary cutaneous large B-cell lymphomas. Blood. 2004;103(10):3662-3668. Willemze R, Kerl H, Sterry W, et al. EORTC classification for primary cutaneous lymphomas: a proposal from the Cutaneous Lymphoma Study Group of the European Organization for Research and Treatment of Cancer. Blood. 1997;90 (1):354-371. Grange F, Bagot M. Prognosis of primary cutaneous lymphomas [in French]. Ann Dermatol Venereol. 2002;129(1, pt 1):30-40. Hembury TA, Lee B, Gascoyne RD, et al. Primary cutaneous diffuse large B-cell lymphoma: a clinicopathologic study of 15 cases. Am J Clin Pathol. 2002;117 (4):574-580. Vermeer MH, Geelen FA, van Haselen CW, et al. Primary cutaneous large B-cell lymphomas of the legs: a distinct type of cutaneous B-cell lymphoma with an intermediate prognosis. Arch Dermatol. 1996;132(11):1304-1308. Grange F, Bekkenk MW, Wechsler J, et al. Prognostic factors in primary cutaneous large B-cell lymphomas: a European Multicenter Study. J Clin Oncol. 2001; 19(16):3602-3610. Joly P, Vasseur E, Esteve E, et al; French Study Group for Cutaneous Lymphomas. Primary cutaneous medium and large cell lymphomas other than mycosis fungoides: an immunohistological and follow-up study of 54 cases. Br J Dermatol. 1995;132(4):506-512. Coiffier B, Lepage E. Prognosis of aggressive lymphomas: a study of five prognostic models with patients included in the LNH-84 regimen. Blood. 1989; 74(2):558-564. Geelen FA, Vermeer MH, Meijer CJ, et al. Bcl-2 protein expression in primary cutaneous large B-cell lymphoma is site-related. J Clin Oncol. 1998;16(6):20802085. Paulli M, Viglio A, Vivenza D, et al. Primary cutaneous large B-cell lymphomas of the leg: histogenetic analysis of a controversial clinicopathologic entity. Hum Pathol. 2002;33(9):937-943. Hoefnagel JJ, Dijkman R, Basso K, et al. Distinct types of primary cutaneous large B-cell lymphoma identified by gene expression profiling. Blood. 2005;105(9): 3671-3678. Coiffier B, Lepage E, Brière J, et al. CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large B-cell lymphoma. N Engl J Med. 2002;346(4):235-242. Mounier N, Brière J, Gisselbrecht C, et al. Rituximab plus CHOP (R-CHOP) overcomes bcl-2–associated resistance to chemotherapy in elderly patients with diffuse large B-cell lymphoma. Blood. 2003;101(11):4279-4284. WWW.ARCHDERMATOL.COM OBSERVATION Familial Acanthosis Nigricans Due to K650T FGFR3 Mutation David R. Berk, MD; Elaine B. Spector, PhD; Susan J. Bayliss, MD Background: Acanthosis nigricans is a feature of several syndromes caused by activating mutations of the fibroblast growth factor receptor 3 gene (FGFR3), including Crouzon syndrome with acanthosis nigricans, thanatophoric dysplasia, and severe achondroplasia with developmental delay and acanthosis nigricans (SADDAN syndrome). numerous affected family members was constructed. Other than slightly short stature, no associated anomalies were found, including dysmorphic features or skeletal or neurologic defects. Genetic testing revealed a previously undescribed, heterozygous lysine to threonine mutation at codon 650 of the FGFR3 gene in the 4 affected family members who were tested. Observations: We describe a healthy 4-year-old Afri- Conclusion: Extensive acanthosis nigricans in early child- can American girl with generalized acanthosis nigricans since infancy. Her father had a history of acanthosis nigricans since childhood, in addition to Crohn disease, obesity, and adult-onset diabetes mellitus. A pedigree with hood, especially with a family history of acanthosis nigricans, may warrant testing for FGFR3 mutations. Arch Dermatol. 2007;143(9):1153-1156 N UMEROUS GENETIC SYNdromes are associated with acanthosis nigricans (AN), particularly syndromes characterized by obesity, hyperinsulinemia, and/ or craniosynostosis.1 In a recent review, Torley et al1 divided these genetic syndromes into insulin resistance syndromes and fibroblast growth factor (FGF) defects. Insulin resistance syndromes are caused by mutations in the insulin receptor (leprechaunism and Rabson-Mendenhall syndrome), peroxisome proliferatoractivated receptor-␥ (insulin-resistant See also pages 1125, 1194, and 1209 Author Affiliations: Department of Internal Medicine, Division of Dermatology, and Department of Pediatrics, Washington University School of Medicine, St Louis, Missouri (Drs Berk and Bayliss); and DNA Diagnostic Laboratory and Department of Pediatrics, University of Colorado at Denver and Health and Sciences Center, Aurora (Dr Spector). diabetes mellitus with AN and hypertension), 1-acylglycerol-3-phophate O-acyltransferase-2 (Berardinelli-Seip syndrome), seipin (Berardinelli-Seip syndrome), lamin A/C (Dunnigan syndrome), and Alstrom syndrome genes. Fibroblast growth factor defects associated with AN include specific activating mutations of FGFR2 (Beare-Stevenson syndrome) and FGFR3 (Crouzon syndrome with AN and thanatophoric dysplasia [TD], and severe achondroplasia with developmental delay and AN [SADDAN syndrome]). (REPRINTED) ARCH DERMATOL/ VOL 143 (NO. 9), SEP 2007 1153 We describe herein a family with AN associated with a previously undescribed lysine to threonine mutation at codon 650 of the FGFR3 gene. All 4 affected family members who were tested demonstrated the mutation. The inheritance pattern was autosomal dominant, and there were no obvious associated skeletal or neurological abnormalities other than short stature. REPORT OF CASES A 4-year-old African American girl was referred for evaluation of generalized, minimally pruritic skin thickening since infancy. She was diagnosed as having atopic dermatitis by her pediatrician years earlier but had not responded to treatment with topical corticosteroids. She was otherwise healthy without diabetes mellitus and was taking no medications. Neurological development was normal. Her father (age, 25 years) described having a similar skin condition since early childhood. He was slightly obese and had Crohn disease and mild adultonset diabetes mellitus (diet controlled). There was no history of consanguinity. On physical examination, the patient had generalized, thick, velvety, hyperpigmented plaques that were most prominent on her neck, back, and axillae (Figure 1). There was no erythema or li- WWW.ARCHDERMATOL.COM A C A A G A A/C G A C Figure 1. Patient at age 4 years with thick, velvety, hyperpigmented plaque involving the neck and chest. chenification. Her oral mucosa, palms, and external genitalia were normal. Height and weight at age 5.5 years were 105.5 cm (eighth percentile) and 17.3 kg (20th percentile), respectively. Results from laboratory evaluations (complete blood cell count, urinalysis, and random glucose and hemoglobin A1c measurements) were normal. Examination of the patient’s father revealed similarly thick, velvety, hyperpigmented plaques localized to the neck, back, and axillae. His height was 156 cm (⬍ fifth percentile). Over the past few years, his weight had fluctuated from 48 to 106 kg due to his Crohn disease. Neither the patient nor her father had facial dysmorphism (eg, frontal bossing) or tibial bowing. Familial AN was diagnosed. Because activating FGFR3 mutations have been identified in several forms of syndromic AN, this gene was evaluated for mutations. Genetic testing was performed on DNA isolated from saliva (Oragene; DNA Genotek Inc, Ottawa, Ontario, Canada) followed by sequencing of exons 10, 13, and 15 of the FGFR3 gene. A single nucleotide change was observed in exon 15 (Figure 2). The patient and her father both demonstrated a previously undescribed lysine to threonine mutation at codon 650 (K650T) in one FGFR3 gene, suggesting autosomal dominant inheritance. No mutation was identified in the patient’s mother or the patient’s 3-year-old sister, both of whom were clinically unaffected. Genetic counseling was performed. There was no change with topical pimecrolimus and steroids. The father’s 29-year-old cousin (Figure 3) and her 11year-old daughter (Figure 4) were subsequently evaluated for the same condition and diagnosed as having familial AN, resulting in a pedigree with multiple affected relatives (Figure 5). The daughter’s height and weight at age 11 years were 139 cm (26th percentile) and 40.9 kg (68th percentile), respectively. Her mother’s height and weight were 145 cm (⬍ fifth percentile) and 64.2 kg (25th50th percentile), respectively. No further associated anomalies were identified in these 2 patients or reported in their relatives, including dysmorphic features, diabetes mellitus, Crohn disease, or skeletal or neurologic defects. Both this child and her mother demonstrated heterozygous K650T mutations on genetic testing, identical to their 2 relatives who had been previously tested. B A C A A G A A G A C Figure 2. Sequencing of exon 15 of the FGFR3 gene was performed using the following primers: forward, 5⬘ GTA AAA CGA CGG CCA GT AGG TGT GGG TGG AGT AGG; and reverse, 5⬘ CAG GAA ACA GCT ATG ACC TC AGG CGC CAT CCA CTT 5⬘ CTG TCA CCG TAG CCG TGA AG. Sequencing was performed using an ABI 3130 sequencer (Applied Biosystems, Foster City, California). A, The arrow indicates K650T mutation; A→C change at nucleotide 1950, amino acid 650. B, Normal sequence. COMMENT Acanthosis nigricans is characterized by velvety, hyperpigmented plaques often accentuated in the flexures. Numerous forms of AN have been described including be- (REPRINTED) ARCH DERMATOL/ VOL 143 (NO. 9), SEP 2007 1154 WWW.ARCHDERMATOL.COM Figure 3. Cousin (age, 29 years) demonstrating thick, velvety, hyperpigmented plaques on the neck and posterior auricular region. Figure 4. Cousin (age, 11 years) demonstrating thick, velvety, hyperpigmented plaques on the neck and forehead. nign (nonsyndromic, insulin resistance-associated AN), malignant (paraneoplastic), obesity-associated (pseudoAN), acral, medication-induced (corticosteroids, estrogens, oral contraceptives, niacin, triazinate, somatotrophin, and diethylstilbestrol), and syndromic AN (including isolated, “pure” familial AN).2,3 Generalized AN is rare and often paraneoplastic,4 even in very early childhood. However, generalized AN in early childhood may also suggest isolated (nonsyndromic, noninsulin resistance–associated) familial AN.4-8 Furthermore, there are reports of benign, generalized AN in early childhood without a positive family history, malignancy, associated syndrome, causative medication, or comorbid condition.9-15 Only a few families with isolated (nonsyndromic, noninsulin resistance–associated) familial AN have been reported in the literature.4-8 Inheritance tends to be autosomal dominant with variable penetrance. This “pure” familial AN usually appears in infancy, stabilizes at puberty, and is not associated with obesity or diabetes mellitus. The term familial AN is confusing because AN associated with insulin resistance also tends to be hereditary and the term familial AN has been used in the literature in such cases.16,17 Comorbid conditions have rarely been reported with isolated familial AN. Chuang et al18 reported a family with AN and ectodermal defects including madarosis. In addition, 2 cases of benign AN (no family history) in early childhood have been associated with pyramidal tract degeneration.11,15 Familial AN may be confused with ichthyosis hystrix,5 generalized epidermal nevi, or lichenification in atopic dermatitis. The pathogenesis of AN is poorly understood. In patients with hyperinsulinemia, excess insulin may directly or indirectly stimulate epidermal proliferation through the insulin-like growth factor 1 receptor.19 Growth factors (particularly transforming growth factor-␣) produced by tumors may cause malignant AN through the epidermal growth factor receptor.20 Fibroblast growth factors are involved in angiogenesis, embryogenesis, mitogenesis, and wound healing. There are more than 20 human FGF ligands and 4 human FGF receptors. The FGFR3 gene is located at 4p16.3 and encodes a transmembrane receptor tyrosine kinase, which down-regulates long-bone growth. FGFR3 mutations have been reported in several dermatologic conditions including seborrheic keratoses,21 epidermal nevi,22 and syndromic AN. Several autosomal dominant syndromes are caused by specific FGFR3 mutations, including achondroplasia, Muenke syndrome, hypochondroplasia, TD I and II, Crouzon syndrome with AN, and SADDAN syndrome. The latter 3 disorders demonstrate AN. Codon 650 of FGFR3 is located in its tyrosine kinase domain II. Mutations of this codon have been reported in skeletal disorders including hypochondroplasia (K650N and K650Q), SADDAN syndrome (K650M), TD I (K650M), and TD II (K650E), as well as malignant conditions including bladder cancer and multiple myeloma (K650M, K650E, and K650T). Germline K650T mutations have never been reported. Bellus et al23 studied the effects of various amino acid changes on the activation of FGFR3 in vitro. Constructs were made that contained all of the possible FGFR3 mutations at amino acid 650. (REPRINTED) ARCH DERMATOL/ VOL 143 (NO. 9), SEP 2007 1155 WWW.ARCHDERMATOL.COM port: Berk, Spector, and Bayliss. Study supervision: Berk and Spector. Financial Disclosure: None reported. Of an additional 11 siblings, 4 were affected ∗ ∗ ∗ ∗ ∗ ∗ Figure 5. Pedigree of family. Shaded boxes indicate affected family members. The asterisks indicate family members tested for FGFR3 mutations. In a [32P]-ATP autophosphorylation assay, the relative activity of the mutations compared with that of a wildtype construct was as follows: K650R, 1.5x; K650N, 3.7x; K650Q, 4.9x; K650T, 3.1x; K650E, 9.6x; and K650M, 18.1x. These data suggest that since the K650T mutation was a relatively weak activator of FGFR3, it would have a less severe effect on phenotype than the mutations found in hypochondroplasia, SADDAN syndrome, TD I, and TD II, as was observed in the patients described herein. Activating FGFR3 mutations and/or ectopic overexpression have been reported in a number of tumors, such as bladder,24 cervical,25 multiple myeloma,26 and colorectal cancers.27 Tyrosine kinase inhibitors of FGFR3 are being tested in several hematologic malignancies with positive results.26 Topical preparations of these inhibitors may prove beneficial for seborrheic keratoses, epidermal nevi, and/or AN.22 In summary, we describe a family with AN caused by an autosomal dominant K650T mutation in the FGFR3 gene. Extensive AN in early childhood, especially with a family history of AN, may warrant testing for FGFR3 mutations. Accepted for Publication: March 27, 2007. Correspondence: David R. Berk, MD, Division of Dermatology, Washington University School of Medicine, 660 S Euclid, Campus Box 8123, St Louis, MO 63110 (DBerk @im.wustl.edu). Author Contributions: Dr Berk had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Berk and Bayliss. Acquisition of data: Berk and Spector. Analysis and interpretation of data: Berk and Spector. Drafting of the manuscript: Berk and Spector. Critical revision of the manuscript for important intellectual content: Berk, Spector, and Bayliss. Statistical analysis: Berk. Administrative, technical, and material sup- REFERENCES 1. Torley D, Bellus GA, Munro CS. Genes, growth factors and acanthosis nigricans. Br J Dermatol. 2002;147(6):1096-1101. 2. Curth HO. Classification of acanthosis nigricans. Int J Dermatol. 1976;15(8):592593. 3. Curth HO. Acanthosis nigricans. Birth Defects Orig Artic Ser. 1971;7(8):31-39. 4. Inamadar AC, Palit A. Generalized acanthosis nigricans in childhood. Pediatr Dermatol. 2004;21(3):277-279. 5. Curth HO, Aschner BM. Genetic studies on acanthosis nigricans. AMA Arch Derm. 1959;79(1):55-66. 6. Curth HO. Benign acanthosis nigricans. Arch Dermatol. 1967;96(5):603-604. 7. Tasjian D, Jarratt M. Familial acanthosis nigricans. Arch Dermatol. 1984;120(10): 1351-1354. 8. Dhar S, Dawn G, Kanwar AJ, Nada R. Familial acanthosis nigricans. Int J Dermatol. 1996;35(2):126-127. 9. Curth HO. Benign type of acanthosis nigricans. Arch Derm Syphilol. 1936;34(3): 353-366. 10. Pindborg JJ, Gorlin RJ. Oral changes in acanthosis nigricans (juvenile type): survey of the literature and report of a case. Acta Derm Venereol. 1962;42:63-71. 11. Maranon G, Alvarez Cascos M. Benign juvenile acanthosis nigricans; its relation to congenital abnormalities. Acta Derm Venereol. 1957;37(3):249-258. 12. Skiljevic DS, Nikolic MM, Jakovljevic A, Dobrosavljevic DD. Generalized acanthosis nigricans in early childhood. Pediatr Dermatol. 2001;18(3):213-216. 13. Uyttendaele H, Koss T, Bagheri B, et al. Generalized acanthosis nigricans in an otherwise healthy young child. Pediatr Dermatol. 2003;20(3):254-256. 14. Rai VM, Balachandran C. Generalized acanthosis nigricans in childhood. Dermatol Online J. 2006;12(6):14. 15. Curth HO. Significance of acanthosis nigricans. AMA Arch Derm Syphilol. 1952; 66(1):80-100. 16. Taylor G, James MP, Simpson H. Familial acanthosis nigricans. J R Soc Med. 1994;87(3):169. 17. Friedman CI, Richards S, Kim MH. Familial acanthosis nigricans: a longitudinal study. J Reprod Med. 1987;32(7):531-536. 18. Chuang SD, Jee SH, Chiu HC, Chen JS, Lin JT. Familial acanthosis nigricans with madarosis. Br J Dermatol. 1995;133(1):104-108. 19. Cruz PD Jr, Hud JA Jr. Excess insulin binding to insulin-like growth factor receptors: proposed mechanism for acanthosis nigricans. J Invest Dermatol. 1992; 98(6)(suppl):82S-85S. 20. Haase I, Hunzelmann N. Activation of epidermal growth factor receptor/ERK signaling correlates with suppressed differentiation in malignant acanthosis nigricans. J Invest Dermatol. 2002;118(5):891-893. 21. Logié A, Dunois-Larde C, Rosty C, et al. Activating mutations of the tyrosine kinase receptor FGFR3 are associated with benign skin tumors in mice and humans. Hum Mol Genet. 2005;14(9):1153-1160. 22. Hafner C, van Oers JM, Vogt T, et al. Mosaicism of activating FGFR3 mutations in human skin causes epidermal nevi. J Clin Invest. 2006;116(8):2201-2207. 23. Bellus GA, Spector EB, Speiser PW, et al. Distinct missense mutations of the FGFR3 lys650 codon modulate receptor kinase activation and the severity of the skeletal dysplasia phenotype. Am J Hum Genet. 2000;67(6):1411-1421. 24. van Rhijn BW, van Tilborg AA, Lurkin I, et al. Novel fibroblast growth factor receptor 3 (FGFR3) mutations in bladder cancer previously identified in non-lethal skeletal disorders. Eur J Hum Genet. 2002;10(12):819-824. 25. Cappellen D, De Oliveira C, Ricol D, et al. Frequent activating mutations of FGFR3 in human bladder and cervix carcinomas. Nat Genet. 1999;23(1):18-20. 26. Grand EK, Chase AJ, Heath C, Rahemtulla A, Cross NC. Targeting FGFR3 in multiple myeloma: inhibition of t(4;14)-positive cells by SU5402 and PD173074. Leukemia. 2004;18(5):962-966. 27. Jang JH, Shin KH, Park JG. Mutations in fibroblast growth factor receptor 2 and fibroblast growth factor receptor 3 genes associated with human gastric and colorectal cancers. Cancer Res. 2001;61(9):3541-3543. (REPRINTED) ARCH DERMATOL/ VOL 143 (NO. 9), SEP 2007 1156 WWW.ARCHDERMATOL.COM OBSERVATION Eczematoid Graft-vs-Host Disease A Novel Form of Chronic Cutaneous Graft-vs-Host Disease and Its Response to Psoralen–UV-A Therapy Daniel Creamer, MD; Claire L. Martyn-Simmons, MRCP(England); Genevieve Osborne, MRCP(England); Michelle Kenyon, MSc; Jon R. Salisbury, MD; Stephen Devereux, MD; Antonio Pagliuca, MD; Aloysius Y. Ho, MD; Ghulam J. Mufti, MD; Anthony W. P. du Vivier, MD Background: Chronic cutaneous graft-vs-host disease (GVHD) is generally classified by whether lesions have a lichenoid or sclerodermatous morphology. Other unusual clinical forms have been reported that exhibit the features of dermatomyositis and lupus erythematosus. Within a large population of individuals who underwent allogeneic stem cell transplantation because of hematologic malignancy, a group of patients was identified in whom severe and persistent eczema developed. Observations: We prospectively evaluated 10 adult patients with unexplained eczematous dermatosis after allogeneic hematopoietic stem cell transplantation. The dermatosis developed between 2 and 18 months (mean, 7.5 months) after receipt of the transplant, exhibited the typical clinical features of dermatitis, and became erythrodermic in each case. The patient group had strong risk factors for chronic cutaneous GVHD: 8 had received a transplant from an unrelated donor, 7 had evidence of extracutaneous GVHD, and 7 had a history of acute cutaneous GVHD. Sampling of lesional skin revealed the histologic features of GVHD coexisting with the changes of dermatitis. The patients were treated with topical corticosteroid and systemic immunosuppressive agents. Six patients also received psoralen–UV-A. Four patients achieved prolonged remission. Six patients died, 5 of infective complications and 1 of relapsed leukemia. Conclusions: The eczematous dermatosis observed represents a novel form of chronic cutaneous GVHD that we named eczematoid GVHD. Eczematoid GVHD is an aggressive, chronic dermatosis that requires substantial immunosuppression therapy to achieve control. It is associated with a poor prognosis. Although atopy can be transmitted to an individual from a hematopoietic stem cell transplant, none of the donors in this series gave a history of an atopic disorder. Therefore, other factors must be implicated in provoking the expression of an eczematous phenotype in individuals with underlying chronic graft-vs-host activity. Arch Dermatol. 2007;143(9):1157-1162 G Author Affiliations: Departments of Dermatology (Drs Creamer, MartynSimmons, Osborne, and du Vivier) and Histopathology (Dr Salisbury), King’s College Hospital; and Department of Haematological Medicine, King’s College Hospital and King’s College London (Ms Kenyon and Drs Devereux, Pagliuca, Ho, and Mufti), London, England. RAFT - VS - HOST DISEASE (GVHD) is a multisystem disease initiated by allogeneic T lymphocytes that recognize foreign tissue antigens in the host.1 The disease usually develops after hematopoietic stem cell transplantation (HSCT), a therapeutic method used primarily to treat hematologic malignancy. However, it may also occur after transfusion of nonirradiated blood products, transplantation of solid organs, and maternal blood transfer in an immunodeficient fetus. Graft-vs-host disease results in complications in 40% to 80% of allogeneic HSCTs and is a major cause of morbidity and mortality.2 Graft-vs-host disease is divided into acute and chronic forms that have distinct disease patterns and are conventionally differentiated by whether onset is before or after 100 days following transplantation. Acute GVHD follows a graft-vs-host (GVH) (REPRINTED) ARCH DERMATOL/ VOL 143 (NO. 9), SEP 2007 1157 reaction targeted against epithelia of skin, gastrointestinal tract, and liver and is manifested with rash and diarrhea and with abnormal liver function test results. The eruption of acute GVHD is characterized by maculopapular exanthem with acral accentuation or, rarely, is manifested as widespread epidermal necrolysis.3 Clinically, chronic cutaneous GVHD has been classified by whether lesions have a sclerodermoid or lichenoid appearance.4 Sclerodermoid GVHD has many clinicopathologic patterns including cases resembling morphea, lichen sclerosus, and eosinophilic fasciitis.5 The diffuse form of sclerodermoid GVHD is associated with deepseated fibrosis and joint contractures. Lichenoid GVHD is characterized by the presence of violaceous, indurated papules and plaques that resemble lichen planus. Other papulosquamous GVHD subtypes have been reported including psoriasiform, keratosis pilaris–like, and asteatotic WWW.ARCHDERMATOL.COM A B Figure 1. Widespread, intensely pruritic, eczematous eruption in patient 7 (A) and patient 2 (B). During the course of the illness, all patients developed erythroderma with thermoregulatory dysfunction and dependent edema (B). forms.5 Rarely, GVHD variants occur that exhibit the features of autoimmune connective tissue diseases such as dermatomyositis and lupus erythematosus.6,7 Two reports cite eczemalike GVHD.8,9 We studied patients who developed cutaneous GVHD after HSCT performed in the Department of Haematological Medicine at King’s College Hospital, London, England. Patterns of GVHD manifestation, natural history, response to treatment, and outcome were recorded for all patients. Within this population, a distinct group has been identified characterized by persistent, widespread, chronic eczematous dermatosis occurring several months after allogeneic HSCT. The eruption demonstrates the histopathologic changes of both dermatitis and a GVH reaction, and we, therefore, suggest that it represents a manifestation of chronic cutaneous GVHD that warrants reporting and further investigation. METHODS PATIENTS Between January 1, 2001, and December 31, 2004, 254 patients underwent allogeneic HSCT in the Department of Haematological Medicine at King’s College Hospital. Of these patients, 10 were identified who developed chronic eczematous dermatosis after HSCT (eTable; available at: http://www.archdermatol.com). The group consisted of 8 men and 2 women, with a mean age at onset of dermatosis at 54.5 years (age range, 18-65 years). All patients had undergone allogeneic HSCT for the treatment of a hematologic malignancy (acute myeloid leukemia, 3 patients; chronic myeloid leukemia, 1; myelodyplastic syndrome, 2; chronic myelomonocytic leukemia, 2; myelofibrosis, 1; and acute lymphoblastic leukemia, 1). Dermatosis developed between 2 and 18 months (mean, 7.5 months) after HSCT. One patient had a history of atopic dermatitis, 2 had a history of asthma and hayfever, and 1 had a history of psoriasis. Drugs being taken by patients at the onset of dermatosis included prednisolone cyclosporine, tacrolimus, phenoxymethyl-penicillin, fluconazole, amphotericin B, and acyclovir. HEMATOPOIETIC STEM CELL TRANSPLANTATION All 10 patients received an allogeneic stem cell transplant. Stem cells were derived from the peripheral blood in 7 patients and bone marrow in 3. In 8 patients, the transplant was from a volunteer unrelated donor; in 2, the donor was a sibling (eTable). There was a donor-recipient sex mismatch in 3 of 10 transplantations and a donor-recipient cytomegalovirus mismatch in another 3 transplantations (eTable). None of the donors reported a history of atopy (atopic dermatitis, asthma, or eczema). One donor reported a history of mild psoriasis (the recipient was patient 5). The conditioning regimen, described previously,10 included alemtuzumab (Campath; Genzyme Corp, Cambridge, Massachusetts) in all patients but was otherwise (REPRINTED) ARCH DERMATOL/ VOL 143 (NO. 9), SEP 2007 1158 WWW.ARCHDERMATOL.COM A B Figure 2. Palmoplantar hyperkeratosis was present in 7 of 10 patients. A, Patient 4. B, One patient (patient 3) had marked ichthyotic scaling overlying the eczema. of reduced intensity in 9 patients (fludarabine phosphate, 150 mg/m2; busulfan, 8 mg/kg; and alemtuzumab, 100 mg) and of standard intensity in patient 7 (total body irradiation; cyclophosphamide; busulfan, 8 mg/kg; and alemtuzumab, 100 mg). RISK FACTORS FOR GVHD All 10 patients had received GVHD prophylaxis with cyclosporine and all transplants were T cell depleted in vivo using alemtuzumab in the conditioning regimen. Matching for donor relation, sex, and cytomegalovirus status is described above in “Hematopoietic Stem Cell Transplantation” subsection of the “Methods” section (eTable). Four patients had evidence of chronic hepatic, gastrointestinal GVHD, or both, occurring concurrently with the eczematous dermatosis. Seven patients were known to have had preceding acute cutaneous GVHD (eTable), and, in these patients, the eczematous dermatosis occurred 2 to 16 months (mean, 7.7 months) after acute GVHD. In 6 patients, the eruption appeared some months after acute GVHD (quiescent pattern), and in 1 patient (patient 3), it developed immediately after the acute episode (progressive pattern). Three patients (patients 4, 7, and 9) received donor lymphocyte infusions after HSCT (eTable). In these patients, the donor lymphocyte infusion was administered 13 weeks (patient 7) or 14 weeks (patients 4 and 9) after HSCT and 2 to 6 weeks before the onset of eczematous dermatosis. All patients received standard GVHD prophylaxis with cyclosporine and prednisolone in the first few months after HSCT. In 5 patients, the eczematous dermatosis developed as prophylactic immunosuppression therapy was being tapered in the 2 to 4 months after HSCT. CLINICAL FEATURES The eruption was similar in each patient and consisted of diffuse erythema and fine scaling, suggestive of eczema (Figure 1). Signs of impetiginization (colonization by Staphylococcus aureus) were frequently observed. Weeping in involved skin was common. Vesicles or pustules were not seen. Pruritus was usually severe and accompanied by excoriation. One patient had marked ichthyotic scaling, especially on the face and scalp (Figure 2). Palmoplantar hyperkeratosis was prominent in 7 of 10 patients (Figure 2). In all patients, the eczema rapidly became widespread, leading to erythroderma (exfoliative dermatitis). Erythrodermic involvement was complicated by thermoregulatory dysfunction, thirst, and dependent edema (Figure 1). HISTOPATHOLOGIC FEATURES Biopsy specimens were obtained from the affected skin in all patients. In each case, the histologic features of GVHD coexisted with the changes of dermatitis (Figure 3). The GVH reaction was indicated by satellite cell necrosis, and the presence of parakeratosis, lymphocyte exocytosis, and epidermal spongiosis reflected the clinical appearance of eczema (Figure 3). The dermal changes were less marked, often showing a sparse perivascular lymphocytic infiltrate. Eosinophils were admixed in the infiltrate in 4 patients. The combined features were not always present in the first biopsy specimen, and, in some patients, as many as 3 samples were necessary to indicate the eczematoid pattern of GVHD. TREATMENT First-line therapy for all patients was a regimen of an emollient, a potent topical corticosteroid ointment, and a sedating antihistamine taken at bedtime. Oral antibiotics were given when the dermatosis was complicated by secondary bacterial infection. Nine of 10 patients required hospital admission at least once during the course of their illness. Inpatient management (REPRINTED) ARCH DERMATOL/ VOL 143 (NO. 9), SEP 2007 1159 WWW.ARCHDERMATOL.COM A B Figure 3. A, Note parakeratosis, mild acanthosis, and an upper dermal and intraepidermal lymphocytic infiltrate (hematoxylin-eosin, original magnification ⫻40). B, The dermatopathologic condition exhibits the combined features of both eczema and a graft-vs-host reaction. There is spongiosis (short arrow) and satellite cell necrosis (long arrows) (hematoxylin-eosin, original magnification ⫻100). was considered necessary when systemic symptoms arising from the erythroderma (eg, thirst, shivering, or malaise) were prominent or if first-line therapy was ineffective in controlling the dermatosis. As well as delivering maximal topical therapy, erythroderma was treated with systemic immunosuppression with one or more of the following: psoralen–UV-A (PUVA), prednisolone, methylprednisolone, azathioprine, cyclosporine, tacrolimus, or mycophenolate mofetil (Table). In an attempt to limit systemic immunosuppression, 6 patients were treated with PUVA using oral psoralen (5methoxypsoralen) and a UV-A dosimetry regimen similar to that used to treat atopic dermatitis (Table). Psoralen–UV-A was delivered twice weekly starting at a dose of 0.5 J/cm2 and increasing the dose by 0.5 J/cm2 increments at each treatment to a maximum dose of 5 J/cm2. The duration of PUVA therapy was 12 to 20 weeks. RESULTS The course of dermatosis was prolonged in all 10 patients and did not tend to remit spontaneously. The shortest period of active involvement was 4 months, in 2 patients; both patients died with active eczematoid GVHD 4 months after the onset of dermatosis. The longest period of active involvement was 20 months (mean, 9.2 months; Table). The shortest follow-up was 4 months, and the longest was 42 months (mean, 15.5 months). Seven of the 10 patients also developed features of extracutaneous chronic GVHD, with hepatic involvement in 5 patients, bronchiolitis obliterans in 2, and involvement of the gastrointestinal tract in 2 (Table). In 2 patients, the dermatosis was controlled with topical agents and systemic immunosuppressant agents (prednisolone and mycophenolate mofetil in patient 8 and prednisolone, tacrolimus, and mycophenolate mofetil in patient 10). Four of the 6 patients treated with PUVA responded successfully, achieving complete cutaneous clearance, and remission was maintained with only low-dose systemic immunosuppression therapy (eg, prednisolone, 1-5 mg/d) or no systemic immunosuppression therapy. In 2 of the patients who responded to PUVA (patients 2 and 6), treatment was hampered by the presence of secondary infection with methicillin-resistant S aureus, and the dermatosis resolved only after staphylococcal eradication. Six patients died. The cause of death was considered to be bacterial sepsis in 2 patients, disseminated Aspergillus species infection in 2, and cryptococcosis in 1 (Table); 1 patient had a relapse of acute myelocytic leukemia. Two patients (patients 4 and 7) who died of septic complications had required prolonged exposure to high doses of systemic immunosuppressant agents to control the cutaneous GVHD. Secondary skin infection in patient 4 was probably the source of fatal overwhelming sepsis. Four patients1,5,8,10 have achieved long-term remission (12-42 months; mean, 24 months) of the eczematoid GVHD; 2 (patients 1 and 5) received PUVA and 2 (patients 8 and 10) did not (Table). In these patients, the hematologic malignancy has also remained in remission. COMMENT We describe 10 patients in whom a widespread, chronic dermatitic eruption developed after allogeneic HSCT. The striking feature in all of our patients was the coexistence of eczematous histopathologic features with changes of GVHD. All of the patients had risk factors for the development of chronic cutaneous GVHD: 8 had received a transplant from an unrelated donor, 7 had evidence of extracutaneous GVHD, and at least 5 had a history of acute cutaneous GVHD. We believe there is compelling evidence to suggest that the eczematous dermatosis observed in our patients represents a novel form of chronic cutaneous GVHD that we have named eczematoid GVHD. The differential diagnosis of a dermatitic eruption occurring after allogeneic HSCT should include the following: an eczematous drug reaction, the precipitation of preexisting dermatitis, or the acquisition of atopic diathesis from donor stem cells. Each potential cause of eczema was considered in our patients. All of the patients were receiving multiple drugs, but none of these were known to be associated with the induction of an eczematous drug eruption. Three patients had allergic disorders and 1 had mild eczema during childhood; (REPRINTED) ARCH DERMATOL/ VOL 143 (NO. 9), SEP 2007 1160 WWW.ARCHDERMATOL.COM Table. Treatment and Follow-up of Patients With Chronic Eczematoid GVHD Patient No. Treatment Response Duration of Disease, mo Duration of Follow-up, mo Outcome; Extracutaneous GVHD 1 2 3 4 5 6 7 8 9 10 PUVA, prednisolone, tacrolimus PUVA, prednisolone, tacrolimus Prednisolone, cyclosporine PUVA, methylprednisolone, cyclosporine PUVA PUVA, prednisolone, cyclosporine PUVA, prednisolone, cyclosporine Prednisolone, MMF Prednisolone Prednisolone, tacrolimus, MMF Good Good Good Poor Good Good Poor Good Good Good 20 17 4 12 8 6 9 6 4 6 24 20 4 12 12 7 9 42 4 20 Remission (skin and blood); no extracutaneous GVHD Died (relapse of AML); hepatic GVHD Died (cryptococcosis); hepatic GVHD Died (bacterial sepsis); hepatic and GI tract GVHD Remission (skin and blood); no extracutaneous GVHD Died (aspergillosis); hepatic GVHD Died (aspergillosis); hepatic GVHD Remission (skin and blood); bronchiolitis obliterans Died (bacterial sepsis); GI tract GVHD Remission (skin and blood); bronchiolitis obliterans Abbreviations: AML, acute myeloid leukemia; GI, gastrointestinal; GVHD, graft-vs-host disease; MMF, mycophenolate mofetil; PUVA, psoralen–UV-A. however, the remaining 7 patients had no history suggestive of an atopic susceptibility. None of the patients were known to have another eczematous dermatosis (eg, seborrhoeic dermatitis or allergic contact dermatitis) before HSCT. Although it is recognized that atopy can be transmitted to an individual from HSCT,11 none of the donors in this series gave a history of an atopic disorder. We, therefore, suggest that in these patients, eczema, observed both clinically and histopathologically, was expressed as a manifestation of chronic GVHD. Although the pathophysiology of chronic GVHD remains poorly understood, it is recognized that both alloreactive and autoreactive T cells have a role in mediating tissue damage.12 Thymic injury from acute GVHD may prevent the deletion of autoreactive clones, which can, therefore, promote a range of inflammatory responses.13 In murine chronic cutaneous GVHD, uncontrolled collagen synthesis is driven by transforming growth factor–␤ generated by an inflammatory process with a Th2-predominant cytokine profile.14 In many eczematous diseases, a Th2 response is also typical.15 A model to explain the development of an eczematous GVH response in our patients will, therefore, need to incorporate the complex interaction between antigenpresenting cells (including epidermal dendritic cells of donor origin) and autoreactive and allogenic T cells stimulated in the presence of Th2 cytokines. External stimuli, most notably, bacterial antigens, will influence the severity of eczematoid GVHD, as with other forms of eczema. Alemtuzumab, a monoclonal antibody that targets CD52 on mature T lymphocytes, was administered to all patients as a part of the conditioning regimen before HSCT. Alemtuzumab-induced T-cell depletion may be central to the development of eczematoid GVHD; however, larger studies are needed to explore the relation between conditioning regimens and GVH reactions. The development of GVHD after allogeneic HSCT has potential clinical benefits because concomitant graft-vsleukemia effects can control residual malignancy. In our series, only 1 patient had a relapse of the original hematologic malignancy. Nevertheless, the severity of this form of GVH reaction resulted in substantial morbidity and mortality. All of the patients with eczematoid GVHD developed erythroderma, which was poorly tolerated. The severity of the skin involvement necessitated, in most cases, admission to the hospital for intensive topical therapy and treatment with systemic immunosuppressant agents. Six patients died; in 5, the cause of death was considered to be an infective complication. Three patients had systemic fungal infections, and 1 died of overwhelming bacterial sepsis. In one of these patients, septicemia was probably a complication of intractable skin infection. The need to control the GVHD with systemic immunosuppression therapy may have had a permissive effect in the progression to fatal sepsis. Problems encountered with systemic immunosuppression therapy prompted the use of more effective skin-directed treatment. Six patients were treated with PUVA, and 4 of these responded well, achieving complete cutaneous clearance. Psoralen–UV-A is, therefore, recommended as a useful adjunctive and immunosuppression-sparing treatment in this form of GVHD. Eczematoid GVHD is a severe, often erythrodermic eruption associated with considerable morbidity and mortality. While this dermatosis represents a complex management problem for dermatologists treating patients with hematologic malignancies, the eczematous phenotype points to immunopathologic pathways previously unexplored in the GVH reaction. Accepted for Publication: May 3, 2007. Correspondence: Daniel Creamer, MD, Department of Dermatology, King’s College Hospital, Denmark Hill, London SE5 9RS, England (daniel.creamer@kingsch.nhs.uk). Author Contributions: Dr Creamer had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Creamer, Salisbury, Mufti, and du Vivier. Acquisition of data: Creamer, MartynSimmons, Osborne, Kenyon, Salisbury, Devereux, Pagliuca, Ho, Mufti, and du Vivier. Analysis and interpretation of data: Creamer, Martyn-Simmons, Osborne, Salisbury, Pagliuca, and Mufti. Drafting of the manuscript: Creamer, Salisbury, Mufti, and du Vivier. Critical revision of the manuscript for important intellectual content: Creamer, Martyn-Simmons, Osborne, Kenyon, Salisbury, Devereux, Pagliuca, Ho, Mufti, and du Vivier. Sta- (REPRINTED) ARCH DERMATOL/ VOL 143 (NO. 9), SEP 2007 1161 WWW.ARCHDERMATOL.COM tistical analysis: Mufti. Administrative, technical, or material support: Creamer, Martyn-Simmons, Osborne, Salisbury, Devereux, and Mufti. Study supervision: Creamer, Salisbury, Ho, Mufti, and du Vivier. Financial Disclosure: None reported. Additional Information: The eTable is available at http: //www.archdermatol.com. 8. 9. 10. REFERENCES 1. Billingham RE. The biology of graft-versus-host reactions. Harvey Lect. 1966-1967; 62:21-78. 2. Ferrara JL, Deeg HJ. Graft-versus-host disease. N Engl J Med. 1991;324(10):667674. 3. Johnson ML, Farmer ER. Graft-versus-host reactions in dermatology. J Am Acad Dermatol. 1998;38(3):369-396. 4. Hood AF, Soter NA, Rappeport J, Gigli I. Graft-versus-host reaction: cutaneous manifestations following bone marrow transplantation. Arch Dermatol. 1977; 113(8):1087-1091. 5. Hymes SR, Turner ML, Champlin RE, Couriel DR. Cutaneous manifestations of chronic graft-versus-host disease. Biol Blood Marrow Transplant. 2006;12 (11):1101-1113. 6. Ollivier I, Wolkenstein P, Gherardi R, et al. Dermatomyositis-like graft-versushost disease. Br J Dermatol. 1998;138(3):558-559. 7. Girardi M, Herreid P, Tigelaar R. Specific suppression of lupus-like graft-versus- 11. 12. 13. 14. 15. host disease using extracorporeal photochemical attenuation of effector lymphocytes. J Invest Dermatol. 1995;104(2):177-182. Tanasescu S, Balguerie X, Thomine E, et al. Eczema-like cutaneous graft versus host disease treated by UV-B therapy in a 2-year-old child [in French]. Ann Dermatol Venereol. 1999;126(1):51-53. Sloane JP, Thomas JA, Imrie SF, Easton DF, Powles RL. Morphological and immunohistological changes in the skin in allogeneic bone marrow recipients. J Clin Pathol. 1984;37(8):919-930. Ho AY, Pagliuca A, Kenyon M, et al. Reduced-intensity allogeneic hematopoietic stem cell transplantation for myelodysplastic syndrome and acute myeloid leukemia with multilineage dysplasia using fludarabine, busulphan, and alemtuzumab (FBC) conditioning [published online ahead of print April 1, 2004]. Blood. 2004;104(6):1616-1623. doi:10.1182/blood-2003-12-4207. Bellou A, Kanny G, Fremont S, Moneret-Vautrin DA. Transfer of atopy following bone marrow transplantation. Ann Allergy Asthma Immunol. 1997;78(5):513516. Sullivan KM, Parkman R. The pathophysiology and treatment of graft-versushost disease. Clin Haematol. 1983;12(3):775-789. Weinberg K, Blazar BR, Wagner JE, et al. Factors affecting thymic function after allogeneic hematopoietic stem cell transplantation. Blood. 2001;97(5):14581466. McCormick LL, Zhang Y, Tootell E, Gilliam AC. Anti-TGF-beta treatment prevents skin and lung fibrosis in murine sclerodermatous graft-versus-host disease: a model for human scleroderma. J Immunol. 1999;163(10):5693-5699. van Reijsen FC, Bruijnzeel-Koomen CA, Kalthoff FS, et al. Skin-derived aeroallergenspecific T-cell clones of Th2 phenotype in patients with atopic dermatitis. J Allergy Clin Immunol. 1992;90(2):184-193. Announcement Manuscript Submission v Before preparing a manuscript authors should review the Instructions for Authors available at http:// www.archdermatol.com. v Manuscripts are submitted to all sections of the Archives by Web access at http://manuscripts .archdermatol.com. v Authors may check the status of their manuscript as it proceeds through the review and decision process by logging into http://manuscripts.archdermatol.com. v It is important for authors to update their contact information, especially their e-mail addresses, by logging into http://manuscripts.archdermatol.com. Publication of accepted manuscripts may be delayed by our inability to locate authors, who need to approve copyedited manuscript proofs. (REPRINTED) ARCH DERMATOL/ VOL 143 (NO. 9), SEP 2007 1162 WWW.ARCHDERMATOL.COM WEB-ONLY CONTENT eTable. Chronic Eczematoid GVHD: Patient and Donor Characteristics a Patient No./ Sex/Age, y 1/M/54 2/M/65 3/M/46 4/M/62 5/F/56 6/F/64 7/M/18 8/M/54 9/M/63 10/M/62 Diagnosis Donor Type Donor Sex/ Age, y CMV Status R/D Acute GVHD DLI Onset of Eczematoid GVHD After Transplantion, mo MDS/RAEB MDS/AML Myelofibrosis CML AML MDS ALL CMML CML/AML CMML Unrelated Unrelated Unrelated Sibling Unrelated Unrelated Unrelated Unrelated Unrelated Sibling M/26 M/44 M/25 M/70 M/37 F/34 M/40 M/43 F/26 F/63 −/− −/− ⫹/⫹ ⫹/− −/⫹ −/− ⫹/− ⫹/⫹ −/− −/− Yes No Yes Yes Yes No No Yes No Yes No No No Yes No No Yes No Yes No 18 2 3 5 10 4 4 6 4 18 Abbreviations: ALL, acute lymphoblastic leukemia; AML, acute myeloid leukemia; CML, chronic myeloid leukemia; CMML, chronic myelomonocytic leukemia; CMV, cytomegalovirus; DLI, donor lymphocyte infusion; GVHD, graft-vs-host disease; MDS, myelodysplastic syndrome; RAEB, refractory anemia with excess blasts; R/D, recipient/donor; −, negative; ⫹, positive. a All patients underwent a conditioning regimen with alemtuzumab (Campath; Genzyme Corp, Cambridge, Massachusetts) and received GVHD prophylaxis. (REPRINTED) ARCH DERMATOL/ VOL 143 (NO. 9), SEP 2007 E1 WWW.ARCHDERMATOL.COM OBSERVATION Epidermolysis Bullosa Nevus An Exception to the Clinical and Dermoscopic Criteria for Melanoma Sarah H. Cash, MD; Tara T. Dever, MD; Patrice Hyde, MD; Jason B. Lee, MD Background: Large acquired melanocytic nevi that occur in patients with epidermolysis bullosa (EB), referred to as EB nevi, may pose a diagnostic challenge because of their clinical and dermoscopic resemblance to melanoma. These unconventional melanocytic nevi have been encountered in all categories of hereditary EB, most of them in childhood. Although some of the reported cases have an alarming clinical appearance that is indistinguishable from melanoma, long-term follow-up has confirmed the benign nature of these rarely encountered melanocytic lesions. The histopathologic patterns of these nevi range from a banal congenital pattern to the problematic persistent pseudomelanoma pattern. Observation: We describe the clinical, dermoscopic, and histopathologic features of a large EB nevus in a tod- R Author Affiliations: Department of Dermatology and Cutaneous Biology, Thomas Jefferson University Hospital, Philadelphia, Pennsylvania (Drs Cash, Hyde, and Lee); and National Naval Medical Center, Bethesda, Maryland (Dr Dever). Dr Cash is now in private practice in Dermatology Group of the Carolinas, Concord, North Carolina. dler. Clinically, the lesion was markedly asymmetrical and irregularly pigmented with foci of stippled pigmentation and scarring, which easily fulfilled the ABCD criteria for melanoma. Accordingly, a false-positive score resulted when dermoscopy was performed. Histopathologically, a pattern of persistent melanocytic neoplasm was observed. In the following 18 months, dynamic changes of the lesion included near-complete disappearance of the pigment, which was replaced by scar, milia, and areas of healing ulcers. Conclusion: Epidermolysis bullosa nevi are dynamic melanocytic lesions that may simulate melanoma. Arch Dermatol. 2007;143(9):1164-1167 ECENTLY, BAUER ET AL1 PRO- posed the term epidermolysis bullosa (EB) nevi for large acquired melanocytic nevi that are encountered in all forms of hereditary EB. Their clinical importance lies in the fact that they may simulate melanoma clinically and dermoscopically. In that 20-year prospective study of patients with EB nevi, however, no melanoma arose in association with these melanocytic nevi. We herein describe the clinical, dermoscopic, and histopathologic features of a large EB nevus in a toddler. After 18 months of followup, the pigment almost completely disappeared, with replacement by scar, milia, and areas of healing ulcers. REPORT OF A CASE A 3-year-old Korean boy with a known mutation for recessive dystrophic EB was noted on a routine follow-up visit to have a large pigmented lesion on the right thigh. The mother reported a rapid development of the pigmented lesion during a pe- (REPRINTED) ARCH DERMATOL/ VOL 143 (NO. 9), SEP 2007 1164 riod of several months that coincided with repeated blistering at the site. Physical examination revealed a large (9 ⫻ 10-cm), markedly asymmetric, irregularly pigmented patch on the right lateral thigh (Figure 1). In addition, areas of scarring with stippled pigmentation and regressive changes (ie, hypopigmentation and scarring) were found within the lesion (Figure 1). Results of the examination revealed no palpable lymph nodes. Dermoscopic findings included an atypical network and irregular dots and globules with colors that ranged from blue to varying shades of brown and black (Figure 2). Examination of a shave biopsy specimen from an area with multiple colors revealed a cleft at the dermoepidermal junction consistent with the patient’s known recessive dystrophic EB and increased pigment within the epidermis and dermis (Figure 3). Within the epidermis, there was an uneven distribution of solitary melanocytes and a mild degree of scatter (ie, pagetoid spread) accompanied by the presence of melanin at all levels of the epidermis, including the WWW.ARCHDERMATOL.COM Figure 3. A shave biopsy specimen shows a cleft between the dermoepidermal junction, effaced rete ridges, and pigmented nested melanocytes in the superficial dermis (hematoxylin-eosin, original magnification ⫻40). 100 µm Figure 1. A large pigmented lesion with an irregular border, color variegation, and areas of regression, scarring, and stippled pigmentation (arrow). Figure 4. Higher-power magnification of the specimen from Figure 3 shows fibrosis of the dermis, the presence of numerous melanophages, and nested monomorphous melanocytes (hematoxylin-eosin, original magnification ⫻200). mitotic figures, normal proliferative index, and knowledge of the EB nevus phenomenon eventually led to the diagnosis of EB nevus. Because of the reported benign clinical course of these nevi, no therapeutic intervention was offered, only close clinical follow-up. To our surprise, during 18 months of follow-up, there was complete regression of epidermal pigment. What remained were areas of healing ulcers, hypopigmented scars, and a subtle hue of dermal pigmentation in some foci (Figure 5). Whether or not the melanocytic lesion actually regressed completely was not confirmed by histopathologic evaluation. At 24 months, the patient was well, and development of additional melanocytic lesions was not observed. Figure 2. Dermoscopic image (original magnification ⫻10) shows irregular dots and globules, blue-gray pigment, and hypopigmented areas. cornified layer. Within the dermis, there were discretely nested, heavily melanized monomorphous melanocytes enveloped in fibrosis accompanied by numerous melanophages (Figure 4). No mitotic figures were observed. Immunohistochemical staining for Ki-67 showed no increase in the proliferative index. The histopathologic pattern was consistent with a persistent melanocytic neoplasm and, hence, the differential diagnosis was between a persistent melanocytic nevus and persistent melanoma. The monomorphous melanocytes, lack of any COMMENT Although rarely encountered, EB nevi may not be so rare among patients with EB. Bauer et al1 reported a prevalence rate of 14% (12 of 86) among the patients in their EB registry. The lesions are usually encountered in children with all major categories of hereditary EB. The mean ages of patients in reported cases of recessive dystrophic EB and EB simplex are 7 and 11 years, respectively.1-5 No predilection for sex or site appears to exist, except that the lesions are encountered at the sites of repeated blisters. They are often eruptive in nature, ie, they appear rapidly and enlarge within a few weeks to a few (REPRINTED) ARCH DERMATOL/ VOL 143 (NO. 9), SEP 2007 1165 WWW.ARCHDERMATOL.COM Figure 5. The lesion from Figure 1 after 18 months of follow-up shows regression of epidermal pigment. months. The reported lesions have ranged from 3 to 15 cm in diameter with an appearance that ranged from congenital melanocytic nevus to melanoma. The alarming clinical features included not only their large size but also the presence of marked asymmetry, irregular and/or stippled pigmentation, variegation in color, scarring, and foci of regression. On a morphologic basis alone, without the benefit of knowing the clinical context, the EB nevus may be indistinguishable from melanoma at times. Although Gallardo et al5 observed no melanomaassociated dermoscopic features in their series of EB nevi in a single patient, Lanschuetzer et al6 observed melanomaassociated dermoscopic features that included a multicomponent pattern, an atypical pigment network, and irregular dots and globules in many of the patients in their EB registry. Even the milky red areas highly characteristic of melanoma were present in several of their nevi. When dermoscopic algorithms were performed, a falsepositive score resulted in most of the lesions in their series. According to the authors,6 these apparently alarming clinical and dermoscopic findings can be explained by the known pathogenesis of EB nevi, ie, the repeated disruption of the dermoepidermal junction, fibrosing inflammation, scar formation, and neovascularization account for their clinical and dermoscopic features. Marghoob and Kopf 7 have previously reported that a persistent melanocytic nevus frequently yields a falsepositive dermoscopic score. It should be no surprise then that asymmetrical and irregularly pigmented EB nevi with a histopathologic pattern of persistent melanocytic neoplasm yield a false-positive dermoscopic score. The histopathologic pattern of EB nevus ranges from the readily recognizable congenital pattern to a problematic persistent/pseudomelanoma pattern.1-5 Most persistent patterns occur in patients with recessive dystrophic EB, whereas the congenital pattern occurs more frequently in patients with EB simplex. Obviously, the fibrosing inflammation that is more frequently encountered in recessive dystrophic EB accounts for this observation. Some of the large lesions, even those with an ominous clinical appearance, display a banal compound congenital pattern, ie, monomorphous melanocytes in nests and fascicles spanning the papillary and reticular dermis with angiotropism and adnexotropism.1,3,8 Other patients, like ours, have shown the persistent pattern, ie, uneven distribution of melanocytes within the epidermis and dermal melanocytes enveloped in fibrosis. The persistent pattern raises the differential diagnosis of persistent melanoma vs persistent melanocytic nevus. Diagnosing persistent nevus becomes problematic if sections from the previous procedure are not available and/or if only the portion of the persistent melanocytic neoplasm is biopsied, which may lack the readily recognizable conventional benign melanocytic pattern. In cases of large EB nevi, in which the entire lesion often cannot be sampled, the problem of the persistent pattern may not be resolvable on the basis of histologic sections alone because there are no previous sections to review and the entire lesion may not be available for review. Our patient represented such a dilemma. The clues that the lesion on our patient was benign included melanocytes in the dermis that were monomorphous, a lack of mitosis, and, accordingly, a normal proliferative index. In addition, the lesion in our patient had a striking clinical resemblance to a large superficial spreading melanoma, but this clinical and histopathologic pattern of melanoma, although common in adults, is exceedingly rare in children. Melanomas in children are usually papular or nodular and thus have a prominent vertical orientation clinically and histopathologically rather than the horizontal orientation that is typical of the superficial spreading type of melanoma.9,10 The knowledge of the EB nevus phenomenon and the histopathologic features eventually convinced us of the benign nature of the lesion on our patient. Although it is obvious that the recurrent blisters and the subsequent inflammation and/or fibrosis alter the morphologic features of melanocytic nevi in patients with EB, the exact mechanism by which the recurrent blisters achieve the alteration is unknown. Speculations include (1) induction by the Koebner phenomenon, meaning that disruption of melanocytes at the site of blisters somehow induces proliferation during reepitheliazation,2 and (2) seeding of a blister cavity by melanocytes from a preexisting nevus, which then proliferates owing to cytokines that are released by the inflammatory process caused by the blisters.8 Irrespective of the mechanism, the repeated blisters at the site of the nevi result in a dynamic growth pattern that may lead to clinical lesions, which may be asymmetrical and multicolored and have regressive changes due to chronic fibrosing inflammation rather than to specific immune-mediated process mounted against melanocytes. An EB nevus represents a collision between an inflammatory disease and a melanocytic nevus that results in unconventional phenotypic expression of the nevus. Collision between lichen sclerosus et atrophicus and melanocytic nevus represents an analogous phenomenon.11,12 These collision phenomena have led to diagnostic difficulties for the clinicians and histopathologists because the expected clinical and histopathologic findings of the melanocytic lesions are significantly altered. Similar to the EB nevus, the persistent melanocytic pattern is observed histopathologically in cases of collision with lichen sclerosus.11 The well- (REPRINTED) ARCH DERMATOL/ VOL 143 (NO. 9), SEP 2007 1166 WWW.ARCHDERMATOL.COM circumscribed nature of these lesions allows for correct interpretation in most instances. In cases of a large EB nevus, however, circumscription often cannot be assessed because only a portion of the lesion is available for interpretation. This adds to the diagnostic difficulty compared with the cases of lichen sclerosus. Previously reported cases of eruptive melanocytic nevi that appeared shortly after episodes of Stevens-Johnson syndrome and bullous erythema multiforme have been suggested as analogous phenomena.13-16 In these instances, there is no collision, per se; rather, the 2 phenomena occur metachronously rather than synchronously. Accordingly, diagnostic difficulties are not reported because there are no significant clinical and histopathologic alterations of the nevi’s morphologic features. Curiously, analogous phenomena have not been reported with any frequency in other blistering diseases known to occur in childhood, such as linear IgA dermatosis. In 1 reported case of an 8-year-old girl with bullous pemphigoid of the vulva, a melanocytic lesion at the site of the blisters eventually regressed completely. As in our patient, the lesion resembled melanoma clinically and dermoscopically.17 Although the association between squamous cell carcinoma and chronic scarring inflammatory dermatosis is well known, it is unclear whether such an association exists for melanoma in general. Data suggest that a higher incidence of melanoma may exist in patients with EB,18-20 especially recessive dystrophic EB, but there are no detailed, well-documented cases in the literature, in contrast to the well-documented and now well-known higher incidence of squamous cell carcinoma in patients with EB. Furthermore, the higher incidence has not been corroborated by experience in other countries. Because EB nevi may simulate melanoma, they have the potential to falsely increase the incidence and prevalence of melanoma among patients with EB if they are misconstrued as such. Clinicians and histopathologists should be aware of this phenomenon to avoid misdiagnosis and unnecessary therapeutic intervention. An EB nevus should be considered a distinct diagnostic possibility and should be excluded if melanoma is suspected in a child with EB. Once it has been established clinically, dermoscopically, and histopathologically that a lesion is an EB nevus, close clinical follow-up of these unconventional melanocytic nevi is an acceptable option, especially for nevi that are not amenable to simple excision owing to their large size. Accepted for Publication: February 20, 2007. Correspondence: Jason B. Lee, MD, Department of Dermatology and Cutaneous Biology, Thomas Jefferson University Hospital, 833 Chestnut St, Ste 704, Philadelphia, PA 19107 (Jason.b.lee@jefferson.edu). Author Contributions: Dr Lee had full access to all the data in the study and takes responsibility for the integrity of the data. Study concept and design: Lee. Acquisition of data: Cash and Hyde. Analysis and interpretation of data: Cash, Dever, and Lee. Drafting of the manuscript: Cash, Dever, Hyde, and Lee. Critical revision of the manuscript for important intellectual content: Dever, Hyde, and Lee. Administrative, technical, and material support: Cash and Hyde. Study supervision: Cash, Hyde, and Lee. Financial Disclosure: None reported. REFERENCES 1. Bauer JW, Schaeppi H, Kaserer C, Hantich B, Hintner H. Large melanocytic nevi in hereditary epidermolysis bullosa. J Am Acad Dermatol. 2001;44(4):577584. 2. Soltani K, Pepper MC, Simjee S, Apatoff BR. Large acquired nevocytic nevus induced by the Koebner phenomenon. J Cutan Pathol. 1984;11(4):296-299. 3. Hoss DM, McNutt NS, Carter DM, Rothaus KO, Kenet BJ, Lin AN. Atypical melanocytic lesions in epidermolysis bullosa. J Cutan Pathol. 1994;21(2):164169. 4. Stavrianeas NG, Katoulis AC, Moussatou V, et al. Eruptive large melanocytic nevus in a patient with hereditary epidermolysis bullosa simplex. Dermatology. 2003; 207(4):402-404. 5. Gallardo F, Toll A, Malvehy J, et al. Large atypical melanocytic nevi in recessive dystrophic epidermolysis bullosa: clinicopathological, ultrastructural, and dermoscopic study. Pediatr Dermatol. 2005;22(4):338-343. 6. Lanschuetzer CM, Emberger M, Laimer M, et al. Epidermolysis bullosa naevi reveal distinctive dermoscopic pattern. Br J Dermatol. 2005;153(1):97-102. 7. Marghoob AA, Kopf AW. Persistent nevus: an exception to the ABCD rule of dermoscopy. J Am Acad Dermatol. 1997;36(3, pt 1):474-475. 8. Lanschuetzer CM, Emberger M, Hametner R, et al. Pathogenic mechanisms in epidermolysis bullosa naevi. Acta Derm Venereol. 2003;83(5):332-337. 9. Ferrari A, Bono A, Baldi M, et al. Does melanoma behave differently in younger children than in adults? a retrospective study of 33 cases of childhood melanoma from a single institution. Pediatrics. 2005;115(3):649-654. 10. Mones JM, Ackerman AB. Melanomas in prepubescent children: review comprehensively, critique historically, criteria diagnostically, and course biologically. Am J Dermatopathol. 2003;25(3):223-238. 11. Carlson JA, Mu XC, Slominski A, et al. Melanocytic proliferations associated with lichen sclerosus. Arch Dermatol. 2002;138(1):77-87. 12. El Shabrawi-Caelen L, Soyer HP, Schaeppi H, et al. Genital lentigines and melanocytic nevi with superimposed lichen sclerosus: a diagnostic challenge. J Am Acad Dermatol. 2004;50(5):690-694. 13. Shoji T, Cockerell CJ, Koff AB, Bhawan J. Eruptive melanocytic nevi after StevensJohnson syndrome. J Am Acad Dermatol. 1997;37(2, pt 2):337-339. 14. Kirby JD, Darley CR. Eruptive melanocytic naevi following severe bullous disease. Br J Dermatol. 1978;99(5):575-580. 15. Burns DA, Sarkany I. Junctional naevi following toxic epidermal necrolysis. Clin Exp Dermatol. 1978;3(3):323-326. 16. Kopf AW, Grupper C, Baer RL, Mitchell JC. Eruptive nevocytic nevi after severe bullous disease. Arch Dermatol. 1977;113(8):1080-1084. 17. Lebeau S, Braun RP, Masouyé I, Perrinaud A, Harms M, Borradori L. Acquired melanocytic naevus in childhood vulval pemphigoid. Dermatology. 2006;213 (2):159-162. 18. Chorny JA, Shroyer KR, Golitz LE. Malignant melanoma and a squamous cell carcinoma in recessive dystrophic epidermolysis bullosa. Arch Dermatol. 1993; 129(9):1212. 19. Fine JD, Johnson LB, Tien H, et al. Skin cancer and inherited epidermolysis bullosa (EB): analysis of the National EB Registry cohort by disease type and subtype [abstract 12]. J Invest Dermatol. 1994;103(6):846. 20. Fine JD, Johnson LB, Tien H, et al. Risk of skin cancers and inherited epidermolysis bullosa (EB): determination of differences across major EB subtypes, as assessed by lifetable analysis techniques [abstract 21]. J Invest Dermatol. 1994;103(6):848. (REPRINTED) ARCH DERMATOL/ VOL 143 (NO. 9), SEP 2007 1167 WWW.ARCHDERMATOL.COM OBSERVATION Herpes Gestationis in a Mother and Newborn Immunoclinical Perspectives Based on a Weekly Follow-up of the Enzyme-Linked Immunosorbent Assay Index of a Bullous Pemphigoid Antigen Noncollagenous Domain Yumi Aoyama, MD; Kanako Asai, MD; Kana Hioki, MD; Michinori Funato, MD; Naomi Kondo, MD; Yasuo Kitajima, MD Background: Herpes gestationis (HG) is a rare, autoimmune, bullous disease that occurs during the second or third trimester and usually resolves over weeks or months after delivery. Neonates with HG are rare (estimated at 1 per 100 000 cases). Although anti–180-kDa bullous pemphigoid (BP180) autoantibody and transfer of this autoantibody are known as the cause, to our knowledge, no coordinated analysis of clinical symptoms and antiBP180 antibody enzyme-linked immunosorbent assay titers has been reported in a mother and neonate with HG. Observations: We describe a 33-year-old woman with HG and her neonate with vesicular erythematous lesions and the weekly follow-up results of the BP180 noncollagenous domain (NC16a) enzyme-linked immunosorbent assay. H Author Affiliations: Departments of Dermatology (Drs Aoyama, Asai, Hioki, and Kitajima) and Pediatrics (Drs Funato and Kondo), Gifu University School of Medicine, Gifu City, Japan. Conclusions: Almost the same titer of pathogenic antibody as that in the mother is transferred to the neonate. The plasma elimination half-life of anti-BP180 antibody is approximately 15 days in mother and neonate. An abrupt twin peak increase in the BP180 enzyme-linked immunosorbent assay index from maternal serum was observed just before and after delivery, possibly explaining why HG usually occurs in the last trimester of pregnancy and exacerbates postpartum. Lesions in the neonate resolve without treatment far before pathogenic antibody disappears, suggesting that factors other than anti-BP180 antibodies may be involved in the generation of eruptions. Frequent testing of the BP180 enzyme-linked immunosorbent assay greatly facilitates therapeutic planning. Arch Dermatol. 2007;143(9):1168-1172 ERPES GESTATIONIS (HG), also known as pemphigoid gestationis, is a rare, autoimmune, bullous disease that occurs during the second or third trimester, but it has been reported in the first trimester.1 It flares at delivery and usually resolves spontaneously over weeks or months after delivery. Herpes gestationis is clinically characterized by pruritic urticarial papules or plaques, polymorphous eruptions, and annular or figured erythematous-edematous lesions evolving into vesicles and tense blisters. These skin eruptions usually start on the abdomen and spread over the whole body, including the extremities; the face, scalp, and mucous membranes are much less involved.2,3 Immunologically, HG is characterized by linear deposition of C3 with or without associated IgG at the basement membrane zone on direct immunofluorescence4,5 and by the presence on serum of antibodies to the 180-kDa bullous pemphigoid (BP) antigen (BP180), which is type 17 collagen contained in the hemidesmosomal components. 6,7 Epitope mapping has revealed that HG and (REPRINTED) ARCH DERMATOL/ VOL 143 (NO. 9), SEP 2007 1168 BP autoantibodies primarily bind at a common antigenic site within the noncollagenous domain (NC16a) of BP180.8 Most HG serum samples are positive for the NC16a domain on immunoblot analysis (93%), with enzyme-linked immunosorbent assay (ELISA) (88%) using the BP180 NC16a domain as the antigen.9 We describe herein a mother and neonate with HG, with precise weekly follow-up studies of the BP180 NC16a ELISA (BP180 ELISA) index during treatment. The present case displayed BP180 ELISA titers in the umbilical artery and vein of 1224.5 and 1021.6, respectively, compared with 1521.8 in maternal venous blood; the plasma elimination half-life of BP180 antibody was approximately 15 days during the first 33 days after birth in the mother and neonate. The BP180 ELISA activity had been eliminated by day 112 after delivery in the neonate, but the maternal level remained higher than normal (at 44.3) as of 19 months after delivery. We present an immunoclinical perspective of HG based on BP180 ELISA analysis of the present case. WWW.ARCHDERMATOL.COM A B Figure 1. Exudative and erythematous lesions with clusters of vesicles on the abdomen (A) and vesicles on the palm (B) of the mother. REPORT OF A CASE A 33-year-old woman with a 1-week history of itchy exudative or urticarial erythema in a figurate and annular pattern, with tense vesicles on the abdomen, presented in gestational week 18 of her third pregnancy (Figure 1A). Examination of the skin revealed palmar plantar pruritic dyshidrosislike vesicles (Figure 1B). Her medical history included a presumptive diagnosis of pruritic urticarial papules and plaques of pregnancy in the first pregnancy, with delivery of a healthy neonate, and a spontaneous abortion with pruritic urticarial papules and plaques of pregnancy in her second pregnancy. No other history of diseases was elicited. Because severe itching and extension of lesions to the entire body were identified, the patient was admitted to Gifu University Hospital, Gifu City, for corticosteroid treatment. The otherwise healthy newborn boy, weighing 2264 g, had developed annular erythema, with vesicles ranging from coin to walnut size and appearing when he was 3 days old, involving the face, trunk, and extremities (Figure 2A and B). The neonate also developed dyshidrosislike vesicles on the soles, as did the mother (Figure 2C). These lesions resolved in the neonate by the time he was 10 days old, without treatment. A previous study10 of HG revealed that HLA-DR3 and HLA-DR4 are 2 predominant histocompatibility complex II molecules that are common to patients with HG. In our case, the mother and neonate shared a common HLA-DR antigen, because the mother expressed DR4/15 and the neonate expressed DR4. Skin biopsy specimens were obtained from the edge of erythema with vesicles on the arm of the mother. A histopathological examination using hematoxylineosin staining demonstrated marked subepidermal edema and blisters, with an inflammatory infiltrate mainly comprising eosinophils in blisters and the upper dermis A B C Figure 2. Annular erythematous-edematous lesions on the face (A) and abdomen (B) and vesicles on the soles (C) of the neonate. (Figure 3A). Direct immunofluorescence of the skin biopsy specimens showed linear C3 deposits in the basement membrane zone (Figure 3B), whereas IgG was weakly positive and IgA and IgM were not detected. The BP180 ELISA titers were determined using a BP180 NC16a ELISA kit (MBL, Nagoya, Japan). Briefly, each well (REPRINTED) ARCH DERMATOL/ VOL 143 (NO. 9), SEP 2007 1169 WWW.ARCHDERMATOL.COM B A Figure 3. Hematoxylin-eosin staining of a vesicular erythematous lesion from the mother (A) and a clear linear deposit of C3 shown on direct immunofluorescence of biopsy specimens from perilesional skin of the mother (B). In A, papillary dermis shows marked edema associated with eosinophils and blisters in which eosinophils and fibrin strands are contained. The epidermis appears intact. Prednisolone, mg/d 30 25 20 35 15 Azathioprine, mg/d Minomycin, mg/d Erythema 50 100 Vesicles 6000 5500 5000 b 4500 BP180 ELISA Index 4000 3500 a 3000 2500 2000 1500 1000 500 c Delivery 0 Oct Nov Dec Jan 12 12 12 12 2004 Feb Mar Apr May Jun 12 12 12 12 12 Jul 12 Aug 12 2005 Figure 4. Time course of clinical symptoms, treatments, and the 180-kDa bullous pemphigoid (BP180) enzyme-linked immunosorbent assay (ELISA) index of the mother: an abrupt twin peak increase in the BP180 ELISA index is seen in maternal serum just before (a) and after (b) delivery; oral prednisolone, 20 to 30 mg/d, sustains remission, whereas marked exacerbation is seen at the second peak of the BP180 ELISA index just after delivery and mild exacerbation is present 4 months after delivery (c). of standard 96-well microtiter plates was coated with recombinant glutathione S-transferase NC16a or the same amount of recombinant glutathione S-transferase. Serum samples, diluted 101-fold, 16 times 101-fold, or 64 times 101-fold, were incubated in duplicate for reaction, and ELISA indexes were determined in accordance with the instructions of the manufacturer. The mother was initially treated with 30 mg/d (0.6 mg/kg per day) of prednisolone for the first 2 weeks, when the BP180 ELISA index was 2500. By approximately 3 weeks after the initiation of treatment with oral prednisolone at this dosage, eruptions had resolved despite 1 occasion of exacerbation and the ELISA index had also increased once to 5950 before decreasing to 2360 (Figure 4). Because eruptions had mostly resolved, the prednisolone dosage was gradually tapered to 20 mg/d over the following 4 weeks, although the ELISA index remained somewhat higher (approximately ⬎2360) than normal, and this dosage was maintained until delivery, because any further decrease in prednisolone dosage led to flares in disease activity. At 1 week after delivery, prednisolone was decreased by 5 mg/d, resulting in severe clinical recurrence with a marked increase in the BP180 ELISA index. Given this severe recurrence of clinical symptoms and the increased ELISA index, the prednisolone dosage was increased to 35 mg/d for 1 week and gradually decreased to 15 mg/d over 5 months. The mother has been clinically in remission with treatment of 15 mg/d of prednisolone and 100 mg/d of azathioprine. The time course of the BP180 ELISA index in the mother revealed that anti-BP180 activity increased dramatically 1 month before and 2 weeks after delivery to maximum indexes of 2955 and 4300, respectively, and gradually decreased with prednisolone treatment to approximately 50 by 9 months after delivery. The BP180 ELISA indexes in the umbilical artery and vein were 1225 and 1022, respectively, compared with 1522 in maternal venous blood. Furthermore, the plasma elimination half-life of the BP180 antibody in the neonate was approximately 15 days during the initial 33 days after delivery (Figure 5). Anti-BP180 antibody activity in the neonate, as determined by the BP180 ELISA, was completely eliminated by the time the neonate was 112 days old. Eruptions in the neonate resolved even when the titer of pathogenic antibody was still high (BP180 ELISA index, approximately 770), far before the pathogenic antibody titer disappeared. This may suggest that anti-BP180 antibody is insufficient to generate skin lesions. (REPRINTED) ARCH DERMATOL/ VOL 143 (NO. 9), SEP 2007 1170 WWW.ARCHDERMATOL.COM COMMENT The present case study of a mother and neonate with HG focused on the follow-up of BP180 ELISA levels, providing several novel insights that may lead to a better understanding of HG. This was an extreme rare opportunity to be able to follow the BP180 ELISA index in a mother and neonate, because most neonates of mothers with HG are born with normal skin and neonates with vesicular lesions are rare (estimated at 1 per 100 000 cases).11,12 Our case clearly proves that vesicular erythematous lesions in the neonate are caused by transplacental passage of pathogenic antibodies against BP180 NC16a, from the mother to the neonate, as shown by the fact that BP180 ELISA indexes in the umbilical artery and vein were 1225 and 1022, respectively, compared with 1522 in maternal venous blood. Interestingly, indexes from the neonate at 1 and 4 days after birth were 1154 and 784, respectively. Also, eruptions in the neonate disappeared by the age of 8 days, much faster than the disappearance of anti-BP180 activity, suggesting that some unknown factors may be involved in the generation of blisters. The plasma elimination half-life of IgG is thought to be around 14 days in the average human adult. The present neonatal case revealed for the first time, to our knowledge, a plasma elimination half-life for anti-BP180 antibody of approximately 15 days during the first 33 days after birth. The pathway of anti-BP180 antibody elimination from plasma may involve consumption by binding to antigen in patients with BP in addition to physiological degradation of other IgG levels. Antibody bound to BP180, which is expressed over the entire basal cell surface and on hemidesmosomes in the basement membrane zone, is degraded by internalization from the membrane surface into basal cells13 and by several proteolytic enzymes generated during the inflammation process because of compliment activation at the basement membrane zone. However, the present study suggests that the consumption of pathogenic IgG in the basement membrane zone is not substantial, because the 15-day elimination half-life of pathogenic IgG in the first 33 days is approximately the same as the physiological elimination half-life of IgG. Herpes gestationis occurs during the second or third trimester (mean onset, 21 weeks) or, in some cases, during the first trimester.1 It flares at delivery in 75% of cases.14 In most cases, it regresses spontaneously over weeks or months after delivery. This seems to be associated with anti-BP180 antibody activity, as shown in an abrupt twin peak increase in the BP180 ELISA index from maternal serum just before and after delivery (Figure 4). Exactly why pathogenic antibody increases before and after delivery remains unclear, but the chorionic membrane, which is rich in BP180 antigen, may become labile at this stage of pregnancy and delivery, resulting in the release of antigen into the maternal bloodstream, in turn activating the production of pathogenic antibody. The elimination rate of pathogenic antibody from the second peak on day 40 (shown as “b” in Figure 4) to the trough level on day 64 after delivery in maternal serum closely parallels that in the neonate (Figure 5), for the baseline BP180 ELISA indexes of the mother (2955) and BP180 ELISA Index, % 100 Mother Neonate 80 60 50 40 25 20 0 0 8~11 33 50 100 150 Time After Delivery, d Figure 5. Elimination curve of the 180-kDa bullous pemphigoid (BP180) enzyme-linked immunosorbent assay (ELISA) index for mother and neonate. Starting points for the ELISA index of the mother (2955) and neonate (1154) were normalized as 100%. The elimination half-life of anti-BP180 antibody is initially approximately 15 days in mother and neonate in the first 33 days after delivery. neonate (1154) normalized to 100%. After postdelivery day 60, pathogenic antibody disappeared from the neonate, whereas antibody in the mother continued to show a mild up-and-down slope (peak “c” in Figure 4) and stayed in the abnormal range, with a BP180 ELISA index of 43.3, suggesting that the disease activity to produce pathogenic antibody remains present, although much less extensive. This suggests a diagnosis of chronic persistent HG or progression to bullous pemphigoid. Monitoring the ELISA index is useful when corticosteroid tapering is planned after all skin lesions are gone. Even if all the lesions are gone, we may have to think of keeping a minimum dosage of corticosteroids to suppress antibody production to prevent recurrence, when ELISA indexes remain in high titer, as shown in the mother’s case (Figure 4). In summary, we have presented herein an interesting coordinate analysis of clinical severity and time course of the BP180 ELISA index, demonstrating the following: (1) almost the same titer of pathogenic antibody as that in the mother is transferred to the neonate; (2) the plasma elimination half-life of anti-BP180 antibody is approximately 15 days during the first 33 days after delivery in mother and neonate; (3) an abrupt twin peak increase in the BP180 ELISA index from maternal serum was observed just before and after delivery, possibly explaining why HG usually occurs in the last trimester of pregnancy and exacerbates postpartum; (4) lesions in the neonate resolve far before pathogenic antibody disappears, and without treatment, suggesting that factors other than anti-BP180 antibodies may be involved in the generation of the eruption; and (5) frequently testing the BP180 ELISA index greatly facilitates treatment planning. Accepted for Publication: February 20, 2007. Correspondence: Yumi Aoyama, MD, Department of Dermatology, Gifu University School of Medicine, Yanagido 1-1, Gifu City 501-1194, Japan (ymaoyama@gifu-u.ac.jp). Author Contributions: Dr Aoyama had full access to all the data in this study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Aoyama. Acquisition of data: Aoyama, Asai, Hioki, Funato, and Kondo. Analysis and (REPRINTED) ARCH DERMATOL/ VOL 143 (NO. 9), SEP 2007 1171 WWW.ARCHDERMATOL.COM interpretation of data: Aoyama and Kitajima. Drafting of the manuscript: Aoyama. Critical revision of the manuscript for important intellectual content: Aoyama, Asai, Hioki, Funato, Kondo, and Kitajima. Obtained funding: Aoyama. Administrative, technical, and material support: Kondo. Study supervision: Kitajima. Financial Disclosure: None reported. Funding/Support: This study was supported by grantsin-aid for scientific research from the Ministry of Education, Culture, Sports, Science, and Technology of Japan; Health and Labor Sciences Research Grants for Research on Measures for Intractable Disease; and the Ministry of Health, Labor, and Welfare of Japan. REFERENCES 1. Jenkins RE, Hern S, Black MM. Clinical features and management of 87 patients with pemphigoid gestationis. Clin Exp Dermatol. 1999;24(4):255-259. 2. Shornick JK, Bangert JL, Freeman RG, Gilliam JN. Herpes gestationis: clinical and histologic features of twenty-eight cases. J Am Acad Dermatol. 1983;8 (2):214-224. 3. Lin MS, Arteaga LA, Diaz LA. Herpes gestationis. Clin Dermatol. 2001;19(6):697702. 4. Provost TT, Tomasi TB Jr. Evidence for complement activation via the alternate pathway in skin diseases, I: herpes gestationis, systemic lupus erythematosus, and bullous pemphigoid. J Clin Invest. 1973;52(7):1779-1787. 5. Bushkell LL, Jordon RE, Goltz RW. Herpes gestationis: new immunologic findings. Arch Dermatol. 1974;110(1):65-69. 6. Giudice GJ, Wilske KC, Anhalt GJ, et al. Development of an ELISA to detect antiBP180 autoantibodies in bullous pemphigoid and herpes gestationis. J Invest Dermatol. 1994;102(6):878-881. 7. Matsumura K, Amagai M, Nishikawa T, Hashimoto T. The majority of bullous pemphigoid and herpes gestationis serum samples react with the NC16a domain of the 180-kDa bullous pemphigoid antigen. Arch Dermatol Res. 1996;288(9): 507-509. 8. Lin MS, Gharia M, Fu CL, et al. Molecular mapping of the major epitopes of BP180 recognized by herpes gestationis autoantibodies. Clin Immunol. 1999;92(3): 285-292. 9. Sitaru C, Powell J, Messer G, Brocker EB, Wojnarowska F, Zillikens D. Immunoblotting and enzyme-linked immunosorbent assay for the diagnosis of pemphigoid gestationis. Obstet Gynecol. 2004;103(4):757-763. 10. Shornick JK, Stastny P, Gilliam JN. High frequency of histocompatibility antigens HLA-DR3 and DR4 in herpes gestations. J Clin Invest. 1981;68(2):553555. 11. Chorzelski TP, Jablonska S, Beutner EH, Maciejowska E, Jarzabek-Chorzelska M. Herpes gestations with identical lesions in the newborn: passive transfer of the disease? Arch Dermatol. 1976;112(8):1129-1131. 12. Katz A, Minto JO, Toole JW, Medwidsky W. Immunopathologic study of herpes gestationis in mother and infant. Arch Dermatol. 1977;113(8):1069-1072. 13. Kitajima Y, Nojiri M, Yamada T, Hirako Y, Owaribe K. Internalization of the 180 kDa bullous pemphigoid antigen as immune complexes in basal keratinocytes: an important early event in blister formation in bullous pemphigoid. Br J Dermatol. 1998;138(1):71-76. 14. Baxi LV, Kovilam OP, Collins MH, Walther RR. Recurrent herpes gestationis with postpartum flare: a case report. Am J Obstet Gynecol. 1991;164(3):778-780. (REPRINTED) ARCH DERMATOL/ VOL 143 (NO. 9), SEP 2007 1172 WWW.ARCHDERMATOL.COM EVIDENCE-BASED DERMATOLOGY: STUDY SECTION EDITOR: MICHAEL BIGBY, MD; ASSISTANT SECTION EDITORS: DAMIANO ABENI, MD, MPH; ROSAMARIA CORONA, DSc, MD; URBÀ GONZÁLEZ, MD, PhD; ABRAR A. QURESHI, MD, MPH; HYWEL WILLIAMS, MSc, PhD, FRCP; CRITICALLY APPRAISED TOPIC FEATURE EDITOR: MICHAEL J. SLADDEN, MAE, MRCP(UK) Balancing the Benefits and Risks of Drug Treatment A Stated-Preference, Discrete Choice Experiment With Patients With Psoriasis Elizabeth M. Seston, PhD; Darren M. Ashcroft, PhD; Christopher E. M. Griffiths, MD, FRCP Objective: To examine the extent to which the attributes of a treatment affect patients’ choice of treatment for psoriasis and the magnitude and nature of trade-offs between risks and benefits of treatment. Design: A questionnaire, including a stated-preference, discrete choice experiment, was used to elicit patients’ preferences for the treatment of psoriasis. Setting: Dermatology clinics in England. Patients: A total of 126 patients with psoriasis. the mean duration of psoriasis was 23 years. All 6 attributes were important factors affecting choice of treatment. The results indicated that patients with psoriasis prioritized low risk of skin cancer (␤=−0.054; P⬍.01) and liver damage (␤ = −0.054; P ⬍ .01) and preferred treatment that resulted in a shorter time to achieve a moderate improvement (␤=−0.034; P⬍.01) over a longer time to relapse (␤=0.028; P⬍.01). Patients were most willing to wait longer for a treatment to work if the likelihood of skin cancer or liver damage was reduced. Main Outcome Measures: Preferences of patients for, and trade-offs between, the 6 attributes of time to moderate (50%) improvement, relapse, and risks of experiencing skin irritation, high blood pressure, liver damage, and skin cancer. Conclusions: This study shows that treatment attributes influence patients with psoriasis in their choice of treatment. The results of the discrete choice experiment presented herein indicate that most respondents would be willing to trade between different aspects of treatment to achieve improvements in their psoriasis and minimize the risks of adverse events. Results: The mean age of respondents was 47.6 years, and Arch Dermatol. 2007;143(9):1175-1179 P Author Affiliations: School of Pharmacy and Pharmaceutical Sciences (Drs Seston and Ashcroft) and Dermatology Centre, Hope Hospital (Dr Griffiths), University of Manchester, Manchester, England. SORIASIS IS A CHRONIC IN - flammatory, hyperproliferative skin disease that affects approximately 1% to 2% of the general population in the United Kingdom.1 The morbidity associated with psoriasis is well documented in terms of its impact on patients’ quality of life.2-4 Many patients experience problems with body image, self-esteem and selfconcept, poor psychological adaptation, and feelings of stigmatization, shame, and embarrassment concerning their appearance.2,5,6 The disease also places an economic burden on patients, particularly those with severe psoriasis, because they incur out-of-pocket expenses.7 There is currently no cure for psoriasis, although a wide range of therapies are available, varying considerably in terms of efficacy and toxic effects.8 Levels of adherence to treatment among patients with psoriasis are low, with nonadherence rates reported in 40% of patients.9,10 Factors such as efficacy9,11 and duration of treatment10 can influence the decision whether to con- (REPRINTED) ARCH DERMATOL/ VOL 143 (NO. 9), SEP 2007 1175 tinue with treatment. Previous studies12,13 have shown that many patients with psoriasis often feel frustrated with the ineffectiveness of current therapies and want treatment to be more aggressive. It has also been suggested that dermatologists (and other physicians) may not appreciate fully the impact that skin diseases have on individual patients.14,15 Little is known about how patients with psoriasis evaluate the risks and benefits of the treatments they are offered. Given the low levels of adherence among these patients, information about the decisionmaking process could be useful for physicians considering which treatment to offer. This study used a stated-preference, discrete choice experiment (DCE)16 to explore the attitudes of patients toward the risks and benefits of drug treatment for psoriasis. The objectives were to (1) identify the extent to which the attributes of a treatment (eg, degree of improvement, duration of remission, and adverse effects) affected patients’ choice of treatment for their psoriasis, (2) determine the hierarchical im- WWW.ARCHDERMATOL.COM Section Editor’s Note Table 1. Treatment Attributes, Definitions, and Levels Used in the Discrete Choice Experiment Treatment Attribute Definition Time to achieve moderate (50%) improvement in psoriasis Time to relapse Time taken for psoriasis to improve by 50% following treatment 4, 8, 12, or 24 wk Time taken to lose the improvement in psoriasis obtained from the treatment once the treatment is stopped Percentage risk of experiencing skin irritation while using treatment Percentage risk of experiencing high blood pressure while using treatment Percentage risk of liver damage from treatment over a 20-y period Percentage risk of developing squamous cell or basal cell skin cancer as a result of treatment over a 20-y period 2, 6, 12, or 24 wk Risk of experiencing skin irritation during treatment Risk of high blood pressure during treatment 20-y risk of experiencing liver damage 20-y risk of experiencing skin cancer 0%, 10%, 20%, or 50% 1. Ryan M, Scott DA, Reeves C, et al. Eliciting public preferences for healthcare: a systematic review of techniques. Health Technol Assess. 2001;5(5):1-186.. 2. Ryan M, Bate A, Eastmond CJ, Ludbrook A. Use of discrete choice experiments to elicit preferences. Qual Health Care. 2001;(10 suppl 1):i55-i60. 0% or 10% 0% or 20% Table 2. Example of Choice Set Used in the Discrete Choice Experiment Time to achieve moderate (50%) improvement in psoriasis, wk Time to relapse, wk Risk of experiencing skin irritation during treatment, % Risk of high blood pressure during treatment, % 20-y risk of experiencing liver damage,% 20-y risk of experiencing skin cancer, % Which treatment would you prefer? (Please choose 1 only.) Michael Bigby, MD 0% or 10% a See the “Methods” section. Treatment Attribute Does determining patients’ preferences have to be so complicated? Probably. Ryan et al1 reviewed the state of the art of eliciting public preferences for health care. Quantitative techniques include ranking exercises, rating scales, and choice-based techniques (as used in this article by Seston et al). Qualitative techniques include interviews, case study analyses, the Delphi technique, complaints procedures, focus groups, concept mapping, citizens’ juries, consensus panels, public meetings, and nominal group techniques. All techniques have strengths and limitations that were well reviewed by Ryan et al.1 A thorough description of discrete choice experiments and an example of their use in rheumatology can be found in a second article by Ryan et al.2 Attribute Levels a Treatment A Treatment B 4 12 2 0a 24 10 b 10 b 0a 0a 20 c A 10 b 0a B a No risk. b One in 10 people. c Two in 10 people. portance of these attributes, and (3) explore the extent to which patients make trade-offs between risks and benefits of drug treatment for psoriasis. METHODS TREATMENT ATTRIBUTES Using a DCE, we explored patients’ preferences.16 In a DCE, key attributes of a good or service are identified. Realistic and tradable levels are assigned to these attributes, and scenarios containing the attributes are created. Scenarios are paired together, and respondents are asked to choose between the scenarios on the basis of the levels presented. The exercise is then repeated with the values of the attributes within the scenarios being altered systematically. The treatment attributes used in the DCE were derived from a review of the published literature, and their relevance was confirmed through discussions with 3 consultant dermatologists (one of whom was C.E.M.G.).17-21 In all, 6 attributes were included, namely: (1) time to achieve a moderate (50%) improvement, (2) time to relapse, (3) risk of skin irritation, (4) risk of high blood pressure, (5) 20-year risk of liver damage, and (6) 20-year risk of skin cancer. Our survey was administered to patients currently being treated for psoriasis in routine practice and not in a trial setting. We therefore chose a 50% improvement as one of the attributes because this has previously been acknowledged to be a clinically important end point in the assessment of psoriasis.22,23 The levels used for each of these attributes are shown in Table 1. The levels were organized into treatment scenarios using a fractional factorial design. This type of design was used because a full factorial design would have produced 512 (4⫻4 ⫻ 4⫻2 ⫻ 2⫻2) treatment scenarios, which was felt to be too burdensome for respondents. Using experimental design theory, we were able to identify 16 pair-wise treatment choices in which the levels were varied independently, thus avoiding multicollinearity24 (a situation in which 2 variables within the model are highly correlated). These 16 choice sets were split randomly into 2 separate versions of the questionnaire, each containing 8 choice sets, which were distributed to patients. For each choice set, the respondents were asked to select which treatment scenario they would prefer for the management of their psoriasis. Each version of the questionnaire also included a single choice set in which 1 of the treatment options would always be expected to be chosen as a test for consistency. Each patient, therefore, completed 8 pair-wise choices and 1 test of consistency. Table 2 shows an example of a choice set presented to respondents. Demographic data were also collected from each patient relating to age, sex, duration of psoriasis, and age at onset. The Self-Assessment Psoriasis Area and Severity Index, which has a 0 to 72-point scale, was used to determine clinical severity of a patient’s psoriasis, with a higher score indicating greater se- (REPRINTED) ARCH DERMATOL/ VOL 143 (NO. 9), SEP 2007 1176 WWW.ARCHDERMATOL.COM Table 3. Regression Results From Random Effects Probit Model and Marginal Rates of Substitution in 126 Patients With Psoriasis Coefficient (95% CI) a Trade-offs Relative to Time to Improvement, wk Preference Interpretation −0.034 (−0.042 to −0.026) 0.028 (0.020 to 0.035) −0.010 (−0.017 to −0.007) −0.038 (−0.051 to −0.026) −0.054 (−0.068 to −0.042) −0.054 (−0.0629 to −0.049) 1.331 (1.135 to 1.555) NA 0.8 (0.6 to 1.0) 0.3 (0.2 to 4.0) 1.1 (0.8 to 1.5) 1.6 (1.2 to 1.9) 1.6 (1.4 to 1.8) NA NA 1-wk increase in time to relapse 1% Reduction in risk of skin irritation 1% Reduction in risk of high blood pressure 1% Reduction in 20-y risk of liver damage 1% Reduction in 20-y risk of skin cancer NA Treatment Attribute Time to achieve moderate (50%) improvement Time to relapse Risk of experiencing skin irritation during treatment Risk of high blood pressure during treatment 20-y risk of experiencing liver damage 20-y risk of experiencing skin cancer Constant term b Abbreviations: CI, confidence interval; NA, not applicable. a Data are presented as ␤ values (range). b The constant term is automatically included in the Stata software model (StataCorp LP, College Station, Texas) and indicates that unobserved attributes (ie, attributes not included in our model) are also influencing treatment choices. verity.25 In addition, respondents were asked to rank the 6 treatment attributes in order of importance ranging from 1 (most important) to 6 (least important). The study was approved by the local National Health Service research ethics committees in the 3 areas where the study was conducted and also by the University of Manchester Ethics Committee. STUDY SAMPLE AND DATA ANALYSIS Patients were recruited from the dermatology departments of 3 Acute National Health Service Hospital Trusts located in northwest England. Questionnaires were distributed to patients who were attending a dermatology outpatient clinic, and postagepaid envelopes were provided for the returns. Because each respondent provided up to 8 responses (having completed 8 choice sets), a random effects probit model was considered appropriate, as this accounts for correlations between responses given by the same individual. A probit model is a popular specification of a generalized linear model, using the probit link function. Because the response is a series of binomial results, the likelihood is often assumed to follow the binomial distribution. Let Y be a binary outcome variable, and let X be a vector of regressors. The probit model assumes that all expected to have negative coefficients, whereas the longer the time to relapse was expected to have a positive coefficient. The trade-offs that patients were willing to make were determined by calculating the marginal rate of substitution, that is, the ratio of any 2 attributes.27 Trade-offs were calculated by dividing the coefficients of the attributes by the coefficient for time to improvement (␤1), giving the estimated trade-offs in time to improvement for a 1-unit change in each of the other attributes. Confidence intervals for coefficients and the marginal rate of substitution were derived using nonparametric bootstrapping with Stata software (StataCorp LP).28 Bootstrapping allows the confidence intervals to be determined through repeated sampling with replacement, using parameter point estimates and their estimated variance-covariance matrix. The respondents’ treatment choices were explored to see if they showed evidence of nontrading behavior among the different treatment attributes. Respondents were classified as having a dominant preference if they always chose the “best” level of a particular attribute and if they also ranked that attribute as the most important in the ranking exercise.29 To determine whether including respondents with dominant preferences affected the results of the random effects probit model, the data were analyzed in 2 separate models by including and excluding these respondents. RESULTS Pr (Y=1|X=x)=⌽(x⬘␤), where ⌽ is the cumulative distribution function of the standard normal distribution. Parameters for ␤ are typically estimated by maximum likelihood.26 All calculations were conducted using Intercooled Stata statistical software (version 8.0; StataCorp LP, College Station, Texas). In the model, the choice of treatment option was the binary-dependent variable, and the differences in levels for each of the 6 attributes were the independent variables. Differences were calculated by subtracting the levels. A main-effects linear additive model was estimated in which ⌬␤ is the dependent variable; ␤o is the constant, representing unobserved influences on choices, ␤j is the coefficient of the attributes included in the design, e represents the error term due to differences among observations, and u represents the error terms due to differences among respondents26: ⌬␤ = ␤o ⫹␤1IMPROVE⫹␤2RELAPSE⫹␤3SKIN ⫹␤4BLOOD ⫹␤5LIVER⫹␤6CANCER⫹ e⫹ u. The theoretical validity of the model was tested by examining the signs and significance of coefficient estimates in relation to a priori hypotheses. The longer the time to improvement and increased risks of adverse effects of treatment were INFLUENCE OF ATTRIBUTES ON TREATMENT CHOICES In all, 126 patients with psoriasis completed the questionnaire. A total of 64 respondents (51%) were female, and 62 (49%) were male. Their mean age was 47.6 years (range, 21-82 years), the mean duration of their psoriasis was 22.8 years (range, 1-63 years), their mean age at onset of psoriasis was 24.9 years (range, birth to 67 years), and the mean Self-Assessment Psoriasis Area and Severity Index score was 11.1 (range, 0.4-55.2). All 126 respondents passed the consistency test, suggesting that they had understood the DCE. Twenty-nine respondents (23%) showed evidence of dominant preferences for specific treatment attributes. Most of these (19/29) always chose the option for which there was no risk of experiencing skin cancer. A few respondents also showed evidence of dominant preferences for time to relapse (5 subjects), no risk of liver damage (3 subjects), and no risk of high blood pressure (2 subjects). (REPRINTED) ARCH DERMATOL/ VOL 143 (NO. 9), SEP 2007 1177 WWW.ARCHDERMATOL.COM TRADE-OFFS BETWEEN THE BENEFITS AND RISKS OF TREATMENT Table 4. Ranking of Attributes by 103 Respondents a Treatment Attribute Time to achieve moderate (50%) improvement Time to relapse Risk of experiencing skin irritation during treatment Risk of high blood pressure during treatment 20-y risk of experiencing liver damage 20-y risk of experiencing skin cancer a There Respondents Ranking It as “Most Important,” No. (%) 30 (29.1) 17 (16.5) 2 (1.9) 9 (8.7) 17 (16.6) 28 (27.2) are some missing values. Two random effects probit models were estimated; 1 with all respondents and 1 with “dominant” respondents excluded. A comparison of the models indicated no significant differences in coefficient estimates, relative size of the coefficients, or the significance of the fit of the models. Therefore, only the model that included all respondents is presented in Table 3. The coefficients for all 6 treatment attributes were statistically significantly different from zero (P ⬍.01), indicating that all the attributes were important factors affecting patients’ choice of treatment. The constant term was also significant (P ⬍ .05), indicating that other unobserved attributes were also likely to influence treatment preferences. The size and direction of the coefficients were in accordance with our a priori hypotheses. The negative signs on the coefficient for the adverse effects indicated that the higher the risk of experiencing these events, the less likely patients were to choose this scenario. Similarly, the negative sign for the time to improvement attribute indicated that the longer the time to achieve a moderate improvement, the less likely the patients were to choose that scenario. Positive values for the time to relapse indicated that the greater the duration of time to relapse, the more likely the patients were to choose that scenario. RELATIVE IMPORTANCE OF THE TREATMENT ATTRIBUTES Comparison of the magnitude of the coefficients indicated that respondents considered both the long-term risks of experiencing skin cancer and liver damage to be the most important adverse events influencing their choice of treatment, followed by the risk of experiencing high blood pressure. The risk of skin irritation was considered to be least important. The patients also prioritized time to moderate improvement over time to relapse. This corresponds with the results of the ranking exercise in which 30 of 103 respondents ranked the time to achieving a moderate improvement in psoriasis as the most important attribute (29.1%), whereas 17 of 103 (16.5%) ranked time to relapse as the most important, as shown in Table 4. (It should be noted that 23 respondents [18.3%] did not complete the ranking exercise.) Table 3 also shows the marginal rates of substitution between time to achieve a moderate improvement in the severity of psoriasis and the other attributes; that is, how much more time to improvement the respondents were willing to trade off to achieve an improvement in 1 level of the other treatment attributes. For example, the results show that respondents were willing to wait 0.8 weeks longer to achieve a moderate improvement if the treatment prolonged the time to relapse following such improvement by 1 week. The least important marginal rates of substitution were for the risk of skin irritation during treatment, and the most important were for the 20-year risks of liver damage and skin cancer. COMMENT This study has shown that treatment attributes, such as adverse effects, time to improvement, and time to relapse, influence the treatment preferences of patients with psoriasis. Most respondents would be willing to trade among different aspects of treatment to achieve an improvement in their psoriasis with minimal adverse effects. In other words, patients indicated that they would wait longer for a treatment to work if the chance of a severe adverse effect, such as skin cancer or liver damage, was considerably reduced. Respondents considered the long-term risks of skin cancer and liver damage to be the most important adverse effects and were prioritized above short-term risks of drug-induced hypertension or skin irritation. Almost a quarter of the sample were unwilling to trade among the attributes and always chose the treatment option with a particular level of their chosen attribute, most often no risk of skin cancer. The level of nontrading in this study was low compared with other DCE studies16,29 in which nontrading respondents have accounted for 30% to 71% of all respondents. It is important to take these into account because they reveal strong preferences on the part of some respondents. These studies suggest that some patients may not accept a treatment offered to them, no matter how efficacious, if they have serious concerns about adverse effects. These findings may provide some insight into why patients demonstrate intentional nonadherence to treatments for psoriasis and provide a useful starting point for meaningful dialogue between patients and physicians about choice of treatment. Previous studies have explored attitudes to risks and benefits of treatments in patients with rheumatoid arthritis and other musculoskeletal conditions. Fraenkel et al30 found that as many as 60% of respondents would not accept an arthritis treatment if there was a risk, however small, of developing cancer. Another study31 showed that patients would be willing to accept the risk of treatment if the benefits were seen to be high. More recently, it was reported that patients with arthritis prioritized eliminating the risk of adverse effects, whether short- or longterm, much more highly than the chance of the treatment providing benefit.32 (REPRINTED) ARCH DERMATOL/ VOL 143 (NO. 9), SEP 2007 1178 WWW.ARCHDERMATOL.COM To our knowledge, this is the first study to examine the nature and extent of some of the specific trade-offs that patients routinely face when choosing among the risks and benefits of drug treatments for psoriasis. However, there are several limitations that should be taken into account in interpreting the findings. First, the patients were presented with scenarios in which we systematically manipulated specific treatment attributes. Respondents were making decisions based on the state of their psoriasis at the time of the study; however, their attitudes may have varied according to the severity of their psoriasis. In the words of one patient, who provided written comments to support her answers, “If my psoriasis was severe, which indeed it has been at various times of my life, if I look back . . . I would probably, in desperation, have agreed to any treatment that would improve my skin condition.” The results were averaged across the sample, and as a result there is inevitable variation between patients. It is likely that our sample does not represent fully the general population of patients with psoriasis; rather, it is more representative of those being treated in dermatology clinics in the hospital setting. Future work should explore whether these findings are mirrored by those derived from patients who are being cared for in ambulatory care alone. Likewise, it would also be of interest to explore patients’ preferences toward other treatment attributes, such as the route or mode of administration and the associated treatment costs. Nonetheless, this study has provided novel insight into the attitudes of patients with psoriasis toward the risks and benefits of the treatments they receive. Given the heavy psychological burden associated with psoriasis, the high levels of dissatisfaction with the effectiveness of current treatment, and poor levels of adherence, a greater understanding of how these patients perceive their treatment may enhance the dialogue between them and their physicians. Accepted for Publication: March 16, 2007. Correspondence: Elizabeth M. Seston, PhD, School of Pharmacy and Pharmaceutical Sciences, Stopford Building, Oxford Road, University of Manchester, Manchester M13 9PT, England (liz.seston@gmail.com). Author Contributions: Dr Ashcroft had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Seston, Ashcroft, and Griffiths. Acquisition of data: Seston and Ashcroft. Analysis and interpretation of data: Seston, Ashcroft, and Griffiths. Drafting of the manuscript: Seston and Ashcroft. Critical revision of the manuscript for important intellectual content: Seston, Ashcroft, and Griffiths. Statistical analysis: Seston and Ashcroft. Obtained funding: Ashcroft and Griffiths. Administrative, technical, and material support: Ashcroft. Study supervision: Ashcroft and Griffiths. Financial Disclosure: None reported. Funding/Support: Galderma International Ltd provided financial support for the study via an unrestricted educational grant. Disclaimer: The views expressed in this article are those of the authors alone. Additional Contributions: The staff at the hospitals assisted with the distribution of questionnaires. We thank all of the patients who took part in the study. REFERENCES 1. Nevitt GJ, Hutchinson PE. Psoriasis in the community: prevalence, severity and patients’ beliefs and attitudes towards the disease. Br J Dermatol. 1996;135 (4):533-537. 2. Ramsay B, O’Reagan M. A survey of the social and psychological effects of psoriasis. 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(REPRINTED) ARCH DERMATOL/ VOL 143 (NO. 9), SEP 2007 1179 WWW.ARCHDERMATOL.COM EVIDENCE-BASED DERMATOLOGY: RESEARCH COMMENTARY Use of Antibiotic Ointment After Clean Cutaneous Surgery Michael Bigby, MD; Department of Dermatology, Harvard Medical School, Boston, Massachusetts, and Beth Israel Deaconess Medical Center, Boston Commentary on: Randomized clinical trial of the effect of applying ointment to surgical wounds before occlusive dressing Dixon AJ, Dixon MP, Dixon JB Br J Surg. 2006;93(8):937-943 Ointments are often applied to surgical wounds after clean cutaneous surgery in the belief that they speed and improve wound healing. The effectiveness of this practice was tested in a large randomized control trial. Question: Does application of no ointment, paraffin ointment, or mupirocin ointment lower complication rates or improve wound healing after clean cutaneous surgery when occlusive dressings are applied? Design: A blinded randomized clinical trial was undertaken to evaluate the effect of applying mupirocin ointment to a wound before occlusive dressing, in comparison with no ointment or sterile paraffin. Setting: Skincanceronly Clinic, Geelong, Alfred Hospital, Melbourne, Australia. Patients: All patients were newly referred to the Skincanceronly Clinic from July 1, 2002, to December 31, 2003. One surgeon performed all procedures, which included punch biopsy, elliptical excision, incisional biopsy, skin grafts, and skin flaps. Interventions: No ointment, paraffin ointment, or mupirocin ointment was placed on sutured wounds of patients prior to application of moist occlusive dressings. All patients were given a detailed instruction sheet regarding wound treatment, warning signs, and details of return appointments. At 6 to 9 months after surgery, patients were surveyed to assess the wounds, with a response rate of 74.0%. Main Outcome Measures: The primary outcome was development of a wound infection defined as purulent suture site, suture abscess, cellulitis, infective necrosis, large subcuticular abscess, regional lymphadenitis, or septicemia assessed at suture removal. When there was abscess formation or evidence of involvement beyond the local site, a wound swab was taken for culture; otherwise, the infection was assessed clinically. In the absence of suppuration, a wound was considered infected if 3 of the following 4 signs were present: discharge, pain, erythema, or induration. Secondary outcomes included scarring, suture markings, suture reaction, hypertrophy, keloid formation, discoloration, wound depres- sion, wound elevation, dog ears, and contracture. Recorded adverse reactions included postoperative bleeding, allergy to dressing, allergy to skin preparation, contact dermatitis, local recurrence, subcutaneous fibrosis, granuloma, dehiscence, pruritus, persistent pain, nerve damage, ectropion, nodal involvement, and distant metastases. All key outcome incidences were analyzed with the ␹2 test. Results: Some 778 patients with 1801 surgical wounds following excision of skin lesions were enrolled in the trial. No ointment was placed on 510 sutured wounds of 247 patients, paraffin ointment was placed on 729 wounds of 269 patients, and mupirocin ointment on 562 wounds of 262 patients. There were no significant differences in outcome for all primary end points evaluated (Table 1). The infection rate was 1.4% with no ointment, 1.6% for paraffin, and 2.3% for mupirocin (P= .49). Total complication rates were 3.5%, 4.7%, and 4.8% for no ointment, paraffin, and mupirocin, respectively (P= .59). Skin necrosis occurred in 0, 1, and 6 patients, respectively. There was a clinical and statistical increase in wound infections in lower limb lesions. At 6 to 9 months after surgery, patients were surveyed to assess the wounds, with a response rate of 74.0%. Some 10.9%, 10.3%, and 8.2% of patients had a neutral or negative perception of their wounds at 6 to 9 months after surgery with no ointment, paraffin ointment, and mupirocin ointment, respectively (P= .65). There was no difference in postoperative pain, degree of inconvenience, or overall level of satisfaction with treatment. Authors’ Conclusions: Putting ointment on a surgical wound before occlusive dressing does not benefit the patient. In view of the risk of antibiotic resistance, mupirocin ointment is not indicated for clean surgical wounds. Comment The trial was well reported. A sample size calculation was performed, and adequate numbers of patients were recruited. Patients (not wounds) were randomized prospectively. The randomization process (an independent person drew 1 of 150 disks [50 each of 3 different colors from a barrel] without replacement) was well described. Drawing disks without replacement results in “block randomization,” designed to produce groups of (REPRINTED) ARCH DERMATOL/ VOL 143 (NO. 9), SEP 2007 1180 WWW.ARCHDERMATOL.COM Table 1. Postoperative Occlusive Dressinga Complication Wound infection Skin necrosis No Ointment (n = 510 Wounds) 95% CI Paraffin (n = 729 Wounds) 95% CI Mupirocin (n = 562 Wounds) 95% CI 7 (1.4) (0.4-2.4) 12 (1.6) (0.7-2.6) 13 (2.3) (1.1-3.6) .49 0 (0) (0-0.6) 6 (1.1) (0.2-1.9) .007, 1 (0.1) (0-0.4) P Valueb Abbreviation: CI, confidence interval. a Data are given as the number of events (percentage). b For the ␹2 test. Table 2. Postoperative Nonocclusive Dressing Complication Infection (evaluable) Infection (ITT) Contact dermatitis (evaluable) Contact dermatitis (ITT) White Petrolatum a (n = 610 Wounds) Bacitracin a (n = 597 Wounds) Difference (95% CI) NNT (95% CI) 9 (2.0) 9 (1.5) 0 (0) 0 (0) 4 (0.9) 4 (0.7) 4 (0.9) 4 (0.7) 0.011 (−0.004 to 0.027) 0.008 (−0.004 to 0.019) −0.009 (NP) −0.007 (−0.015 to 0.002) 91 (−250 to 37) 127 (−280 to 52) −112 (NP) −150 (−68 to 667) Abbreviations: CI, confidence interval; ITT, intention to treat; NNT, number needed to treat; NP, not provided. a Data are given as number (percentage). equal size. The authors state on page 938 that, “The surgeon and the patients were not aware of the allocation” but the means of concealment of allocation were not described. Multiple wounds were evaluated in randomized patients. Because 1 group received no ointment, masking was not entirely possible. Intention-to-treat analysis (ITT) was performed for wound healing and development of infection because all wounds were followed up until healing was complete (to time of suture removal or longer if healing was slow or complications were experienced). Intention-to-treat analysis was not performed but was calculable for long-term results with the data provided from survey results. Equal numbers of patients failed to return surveys of long-term results from the groups receiving no ointment, paraffin ointment, and mupirocin ointment. All patients had a “moist occlusive dressing,” although the specifics of the dressing and its aftercare were not described. The corresponding author supplied the information on my request. The dressings were variable but were all of a moist occlusive type as described by Eaglestein et al.1 In the main, an initial cover like Melolin or Telfa was used. Then the dressing was sealed with tape circumferentially. Patients were asked to leave the dressing on until review. If they wanted to take it off, they were encouraged to reinforce the dressing and leave it on. This trial was well conducted and reported. Two flaws deserve comment. The first is the lack of detailed description of the occlusive dressing used in the published report. The second relates to the unit of analysis. Although individual patients were randomized into the study, analysis was performed using the wound as the unit of analysis—an approach that is problematic if responses to treatment are clustered within a few individuals with multiple wounds who might be overrepresented in one of the treatment groups. The number of wounds was quite different in the 3 groups (510, 729, and 562 wounds compared with 247, 269, and 262 individual patients, respectively), yet no adjustment for clustering effects was made in the analysis. The authors recognized this flaw and commented that the differences in infection rates for just the first wound were similar to the findings when all wounds were considered. The results (Table 1) fully justify the authors’ conclusions. This article should lead to a paradigm shift in the management of postoperative wound care. In a similar randomized, double-blind study published more than 10 years ago, Smack et al2 demonstrated that, compared with bacitracin ointment, white petrolatum is a safe, effective wound care ointment for postoperative wound care using nonocclusive dressings that are changed daily. Procedures included shave and punch biopsy, electrodessication and curettage, excision, Mohs surgery, and dermabrasion. Compared with bacitracin ointment, white petrolatum possesses a nearly equally low infection rate and minimal risk for induction of allergy (Table 2). Their data2 indicated that using white petrolatum would produce an insignificantly higher infection rate (number needed to harm [NNH] 91, evaluable; 127 ITT) and a lower rate of contact allergy (NNH −112, evaluable; −150 ITT). This study was also well reported. A power calculations was performed; however, adequate numbers of subjects were not recruited because the actual infection rate was lower than the 3% that was assumed in the calculation. Because of the less-than-adequate number of subjects recruited, the authors could not exclude the possibility that using white petrolatum would produce a higher infection rate with an NNH as high as 37, evaluable or 52 ITT. The method of randomization and concealment of allocation were adequate. Patient and evaluator blinding was successful. An ITT analysis was not performed (REPRINTED) ARCH DERMATOL/ VOL 143 (NO. 9), SEP 2007 1181 WWW.ARCHDERMATOL.COM but was calculable. The results (Table 2) justify the authors’ conclusions. Bottom Line: No ointment is necessary when postoperative wounds are covered with occlusive dressings. Petrolatum is an acceptable ointment for use when nonocclusive dressings that are changed daily are used. Adoption of these changes instead of using antibiotic ointments on postoperative wounds will result in considerable cost savings. Accepted for Publication: March 14, 2007. Correspondence: Michael Bigby, MD, Department of Dermatology, Beth Israel Hospital, 330 Brookline Ave, Boston, MA 02215 (mbigby@bidmc.harvard.edu). Financial Disclosure: None reported. 1. Eaglstein WH, Davis SC, Mehle AL, Mertz PM. Optimal use of an occlusive dressing to enhance healing: effect of delayed application and early removal on wound healing. Arch Dermatol. 1988;124(3):392-395. 2. Smack DP, Harrington AC, Dunn C, et al. Infection and allergy incidence in ambulatory surgery patients using white petrolatum vs. bacitracin ointment: a randomized controlled trial. JAMA. 1996;276(12):972-977. Archives Web Quiz Winner C ongratulations to the winner of our June quiz, Farzam Gorouhi, MD, Center for Research and Training in Skin Diseases and Leprosy, Medical Sciences, University of Tehran, Tehran, Iran. The correct answer to our May challenge was factitial dermatitis. For a complete discussion of this case, see the Off-Center Fold section in the July Archives (Heydendael VMR, Hoekzema R. Acute blue patch on the forearm. Arch Dermatol. 2007; 143[7]:937-942). Be sure to visit the Archives of Dermatology Web site (http://www.archdermatol.com) to try your hand at the interactive quiz. We invite visitors to make a diagnosis based on selected information from a case report or other feature scheduled to be published in the following month’s print edition of the Archives. The first visitor to e-mail our Web editors with the correct answer will be recognized in the print journal and on our Web site and will also receive a free copy of The Art of JAMA II. (REPRINTED) ARCH DERMATOL/ VOL 143 (NO. 9), SEP 2007 1182 WWW.ARCHDERMATOL.COM EDITORIAL Evidence-Based Dermatology Section Welcomes a New Feature: Critically Appraised Topic S INCE 1999, THE EVIDENCE-BASED DERMATOL- ogy (EBD) section has fulfilled its purpose of alerting clinicians to important advances in dermatology to help them use the best and most up-to date evidence when making decisions about patient care. My assistant editors and I select original articles from the biomedical literature to summarize in structured, value-added abstracts, and clinical experts comment on them. The procedures we follow as we attempt to achieve this purpose are (1) detecting, using prestated criteria, the best original and systematic review articles, which may or may not include metaanalysis, on the cause, course, diagnosis, prevention, and treatment of disorders and quality of care or economics in dermatology; (2) introducing these articles with declarative titles and summarizing them accurately in structured abstracts that describe their objectives, methods, results, and evidence-based conclusions; (3) adding brief, Michael Bigby, MD, Section Editor Damiano Abeni, MD, MPH Abrar A. Qureshi, MD, MPH highly expert commentaries to place each of these summaries in its proper clinical and health care context; and (4) disseminating the summaries to clinicians in a timely fashion. See also page 1187 In this issue of the Archives, we introduce critically appraised topics (CATs) and the CATs’ feature editor, Michael J. Sladden, MAE, MRCP(UK), to the EBD section. CATs are written summaries of the application of the practice of evidence-based medicine to specific problems that are commonly encountered in clinical practice (ie, translating the problem into an answerable, 4-part, well-built question; finding the best evidence to answer the question; critically appraising the evidence for its validity, magnitude, and precision; and applying the evidence to specific patients). In short, CATs are mini- Rosamaria Corona, DSc, MD Michael J. Sladden, MAE, MRCP(UK) (REPRINTED) ARCH DERMATOL/ VOL 143 (NO. 9), SEP 2007 1185 Urbà González, MD, PhD Hywel Williams, MSc, PhD, FRCP WWW.ARCHDERMATOL.COM systematic reviews of narrow, patient-focused questions that are not easy to find in a textbook. For example, after a clinical encounter, a patient-oriented question might be developed, which would then be followed by a search for relevant high-quality information to answer that question. The studies that are found will be briefly and critically appraised and then applied back to the patient along with the commentary. If you are interested in contributing to the EBD section and wish to discuss the topic with the section editor, please e-mail your note of interest to mbigby@bidmc .harvard.edu. Please specify which kind of contribution you are interested in providing: v Critical Appraisal of published articles, whose authors are invited to reply. v Systematic Reviews, which may or may not include meta-analysis. v Original Contributions. v Evidence-Based Reports, which are original manuscripts that are often the work of a consensus conference using the evidence-based approach to evaluate the status of a disease and its therapy or to formulate a public health policy. v CATs. Once the manuscript is complete, it is submitted via Webbased process at http://manuscripts.archdermatol.com. The author designates 1 of the 5 categories of submissions to the EBD section. The assistant section editors and I look forward to reviewing your submissions. Michael Bigby, MD Section Editor Correspondence: Dr Bigby, Beth Israel Deaconess Medical Center, TCC-2, 330 Brookline Ave, Boston, MA 02215 (mbigby@bidmc.harvard.edu). Correction Error in Byline. In the article titled “Breaking Strength of Barbed Polypropylene Sutures: Rater-Blinded, Controlled Comparison With Nonbarbed Sutures of Various Calibers,” by Rashid et al, published in the July issue of the Archives (2007;143[7]:869-872), the first author’s name should have read as follows: Rashid M. Rashid, MD, PhD. (REPRINTED) ARCH DERMATOL/ VOL 143 (NO. 9), SEP 2007 1186 WWW.ARCHDERMATOL.COM EVIDENCE-BASED DERMATOLOGY: CRITICALLY APPRAISED TOPIC What Is the Chance of a Normal Pregnancy in a Woman Whose Fetus Has Been Exposed to Isotretinoin? Michael J. Sladden, MAE, MRCP(UK); Karen E. Harman, MD, MRCP; Department of Medicine, University of Tasmania, Launceston, Australia (Dr Sladden), and Department of Dermatology, Leicester Royal Infirmary, Leicester, England (Dr Harman) Clinical Question: Recently, one of our patients who was taking isotretinoin became pregnant. This occurred despite appropriate counseling, a negative pregnancy test result before commencing treatment, and use of the combined oral contraceptive pill Microgynon 30 (Schering Health Care, West Sussex, England) (levonorgestrel, 150 µg, ethinylestradiol, 30 µg). The patient did not want to terminate her pregnancy. The aim of this Critically Appraised Topic is to explore the literature to determine the chance of delivering a healthy child after fetal exposure to isotretinoin; the types of fetal malformations associated with it; and what monitoring should be performed. Background Since introduction of the drug in 1982, over 2000 pregnancies in the United States have been affected by fetal exposure to isotretinoin,1 most resulting in spontaneous or elective abortions.2-6 Literature Search We searched the Medline and EmBase databases from 1966 to March 2007 using the terms isotretinoin or Accutane or Roaccutane and pregnancy or birth defect. Appraisal of the Evidence We found 469 articles in the literature search and chose 2 case series3,4 that prospectively identified and followed up pregnancies in which the fetus was exposed to isotretinoin for which abortion was not elected.3,4 We extracted data from these 2 prospective studies to develop our clinical bottom line because these studies are likely to be less biased than the retrospective studies. These 2 studies collected data from a combined total of 151 pregnant women in the United States aged 14 years to older than 35 years whose fetuses were exposed to isotretinoin. v In one study3 of 115 pregnancies, there were 21 spontaneous abortions (18%). Of the 94 live births, 61 were healthy infants (65% of births, 53% of pregnancies), 26 had congenital malformations consistent with isotretinoin embryopathy (28% of births, 23% of pregnancies), and 7 had other problems (7% of births). Therefore, 28% of live births had congenital malformations consistent with isotretinoin embryopathy (95% confidence interval, 19%37%).3 v In the second study4 of 36 pregnancies, there were 8 spontaneous abortions (22%). Of the 28 live births, 23 were healthy infants (82% of births, 64% of pregnancies), and 5 had congenital malformations (18% of births, 14% of pregnancies). The main abnormalities found in isotretinoin embryopathy are craniofacial, central nervous system, cardiovascular, and thymic.1,3,4,7,8 v Craniofacial: ear defects, dysmorphism, cleft palate, depressed nasal bridge, hypertelorism; v Central nervous system: hydrocephalus, microcephaly, facial nerve palsy, cortical and cerebellar defects; v Cardiovascular: Fallot’s tetralogy, transposition of great vessels, septal defects, aortic arch hypoplasia; v Thymic: ectopia, hypoplasia, aplasia; and v Miscellaneous: spina bifida, limb reduction. In addition, fetal exposure to isotretinoin is associated with high risk of adverse outcome with respect to mental functioning.9 The United Kingdom National Teratology Information Service10 estimates that in fetal exposure to isotretinoin, 30% of infants with no gross malformations have mental retardation, and up to 60% have impaired neuropsychological function. For editorial comment see page 1185 The National Teratology Information Service recommends that women who wish to continue their pregnancy after fetal exposure to isotretinoin should have alpha-fetoprotein testing at 16 to 19 weeks’ gestation and undergo a targeted ultrasound scan and echocardiography at 20 to 21 weeks’ gestation.10 These investigations would give some indication of the risks of structural malformations so that parents can plan support services and, in rare instances, in utero intervention could be performed, if appropriate. The high rate of fetal exposure to isotretinoin and its serious teratogenicity are clearly illustrated. The US Food and Drug Administration has recently approved the “iPLEDGE” risk management program,11 which is designed to reduce the risk of fetal exposure to isotreti- (REPRINTED) ARCH DERMATOL/ VOL 143 (NO. 9), SEP 2007 1187 WWW.ARCHDERMATOL.COM noin. However, it is also important that dermatologists prevent pregnant women from taking the medication (document proof of no pregnancy) and prevent women who are taking it from getting pregnant (use of 2 forms of birth control). v Women who choose to continue their pregnancy require careful support and monitoring. Finally, it is important that dermatologists prevent pregnant women from taking isotretinoin and prevent women who are taking it from getting pregnant. Limitations There is no dose of oral isotretinoin that is safe for use in pregnant women3,12 and, consequently, there are no published studies of women who took isotretinoin throughout pregnancy. Therefore, information about safety must be obtained from studies in which isotretinoin was taken for acne during some portion of pregnancy.13 Reported outcomes of retrospectively and prospectively ascertained cases differ considerably.3 Therefore, we have based our conclusions on data from prospective studies because of the strong likelihood of bias (especially reporting bias) associated with retrospective studies. Published prospective outcome data are available for only a small proportion of pregnancies in which the fetus was exposed to isotretinoin because most of these pregnancies are not reported in the literature. The level of fetal exposure to isotretinoin varies from pregnancy to pregnancy so it is possible that isotretinoinrelated problems may be higher for women who continue taking isotretinoin for a longer duration before discovering that they are pregnant. However, there is insufficient data to address this issue. There is little information about the timing of spontaneous abortions, either in weeks or trimesters. There is little follow-up data on infants with no gross malformation to determine the risk of developmental disabilities later in life. Clinical Bottom Line In pregnancies in which the fetus is exposed to isotretinoin, v The risk of spontaneous abortion is approximately 20%; v In pregnancies that progress, 65% to 82% of neonates appear normal at birth, but there is insufficient data to determine how many will later develop isotretinoinrelated problems; v There is an 18% to 28% risk of isotretinoin embryopathy; v There is no safe level of exposure: any exposure can cause malformation; v The main abnormalities are craniofacial, cardiac, central nervous system, and thymic; and What Happened to Our Patient? Our patient ceased taking isotretinoin as soon as she discovered that she was pregnant, at approximately 6 to 7 weeks’ gestation. We discussed with her the evidence regarding isotretinoin and birth defects. She elected to continue with her pregnancy and underwent regular ultrasound scans, performed by her obstetrician. She delivered a healthy baby girl, with no apparent birth defect. At age 18 months, her daughter was developing normally. REFERENCES 1. Lindstrom J. Isotretinoin: background and regulatory history. FDA Joint Dermatologic and Ophthalmic Drugs & Drug Safety and Risk Management Advisory Committee Meeting; February 26–27, 2004; Gaithersburg, MD. http://www.fda .gov/ohrms/dockets/ac/04/slides/4017s1.htm. Accessed March 12, 2007. 2. Abroms L, Maibach E, Lyon-Daniel K, Feldman SR. What is the best approach to reducing birth defects associated with isotretinoin? PLoS Med. 2006;3(11): e483. 3. Dai WS, LaBraico JM, Stern RS. Epidemiology of isotretinoin exposure during pregnancy. J Am Acad Dermatol. 1992;26(4):599-606. 4. Lammer EJ, Chen DT, Hoar RM, et al. Retinoic acid embryopathy. N Engl J Med. 1985;313(14):837-841. 5. Mitchell AA, Van Bennekom CM, Louik C. A pregnancy-prevention program in women of childbearing age receiving Isotretinoin. N Engl J Med. 1995;333 (2):101-106. 6. Bérard A, Azoulay L, Koren G, Blais L, Perreault S, Oraichi D. Isotretinoin, pregnancies, abortions and birth defects: a population-based perspective. Br J Clin Pharmacol. 2007;63(2):196-205. 7. Lynberg MC, Khoury MJ, Lammer EJ, Waller KO, Cordero JF, Erickson JD. Sensitivity, specificity, and positive predictive value of multiple malformations in isotretinoin embryopathy surveillance. Teratology. 1990;42(5):513-519. 8. Stern RS, Rosa F, Baum C. Isotretinoin and pregnancy. J Am Acad Dermatol. 1984;10(5, pt 1):851-854. 9. Adams J, Lammer EJ. Neurobehavioral teratology of isotretinoin. Reprod Toxicol. 1993;7(2):175-177. 10. National Teratology Information Service. Exposure to Isotretinoin During Pregnancy. Newcastle upon Tyne, England: National Teratology Information Service, Regional Drug and Therapeutics Centre; 2001. 11. Food and Drug Administration. iPLEDGE update. 2006. http://www.fda.gov/cder /drug/infopage/accutane/iPLEDGEupdate200603.htm. Accessed May 28, 2007. 12. Goldsmith LA, Bolognia JL, Callen JP, et al. American Academy of Dermatology Consensus Conference on the safe and optimal use of isotretinoin: summary and recommendations [published correction for a dosage error appears in J Am Acad Dermatol. 2004;51(3):348]. J Am Acad Dermatol. 2004;50(6):900-906. 13. Rothman KF, Pochi PE. Use of oral and topical agents for acne in pregnancy. J Am Acad Dermatol. 1988;19(3):431-442. (REPRINTED) ARCH DERMATOL/ VOL 143 (NO. 9), SEP 2007 1188 WWW.ARCHDERMATOL.COM ON THE HORIZON SECTION EDITOR: GARY S. WOOD, MD; ASSISTANT SECTION EDITORS: CRAIG A. ELMETS, MD; MOLLY A. HINSHAW, MD; JAY C. KLEMME, MD, MPH; MARK R. PITTELKOW, MD; MARTIN A. WEINSTOCK, MD, PhD; DAVID T. WOODLEY, MD Accessible Evidence-Based Medicine Critically Appraised Topics David A. Barzilai, MD, PhD; Martin A. Weinstock, MD, PhD; Department of Dermatology (Drs Barzilai and Weinstock), Brown University, and Department of Veterans Affairs Medical Center (Dr Weinstock), Providence, Rhode Island Learning Evidence-Based Veterinary Medicine Through Development of a Critically Appraised Topic Hardin LE, Robertson S J Vet Med Educ. 2006;33(3):474-478 Evidence-based veterinary medicine is a relatively new field of study. Increased knowledge of medicine coupled with the increased ability of computers and other electronic devices present overwhelming information. The critically appraised topic (CAT) is one method to gather and evaluate information related to a clinical question. CATs in informatics are short summaries of evidence, usually found through literature searches, in response to a specifically stated, clinically oriented problem or question. This article describes a study in which each firstyear veterinary student developed a CAT as a class project. The results of this project indicate that students were able to successfully develop CATs and that this exercise helped them understand evidence-based veterinary medicine concepts. Though some modification in this project will be made in the future, overall it was a worthwhile effort and will remain as an activity in the course. COMMENT The cumulative knowledge base of pertinent data for patient management is tremendous and rapidly growing in dermatology. To facilitate efficient and accurate acquisition of the best current knowledge, evidence-based medicine (EBM) has emerged as the science of integrating “the best research evidence with our clinical expertise and our patient’s unique values and circumstances.”1(p1) CATs and CAT banks (collections of CATs) will become an important part of this effort in the future. In the evidencebased hierarchy, CATs are between narrative reviews and systematic reviews in quality and come in handy when systematic reviews are not available. See also page 1187 While a full discussion of EBM is beyond the scope of this brief discussion,1-5 using EBM to answer a clinical query involves the following steps: (1) formalizing the question into a precisely worded, answerable ques(REPRINTED) ARCH DERMATOL/ VOL 143 (NO. 9), 2007 1189 tion; (2) systematically searching out the best evidence available; (3) critically appraising the evidence; (4) integrating the data with clinical expertise and patient values; and (5) archiving the results and learning from steps 1 through 4. In clinical practice, steps 2 and 3 (searching out and critically appraising the best evidence) are often the most challenging. Step 5 is essential to allow others to benefit from an EBM review, and this is where the CATs and a CAT bank are useful. The quality of clinical evidence can be categorized in a continuum ranging from lower-level evidence such as a colleague’s subjective opinion or a solitary case report to systematic reviews based on double-blind, randomized, controlled trials. Systematic reviews are regarded as the highest level of data because they involve comprehensive searches of the literature and use explicit criteria for evaluating and incorporating data into the conclusions. A frequent challenge in clinical practice, however, is to find a systematic review that addresses a particular query. Such Editor’s Note Critically Appraised Topics How wonderfully appropriate that the benefits of CATs are recognized in evidence-based veterinary medicine! The medical care providers for our feline friends wrap the methods of informatics around clinical questions just as those felines that we share living space with wrap themselves around our legs. In this issue, the Archives introduces the CATs feature of the Evidence-Based Dermatology section. Our planning for this feature began in January 2007. We are delighted to be able to implement this clinically relevant feature for our readers and invite you to send your suggestions for topics to be addressed to the CATs feature editor, Michael Sladden, MAE, MRCP(UK) at m.sladden@doctors.org.uk. Now our canine pals are begging for equal representation, and who can resist those wet noses and wagging tails. We must recognize DOGs, disease-oriented groups. In recent years, the Archives published the work of several multicenter groups who focus on a single disease to perform randomized clinical trials to provide the highest level of evidence for therapeutic interventions. The challenging work of these visionary seeing eye DOGs is leading the way to improve therapy for our patients. June K. Robinson, MD WWW.ARCHDERMATOL.COM Table. Critically Appraised Topic (CAT) Web Sites Name BestBets CAT bank Dermatoscopia ebDerm.org (evidence-based dermatology) Description URL CATs in a variety of clinical areas CATs in a variety of clinical areas Spanish language dermatology CATs Will host English language CATs in August 2008 www.bestbets.org www.minervation.com/cebm2/cats/allcats.html www.dermatoscopio.cl ebDerm.org reviews are often not available, and to create one could take a year or more to reach a conclusion (by which time the question might no longer be relevant to the case that prompted the query). Narrative reviews are more likely to have some answer, but these are a poor solution because they do not reliably, comprehensively, or critically appraise the evidence and hence ultimately resemble expert opinion. In practice, dermatologists may use medical search engines like PubMed or even Web search engines like Google to find their answers, but the first answer is often not the most current, representative, or accurate. Finally, none of these methods permits an easy system for storing the answer for future reference or sharing results with colleagues. What if a tool existed to help rapidly identify valuable data, critically appraise its quality, and then store it as a 1-page summary for future reference? There is such a tool, the CAT. Literally speaking, CATs are 1-page summaries of evidence, but what makes them so powerful is the standardized approach to conducting evidencebased searches and appraising the evidence. The other premise behind CATs is that they are educational. The best way to learn EBM is through answering real-life clinical queries developed in practice. The Centre for Evidence-Based Medicine, Headington, England, has developed publicly accessible and free software for generating CATs, CATMaker. This software can be downloaded to any personal computer with access to the Web (www.cebm.net/catmaker.asp). CATMaker software facilitates data entry, helps carry out calculations to determine the clinical importance of differences detected in the study, and generates an output file that can be edited by a word processor. In addition, the software is equipped with an online help system designed for novices to EBM searches. The output of this process is a simple 1-page CAT summary that can readily be shared with colleagues. With this software, the output can be converted to HTML format for Web-based searching, printed out locally for filing away the results, and saved as a “Kitten,” which serves as the basis of future updates to the CAT. The clinical bottom-line section of the CAT summarizes the results. Multiple online CAT banks are currently available (Table). By August 2007, ebDerm.org will be releasing a user community–generated international database of dermatology CATs. The ebDerm.org CATs will be constructed using CATMaker software. (REPRINTED) ARCH DERMATOL/ VOL 143 (NO. 9), 2007 1190 Several important limitations of CATs should be noted. First, the study or studies under inquiry, in contrast with systematic reviews, may not represent the best or only data on a subject.1 Second, because CATs are userdriven and generally not subject to the highest level of peer review, they are vulnerable to bias. Third, CATs, like other data sources, may no longer represent the most recent best data if they are not periodically updated. For these reasons, if a systematic review can be found to answer a clinical question (such as through the Cochrane Skin Group), this, rather than a CAT, would be the best source of data. Finally, the generalizability of a CAT to any individual practice setting must be considered. CAT summaries of severe psoriasis cases seen in the dermatology department of an urban tertiary medical center might have limited application to moderate psoriasis cases found in a rural middle class setting. Despite these limitations, the CAT is a powerful tool for improving the quality of evidence-based searches and for practicing EBM skills. CATs can also save tremendous time when a previously generated CAT resembles your query and can be quickly updated to reflect the best current data. In the future, CATs may also be incorporated as a method for practicing evidence-based search and critical appraisal skills in dermatology residency or as continuing medical education for dermatologists. Correspondence: David A. Barzilai, MD, PhD, Department of Dermatology, Brown University, 593 Eddy St, APC 10th Floor, Providence, RI 02903 (david @skinresearch.org). Financial Disclosure: Dr Barzilai is the founder of ebDerm.org. Dr Weinstock is on the advisory board of ebDerm.org. REFERENCES 1. Straus SE, Richardson WS, Glasziou P, Haynes RB. Evidence-Based Medicine: How to Practice and Teach EBM. 3rd ed. New York, NY: Churchill Livingstone; 2005. 2. Hardin LE, Robertson S. Learning evidence-based veterinary medicine through development of a critically appraised topic. J Vet Med Educ. 2006;33(3):474-478. 3. Barzilai DA, Freiman A, Dellavalle RP, Weinstock MA, Mostow EN. Dermatoepidemiology. J Am Acad Dermatol. 2005;52(4):559-578. 4. Barzilai DA. Evidence-based dermatology: a brief introduction. http://www.vgrd .org/archive/cases/2007/ebd/ebd.htm. Accessed May 2, 2007. 5. Bigby M. Evidence-based medicine in a nutshell: a guide to finding and using the best evidence in caring for patients. Arch Dermatol. 1998;134(12):1609-1618. WWW.ARCHDERMATOL.COM EDITORIAL Long-term Treatment for Severe Psoriasis We’re Halfway There, With a Long Way to Go O VER THE LAST 30 YEARS, THE LANDMARK PUVA [psoralen–UV-A] Follow-up Study has demonstrated the importance of clinical epidemiology research in making informed treatment decisions for patients with psoriasis. When PUVA was first introduced, psoriasis was widely believed to be an epidermal cell proliferation disorder, and there were few systemic treatment options available at that time.1 Thirty years later, psoriasis is believed to be an immunologic disorder, and more new systemic therapies have been approved to treat it in the last 4 years than in the previous 30 years combined.2-8 Our objective criterion regarding which patients have severe psoriasis and therefore are candidates for systemic therapy has also evolved during this period, declining from 20% to 30% body surface area (BSA) in the 1970s to 1990s to 5% more recently.9,10 With the increasing recognition of the impact of psoriasis on health-related quality of life and the advent of novel therapies targeting its immunopathogenesis, the treatment of psoriasis is undergoing a revolution. As patients with psoriasis are increasingly being treated with systemic agents on a long-term basis, the PUVA study provides an important reminder of the challenge involved in making clinical decisions based on a scientific understanding of the disease’s natural history and the robust long-term safety and efficacy data of its treatments. See also page 1113 First, the PUVA experience exemplifies the critical importance of long-term studies to fully define the risks and benefits of a novel treatment. In 1974, years before the importance of PUVA in targeting T cells and dendritic cells was recognized, this treatment was first shown to be effective for severe psoriasis in 21 patients who had at least 50% BSA involvement.1,11 The use of PUVA for treating very severe psoriasis was a major development, as all patients in the trial achieved complete clearance and reported adverse effects were minimal. In 1977, a large multicenter clinical trial involving more than 1300 patients who received more than 45 000 treatments demonstrated that only 3% of patients failed to achieve clearance with this regimen and that adverse effects due to PUVA therapy were uncommon, temporary, and generally mild.12 Although PUVA therapy was considered an experimental technique, with limited long-term safety data, it was widely used in the United States, with an estimated 35 000 patients being treated in 1978 alone.13 In 1979, the first observations of cutaneous carcinoma were reported in the cohort; however, it was not clear if PUVA therapy was responsible for the excess number of skin cancers, as affected patients had a history of treatment with ionizing radiation or a history of skin cancer.13 In 1984, about 2 years after being approved by the Food and Drug Administration, PUVA was definitively linked to an excess risk of squamous cell carcinoma when the cohort had an average follow-up of 5.7 years.14 In 1997, when the median follow-up of patients reached 19 years, PUVA use was associated with an increased risk of melanoma, a finding that remains controversial.15 Although it took 10 years to clearly demonstrate the risk of squamous cell carcinoma from PUVA therapy and even longer to detect a potential association with melanoma, the PUVA study represents a success in defining the long-term safety of a systemic psoriasis treatment. Currently, the most robust safety data for psoriasis treatments are derived predominantly from randomized controlled clinical trials. However, these trials are generally of short duration, measured in weeks to months, whereas psoriasis is a lifelong disease that requires several decades of treatment for control.16 Although clinical trials are well suited to define the efficacy of an agent, they are particularly prone to miss the effects of drugs that are delayed and/or uncommon (eg, cancer, cardiovascular disease, and serious infections).17 The current drug approval process leaves us with wide gaps in our knowledge of treatment safety, which is particularly problematic when the therapy is to be used in large populations of patients on a long-term basis.18 In particular, existing safety data of systemic therapies for severe psoriasis are limited in the duration of drug exposure and in the number of patients who are receiving follow-up. Therefore, the potential risks associated with truly long-term treatment of psoriasis remain to be further defined for serious end points such as malignancy.19 The current PUVA Follow-up Study, as analyzed by Nijsten et al,20 also provides unique data regarding the effectiveness of long-term treatment of severe psoriasis. During the follow-up of 815 patients who underwent 2378 skin examinations from 1985 to 2005, approximately 50% of such examinations demonstrated that patients had mild to no skin disease. Moreover, Nijsten and coauthors note that the likelihood that the extent of psoriasis will change more than 1 physician global assessment level over 1 year and over 10 years is relatively small. These observations suggest that our treatment approach is about 50% effective over the long term, given that the average BSA of patients who initially entered the multicenter PUVA trial (REPRINTED) ARCH DERMATOL/ VOL 143 (NO. 9), SEP 2007 1191 WWW.ARCHDERMATOL.COM was 33%. Based on the ecological design used for the PUVA study, in which treatment use and psoriasis severity were not linked at the individual level, it is unclear if these patients had mild or no psoriasis because of the natural history of psoriasis or because of the use of psoriasis treatments. The natural history and determinants of psoriasis remission and flare remain poorly understood as reviewed by Nijsten and colleagues. This study therefore underscores the need for further prospective epidemiological investigations to determine the true rate and determinants of spontaneous psoriasis improvement and flare, as well as how psoriasis may lead to other disease states that are associated with chronic TH1 inflammation, such as psoriatic arthritis, metabolic disease, atherosclerosis, and myocardial infarction.21-24 Such information would better inform patients about the natural history of their psoriasis, would improve clinical trial designs and the interpretation of safety data, and would allow clinicians and patients to make more informed decisions about long-term vs intermittent therapy. Remarkably, Nijsten et al20 report that despite having access to a wide array of dermatologic therapeutic modalities, including extensive use of phototherapy and methotrexate in the study population, about 50% of patients continued to have moderate to severe psoriasis on their follow-up examinations. This observation demonstrates that we still have a long way to go when it comes to consistently controlling severe psoriasis. For example, a recent study of 1657 contacts of the National Psoriasis Foundation demonstrated that 37% of patients with moderate psoriasis (defined as 3%-10% BSA) and 39% of patients with severe disease (⬎10% BSA) were not receiving any therapy.25 Furthermore, more than 80% of patients with severe psoriasis were not receiving systemic therapy or phototherapy. These data suggest that severe psoriasis remains uncontrolled in the majority of patients affected. Further studies are necessary to determine the degree to which this is attributable to patient factors (such as changing treatment preference, adherence, or access to therapies) or to factors related to treatment failure over time. Although short-term clinical trials in highly selected patient populations have shown the efficacy of systemic therapies for psoriasis, we have large gaps in our knowledge of the long-term effectiveness of these treatments when they are used on a long-term basis in a broader population of patients with psoriasis. For example, the limited data we have on methotrexate suggest that the drug is highly efficacious over the short term (16 weeks) but that over 1 year of follow-up about 25% of patients discontinue therapy because of adverse effects, indicating that long-term effectiveness is well below short-term efficacy.26 Similarly, long-term studies of biologic antibody therapy (chimeric and humanized) for inflammatory diseases show high short-term efficacy but lower long-term effectiveness as a result of drug discontinuation associated with adverse effects or loss of treatment response during extended periods of treatment.7,27,28 Dermatologists and patients have scant data to make head-to-head comparisons of systemic therapies, and our general assumptions about which treatments are most safe, efficacious, and cost-effective based on short-term trial data may not be valid when the end point is more clinically relevant (eg, long-term effectiveness). The burden of treatment success and failure over the patient’s lifetime is eloquently described by John Updike,29 who wrote,“ . . . when I am at last too ill for all of these demanding and perilous palliatives, the psoriasis like a smoldering fire in damp peat will break out and spread triumphantly; in my dying I will become hideous, I will become what I am.” Over the last 30 years, tremendous progress has been made in our knowledge of the pathogenesis of psoriasis and in the development of systemic therapies to treat this disease. This progress has been well documented by the more than 20 000 medical publications related to psoriasis since PUVA was introduced. Despite this progress, we still have major gaps in our basic knowledge of the natural history of psoriasis, and a large percentage of patients with extensive psoriasis will continue to suffer from the burden of this disease for decades. Joel M. Gelfand, MD, MSCE Correspondence: Dr Gelfand, Department of Dermatology and Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania, 3600 Spruce St, 2 Maloney Bldg, Philadelphia, PA 19104 (Joel.Gelfand@uphs .upenn.edu). Financial Disclosure: Dr Gelfand has been a consultant for Genentech, Centocor, Amgen Inc, Wyeth, WarnerChilcott, Novartis, Signum, Follica, and Therakos and has received honoraria from CME Consultants and Emeritus Educational Sciences as well as grants from Biogenidec, AMGEN, Astellas, Centocor, and Longport Inc. He is also on the Medical Advisory Board for the National Psoriasis Foundation and on the Clinical Guidelines Committee for the American Academy of Dermatology. Funding/Support: Dr Gelfand is supported by grant K23AR051125 from the National Institute of Arthritis and Musculoskeletal and Skin Diseases. Role of the Sponsor: The sponsor had no role in this editorial. Additional Contributions: John R. Stanley, MD, and Daniel Roling, MD, provided helpful feedback on early drafts of this manuscript. 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; 291(23):1207-1211. 2. Gottlieb AB. Immunologic mechanisms in psoriasis. J Am Acad Dermatol. 1988; 18(6):1376-1380. 3. Krueger JG, Bowcock A. Psoriasis pathophysiology: current concepts of pathogenesis. Ann Rheum Dis. 2005;64(suppl 2):ii30-ii36. 4. Leonardi CL, Powers JL, Matheson RT, et al. Etanercept as monotherapy in patients with psoriasis. N Engl J Med. 2003;349(21):2014-2022. 5. Gordon KB, Papp KA, Hamilton TK, et al. Efalizumab for patients with moderate to severe plaque psoriasis: a randomized controlled trial. JAMA. 2003;290(23): 3073-3080. 6. Ellis CN, Krueger GG. Treatment of chronic plaque psoriasis by selective targeting of memory effector T lymphocytes. N Engl J Med. 2001;345(4):248-255. 7. Menter A, Feldman SR, Weinstein GD, et al. A randomized comparison of continuous vs. intermittent infliximab maintenance regimens over 1 year in the treatment of moderate-to-severe plaque psoriasis. J Am Acad Dermatol. 2007;56 (1):31.e1-e15. (REPRINTED) ARCH DERMATOL/ VOL 143 (NO. 9), SEP 2007 1192 WWW.ARCHDERMATOL.COM 8. Gordon KB, Langley RG, Leonardi C, et al. Clinical response to adalimumab treatment in patients with moderate to severe psoriasis: double-blind, randomized controlled trial and open-label extension study. J Am Acad Dermatol. 2006; 55(4):598-606. 9. Roenigk HH Jr, Auerbach R, Maibach H, Weinstein G, Lebwohl M. Methotrexate in psoriasis: consensus conference. J Am Acad Dermatol. 1998;38(3):478485. 10. Pariser DM, Bagel J, Gelfand JM, et al. National Psoriasis Foundation clinical consensus on disease severity. Arch Dermatol. 2007;143(2):239-242. 11. Baker BS, Swain AF, Griffiths CE, Leonard JN, Fry L, Valdimarsson H. Epidermal T lymphocytes and dendritic cells in chronic plaque psoriasis: the effects of PUVA treatment. Clin Exp Immunol. 1985;61(3):526-534. 12. Melski JW, Tanenbaum L, Parrish JA, Fitzpatrick TB, Bleich HL. Oral methoxsalen photochemotherapy for the treatment of psoriasis: a cooperative clinical trial. J Invest Dermatol. 1977;68(6):328-335. 13. Stern RS, Thibodeau LA, Kleinerman RA, Parrish JA, Fitzpatrick TB. Risk of cutaneous carcinoma in patients treated with oral methoxsalen photochemotherapy for psoriasis. N Engl J Med. 1979;300(15):809-813. 14. Stern RS, Laird N, Melski J, Parrish JA, Fitzpatrick TB, Bleich HL. Cutaneous squamous-cell carcinoma in patients treated with PUVA. N Engl J Med. 1984;310 (18):1156-1161. 15. Stern RS, Nichols KT, Vakeva LH. Malignant melanoma in patients treated for psoriasis with methoxsalen (psoralen) and ultraviolet A radiation (PUVA): the PUVA Follow-up Study. N Engl J Med. 1997;336(15):1041-1045. 16. Naldi L, Svensson A, Diepgen T, et al. Randomized clinical trials for psoriasis 1977-2000: the EDEN survey. J Invest Dermatol. 2003;120(5):738-741. 17. Gelfand JM. Pharmacovigilance: verifying that drugs remain safe. In: Wolverton S, ed. Comprehensive Dermatologic Drug Therapy. 2nd ed. Philadelphia, PA: Elsevier; 2007:1017-1026. 18. Okie S. Safety in numbers—monitoring risk in approved drugs. N Engl J Med. 2005;352(12):1173-1176. 19. Gelfand JM, Shin DB, Neimann AL, Wang X, Margolis DJ, Troxel AB. The risk of lymphoma in patients with psoriasis. J Invest Dermatol. 2006;126(10):21942201. 20. Nijsten T, Looman CWN, Stern RS. Clinical severity of psoriasis in last 20 years of PUVA Study. Arch Dermatol. 2007;143(9):1113-1121. 21. Gelfand JM, Neimann AL, Shin DB, Wang X, Margolis DJ, Troxel AB. Risk of myocardial infarction in patients with psoriasis. JAMA. 2006;296(14):1735-1741. 22. Neimann AL, Shin DB, Wang X, Margolis DJ, Troxel AB, Gelfand JM. Prevalence of cardiovascular risk factors in patients with psoriasis. J Am Acad Dermatol. 2006;55(5):829-835. 23. Gelfand JM, Gladman DD, Mease PJ, et al. Epidemiology of psoriatic arthritis in the population of the United States. J Am Acad Dermatol. 2005;53(4):573. 24. Ludwig RJ, Herzog C, Rostock A, et al. Psoriasis: a possible risk factor for development of coronary artery calcification. Br J Dermatol. 2007;156(2):271276. 25. Horn EJ, Patel KM, Fox C, Chiou F, Dann F, Lebwohl M. Treatment patterns and utilization of systemic therapy and phototherapy among psoriasis patients [abstract]. J Am Acad Dermatol. 2007;56:2725. 26. Heydendael VM, Spuls PI, Opmeer BC, et al. Methotrexate versus cyclosporine in moderate-to-severe chronic plaque psoriasis. N Engl J Med. 2003;349(7): 658-665. 27. Bartelds GM, Wijbrandts CA, Nurmohamed MT, et al. Clinical response to adalimumab: the relationship with anti-adalimumab antibodies and serum adalimumab concentrations in rheumatoid arthritis [published online ahead of print March 9, 2007]. Ann Rheum Dis. 28. Hyrich KL, Lunt M, Watson KD, Symmons DP, Silman AJ. Outcomes after switching from one anti–tumor necrosis factor alpha agent to a second anti–tumor necrosis factor alpha agent in patients with rheumatoid arthritis: results from a large UK national cohort study. Arthritis Rheum. 2007;56(1):13-20. 29. Updike J. Self-Consciousness. New York, NY: Alfred A Knopf Inc; 1989. (REPRINTED) ARCH DERMATOL/ VOL 143 (NO. 9), SEP 2007 1193 WWW.ARCHDERMATOL.COM EDITORIAL Dermatology and the Human Genome An Epidemiologic Approach A S THE BODY’S MOST ACCESSIBLE ORGAN, SKIN provides a unique window on physiologic processes governed ultimately by the genome. Cutaneous signs have long been used to diagnose systemic disease, from hypothyroidism to syphilis,1 and many genetic syndromes include pathognomonic skin findings. The field of medical genetics extends the search for patterns beyond individual patients to inheritance within families; statistical genetics and genetic epidemiology use quantitative methods to analyze these patterns in families and populations. Now the tools of molecular genetics are being used to identify thousands of mutations associated with hundreds of mostly rare genetic diseases. In the process, they are revealing unexpected genetic complexity, blurring the distinction between Mendelian and complex disorders.2 New approaches are needed to find meaningful patterns in the outpouring of genomic data; we believe that epidemiology will provide a crucial link between dermatology and the human genome. Three articles in this issue of the Archives describe novel mutations in genes associated with inherited dermatoses: FGFR3 with acanthosis nigricans (AN),3 CYLD with See also pages 1125, 1153, and 1209 multiple familial trichoepithelioma,4 and FECH with erythropoietic protoporphyria (EPP).5 Each of these findings adds incrementally to the growing web of knowledge that connects variations in genetic sequences with biologic processes, clinical findings, and epidemiologic observations. For example, some FGFR3 mutations that produce amino acid substitutions at position 650 are known to cause severe skeletal dysplasias; association of the K650R mutation with AN, a relatively mild condition, is consistent with its small effect on function in a systematic study of all possible FGFR3 missense mutations at that locus.3 Variation in CYLD affects its negative regulation of nuclear factor–kappa B, a key signaling protein in a pathway that has been implicated in cancer and many other diseases.6 Confirmation that FECH mutations cause EPP only when coinherited with another lowexpression allele is consistent with the autosomal dominant inheritance pattern observed in European populations, where one such allele is common.7 How will larger patterns emerge from the accumulation of thousands of small studies? The first systematic catalog of inherited diseases and their genetic causes was published in 1966 by Victor A. McKusick,8 a founder of modern medical genetics. Now in its 12th edition, Mendelian Inheritance in Man8 has a continuously updated, online counterpart known as OMIM (Online Mendelian Inheritance in Man).9 The OMIM editors regularly append newly reported findings, creating essentially chronological summaries. Currently, OMIM includes more than 2000 summaries that refer to genes or syndromes associated with skin changes. In addition, various diseaseor gene-focused databases have been created to serve particular research communities, such as the Human Intermediate Filament Database, which catalogs mutations in epithelial keratin and related genes.10 Several journals, including Human Mutation and Human Genetics, publish brief descriptions of novel mutations along with names of authors and digital object identifiers (DOIs) that permit their retrieval by PubMed. The Human Genome Variation Society (HGVS), which promotes the “collection, documentation and free distribution of genomic variation information and associated clinical variations,”11 recently announced a new initiative, the Human Variome Project, which aims to catalog all human mutations worldwide and make the information freely available online.12 Most mutation databases are essentially lists based on investigations of the genetic characteristics of individual persons and families—the information equivalent of a case series. In contrast, epidemiologic studies that link a genotype with phenotypic and environmental variables produce multidimensional data. The epidemiologic approach, which is based on precise definitions, careful sampling, and systematic analysis, allows investigators to interpret their findings in a context larger than that of individual persons or families. Molecular genetic analysis became practical for use in epidemiologic studies only in the last 10 years or so; however, published reports already number in the thousands. The most popular design for studies of genetic associations compares the distributions of genotypes between affected and unaffected groups, which is equivalent to an epidemiologic case-control study. Because the inherited genotype is invariant, studies of gene-disease associations are able to avoid bias related to concurrent ascertainment of cause and effect, which is an important limitation of traditional case-control studies. When based on sound epidemiologic research methods, such studies can provide a strong basis for inference.13 The term human genome epidemiology (HuGE) was proposed to distinguish population-based analyses of genotype frequencies, gene-disease associations, and genegene and gene-environment interactions from the traditional studies of genetic epidemiology, which fo- (REPRINTED) ARCH DERMATOL/ VOL 143 (NO. 9), SEP 2007 1194 WWW.ARCHDERMATOL.COM cus on heritability analysis and gene discovery.14 The HuGE Network (HuGENet) is an international, voluntary collaboration for promoting this population perspective and encouraging the synthesis of published and unpublished data by consortiums of investigators.15 In addition to devising a “road map” for this endeavor,16 HuGENet has focused on developing tools to support researchers, including a curated, searchable, online database of PubMed abstracts reporting studies in human genome epidemiology.17,18 As of April 16, 2007, the database contained abstracts for 26 635 articles, including 247 related to dermatology. These articles, which were published in more than 50 journals in the United States, Europe, and Asia, examined 145 genes and more than 100 conditions, of which the most frequently studied were psoriasis (61 articles), melanoma (34 articles), and atopic dermatitis (22 articles). The systematic review and synthesis of information on human genetic variation in relation to health and disease is increasingly recognized as crucial to realizing the promised medical and public health benefits of genomic research.16 This challenge is too large and complex to undertake individually or to base on a single discipline, methodology, database, or other infrastructure; a networked approach may have a better chance of success.19 Advocacy groups like PXE International can play an important role by creating registries and organizing research consortiums.20 By promoting partnerships among clinicians, basic scientists, and epidemiologists, the field of dermatology can help promote the productive integration and translation of research findings into better preventive medicine and clinical care. The editors of the Archives of Dermatology would like to encourage the submission of articles that synthesize information on genetic variants in relation to diseases, both common and rare, in the form of HuGE reviews and meta-analyses that will integrate these findings into a larger context. An online handbook published by HuGENet and available online provides methodologic guidance in developing, conducting, and reporting individual associations and their integration into systematic reviews.21 Marta Gwinn, MD, MPH Muin J. Khoury, MD, PhD Correspondence: Dr Gwinn, National Office of Public Health Genomics, Centers for Disease Control and Pre- vention, 4770 Buford Hwy, MS K-89, Atlanta, GA 30341 (mgwinn@cdc.gov). Financial Disclosure: None reported. REFERENCES 1. Templeton HJ Skin lesions as diagnostic aids in general medicine. http://www .pubmedcentral.nih.gov/articlerender.fcgi?artid=1655038. Accessed April 16, 2007. 2. Sidransky E. Heterozygosity for a Mendelian disorder as a risk factor for complex disease. Clin Genet. 2006;70(4):275-282. 3. Berk DR, Spector EB, Bayliss SJ. Familial acanthosis nigricans due to K650T FGFR3 mutation. Arch Dermatol. 2007;143(9):1153-1156. 4. España A, Garcı́a-Amigot F, Aguado L, Garcı́a-Foncillas J. A novel missense mutation in the CYLD gene in a Spanish family with multiple familial trichoepithelioma. Arch Dermatol. 2007;143(9):1209-1210. 5. Herrero C, To-Figueras J, Badenas C, et al. Clinical, biochemical, and genetic study of 11 patients with erythropoietic protoporphyria including one with homozygous disease. Arch Dermatol. 2007;143(9):1125-1129. 6. Courtois G, Gilmore TD. Mutations in the NF-kappaB signaling pathway: implications for human disease. Oncogene. 2006;25(51):6831-6843. 7. Gouya L, Puy H, Robreau AM, et al. The penetrance of dominant erythropoietic protoporphyria is modulated by expression of wildtype FECH. Nat Genet. 2002; 30(1):27-28. 8. McKusick VA. Mendelian Inheritance in Man: A Catalog of Human Genes and Genetic Disorders. Baltimore, MD: Johns Hopkins University Press; 1998. 9. OMIM—Online Mendelian Inheritance in Man. http://www.ncbi.nlm.nih.gov /entrez/query.fcgi?db=OMIM. Accessed April 16, 2007. 10. Human Intermediate Filament Database. http://www.interfil.org. Accessed April 16, 2007. 11. HGVS—Human Genome Variation Society. http://www.hgvs.org. Accessed April 16, 2007. 12. Cotton RG; Participants in the 2006 Human Variome Project meeting. Recommendations of the 2006 Human Variome Project meeting. Nat Genet. 2007; 39(4):433-436. 13. Hattersley AT, McCarthy MI. What makes a good genetic association study? Lancet. 2005;366(9493):1315-1323. 14. Khoury MJ, Little J, Burke W, eds. Human Genome Epidemiology: A Scientific Foundation for Using Genetic Information to Improve Health and Prevent Disease. New York, NY: Oxford University Press; 2004. 15. National Office of Public Health Genomics. Human Genome Epidemiology Network. http://www.cdc.gov/genomics/hugenet/. Accessed April 16, 2007. 16. Ioannidis JP, Gwinn M, Little J, et al. A road map for efficient and reliable human genome epidemiology. Nat Genet. 2006;38(1):3-5. 17. GDPInfo. Genomics and Disease Prevention Information System. http://apps .nccd.cdc.gov/genomics/GDPQueryTool/default.asp. Accessed April 16, 2007. 18. Lin BK, Clyne M, Walsh M, et al. Tracking the epidemiology of human genes in the literature: the HuGE Published Literature database. Am J Epidemiol. 2006; 164(1):1-4. 19. Ioannidis JP, Bernstein J, Boffetta P, et al. A network of investigator networks in human genome epidemiology. Am J Epidemiol. 2005;162(4):302-304. 20. Terry SF, Terry PF, Rauen KA, Uitto J, Bercovitch LG. Advocacy groups as research organizations: the PXE International example. Nat Rev Genet. 2007; 8(2):157-164. 21. Little J, Higgins J, eds. The HuGENet HuGE Review Handbook, Version 1.0. http: //www.genesens.net/_intranet/doc_nouvelles/HuGE%20Review%20Handbook %20v11.pdf. Accessed April 16, 2006. (REPRINTED) ARCH DERMATOL/ VOL 143 (NO. 9), SEP 2007 1195 WWW.ARCHDERMATOL.COM Editor’s Note The Next Frontier of Dermatologic Research Recently, dermatology research has identified new genetic alterations associated with diseases. In 2005, the Archives was privileged to publish the first of these reports, which can be summarized as “name that tune” by identifying the single erroneous note causing the disease.1 Clinicians longed for progress beyond the stupefying identification of variants of genetic disorders, dared to hope for gene therapy for dermatologic diseases, and questioned the relevance of ever increasing reports of 2 or 3 cases with a few codons different from other cases of the same disease. The “tune” can be named in 1 note. Now, we hear the sweet melody of therapy in at least 1 case of junctional epidermolysis bullosa!2 Our next frontier is prevention of dermatologic diseases by the identification and modification of environmental risk factors among persons susceptible to disease due to genotype.3 To realize this goal, the principles of epidemiologic research will be applied to molecular genetic analysis of populations.4 The Archives invites HuGE Reviews and meta-analyses submitted under the article category “Reviews” as described in our Instructions for Authors at http://archderm.ama-assn.org/misc/ifora.dtl. June K. Robinson, MD Editor 1. Gao M, Wang PG, Yang S, et al. Two frameshift mutations in the RNA-specific adenosine deaminase gene associated with dyschromatosis symmetrica hereditaria. Arch Dermatol. 2005;141(2):193-196. 2. Mavilio F, Pellegrini G, Ferrari S, et al. Correction of junctional epidermolysis bullosa by transplantation of genetically modified epidermal stem cells. Nat Med. 2006;12(12):1397-1402. 3. Coughlin SS. The intersection of genetics, public health, and preventive medicine. Am J Prev Med. 1999;16(2):89-90. 4. Gwinn M, Khoury MJ. Dermatology and the human genome: an epidemiologic approach. Arch Dermatol. 2007;143(9):1194-1195. (REPRINTED) ARCH DERMATOL/ VOL 143 (NO. 9), SEP 2007 1196 WWW.ARCHDERMATOL.COM OFF-CENTER FOLD SECTION EDITORS: MICHAEL E. MING, MD, MSCE; ASSISTANT SECTION EDITORS: CARRIE ANN R. CUSACK, MD; SENAIT W. DYSON, MD; JACQUELINE M. JUNKINS-HOPKINS, MD; VINCENT LIU, MD; KARLA S. ROSENMAN, MD Hyperpigmented Keratotic Nodules Ser Ling Chua, MRCP; Kusum Kulkarni, MRCPath; Eric Saihan, FRCP; Queen’s Medical Centre, Nottingham, England A 59-year-old woman of Indian descent presented with a 6-month history of an increasing number of itchy hyperpigmented nodules on her trunk and limbs. The lesions were preceded by pruritus. Treatment with topical 0.05% clobetasone butyrate cream and oral cetirizine reduced the pruritus but did not affect the appearance of the lesions. The patient had a history of type 2 diabetes mellitus and hypertension. Ultrasonography showed that her liver was enlarged, with a fatty echo texture. Physical examination revealed multiple 3- to 15-mm-diameter hyperpigmented lesions with a central keratotic plug (Figure 1). The Koebner phenomenon was seen (Figure 2). There was sparing of her back in “difficult-to-reach” areas. A 4-mm punch biopsy specimen obtained from a lesion on the left upper back area was sent for histopathologic examination (Figure 3). What is your diagnosis? Figure 1. Figure 2. Figure 3. REPORT OF A CASE Verrucous Papules and Plaques in a Pediatric Patient Mercedes E. Gonzalez, MD; Fiona P. Blanco, MD; Maria C. Garzon, MD; Columbia University, New York, New York extensor surface of the left forearm (Figure 2), from which a shave biopsy specimen was obtained. REPORT OF A CASE A 12-year-old boy presented with a several-month history of enlarging verrucous lesions on his face and left forearm. Similar lesions had first appeared on the central area of his face 3 years earlier and had been excised. His medical history included failure to thrive, which required gastrostomy tube feeding; Arnold-Chiari malformation, which had been corrected when he was 1 year old; idiopathic hypertrophic subaortic stenosis, which required 2 corrective surgical procedures; global developmental delay; and hypertension, which required propranolol therapy. His family history was unremarkable. Physical examination revealed coarse facial features, large lips, a short neck, and 4 facial verrucous papules (Figure 1). Follicular papules were present over the lateral surface of both arms and on the face. The palms were hyperkeratotic, with accentuation of the creases. There was a large 2 ⫻ 2-cm verrucous plaque on the Figure 1. What is your diagnosis? Figure 2. Diffuse Nodules in a Woman With Renal Failure Erin B. Lesesky, MD; Michelle T. Pelle, MD; Terence C. O’Grady, MD; University of California, San Diego A 47-year-old woman presented with a 1-year history of an erythematous plaque on her left leg. The plaque was not painful when it first developed, but it became tender when it ulcerated. She denied trauma and systemic symptoms. There was no previous treatment. Her medical history was significant for type 2 diabetes, chronic renal failure, cardiomyopathy, and gouty arthritis. Physical examination revealed an 11 ⫻ 21-cm erythematous plaque on the lower area of the left leg, with scattered firm, white papules and areas of ulceration (Figure 1), and a 7-cm, rubbery, nontender, reddish yellow nodule on the dorsal aspect of the right hand (Figure 2). Also, pink to white firm nodules were seen in a linear distribution on the lateral aspect of the fingers, the dorsal aspect of both hands, and the extensor aspect of the forearms. A punch biopsy specimen was obtained from the plaque on the left lower leg area (Figure 3). What is your diagnosis? Figure 1. Figure 2. Figure 3. REPORT OF A CASE Tender Nodules on the Palms and Soles Lisa Esler-Brauer, MD; Ilene Rothman, MD; University at Buffalo School of Medicine and The Women and Children’s Hospital of Buffalo, Buffalo, New York A 10-year-old white boy presented with a 3-day history of painful, red, swollen hands. Physical examination revealed multiple, erythematous, 1- to 3-cm, tender nodules on his palms (Figure 1). A few similar smaller nodules were present on the plantar aspect of the middle of both heels. The patient had an associated low-grade fever but was otherwise healthy and active. He had recently spent a lot of time in ice hockey practice. His primary care physician had initially evaluated him, and the results of rapid streptococcal screening were negative, no murmur was appreciated, and no treatment had been initiated. A 4-mm punch biopsy specimen was obtained from a palmar lesion for microscopic evaluation (Figure 2 and Figure 3). What is your diagnosis? Figure 1. Figure 2. Figure 3. REPORT OF A CASE (REPRINTED) ARCH DERMATOL/ VOL 143 (NO. 9), SEP 2007 1201-1206 WWW.ARCHDERMATOL.COM Hyperpigmented Keratotic Nodules Diagnosis: Acquired perforating collagenosis. MICROSCOPIC FINDINGS Microscopic examination showed a cup-shaped deformity of the epidermis that was filled with a plug consisting of collagen, parakeratosis, and inflammatory exudate. The underlying epidermis was atrophic, but the adjacent epidermis was acanthotic. Dermal collagen at the base of the plug was almost perpendicular to the overlying epidermis. There was a sparse mixed inflammatory exudate around the upper dermal vessels. DISCUSSION The main histologic abnormality in perforating dermatoses is the transepithelial elimination of material from the dermis. There are 4 main types of primary perforating dermatoses: Kyrle disease, elastosis perforans serpiginosa, reactive perforating collagenosis, and perforating folliculitis. Perforating dermatoses have also been reported in association with chronic renal failure and diabetes mellitus. The term acquired perforating dermatoses has been used to describe them. The lesions are typically dome-shaped papules and nodules with a central keratotic plug. They have been considered a distinct entity from primary perforating dermatoses owing to their differences in clinical and histologic presentation from the original descriptions of the primary perforating dermatoses.1-3 Acquired perforating dermatosis has been reported to occur in 4.5% to 10% of patients receiving hemodialysis in North America. In Dundee, Scotland, the reported prevalence was 11% in patients who were undergoing dialysis, 78% of whom were diabetic.2 In most patients, pruritus precedes or develops at the same time as the skin lesions. The Koebner phenomenon is frequently observed. Acquired perforating dermatosis is also associated with lymphoma, nephropathy of various causes (including obstructive nephropathy, glomerulonephritis, hypertensive nephrosclerosis, heroin use, and human immunodeficiency virus infection), hypothyroidism, hyperparathyroidism, neurodermatitis, liver dysfunction, and hypertension.4 The pathogenesis of acquired perforating dermatosis is unknown. Trauma due to scratching has been postulated as a precipitating factor. This theory is supported by the linear distribution and reproducibility of the lesions by scratching of the skin.4 In diabetic patients, it has been suggested that scratching results in localized dermal necrosis due to poor blood supply as a result of diabetic vasculopathy. The necrotic tissue is then extruded through the epidermis.5 In patients with renal impairment, the dermal microdeposition of substances such as uric acid has been suggested as a cause of acquired perforating dermatosis.6 To our knowledge, there is no well-established therapy for acquired perforating dermatosis. In some patients, the skin lesions resolve spontaneously. There have been reports of successful treatment of both primary and acquired perforating dermatoses with topical, intradermal, and systemic corticosteroids; topical and systemic retinoids; UV-B phototherapy; methotrexate; and allopurinol.1,2,4 REFERENCES 1. Patterson JW, Richmond VA. The perforating disorders. J Am Acad Dermatol. 1984; 10(4):561-581. 2. Morton CA, Henderson IS, Jones MC, et al. Acquired perforating dermatosis in a British dialysis population. Br J Dermatol. 1996;135(5):671-677. 3. Rapini RP, Hebert AA, Drucker CR. Acquired perforating dermatosis. Arch Dermatol. 1989;125(8):1074-1078. 4. Faver IR, Daoud MS, Daniel Su WP. Acquired reactive perforating collagenosis. J Am Acad Dermatol. 1994;30(4):575-580. 5. Cochran RJ, Tucker SB, Wilkin JK. Reactive perforating collagenosis of diabetes mellitus and renal failure. Cutis. 1983;31(1):55-58. 6. Haftek M, Euvrard S, Kanitakis J, et al. Acquired perforating dermatosis of diabetes mellitus and renal failure: further ultrastructural clues to its pathogenosis. J Cutan Pathol. 1993;20(4):350-355. Verrucous Papules and Plaques in a Pediatric Patient Diagnosis: Cutaneous papillomas associated with Costello syndrome. MICROSCOPIC FINDINGS AND CLINICAL COURSE Histopathologic examination of the left arm lesion showed a hyperplastic epidermis with vascular ectasia and a mononuclear cell infiltrate in the dermis. The findings were consistent with verrucous acanthoma (papilloma). The patient was referred to the plastic surgery department to discuss treatment options for the facial papillomas. DISCUSSION Approximately 150 cases of Costello syndrome have been identified since the condition was described in 1977 by Costello1 and later named by Der Kaloustian et al2 in 1991. The major features include growth and mental retardation, with a sociable personality; coarse facies (macrocephaly, thick lips, big tongue, depressed nasal bridge, and low-set ears with thick lobes); short neck; musculoskeletal abnormalities (tight Achilles tendon, hyperextensible fingers, and limited joint mobility), cardiac defects (hypertrophic cardiomyopathy, cardiac malformations, and supraventricular arrhythmias); increased risk for malignant tumors (rhabdomyosarcoma, ganglioneuroblastoma, neuroblastoma, and bladder carcinoma); and distinctive cutaneous findings.3 Cutaneous papillomas are a unique skin manifestation of Costello syndrome, although they are present in only about 50% of patients.4 Papillomas occur on the face, anus, axillae, elbows, knees, vocal cords, and abdomen and usually develop between the 2nd and 15th years of life. The pathogenesis is unknown, but mechanical stress and human papillomavirus have been implicated.5 Clinically, the papillomas resemble verrucae, but histologically, verrucae can be distinguished by the presence of koilocytes, vertical columns of parakeratosis, and foci of clumped keratohyaline granules. In addition to verrucae, the differential diagnosis includes epidermal nevus, verrucous carcinoma, keratoacanthoma, actinic keratosis, squamous cell carcinoma, lipoid proteinosis, deep fungal infections, and epidermodysplasia verruciformis. Treatment options are limited to destruction and excision of the lesions, both of which may result in profound scarring. Patients with Costello syndrome also invariably have loose, redundant skin, especially of the neck, hands, and feet, which results in the appearance of deep creases on the palms and soles, as seen in our patient. Acanthosis nigricans, pigmented acral nevi, vascular birthmarks, hyperkeratosis, hyperpigmentation of the skin, thin deepset nails, thick eyebrows, and sparse curly scalp hair also frequently occur.4 Historically, Costello syndrome was considered a variant of Noonan syndrome and was synonymous with cardiofaciocutaneous syndrome, but these 3 conditions were found to have separate genetic loci.6 The derangement in Costello syndrome is a de novo mutation of the HRAS gene (v-Ha-ras Harvey rat sarcoma viral oncogene homologue), located on chromosome 11, resulting in permanent activation of the HRAS protein and uncontrolled cell division.7 Our patient was diagnosed as having both Noonan syndrome and cardiofaciocutaneous syndrome before receiving the diagnosis of Costello syndrome at the age of 6 years. The average age at diagnosis in 1 review was 14 years, which further indicates that establishing the correct diagnosis may be a challenge.8 Genetic testing is now possible, but the diagnosis of Costello syndrome still relies heavily on clinical recognition of the pattern of malformations. Characteristic skin features provide early clues to the diagnosis, thereby facilitating the prevention and management of the more serious systemic effects of Costello syndrome. REFERENCES 1. Costello JM. A new syndrome: mental subnormality and nasal papillomata. Aust Paediatr J. 1977;13(2):114-118. 2. Der Kaloustian VM, Moroz B, McIntosh N, Watters AK, Blaichman S. Costello syndrome. Am J Med Genet. 1991;41(1):69-73. 3. Costello syndrome. http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi ?id=218040. Accessed June 11, 2007. 4. Hennekam RC. Costello syndrome: an overview. Am J Med Genet C Semin Med Genet. 2003;117(1):42-48. 5. Torrelo A, Lopez-Avila A, Medeiro IG, Zambrano A. Costello syndrome. J Am Acad Dermatol. 1995;32(5, pt 2):904-907. 6. Wieczorek D, Majewski F, Gillessen-Kaesbach G. Cardio-facio-cutaneous (CFC) syndrome—a distinct entity? report of three patients demonstrating the diagnostic difficulties in delineation of CFC syndrome. Clin Genet. 1997;52(1):37-46. 7. Gripp KW, Lin AE, Stabley DL, et al. HRAS mutation analysis in Costello syndrome: genotype and phenotype correlation. Am J Med Genet A. 2006;140(1): 1-7. 8. White SM, Graham JM Jr, Kerr B, et al. The adult phenotype in Costello syndrome. Am J Med Genet A. 2005;136(2):128-135. Diffuse Nodules in a Woman With Renal Failure DISCUSSION Diagnosis: Chronic tophaceous gout. MICROSCOPIC FINDINGS AND CLINICAL COURSE The biopsy specimen revealed amorphous pink to gray material in the dermis, surrounded by lymphocytes and multinucleated foreign body–type giant cells, with no evidence of vasculitis or panniculitis. A von Kossa stain was negative for calcium. These microscopic findings were consistent with a diagnosis of a gouty tophus. Laboratory data revealed normal levels of serum calcium and phosphorus and an elevated level of uric acid (12.2 mg/dL [to convert to micromoles per liter, multiply by 59.485]; reference range, 2.6-7.5 mg/dL). Oral allopurinol therapy (100 mg every other day; alternate-day dosing because of renal failure) was initiated, and hemodialysis was started 3 months later. The patient’s uric acid level decreased markedly to 5.6 mg/dL over a 5-month period. No new tophi have developed since the allopurinol therapy was begun. In this case, transepidermal elimination of the tophi caused multiple large ulcers and subsequent pyodermas that yielded methicillinresistant Staphylococcus aureus and vancomycinresistant Enterococcus faecalis on culture. Meticulous wound care, frequent surveillance for infection, allopurinol, and antibiotics as needed are the mainstays of our patient’s treatment. Gout, one of the cutaneous deposition disorders, is a metabolic disease in which the underlying abnormality is hyperuricemia. The clinical manifestations include acute gouty arthritis, cutaneous tophi, and uric acid nephrolithiasis and nephropathy.1 Hyperuricemia can result from overproduction or underexcretion of uric acid, which is the end product of the catabolism of purines and is primarily excreted by the kidneys.1 Predisposing factors for the development of gout include dietary overindulgence, obesity, excessive alcohol intake, renal insufficiency, and ingestion of certain medications, including diuretics and cyclosporine.2,3 The 3 classic stages of gout, which can occur after years of asymptomatic hyperuricemia, are acute gouty arthritis; intercritical gout, which includes the intervals between attacks; and chronic tophaceous gout.2 Chronic tophaceous gout has a prevalence of less than 5% among patients with gout because of the availability of effective antihyperuricemic medications.2 The average interval from the first gouty attack to the onset of tophi is 12 years.4 Tophi present as firm, smooth or multilobulated, white to red dermal or subcutaneous nodules. They are most commonly located in the skin overlying joints or the helix of the ear and are often nontender.1 Diagnosis of gout during an acute attack is made by demonstration of urate crystals in synovial fluid. However, urate crystals can also be obtained from a tophus or visualized histologically in excised tissue. Ideally, specimens are placed in alcohol, which preserves the crystals, but formalin-fixed tissue also exhibits key features, including deposits of amorphous material containing needlelike clefts within the dermis or subcutis and a surrounding infiltrate of lymphocytes and foreign body–type giant cells.1 Treatment of acute attacks includes colchicine and nonsteroidal antiinflammatory drugs. Chronic tophaceous gout is best treated by allopurinol and reduction of risk factors, with a goal of lowering the serum uric acid level to less than 6 mg/dL, which will prevent further attacks and can lead to resorption of tophi.5 Our patient improved markedly with allopurinol therapy and the discontinuation of diuretic treatment once hemodialysis was started. REFERENCES 1. Franke I, Gollnick H. Deposition diseases. In: Bolognia J, Jorizzo J, Rapini R, eds. Dermatology. New York, NY: Mosby Elsevier Ltd; 2003:669-672. 2. O’Duffy JD, Hunder GG, Kelly PJ. Decreasing prevalence of tophaceous gout. Mayo Clin Proc. 1975;50(5):227-228. 3. Fam AG, Assaad D. Intradermal urate tophi. J Rheumatol. 1997;24(6):1126-1131. 4. Gutman AB. The past four decades of progress in the knowledge of gout, with an assessment of the present status. Arthritis Rheum. 1973;16(4):431-445. 5. Yamanaka H, Togashi R, Hakoda M, et al. Optimal range of serum urate concentrations to minimize risk of gouty attacks during anti-hyperuricemic treatment. Adv Exp Med Biol. 1998;431:13-18. Tender Nodules on the Palms and Soles Diagnosis: Palmoplantar eccrine hidradenitis (PEH). MICROSCOPIC FINDINGS Examination of the hematoxylin-eosin–stained skin biopsy specimen from the erythematous tender nodule revealed a dense neutrophilic inflammatory infiltrate around the eccrine sweat glands. DISCUSSION Palmoplantar eccrine hidradenitis is a distinct entity with characteristic clinical findings. First reported in 1988, it was named traumatic plantar urticaria.1 Since then, 47 cases have been reported under 5 different names, including idiopathic (palmo)plantar hidradenitis and recurrent palmoplantar hidradenitis.2 It primarily affects healthy children and is characterized by an abrupt appearance of erythematous, tender nodules on the palms and soles that may last 1 to 4 weeks and cause considerable difficulty in walking.2 Most eruptions are limited to the plantar surfaces, although palmar lesions have been documented.3 Typical histiologic findings include a neutrophilic perieccrine infiltrate in the setting of varying degrees of superficial and deep perivascular infiltrates of neutrophils, lymphocytes, and histiocytes as well as septal panniculitis.3 The etiology of PEH remains unknown. Local mechanical or thermal trauma, moisture, recent streptococcal infection, and hypersensitivity reaction have all been considered.3 Naimer et al4 postulate that it is exposure to wet footwear that triggers PEH, as a correlation was noted between the eruption and strenuous activity, such as ballet dancing. Interestingly, the majority of the lesions in our case were on the palmar surface and may be attributed to the effect of hockey glove use that created a moist environment similar to a shoe. Some speculate that excessive sweating, whether intrinsic (hyperhidrosis) or extrinisic (exertion induced), may cause obstruction of the eccrine duct, with subsequent rupture leading to the inflammatory cascade.5 This could explain eruptions related to hot tub use. The differential diagnosis of PEH includes erythema nodosum or other atypical panniculitis, erythema multiforme, insect bites, vasculitis, chilblains, migratory angioedema, embolic disease, and cellulitis. Most patients respond to bed rest, which presumptively decreases sweat secretion to allow resolution of inflammation. Gradual resumption of activity after resolution of lesions is recommended. Relapses occur in 50% of patients.6 Topical and systemic steroids as well as systemic antibiotics and nonsteroidal anti-inflammatory drugs have been used to treat PEH, without clear benefit.2,3 Palmoplantar eccrine hidradenitis is a characteristic clinical entity that is benign and self-limiting. It is likely more common than has been realized in the pediatric population and should be recognizable by dermatologists based on its distinctive presentation and clinical findings. REFERENCES 1. Metzker A, Brodsky F. Traumatic plantar urticaria—an unrecognized entity? J Am Acad Dermatol. 1988;18(1, pt 1):144-146. (REPRINTED) ARCH DERMATOL/ VOL 143 (NO. 9), SEP 2007 1201-1206 WWW.ARCHDERMATOL.COM 2. Rubinson R, Larralde M, Santos-Munoz A, Parr V, de Parra NP. Palmoplantar eccrine hidradenitis: seven new cases. Pediatr Dermatol. 2004;21(4):466-468. 3. Landau M, Metzker A, Gat A, Nen-Amitai D, Brenner S. Palmoplantar eccrine hidradenitis: three new cases and review. Pediatr Dermatol. 1998;15(2):97-102. 4. Naimer SA, Zvulunov A, Ben-Amitai D, Landau M. Plantar hidradenitis in children induced by exposure to wet footwear. Pediatr Emerg Care. 2000;16(3):182-183. 5. Ben-Amitai D, Hodak E, Landau M, Metzker A, Feinmesser M, David M. Idiopathic palmoplantar eccrine hidradenitis in children. Eur J Pediatr. 2001;160(3):189-191. 6. Simon M Jr, Cremer H, von den Driesch P. Idiopathic recurrent palmoplantar hidradenitis in children: report of 22 cases. Arch Dermatol. 1998;134(1):76-79. Submissions Clinicians, local and regional societies, and residents and fellows in dermatology are invited to submit quiz cases to this section. Cases should follow the established pattern of a Report of a Case section of less than 150 words, followed by the Diagnosis, Microscopic Findings, and Discussion. The discussion should be between 285 and 350 words. References are limited to 9. The text should be submitted double-spaced, with the right margin ragged. Photomicrographs and illustrations must be wider than they are tall (horizontal orientation), sharply focused with good color balance, and submitted as separate JPG files with each file numbered with the figure number. Material must be accompanied by the required copyright transfer statement (see authorship form in Instructions for Authors [http://archderm.ama-assn.org/misc/auinst_crit.pdf]). Manuscripts should be submitted via our online manuscript submission and review system (http://manuscripts .archdermatol.com). Please indicate in your cover letter that the manuscript is a submission to Off-Center Fold. CORRESPONDENCE ase chain reaction; and further sequencing analysis was performed. We identified 1 mutation not previously reported. The mutation was found in all patients but not in the healthy members of this family. The change was a point mutation in exon 20 (G2687C) that resulted in substitution of glycine at 896 by alanine (Figure 2). The mutation was not detected in 110 unrelated controls. RESEARCH LETTERS A Novel Missense Mutation in the CYLD Gene in a Spanish Family With Multiple Familial Trichoepithelioma Comment. Herein, we report a novel CYLD gene mutation at nucleotide 2687 that carries out 1 amino acid change at glycine 896 in the 4 affected members of this family but not in the proband. The fact that we have not detected this change in 110 unaffected controls makes a contribution to the genotype-phenotype correlation in MFT. The CYLD gene is considered a negative regulator of nuclear factor kappa B(NF-␬B).5 Thereby, inhibition or B rooke-Spiegler syndrome (BSS) includes the combination of spiradenomas, cylindromas, and trichoepitheliomas. It has been postulated that BSS results from defects in the regulation of putative stem cells of the folliculosebaceous-apocrine unit.1 This follicular dysregulation may give rise to 3 different genodermatoses: familial cylindromatosis (FC), multiple familial trichoepithelioma (MFT), or the classic triad of BSS. See also pages 1125, 1153, and 1194 A B I. The gene for FC was mapped to chromosome 16q12-q13.2 At present, 32 different germline mutations in the CYLD gene have been described,3 20 in families with FC, 8 in families with MFT, and 4 in families with BSS. Taken together, these observations suggest that these inherited syndromes associated with skin appendage tumors not only share a common genetic basis but also may represent phenotypic variation of the same disease.4 1 G/A II. 1 G/A 1 G/G C T C T G T G C Figure 1. Clinical picture (A) and family pedigree (B) for the present case. A, Multiple trichoepitheliomas are present on the upper eyelids, nose, nasolabial folds, and the upper lip in the mother of the proband. B, Pedigree of the family: for individuals whose DNA samples have been analyzed, the allele sequences at codon 896 have been indicated as G (glycine) or A (alanine). The proband (arrow) encodes for a G on both alleles (G/G), whereas the affected family members are heterozygous for the mutation (black circles) encode an A on the mutant allele. B Wild-type sequence Intron 19 Mutant sequence G896A Exon 20 C A T A G G T G G T C A G A A T G 3 G/A III. Report of a Case. An 8-year-old girl came to our department with her parents. Her mother, grandmother, and 2 aunts were diagnosed as having trichoepithelioma since childhood (Figure 1). The parents of our patient wanted to know if their daughter might harbor any genetic susceptibility for these cutaneous lesions. Blood samples were obtained from available family members and 110 unrelated controls. Genomic DNA was extracted; all coding exons were amplified by polymerA 2 G/A C T C T G T G C C A T A G S T G G T C A G A A T G Figure 2. Genetic analysis of the family with multiple familial trichoepithelioma. Shown are wild-type DNA (A) and mutant sequences (B) of exon 20 of CYLD from control and affected members, respectively. (REPRINTED) ARCH DERMATOL/ VOL 143 (NO. 9), SEP 2007 1209 WWW.ARCHDERMATOL.COM inactivation of CYLD enhances the action of NF-kB and leads to increased resistance to apoptosis and carcinogenesis.6 To our knowledge, this mutation has not been previously described. The known mutations of the CYLD gene are mostly located in the C-terminal portion. Germline mutations display tissue-specific function loss. Another possibility would be that the germline mutation determines the tissues where the preferred second hit occurs. When the second hit occurs in eccrineapocrine cells, the patients become susceptible to multiple cylindromas; in hair follicle cells, the patients exhibit susceptibility to multiple cylindromas or MFT.6 Our study shows the importance of mutation screening of the CYLD gene in patients affected with FC and MFT as well as their relatives to identify early clinical manifestations. Analysis of control volunteers in this report confirms the role of this missense mutation as the cause of this syndrome. Further studies evaluating the effect of this mutation in animal models must be considered. Agustı́n España, MD Fermin Garcı́a-Amigot, PhD Leyre Aguado, MD Jesús Garcı́a-Foncillas, MD Correspondence: Dr España, Department of Dermatology, University Clinic of Navarra, University of Navarra, PO Box 31080, Pamplona, Navarra, Spain (aespana @unav.es). Financial Disclosure: None reported. Funding/Support: This study was supported in part by the Spanish Academy of Dermatology. Role of the Sponsor: The sponsor had no role in the design and conduct of the study, in the collection, analysis and interpretation of data, or in the preparation review, or approval of the manuscript. 1. Clarke J, Ioffreda M, Helm KF. Multiple trichoepithelioma: a folliculosebaceousapocrine genodermatosis. Am J Dermatopathol. 2002;24(5):402-405. 2. Fenske C, Banerjee P, Holden C, Carter N. Brooke-Spiegler syndrome locus assigned to 16q12-q13. J Invest Dermatol. 2000;114(5):1057-1058. 3. The Human Gene Mutation Database at the Institute of Medical Genetics in Cardiff [registration required]. http://www.hgmd.cf.ac.uk/ac/all/php ?gene=CYLD. Accessed February 9, 2007. 4. Bowen S, Gill M, Lee DA, et al. Mutations in the CYLD gene in BrookeSpiegler syndrome, familial cylindromatosis, and multiple trichoepithelioma: lack of genotype-phenotype correlation. J Invest Dermatol. 2005;124 (5):919-920. 5. Regamey A, Hohl D, Liu JW, et al. The tumor suppressor CYLD interacts with TRIP and regulates negatively nuclear factor kB activation by tumor necrosis factor. J Exp Med. 2003;198(12):1959-1964. 6. Liang YH, Gao M, Sun LD, et al. Two novel CYLD gene mutations in Chinese families with trichoepithelioma and a literature review of 16 families with trichoepithelioma reported in China. Br J Dermatol. 2005;153(6):1213-1215. phatase, nonreceptor type 11), a gene encoding a tyrosinephosphatase protein named SHP-2, with 2 particular “hot spots” in exons 7 and 12.2-5 Despite overlapping clinical manifestations, LS is distinct from Noonan syndrome, another PTPN11 gene mutation–related disorder but with a different mutation spectrum. Herein we report the first case to our knowledge of typical LS featuring a new PTPN11 gene mutation. Report of a Case. A 39-year-old woman with a medical history of deafness and a familial background of Down syndrome in a sister was referred for evaluation of pigmentary changes that first appeared during infancy associated with mild facial dysmorphism. Clinical examination disclosed multiple light or dark brown macules of varied sizes scattered throughout her whole body surface including her face, palmoplantar areas, lips, and conjunctiva (Figure 1). There were no lentigines on the other mucous membranes. Facial examination revealed hypertelorism. Electrocardiography showed a first-degree atrioventricular block, whereas heart ultrasound evaluation did not find any valve abnormality. Hearing investigations confirmed sensorineural deafness. There were no urogenital abnormalities, endocrinopathy, or growth retardation. A diagnosis of LS was established based on the presence of 4 criteria. After obtaining the patient’s consent, we undertook direct sequencing of the PTPN11 coding region and discovered a previously undescribed (to our knowledge) heterozygous missense mutation in exon 13, namely a G1493T transversion leading to an R498L change in amino acid sequence (Figure 2). No genetic analysis of her relatives could be carried out to establish a diagnosis of de novo or inherited mutation. Comment. The SHP-2 phosphatase plays several important roles in cellular physiologic function, mainly in cell proliferation, differentiation, migration, and adhesion.6-8 This protein contains 2 main domains: a Cterminal protein-tyrosine phosphatase (PTP) domain involved in catalytic activity and 2 N-terminal Src homology 2 (SH2) domains interacting with the PTP domain, keeping it folded and inactive (Figure 2).3 To our knowledge, only 7 PTPN11 mutations have been reported in patients with LS, all of them in the PTP domain in exons 7 (Y279C and Y279S), 12 (T468M and A461T), and 13 A Novel PTPN11 Gene Mutation in a Patient With LEOPARD Syndrome I n 1969, Gorlin et al1 described an autosomal dominant syndrome encompassing multiple lentigines, electrocardiographic abnormalities, ocular hypertelorism, pulmonary stenosis, abnormal genitalia, retardation of growth, and sensorineural deafness, currently known as LEOPARD syndrome (LS). Recently, it has been reported that most cases of LS are probably related to heterozygous mutations of PTPN11 (protein-tyrosine phos- Figure 1. Numerous lentiginous elements scattered throughout the trunk. (REPRINTED) ARCH DERMATOL/ VOL 143 (NO. 9), SEP 2007 1210 WWW.ARCHDERMATOL.COM 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 5′ 3′ Y279 N N-SH2 3 T468M C-SH2 104 112 R498L Catalytic region (PTP) 216 221 C 524 Figure 2. Genomic structure of the PTPN11 gene and corresponding functional organization of the PTPN11-encoded SHP-2 phosphatase. Exons are represented as shaded boxes. Also shown are the main LEOPARD syndrome–associated mutations (hot spots Y279C and T468M) and our patient’s R498L mutation affecting exon 13. N and C are terminal indicators; PTP indicates protein-tyrosine phosphatase; SH2, Src homology 2. (Q506P, Q510E, and Q510G).2,4,9-11 Two of them (Y279C and T468M) represent more than 90% of the identified changes. The mutational site in our patient is close to the PTP-SH2 domains interacting tract and to the previously reported mutations affecting exon 13. Accordingly, this change is probably relevant as to LS pathomechanisms. PTPN11 mutations in Noonan syndrome are likely to result in a gain of function with “permanent” catalytic activity of the protein, whereas recent results unexpectedly suggest that LS-related PTPN11 mutations result in a decrease in the phosphatase function of SHP-2.12-14 Understanding why topographically closely related mutations on the same gene may have opposite functional consequences but still result in close phenotypes will be a rewarding challenge. Aurélie Du-Thanh, MD Hélène Cave, PharmD, PhD Didier Bessis, MD Carine Puso, MD Jean-Jacques Guilhou, MD Olivier Dereure, MD, PhD Correspondence: Dr Dereure, Department of Dermatology, University of Montpellier I, Hôpital Saint-Eloi, 80 Ave A. Fliche, 34295 Montpellier CEDEX 5, France (o-dereure@chu-montpellier.fr). Financial Disclosure: None reported. 1. Gorlin RJ, Anderson RC, Blaw M. Multiple lentigenes syndrome. Am J Dis Child. 1969;117(6):652-662. 2. Digilio MC, Conti E, Sarkozy A, et al. Grouping of multiple-lentigines/ LEOPARD and Noonan syndromes on the PTPN11 gene. Am J Hum Genet. 2002;71(2):389-394. 3. Legius E, Schrander-Stumpel C, Schollen E, Pulles-Heintzberger C, Gewillig M, Fryns JP. PTPN11 mutations in LEOPARD syndrome. J Med Genet. 2002;39(8):571-574. 4. Keren B, Hadchouel A, Saba S, et al. PTPN11 mutations in patients with LEOPARD syndrome: a French multicentric experience. J Med Genet. 2004; 41(11):e117. 5. Ogata T, Yoshida R. PTPN11 mutations and genotype-phenotype correlations in Noonan and LEOPARD syndromes. Pediatr Endocrinol Rev. 2005; 2(4):669-674. 6. Kroll J, Waltenberger J. The vascular endothelial growth factor receptor KDR activates multiple signal transduction pathways in porcine aortic endothelial cells. J Biol Chem. 1997;272(51):32521-32527. 7. Chang Y, Ceacareanu B, Dixit M, Sreejayan N, Hassid A. Nitric oxide-induced motility in aortic smooth muscle cells: role of protein tyrosine phosphatase SHP-2 and GTP-binding protein Rho. Circ Res. 2002;91(5):390-397. 8. Maheshwari M, Belmont J, Fernbach S, et al. PTPN11 mutations in Noonan syndrome type I: detection of recurrent mutations in exon 3 and 13. Hum Mutat. 2002;20(4):298-304. 9. Conti E, Dottorino T, Sarkozy A, et al. A novel PTPN11 mutation in LEOPARD syndrome. Hum Mutat. 2003;21(6):654. 10. Sarkozy A, Obregon MG, Conti E, et al. A novelPTPN11 gene mutation bridges Noonan syndrome, multiple lentigines/LEOPARD syndrome and Noonanlike/multiple giant cell lesion syndrome. Eur J Hum Genet. 2004;12(12): 1069-1072. 11. Digilio MC, Sarkozy A, Pacileo G, Limongelli G, Marino B, Dallapiccola B. PTPN11 gene mutations: linking the Gln510Glu mutation to the “LEOPARD syndrome phenotype.” Eur J Pediatr. 2006;165(11):803-805. 12. Hanna N, Montagner A, Lee WH, et al. Reduced phosphatase activity of SHP-2 in LEOPARD syndrome: consequences for PI3K binding on Gab1. FEBS Lett. 2006;580(10):2477-2482. 13. Tartaglia M, Martinelli S, Stella L, et al. Diversity and functional consequences of germline and somatic PTPN11 mutations in human disease. Am J Hum Genet. 2006;78(2):279-290. 14. Kontaridis MI, Swanson KD, David FS, Barford D, Neel BG. PTPN11 (SHP2) mutations in LEOPARD syndrome have dominant negative, not activating, effects. J Biol Chem. 2006;281(10):6785-6792. COMMENTS AND OPINIONS Sponsorship of Graduate Medical Education: One Successful Model I n the March 2007 issue of the Archives, Loo et al1 discuss the recruitment and retention of academic dermatologic clinician-educators. They call for new ideas to help provide needed support for teaching and mentorship, suggesting that this will lead to better job satisfaction and retention rates. It is my strong belief that robust departmental mentoring programs supported by active, dedicated senior faculty members working in concert with junior faculty members and residents is the key to increasing recruitment and retention of academic dermatologists. Implementing effective role modeling and mentorship involves a wide array of necessary elements that I will not expand on other than to say that the educational environment requires the philosophical, physical, and monetary support of the leadership. From where does the last of these, money, become available? Medical schools and institutions concerned with the advancement of medicine and the development of the next (REPRINTED) ARCH DERMATOL/ VOL 143 (NO. 9), SEP 2007 1211 WWW.ARCHDERMATOL.COM Paul Gross, MD generation of physicians cite their commitment to the triad of patient care, research, and education. The relative value an institution places on each of these areas dictates which will be most scrutinized in evaluation, promotion, and retention decisions. If research is the driving value, National Institutes of Health grants and other funding sources provide the currency to support these endeavors. Institutions that claim superior patient care as their driving force have an obvious source of funds—those generated by the activity itself. Education alone among the triumvirate is an unfunded priority. How has graduate medical education survived to this point without a sponsor, a source of dollars seemingly necessary to support any endeavor? Excess funds from clinical revenue helped support education until the 1990s, but certainly such funds have disappeared with the advent of managed care. There has been a move among a small number of institutions to dedicate dollars to this mission and provide graded stipends based on teaching time. However, this is not a widespread phenomenon, and the compensation is sparse relative to the effort expended. Generally, then, graduate medical education is an unfunded priority that has been considered a calling and kept alive by the volunteer efforts of dedicated, supportive practitioners from the community as well as idealistic, committed faculty educators. In Philadelphia, Pennsylvania, Paul Gross, MD (Figure), is an example of the former and an innovator of a welcome new kind of support for graduate medical education. Dr Gross graduated from the University of Pennsylvania School of Medicine in 1962 and completed his residency in dermatology at the same institution in 1968. From then until 2006, he headed the dermatology service at one of our affiliated teaching hospitals, Pennsylvania Hospital, in the Center City neighborhood of Philadelphia. Without compensation, Paul anchored the dermatology residency teaching rotation, provided in-patient consultation services, and educated scores of internists, family practitioners, and interns in his private practice office. He is a stalwart attendee at our weekly “Duhring Conference” grand rounds, sharing his clinical expertise to help diagnose and treat patients with uncommon clinical diseases. He and his wife, Anita, are regular attendees at all of our departmental get-togethers, graduation dinners, named lectures, and alumni reunions. In short, he is the epitome of the dedicated, supportive practitioner who daily contributes voluntarily of his time and expertise to help guarantee the future of our specialty. Dr Gross has, however, taken his support to a higher level, one that might also serve as a model to promote muchneeded funding for full-time dermatologic clinicianeducators and departmental education initiatives. He astutely recognizes not only that we need to educate young academic clinician-educators but also that to do so requires financial support. Acting on this insight, he has been able to secure philanthropic contributions from his grateful patients to support an innovative Clinical-Educator Fellowship at the University of Pennsylvania. This postresidency experience helps interested dermatologists obtain needed skills to excel in academic medicine. In addition, Dr Gross understands that the teaching of dermatology residents requires the program director to spend a growing amount of time to effectively fulfill this role. A grateful patient has donated the funds to endow a chair for dermatologic education, with the condition that it be named in Dr Gross’ honor. Endowment of professorial chairs to support basic science researchers and/or chairs of departments is the most common among these types of generous philanthropic ventures. Chairs for directors of education are unusual, and it is a testament of Dr Gross’ vision that he was able to establish one at the University of Pennsylvania. Such professorships help the department to ensure that the third pillar of excellence, education, will be supported in perpetuity. While education is a shared responsibility among faculty members, as are all areas of scholarship, these gifts guarantee the permanent presence of a dedicated expert whose main mission is to bolster the training program, mentor the young, fulfill the educational administrative requirements, and initiate innovative learning experiences and techniques. Dr Gross has provided a role model to our residents of how important private practice volunteer educators are to academic departments. We are fortunate to have more than 50 volunteers from the community who give at least 50 hours of teaching a year to the University of Pennsylvania Department of Dermatology. I see a direct connection between these exceptional men and women and the fact that the vast majority of our graduates over the past 10 years are involved in full-time or voluntary teaching activities. (REPRINTED) ARCH DERMATOL/ VOL 143 (NO. 9), SEP 2007 1212 WWW.ARCHDERMATOL.COM The overlay of philanthropic monetary support directed to fellowships and professorships will help sustain our next generation of learners and educators in a different way. As has been documented, approximately 10% of our clinician-educators leave academic medicine yearly.1 Residency program directors have a 15% to 20% turnover (unpublished data, W.D.J., 2004). Chairs for mid-level and senior educators validate the importance of this method of scholarship to the department and the university. They provide a tangible goal to aspire to, help sustain careers, and stabilize tenure in important positions such as residency program directorships. I hope that Dr Gross’ vision, and the resulting positive experience at the University of Pennsylvania, stimulates additional discussion of support for resident and student education and invigorates funding of their endeavors in innovative ways. William D. James, MD Correspondence: Dr James, Department of Dermatology, Hospital of the University of Pennsylvania, 3600 Spruce St, 2 Rhoads Pavilion, Philadelphia, PA 19104 (william.james@uphs.upenn.edu). Financial Disclosure: None reported. 1. Loo DS, Liu CL, Geller AC, Gilchrest BA. Academic dermatology manpower: issues of recruitment and retention. Arch Dermatol. 2007;143(3):341-347. Narrowband UV-B Phototherapy for Extragenital Lichen Sclerosus I n the January issue of the Archives, Colbert and colleagues1 report on the successful use of narrowband (NB) UV-B phototherapy in a patient with widespread extragenital lichen sclerosus (LS). We fully agree that NB UV-B is an attractive alternative for patients with extragenital LS if UV-A1 devices are not available. After having treated several patients with NB UV-B, we believe that at least 30 irradiation sessions (similar to NB UV-B treatment for localized scleroderma) are necessary to produce significant changes in the clinical status.2 Importantly, patients must be advised that their skin disease might appear “deteriorated” during phototherapy because the healthy surrounding skin tans more strongly than LS lesions. Colbert and colleagues1 have speculated that the main mechanism of action of NB UV-B in LS might be the increase of matrix metalloproteinase (MMP) levels, finally resulting in a reduction of skin sclerosis. This inspired us to perform MMP-1 immunostaining in a patient with LS treated with NB UV-B. The Figure shows strong MMP-1 immunopositivity in the cytoplasm of several fibroblasts after NB UV-B phototherapy. Our research group3 has recently demonstrated that interleukin 6 (IL6), a multifunctional cytokine that has been shown to increase the production of collagen and glycosaminoglycans, is significantly down-regulated during UV-A1 phototherapy in morphea.3 Since IL-6 concentration has also been reported to be increased in LS,4 the efficacy of NB UV-B might be explained by a depletion of proinflammatory cytokines such as IL-6 in addition to the induc- A B Figure. Immunohistochemical staining for matrix metalloproteinase (MMP) 1 in a patient with extragenital lichen sclerosus before (A) and after (B) narrowband UV-B phototherapy (hematoxylin-eosin, original magnification ⫻40 for both panels). B, The cytoplasm of lesional fibroblasts (arrows) shows strong immunopositivity for MMP-1 after phototherapy. tion of MMPs. Data recently reported by Choi et al5 indicate that NB UV-B irradiation reduces type 1 collagen concentrations in human skin fibroblasts by inhibiting transforming growth factor ␤1 expression and stimulating the release of MMP-1. The good tolerability and low carcinogenicity linked to NB UV-B should also give rise to future studies on phototherapy for genital LS,6 which is much more common and more afflicting for the patient than extragenital disease. Alexander Kreuter, MD Thilo Gambichler, MD Correspondence: Dr Kreuter, Department of Dermatology and Allergology, Ruhr University Bochum, Gudrunstrasse 56, D-44791 Bochum, Germany (a.kreuter@derma .de). Financial Disclosure: None reported. 1. Colbert RL, Chiang MP, Carlin CS, Fleming M. Progressive extragenital lichen sclerosus successfully treated with narrowband UV-B phototherapy. Arch Dermatol. 2007;143(1):19-20. 2. Kreuter A, Hyun J, Stücker M, et al. A randomized controlled study of low-dose UVA1, medium-dose UVA1, and narrowband UVB phototherapy in the treatment of localized scleroderma. J Am Acad Dermatol. 2006;54(3):440-447. 3. Kreuter A, Hyun J, Skrygan M, et al. Ultraviolet A1-induced downregulation of human beta-defensins and interleukin-6 and interleukin-8 correlates with clinical improvement in localized scleroderma. Br J Dermatol. 2006;155(3): 600-607. 4. Romero LI, Pincus SH. In situ localization of interleukin-6 in normal skin and atrophic cutaneous disease. Int Arch Allergy Immunol. 1992;99(1):44-49. 5. Choi CP, Kim YI, Lee JW, Lee MH. The effect of narrowband ultraviolet B on the expression of matrix metalloproteinase-1, transforming growth factorbeta1 and type I collagen in human skin fibroblasts. Clin Exp Dermatol. 2007; 32(2):180-185. 6. Gambichler T, Breuckmann F, Boms S, Altmeyer P, Kreuter A. Narrowband UVB phototherapy in skin conditions beyond psoriasis. J Am Acad Dermatol. 2005;52(4):660-670. Exclusively Benign Dermoscopic Pattern in a Patient With Acral Melanoma T he article by Saida et al1 on the significance of dermoscopic patterns in detecting malignant melanoma is of great importance to us. Based on the results of this large multicenter study conducted in (REPRINTED) ARCH DERMATOL/ VOL 143 (NO. 9), SEP 2007 1213 WWW.ARCHDERMATOL.COM Figure 1. Clinical image of an acquired pigmented lesion on the right heel of a 28-year-old woman. Figure 3. Histologic image of the lesion showing a very atypical melanocytic pattern at the dermoepidermal junction with numerous confluent nests of atypical melanocytes (Fontana-Masson stain, original magnification ⫻5). sion, then, and only then, should he or she look for the presence of benign dermoscopy patterns. Figure 2. Dermoscopy image of the same lesion shown in Figure 1 showing a benign dermoscopy pattern throughout the lesion. The pigmentation follows the furrows, and the ridges are relatively hypopigmented (double-line parallel furrow pattern associated with dots and globules). No malignant dermoscopy pattern can be observed. Japan, the authors reported that 2 dermoscopic patterns, the parallel ridge pattern and irregular diffuse pigmentation pattern, were highly specific for the diagnosis of acral melanoma. They found that 7 of 103 melanomas revealed a benign dermoscopic pattern consisting of either a parallel furrow pattern or a latticelike pattern.2 However, the authors1 also mention that in all melanomas displaying benign dermoscopy patterns, this benign pattern was observed only focally and that the predominant pattern was the malignant pattern. We completely agree that both benign and malignant patterns can coexist within the same lesion. Thus, to avoid misdiagnosing acral melanoma, we recommend that acral lesions be scanned in their entirety, under dermoscopy, to determine the presence or absence of malignant patterns and to ensure that no focal area within the lesion with a malignant pattern is overlooked. Biopsy is recommended for any lesion that reveals a malignant pattern, no matter how small the focus.3 If after scanning the entire lesion the dermoscopist is reassured that no malignant patterns are present within any part of the le- Report of a Case. Unfortunately, exceptions occur: on rare occasions, melanomas can present with an exclusively benign dermoscopy pattern. We describe a 28year-old woman of Italian descent who presented with a pigmented lesion on the heel, which first appeared 2 years earlier and progressively enlarged. Clinical examination revealed a 13-mm, brown, homogeneous, and symmetric macule (Figure 1). Under dermoscopy, no malignant dermoscopy patterns were evident anywhere within the lesion (Figure 2). The lesion displayed a homogeneous, parallel furrow pattern with dots and globules, which best fit the double-line parallel furrow pattern associated with dots and globules, a variant of the benign parallel furrow pattern.4,5 However, owing to the disconcerting history of its recent onset and growth we were prompted to override our dermoscopic diagnosis and take biopsy specimens of the lesion. The lesion was surgically removed and histopathologic analysis revealed the presence of an atypical melanocytic proliferation at the dermoepidermal junction with confluent nests of atypical melanocytes and pagetoid spread—findings consistent with a diagnosis of melanoma in situ (Figure 3 and Figure 4). Comment. What can we learn from this case? First, it is important to remember not to disregard a patient’s medical history. Our patient reported that her heel lesion was relatively new and was enlarging. This fact alone should raise suspicion, since a new or changing lesion is a sensitive indicator of melanoma. Despite the fact that the lesion had a benign dermoscopy pattern, the patient’s medical history was the main impetus for us to take biopsy specimens and correctly identify her melanoma. Second, the size of an acral lesion appears to be important. Several studies have shown that acquired acral lesions larger than 7 mm in diameter have a higher probability of being melanoma, regardless of other morphologic criteria.6-8 Third, the presence of large globules is an unusual feature for benign lesions on palms and soles. It is our sin- (REPRINTED) ARCH DERMATOL/ VOL 143 (NO. 9), SEP 2007 1214 WWW.ARCHDERMATOL.COM Figure 4. Detail ofFigure 3 showing confluent nests of atypical melanocytes as well as pagetoid spread of suprabasal cells. There is some fibrosis as well as pigment incontinence in the dermis. Histopathologic diagnosis was melanoma in situ (hematoxylin-eosin, original magnification ⫻20). cere hope that some of our observations will result in the timely detection of acral melanomas. Ralph P. Braun, MD Olivier Gaide, MD Andreas M. Skaria, MD Alfred W. Kopf, MD Jean-Hilaire Saurat, MD Ashfaq A. Marghoob, MD Correspondence: Dr Braun, Department of Dermatology, University Hospital Zürich, Gloriastr 31, Zürich 8091, Switzerland (braun@melanoma.ch). Financial Disclosure: None reported. 1. Saida T, Miyazaki A, Oguchi S, et al. Significance of dermoscopic patterns in detecting malignant melanoma on acral volar skin: results of a multicenter study in Japan. Arch Dermatol. 2004;140(10):1233-1238. 2. Menzies SW, Zalaudek I. Why perform dermoscopy? the evidence for its role in the routine management of pigmented skin lesions. Arch Dermatol. 2006; 142(9):1211-1212. 3. Altamura D, Altobelli E, Micantonio T, Piccolo D, Fargnoli MC, Peris K. Dermoscopic patterns of acral melanocytic nevi and melanomas in a white population in central Italy. Arch Dermatol. 2006;142(9):1123-1128. 4. Saida T, Oguchi S, Miyazaki A. Dermoscopy for acral pigmented skin lesions. Clin Dermatol. 2002;20(3):279-285. 5. Marghoob AA, Braun RP, Kopf AW. Atlas of Dermoscopy. New York, NY: Taylor Francis; 2005. 6. Saida T, Yoshida N, Ikegawa S, Ishihara K, Nakajima T. Clinical guidelines for the early detection of plantar malignant melanoma. J Am Acad Dermatol. 1990;23(1):37-40. 7. Saida T, Ishihara Y, Tokuda Y. Effective detection of plantar malignant melanoma. Int J Dermatol. 1993;32(10):722-725. 8. Saida T. Malignant melanoma on the sole: how to detect the early lesions efficiently. Pigment Cell Res. 2000;13(suppl 8):135-139. In reply I enjoyed reading the comments from Braun et al on the significance of the dermoscopic patterns seen in acral melanocytic lesions. Acral volar skin is the most prevalent site of malignant melanoma in nonwhite populations. In Japanese patients, about half of all cutaneous melanomas affect this anatomic site. Therefore, early accurate detection of malignant melanoma of this site is essential to improve the prognosis, particularly for nonwhites. The introduction of dermoscopy has immensely contributed to the early detection of acral melanoma. Early acral melanoma shows a unique dermoscopic pattern of bandlike pigmentation on the ridges of the skin markings, which my research groups have called the parallel ridge pattern.1,2 A previous study performed by my group revealed that, in early acral melanoma, the sensitivity and the specificity of this pattern is 86% and 99%, respectively.3 Irregular diffuse pigmentation is another important pattern, also often detected in more or less advanced acral melanoma. In contrast, the major dermoscopic patterns of melanocytic nevi on acral volar skin are the parallel furrow pattern, the latticelike pattern, and the fibrillar pattern.4 I completely agree with Braun et al in emphasizing the importance of careful examination of an entire lesion because the malignant patterns of acral melanoma are only partly detected in some cases. I also agree with them that the benign dermoscopic patterns can be detected also in acral melanoma. However, in melanoma, the benign patterns are found only focally or irregularly distributed within a lesion. In my experience, if a melanocytic lesion on volar skin exhibits 1 of these benign dermoscopic patterns in a monotonous fashion, the lesion is histopathologically diagnosed as a benign nevus without exception. Thus, the case presented by Braun et al is very interesting. Clinically, the lesion was oval in shape and regular in shades of brown color. However, the rapid growth and the larger size, 13 mm in diameter, are exceptional in a benign nevus. The dermoscopic finding of this lesion was the typical feature of the parallel furrow pattern associated with the brown globules regularly distributed along both sides of the sulci. No malignant dermoscopic patterns were detected within the lesions. Except for the larger size and the rapid growth, all of these clinical and dermoscopic findings strongly suggested that this was a benign nevus. Unexpectedly, however, histopathologic examination revealed confluent nests of atypical melanocytes as well as pagetoid spread in the lower epidermis. Braun et al finally diagnosed this case as melanoma in situ. Histopathologic analysis is still the gold standard to determine the diagnosis of melanocytic neoplasm. Thus, this case could really be melanoma in situ. Under the principle that every rule has its exceptions, acral melanoma could exceptionally show the typical parallel furrow pattern. But in this particular case, I wish to be prudent and agree with the diagnosis of Braun et al. Conflict between dermoscopic and histopathologic findings is emerging as an important subject. Soyer et al5 have noted that dermoscopy could challenge the monopoly of dermatopathology in determining the diagnosis of malignant melanoma. In my opinion, the lesion described by Braun et al shows completely regular, symmetric, homogeneous, and orderly dermoscopic features, thereby strongly suggesting a benign nature. Furthermore, regarding the histopathologic findings of this case, I want to add 1 comment. My group has recently noticed that despite banal clinical features, some melanocytic nevi located at transition portions between glabrous and nonglabrous skin and also in interdigital areas often histopathologically exhibit random, irregular distribution of melanocytes as solitary units as well as in nests within the epidermis, mimicking the findings of melanoma in situ (unpublished data, 2007). Owing to these histopathologic findings, melanocytic nevi on these areas could be overdi- (REPRINTED) ARCH DERMATOL/ VOL 143 (NO. 9), SEP 2007 1215 WWW.ARCHDERMATOL.COM agnosed as melanoma (“pseudomelanoma”), as is the case of melanocytic nevus of a young woman’s genitalia. The melanocytic lesion described by Braun et al seems to be located at this transition zone, and thus, in my view, the histopathologic findings must be carefully interpreted. Of course, validity of this concept of pseudomelanoma at the transition areas must be critically evaluated in further studies. Toshiaki Saida, MD, PhD Correspondence: Dr Saida, Department of Dermatology, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto 390-8621, Japan (tosaida@hsp.md.shinshu-u .ac.jp). 1. Oguchi S, Saida T, Koganehira Y, Ohkubo S, Ishihara Y, Kawachi S. Characteristic epiluminescent microscopic features of early malignant melanoma on glabrous skin. Arch Dermatol. 1998;134(5):563-568. 2. Saida T, Oguchi S, Miyazaki A. Dermoscopy for acral pigmented skin lesions. Clin Dermatol. 2002;20(3):279-285. 3. Saida T, Miyazaki A, Oguchi S, et al. Significance of dermoscopic patterns in detecting malignant melanoma on acral volar skin. Arch Dermatol. 2004;140 (10):1233-1238. 4. Saida T, Oguchi S, Ishihara Y. In vivo observation of magnified features of pigmented lesions on volar skin using video macroscope. Arch Dermatol. 1995; 131(3):298-304. 5. Soyer HP, Massone C, Ferrara G, Argenziano G. Limitations of histopathologic analysis in the recognition of melanoma: a plea for a combined diagnostic approach of histopathologic and dermoscopic evaluation. Arch Dermatol. 2005;141(2):209-211. noma is not a trivial matter. Much more evidence than was provided by Matichard et al1 is needed before it can be recommended. Thomas B. Newman, MD, MPH M. Jeffrey Maisels, MB BCh Correspondence: Dr Newman, Department of Epidemiology and Biostatistics, 185 Berry St, Ste 5700, San Francisco, CA 94107-1762 (newman@epi.ucsf.edu). Financial Disclosure: None reported. 1. Matichard E, Le Henanff A, Sanders A, Leguyadec J, Crickx B, Descamps V. Effect of neonatal phototherapy on melanocytic nevus count in children. Arch Dermatol. 2006;142(12):1599-1604. 2. Wiecker TS, Luther H, Buettner P, Bauer J, Garbe C. Moderate sun exposure and nevus counts in parents are associated with development of melanocytic nevi in childhood: a risk factor study in 1,812 kindergarten children. Cancer. 2003;97(3):628-638. 3. Bauer J, Buttner P, Luther H, Wiecker TS, Mohrle M, Garbe C. Blue-light phototherapy of neonatal jaundice does not increase the risk for melanocytic nevus development. Arch Dermatol. 2004;140(4):493-494. 4. Berg P, Lindelof B. Is phototherapy in neonates a risk factor for malignant melanoma development? Arch Pediatr Adolesc Med. 1997;151(12):1185-1187. 5. Dean AG, Dean JA, Burton AH, Dicker RC. Epi Info: a general-purpose microcomputer program for public health information systems. Am J Prev Med. 1991;7(3):178-182. In reply 1 Evidence Insufficient to Recommend Melanoma Surveillance Following Phototherapy for Jaundice M atichard et al1 reported an association between receipt of blue-light phototherapy for neonatal jaundice and numbers of melanocytic nevi at least 2 mm in diameter at age 8 or 9 years. Although they stated that their results “should be interpreted with caution,”1(p1603) they concluded that exposed children “should undergo dermatologic preventive measures and surveillance for the development of melanoma.”1(p1599) We believe that this recommendation is premature. The authors studied only 18 children who had been exposed to phototherapy, and the selection of these exposed children was via an entirely different mechanism from the selection of the control group. This could easily have introduced confounding factors that were not measured. It appears that the original hypothesis that the authors sought to test was that phototherapy might increase the total nevus count, which it did not: mean counts, 28.5 vs 28.7 (P=.88). The association was present only when attention was restricted to nevi 2 to 5 mm in diameter. The authors do not provide a biological rationale for restriction of the association to nevi of that size. Finally, a larger study of this issue failed to find any association between phototherapy and nevi,2,3 and a study of whether phototherapy was a risk factor for melanoma4 found that 0 of 30 melanoma cases had included exposure to phototherapy, compared with 11 of 120 controls (odds ratio, 0; upper limit of 95% confidence interval, 1.55).5 Counseling families of infants exposed to phototherapy that their child needs to be watched for mela- My group’s study demonstrates that the number of melanocytic nevi larger than 2 mm in diameter is higher in children aged between 8 and 9 years who were exposed to neonatal phototherapy than in those who were not exposed. In a multivariate analysis, we have studied the respective roles of both sun exposure and neonatal phototherapy (Table). As summarized in the Table, sun exposure is the major factor for nevi smaller than 2 mm. In addition, the data in the Table support the fact that neonatal phototherapy is the major risk factor for nevi larger than 2 mm in diameter. It can be postulated that sun exposure is the major risk factor for the most recent melanocytic nevi (< 2 mm). Nevi larger than 5 mm might represent congenital nevi for which the genetic predisposition could be the most important risk factor. This classification of melanocytic nevi into different diameters (larger than 2 mm, 2-5 mm, and larger than 5 mm) is usual in studies evaluating the prevalence of common melanocytic nevi in children and its relationship with pigmentary characteristics and sun exposure.2-5 In most studies, small nevi (< 2 mm) and small dark brown pigmented freckles called lentigo simplex are excluded. But until now, the issue of the size of the nevi has not been totally resolved. However, some authors5 include these small nevi in the total number of nevi, as my group did.1 Retrospective documentation of neonatal phototherapy is often very difficult to find and often lacks important details (eg, bilirubin level throughout therapy, duration of exposure, and dose of phototherapy). Hence the entry criteria for my study group was the presence of complete phototherapy documentation and the ability to find the child. The control group was selected to match for age, geographic area, and Fitzpatrick skin type, thus decreasing both the likelihood of bias and the number and influence of confounding factors. Our method of case selection avoided the problems of recall bias that are inherent in studies based on interviews, as conducted by Bauer and colleagues.6 The different conclusions (REPRINTED) ARCH DERMATOL/ VOL 143 (NO. 9), SEP 2007 1216 WWW.ARCHDERMATOL.COM Table. Statistical Multivariate Analysis of Nevus Risk Factor P Value in the Variance Analysis Model by Lesion Size Exposure Category Intensive phototherapy Solar exposure during holidays Severe sunburns Any Size ⬍2 mm 2-5 mm ⬎ 2 mm ⬎ 5 mm .50 .02 .94 .18 .02 .84 ⬍.001 .40 .51 ⬍.001 .46 .47 .29 .80 .45 drawn by my group’s study and by Bauer et al may be the result of the different methods used to obtain the data. Although the relatively small sample size of my group’s study1 suggests caution in interpreting these data (particularly our multivariate analysis) and may limit generalization of the results, the study poses an important question: can it now be simply stated that phototherapy dose not induce a modification of nevus count? Nonetheless, we strongly recommend that all neonatal phototherapy sessions be meticulously documented for use in further research and risk stratification in patients’ records. We believe that individuals who receive intensive phototherapy should undergo periodic dermatologic follow-up if they develop nevi. Vincent Descamps, MD, PhD Correspondence: Dr Descamps, Bichat-Claude Bernard Hospital, Department of Dermatology, Assistance Publique des Hôpitaux de Paris, 46 rue Henri Huchard, 75018 Paris, France (vincent.descamps@bch.ap-hop-paris .fr). 1. Matichard E, Le Henanff A, Sanders A, Leguyadec J, Crickx B, Descamps V. Effect of neonatal phototherapy on melanocytic nevus count in children. Arch Dermatol. 2006;142(12):1599-1604. 2. Siskind V, Darlington S, Green L, Green A. Evolution of melanocytic nevi on the faces and necks of adolescents: a 4 y longitudinal study. J Invest Dermatol. 2002;118(3):500-504. 3. Autier P, Severi G, Pedeux R, et al; European Organisation for Research and Treatment of Cancer Melanoma Group. Number and size of nevi are influenced by different sun exposure components: implications for the etiology of cutaneous melanoma (Belgium, Germany, France, Italy). Cancer Causes Control. 2003;14(5):453-459. 4. MacLennan R, Kelly JW, Rivers JK, Harrison SL. The Eastern Australian Childhood Nevus Study: site differences in density and size of melanocytic nevi in relation to latitude and phenotype. J Am Acad Dermatol. 2003;48(3):367-375. 5. Valiukeviciene S, Miseviciene I, Gollnick H. The prevalence of common acquired melanocytic nevi and the relationship with skin type characteristics and sun exposure among children in Lithuania. Arch Dermatol. 2005;141 (5):579-586. 6. Bauer J, Buttner P, Luther H, Wiecker TS, Mohrle M, Garbe C. Blue light phototherapy of neonatal jaundice does not increase the risk for melanocytic nevus development. Arch Dermatol. 2004;140(4):493-494. Allergic Contact Dermatitis: Another Adverse Effect of Over-the-counter Topical Hydrocortisone W e read with interest the commentary in the March 2007 issue of the Archives of Dermatology titled “Topical Hydrocortisone From Prescription to Over-the-Counter Sale.”1 While this article aptly describes the historical debate regarding approval for overthe-counter drug (OTC) use, it neglects to include allergic contact dermatitis from corticosteroids as 1 of the adverse effects of topical hydrocortisone.2-9 Corticosteroid allergy was first described in 1959 by Burckhardt10 but has become more widely recognized since the introduction of tixocortol-21-pivalate as a patchtest marker in the late 1980s. Prevalence of allergy to tixocortol, a marker for allergy to hydrocortisone and other group A corticosteroids, has ranged from 2.3% to 2.9% in large patch-tested populations in North America. Clinical relevance to the presenting dermatitis is documented in more than 80% of cases. The ready availability of OTC hydrocortisone products likely contributes to this high prevalence and clinical relevance. Clues to the diagnosis of steroid contact allergy include worsening of dermatitis with use or a change in the clinical pattern of the disease. Importantly, this allergen is not available in commercial patchtest kits such as the T.R.U.E. test (Allerderm, Phoenix, Arizona) in the United States. Clinicians should be aware of the risk of allergic contact dermatitis (ACD) from corticosteroids and be prepared to refer patients for comprehensive patch testing. Kalman L. Watsky, MD Erin M. Warshaw, MD, MS Correspondence: Dr Watsky, 330 Orchard St, Ste 103, New Haven, CT 06511 (kwatsky@snet.net). Financial Disclosure: None reported. 1. Ravis SM, Eaglstein WH. Topical hydrocortisone from prescription to overthe-counter sale. Arch Dermatol. 2007;143(3):413-415. 2. Lutz ME, el-Azhary RA, Gibson LE, Fransway AF. Contact hypersensitivity to tixocortol pivalate. J Am Acad Dermatol. 1998;38(5, pt 1):691-695. 3. Scheuer E, Warshaw E. Allergy to corticosteroids: update and review of epidemiology, clinical characteristics, and structural cross-reactivity. Am J Contact Dermat. 2003;14(4):179-187. 4. Marks JG, Belsito DV, DeLeo VA, et al. North American Contact Dermatitis Group standard tray patch test results (1992 to 1994). Am J Contact Dermat. 1995;6:160-165. 5. Marks JG, Belsito DV, DeLeo VA, et al. North American Contact Dermatitis Group patch test results for the detection of delayed-type hypersensitivity to topical allergens. J Am Acad Dermatol. 1998;38(6, pt 1):911-918. 6. Marks JG Jr, Belsito DV, DeLeo VA, et al. North American Contact Dermatitis Group patch test results, 1996-1998. Arch Dermatol. 2000;136(2): 272-273. 7. Marks JG Jr, Belsito DV, DeLeo VA, et al. North American Contact Dermatitis Group patch test results, 1998 to 2000. Am J Contact Dermat. 2003; 14(2):59-62. 8. Pratt MD, Belsito DV, DeLeo VA, et al. North American Contact Dermatitis Group patch test results, 2001-2002 study period. Dermatitis. 2004;15 (4):176-183. 9. Warshaw EM, Rietschel RL, Sasseville D, et al. North American Contact Dermatitis Group patch test results 2003-2004 study period. Dermatitis. In press. 10. Burckhardt W. Contact eczema caused by hydrocortisone. Hautarzt. 1959; 10:42. In reply We thank Watsky and Warshaw for their interest and insightful comments. As they point out, ACD was not listed as an adverse effect of treatment with topical hydrocorti- (REPRINTED) ARCH DERMATOL/ VOL 143 (NO. 9), SEP 2007 1217 WWW.ARCHDERMATOL.COM sone in our commentary.1 We did not mention the potential adverse effect of ACD to topical hydrocortisone because it did not play a role in the debate regarding the appropriateness of permitting OTC sale of topical hydrocortisone preparations. As pointed out by Watsky and Warshaw, the ready availability of OTC hydrocortisone products (especially in structural class A) likely contributes to a high prevalence of clinically significant positive patch test results to corticosteroid markers in selected patch-tested populations. How this translates to the prevalence of corticosteroidinduced ACD in the population at large is apparently not known. At what level corticosteroid-induced ACD might be a public health concern requiring consideration of removing products from the market is not only an intriguing question but one that could, depending on the answer, result—following the law of unintended consequences—in proving correct, after all, the initial reaction of the dermatology community. William H. Eaglstein, MD Scott M. Ravis Correspondence: Dr Eaglstein, Research and Development, Stiefel Laboratories Inc, 255 Alhambra Cir, Coral Gables, FL 33134 (weaglstein@stiefel.com). 1. Ravis SM, Eaglstein WH. Topical hydrocortisone from prescription to overthe-counter sale. Arch Dermatol. 2007;143(3):413-415. A VIGNETTES Successful Treatment of Pityriasis Versicolor With 5-Aminolevulinic Acid Photodynamic Therapy P ityriasis versicolor is a common chronic superficial fungal infection caused by the organism Malassezia furfur. Although many conventional treatments have been shown to be successful in treating pityriasis versicolor, therapy of long-term duration may be needed in many cases, and recurrence is not uncommon. In vitro experimental investigations have demonstrated that several fungal strains can be effectively inactivated by irradiation with visible light wavelengths in the presence of photosensitizer.1-3 However, to our knowledge, there have been no clinical trials of photodynamic therapy (PDT) against pityriasis versicolor. Report of a Case. A 37-year-old man presented with a 2-year history of asymptomatic, light brown, scaly patches on both axillae (Figure 1A). Microscopic examination of samples stained with 10% potassium hydroxide revealed short, thick, fungal hyphae and spores of various sizes (Figure 2A). We tried to treat the lesions with B Figure 1. A 37-year-old man with a 2-year history of scaly patches on both axillae. A, Sharply marginated, light brown hyperpigmentation with fine scales on the axilla. B, Clearance of pityriasis versicolor without reinfection after 16 weeks of follow-up after treatment with 5-aminolevulinic acid in combination with photodynamic therapy. (REPRINTED) ARCH DERMATOL/ VOL 143 (NO. 9), SEP 2007 1218 WWW.ARCHDERMATOL.COM A B Figure 2. Microscopic examination of samples stained with 10% potassium hydroxide (original magnification ⫻400 for both panels). A, Before treatment, numerous short, thick fungal hyphae and spores of various sizes are seen. B, No fungal hyphae or spores are present 10 weeks after the last treatment. 5-aminolevulinic acid (ALA) in combination with PDT. Topical 20% ALA (Medac, Hamburg, Germany) in petrolatum vehicle was applied to the lesions and covered with an occlusive polyurethane film (Tegaderm; 3M, St Paul, Minnesota). After 4 hours, excess ALA was removed, and the lesions were irradiated with light from light-emitting diodes (mean ± SD wavelength, 630 ± 50 nm). The light intensity was 100 mW/cm2, and the light doses were 70 J/cm2 for the left axilla and 80 J/cm2 for the right axilla. The procedure was repeated 2 weeks later with increased light dose increments of 10 J/cm2 on each side. The area cleared within 4 weeks, and the patient was observed for an additional 3 months without reinfection (Figure 1B). One week after the first treatment and 10 weeks after the last treatment, samples stained with 10% potassium hydroxide were again taken from both axillae and these smears showed no fungal hyphae or spores (Figure 2B). Of note, the clearance was maintained throughout the warm and humid summer of Korea. Comment. To our knowledge, only 1 clinical trial of PDT treatment for mycotic infection has been reported.4 In that study, interdigital mycosis of the feet was irradiated with 75 J/cm2. The clearance was seen in 6 of 9 patients after 1 (n=4) or 4 (n = 2) treatments. However, 4 patients reported recurrences 4 weeks after the last treatment. The authors suggested that in vivo environmental conditions such as temperature, humidity, and pH of the interdigital skin could induce a poor cell uptake of ALA and a deficient biosynthesis of protoporphyrin IX. In addition, the irregular tridimensional shape of this peculiar anatomic area could lead to a nonuniform delivery of light and/or ALA cream. The better outcome in our case with a similar light dose may be due to the different causative fungal strain and relatively uniform delivery of light and ALA cream to the affected sites. In the treatment of pityriasis versicolor, standard drug treatments are prolonged, and the appearance of drugresistant strains is becoming more frequent. The multiplicity of cellular targets in fungi should reduce the risk of selection of photomutant, resistant strains after PDT, and this risk should be further minimized by the lack of mutagenic effects of PDT.5 Our results of prompt clearance and no recurrence of pityriasis versicolor after PDT indicate that this approach may be a promising treatment for pityriasis versicolor. Young Jin Kim, MD You Chan Kim, MD, PhD Correspondence: Dr Y. C. Kim, Department of Dermatology, Ajou University School of Medicine, 5 WonchonDong, Yeongtong-Gu, Suwon 443-721, South Korea (maychan@ajou.ac.kr). Financial Disclosure: None reported. 1. Wainwright M. Photodynamic antimicrobial chemotherapy (PACT). J Antimicrob Chemother. 1998;42(1):13-28. 2. Strakhovskaya MG, Shumarina AO, Fraikin GY, Rubin AB. Synthesis of protoporphyrin IX induced by 5-aminolevulinic acid in yeast cells in the presence of 2,2;-dipyridyl. Biochemistry (Mosc). 1998;63(6):725-728. 3. Smijs TG, van der Haas RN, Lugtenburg J, Liu Y, de Jong RL, Schuitmaker HJ. Photodynamic treatment of the dermatophyte Trichophyton rubrum and its microconidia with porphyrin photosensitizers. Photochem Photobiol. 2004; 80(2):197-202. 4. Calzavara-Pinton PG, Venturini M, Capezzera R, Sala R, Zane C. Photodynamic therapy of interdigital mycoses of the feet with topical application of 5-aminolevulinic acid. Photodermatol Photoimmunol Photomed. 2004;20(3): 144-147. (REPRINTED) ARCH DERMATOL/ VOL 143 (NO. 9), SEP 2007 1219 WWW.ARCHDERMATOL.COM 5. Calzavara-Pinton PG, Venturini M, Sala R. A comprehensive overview of photodynamic therapy in the treatment of superficial fungal infections of the skin. J Photochem Photobiol B. 2005;78(1):1-6. Leukemia Cutis: A Presenting Sign in Acute Promyelocytic Leukemia Report of a Case. A 63-year-old woman developed 3 erythematous, pruritic plaques on her left lower extremity. She called her dermatologist and was prescribed prednisone for likely contact dermatitis from poison ivy. Two weeks later, the patient developed fatigue and bruising. Findings from a complete blood cell count were abnormal, demonstrating blasts (promyelocytes predominant), anemia, and thrombocytopenia. The patient was admitted for workup. On admission, her white blood cell count was 4500 cells/µL (normal range, 4500-11 000 cells/µL); hematocrit level was 31.4% (normal range, 35%-45%); and platelet count was 33⫻ 103/µL (normal range, 153⫻103/µL to 367 ⫻ 103/µL). A manual differential count demonstrated 62% promyelocytes. Analysis of bone marrow biopsy specimens showed markedly hypercellular marrow with 90% promyelocytes and a positive translocation of 15:17 on fluorescence in situ hybridization. Flow cytometry revealed cells positive for CD13, CD33, CD38, and CD117 and negative for CD14, CD64, CD2, CD11, CD3, CD20, CD7, CD34, and HLA-DR, which was consistent with acute promyelocytic anemia. Polymerase chain reaction revealed a 0.436 ratio of the PML-RAR-α oncogene in her bone marrow. A dermatology consultant was called to evaluate 3 erythematous, nontender, indurated plaques with necrotic centers on her left calf, ranging in size from 5 to 9 mm (Figure 1). Scattered petechiae and ecchymoses were present. The differential diagnosis included vasculitis, leukemia cutis, arthropod assault, panniculitis, deep fungal infection, and atypical mycobacteria. Tissue cultures were negative for bacteria, fungal elements, and mycobacteria. Histopathologic analysis revealed, pandermally and in the subcutaneous fat, dense, perivascular, and interstitial infiltrate of malignant, immature, granulocytic cells with extensive tissue hemorrhage. These tumor cells contained polymorphic nuclei with abundant granular cytoplasm. Occasional mitotic figures were present. The immature hematopoietic cells stained diffusely positive for chloracetic esterase by Leder stain and were CD34 negative. A few immature cells contained eosinophilic, cytoplasmic granules. No epidermotropism or vascular or neural invasion was noted (Figure 2). The findings confirmed the diagnosis of leukemia cutis, and the morphologic features were consistent with promyelocytic leukemia. The patient underwent a chemotherapeutic regimen of daunorubicin and all-trans retinoic acid (ATRA) followed by cytarabine, daunorubicin, and arsenic trioxide. Four months after her initial presentation, a bone marrow biopsy specimen showed no abnormalities, and her disease is currently in remission. The leukemia cutis lesions on her calf are well healed. Figure 1. Three erythematous, nontender, indurated plaques with necrotic centers ranging in size from 5 to 9 mm were present on the patient’s left calf. Figure 2. In a biopsy specimen taken from a lesion on the patient’s calf, immature hematopoietic cells stained diffusely positive for chloracetic esterase by Leder stain (original magnification ⫻40). Comment. Leukemia cutis is the dissemination of systemic leukemia and a poor prognostic sign. It presents as papules, plaques, or nodules, with a characteristic violaceous color. Diffuse infiltration of leukemic cells into the dermis, subcutis, blood vessels, and skin adnexa are seen on histologic examination.1 Immunohistochemical study characterizes the immunophenotypes of leukemic cells. Acute promyelocytic leukemia (APL), classified as AML-M3 (acute myeloid leukemia, subtype M3) in the French-American-British classification system, accounts for approximately 10% to 15% of acute myeloid leukemia in adults.2 Patients may have abundant abnormal progranulocytes, severe coagulopathy, and a balanced reciprocal translocation, t(15;17)(q22;q12), in leukemic cells.3 Fusion of the promyelocytic leukemia gene (PML) on chromosome 15 and the retinoic acid receptor ␣ (RAR-␣) on chromosome 17 to form the oncogene PML-RAR-␣ occurs.2 At 5 years, 70% to 80% of patients with APL are disease free with treatment, which includes ATRA and anthracycline-based chemotherapy.2 (REPRINTED) ARCH DERMATOL/ VOL 143 (NO. 9), SEP 2007 1220 WWW.ARCHDERMATOL.COM From 2% to 20% of patients with lymphocytic and granulocytic leukemia and 10% to 50% with monocytic leukemia develop leukemia cutis.4 To our knowledge, fewer than 25 cases of skin infiltration by APL cells have been previously described.5 Interestingly, extramedullary involvement tends to occur after the first remission in APL, perhaps as a complication of ATRA therapy. In contrast, our patient presented with lesions of leukemia cutis prior to diagnosis and treatment. To our knowledge, this represents the first case of leukemia cutis as a presenting sign of APL. Clinicians should have a high suspicion for cutaneous findings in a patient with weakness and fatigue because it may herald the diagnosis of malignancy. Tania R. Markowski, BA Donna Bilu Martin, MD Grace F. Kao, MD Linda Lutz, MD April Deng, MD, PhD Anthony A. Gaspari, MD Figure 1. Bulla on the fourth toe due to mechanical trauma. Correspondence: Dr Martin, Department of Dermatology, University of Maryland School of Medicine, 405 W Redwood St, Sixth Floor, Baltimore, MD 21201 (dbilumartin@gmail.com). Financial Disclosure: None reported. 1. Gambichler T, Herde M, Hoffmann K, Altmeyer P, Jansen T. Poor prognosis of acute myeloid leukemia associated with leukemia cutis. J Eur Acad Dermatol Venereol. 2002;16(2):177-188. 2. Löwenberg B, Griffin JD, Tallman MS. Acute myeloid leukemia and acute promyelocytic leukemia. Hematology Am Soc Hematol Educ Program. 2003:82101. 3. Giralt S, O’Brian S, Weeks E, et al. Leukemia cutis in acute promyelocytic leukemia: reports of three cases after treatment with all-trans retinoic acid. Leuk Lymphoma. 1994;14(5-6):453-456. 4. Ratnam KV, Khor CJL, Su WPD. Leukemia cutis. Dermatol Clin. 1994;12(2): 419-431. 5. Ueda K, Kume A, Furukawa Y, Higashi N. Cutaneous infiltration in acute promyelocytic leukemia. J Am Acad Dermatol. 1997;36(1):104-106. Necrolytic Migratory Erythema: The Outermost Marker for Glucagonoma Syndrome Report of a Case. A 56-year-old woman presented with significant loss of weight, a painful oral inflammation, and a skin eruption on the trunk, lower extremities, and the intertriginous and genital areas. The physical examination showed a patient with cachexia and striking eruptions on the skin and mucous membranes. The lesions consisted of annular, confluent, superficially eroded erythematous plaques with elevated, well-demarcated edges and bullas at the sites of friction (Figure 1). Faint areas of lacy erythema were noted on the buttocks and arms. Severe stomatitis, painful glossitis, and bilateral angular cheilitis were present (Figure 2). Annular erythematous lesions with slightly elevated borders were seen on the genital area. An elevated erythrocyte sedimentation rate (65 mm/h; normal, ⬍12 mm/h), high fasting serum glucose level (155 mg/dL; normal, 63-108 mg/dL) (to convert to millimoles per liter, multiply by 0.0555), and low hemoglo- Figure 2. The tongue is red and atrophic; bilateral angular cheilitis is seen. bin level (100 g/L; normal, 120-140 g/L) were detected. A peripheral blood smear showed microcytic, hypochromic red blood cells with anisocytosis. Histopathologic findings revealed severe parakeratosis, mild acanthosis, and persistent loss of granular layer. Necrosis of keratinocytes in the squamous layer and subcorneal blistering were present. Mild vascular dilatation and perivascular lymphocytic infiltrate were seen in the dermis. An abdominal computed tomographic scan suggested a pancreatic lesion and showed multiple hypoechogenic lesions with diameters of 2 to 3 cm. Magnetic resonance imaging of the pancreas revealed a diffuse mass in the tail. The plasma glucagon level was elevated at 127 ng/L (normal, ⬍ 60 ng/L). The patient underwent pancreatic debulking and partial metastasectomy of the liver. The histologic and immunohistochemical investigations revealed a differentiated endocrine tumor with vascular invasion and somatostatin receptor immunopositivity. Treatment with intramuscular octreotide (30 mg every 28 days) and interferon alfa (6 MU subcutaneously 3 times per week) was introduced together with 6 cycles of hepatic chemoembolization. No remission was achieved, and the patient died 14 months after the first physical examination. (REPRINTED) ARCH DERMATOL/ VOL 143 (NO. 9), SEP 2007 1221 WWW.ARCHDERMATOL.COM Comment. Necrolytic migratory erythema (NME) pathogenesis is quite controversial. In vitro studies have demonstrated that glucagon stimulates epidermal arachidonic acid synthesis1 thus directly affecting the skin structures. The cellular protein p62 (which is an adapter in signaltransducing pathways and a component of the inclusion bodies of various chronic degenerative disorders) is either absent from, or only focally expressed in, glucagonomas in contrast to its abundance in a wellfunctioning pancreas. Since p62 is involved in proapoptotic signal transduction, its loss probably renders tumor cells less sensitive to apoptosis.2 At the same time, p16 and p27 levels are decreased consistently in pancreatic endocrine neoplasms, and because these proteins act as inhibitors of cyclindependent kinases, their insufficiency may stimulate their transformation and migration.3 Very often NME precedes the onset of systemic symptoms and identifies the main pathologic process.4 Owing to its distinct clinical picture and well-defined histopathologic findings, NME seems to be a dependable morphologic clue to a subtle diagnosis.5 Remarkably, clinical presumption and histologic findings were the bases in the present case for the detection of this localized neoplastic proliferation and to confirm the sophisticated clinical entity. Mary L. Gantcheva, MD, PhD Valentina K. Broshtilova, MD Adriana I. Lalova, MD, PhD Correspondence: Dr Gantcheva, Department of Dermatology and Venereology, Faculty of Medicine, Sofia Medical University, 1 St Georgi Sofiisky St, 1431 Sofia, Bulgaria (mary_gant@yahoo.com). Financial Disclosure: None reported. 1. Peterson LL, Shaw JC, Acott KM, Mueggler PA, Parker F. Glucagonoma syndrome increases epidermal arachidonic acid. J Am Acad Dermatol. 1984;11 (3):468-473. 2. Lackner C, Dlaska D, Fuchsbichler A, et al. p62 Protein is expressed in pancreatic beta cells J Pathol. 2005;206(4):402-408. 3. Tomita T. Cyclin-dependent kinase (cdk6) and p16 in pancreatic endocrine neoplasms. Pathology. 2004;36(6):566-570. 4. Chastain MA. The glucagonoma syndrome: a review of its features and discussion of new perspectives. Am J Med Sci. 2001;321(5):306-320. 5. Kheir SM, Omura EF, Grizzle WE, Herrera GA, Lee I. Histologic variation in the skin lesions of the glucagonoma syndrome. Am J Surg Pathol. 1986;10 (7):445-453. Lymphomatoid Granulomatosis Induced by Imatinib-Treatment Report of a Case. An 89-year-old woman with liver metastases from a gastrointestinal stromal tumor (GIST) was treated with imatinib mesylate, initial dose of 400 mg/d. Three months later, the liver tumors decreased. Again 3 months later, a computed tomographic (CT) scan revealed 3 intrapulmonary lesions that radiologically resembled an infectious complication or metastases of the GIST. Owing to the age of the patient and continuous decline of her physical status, a lung biopsy was excluded. The progressing pulmonary tumors were clini- A B Figure 1. Histologic images demonstrating large blastic B cells surrounding the necrosis under hematoxylin-eosin (A) (original magnification ⫻ 20) and CD20 stain (B) (original magnification ⫻ 200). cally interpreted as metastases of the GIST, and therefore imatinib mesylate treatment was continued. Nine months later, the patient presented with multiple subcutaneous nodules as large as 25⫻ 30 mm on both legs and the lower back. Histologic findings revealed a dense lymphocytic infiltrate, mainly of the subcutis, extending through the dermis into the epidermis, with central necrosis and scattered giant cells. The infiltrate was both angiocentric and angiodestructive. Immunohistochemically, the lymphocytes were mainly CD20 positive (Figure 1). Epstein-Barr virus (EBV) in situ hybridization revealed EBV RNA in a distinct population of infiltrating lymphocytes. Clonality analysis of the CDR3 region of the immunoglobulin heavy-chain gene revealed the identical clone in 2 distant biopsy specimens. A large B-cell lymphoma resembling lymphomatoid granulomatosis (LYG) was diagnosed. Whole-body CT scan revealed, in addition to hepatic GIST tumor metastasis, progressive pulmonary tumors that resembled lymphomas or granulomas (Figure 2). Blood cell count findings showed leukopenia (2600 white blood cells/µL) and lymphopenia (10.8% lymphocytes). Immunophenotyping of the peripheral blood showed an increased CD4/CD8 ratio of 9:1 and 1.9% B cells. Cutaneous and most likely pulmonary LYG was diagnosed. As the pulmonic lymphomas lead to progressive dyspnea, imatinib mesylate therapy was discontinued and replaced by a symptomatic dexamethasone treatment, which was stopped by the patient after 4 weeks. Two months after discontinuation, the subcutaneous nodules had vanished completely, and the pulmonary infiltrates could be detected only as small residual nodules (Figure 2). The patient’s physical condition continuously improved, and the leukocyte and lymphocyte counts returned to normal range. The liver metastases of GIST did not show any change in size. Comment. Lymphomatoid granulomatosis is a rare, angiocentric, angioinvasive, EBV-positive, B-cell lymphoproliferative disease that primarily involves the lung and skin,1 histologically characterized by angiocentric and an- (REPRINTED) ARCH DERMATOL/ VOL 143 (NO. 9), SEP 2007 1222 WWW.ARCHDERMATOL.COM A B C Figure 2. Radiologic images. A, Computed tomographic scan showing multiple large pulmonary tumors. B and C, Chest radiographs taken during imatinib therapy (B) and after discontinuation of imatinib treatment (C). gioinvasive lymphoid infiltrates. The presence of EBVpositive B cells is critical for the diagnosis. Imatinib mesylate, a tyrosine kinase inhibitor targeting the Bcr-Abl fusion tyrosine kinase,2 is currently used in the management of metastatic and inoperable GIST. Common adverse effects include eosinophilia, fasciitis, and mycosis fungoides–like reactions.3 Bekkenk et al4 observed the occurrence of EBV-positive, primary, cutaneous, B-cell lymphoma during imatinib mesylate treatment that resolved after the therapy was discontinued. Epstein-Barr virus–associated lymphomas occur most commonly in severely immunosuppressed patients and often spontaneously resolve after reconstitution of the immune system. Imatinib mesylate may act through T-cell depletion; it can inhibit T-cell proliferation and T-cell activation in vitro and reduce the expansion of cytotoxic T lymphocytes in response to EBV.5 Since, in the present case, cutaneous and pulmonary LYG occurred during imatinib mesylate therapy and resolved entirely after the treatment was discontinued, modulation of T-cell function was most likely critically involved in the development of LYG. Amir S. Yazdi, MD Gisela Metzler, MD Susanne Weyrauch, MD Mark Berneburg, MD Michael Bitzer, MD Hans-Konrad Müller-Hermelink, MD Martin Röcken, MD Correspondence: Dr Yazdi, Department of Dermatology, University of Tübingen, Liebermeisterstr 25, 72076 Tübingen, Germany (Amir.Yazdi@med.uni-tuebingen.de). Financial Disclosure: None reported. 1. Fauci AS, Haynes BF, Costa J, et al. Lymphomatoid granulomatosis: prospective clinical and therapeutic experience over 10 years. N Engl J Med. 1982; 306(2):68-74. 2. Druker BJ, Sawyers CL, Kantarjian H, et al. Activity of a specific inhibitor of the BCR-ABL tyrosine kinase in the blast crisis of chronic myeloid leukemia and acute lymphoblastic leukemia with the Philadelphia chromosome. N Engl J Med. 2001;344(14):1038-1042. 3. Jardin F, Courville P, Lenain P, et al. Concomitant eosinophilia, fasciitis, and mycosis fungoides-like reaction with antinuclear autoantibodies in chronic myeloid leukaemia: role of a T-cell clone induced by imatinib. Lancet Oncol. 2005;6(9):728-729. 4. Bekkenk MW, Vermeer MH, Meijer CJ, et al. EBV-positive cutaneous B-cell lymphoproliferative disease after imatinib mesylate. Blood. 2003;102(12): 4243. 5. Seggewiss R, Lore K, Greiner E, et al. Imatinib inhibits T-cell receptormediated T-cell proliferation and activation in a dose-dependent manner. Blood. 2005;105(6):2473-2479. Focal Acne During Topical Tacrolimus Therapy for Vitiligo T acrolimus is a macrolide antibiotic produced by Streptomyces tsukubaensis and with strong Tspecific immunosuppressant activity. Primarily used for treatment of atopic dermatitis, it has been used to treat other inflammatory and immunologic skin disorders, including vitiligo, with encouraging results.1 Focal hypertrichosis has been reported during topical tacrolimus therapy for childhood vitiligo,2 but acne does not seem to be a frequently reported adverse effect. Report of a Case. An 18-year-old woman presented with vitiligo on the left side of her chin and neck and on both sides of the dorsum. The lesions had been present for 4 months and had been enlarging progressively. Findings of clinical evaluation and laboratory tests were all normal. As a first treatment, she had undergone a 3-month course of topical 0.05% desonide cream without any clinical response. She was put on a regimen of topical 0.1% tacrolimus, applied at bedtime, for 3 months, resulting in repigmentation of nearly 90% of the chin and cervical lesions and 50% of the dorsal spots. However, at the end of 3 months, the cervical and chin spots showed an extensive eruption of inflammatory and noninflammatory lesions of acne, with papules, pustules, and closed comedones (Figure) not present previously. The macules of the dorsum did not present any acne lesions. Tacrolimus treatment was discontinued, and the patient was treated with oral doxicycline and topical adapalene, with complete clearance of the eruption in 2 months. Comment. Treatment with topical calcineurin inhibitors is considered a safe and useful therapeutic option for several dermatoses. Rosaceiform reactions have been (REPRINTED) ARCH DERMATOL/ VOL 143 (NO. 9), SEP 2007 1223 WWW.ARCHDERMATOL.COM ment of atopic dermatitis in adults, II: safety. J Am Acad Dermatol. 2001;44 (1)(suppl):S39-S46. Pneumocystis carinii Pneumonia in Infant Treated With Oral Steroids for Hemangioma I Figure. Inflammatory papules, pustules, and closed comedones over partially repigmented lesions of vitiligo on the cervical region and chin. described after topical tacrolimus and even pimecrolimus treatment for inflammatory disorders of the face.3,4 Used in a vehicle-controlled study for atopic dermatitis in adults, 0.1% topical tacrolimus therapy resulted in acne as an adverse event at a mean ± SE rate of 7.1%±2.02% (P⬍.05).5 As mechanisms and incidence of these adverse findings are not well established, a more accurate follow-up of patients undergoing long-term topical therapy with these drugs would perhaps be advisable, to search for possible, although infrequent, unwanted effects on the pilosebaceous units such as acne, hypertrichosis, and rosaceiform reactions. nfantile hemangiomas are common, benign, and selflimited tumors of infancy. A recent multi-institution study found that 30% of infants experience complications related to their hemangioma.1 Of those seen in tertiary medical centers, 12% require treatment with oral corticosteroids.1 Ulceration, ocular compromise, and risk of permanent disfigurement are the most frequent reasons for intervention. There are no agents approved by the US Food and Drug Administration for the treatment of hemangiomas, but current practice includes the use of high-dose corticosteroids. The beneficial effects of corticosteroids were first described in the 1960s, and despite decades of treatment, the literature consists primarily of case reports and small case series. The effects of steroid administration to such a young patient population have not been systematically evaluated. High-dose corticosteroids are an independent risk factor for the development of Pneumocystis carinii pneumonia (PCP).2 However, most physicians treating infants with oral steroids for hemangiomas do not use antimicrobial prophylaxis. We report the second known case of PCP developing in an infant treated with oral corticosteroids for a hemangioma. Correspondence: Dr L. Bakos, Department of Dermatology, Hospital de Clı́nicas de Porto Alegre– Universidade Federal do Rio Grande do Sul, Ramiro Barcellos 2350, Porto Alegre RS 90035003, Brazil (lbakos @portoweb.com.br). Financial Disclosure: None reported. Report of a Case. A girl with a large facial infantile hemangioma not affecting her airway was treated by an outside institution with 15 mg of oral prednisolone daily beginning at age 2 months (Figure). Attempts to wean her from steroids had failed owing to rapid growth of the hemangioma. At age 7 months, she developed severe respiratory distress with fever, increased respiratory rate, intercostal retractions, grunting, and bilateral lung infiltrates on chest radiograph. She was transferred to a pediatric intensive care unit and required mechanical ventilation. Analysis of endotracheal tube aspirates revealed the presence of PCP. She responded well to treatment with intravenous trimethoprim sulfamethoxazole but still required intubation for 10 days. By day 15, she had made a full recovery and was discharged home on a gradual oral corticosteroid taper and oral trimethoprim sulfamethoxazole twice weekly for PCP prophylaxis. An extensive laboratory workup revealed no underlying primary immunodeficiency, and her infection was attributed to immunosuppression secondary to oral corticosteroid therapy. 1. Travis LB, Weinberg JM, Silverberg NB. Successful treatment of vitiligo with 0.1% tacrolimus ointment. Arch Dermatol. 2003;139(5):571-574. 2. Prats Caelles I, Pinto PH, Casado ELA, Laguna RL. Focal hypertrichosis during topical tacrolimus therapy for childhood vitiligo. Pediatr Dermatol. 2005; 22(1):86-87. 3. Antille C, Saurat JH, Lübbe J. Induction of rosaceiform dermatitis during treatment of facial inflammatory dermatoses with tacrolimus ointment. Arch Dermatol. 2004;140(4):457-460. 4. El Sayed F, Ammoury A, Dhaybi R, et al. Rosaceiform eruption to pimecrolimus. J Am Acad Dermatol. 2006;54(3):548-549. 5. Soter NA, Fleiscer AB, Webster GF, et al. Tacrolimus ointment for the treat- Comment. Pneumocystis carinii pneumonia is a potentially devastating opportunistic infection that is common in patients with AIDS. Less frequently, PCP is seen in patients with hematologic malignancies, organ transplantation, inflammatory disorders, and solid tumors. In patients without AIDS who develop PCP, greater than 90% of them were undergoing treatment with systemic corticosteroids when diagnosed.2 Lucio Bakos, MD, PhD Renato Marchiori Bakos, MD, MSc (REPRINTED) ARCH DERMATOL/ VOL 143 (NO. 9), SEP 2007 1224 WWW.ARCHDERMATOL.COM phylaxis for Pneumocystis carinii pneumonitis. N Engl J Med. 1987;316(26): 1627-1632. Clinical and Dermoscopic Features of Agminated Blue Nevus B lue nevi are usually solitary but may rarely appear grouped in an agminated pattern. Clinically, they present as a group of multiple blue nevi in a circumscribed skin area smaller than 10 cm in diameter.1 The skin between the papules may not be discolored and may show a speckled or uniform blueblack or brown pigmentation.1 We report a case of agminated blue nevus. Report of a Case. A 59-year-old woman presented with an asymptomatic dermatosis localized on the anterior lower extremity of her left leg characterized by brownblue macules and papules. It initially developed during her late teens, and although its size had increased slightly over the earlier years, during the last 20 years, its size, color, and texture had not changed. No family history Figure. Girl with large facial infantile hemangioma. To our knowledge only 1 similar case has been reported.3 A 2-month-old infant developed severe respiratory distress from diffuse airway hemangiomas and was treated with 3.5 mg/kg per day of prednisone. After 5 weeks of therapy, she was readmitted to the hospital with labored breathing and required mechanical ventilation. A bronchoalveolar lavage revealed PCP. Intravenous trimethoprim sulfamethoxazole was administered, and mechanical ventilation was discontinued after 3 days.3 Trimethoprim sulfamethoxazole is effective prophylaxis against the development of PCP. The most accepted regimen is 150 mg of trimethoprim/m2 per day plus 750 mg of sulfamethoxazole/m2 per day divided twice daily on 3 consecutive days weekly.4 Currently, there are no PCP prophylaxis guidelines for infants undergoing oral corticosteroid treatment for hemangiomas. Prophylaxis for PCP should be a consideration in this setting, given the 2 case reports now in the literature. Figure 1. Clinical image revealing numerous grouped pigmented lesions on the left leg of a 59-year-old woman. A cluster of about 20 blue-brown to slate gray macules and papules of various sizes, some of which were confluent, can be observed (original magnification ⫻10). ∗ Mandi L. Maronn, MD Timothy Corden, MD Beth A. Drolet, MD Correspondence: Dr Maronn, Department of Dermatology, Medical College of Wisconsin, 9200 W Wisconsin Ave, Milwaukee, WI 53226 (mmaronn@mcw.edu). Financial Disclosure: None reported. 1. Haggstrom A, Drolet BA, Chamlin SL, et al. Prospective study of infantile hemangiomas: demographic, prenatal and perinatal characteristics. J Pediatr. 2007; 150(3):291-294. 2. Yale SH, Limper AH. Pneumocystis carinii pneumonia in patients without acquired immunodeficiency syndrome: associated illnesses and prior corticosteroid therapy. Mayo Clin Proc. 1996;71(1):5-13. 3. Aviles R, Boyce TG, Thompson DM. Pneumocystis carinii pneumonia in a 3-month-old infant receiving high-dose corticosteroid therapy for airway hemangiomas. Mayo Clin Proc. 2004;79(2):243-245. 4. Hughes WT, Rivera GK, Schell MJ, et al. Successful intermittent chemopro- Figure 2. Dermoscopic image of part of the lesion exhibiting a cluster of blue nevi on the anterior lower extremity on the left leg of a 59-year-old woman. Multiple, grouped, homogeneous, confluent, steel blue to brown-blue pigmented areas fading into the surrounding skin can be seen. On the surface of some steel blue areas, linear pigmented structures appear as darker sulci (diamond). In addition, blue areas, some globules and dots (black arrow), a brown veil (black arrowhead), and brown-blue and out-of-focus pseudopods (white arrows) can be recognized. A small rim of tan pigmentation (asterisk) can also be seen around some blue nevi (original magnification ⫻10). (REPRINTED) ARCH DERMATOL/ VOL 143 (NO. 9), SEP 2007 1225 WWW.ARCHDERMATOL.COM A B C Figure 3. Histopathologic examination revealed a superficial type of blue nevus characterized by a bandlike proliferation of dendritic melanocytes in the superficial dermis. A, Dense, diffuse, bandlike proliferation of dendritic melanocytes in the superficial dermis. Note that there is no junctional involvement at all. An increased melanin pigmentation of the epidermal basal layer can also be seen (hematoxylin-eosin, original magnification ⫻ 40). B, Higher magnification reveals morphologic details of numerous dendritic melanocytes and also a few melanophages (hematoxylin-eosin, original magnification ⫻ 400). C, Scanning magnification nicely shows that all the dendritic melanocytes are clearly S-100 positive (S-100 staining, original magnification ⫻ 40). of melanoma or similar nevi was reported. Clinical examination revealed a group of approximately 20 bluebrown to slate gray macules and papules of various sizes, some confluent, and within a perimeter of 4 ⫻2 cm; the skin between the macules and papules had either the color of the surrounding normal skin or a brown-gray pigmentation (Figure 1). In the dermoscopic image (Figure 2), a cluster of lesions was recognizable, all with a homogeneous pattern, the morphologic hallmark of blue nevus, characterized by multiple, grouped, homogeneous, confluent, steel blue to brown-blue pigmented areas. On the surface of some of the steel blue areas, typical linear pigmented structures2 were present (Figure 2). A brown veil, a small rim of tan pigmentation, gray-blue globules and dots, and out-of-focus pseudopods were also seen within the diffuse pigmentation (Figure 2). Two biopsy specimens were taken with a 5-mm skin punch, one of a steel blue macule, the other of a brownblue papule. The histopathologic examination revealed a superficial type of blue nevus characterized by a bandlike proliferation of dendritic melanocytes in the superficial dermis (Figure 3). Both biopsy specimens showed identical features of a superficial blue nevus, but the second one showed a slightly more pronounced melanin pigmentation of the epidermal basal layer (Figure 3A). Using both the clinical and dermoscopic images, we diagnosed the lesion as a speckled or agminated blue nevus. Comment. The few cases of agminated nevi described in the literature have been reported as plaque type,3 eruptive,4 and patch type,5 corresponding histopathologically to common or cellular blue nevus.1 Our case was clinically similar to one described by Hendricks4 as an eruptive blue nevus. Dermoscopically, in addition to structureless areas, our case presented the local features associated with blue nevi already reported in the literature.2 Agminated blue nevi may present a diagnostic problem in that the differential diagnosis includes agminated blue nevus or agminated intradermal Spitz nevus combined with speckled lentiginous nevus.5 Since differential diagnosis of these nevi must also include melanoma and malignant blue nevus, a biopsy and histopathologic examination are necessary for the diagnosis.4 Our case is of special interest because for the first time to our knowledge, the dermoscopic features of this rare entity are described. Maria A. Pizzichetta, MD H. Peter Soyer, MD Cesare Massone, MD Lorenzo Cerroni, MD Correspondence: Dr Pizzichetta, Division of Medical Oncology C–Preventive Oncology, Centro di Riferimento Oncologico, Via Pedemontana Occidentale 12, I-33081 Aviano, Italy (pizzichetta@cro.it). Financial Disclosure: None reported. Additional Contributions: Anna Maria Colussi, RN, performed editing for this article. 1. Vélez A, del-Rio E, Martin-de-Hijas C, Furio V, Sanchez Yus E. Agminated blue nevi: case report and review of the literature. Dermatology. 1993;186 (2):144-148. 2. Stolz W, Braun-Falco O, Bilek P, Landthaler M, Burgdorf WC, Cognetta AB. Color Atlas of Dermoscopy. 2nd ed. Berlin, Germany: Blackwell Publishing; 2002. 3. Pittman JL, Fisher BK. Plaque-type blue nevus. Arch Dermatol. 1976;112(8): 1127-1128. 4. Hendricks WM. Eruptive blue nevi. J Am Acad Dermatol. 1981;4(1):50-53. 5. Misago N, Narisawa Y, Kohda H. A combination of speckled lentiginous nevus with patch-type blue nevus. J Dermatol. 1993;20(10):643-647. (REPRINTED) ARCH DERMATOL/ VOL 143 (NO. 9), SEP 2007 1226 WWW.ARCHDERMATOL.COM skINsight SECTION EDITOR: JAMES M. GRICHNIK, MD, PhD Subungual Exostosis Marı́a Elena Sánchez-Castellanos, MD; Cecilia Sandoval-Tress, MD; Patricia Ramı́rez-Bárcena, MD; Instituto Dermatológico de Jalisco “Dr. José Barba Rubio,” Jalisco, Mexico (Drs Sánchez-Castellanos and Ramı́rez-Bárcena). Dr Sandoval-Tress is in private practice in Jalisco. S UBUNGUAL EXOSTOSIS IS AN OUTGROWTH OF normal bone or calcified cartilaginous remains characterized by the triad of pain, nail dystrophy, and characteristic radiographic features. Case 1 involves a 13-year-old boy who presented with a 12-month history of an enlarging and painful lesion localized on the dorsum of the right great toe that appeared after a trauma. Physical examination revealed the presence of a flesh-colored, well-circumscribed elevation that measured 2.0 ⫻1.5 cm that caused onycholysis of the affected nail (Figure 1A). In case 2, a 17-year-old boy presented with a 4-year history of an asymptomatic growth localized on A the third right toe. Physical examination revealed an erythematous, well-defined growth that measured 1.5 ⫻1.0 cm that caused onycholysis of the affected nail (Figure 2A). In both cases, clinical diagnosis of subungual exostosis was established and confirmed by radiographic examination that showed a well-defined osseous growth (Figure 1B and Figure 2B). Histologic analysis showed a proliferative fibrocartilaginous cap that merged into hyaline cartilage forming mature trabecular bone at its base by enchondral ossification. Both lesions were removed surgically, resulting in complete relief of symptoms with no signs of recurrence. B Figure 1. A B Figure 2. (REPRINTED) ARCH DERMATOL/ VOL 143 (NO. 9), SEP 2007 1234 WWW.ARCHDERMATOL.COM

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