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July/August 2010 • Volume 8 • Issue 4 EDITORIAL Updating the Dermatologic Nomenclature: Names That Are Good or Bad LETTER TO THE EDITOR Prolactinoma Can Be Associated With Gynecomastia Cohen, Robinson, and Gray Parish and Witkowski ORIGINAL CONTRIBUTIONS Serum Lipid Level in Iraqi Patients With Psoriasis Aldhalimi, Almuhanna, and Alrikabi Clinical Features and Treatment of Dermatosis Papulosa Nigra in Migrants to Italy Calcaterra, Franco, Valenzano, Fazio, and Morrone DEPARTMENTS New Therapy Update Zyclara (Imiquimod) Cream, 3.75% Gupta, Cooper, and Abramovits Perils of Dermatopathology Newtonian Dermatopathology: When the Reaction to a Lesion Obfuscates the Diagnosis Rojas, Sarkissian, Heller, and Lambert REVIEWS Acute Generalized Exanthematous Pustulosis Pecina and Cappel Sporotrichosis: Part I Schechtman COMMENTARIES Sentinel Lymph Node Biopsy in Melanoma: The Gulf Between Presentation and Reality Thomas Sentinel Lymph Node Biopsy in Melanoma: Coping With Incomplete Information; Call for Further Investigations Lambert Congress Report Highlights From the 7th EADV Spring Symposium, Cavtat, Croatia, May 13–16, 2010 Lipozenčić CASE STUDIES Segmental Cutaneous Piloleiomyomata Cook-Norris, Rodriguez, Kovach, Boyd, and Zic Vulvoperineal Crohn’s Disease: Response to Metronidazole Khaled, Ezzine-Sebai, Fazaa, Zeglaoui, Zermani, and Kamoun Folliculocentric Lichen Sclerosus et Atrophicus Mann, Vergilis-Kalner, Wasserman, and Petronic-Rosic Poorly Growing Hair in a Child Bolotin, Ortel, and Stein When she asks about her scar, recommend Mederma® with confidence. In a recent clinical study,1 77% of subjects noted moderate to significant improvement in scars treated with Mederma® in terms of redness, texture and overall appearance. 98% of patients completed the study without any adverse events. 1 Draelos, Z., The ability of onion extract gel to improve the cosmetic appearance of postsurgical scars, Cosmetic Dermatology, June 2008. 2 IMS Health, NDTI, December 2008. 3 Pharmacy Times, OTC Supplement, June 2009. The #1 doctor-2 and pharmacist-recommended3 brand for scars helps empower your patients to take charge of their appearance so they can get back their confidence. And you get a very satisfied patient. Available for office dispensing. mederma.com 888.925.8989 TABLE OF CONTENTS July/August 2010 • Volume 8 • Issue 4 EDITORIAL Updating the Dermatologic Nomenclature: Names That Are Good or Bad....................................................... 199 Lawrence Charles Parish, MD, MD (Hon); Joseph A. Witkowski, MD LETTER TO THE EDITOR Prolactinoma Can Be Associated With Gynecomastia.................................................................................... 201 Philip R. Cohen, MD; Floyd W. Robinson, BS; James M. Gray, MD ORIGINAL CONTRIBUTIONS Serum Lipid Level in Iraqi Patients With Psoriasis.......................................................................................... 204 Muhsin A. Aldhalimi, CABDV; Sadiq J. Almuhanna, FICMS; Samir H. Alrikabi, MSc Clinical Features and Treatment of Dermatosis Papulosa Nigra in Migrants to Italy........................................ 207 Roberta Calcaterra, MD; Gennaro Franco, MD; Mariacarla Valenzano, MD; Raffaella Fazio, MD; Aldo Morrone, MD REVIEWS Acute Generalized Exanthematous Pustulosis............................................................................................... 210 Jennifer L. Pecina, MD; Mark A. Cappel, MD Sporotrichosis: Part I................................................................................................................................... 216 Regina Casz Schechtman, MD, PhD Self-Test Review Questions (p. 221) COMMENTARIES Sentinel Lymph Node Biopsy in Melanoma: The Gulf Between Presentation and Reality.................................. 222 J. Meirion Thomas, MS, FRCP, FRCS Sentinel Lymph Node Biopsy in Melanoma: Coping With Incomplete Information; Call for Further Investigations............................................................... 226 W. Clark Lambert, MD, PhD Departments New Therapy Update William Abramovits, MD; Aditya K. Gupta, MD, Section Editors Zyclara (Imiquimod) Cream, 3.75%.............................................................................................................. 227 Aditya K. Gupta, MD; Elizabeth A. Cooper, HBSc; William Abramovits, MD Perils of Dermatopathology W. Clark Lambert, MD, PhD, Editor Newtonian Dermatopathology: When the Reaction to a Lesion Obfuscates the Diagnosis................................ 231 Javier Rojas, MD; Navér Sarkissian, MD, PhD; Debra S. Heller, MD; W. Clark Lambert, MD, PhD 193 July/August 2010 TABLE OF CONTENTS Departments (continued) Congress Report Marcia Ramos-e-Silva, MD, PhD, Section Editor Highlights From the 7th EADV Spring Symposium, Cavtat, Croatia, May 13–16, 2010.................................... 235 Jasna Lipozenčić, MD, PhD, Chairperson CASE STUDIES Vesna Petronic-Rosic, MD, MSc, Section Editor Segmental Cutaneous Piloleiomyomata........................................................................................................ 238 Robert H. Cook-Norris, MD; Adrian O. Rodriguez, MD; Bradley T. Kovach, MD; Alan S. Boyd, MD; John A. Zic, MD Vulvoperineal Crohn’s Disease: Response to Metronidazole........................................................................... 240 Aida Khaled, MD; Nadia Ezzine-Sebai, MD; Becima Fazaa, MD; Faten Zeglaoui, MD; Rachida Zermani, MD; Mohamed Ridha Kamoun, MD Folliculocentric Lichen Sclerosus et Atrophicus............................................................................................. 242 David J. Mann, MD; Irene J. Vergilis-Kalner, MD; Justin R. Wasserman, MD; Vesna Petronic-Rosic, MD, MSc Poorly Growing Hair in a Child...................................................................................................................... 246 Diana Bolotin, MD, PhD; Bernhard Ortel, MD; Sarah L. Stein, MD VINTAGE LABEL Courtesy of BuyEnlarge, Philadelphia, PA 194 For your patients with tinea pedis, tinea cruris, and tinea corporis For the fungicidal power you trust, turn to Naftin® (naftifine HCl 1%). Designed to suit a range of patients and preferences, Naftin® delivers power against tinea pedis, cruris and corporis. Choose Naftin® Gel, Naftin® Cream, or the innovative Naftin® Cream Pump and give your patients the customized care they deserve. Naftin® (naftifine HCl 1%) Cream and Gel are indicated for the topical treatment of tinea pedis, tinea cruris and tinea corporis caused by Trichophyton rubrum, Trichophyton mentagrophytes, Epidermophyton floccosum and Trichophyton tonsurans (Gel only). Naftin® Cream and Gel are contraindicated in individuals who have shown hypersensitivity to any of their components and are for topical use only. During clinical trials with Naftin® Cream and Gel, the following side effects were most commonly reported: burning/stinging, dryness, erythema, itching, local irritation, skin tenderness and rash. Please see brief summary on the following page. ©2010 Merz Pharmaceuticals All rights reserved. 5/10 Power made personal July/August 2010 Volume 8 • Issue 4 ABOUT OUR JOURNAL SKINmed: Dermatology for the Clinician®, print ISSN 1540-9740, online ISSN 1751-7125, is published bimonthly by Pulse Marketing & Communications, LLC, located at 4 Peninsula Avenue, Sea Bright, NJ 07760. BRIEF SUMMARY Rx ONLY INDICATIONS AND USAGE: Naftin® Cream, 1% is indicated for the topical treatment of tinea pedis, tinea cruris, and tinea corporis caused by the organisms Trichophyton rubrum, Trichophyton mentagrophytes, and Epidermophyton floccosum. Naftin® Gel, 1% is indicated for the topical treatment of tinea pedis, tinea cruris, and tinea corporis caused by the organisms Trichophyton rubrum, Trichophyton mentagrophytes, Trichophyton tonsurans*, Epidermophyton floccosum*. *Efficacy for this organism in this organ system was studied in fewer than 10 infections. CONTRAINDICATIONS: Naftin® Cream and Gel, 1% are contraindicated in individuals who have shown hypersensitivity to any of their components. WARNINGS: Naftin® Cream and Gel, 1% are for topical use only and not for ophthalmic use. PRECAUTIONS: General: Naftin® Cream and Gel, 1%, are for external use only. If irritation or sensitivity develops with the use of Naftin® Cream or Gel, 1%, treatment should be discontinued and appropriate therapy instituted. Diagnosis of the disease should be confirmed either by direct microscopic examination of a mounting of infected tissue in a solution of potassium hydroxide or by culture on an appropriate medium. Information for patients: The patient should be told to: 1. Avoid the use of occlusive dressings or wrappings unless otherwise directed by the physician. 2. Keep Naftin® Cream and Gel, 1% away from the eyes, nose, mouth and other mucous membranes. Carcinogenesis, mutagenesis, impairment of fertility: Long-term studies to evaluate the carcinogenic potential of Naftin® Cream and Gel, 1% have not been performed. In vitro and animal studies have not demonstrated any mutagenic effect or effect on fertility. Printed in the USA. Disclaimer: The Publisher, Editors, and Editorial Board cannot be held responsible for errors or any consequences arising from the use of information contained in this journal; the views and opinions expressed herein do not necessarily reflect those of the Publisher, Editors, and Editorial Board, neither does the publication of advertisements constitute any endorsement by the Publisher, Editors, and Editorial Board of the products or services advertised. The Publisher, Editors, Editorial Board, Reviewers, Authors, and Affiliated Agents shall not be held responsible or in any way liable for the continued accuracy of the information or for any errors, inaccuracies, or omissions of any kind in this publication, whether arising from negligence or otherwise, or for any consequences arising thereafter. Copyright: ©2010 Pulse Marketing & Communications, LLC. All rights reserved. No part of this publication may be reproduced, stored, or transmitted in any form or by any means without the prior permission in writing from the Publisher. Requests should be addressed to the Permissions Editor at: Pulse Marketing & Communications, LLC, 4 Peninsula Avenue, Sea Bright, NJ 07760. Abstracting & Indexing: The journal is indexed in Index Medicus/MEDLINE. Editorial MANAGING EDITOR Sarah D. Staats [email protected] PRODUCTION DIRECTOR Scott C. Bouchard Distinct Layouts, LLC www.distinctlayouts.com EDITORIAL DIRECTOR Gila Berkowitz [email protected] ASSOCIATE MANAGING EDITOR Elizabeth Holcomb [email protected] Pregnancy: Teratogenic Effects: Pregnancy Category B: Reproduction studies have been performed in rats and rabbits (via oral administration) at doses 150 times or more than the topical human dose and have revealed no evidence of impaired fertility or harm to the fetus due to naftifine. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. Nursing mothers: It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Naftin® Cream or Gel,1% are administered to a nursing woman. Pediatric use: Safety and effectiveness in pediatric patients have not been established. Publishing PUBLISHER Art Kalaka Corporate President Arthur Kalaka [email protected] skinmedbriefPI.indd 1 Chief Executive Officer Jo-Ann Kalaka-Adams [email protected] General Counsel Marianne Mckenzie [email protected] ADVERSE REACTIONS: During clinical trials with Naftin® Cream, 1%, the incidence of adverse reactions was as follows: burning/stinging (6%), dryness (3%) erythema (2%), itching (2%), local irritation (2%). During clinical trials with Naftin® Gel, 1%, the incidence of adverse reactions was as follows: burning/stinging (5.0%), itching (1.0%), erythema (0.5%), rash (0.5%), skin tenderness (0.5%). Manufactured for Merz Pharmaceuticals, Greensboro, NC 27410 © 2010 Merz Pharmaceuticals Rev 3/10 Associate Publisher James R. Adams [email protected] Pulse Marketing & Communications, LLC 4 Peninsula Avenue • Suite 401 • Sea Bright, NJ 07760 • Tel (732) 747-6525 • Fax (732) 747-7010 6/11/10 12:05 PM 196 July/August 2010 EDITORIAL BOARD EDITOR IN CHIEF Lawrence Charles Parish, MD, MD (Hon) Philadelphia, PA DEPUTY EDITORS William Abramovits, MD Dallas, TX Larry E. Millikan, MD Meridian, MS Jennifer L. Parish, MD Philadelphia, PA Marcia Ramos-e-Silva, MD, PhD Rio de Janeiro, Brazil EDITORIAL BOARD Mohamed Amer, MD Cairo, Egypt Ibrahim Hassan Galadari, MD, PhD, FRCP Dubai, United Arab Emirates Jasna Lipozencic, MD, PhD Zagreb, Croatia Noah S. Scheinfeld, MD, JD New York, NY Robert L. Baran, MD Cannes, France Anthony A. Gaspari, MD Baltimore, MD George M. Martin, MD Kihei, HI Virendra N. Sehgal, MD Delhi, India Anthony V. Benedetto, DO Philadelphia, PA Michael Geiges, MD Zurich, Switzerland David I. McLean, MD Vancouver, British Columbia Charles Steffen, MD Oceanside, CA Brian Berman, MD, PhD Miami, FL Michael H. Gold, MD Nashville, TN Marc S. Micozzi, MD, PhD Bethesda, MD Alexander J. Stratigos, MD Athens, Greece Jack M. Bernstein, MD Dayton, OH Orin M. Goldblum, MD Abbott Park, IL George F. Murphy, MD Boston, MA James S. Studdiford III, MD Philadelphia, PA Sarah Brenner, MD Tel Aviv, Israel Lowell A. Goldsmith, MD, MPH Chapel Hill, NC Oumeish Youssef Oumeish, MD, FRCP Amman, Jordan Robert J. Thomsen, MD Los Alamos, NM Joaquin Calap Calatayud, MD Cadiz, Spain Aditya K. Gupta, MD, PhD, FRCP(C) London, Ontario Joseph L. Pace, MD, FRCP Naxxar, Malta Julian Trevino, MD Dayton, OH Henry H.L. Chan, MB, MD, PhD, FRCP Hong Kong, China Seung-Kyung Hann, MD, PhD Seoul, Korea Art Papier, MD Rochester, NY Snejina Vassileva, MD, PhD Sofia, Bulgaria Ncoza C. Dlova, MBChB, FCDerm Durban, South Africa Roderick J. Hay, BCh, DM, FRCP, FRCPath London, UK Vesna Petronic-Rosic, MD, MSc Chicago, IL Daniel Wallach, MD Paris, France Richard L. Dobson, MD Mt Pleasant, SC Tanya R. Humphreys, MD Philadelphia, PA Johannes Ring, MD, DPhil Munich, Germany Michael A. Waugh, MB, FRCP Leeds, UK William H. Eaglstein, MD Palo Alto, CA Camila K. Janniger, MD Englewood, NJ Roy S. Rogers III, MD Rochester, MN Wm. Philip Werschler, MD Spokane, WA Boni E. Elewski, MD Birmingham, AL Abdul-Ghani Kibbi, MD Beirut, Lebanon Donald Rudikoff, MD New York, NY Joseph A. Witkowski, MD Philadelphia, PA Charles N. Ellis, MD Ann Arbor, MI W. Clark Lambert, MD, PhD Newark, NJ Robert I. Rudolph, MD Wyomissing, PA Ronni Wolf, MD Rechovot, Israel Howard A. Epstein, PhD Gibbstown, NJ Andrew P. Lazar, MD Highland Park, IL Vincenzo Ruocco, MD Naples, Italy 197 July/August 2010 Volume 8 • Issue 4 EDITORIAL Updating the Dermatologic Nomenclature: Names That Are Good or Bad Lawrence Charles Parish, MD, MD (Hon);1 Joseph A. Witkowski, MD2 D ermatology probably has the largest vocabulary of any of the medical specialties,1 a statement to which we can attest when we reviewed aspects of the Dermatology Lexicon project. Some terms are derived from Latin or Greek and present spelling problems to all but a select few. Examples include acrokeratosis verruciformis and pterigium. Other diseases carry names that are such a mouthful that few can call them out without the interruption of breathing. These might include erosio interdigitalis blastomycetica and exudative discoid and lichenoid chronic dermatosis of Sulzberger and Garbe. No wonder the former is now referred to simply as candidosis, or is it, candidiasis, and the latter as oid-oid disease or Sulzberger-Garbe disease. Mediocre Names •Neurodermatitis denotes red scaling patches on the body, often with lichenification. Should there be history of allergic rhinitis or asthma, a new diagnosis might be used: atopic dermatitis. This has its problems, however, as the causative allergens are rarely found, contrary to the case with hayfever or asthma. Neurodermatitis is better than the synonym of lichen simplex of Brocq, but, once again, the person is led astray into believing that “nerves” or the proverbial stress is the etiologic agent. •Lichen sclerosus atrophicus represents an atrophic process that is often found on the female genitalia. Its male counterpart is called balnaitis xerotica. Do the red, scaling, and atrophic lesions really need 9-syllable terminology, let alone challenges to the spelling capabilities of the clinician? Bad Names Be that as it may, we would like to focus on disease names that we should consider avoiding, because they unnecessarily connote ideas that are not germane to patient welfare. These diseases can be easily called by other terms. •Paget’s disease would seem to be a harmless eponym, honoring Sir William Paget who described: oBone disease oSquamous cell carcinoma in situ of the areola, being more common in women •Chondrodermatitis nodularis chronica helicis: This may sound more important in its Latinate form; simplifying the diagnosis to chondrodermatitis of the ear is much more understandable. The cartilage can still be inflamed, and the annoying pain and tenderness will exist with the simplified terminology. •Senile keratoses: These represent the overproduction of keratin due to excessive exposure to sunlight. While it may take many years of such exposure, not every patient with this possible premalignant condition is approaching Alzheimer’s disease. Even knowing that the histopathology demonstrates squamous cell carcinoma, grade 1 or 2, use of the term actinic keratosis would be preferred. oSquamous cell carcinoma in situ in areas other than the breast (extramammary) Using the word Paget then denotes 3 different diseases. Were not the terms so well established, it might be more appropriate to select nomenclature that was less confusing and possibly more explicit. Good Names •Senile purpura: While nonpalpable purpura is often seen in older patients, there is no reason to cast aspersions on the chronologically challenged. Possibly, just calling the red collections, often found on the arms, nonpalpable purpura would suffice. Chronic purpura is just not helpful. •Basal cell carcinoma is a very descriptive name, an improvement over basal cell epithelioma, and a significant change for the better over rodent ulcer. The patient is anxious enough over the possible scarring to be caused by the surgical removal of this malignancy. There is no good reason to add to the worry by suggesting that a rat created the problem. •Acne represents a sebaceous gland disorder where many of From the Departments of Dermatology and Cutaneous Biology, Jefferson Medical College of Thomas Jefferson University, Philadelphia, PA;1 and the Department of Dermatology, University of Pennsylvania School of Medicine, Philadelphia, PA2 Address for Correspondence: Lawrence Charles Parish, MD, MD (Hon), 1760 Market Street, Suite 301, Philadelphia, PA 19103 • E-mail: [email protected] SKINmed. 2010;8:199–200 199 © 2010 Pulse Marketing & Communications, LLC July/August 2010 EDITORIAL the lesions can be pointed and so, the misconstruing of acne to acme is not so terrible. Acne vulgaris is another mouthful that is unnecessary to perpetuate, while acne rosacea does not provide more information over the one-word, rosacea. •Contact dermatitis says just what it means: a reaction due to contact with a substance. Adding irritant or allergic to the terminology may be informative, but equally so, causes problems for the simplicity of the term contact dermatitis. Conclusions Perhaps, we have just scratched the surface. While we may not have reformed dermatologic nomenclature, we have presented some of our thoughts. Reference 1 Leider M, Rosenblum M. A dictionary of dermatological words, terms and phrases. New York, NY: Blakiston; 1968:440. Wax Moulage Kerion celsi, Trichophytia profunda capillitii. Moulage Nr. 218, made by Otto Vogelbacher ca. 1920 at the Dermatology Clinic in Freiburg i.Br. (Germany). Museum of Wax Moulages Zurich, www.moulagen.ch Courtesy of Michael Geiges, MD SKINmed. 2010;8:199–200 200 Updating the Dermatologic Nomenclature July/August 2010 Volume 8 • Issue 4 LETTER TO THE EDITOR Prolactinoma Can Be Associated With Gynecomastia Philip R. Cohen, MD;1,2,3 Floyd W. Robinson, BS;1 James M. Gray, MD1 To the Editor: Dr Kapoor’s review provides an excellent summary of the cutaneous manifestations that characterize the systemic conditions associated with gynecomastia. In addition, the pathogenesis of gynecomastia in the included chronic metabolic disorders (cirrhosis and chronic renal failure), endocrine disorders (Graves’ disease and hypopituitarism), systemic infections (leprosy and human immunodeficiency virus), gastrointestinal malignancies, genetic syndromes (lentiginosis syndrome and Klinefelter syndrome), and alcohol abuse is discussed.1 We respectfully add prolactinoma to the conditions that can be associated with gynecomastia. Prolactinoma, the most common secretory pituitary tumor, can be classified by tumor size: microadenoma (<10 mm), macroadenoma (>10 mm), and giant (a macroadenoma >40 mm). Clinical symptoms are secondary to either tumor-associated hy- perprolactinemia (gonadal and sexual dysfunction) or adenomarelated growth (visual field defects, cranial nerve palsies, and headaches). Prolactinoma typically presents as a microadenoma with amenorrhea, infertility, and galactorrhea in women.2,3 In men, since the prolactinoma is more often diagnosed as a macroadenoma, initial symptoms may be associated with the tumor’s larger size: neurologic and vision dysfunction. Endocrine-related symptoms from hyperprolactinemia (such as hypogonadism, infertility, and impotence with decreased libido and erectile dysfunction), however, can be the presenting finding or a subsequent manifestation in men. In addition, albeit less common, gynecomastia, galactorrhea, and abnormally sparse body hair can occur.2–5 Prolactinoma-associated gynecomastia results from tumor-associated hyperprolactinemia. Prolactin inhibits the pulsatile secretion Figure. (A) Distant and (B) closer views of the left chest of a 36-year-old Ukranian man who presented with unilateral galactorrhea and fatigue. At 13 years of age, he had been exposed to radioactivity for 2 weeks following the Chernobyl nuclear power plant reactor 4 explosion. White liquid, elicited by palpation of the breast, is visible on the left nipple and areola. A large intrasellar macroadenoma (2.6 × 2.7 × 2.5 cm), which neither compressed the optic apparatus nor invaded the cavernous sinuses, was detected on the brain magnetic resonance imaging scan. His serum testosterone level was decreased (147 ng/dL, normal = 214–827 ng/ dL) and his serum prolactin level was markedly increased (3440.2 ng/mL, normal = 3.0–30.0 ng/mL); the latter observation confirming the suspected diagnosis of prolactinoma. Follow-up evaluation after 6 weeks of cabergoline treatment showed diminished left nipple lactation and decreasing serum prolactin level (200 ng/mL).7,8 From the University of Houston Health Center, University of Houston;1 the Department of Dermatology, The University of Texas M.D. Anderson Cancer Center;2 and the Department of Dermatology, University of Texas-Houston Medical School,3 Houston, TX Address for Correspondence: Philip R. Cohen, MD, 805 Anderson Street, Bellaire, TX 77401-2806 • E-mail: [email protected] SKINmed. 2010;8:201–202 201 © 2010 Pulse Marketing & Communications, LLC July/August 2010 LETTER TO THE EDITOR of gonadotropin-releasing hormone from the hypothalamus, resulting in suppression of the hypothalamic-pituitary-gonadal axis. In addition, prolactin directly impairs gonadal steroidogenesis by inhibiting the pituitary release of follicle-stimulating hormone and luteinizing hormone.3,4 A prior history of therapeutic or accidental exposure to radioactivity should be sought in all patients with sporadic prolactinoma. References Prolactinoma can be associated with the coexistence of parathyroid and pancreatic neoplasms in patients with multiple endocrine neoplasia type 1 syndrome.2,3,6; however, the adenoma usually presents as a sporadic tumor.2 For example, we recently observed a man with previous radiation exposure who subsequently developed a prolactinoma that presented with unilateral galactorrhea (Figure) and fatigue.7,8 Currently, “no risk factors have been identified for sporadic prolactinomas.”2 We hypothesize, however, that a previously unrecognized risk factor for prolactinoma is exposure to accidental or therapeutic radiation.7–9 We therefore suggest that patients who present with sporadic prolactinoma be asked whether they have a prior history of radiation exposure. In summary, gynecomastia can either be the presenting symptom or a subsequent development in men with a prolactinoma. Sparse body hair, secondary to hyperprolactinemia-associated hypogonadism, is a cutaneous manifestation that can be observed in these individuals. 1 Kapoor S. Cutaneous manifestations of systemic conditions associated with gynecomastia. Skinmed. 2010;8:87–92. 2 Klibanski A. Prolactinomas. N Engl J Med. 2010;362:1219–1226. 3 Mancini T, Casanueva FF, Giustina A. Hyperprolactinemia and prolactinomas. Endocrinol Metab Clin North Am. 2008;37:67–99. 4 Creyghton WM, Custers M. Gynaecomastia: is one cause enough? Neth J Med. 2004;62:257–259. 5 Walsh JP, Pullan PT. Hyperprolactinaemia in males: a heterogeneous disorder. Aust N Z J Med. 1997;27:385–390. 6 Piecha G, Chudek J, Wiecek A. Multiple endocrine neoplasia type 1. Eur J Intern Med. 2008;19:99–103. 7 Cohen PR, Robinson FW, Gray JM. Pituitary tumor following radiation exposure: prolactinoma in a man exposed to radioactivity from the Chernobyl accident. [Poster Abstract] The University of Texas MD Anderson Cancer Center Division of Internal Medicine 2010 Research Retreat. Houston, TX, May 14, 2010. 8 Cohen PR, Robinson FW, Gray JM. Prolactinoma presenting as unilateral galactorrhea in a man exposed to radioactivity from the Chernobyl accident: radiation-induced pituitary tumor? Int J Dermatol. In press. 9 Cohen PR, Robinson FW, Gray JM. Radiation-associated prolactinoma [letter]. South Med J. In press. VINTAGE LABEL Courtesy of BuyEnlarge, Philadelphia, PA SKINmed. 2010;8:201–202 202 Prolactinoma Can Be Associated With Gynecomastia SAVE THE DATE FOR THE 7th Annual Maui Derm A Pan-Pacific Thought Leaders Meeting FEBRUARY 23-27, 2011 GRAND WAILEA, MAUI Save the Date & Register Early! $395 before June 30th! Plan to attend the 7th Annual Maui Derm Conference! “Cutting edge, a great blend of science and clinical medicine and a world class faculty” describe Maui Derm 2011. Our faculty will share with you the most important developments in medical and cosmetic dermatology vital to your practice. Our live patient demonstration workshops in lasers, Botulinum Toxin A and fillers have set the standard for “hands on” workshops. Our format has been specifically designed to allow optimal time for discussion with our faculty. We are certain that you will find this to be an outstanding and memorable educational event that you will not want to miss. Put Maui Derm on your calendar for 2011! FEATURED LECTURES MAUI DERM 2011 FACULTY Skin Cancer/Chemoprevention • Acne/Rosacea • Pediatric Dermatology • Infectious Diseases • Psoriasis • Pigmentary Disorders • Contact Dermatitis • Cosmeceuticals • Collagen Vascular Diseases • Office Surgery Tips Practice Management • Skin of Color Dr. Rox Anderson Dr. Andrew Blauvelt Dr. Joel Cohen Dr. Lawrence Eichenfield Dr. Ilona Frieden Dr. Sheila Fallon-Friedlander Dr. Michael Gold Dr. Mitchel Goldman Dr. Pearl Grimes Dr. Arthur Kavanaugh Dr. Suzanne Kilmer Dr. David Laub Dr. Craig Leonardi Medical Dermatology Cosmetic Dermatology Botulinum Toxin A and Fillers • Lasers • Skin of Color “Lunch with the Faculty” – Controversial Topics, Case-based Discussions Interactive Workshops Small Group, Live Patient, Hands-On Demonstrations: Botulinum Toxins/Fillers Chairman: Dr. George Martin Dr. Stuart Maddin Dr. Sam Moschella Dr. Stuart Nelson Dr. Kevin Pinski Dr. Ted Rosen Dr. Vic Ross Dr. Alan Shalita Dr. Bruce Strober Dr. Hensin Tsao Dr. Sandy Tsao Dr. Guy Webster Dr. Philip Werscheler * Subject to Change Official Meeting Publication Sponsor Maui Derm 2011 has special/reduced rates at the Grand Wailea and the Wailea Marriott For more details, visit our website at www.acmd-derm-hawaii.com July/August 2010 Volume 8 • Issue 4 Original Contribution Serum Lipid Level in Iraqi Patients With Psoriasis Muhsin A. Aldhalimi, CABDV;1 Sadiq J. Almuhanna, FICMS;2 Samir H. Alrikabi, MSc3 Abstract Psoriasis is a chronic inflammatory and proliferative dermatosis. Previous studies have demonstrated that patients with psoriasis may have an increased risk of occlusive vascular disease. High serum lipid level has been suggested in the pathogenesis of this phenomenon. In this study, the authors assess the lipid profile in Iraqi patients with psoriasis and compare it with that of nonaffected persons. This study was designed and conducted as a cross-sectional study with 50 cases in the patient group and 50 patients in the control group. It was performed in the department of dermatology at Al-Sadr Teaching Hospital in Najaf, Iraq. The lipid profile, including serum levels of triglycerides, total cholesterol, low-density lipoprotein (LDL), and high-density lipoprotein, were assessed in both groups. The patient and control groups each consisted of 39 men and 11 women. The serum triglyceride, cholesterol, LDL, and very LDL levels were significantly higher in psoriatic patients (P<.05) but not for highdensity lipoprotein (P>.05). Serum lipid level was found to be significantly higher in Iraqi patients with psoriasis. It may be useful to do early screening and treatment of hyperlipidemia in psoriasis to prevent atherosclerosis and its complications. (SKINmed. 2010;8:204–206) P soriasis is a chronic inflammatory skin disorder that affects more than 2% of the population worldwide.1 It is characterized by an increase in keratinocyte proliferation and alterations in dermal and epidermal T cells, monocytes/macrophages, and neutrophils.2 Although several previous studies suggest that patients with psoriasis have abnormalities of plasma lipids and lipoproteins as an important risk factor for cardiovascular disease, many of the results remain controversial.3–7 Many of these reports suggest that persons with psoriasis have a proatherogenic lipoprotein profile that includes hypertriglyceridemia, raised plasma concentrations of low-density lipoprotein cholesterol (LDL-C), very low-density lipoprotein cholesterol (VLDL-C), and lipoprotein (a) and a lowered high-density lipoprotein cholesterol (HDL-C) concentration,3,4,7–19 High HDL-C concentrations are well established as a major protective factor against coronary heart disease because of their ability to remove unesterified cholesterol from cells and other lipoproteins, where it may have accumulated, and return it to the liver for excretion in the bile.10 The aim of this study was to investigate the plasma lipid profile in psoriasis in the Middle Euphrates region in Iraq in comparison with nonaffected persons. Patients and Methods The study was done in the dermatology outpatient department at Al-Sadr Teaching Hospital, Najaf, Iraq, during the period from January to August 2007. It is a cross-sectional study that included 50 adult patients with psoriasis and 50 sex-, age-, and body mass index (BMI)–matched healthy individuals as the control group. The diagnosis of psoriasis was mainly clinical and all doubtful cases were excluded. Smokers, alcoholics, pregnant women, and those with a BMI >30 kg/m2 were not included in the study. BMI was calculated as weight (in kilograms) divided by the square of height (in meters). Weight and height were recorded as the persons were wearing light clothes and not wearing shoes.16 Psoriasis area severity index (PASI) was evaluated using the standard formula.17 Mild PASI score was defined as 0.1 to 10.9 and moderate PASI score was defined as 11 to 49.9.14 Patients with severe (PASI >50), erythrodermic, and pustular types of disease were excluded from the study. Other exclusion criteria included patients with diseases that may cause secondary hyperlipidemia such as diabetes mellitus, hypothyroidism, nephritic syndrome, chronic renal insufficiency, obstructive liver disease, and connective tissue diseases, as well as patients taking medications such as b-blockers, thiazide diuretics, corticosteroids, cyclosporine, retinoids, and lipid-lowering agents in the past 6 months. Blood samples were taken after 12 hours of overnight fasting. Serum levels of total cholesterol, triglycerides (TGs) and HDL-C were measured by enzymatic colorimetric methods using a Hitachi 704 auto-analyser (Tokyo, Japan) and commercially available kits (Diasys Diagnostic System, GmbH and Co, Holzheim, Germany). LDL-C was estimated by the Friedewald formula (LDL-C = total cholesterol – HDL-C – VLDL-C). VLDL-C was calculated as 0.456 × total TG concentration expressed in mmol/L.15 From the Departments of Dermatology,1 Medicine,2 and Pharmacology,3 University of Kufa College of Medicine, Najaf, Iraq Address for Correspondence: Muhsin A. Aldhalimi, CABDV, PO Box 18, Kufa Post Office, Najaf, Iraq • E-mail: [email protected] SKINmed. 2010;8:204–206 204 © 2010 Pulse Marketing & Communications, LLC July/August 2010 ORIGINAL CONTRIBUTION Table. Comparison of Lipid Profile Between Patients With Psoriasis and Control Patients Patients With Psoriasis (N=50) Control Group (N=50) Mean SD Mean SD P Value Total cholesterol, mg/dL 216.4 20.16 208.8 22.09 <.05 Triglycerides, mg/dL 172.6 14.34 139.7 13.93 <.05 HDL-C, mg/dL 39.62 3.76 43.88 3.52 >.05 LDL-C, mg/dL 146.22 25.62 134.56 23.73 <.05 34.52 12.35 27.9 11.67 <.05 VLDL-C, mg/dL Abbreviations: HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; SD, standard deviation; VLDL-C, very low-density lipoprotein cholesterol. This study was approved by the ethics committee of our university, and all patients gave their informed consent. Statistical Analyses Values are presented as mean ± standard deviation. Comparison between patients with and without psoriasis was performed by Student t test and Pearson correlation coefficients. P value <.05 was considered statistically significant. Results The age of the patients ranged from 20 to 67 years, with a mean of 37.6 years. There were 39 men and 11 women. The age of the control group ranged from 21 to 65 years, with a mean of 37.4 years. The sex distribution was the same as that of the patients. PASI score ranged from 2.3 to 24.7, with a mean of 19.6. The mean duration of disease was 5.45 years (range 0.8–19 years). There was no difference between patients and the control group with regard to BMI, systolic and diastolic blood pressures, and physical activity. Serum lipid levels in patients with psoriasis and in controls are shown in the Table. In the patient group, serum total cholesterol, LDL-C, VLDL-C, and TG levels were significantly higher than those of controls (P<.05). HDL-C was slightly higher in the control group, but the difference was not statistically significant (P>.05). There was no significant association between PASI and serum lipid profile in the present work (Pearson correlation coefficients P>.05). Discussion In spite of an increasing number of studies dealing with plasma lipid levels in patients with psoriasis, the results are still conflicting.3–13,15–18 It is still controversial whether changes in lipid composition are primary events or secondary to psoriasis or perhaps due to medications such as cyclosporine and retinoids.5,7,19 In this study we try to assess this relation in a group of Iraqi patients. The measured lipid parameters in this work were significantSKINmed. 2010;8:204–206 ly higher in patients with psoriasis than the control group, apart from HDL-C, which was slightly higher in the control group. The results of previous studies were greatly variable. High,3,11,17,19 low,20 or even normal4,5,7,18 values of serum cholesterol levels in patients with psoriasis have been reported. In this study we found a significantly higher level of total cholesterol values in the psoriatic group (P<.05). Similar conflicting results of plasma TG level were observed in the published literature. The previous results varied from high3,4,7,17 to low20 or even normal5,6,8,18,19 values. This work showed a significant higher value of serum TG levels in the psoriatic group. A similar controversy was found regarding HDL-C and VLDL-C values in patients with psoriasis. Normal4,5,7,8,17–19 and low3,10,12 levels of serum HDL-C and high3,6,11,12 levels of VLDL-C have been reported. Although the values of HDL-C in the present study were lower in the psoriasis group than in the control group, the difference was not statistically significant (P>.05). The recorded values of VLDL-C level in this work were significantly higher in the psoriatic group (P<.05). The discrepancy in data from different studies may be due to the fact that patients included in statistical analysis have different phases and forms of psoriasis and undergo various treatments. The other cause may be a result of differences in lipid referential values, such as sex and age, which considerably change the results when young and old patients and men and women are collectively investigated.5 Different methods used in disease scoring and laboratory assessment may be another cause of the discrepancy. The values of serum lipid in psoriatic patients have been studied since almost half a century ago. Lea and colleagues21 reported increased serum lipid concentrations in patients with psoriasis. Since then, much research has been performed in this area, most of which consistently points to a raised prevalence of lipid abnormalities in individuals diagnosed with psoriasis. The exact cause of these changes in lipid metabolism in patients with psoriasis is not yet confirmed. The activation of the immune system in psoriasis 205 Serum Lipid Level in Iraqi Patients With Psoriasis July/August 2010 ORIGINAL CONTRIBUTION may cause some changes in patients’ lipid profiles. They may be related, however, to some structural and functional abnormalities in the digestive system, which are shown to be found in nearly all the segments of the digestive system.22 These abnormalities may cause alteration in decomposition, modification, and synthesis of many organic compounds, including lipids. Knowing that psoriasis is a genetic disorder, however, there is a possibility that genetic alterations in the HDL-C and/or apolipoprotein A-I genes may be linked with this disease. This genetic hypothesis is supported by a study on lipid and lipoprotein profile among Swedish patients with psoriasis at the initial stages of the disease.11 It demonstrated that patients with psoriasis manifest significant lipid abnormalities and support the notion that the abnormal lipid profile seen in such patients might be genetically determined rather than acquired. Previous studies have shown a high prevalence of atherosclerosis in psoriatic patients.3,19,23,24 High serum lipid level has been suggested in the pathogenesis of this phenomenon. Early assessment and treatment of abnormal lipid profile may reduce atherosclerosis and cardiovascular accidents in these patients. References 1 Christophers E. Psoriasis—epidemiology and clinical spectrum. Clin Exp Dermatol. 2001;26:314–320. 2 Ortonne JP. Recent developments in the understanding of the pathogenesis of psoriasis. Br J Dermatol. 1999;140:1–7. 3 Rocha-Pereira P, Santos-Silva A, Rebelo I, et al. Dislipidemia and oxidative stress in mild and in severe psoriasis as a risk for cardiovascular disease. Clin Chim Acta. 2001;303:33–39. 4 Uyanik BS, Ari Z, Onur E, et al. Serum lipids and apolipoproteins in patients with psoriasis. Clin Chem Lab Med. 2002;40:65–68. 5 Seckin D, Tokgozoglu L, Akkaya S. Are lipoprotein profile and lipoprotein (a) levels altered in men with psoriasis? J Am Acad Dermatol. 1994;31:445–449. 6 Simonetti O, Ferretti G, Salvi A, et al. Plasma lipid changes in psoriatic children. Dermatology. 1992;185:96–100. 7 Seishima M, Seishima M, Mori S, et al. Serum lipid and apolipoprotein levels in patients with psoriasis. Br J Dermatol. 1994;130:738–742. 8 Piskin S, Gurkok F, Ekuklu G, et al. Serum lipid levels in psoriasis. Yonsei Med J. 2003;44:24–26. 9 Pietrzak A, Lecewicz-Torun B. Activity of serum lipase [EC SKINmed. 2010;8:204–206 206 3.1.1.3] and the diversity of serum lipid profile in psoriasis. Med Sci Monit. 2002;8:CR9–CR13. 10 Reynoso-von Drateln C, Martinez-Abundis E, Balcazar-Munoz BR, et al. Lipid profile, insulin secretion and insulin sensitivity in psoriasis. J Am Acad Dermatol. 2003;48:882–885. 11 Mallbris L, Granath F, Hamsten A, et al. Psoriasis is associated with lipid abnormalities at the onset of skin disease. J Am Acad Dermatol. 2006;54:614–621. 12 Vahlquist C, Michaelsson G, Vessby B. Serum lipoproteins in middleaged men with psoriasis. Acta Derm Venereol. 1987;67:12–15. 13 Cimsit G, Orem A, Deger O, et al. The variation of serum lipoprotein (a) level with disease activity in psoriasis. Br J Dermatol. 1998;138:917–919. 14 Vanizor Kural B, Orem A, Cimsit G, et al. Evaluation of the atherogenic tendency of lipids and lipoprotein content and their relationships with oxidant-antioxidant system in patients with psoriasis. Clin Chim Acta. 2003;328:71–82. 15 Friedewald WT, Levy RI, Fredrickson DS. Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge. Clin Chem. 1972;18:499–502. 16 Mallbris L, Akre O, Granath F, et al. Increased risk for cardiovascular mortality in psoriasis inpatients but not in outpatients. Eur J Epidemiol. 2004;19:225–230. 17 Akhyani M, Ehsani AH, Robati RM, et al. The lipid profile in psoriasis: a controlled study. J Eur Acad Dermatol Venereol. 2007;21:1330–1332. 18 Farshchian M, Zamanian A, Farshchian M, et al. Serum lipid level in Iranian patients with psoriasis. J Eur Acad Dermatol Venereol. 2007;21:802–805. 19 Gurkok F, Piskin S, Ekuklu G. Serum lipid and lipoprotein levels in psoriasis. Bull Leprosy. 1999;30:105–111. 20 Fortinskaia ES, Torkhavskia TI, Sharapova GI, et al. Features of distribution of free and esterified cholesterol in the epidermis, biological membrane and plasma lipoproteins in psoriasis. Klin Lab Diagn. 1996;4:38–43. 21 Lea WA Jr, Cornish HH, Block WD. Studies on serum lipids, proteins, and lipoproteins in psoriasis. J Invest Dermatol. 1958;30:181–185. 22 Pietrzak A, Lecewicz-Torun B, Kadziela-Wypyska G. Changes in the digestive system in patients suffering from psoriasis. Ann Univ Mariae Cruie Sklodowska. 1998;53:187–194. 23 McDonald CJ, Calabresi P. Psoriasis and occlusive vascular disease. Br J Dermatol. 1978;99:469–475. 24 Gelfand JM, Neimann AL, Shin DB, et al. Risk of myocardial infarction in patients with psoriasis. JAMA. 2006;296:1735–1741. Serum Lipid Level in Iraqi Patients With Psoriasis July/August 2010 Volume 8 • Issue 4 Original Contribution Clinical Features and Treatment of Dermatosis Papulosa Nigra in Migrants to Italy Roberta Calcaterra, MD;1 Gennaro Franco, MD;2 Mariacarla Valenzano, MD;2 Raffaella Fazio, MD;2 Aldo Morrone, MD1 Abstract Dermatosis papulosa nigra (DPN) is a benign epithelial tumor that is common in dark-skinned people. Although the diagnosis is easily made on medical examination, DPN is characterized by a chronic and worsening course. Therefore, even if DPN is a benign disease, the lesions are unaesthetic and the therapeutic options are quite inefficient. A prospective study was carried out during a period of 24 months (January 2006 to December 2007) at the Department for Preventive Medicine for Migration, Tourism and Tropical Dermatology of San Gallicano Dermatological Institute in Rome. Among 58 patients, 41 (71%) were women and 17 (29%) were men. The mean age was 33.5 years (range, 8–45 years). One pediatric patient was observed. This study is the first in Italy that, in recent years, has observed an important growth of the migration. The classic female predominance, family predisposition, and photodistribution of the lesion were found. DPN is frequently associated with patient discomfort, therefore the education of patients to reduce self-treatment is important. (SKINmed. 2010;8:207–209) D ermatosis papulosa nigra (DPN) is a nevoid condition of the pilosebaceous apparatus that predominantly affects adult black persons.1,2 It is characterized by black or dark brown flattened or cupuliform papules, with a diameter ranging from 1 mm to 5 mm. The lesions do not itch or hurt (are asymptomatic) and occur on the face, neck, and trunk. DPN is a frequent disease among black persons, above all Africans and African-Americans, but is also common in Native Americans and persons from Malaysia. sites involved at onset, morphology of lesions, clinical course, and psychological impact of the disease. Despite the diagnosis being easily made at medical examination, DPN is characterized by a chronic and worsening course. Therefore, even though DPN is a benign disease, the lesions are unaesthetic and the therapeutic options are quite inefficient. Results Materials And Methods A prospective study was performed during a 24-month period (January 2006 to December 2007) at the Department for Preventive Medicine for Migration, Tourism and Tropical Dermatology of San Gallicano Dermatological Institute in Rome, Italy. All patients attending our department for this or any other dermatologic reason were assessed. For each patient, the following data were obtained: sex, age, country of origin, family history of DPN, age at onset of disease, A careful clinical examination was performed. Histologic examination was carried out when necessary to confirm the clinical diagnosis. If required by the patient, the lesions were excised using fine-needle or fine-scissor electrosurgery after the application of lidocaine-prilocaine cream. The follow-up of the aesthetic results were evaluated during a 3-month period. Fifty-eight patients were evaluated, 41 (71%) were women and 17 (29%) were men. The mean age was 33.5 years (range, 8–45 years). One pediatric patient was observed. All patients had dark skin, in particular, 35 (61%) were Africans and 23 (39%) were Indomalesian. More than half the patients (42 [73%]) had a family member with the same disease. After analysis of the anamnestic data, results showed that lesions developed gradually during the years. The age of onset of the lesions ranged from 8 to 45 years, with a mean of 25 years. All the patients presented with lesions on the face (100%), mostly on the temples, malar regions, and on the forehead (Figure 1 and Figure 2). They were uncommon on the lower parts of the face and chin, but they were also found on the neck (8%) and on the trunk (4%). From the National Institute for Health, Migration and Poverty,1 and San Gallicano Dermatological Institute,2 Rome, Italy Address for Correspondence: Roberta Calcaterra, MD, National Institute for Health, Migration and Poverty, Via di San Gallicano 25/a Roma, Italy • E-mail: [email protected] SKINmed. 2010;8:207–209 207 © 2010 Pulse Marketing & Communications, LLC July/August 2010 ORIGINAL CONTRIBUTION Clinically, the lesions that we found were round, smooth, brown or black papules, ranging in size from 1 mm to 5 mm. Rarely we observed, only on the trunk, nodules or pedunculated papules (14%). These lesions were commonly asymptomatic, although 5 patients (8.4%) reported transitory itch. Twenty-three women (39.6%) reported the application of bleaching cream (most containing high-strength corticosteroids) for a period ranging from 4 months to 5 years, without any improvement. The histopathologic examination was performed in 3 cases and confirmed the diagnosis of DPN (Figure 3). Regarding psychological impact, discomfort described by these patients, above all among young adults and women, was remarkable. In fact, aesthetic considerations were the reason for consultation in 43 patients (74%), 35 of whom were women. Moreover, in 37 patients (63.8%), DPN caused anxiety and fear of professional concerns. Figure 1. Multiple pigmented papules of the face. All patients were informed that the treatment may be temporary and could result, above all in black skin, in important dyschromia. Electrosurgery was performed in 20 patients after the application of 30 minutes of lidocaine-prilocaine cream. At 1-month followup examination, hypochromia in 15 patients and hyperchromia in 5 patients were detected. At 3-month follow-up, dyschromia persisted in only 2 cases; 3 patients were lost to follow-up. Discussion DPN was first described by Castellani in 1925 while visiting Central America and Jamaica. He noted that this condition was common in adult black persons and was usually localized on the face.1 Different from that previously reported, we found that DPN occurs in all people with high Fitzpatrick skin phototype classification (skin phototype IV, V, or VI), not only in African descendants.1 The incidence of DPN among black persons rises from about 5% to 40%, and women, especially adolescents, are more commonly affected than men.1,3–5 The lesions usually develop during puberty and become more pronounced by the sixth decade; they are rare during childhood. Some studies have demonstrated the family predisposition of DPN. DPN is likely to be genetically determined, with 40% to 54% of patients having a family history of involvement. DPN is believed to be caused by a nevoid developmental defect of the pilosebaceous follicle. Some researchers have suggested that DPN should be classified within the group of epithelial nevi.6,7 Figure 2. Multiple pigmented papules of the face. SKINmed. 2010;8:207–209 Clinically, the single lesions are 1-mm to 5-mm black or dark brown cupuliform and usually asymptomatic. DPN is localized on the malar regions and on the forehead, is rare on the lower 208 Dermatosis Papulosa Nigra in Migrants to Italy July/August 2010 ORIGINAL CONTRIBUTION parts of the face and the chin, and can sometimes be found on the neck, chest, and back. The differential diagnosis of DPN include melanocytic nevi, warts, acrochordons, adenoma sebaceum, follicular hamartoma, and seborrheic keratosis. The diagnosis may be confirmed by biopsy, with DPN resembling an acanthotic seborrheic keratosis. Lesions of dermatosis papulosa nigra have the histologic appearance of seborrheic keratoses; they display hyperkeratosis, irregular acanthosis, keratin-filled invaginations of the epidermis (horn cysts), and marked hyperpigmentation of the basal layer. Although most lesions are of the acanthotic type and show thick interwoven tracts of epidermal cells, they may have a reticulated pattern in which the tracts consist of a double row of basaloid cells.8,9 Although DPN could exhibit thick interwoven tracts of epithelial cells, the proliferation of small basal cells is not common in DPN, such as in seborrheic keratosis. Treatment is seldom requested because of DPN’s benign nature, but patients often request some treatment to improve their aspect and reduce discomfort. Figure 3. Epidermal acantholysis and mild papillomatosis. 2 Micheal JC, Seale ER. Dermatosis papulosa nigra. Arch Dermatol Syph. 1929;20:629. 3 Grimes PE, Arora S, Minus HR, et al. Dermatosis papulosa nigra. Cutis. 1983;32:385. 4 Hairston MA Jr, Reed RJ, Derbes VJ. Dermatosis papulosa nigra. Arch Dermatol. 1964;89:655–658. 5 Dunwell P, Rose A. Study of the skin disease spectrum occurring in an Afro-Caribbean. Int J Dermatol. 2003;42:287–289. 6 Hairston MA Jr, Reed RJ, Derbes VJ. Dermatosis papulosa nigra. Arch Dermatol. 1964;89:655–658. The papules may be removed with diathermy or cautery; cryotherapy has also be used, but it is important to inform the patient that all this treatment may be temporary and could result in, above all in black skin, important hypopigmentation or hyperpigmentation and sometimes in keloids.10–13 8 Niang SO, Kane A, Diallo M, et al. Dermatosis papulosa nigra in Dakar, Senegal. Int J Dermatol. 2007;46:45–47. Other therapies include keratolytic creams associated with electrodessication, electrodessication, fractional photothermolysis, and long-pulsed 1064 nm Nd:YAG laser.14,15 10 Kaun YC. A surgical approach for dermatosis papulosa nigra. Int J Dermatol. 1983;22:1013–1015. We performed excision using fine-needle electrosurgery to minimize the risk of unaesthetic scarring, and the use of anesthetic cream was permitted to treat more lesions at the same time. Conclusions Although DPN is benign and the treatment, however easy to perform, is not always required, it is important to promote the knowledge of this condition common among black persons to provide the right assistance and treatment. References 1 Castellani A. Observations on some diseases of Central America. J Trop Med Hyg. 1925;28:1. SKINmed. 2010;8:207–209 209 7 Hafner C, Landthaler M, Mentzel T, et al. FGFR3 and PIK3CA mutations in stucco keratosis and dermatosis papulosa nigra. Br J Dermatol. 2010;162:508–512. 9 Binazzi M, Simonetti S. Dermatosis papulosa nigra in a white man. Ann Derm Venereol. 1984;111:1013–1015. 11 Schweiger ES, Kwasniak L, Aires DJ. Treatment of dermatosis papulosa nigra with a 106 nm Nd:YAG laser: report of two cases. J Cosmet Laser Ther. 2008;10:120–122. 12 Schwartzberg JB, Ricotti CA Jr, Ballard CJ, et al. Eruptive dermatosis papulosa nigra as a possible sign of internal malignancy. Int J Dermatol. 2007;46:186–187. 13 Carter EL, Coppola CA, Barsanti FA. A randomized, double-blind comparison of two topical anesthetic formulations prior to electrodesiccation of dermatosis papulosa nigra. Dermatol Surg. 2006;32:1–6. 14 Kundu RV, Joshi SS, Suh KY, et al. Comparison of electrodesiccation and potassium-titanyl-phosphate laser for treatment of dermatosis papulosa nigra. Dermatol Surg. 2009;35:1079–1083. 15 Katz TM, Goldberg LH, Friedman PM. Dermatosis papulosa nigra treatment with fractional photothermolysis. Dermatol Surg. 2009;35:1840–1843. Dermatosis Papulosa Nigra in Migrants to Italy July/August 2010 Volume 8 • Issue 4 REVIEW Acute Generalized Exanthematous Pustulosis Jennifer L. Pecina, MD;1 Mark A. Cappel, MD2 Abstract Acute generalized exanthematous pustulosis is a cutaneous reaction pattern typically precipitated by medication exposure. It has an estimated incidence of 1 to 5 cases per million per year and can occur in all age groups. Diagnosis is based on typical rash morphology, histopathology, and clinical course. Treatment consists of withdrawing the causative agent and providing supportive care. Prognosis for full recovery is excellent. Patients should be counseled to avoid any future use of the causative medication. (SKINmed. 2010;8:210–214) F irst described as a distinct entity in 1968,1 acute generalized exanthematous pustulosis (AGEP) is a relatively uncommon cutaneous reaction pattern typically precipitated by medication exposure. The disease has been variably termed pustular drug rash, generalized pustular dermatosis, and toxic pustuloderma. The current nomenclature was proposed in the French literature in 1980.2 Clinical Presentation AGEP is characterized by acute onset of an edematous erythematous dermatitis with overlying small pustules, frequently accompanied by a temperature >38°C. Leukocytosis is common, predominantly as neutrophilia, although eosinophilia may also occur. Serum chemistry values may show a slight elevation in hepatic transaminases, hypocalcemia, and a transient decrease in creatinine clearance.3 The typical dermatologic appearance is that of an edematous erythematous dermatitis that frequently begins on the face or in intertriginous regions. Patients often describe the dermatitis as burning and pruritic. This dermatitis is followed by the appearance of numerous small (<5 mm) nonfollicular sterile pustules in the involved areas (Figure 1). By definition, the pustules in AGEP are sterile, but, as with any diffuse dermatitis, staphylococcal and other bacterial superinfections can occur. Mucous membrane involvement occurs in 20% of the patients. Occasionally, blisters, target lesions, and purpura are seen.3 Individual pustules can expand and coalesce, thereby forming larger confluent pustules. Biopsy may be required to confirm the diagnosis, and histopathology typically shows spongiform subcorneal pustules or intraepidermal pustules with papillary dermal edema and perivascular infiltrates of neutrophils and sometimes eosinophils.4 An AGEP validation score proposed for diagnosis is based on a combination of features of the morphology, histopathology, and clinical course (Table I).5 Often, however, patients with cutaneous drug reactions have been simultaneously exposed to multiple new medications, making determination of the particular causative agent challenging. Inadvertent reexposure has been reported to provoke recurrent episodes of AGEP; thus, rechallenge could be used to confirm clinical suspicions of a causative agent.3,6 Reexposure is potentially unsafe, however, and may raise ethical concerns. Since patch testing results are positive in 50% of patients, it is a reasonable method for attempting to elucidate the inciting medication.7 Patch tests are generally considered safe, although an AGEP reaction provoked by patch testing has been reported.8 Incidence The incidence of AGEP is estimated to be approximately 1 in 5 cases per million per year, and all age groups may be affected.5 Two studies suggested a female predilection, but this has not been a consistent finding.3,9,10 One study found a disproportionate association with the HLA B51, DR11, and DQ3 genotypes compared with the general population. A personal or family history of psoriasis is slightly more common than would be expected in the general population, but most cases of AGEP occur in patients without any psoriatic history. Etiology The underlying pathogenic mechanism for AGEP remains unclear; however, on the basis of several studies, a T-cell–mediated process has been hypothesized. In vitro tests have demonstrated that drug-specific T lymphocytes from AGEP patients produce chemokines that attract neutrophils as well as prolong their From the Department of Family Medicine,1 and the Division of Laboratory Dermatology,2 Mayo Clinic, Rochester, MN Address for Correspondence: Jennifer L. Pecina, MD, Department of Family Medicine, Mayo Clinic, 200 First Street SW, Rochester, MN 55905 • E-mail: [email protected] SKINmed. 2010;8:210–214 210 © 2010 Pulse Marketing & Communications, LLC July/August 2010 REVIEW Figure 1. Acute generalized exanthematous pustulosis. Anterior surfaces of legs (A); back (B). survival, thus leading to the sterile inflammatory pustules that are clinically observed.11,12 AGEP is precipitated by systemic drugs in approximately 90% of patients. Historically, b-lactam and macrolide antibiotics are the most frequent causative agents, although multiple drugs have been implicated (Table II). AGEP has been reported to occur from multiple antibiotics within the same class: in 1 patient, AGEP developed from 2 different macrolides,13 and in another patient, AGEP developed from 3 different b-lactam antibiotics (piperacillin, ceftazidime, and meropenem).15 A bimodal pattern has been seen for the interval to onset after starting administration of an inciting drug. With antibiotics, the onset of dermatitis usually occurs within 2 days (mean, 2.5 days), whereas with other medications there is often a delay of 1 to 3 weeks (mean, 18 days).3 AGEP has been associated with viral infections (including enteroviruses, cytomegalovirus, and human parvovirus B19),3 spider bites,2,3 and mercury exposure.3 Differential Diagnosis The differential diagnosis of AGEP includes various dermatoses that have a pustular component with a background of diffuse erythema. Folliculitis, impetigo, and Sweet syndrome can appear pustular but are typically not associated with a background of diffuse erythema. Blistering diseases such as Sneddon-Wilkinson disease, immunoglobulin A pemphigus, and pemphigus foliaceus can form pustules but often have more chronic and discrete lesions. Impetigo typically presents with larger, flaccid, and nonsterile pustules that remain relatively localized. Sweet syndrome can occur suddenly and the lesions may appear pustular, but these SKINmed. 2010;8:210–214 lesions are also relatively localized and discrete. Pustular contact dermatitis, superinfected eczematous dermatitis, pustular psoriasis, staphylococcal scalded skin syndrome, and drug rash with eosinophilia and systemic symptoms can present with diffuse erythematous dermatitis associated with pustules. Staphylococcal scalded skin syndrome is associated with staphylococcal infection, and drug rash with eosinophilia and systemic symptoms is associated with significant systemic symptoms. Both tend to be characterized by exfoliation rather than pustule formation. Most of the above entities are easily distinguished from AGEP on the basis of clinical findings and history. The primary disease process to be excluded is generalized pustular psoriasis (von Zumbusch psoriasis) (Figure 2), which has a longer clinical course than AGEP and is not associated with drug administration. Treatment Treatment consists of discontinuing use of the suspected offending agent and providing supportive care. If they are not thought to be causative agents, antipyretics and antihistamines can be used for symptomatic relief. Various topical treatments, including topical corticosteroids and cool compresses, can also be considered, but they may provide only mild symptomatic relief. Systemic corticosteroids may be empirically used, but supportive evidence is lacking. In at least two published reports, pretreatment with corticosteroids did not prevent AGEP from occurring.6,18 Paradoxically, there are also reports of corticosteroids provoking an AGEP reaction.19,20 Patients should be counseled to avoid use of the offending drug in the future, and their 211 Acute Generalized Exanthematous Pustulosis July/August 2010 REVIEW Table I. AGEP: Validation Scorea of the EuroSCAR Study Groupb (1 of 2) Table I. AGEP: Validation Scorea of the EuroSCAR Study Groupb (2 of 2) Feature Feature Points Morphology Points Histology Pustules Other disease Typical -10 +2 Not representative/no histology Compatible +1 Exocytosis of PNN +1 Insufficient 0 Subcorneal and/or intraepidermal nonspongiform or NOS pustule(s) with papillary edema or subcorneal and/or intraepidermal spongiform or NOS pustule(s) without papillary edema +2 Spongiform subcorneal and/or intraepidermal pustule(s) with papillary edema +3 c d e Erythema Typical +2 Compatible +1 Insufficient 0 Abbreviations: AGEP, acute generalized exanthematous pustulosis; EuroSCAR, European Study of Severe Cutaneous Adverse Drug Reactions; NOS, not otherwise specified; PNN, polynuclear neutrophil count. aInterpretation: ≤0, no AGEP; 1–4, possible; 5–7, probable; 8–12, definite. bPatients were not included in the study if only localized pustules were reported, the pustular dermatitis already lasted longer than 3 weeks, or a clear alternative diagnosis was made by a dermatologist. cTypical: typical morphology. dCompatible: not typical, but not strongly suggestive of other disease. eInsufficient: lesions cannot be judged (mostly because of late stage of the disease or poor quality of pictures). Adapted with permission from Sidoroff et al.5 Distribution/pattern Typical +2 Compatible +1 Insufficient 0 Postpustular desquamation Yes +1 No/insufficient +0 0 Course Outcomes Mucosal involvement Yes -2 No 0 Outcomes in AGEP are uniformly excellent. The dermatitis is topographically self-limited in distribution and usually spontaneously resolves in less than 15 days. Resolution is followed by pinpoint cutaneous desquamation and eventual healing.5 No data exist on cross-sensitization between similar classes of medications (eg, penicillins and cephalosporins). Serious consequences are extremely rare: an early article reported a 5% mortality rate,24 but this has not been substantiated in later reports. Two cases of AGEP-related death have been described; however, 1 patient died of hepatic coma and had other comorbidities15 and the other died of acute renal failure and sepsis.9 Acute onset (≤10 d) Yes 0 No -2 Resolution ≤15 d Yes 0 No -4 Temperature ≥38°C Yes +1 No 0 Conclusions AGEP is a relatively rare dermatologic disease typically provoked by medication exposure. Specific criteria exist for establishing the diagnosis. Symptoms usually spontaneously resolve after withdrawal of the precipitating medication. PNN ≥7000/μL Yes +1 No 0 adverse reaction should be documented in their medical record. Although no specific guidelines are available, it may be prudent to recommend that patients avoid future exposure to medications in the same class. SKINmed. 2010;8:210–214 References 212 1 Baker H, Ryan TJ. Generalized pustular psoriasis: a clinical and epidemiological study of 104 cases. Br J Dermatol. 1968;80:771–793. 2 Beylot C, Bioulac P, Doutre MS. Acute generalized exanthematic Acute Generalized Exanthematous Pustulosis July/August 2010 REVIEW Table II. Drugs and Miscellaneous Causes Reported to Be Implicated in Acute Generalized Exanthematous Pustulosis Antibiotics Antihypertensives Amoxicillin13 Diltiazem7 Ampicillin13 Enalapril5 Azithromycin14 Nifedipine3 Cefaclor13 Corticosteroids Cefazolin Dexamethosone19 Ceftazidime15 Methylprednisolone20 14 Cefuroxime13 Antiepileptics Cephalexin13 Carbamazepine3,7 Chloramphenicol13 Phenobarbital7 Ciprofloxacin9 Other medications Clindamycin Allopurinol5 Doxycycline17 Chromium picolinate5 Erythromycin13 Cimetidine5 Gentamicin5 Disulfiram5 Imipenem13 Ferrous fumarate5 Isoniazid13 Furosemide5 Meropenem15 Ginkgo biloba21 Metronidazole5 Intravenous contrast media22 Penicillin13 Lansoprazole5 Piperacillin15 Quinidine3 Trimethoprim-sulfamethoxazole5 Sulfasalazine5 16 Vancomycin3 Figure 2. Pustular psoriasis on posterior surface of leg. Miscellaneous Other antimicrobials pustuloses (four cases) (author’s transl) [in French]. Ann Dermatol Venereol. 1980;107:37–48. Enterovirus3 Acyclovir9 Human parvovirus B1923 Griseofulvin5 Influenza vaccine9 Hydroxychloroquine5 Mercury3 Itraconazole5 Pneumococcal vaccine17 Mefloquine14 Psoralen–UV-A5 Nystatin5 Spider bites23 Terbinafine18 Tonsillitis9 3 Roujeau JC, Bioulac-Sage P, Bourseau C, et al. Acute generalized exanthematous pustulosis: analysis of 63 cases. Arch Dermatol. 1991;127:1333–1338. 4 James WD, Berger TG, Elston DM. Andrews’ Diseases of the Skin: Clinical Dermatology. 10th ed. Philadelphia, PA: Saunders Elsevier; 2006:125. 5 Sidoroff A, Halevy S, Bavinck JN, et al. Acute generalized exanthematous pustulosis (AGEP): a clinical reaction pattern. J Cutan Pathol. 2001;28:113–119. 6 Bracke A, Van Marck E, Lambert J. Acute generalized exanthematous pustulosis after pemetrexed, and recurrence after re-introduction. Clin Exp Dermatol. 2009;34:337–339. Epub 2008 Aug 9. Analgesics 7 Wolkenstein P, Chosidow O, Fléchet ML, et al. Patch testing in severe cutaneous adverse drug reactions, including StevensJohnson syndrome and toxic epidermal necrolysis. Contact Dermatitis. 1996;35:234–236. Acetaminophen8 Diclofenac14 Paracetamol17 8 Mashiah J, Brenner S. A systemic reaction to patch testing for the evaluation of acute generalized exanthematous pustulosis. SKINmed. 2010;8:210–214 213 Acute Generalized Exanthematous Pustulosis July/August 2010 REVIEW Arch Dermatol. 2003;139:1181–1183. 9 Tamir E, Wohl Y, Mashiah J, et al. Acute generalized exanthematous pustulosis: a retrospective analysis showing a clear predilection for women. Skinmed. 2006;5:186–188. 10 Davidovici B, Dodiuk-Gad R, Rozenman D, et al. Israeli RegiSCAR Network. Profile of acute generalized exanthematous pustulosis in Israel during 2002–2005: results of the RegiSCAR Study. Isr Med Assoc J. 2008;10:410–412. 11 Schmid S, Kuechler PC, Britschgi M, et al. Acute generalized exanthematous pustulosis: role of cytotoxic T cells in pustule formation. Am J Pathol. 2002;161:2079–2086. 12 Britschgi M, Steiner UC, Schmid S, et al. T-cell involvement in drug-induced acute generalized exanthematous pustulosis. J Clin Invest. 2001;107:1433–1441. 13 Moreau A, Dompmartin A, Castel B, et al. Drug-induced acute generalized exanthematous pustulosis with positive patch tests. Int J Dermatol. 1995;34:263–266. 14 Beylot C, Doutre MS, Beylot-Barry M. Acute generalized exanthematous pustulosis. Semin Cutan Med Surg. 1996;15:244–249. 15 Mysore V, Ghuloom A. A case of recurrent acute generalized exanthematous pustulosis due to beta-lactam antibiotics: a case report. J Dermatolog Treat. 2003;14:54–56. 16 Sulewski RJ Jr, Blyumin M, Kerdel FA. Acute generalized exanthematous pustulosis due to clindamycin. Dermatol Online J. 2008;14:14. 17 De Coninck AL, Van Strubarq AS, Pipeleers-Marichal MA, et al. Acute generalized exanthematous pustulosis induced by paracetamol: a case with severe hemodynamic disturbances. Dermatology. 1996;193:338–341. 18 Bajaj V, Simpson N. Oral corticosteroids did not prevent AGEP due to terbinafine. Acta Derm Venereol. 2006;86:448–449. 19 Demitsu T, Kosuge A, Yamada T, et al. Acute generalized exanthematous pustulosis induced by dexamethasone injection. Dermatology. 1996;193:56–58. 20 Mussot-Chia C, Flechet ML, Napolitano M, et al. Methylprednisolone-induced acute generalized exanthematous pustulosis [in French]. Ann Dermatol Venereol. 2001;128(3 pt 1):241–243. 21 Pennisi RS. Acute generalised exanthematous pustulosis induced by the herbal remedy Ginkgo biloba. Med J Aust. 2006;184:583–584. 22 Peterson A, Katzberg RW, Fung MA, et al. Acute generalized exanthematous pustulosis as a delayed dermatotoxic reaction to IV-administered nonionic contrast media. AJR Am J Roentgenol. 2006;187:W198–W201. 23 Davidovici BB, Pavel D, Cagnano E, et al. EuroSCAR; RegiSCAR study group. Acute generalized exanthematous pustulosis following a spider bite: report of 3 cases. J Am Acad Dermatol. 2006;55:525–529. 24 Roujeau JC. Clinical heterogeneity of drug hypersensitivity. Toxicology. 2005;209:123–129. VINTAGE LABEL Courtesy of BuyEnlarge, Philadelphia, PA SKINmed. 2010;8:210–214 214 Acute Generalized Exanthematous Pustulosis Available soon... % A New Tretinoin Therapy From Triax Pharmaceuticals ©2010 Triax Pharmaceuticals, LLC. All Rights Reserved. Printed in USA TX-0610-02 July/August 2010 Volume 8 • Issue 4 REVIEW Sporotrichosis: Part I Regina Casz Schechtman, MD, PhD Abstract Sporotrichosis is the most common subcutaneous mycosis in South America. Classic infection is associated with traumatic inoculation of soil, vegetables, and organic material contaminated with Sporothix schenckii. Animals of various species, including humans, are affected by this disease. This subcutaneous mycosis is an infection of implantation. The most frequent clinical form is the lymphocutaneous form. The fixed cutaneous form is characterized by infiltrated nodular, ulcerated, or erythematosquamous lesions located on exposed areas where fungal inoculation occurred. The disseminated cutaneous forms have mainly been observed among immunosuppressed patients, especially human immunodeficiency virus–positive individuals. Sporotrichosis is the only subcutaneous mycosis for which direct examination or histology is of little or no value for diagnosis. The diagnosis rests solely on the isolation of S schenckii in culture. Since 1998, researchers from Brazil suggested that feline transmission of sporotrichosis was associated with a large and long-lasting outbreak of the disease in the city of Rio de Janeiro. (SKINmed. 2010;8:216–220) S porotrichosis is the most common subcutaneous mycosis in South America. Classic infection is associated with traumatic inoculation of soil, vegetables, and organic material contaminated with Sporothix schenckii. Zoonotic transmit ion has been described in isolated cases or in small outbreaks. Since 1998, researchers from Fiocruz Institute have been observing an increasing number of cases of sporotrichosis in the population of the city of Rio de Janeiro, Brazil. According to researchers,1 their study suggests that feline transmission of sporotrichosis was associated with a large and long-lasting outbreak of the disease in Rio de Janeiro city and surroundings. Sporotrichosis is a subcutaneous subacute or chronic mycosis caused by the dimorphic fungus S schenckii, which is found in the soil, on plant debris, and on decaying vegetable material. Animals of various species, including humans, are affected by this disease. This subcutaneous mycosis is an infection of implantation. In most cases it develops following traumatic injury and the inoculation of environmental organisms into the host where they affect the subcutaneous tissue, skin, and other adjacent structures. It usually presents as a skin infection, cutaneous sporotrichosis, when the organism gains entry by traumatic injury. Persons in certain occupational groups, such as those who handle plant materials or soil, are frequently exposed to the organism and have been known to become infected.2,3 In 1998, an outbreak of in-house sporotrichosis transmitted by domestic cats was reported in the city of Rio de Janeiro. Since then, human sporotrichosis with feline transmission took place as a public health disease in Brazil, and domestic cats are considered an important vector of sporotrichosis.1 In July 2006, Brazilian researchers demonstrated 44 cases of street dogs with sporotrichosis in the city of Rio de Janeiro. In the near future, dogs may play an important role in the transmission of Brazilian zoonotic sporotrichosis as well as cats.4 History In 1898, Bernard Schenck first isolated and described S schenckii. He was attending medical school at Johns Hopkins University at the time, and he had the assistance of a US Department of Agriculture mycologist, Erwin Smith, who identified the organism and classified it as “sporotricha.”5 In 1900, the disease was reported for the second time by Hektoen and Perkins, who classified the etiologic agent as S schenckii, with the pathogen being isolated from a specimen aspirated from the cutaneous lesions of a patient.6 In Europe, the first case was described in 1903, and more than 200 cases were reported during the following 10 years.7 The first sporotrichosis in Brazil was reported in 1907 by Lutz and Splendore, who also found that it was possible to culture the yeast form in vitro.8 The dimorphic transition of this fungus was described by Howard in 1961.9 Taxonomy S schenckii is, therefore, a dimorphic pathogenic fungus and the etiologic agent of human and animal sporotrichosis. The fungus From the Instituto de Dermatologia Prof Rubem David Azulay (IDPRDA), Santa Casa da Misericórdia do Rio de Janeiro, Rio de Janeiro, Brazil Address for Correspondence: Regina Casz Schechtman, MD, PhD, rua Ribeiro de Almeida 44 Apt 102, Rio de Janeiro, Brazil, CEP 22240-060 • E mail: [email protected] SKINmed. 2010;8:216–220 216 © 2010 Pulse Marketing & Communications, LLC July/August 2010 REVIEW belongs to the subdivision Deuteromycotina, class Hyphomycetes.3 According to Mariat and Taylor, the fungus Ceratocystis stenoceras (Ophiostoma stenoceras) presents a conidial stage similar to that of S schenckii; however, no conclusions exist regarding the description of the teleomorphic phase of this species.10 Other investigators have recently postulated that stenoceras may correspond with the teleomorph of S schenckii.2 Previous studies based on DNA hybridization experiments, however, provided strong evidence that stenoceras is not the teleomorph of S schenckii. The degree of hybridization observed among S scheckii and O stenoceras DNAs was as low as 30% while a high degree of cross-hybridization was observed among 4 S schenckii strains studied.10 Epidemiology Figure 1. Initial presentation of sporotrichosis. Single eroded papule on the hand. S schenckii is widely distributed in nature and can be found in soil associated with plant organic matter (eg, thorns, dry leaves, and wood), water, and decomposing organic matter, among others. S schenckii is present in the soil throughout the world. Sporotrichosis is more frequent in tropical and subtropical countries, however, and is endemic in many parts of Latin America. Sporotrichosis has been mainly reported in tropical and temperate zones.11,12 It is endemic in Mexico, Central America, and South America, as well as other areas such as South Africa. It can also occur in temperate climates such as in southern United States, Japan, and Australia. In the south of the American continent, the disease more frequently occurs in humid autumn or summer seasons,13,14 whereas in Mexico, the highest incidence is observed in cold and dry seasons.15 No seasonal difference, however, has been reported by other authors.11,16 Figure 2. Dermal and subcutaneous eroded nodules and ulcers up the arm along the path of lymphatic drainage. Sporotrichosis can affect persons of all ages,17 and the number of cases involving men and women varies from region to region.11,17 In some regions, the difference in the distribution of cases according to age and sex might be explained by the type of fungal exposure, but no association has been found in other regions. Generally, infection results from inoculation of the fungus through thorns, splinters, scratches, and small traumas during leisure and occupational activities such as floriculture, horticulture, gardening, fishing, hunting, farming and cattle raising, mining, and wood exploration.13,14,17–22 Laboratory professionals can be accidentally infected while manipulating S schenckii cultures.23,24 Sporotrichin skin test is mainly applied for epidemiologic studies and is not commercially available in Brazil. Figure 3. Sporotrichosis. Initial ulcerated lesion with additional subcutaneous nodules up the arm along the path of lymphatic drainage. Epidemic Outbreaks Sporotrichosis usually occurs in isolated cases or in small family or professional outbreaks. Epidemics are rare and, if present, have been related to a single source of infection.25 The largest reported epidemic occurred in South Africa, with about 3000 gold miners SKINmed. 2010;8:216–220 infected with the fungus, which occurred in the wood girders of the mine structure.26 Another epidemic burst affected 84 workers who participated in reforestation programs in 15 states of the 217 Sporotrichosis: Part I July/August 2010 REVIEW in various species such as horses, rats, dolphins, cows, and fish.2 Animal to human transmission is rare, however, and there are few reports on animal transmission of sporotrichosis to humans, with the exception of some cases of armadillo transmission in Uruguay35 and feline transmission in Brazil. Other risk groups include animal health personnel, such as veterinary doctors and technicians, and animal owners as a result of the increasing number of sporotrichosis case reports transmitted by domestic cats. Domestic cats can acquire the disease following traumatic injury from infected street cats during fights or from direct inoculation of environmental organisms that inhabit soil and vegetation. They transmit the infection to humans in the domestic environment through biting or scratching human skin and consequently inoculating the organisms that are present under the nails. Another way of transmission is through direct contact of human skin with the infected cat skin, mucous membranes, or exudates from open lesions. Domestic dogs have been identified with sporotrichosis, probably transmitted by domestic cats.1,4 Figure 4. Sporotrichosis. Fixed cutaneous form. Infiltrated nodular eroded papule on the leg. Pathogenesis This subcutaneous mycosis is an infection of implantation. In most cases it develops following traumatic injury, especially by vegetation such as thorns and wood, and the inoculation of environmental organisms into the host where they affect the subcutaneous tissue, skin, and other adjacent structures. Certain occupational groups such as those who handle plant materials or soil are frequently exposed to the organism and have been known to become infected. Multiple inoculations may occur simultaneously, not to be confused with spread of a single primary lesion. The presentation and course of sporotrichosis depends on the host immune response as well as the size and virulence of the inoculums. In hosts not previously inoculated, involvement of regional lymphatic ensues. In those with a prior history of exposure to S schenckii, no lymphatic spread occurs and a “fixed ulcer” develops at the site of inoculums or granulomatous plaque (particularly on the face).36 Figure 5. Sporotrichosis. Fixed cutaneous form. Infiltrated nodular eroded papule on the nose. United States and was associated with the sphagnum moss used to store the seedlings that originated from Pennsylvania.27 Zoonotic Sporotrichosis Human sporotrichosis has been sporadically related to the scratch or bite of animals.21,28 The presence of the fungus in the mouth or nails of the animals, however, was not demonstrated in any of the cases described.28,29 Since the 1980s, domestic cats have gained importance in the transmission of the mycosis to humans.20,30–34 Between animals, the acquired infection is reported in various species. There are few reports, however, on animal transmission of sporotrichosis to humans. The acquired infection is reported SKINmed. 2010;8:216–220 Extensive cutaneous disease with or without systemic involvement is also possible, especially in an immunocompromised host. Cases of inhaled sporotrichosis have been reported with systemic and cutaneous dissemination, similar to disseminated histoplasmosis and other dimorphic fungal infections. Clinical Features Sporotrichosis has diverse clinical manifestations, and investigators disagree regarding the clinical classification of the disease.2 The most frequent clinical form (about 80%) is the lymphocutaneous form. The initial presentation of sporotrichosis is that of a single papule at the precise location of injury, most commonly on the hand, that 218 Sporotrichosis: Part I July/August 2010 REVIEW appears several weeks after inoculation. The lesion then becomes eroded or ulcerated with purulent drainage, and is generally not painful (Figure 1). Weeks after development of the initial lesion, additional lesions appear, typically as dermal and subcutaneous nodules and ulcers along the path of lymphatic drainage (often up the arm) (Figure 2). This clinical description led to naming the disease as “ascending nodular lymphangitis.”37 This is the well-known “sporotrichoid” pattern (Figure 3). Usually, lesions located in the deep dermis or subcutaneous tissue result in skin scars. In general, the fixed cutaneous form is characterized by infiltrated nodular, ulcerated, or erythematosquamous lesions located on exposed areas where fungal inoculation occurred (Figure 4 and Figure 5) The lesions of fixed cutaneous sporotrichosis can appear granulomatous (Figure 6), and disseminated lesions typically present as subcutaneous nodules. The disseminated cutaneous forms have mainly been observed among immunosuppressed patients, especially human immunodeficiency virus–positive individuals.38,39 Mucosal involvement is not common but may occur and preferentially affects the ocular mucosa (Figure 7).40 Among the extracutaneous forms, osteoarticular and pulmonary involvement are the most common, but there are reports of cases of severe hematogenic dissemination with involvement of multiple organs. Figure 6. Sporotrichosis. Fixed cutaneous form. Granulomatous lesion typically on the face. Differential Diagnosis Due to the diversity of the clinical forms of sporotrichosis, there is also a vast set of differential diagnoses with other pathologic conditions. Examples include leishmaniasis, nocardiosis, chromomycosis, tuberculosis, rosacea, noninfectious granulomatous diseases, and psoriasis, among others. When there is a sporotrichoid pattern, the major entity to be excluded in endemic areas from Brazil is leishmaniasis. In Europe, Canada, and the United States, the major differential diagnosis is an atypical mycobacterial infection, in particular Mycobacterium marinum. Other less common causes are rhinoscleroma, granuloma inguinale, histoplasmosis, leishmaniosis, and Penicillium marneffei infection. The differential diagnosis of fixed plaque sporotrichosis and disseminated lesions is broad and includes other granulomatous disorders, both infectious and inflammatory. References 1 de Lima Barros MB, Schubach TM, Gutierrez-Galhardo MC, et al. Sporotrichosis: an emergent zoonosis in Rio de Janeiro. Mem Inst Oswaldo Cruz. 2001;96:777–779. 2 da Silva Lacaz CS, Porto E, Martins JE, Heins-Vaccari EM, Melo NT, eds. Tratado De Micologia Médica. Sao Paulo, Brazil: Sarvier; 2002:479–497. 3 Bennett JE. Sporothricosis. In: Kwon-Chung K, Bennett J, eds. Medical Mycology. 2nd ed. Philadelphia, PA: Lea & Febiger; 1992:707–729. SKINmed. 2010;8:216–220 219 Figure 7. Sporotrichosis with ocular mucosal involvement. 4 Schubach TMP, Schubach A, Okamoto T, et al. Canine sporotrichosis in Rio de Janeiro, Brazil: clinical presentation, laboratory diagnosis and therapeutic response in 44 cases (1998–2003). Med Mycol. 2006;44:87–92. 5 Davis BA. Sporotrichosis. Dermatol Clin. 1996;14:69–76. 6 Hektoen L, Perkins CF. Refractory subcutaneous abcesses caused by sporothrix schenkii. a new pathogenic fungus. J Exp Med. 1900;5:77–89. 7 Mariat F. The epidemiology of sporotrichosis. In: Wolstenholme GE, Porter R, eds. Systemic Mycoses. London, England: Little, Brown Book Group; 1968:144–159. 8 Lutz A, Splendore A. Ueber eine bei menschen und ratten beobachtete mykose: ein beitrag zur kenntnis der sogenannten Sporotrichosis: Part I July/August 2010 REVIEW sporotrichosen. Centralblatt Bakteriologie, Parasitenkunde und Infektionskrankheiten. 1907;45:631–637. 24 Cooper CR, Dixon DM, Salkin IF. Laboratory-acquired sporotrichosis. J Med Vet Mycol. 1992;30:169–171. 9 Howard DH. Dimorphism of sporotrichum schenckii. J Bacteriol. 1961;81:464–469. 25 Bustamante B, Campos PE. Endemic sporotrichosis. Curr Opin Infect Dis. 2001;14:145–149. 10 Travassos LR, Lloyd KO. Sporothrix schenckii and related species of ceratocystis. Microbiol Rev. 1980;44:683–721. 26 Quintal D. Sporotrichosis infection on mines of the Witwatersrand. J Cutan Med Surg. 2000;4:51–54. 11 de Lima Barros MB. Estudo de uma série de casos de esporotricose atendidos no instituto de pesquisa clínica evandro chagas, Rio de Janeiro. Universidade Federal do Rio de Janeiro, Faculdade de Medicina. 2004. 27 Centers for Disease Control (CDC). Multistate outbreak of sporotrichosis in seedling handlers. Morb Mortal Wkly Rep. 1988;37:652–653. 12 Schubach TM, Schubach A, Okamoto T, et al. Evaluation of an epidemic of sporotrichosis in cats: 347 cases (1998–2001). J Am Vet Med Assoc. 2004;224:1623–1629. 13 Mackinnon JE, Conti-Diaz IA, Gezuele E, et al. Isolation of sporothrix schenckii from nature and considerations on its pathogenicity and ecology. Sabouraudia. 1969;7:38–45. 14 Lopes JO, Alves SH, Mari CR, et al. Epidemiology of sporotrichosis in the central region of Rio Grande do Sul [in Portuguese]. Rev Soc Bras Med Trop. 1999;32:541–545. 15 Gonzalez-Ochoa A. Contribuciones recientes al conociemiento de la esporotrichosis. Gac Med Mex. 1965;95:463–474. 16 de Lima Barros MB, Schubach ADO, do Valle ACF, et al. Cat-transmitted sporotrichosis epidemic in Rio de Janeiro, Brazil: description of a series of cases. Clin Infect Dis. 2004;38:529–535. 17 Rippon JW. Medical Mycology: The Pathogenic Fungi and the Pathogenic Actinomycetes. Philadelphia, PA: WB Saunders; 1988:325–352. 18 Mayorga R, Caceres A, Toriello C, et al. An endemic area of sporotrichosis in Guatemala [in French]. Sabouraudia. 1978;16:185–198. 19 Mayorga R, Caceres A, Toriello C, et al. Study of an endemic sporotrichosis zone in the Ayarza lake region of Guatemala [in Spanish]. Bol Oficina Sanit Panam. 1979;87:20–34. 20 Read SI, Sperling LC. Feline sporotrichosis. Transmission to man. Arch Dermatol. 1982;118:429–431. 21 Kauffman CA. Sporotrichosis. Clin Infect Dis. 1999;29:231– 236; quiz 237. 22 de Lima Barros MB, de Oliveira Schubach A, Galhardo MC, et al. Sporotrichosis with widespread cutaneous lesions: report of 24 cases related to transmission by domestic cats in Rio de Janeiro, Brazil. Int J Dermatol. 2003;42:677–681. 23 Thompson DW, Kaplan W. Laboratory-acquired sporotrichosis. Sabouraudia. 1977;15:167–170. SKINmed. 2010;8:216–220 220 28 Moore JJ, Davis DJ. Sporotrichosis following mouse bite, with certain immunologic data. J Infect Dis. 1918;23:252–266. 29 Fischman O, Alchorne MM, Portugal MA. Human sporotricosis following rat bite. Rev Inst Med Trop Sao Paulo. 1973;15:99–102. 30 Dunstan RW, Reimann KA, Langham RF. Feline sporotrichosis. J Am Vet Med Assoc. 1986;189:880–883. 31 Schubach TMP, Schubach A. Sporotrichosis of cat and dog: review. Clin Vet (Milano). 2000;29:21–24. 32 Werner AH, Werner BE. Sporotrichosis in man and animal. Int J Dermatol. 1994;33:692–700. 33 Reed KD, Moore FM, Geiger GE, et al. Zoonotic transmission of sporotrichosis: case report and review. Clin Infect Dis. 1993;16:384–387. 34 Larsson CE, Goncalves MD, Araujo VC, et al. Feline sporotrichosis: clinical and zoonotic aspects. Rev Inst Med Trop Sao Paulo. 1989;31:351–358. 35 Conti-Diaz IA. Sporotrichosis in Uruguay: epidemiologic and clinical aspects. Pan American Health Organization Scientific Publication. Washington, DC: PAHO; 1980:312–321. 36 Elgart ML. Subcutaneous and miscellaneous mycoses. In: Elewski BE, ed. Cutaneous Fungal Infections. New York, NY: Igaku-Shoin Medical Publishers; 1998:155–197. 37 Hoeprich PD. Sporotrichosis. In: Hoeprich PD, Jordan MC, Ronald AR, eds. Infectious Diseases. Philadelphia, PA: Lippincott Williams and Wilkins; 1994:1050–1054. 38 Shaw JC, Levinson W, Montanaro A. Sporotrichosis in the acquired immunodeficiency syndrome. J Am Acad Dermatol. 1989;21:1145–1147. 39 Donabedian H, O’Donnell E, Olszewski C, et al. Disseminated cutaneous and meningeal sporotrichosis in an AIDS patient. Diagn Microbiol Infect Dis. 1994;18:111–115. 40 Vieira-Dias D, Sena CM, Orefice F, et al. Ocular and concomitant cutaneous sporotrichosis. Mycoses. 1997;40:197–201. Sporotrichosis: Part I July/August 2010 Volume 8 • Issue 4 SELF-TEST REVIEW QUESTIONS W. Clark Lambert, MD, PhD, Editor Instructions: For each of the following numbered questions, choose the single most appropriate lettered response. 1) Sporotrichosis is most commonly transmitted to humans by contact with: 4) Of the following, the organ most likely to be involved by extracutaneous sporotrichosis is the: a. cats a. colon b. dogs b. kidney c. hamsters c. liver d. lice d. lung e. snakes e. stomach 2) The “sporotrichoid pattern” is best described as a/an: 5) Of the following, the tissue most likely to be involved by extracutaneous sporotrichosis is: a. acral ulcerating dermatosis a. central nervous system tissue b. ascending nodular lymphangitis b. endometrial tissue c. dependent edematous erythema c. osteoarticular tissue d. nodular intertrigo d. peritoneal tissue e. reticulated mucinosis e. retroperitoneal tissue 3) Of the following, the most common mucosal site to be involved with sporotrichosis is the: a. conjunctiva b. oral cavity c. urethra d. vagina e. vulva ANSWERS TO SELF-TEST REVIEW QUESTIONS: 1) a, 2) b, 3) a, 4) d, 5) c From the Departments of Pathology and Dermatology, UMDNJ-New Jersey Medical School, Newark, NJ Address for Correspondence: W. Clark Lambert, MD, PhD, Room C520 MSB, UMDNJ-NJMS, 185 South Orange Avenue, Newark, NJ 07101 • E-mail: [email protected] 221 July/August 2010 Volume 8 • Issue 4 COMMENTARY Sentinel Lymph Node Biopsy in Melanoma: The Gulf Between Presentation and Reality J. Meirion Thomas, MS, FRCP, FRCS P atients with newly diagnosed melanoma are frightened and vulnerable. At times of crisis, pessimism prevails and patients inevitably consider the worst possible outcome as one of the range of possibilities. That fear is compounded when they realize that, unlike most other malignancies, there is no systemic therapy that can prolong overall survival. In this frame of mind, patients are offered sentinel lymph node biopsy (SLNB), which, like ultrasound, in the best of hands,1 is an effective staging and prognostic tool.2 Inevitably, many patients accept SLNB in the hope that their disease proves to be sentinel node (SN)– negative; however, during the consent process, 3 other possible benefits of SLNB in melanoma may be mentioned that are either speculative or unproven. First, it is suggested that even if the disease is SN-positive, then immediate (early) lymphadenectomy vs delayed lymphadenectomy (when the nodal disease becomes palpable) may provide a survival advantage. This was a conclusion of the first Multicenter Selective Lymphadenectomy Trial (MSLT-1),2 but the observation is better explained by an incidence of false-positivity within the SN.3 Second, it is suggested that immediate vs delayed lymphadenectomy provides a benefit in disease-free survival (DFS), but this outcome is an inevitable consequence of the MSLT-1 trial design and does not amount to a therapeutic advantage for patients.4 Third, it is suggested that immediate lymphadenectomy is associated with fewer complications than delayed lymphadenectomy. This contribution will address these 3 issues and will argue that the benefits of SLNB in melanoma have been overstated. It will conclude that the procedure is merely a staging and prognostic tool and, for most patients, represents excessive and unnecessary treatment. diate lymphadenectomy comparing 2 computer-selected groups of patients matched for all other prognostic factors.5 Sadly, this survival advantage was not confirmed by the results of MSLT-1, which showed no difference in overall survival from the point of randomization, when immediate and delayed lymphadenectomy were compared in the context of a randomized controlled trial.2 The authors of these papers2,5 have declined to explain the large difference in survival between the 2 studies, but the most likely explanation is that some of the minimally involved SNs in the matched-pair analysis were prognostically false-positive, which means that they were destined for dormancy or destruction and not for progression to palpable nodal recurrence. Breast cancer is another disease where SN status directs treatment options, but microscopic tumor deposits in the SN are believed to be of no adverse prognostic significance and, according to size, are not an indication for completion lymphadenectomy nor necessarily for adjuvant systemic therapy.6 In biological terms, why should it be assumed that tiny subcapsular deposits of melanoma in the SN will behave so differently and require more radical treatment? False-Positivity in the SN The authors of MSLT-1 and others refuse to consider the possibility of false-positivity in the SN in melanoma, possibly because the statistical analysis of MSLT-1 assumes, without proof, that all positive SNs will inevitably progress to palpable nodal recurrence if not removed. The incidence of false-positivity in the SN in MSLT-1 at the third interim analysis has been estimated to be 24% for patients with intermediate thickness tumors and 34% for all patients entered into the trial.3 These figures suggest that a large number of patients may have been wrongly up-staged and may have had unnecessary completion lymphadenectomy and possibly unnecessary adjuvant therapy.3,4,7 It was the matched-pair analysis that first concluded that immediate vs delayed lymphadenectomy provided a survival advantage.5 In that study, a survival advantage of 22%, 32%, and 37% at 5, 10, and 15 years, respectively, was claimed for imme- In a remarkable paper, investigators8 describe performing delayed SLNB in 6 patients at a median of 3.9 years after wide excision of the primary melanoma. Two patients were found to have tiny subcapsular deposits of melanoma in the SN 4 years From the Department of Surgery, Royal Marsden Hospital and Imperial College, London, England Address for Correspondence: J. Meirion Thomas, MS, FRCP, FRCS, Department of Surgery, Royal Marsden Hospital, Fulham Road, London SW3 6JJ, UK • E-mail: [email protected] SKINmed. 2010;8:222–224 222 © 2010 Pulse Marketing & Communications, LLC July/August 2010 COMMENTARY and 4.9 years after the removal of their primary tumor (Figure). Were these patients destined for late nodal recurrence, or is this a perfect, if unintended, illustration of prognostic false-positivity? Disease-Free Survival Neither is it correct to claim, as was published,2 that immediate vs delayed lymphadenectomy provides an advantage in DFS. A benefit in DFS in the biopsy arm of MSLT-1 was inevitable due to trial design.4 The most likely site of first recurrence in patients with intermediate thickness primary melanoma (1.2 mm to 3.5 mm) is the regional lymph nodes, and, in the biopsy arm of MSLT-1, the patients most likely to develop nodal metastases were identified as being SN-positive at the outset and were treated with prophylactic lymphadenectomy. Therefore, it is inevitable that there are more regional node recurrences as site of first recurrence in the observation arm. When the incidence of first recurrence was broken down by site,2 nodal recurrence was more than 3 times more common in the observation arm than in the biopsy arm. Consequently, the advantage in DFS simply amounts to lead-time bias and is of no therapeutic advantage. This error was successfully challenged with the National Cancer Institute (NCI), who funded the MSLT trials. They issued guidance in June 20074 that stated the following: We agree that in a trial where one arm has nodal disease removed at the outset, and the other arm does not, calculation of either distant DFS or exclusion of nodal recurrences from the DFS calculation is appropriate. We have indicated to Dr Morton our belief that he should include a DFS analysis in the next update of study, that excludes nodal recurrences. Patients who die of melanoma succumb to distant metastasis; therefore, the most important end point for the fourth interim analysis and (fifth) final analysis of MSLT-1 is distant DFS. Despite this guidance from NCI, the authors of MSLT-1 and others have continued to stress the importance of DFS as previously calculated.9–13 It is surprising that this crucial error was not identified before publication.2 Comparing Morbidity Following Lymphadenectomy Patients are also encouraged to undergo SLNB for the following reason: We must also understand the safety and efficacy of salvage node dissection at the time of nodal relapse. Available data suggests that lymphadenectomy performed for clinically evident nodal disease is associated with more complications and poorer regional control rates than when the same procedure is done for microscopic disease.13 SKINmed. 2010;8:222–224 Figure. Delayed sentinel lymph node biopsy: subcapsular deposits of melanoma in the sentinel node 4 years (A) and 4.9 years (B) after wide excision of the primary tumor.8 Statements similar to this are used frequently by advocates of SLNB but are not evidence-based. The only randomized controlled trial of immediate vs delayed lymphadenectomy is MSLT1, which does not describe any greater morbidity following delayed lymphadenectomy in patients with intermediate thickness tumors.2 It is conceded that retrospective studies of therapeutic lymph node dissection do show a high incidence of complications, but this is due to the inclusion of patients who, for a variety of reasons, present with advanced, neglected nodal disease and who, unlike patients in the observation arm of MSLT-1, did not undergo regular follow-up, with or without ultrasound surveillance, after wide excision of their primary tumor. In other words, there is no evidence that patients who are closely observed by clinical or ultrasound surveillance following wide excision of their primary melanoma and who then develop palpable nodal recurrence, have more complications or more nodal basin recurrences following delayed lymphadenectomy. Excessive and Unnecessary Surgery Patients must understand that the SLNB procedure involves excessive and unnecessary surgery for the vast majority, and that SLNB alone carries a risk of immediate and late complications. We know that the incidence of SN-positivity is about 20% and that only 20% of SN-positive patients will have positive nonSNs on completion lymphadenectomy. Of 100 patients undergoing SLNB, at least 80 will be SN-negative and will have had an unnecessary operation. The prevailing opinion among SLNB experts is that all patients with positive SNs should have completion lymphadenectomy, irrespective of the tumor burden12,13; therefore, 16 patients will have unnecessary completion lymphadenectomy and only 4 of the original 100 patients will have the exact amount of surgery required. In terms of complications of SLNB alone, 13.8% of patients will have minor complications14 and 12% will have permanent lymphedema at 6 years.15 Patients should also understand that although SN status is an important 223 Sentinel Lymph Node Biopsy in Melanoma July/August 2010 COMMENTARY prognostic factor, it is no guarantee of remaining disease-free. In MSLT-1, approximately 17% of SN-negative patients had recurrence by 5 years and 9.7% had died of metastatic melanoma. Conclusions When considering complex management issues, physicians and patients have the right to expect accurate information from opinion leaders, untainted by personal preference, creative statistical interpretation, or unjustified extrapolation. Patients who consider the SLNB procedure should understand that it is a staging and prognostic tool and nothing more. There is no evidence at present that the procedure offers an advantage in DFS or that any subgroup of patients benefits from a survival advantage. There is also no evidence that delayed lymphadenectomy results in more complications than immediate lymphadenectomy, providing that patients are effectively followed-up after wide excision of their primary tumor by regular clinical examination, preferably with ultrasound surveillance. There has been a reluctance to disclose and discuss the arguments against SLNB in melanoma, and it has even been suggested that “… to deny the patient the opportunity of a successful SLNB may have medicolegal consequences.”16 Prognostic false-positivity in the SN in melanoma is potentially the most serious error in the SLNB hypothesis, a suggestion that advocates of the procedure refuse to consider at present. Some tiny deposits of melanoma in the subcapsular sinus of SNs are of no adverse prognostic significance and are destined for dormancy or destruction. Such patients are at risk for being wrongly up-staged with the inevitable consequences described. This risk has been compounded by the 2009 American Joint Committee on Cancer melanoma staging classification, which classifies all micrometastasis in the SN, including solitary tumor cells, as node-positive.17 Inevitably, this change, which is not evidencebased, will result in more unnecessary completion lymphadenectomies and will not enrich the pool of patients most suitable for studies of adjuvant therapy. This commentary highlights clinical, biological, and ethical issues relating to the initial treatment of melanoma. The term standard of care has no authenticity in medicine.18 Physicians and patients should focus on reality rather than presentation. References 1 Voit C, van Akkooi AC, Schafer-Hesterberg G, et al. Rotterdam criteria for sentinel node (SN) tumour burden and the accuracy of ultrasound (US)-guided fine-needle aspiration cytology SKINmed. 2010;8:222–224 224 (FNAC): can US-guided FNAC replace SN staging in patients with melanoma? J Clin Oncol. 2009;27:4994–5000. 2 Morton DL, Thompson JF, Cochran AJ, et al. Sentinel-node biopsy or nodal observation in melanoma. N Engl J Med. 2006;355:1307–1317. 3 Thomas JM. Prognostic false-positivity of the sentinel node in melanoma. Nat Clin Pract Oncol. 2008;5:18–23. 4 Thomas JM. Concerns relating to the conduct and statistical analysis of the Multicenter Selective Lymphadenopathy Trial (MSLT-1) in patients with melanoma. J Plast Reconstr Aesthet Surg. 2009;62:442–446. 5 Morton DL, Hoon DSB, Cochran AJ, et al. Lymphatic mapping and sentinel lymphadenectomy for early-stage melanoma. Ann Surg. 2003;238:538–549. 6 Langer I, Guller U, Viehl CT. Axillary lymph node dissection for sentinel lymph node metastases may be safely omitted in early-stage breast cancer patients. Ann Surg Oncol. 2009;16:3366–3374. 7 van Akkooi AC, de Wilt JH, Verhoef C, et al. Clinical relevance of melanoma micrometastases (<0.1 mm) in sentinel nodes: are these nodes to be considered negative? Ann Oncol. 2006;17:1578–1585. 8 Murughar P, Azawi K, Humzah D. The sleeper cells: delayed sentinel lymph node biopsy. J Plast Reconstr Aesthet Surg. 2007;60:1357–1360. 9 Cochran AJ, Thompson JF. Lymphatic mapping in sentinel node biopsy: the data unchanged by speculation. Arch Dermatol. 2008;144:687–689. 10 Morton DL, Elashoff R. Sentinel node biopsy: facts to clear the alleged clouds. Arch Dermatol. 2008;144:685–687. 11 Cochran AJ, Ohsie SJ, Binder SW. Pathology of the sentinel node. Curr Opin Oncol. 2008;20:190–195. 12 Balch CM, Morton DL, Gershenwald JE, et al. Sentinel node biopsy and standard of care for melanoma. J Am Acad Dermatol. 2009;60:872–875. 13 Sondak VK. Nonsentinel node metatases in melanoma: do they reflect the biology of the tumour, the lymph node or the surgeon? Ann Surg Oncol. 2009;16:2965–2967. 14 Kretschmer L, Thomas KM, Peeters S, et al. Postoperative morbidity of lymph node excision for cutaneous melanoma-sentinel lymphonodectomy versus complete regional lymph node dissection. Melanoma Res. 2008;18:16–21. 15 Estourgie SH, Nieweg OE, Valdes Olmos RA, et al. Review and evaluation of sentinel node procedures in 250 melanoma patients with a median follow-up of 6 years. Ann Surg Oncol. 2003;10:681–688. 16 Thompson JF, Scolyer RA, Kefford RF, et al. Melanoma management in 2007. Aust Fam Physician. 2007;36:487–488. 17 Balch CM, Gershenwald JE, Soong SJ, et al. Final version of 2009 AJCC melanoma staging and classification. J Clin Oncol. 2009;27:6199–6206. 18 Strauss DC, Thomas JM. What does the medical profession mean by “standard of care”? J Clin Oncol. 2009;27:e192–e193. Sentinel Lymph Node Biopsy in Melanoma July/August 2010 Volume 8 • Issue 4 COMMENTARY Sentinel Lymph Node Biopsy in Melanoma: Coping With Incomplete Information; Call for Further Investigations W. Clark Lambert, MD, PhD T he commentary in this issue of SKINmed, “Sentinel Lymph Node Biopsy in Melanoma: The Gulf Between Presentation and Reality,”1 makes a very valid point: that in evaluating sentinel lymph node biopsies (SLNBs), statistical analyses performed to date have lumped together all positive biopsies, regardless of whether only a few cells (ie, a “micrometastasis”) or larger masses of tumor cells have been detected. Some or all of those biopsies read as positive on the basis of only small tumor volumes may not be prognostically significant, and this may, in turn, lead to unnecessary surgery to remove whole fields of lymph nodes with attendant morbidity. Limitations This may also limit the value of SNLBs as a starter. The author correctly points out that breast surgeons have recommended that small metastases in lymph node biopsies may not be considered significant, and may not recommend additional surgery in some instances. It may also be self-serving for the physician to recommend SLNB, as well as additional surgery, if the biopsy is positive, even with a micrometastasis. He or she becomes more important, and he or a colleague gets paid for the surgery. The problem is that no one knows whether such micrometastases in SNLBs of melanomas can or should be ignored. The studies simply have not been performed as of this date. Thus, the physicians recommending further surgery after detecting such metastases may in fact be benefitting the patient, even if they are not without bias in recommending this course of action. Recommendations What is needed are additional studies to examine the point raised by the author. Until these are done, it may indeed be proper to advise patients differently who face the prospect of a possible SLNB. They are indeed “frightened and vulnerable,” but with good reason. Thus, a recommendation for more restraint in advising the patient needs to be carefully considered. It may be appropriate for the patient to be advised differently before giving consent for an SNLB. It may also be advisable for the patient to be advised differently if a micrometastasis is found. The patient should be told objectively of the potential risks and benefits at each step, allowing them to make decisions based on the best evidence available. They may well still opt for the procedure, and then may or may not opt for further surgery if a micrometastasis is found. One of the major problems with SNLB is that it is still relatively new, and much relevant data have not yet been compiled and analyzed. We need to give patients our best information and advice in the meantime. Conclusions Knowing what I know, I would probably accept SNLB, even though I may well have less faith in it than the physician who recommended it to me. If a metastasis is found it may be larger than a micrometastasis, making the decision for further surgery less challenging. If I were a patient in this situation, even if informed that SNLB has value only as a staging procedure, I might opt for it simply so that I could have better knowledge of my prognosis. This may not only affect my anxiety level, but also influence decisions such as whether to have more children or to hurry up in writing that “great American novel.” We need to give patients the best advice we can and allow them to make such decisions. Most importantly, as much as possible, we need to remove our own self interests from all of this, as the accompanying commentary states very clearly. I know a name for this, it is called “honesty.” Reference 1 Thomas JM. Sentinel lymph node biopsy in melanoma: the gulf between presentation and reality. SKINmed. 2010;8:222–224. From the Departments of Pathology and Dermatology, UMDNJ-New Jersey Medical School, Newark, NJ Address for Correspondence: W. Clark Lambert, MD, PhD, Room C520 MSB, UMDNJ-NJMS, 185 South Orange Avenue, Newark, NJ 07103 • E-mail: [email protected] SKINmed. 2010;8:226 226 © 2010 Pulse Marketing & Communications, LLC July/August 2010 Volume 8 • Issue 4 New Therapy Update William Abramovits, MD; Aditya K. Gupta, MD, Section Editors Zyclara (Imiquimod) Cream, 3.75% Aditya K. Gupta, MD;1,2 Elizabeth A. Cooper, HBSc;2 William Abramovits, MD3 Description Zyclara has recently been approved by both the US Food and Drug Administration (FDA) and Health Canada as a new topical therapy for multiple actinic keratoses (AKs) of the face and balding scalp. Topical imiquimod 5% cream (Aldara cream, 5%) has been available for many years as a 25 cm2 field treatment for AKs. Dosage uses application 2 times per week for periods of 8 to 10 hours for 16 weeks.1,2 The lower concentration of imiquimod in Zyclara allows for a daily-use schedule and application over larger areas than the 5% cream, with a much shorter application period of 6 weeks. It may also increase antigen-presenting cell antigen presentation to T cells, leading to a strong T-helper type I immune response.3 Pharmacokinetics Mean peak serum drug concentration for patients with AK (n=17) was approximately 0.323 ng/mL at the end of a 3-week treatment period, using once-daily applications of Zyclara (2 packets, 18.75 mg) to the entire face and/or balding scalp.4,5 Steady state levels were achieved in 2 weeks, and the Tmax ranged from 6 to 9 hours.4 Clinical Studies AK lesions appear in areas of sun-damaged skin and have some potential to transform into squamous cell carcinoma, although there are currently no markers to indicate which lesions may become malignant.3 Treatment of all AKs is therefore prudent in prevention of more serious outcomes. The mode of action of imiquimod is stimulation of immune response to destroy abnormal cells within the field of drug application. The resultant immune response to imiquimod can also reveal subclinical lesions not previously detected in the sun-damaged areas, providing effective early destruction that may help sustain clearance rates post-treatment.3 Overall, imiquimod cream provides good field destruction of multiple AKs. Clinical efficacy was studied for both a 2.5% and a 3.75% formulation of imiquimod (Zyclara), compared with placebo (identical excipients to the active formulations). The treatment regimen for all arms was once-daily application for two 2-week cycles, with a 2-week no-treatment interval between cycles.6 Eligible patients had 5 to 20 visible or palpable AK lesions in an area >25 cm2 on either the face or the balding scalp, but not both. Patients applied cream to either the total face or the total balding scalp, but not both, as selected by the investigator. A total of 479 patients were enrolled in the trial (3.75% cream = 160 patients; 2.5% cream = 160 patients; and placebo = 159 patients). Clinical Pharmacology Efficacy Mechanism of Action Although the mechanism of action of imiquimod has not been studied or conclusively defined in AK, there are many known actions produced by imiquimod that may be involved. Imiquimod is a toll-like receptor-7 agonist and has been shown to induce the release of interferon-a and other cytokines from human monophages/macrophages and keratinocytes in vitro.3,4 The upregulation of cytokines may enhance apoptosis of neoplastic epidermal cells and upregulation of DNA repair enzymes after UV damage.3 Final efficacy was evaluated 8 weeks after the end of treatment.6 Primary efficacy measured was complete clearance, defined as proportion of patients with zero lesions in the treatment area. Complete clearance was found in 35.6% of patients in the Zyclara group, vs 30.6% in the 2.5% imiquimod group and 6.3% in the placebo group. Both active formulations showed significantly higher complete clearance than placebo (P<.001 for pairwise comparison vs placebo). Considering partial clearance (≥75% reduction in AK lesions compared with baseline), the clearance rates were 59.4% for Zyclara, 48.1% for 2.5% imiquimod, and 22.6% for placebo. From the Department of Medicine, University of Toronto, Toronto, Canada;1 Mediprobe Research Inc, London, Ontario, Canada;2 and the Department of Medicine, Baylor University Medical Center, and Department of Dermatology & Family Practice, The University of Texas Southwestern Medical School, Dallas, Dermatology Treatment and Research Center, Dallas, TX3 Address for Correspondence: Elizabeth A. Cooper, HBSc, Mediprobe Research Inc, 645 Windermere Road, London, Ontario, N5X 2P1 Canada • E-mail: [email protected] SKINmed. 2010;8:227–229 227 © 2010 Pulse Marketing & Communications, LLC July/August 2010 NEW THERAPY UPDATE Table. Local Skin Reactions in the Treatment Area as Assessed by the Investigator Zyclara (n=160) Placebo (n=159) All Grades Severe All Grades Severe Erythema 154 (96%) 40 (25%) 124 (78%) 0 (0%) Edema 120 (75%) 9 (6%) 31 (19%) 0 (0%) Weeping/exudate 81 (51%) 9 (6%) 6 (4%) 0 (0%) Flaking/scaling/dryness 147 (92%) 13 (8%) 123 (77%) 2 (1%) Scabbing/crusting 149 (93%) 22 (14%) 72 (45%) 0 (0%) Erosion/ulceration 99 (62%) 17 (11%) 14 (9%) 0 (0%) Again, both active treatment groups showed significantly higher partial clearance rates than placebo (P<.001), and Zyclara showed higher partial clearance than the 2.5% imiquimod (P=.047). Patients receiving Zyclara showed a higher frequency of need for a rest period during treatment, with 10.6% (17 of 160) requiring at least 1 treatment rest period, compared with 6.9% in the 2.5% cream group and 0% in placebo.6 Safety/Adverse Events In postmarketing surveillance of imiquimod 5% cream, rare reports have been received of either onset or exacerbation of autoimmune conditions (including thyroiditis, multiple sclerosis, spondyloarthropathy, psoriasis, and ulcerative colitis).4 No unexpected safety issues were found in any group, and vital sign measure/physical examination did not show any significant safety issues during the trial.6 The most frequently reported adverse events (AEs) on nonapplication sites with use of 3.75% imiquimod were headache (6.3%), fatigue (4.4%), nausea (3.8%), and pyrexia (3.1%). Treatment-related AEs were reported in 19.4% of the 3.75% cream group (31 of 160), compared with 11.9% in the 2.5% cream group and 2.5% in the placebo group. One case of severe diarrhea was reported as probably related to use of Zyclara. Local skin reactions (LSRs) were independently collected of other AEs/application site reactions (ASRs) and were reported in almost all patients using Zyclara4–6 (Table). Severe erythema was found in 25.2% of Zyclara patients, with severe scabbing/ crusting in 13.8%. The other LSR groups had severe grades in approximately 5% to 10% of patients (Table). The mean erythema score increased during the treatment periods but was reduced below baseline level during the follow-up period for both imiquimod groups.6 ASRs were reported in 10.6% (17 of 160) of the 3.75% cream group, compared with 6.3% in the 2.5% cream group and 1.3% in the placebo group.6 Pruritus was the most frequently reported ASR in the Zyclara group (4.4%), followed by irritation (3.1%), pain (3.1%), and swelling (1.3%). Of the 6 patients who discontinued the study due to AEs, 2 were in the Zyclara group.6 Only 2 AEs leading to discontinuation were considered related to study treatment: 1 Zyclara patient had headache, fatigue, pain, and application site pain, and 1 placebo patient had headache. SKINmed. 2010;8:227–229 A second Zyclara study used a similar design to investigate two 3-week application cycles, with a 3-week no-treatment interval between cycles, vs 2.5% imiquimod cream and placebo.7 Although the safety profiles were similar between 2-week and 3-week cycles, the increased duration of use did not appear to increase efficacy compared with the 2-week cycle. Use of imiquimod may reveal the presence of subclinical AKs during therapy. This was noted as a transient increase in AK counts during trial therapy and did not reduce treatment efficacy.6,7 This effect has been noted in previous imiquimod studies. The clearance of subclinical lesions may result in sustained lesion clearance and could be an advantage compared with other treatment methods that do not reveal subclinical lesions, reducing the need for future treatment. Almost half of patients treated with Zyclara (78 of 160) were 65 years and older. No overall differences in safety or effectiveness were detected in these patients vs younger patients, although greater sensitivity of some older individuals cannot be ruled out. Indication, Dosage, and Administration Zyclara is indicated for the topical field (area) treatment of multiple clinically typical, visible, or palpable actinic keratoses, presented at start of therapy or revealed during therapy, of the face or balding scalp in adults.4,5 The cream is provided in 250-mg single-dose packets containing 9.4 mg of imiquimod (3.75% w/w). Up to 2 packets are applied once daily before bedtime 228 Zyclara (Imiquimod) Cream, 3.75% July/August 2010 NEW THERAPY UPDATE to the affected treatment field for 2 treatment cycles of 2 weeks each, separated by a 2-week no-treatment period. Prior to application, patients should wash the treatment area with mild soap and water and allow the area to dry thoroughly. A thin film of imiquimod should be applied to the entire treatment area and rubbed in until the cream is no longer visible, and hands should be washed after application. Use near eyes, lips, and nostrils should be avoided, and the application site should not be occluded. Zyclara should be left on the skin for approximately 8 hours overnight and then removed by washing the area and hands with mild soap and water. Most patients will experience some LSRs, which may include erythema, scabbing/crusting, flaking/scaling/dryness, and edema. These LSRs may require an interruption of dosing for several days if the reaction is severe or produces intolerable patient discomfort. Treatment may be continued after consulting with a physician. The dosage period should not be prolonged to make up for missed doses and rest periods. Safety has not been established in pregnant women, and use should be restricted to cases where the potential benefit outweighs the potential risk to the fetus. It is not known whether topical imiquimod is excreted in human breast milk, therefore caution should be used in nursing women. The maximum treated area tested is approximately 200 cm2. Safety and efficacy of application over larger areas has not been established and is not recommended. Discussion The new imiquimod formulation provides a lower potency preparation and a less taxing protocol of therapy for the patient (2 weeks on, 2 weeks off, 2 weeks on, and stop). This results in a shorter course of therapy, with no loss of efficacy in eradicating actinic keratosis. This formulation should be a welcome addition to the dermatologist’s armamentarium for the management of actinic damage. References 1 Aldara (imiquimod) cream, 5% [product monograph]. London, ON, Canada: Graceway Pharmaceuticals; March 04, 2009. Safety and Precautions Some patients may experience flu-like signs and symptoms including fatigue, nausea, fever, myalgias, arthralgias, and chills preceding or accompanying LSRs. A patient assessment should be considered, and dosing may need to be interrupted or adjusted. Patients should minimize or avoid natural or artificial sunlight exposure during treatment, due to concerns of heightened sunburn susceptibility and reports of shortened tumor formation time in an animal photocarcinogenicity study. Protective clothing (eg, hat) should be used during treatment. Safety in immunosuppressed patients has not been established, and imiquimod should be used with caution in patients with preexisting autoimmune conditions including thyroiditis, multiple sclerosis, spondyloarthropathy, psoriasis, and ulcerative colitis. SKINmed. 2010;8:227–229 229 2 Aldara cream, 5% (imiquimod) [prescribing information]. Bristol, TN: Graceway Pharmaceuticals, LLC; April 2009. 3 Gaspari AA, Tyring SK, Rosen T. Beyond a decade of 5% imiquimod topical therapy. J Drugs Dermatol. 2009;8:467–474. 4 Zyclara (imiquimod) cream, 3.75% [product monograph]. London, ON, Canada: Graceway Pharmaceuticals; December 31, 2009. 5 Zyclara (imiquimod) cream, 3.75% [product monograph]. Bristol, TN: Graceway Pharmaceuticals, LLC; March 2010. 6 Swanson N, Abramovits W, Berman B, et al. Imiquimod 2.5% and 3.75% for the treatment of actinic keratoses: results of two placebo-controlled studies of daily application to the face and balding scalp for two 2-week cycles. J Am Acad Dermatol. 2010;62:582–590. 7 Hanke CW, Beer KR, Stockfleth E, et al. Imiquimod 2.5% and 3.75% for the treatment of actinic keratoses: results of two placebo-controlled studies of daily application to the face and balding scalp for two 3-week cycles. J Am Acad Dermatol. 2010;62:573–581. Zyclara (Imiquimod) Cream, 3.75% July/August 2010 Volume 8 • Issue 4 Perils of Dermatopathology W. Clark Lambert, MD, PhD, Editor Newtonian Dermatopathology: When the Reaction to a Lesion Obfuscates the Diagnosis Javier Rojas, MD;1 Navér Sarkissian, MD, PhD;1,2,3 Debra S. Heller, MD;1 W. Clark Lambert, MD, PhD1,2,3 S ir Isaac Newton’s third law states that for every action there is an equal and opposite reaction.1 The same may be said of many biological phenomena, except that the reaction is rarely equal and may, in fact, vastly exceed the impetus. Causes include trauma, stasis, and masses, including tumors. Many of the latter, such as desmoplastic basal cell carcinomas and melanomas, induce marked connective tissue reactions. Other such reactive phenomena include vascular reactions, several types of inflammation, and reactions including granulation tissue. In the preceding column in this series we examined ways in which the latter, on the surface, may obfuscate diagnosis of a skin or mucus membrane biopsy.2 We now consider how such reactions in deeper tissues may produce similar diagnostic misdirection. A Masson tumor may occur anywhere a venous thrombus may arise. It commonly occurs in the hemorrhoidal veins. We have previously reported its occurrence on the vulva.3 Case 2 A painless, nontender deep nodular lesion on the thigh of a 38-yearold man was biopsied near its edge. Histopathologic examination showed a somewhat storiform spindle cell lesion (Figure 2), which was initially suspected to be a possible dermatofibrosarcoma protuberans. A CD34 immunohistochemical stain, which is characteristically positive in dermatofibrosarcoma protuberans, was reactive in lesional cells (Figure 3), consistent with this diagnosis. This stain also Case 1 A painless, slightly tender bluish nodule on the upper lip of a 48-yearold human immunodeficiency virus–positive woman was biopsied and read by the referring pathologist as an angiosarcoma, possibly Kaposi sarcoma. Review of slides received in consultation showed a poorly defined nodular lesion composed of numerous dissecting vascular channels lined by a single layer of prominent endothelial cells (Figure 1). Further evaluation revealed overlying lichen simplex chronicus, indicative of chronic trauma or manipulation, and areas in which the lesion was bounded by a thin remnant of a venous wall. The final diagnosis was Masson tumor (Masson pseudotumor; intravascular papillary endothelial hyperplasia). A Masson tumor is formed when a venous thrombus is invaded by normal reactive endothelial cells attempting to recanalize the lesion. Diagnosis in early lesions is facilitated by the presence of fibrin within the connective tissue. Diagnosis in later lesions is made by identification of the remnant of a venous wall at the border of the lesion, but chronic trauma may cause the thrombus and, therefore, the reactive lesion to extend beyond the vessel wall in places. Thus the lesion is not actually a tumor (neoplasm) and is not papillary, and the terms Masson tumor and intravascular papillary endothelial hyperplasia are not really appropriate. Figure 1. Case 1: Dissecting endovascular channels (Hematoxylin and eosin stain, magnification ×380). From the Department of Pathology, Divisions of Anatomic Pathology1 and Dermatopathology2 and the Department of Dermatology,3 University of Medicine and Dentistry of New Jersey, New Jersey Medical School, Newark, NJ Address for Correspondence: W. Clark Lambert, MD, PhD, Room C520 MSB, UMDNJ-NJMS, 185 South Orange Avenue, Newark, NJ 07103 • E-mail: [email protected] SKINmed. 2010;8:231–233 231 © 2010 Pulse Marketing & Communications, LLC July/August 2010 Perils of Dermatopathology Figure 2. Case 2: Spindle cells forming a vaguely storiform pattern (Hematoxylin and eosin stain, magnification ×380). Figure 3. Case 2: CD34 immunohistochemical staining of spindle cell lesion (magnification ×380). histochemical staining for smooth muscle actin within this portion of the lesion (Figure 4). The final diagnosis was leiomyoma with a peripheral vascular reaction. Although leiomyomas may be tender, many lack this characteristic. Notifying the pathologist that the lesion was biopsied at its periphery may have helped in its evaluation. Cutaneous leiomyomas may arise from multiple sites within the skin and subcutis, including blood vessels and pilar erectus muscles, and may occur anywhere. Discussion The issue of whether a lesion or tissue reacting to it is biopsied is very much a matter of discussion between the dermatopathologist and the clinician, because, unless an excisional biopsy is performed, the clinician chooses which portion of the lesion to biopsy. In addition to obtaining diagnostic tissue, this decision is influenced by factors such as cosmetic result and other disabilities resulting from the biopsy. If a lesion is biopsied at its edge, or at another special site, this information needs to be communicated to the pathologist. Figure 4. Case 2: Smooth muscle actin immunohistochemical staining of different area of spindle cell lesion (magnification ×380). decorates endothelial cells, however, and immunohistochemical staining with CD31, which stains only the latter, was also positive. Further examination of deeper levels revealed a part of the lesion consistent with a leiomyoma, and this diagnosis was confirmed by immunoSKINmed. 2010;8:231–233 As the dermatopathology laboratory continues to become more remote from the clinical setting, the lines of communication between clinician and dermatopathologist may become more tenuous. Use of electronic medical records, whatever their other advantages and limitations, may facilitate this process, provided that a complete and accurate record of the biopsy procedure is entered into the patient’s record and this portion of the chart is transmitted to the pathologist. 232 Newtonian Dermatopathology July/August 2010 Perils of Dermatopathology References 1 Guicciardini N. Isaac Newton on Mathematical Certainty and Method. Cambridge, MA: The MIT Press; 2009:422. 2 Sarkissian N, Patel PP, Fleeger EJ, et al. Anatomically correct, histopathologically correct, diagnostically disastrous biopsies. Skinmed. 2010;8:98–99. 3 Maghari A, Lambert WC, Sherman N, et al. Intravascular papillary endothelial hyperplasia (Masson’s tumor) manifesting as a cystic vulvar lesion. J Lower Gen Tract D. In press. HISTORICAL DIAGNOSIS & Treatment Diagnosis and treatments have advanced over the past century. This feature depicts conditions from a collection of steroptic cards published in 1910 by The Stereoscopic Skin Clinic, by Dr. S. I. Rainforth. Synonyms: Pediculosis vestimenti seu vestimentorum; Phthiriasis capitis; Vagabond’s disease; Body-lousiness. DIAGNOSIS: The discovery of a louse or the nits in the seams of the underclothes is sufficient, but even in their absence,—as when the patient has recently changed his clothing,—the distribution of the lesions, the punctiform hemorrhages, parallel excoriations and pigmentation make the diagnosis comparatively easy. TREATMENT: Attention should be directed mainly toward the clothing and bed linen, which are to be immersed in boiling water or subjected to a temperature of 165° or 170° F. in an oven. To destroy any nits that may be present on the body, the latter should be anointed with a 20 per cent ointment of staphisagria, made by adding two drachms of the freshly powdered seed to the ounce of hot lard, which is then to be strained and cooled. SKINmed. 2010;8:231–233 233 Newtonian Dermatopathology Aklarus Multi-Wavelength Phototherapy System The Aklarus is a multi-wavelength phototherapy system FDA cleared and medically proven to provide a drug-free and pain-free treatment for acne, photodamaged skin and wrinkles. HA90D Chair Shown with optional contour seat and back and removable fold-down armrests. See Before and After Photos and Video at www.HillTherapy.com The Versatile, Affordable Chair for Dermatology! $9650 $8150 Includes cart, treatment arm and accessories Working closely with a leading dermatologist, Hill Laboratories has designed the ideal chair for dermatology... • Electrically controlled height - 22”-35” • Standard width - 26” or 24” • Length - 70" • 2.5” Foam top • Electric Lift back • Full-width foot section-locks at any angle • Adjustable headrest • Standard Flat Cushions • Paper retainer on headpiece • Paper roll bracket on foot cushion • One-year warranty Starts at $3495 HA90D fully reclined with matching stool Since 1945 Optional Tapered-Top & headpiece 90ALB for Aesthetics starts $3175 Call Today! 1-877-445-5020 www.HillLabs.com Optional Removable, FoldDown Armrests July/August 2010 Volume 8 • Issue 4 Congress Report Marcia Ramos-e-Silva, MD, PhD, Section Editor Highlights From the 7th EADV Spring Symposium, Cavtat, Croatia, May 13–16, 2010 Jasna Lipozenčić, MD, PhD, Chairperson T he 7th Spring Symposium of the European Academy of Dermatology and Venereology (EADV) took place with more than 2000 participants, gathering at the Congress Centre of the Hotel Croatia in Cavtat (antique Epidaurus) near Dubrovnik (antique Ragusa and called “South Pearl of the Adriatic Sea”). The locale is located on the beautiful Croatian coast, which boasts of 1244 islands and peninsula sand overwhelmed with rich and unique vegetation. matology and Venereology” and by Professor Stefan Beissert entitled “Nowdays and Future of Dermatovenereological Research.” Background This 7th EADV Spring Symposium was organized under the high auspice of the president of the Republic of Croatia, Professor Ivo Josipović. Participants came from 78 countries worldwide. We wanted to achieve harmony in dermatology and venereology, and we succeeded with a successful blend of the scientific program and the social events. The president of EADV, Professor Andreas Katsambas, expressed his sincere thanks to each and every one of the organizers and board members for their support and valuable input for Cavtat (Figure 1). He congratulated them for “their amazing job in organizing such a terrific meeting.” There were positive comments from the many who attended the meeting, giving proof of its success. “Everything was more than perfect” (Figure 2). Figure 1. Jasna Lipozenčić (center, left) and Andreas Katsambas (center, right) during the welcome reception with Penny Emmanouil (far left) and Electra Nikolaidau (far right). In the opening ceremony, the traditional good spirit of Dubrovnik was demonstrated by the folk dance Ensemble Linđo with two performances and by the renaissance Ragvseum Ensemble Plazzarius with three presentations: La Magdalena, Branle, and Troto. The biggest confirmation for the organizers of the 7th EADV Spring Symposium was the compliment paid that we have done for Croatian dermatology today just as the famous Academician Franjo Kogoj (1894–1983) did in his time. Scientific Program The highlights of the Symposium were the opening lectures by Professor Amir Muzur entitled “Milestones in the History of Croatian Der- Figure 2. From left to right: Bruce Thiers, Stefan Beissert, Angela Robinson, and Steingrimur Davidsson at the opening reception. From the University Department of Dermatology and Venereology, Zagreb University Hospital Center and School of Medicine, Zagreb, Croatia Address for Correspondence: Jasna Lipozenčić, MD, PhD, Professor, University Department of Dermatology and Venereology, Zagreb University Hospital Center and School of Medicine, Salata 4, 10000 Zagreb, Croatia • E-mail: [email protected] SKINmed. 2010;8:235–237 235 © 2010 Pulse Marketing & Communications, LLC July/August 2010 CONGRESS REPORT Friday, May 14, 2010, had a packed program with: oPractical Considerations in Cutaneous Lymphomas oHair and Nail Diseases •Free Communications •Symposia •Case Report Sessions •Scholarship Ceremony oAcne and Rosacea •Continuing Medical Education/Continuing Professional Development oBullous Diseases Revisited oSkin Diseases in the Mediterranean •Media Committee •Workshops •Scientific Programming Committee oApproaches to Wound Healing and Leg Vein Treatment •Fostering Trainee Committee oManagement of Chronic Urticaria •Euromelanoma Meeting oVitiligo and Pigmentary Disorders •Fostering Skill Specialists Committee On Saturday, May 15, 2010, the program was just as exciting: •Statutes Committee •Forum Session •Free Communications •Update on Melanoma Management •Poster Forum (awards given to presenters from Denmark, Iran, and Moldavia) •Psoriasis •Case Report Sessions •Skin Conditions and Endocrinology •President’s Symposium •Workshops oMetabolic Comorbidities and Psoriasis oSyphilis: The Resurgence of an Old Problem oPearls in Dermatological Surgery oNovel Drugs and Adverse Reactions in Dermatovenereology •Plenary Sessions oCumulative Experience From the Sexually Transmitted Disease Clinic oMelanocytes and Melanogenesis: News to Tell •Symposia oAllergy, Environment, and the Skin oSkin Clues of Systemic and Connective Tissue Diseases oBrain-Skin-Axis oImmunotherapy for Skin Diseases in the Molecular Era •Satellite Symposia oPhotodermatology oAtopic Dermatitis oNonsurgical Treatment of Non-Melanoma Skin Cancer oAzithromycin in Dermatovenereology o Optimizing Psoriasis Treatment Outcomes With Adalimumab oDilemmas in Prevention of Superinfections in Dermatology oGeneral Topics in Sirolimus oNew Approach in Sun Protection for Allergy-Prone Skin oTopical Retinoids in Treatment of Acne oHuman Immunodeficiency Virus Infection in Dermatology oDermatomycoses •Workshops oLaser Therapy oSexually Transmitted Infections (STIs) oPediatric Dermatology oWhat’s New in Photoprotection in 2010? oPsyche and the Skin oThe Human Papillomavirus (HPV) Vaccine—Impossible Without Dermatology and Venereology oHPV in Dermatovenereology oFacial Rejuvenation •Plenary Sessions •Focus Sessions oBotulinum Toxin: Use and Misuse oNovel Imaging Techniques for Diagnosis of Skin Disorders oThe Skin and Internal Malignancy oExogenous Acne Revisited oTest Yourself in Dermoscopy oSTIs: Progress, Challenges, and Opportunities •Focus Sessions •Forum Sessions SKINmed. 2010;8:235–237 236 Highlights From the 7th EADV Spring Symposium July/August 2010 CONGRESS REPORT oManaging Adult-Onset Acne oSTIs and Adolescence oOffice-Based Cryotherapy oPractical Consideration in Treating Cutaneous Lupus Erythematosus •Forum Sessions oBiologicals in Psoriasis: When and Which to Use? oDermatoses in the Genital Area Closing Ceremony •What’s New Sessions Figure 3. From left to right: Jasna Lipozenčić and Andreas Katsambas hand over the EADV flag to Peter Arenberger, the next EADV Spring Symposium chairperson. The next EADV Spring Symposium will be held April 14–17, 2011, at Karlovy Vary, Czech Republic. oWhat’s New in Clinical Dermatology oWhat’s New in Venereology oWhat’s New in Pediatric Dermatology Conclusions As one participant remarked: “It was a wonderful meeting! Perfectly organized, good science, nice atmosphere. I not only enjoyed the EADV Spring Symposium but I also found the organization to be perfect” (Figure 3). VINTAGE LABEL Courtesy of BuyEnlarge, Philadelphia, PA SKINmed. 2010;8:235–237 237 Highlights From the 7th EADV Spring Symposium July/August 2010 Volume 8 • Issue 4 CASE STUDY Vesna Petronic-Rosic, MD, MSc, Section Editor Segmental Cutaneous Piloleiomyomata Robert H. Cook-Norris, MD;1,2 Adrian O. Rodriguez, MD;2 Bradley T. Kovach, MD;2 Alan S. Boyd, MD;2 John A. Zic, MD2 A 60-year-old white man seen in consultation for “chronic zoster” presented with a 30-year history of persistent, painful cutaneous lesions on his right flank. His pain was episodic and exacerbated by physical touch and emotional stress. He denied lesion sensitivity to cold or heat. Application of capsaicin cream had been without benefit. There was no family history of similar lesions. Physical examination revealed multiple, pink to violaceous, firm, tender nodules (3–7 mm) arising on the right flank in a segmental distribution (Figure 1). No other lesions were noted. A biopsy specimen showed findings of dermal proliferation of spindle-shaped cells with eosinophilic cytoplasm and blunt-ended nuclei without cytologic atypia (Figure 2A and Figure 2B). All of these findings were compatible with a diagnosis of segmental cutaneous piloleiomyomata. He declined surgical or medical intervention. C utaneous piloleiomyomata (CPL) are benign smooth muscle tumors most commonly presenting as multiple, grouped, red to dark brown, firm, dermal papules and nod- Figure 1. Multiple pink nodules in a segmental distribution on the right flank. ules, typically no larger than 1.5 cm.1,2 An unusual and suggestive clinical finding is sharp, shooting pain, resulting from cold contact, emotional stress, or physical trauma.3 CPL tends to occur in the second and third decades without sex predilection.3 Common lesion locations include the extensor surfaces of the extremities, trunk, and face. Linear or segmental distribution is rare. Some authors have described the segmental pattern as zosteriform leiomyomatosis but, as stated by some experts,4 the term segmental is preferred since the lesions do not follow a true dermatomal distribution. The pathophysiology of segmental cutaneous leiomyomatosis (SCL) is unknown but may represent an autosomal dominant genetic mosaicism.5 SCL has since been divided into two distinct segmental patterns, type 1 and 2, based on a loss of wild-type allele(s) following a mutational event.4 Type 1 SCL manifests as purely segmental lesions reflecting heterozygosity for the underlying mutation. In type 2 SCL, a postzygotic mutation in a heterozygous embryo results in a loss of heterozygosity, leading to a segmental pattern superimposed on disseminated areas of involvement. Our patient, with only segmental lesions, would best fit type 1 SCL. The etiology of the pain associated with CPL is unclear but thought to be either the result of smooth muscle contraction, an increased number of nerve bundles, or pressure on surrounding cutaneous nerves.3,6 Treatment depends on the severity of symptoms and extent of skin involvement. Surgical excision is possible in patients with limited skin involvement. Recurrence is common, however, particularly in patients with multiple lesions.1 If extensive involvement is present, From the Department of Dermatology, Mayo Clinic College of Medicine, Rochester, MN;1 and the Department of Dermatology, Vanderbilt University Medical Center, Nashville, TN2 Address for Correspondence: Alan S. Boyd, MD, Vanderbilt Health - One Hundred Oaks, 719 Thompson Lane, Suite 26300, Nashville, TN 37204 • E-mail: [email protected] SKINmed. 2010;8:238–239 238 © 2010 Pulse Marketing & Communications, LLC July/August 2010 CASE STUDY medications including nifedipine, nitroglycerin, and phenoxybenzamine have been used with limited success.7 This rare neoplasm is likely clinically underrecognized,7 particularly when presenting in a segmental distribution. Increased awareness of this unusual presentation is important due to the associated risks of uterine fibroids and aggressive renal malignancies in these patients and their offspring if germline mosaicism is present. References 1 Smith CG, Glaser DA, Leonardi C. Zosteriform multiple leiomyomas. J Am Acad Dermatol. 1998;38:272–273. 2 Sahoo B, Radotra BD, Kaur I, et al. Zosteriform pilar leiomyoma. J Dermatol. 2001;28:759–761. 3 Agarwalla A, Thakur A, Jacob M, et al. Zosteriform and disseminated lesions in a cutaneous leiomyoma. Acta Derm Venereol. 2000;80:446–458. 4 Lang K, Reifenberger J, Ruzicka T, et al. Type 1 segmental cutaneous leiomyomatosis. Clin Exp Dermatol. 2002;27:649–650. 5 Happle R. Loss of heterozygosity in human skin. J Am Acad Dermatol. 1999;41:143–161. 6 Raj S, Calonje E, Kraus M, et al. Cutaneous pilar leiomyoma: clinicopathologic analysis of 53 lesions in 45 patients. Am J Dermatopathol. 1997;19:2–9. 7 Holst VA, Junkins-Hopkins JM, Elenitsas R. Cutaneous smooth muscle neoplasms: clinical features, histologic findings, and treatment options. J Am Acad Dermatol. 2002;46:477–490. Figure 2. Photomicrograph showing abundant spindle-shaped smooth muscle cells (hematoxylin and eosin original magnification [A] ×4 and [B] ×40). VINTAGE LABEL Courtesy of BuyEnlarge, Philadelphia, PA SKINmed. 2010;8:238–239 239 Segmental Cutaneous Piloleiomyomata July/August 2010 Volume 8 • Issue 4 CASE STUDY Vulvoperineal Crohn’s Disease: Response to Metronidazole Aida Khaled, MD;1 Nadia Ezzine-Sebai, MD;1 Becima Fazaa, MD;1 Faten Zeglaoui, MD;1 Rachida Zermani, MD;2 Mohamed Ridha Kamoun, MD1 A 46-year-old woman with a medical history of chronic juvenile arthritis with bilateral prosthetic hips presented with vulvoperineal ulcerations of 3 years’ duration. There was no diarrhea or recent weight loss. Cutaneous examination showed asymmetrical vulvar edema of the labia minora and labia majora with deep and linear ulcerations having verrucous borders located on the inguinocrural regions and the buttocks fold (Figure 1). On physical examination there was bilateral limited mobilization of the hips. A biopsy specimen was taken from the border of the vulvar ulceration and histologic examination showed under a hyperplasic epidermis an epithelioid granuloma with multinucleated giant cells of the dermis without caseification. Laboratory analyses and results from chest x-ray were normal. Results for Koch bacilla in the spittle, microbiologic studies (staining for microorganisms and cultures), and tuberculin intradermoreaction were negative. There was no Crohn’s disease aspect on colonoscopy, and there was normal small bowel enterography. Systematic intestinal biopsies were also with normal aspect. Based on the clinical data and granulomatous histologic characteristics, the diagnosis of metastatic Crohn’s disease without digestive involvement was obtained. The patient was started on metronidazole 1 g/d. After 6 months of treatment, there was an almost-complete healing of ulcerations (Figure 2). Treatment was well-tolerated. V ulvoperineal involvement in Crohn’s disease is rare and may constitute the sole manifestation of the disease since it may precede bowel symptoms by several months to years in 20% of cases. In this localization, treatment of Crohn’s disease is difficult and not standardized.1 We report a case of vulvoperineal Crohn’s disease that responded to metronidazole in a 46-year-old woman. Figure 1. Asymmetric vulvar edema with deep and linear ulcerations of the inguinocrural regions. Our patient had cutaneous Crohn’s disease without digestive involvement. Diagnosis may not be obvious if vulvoperineal involvement precedes active bowel disease. Abscesses, draining sinuses, edema, and sharply demarcated ulceration of the perineum and/ or vulva with usually verrucous borders (as demonstrated by our case) are the characteristic manifestations of the disease. They are caused by direct extension from the involved bowel or by granulomas separated from the bowel by normal tissue. The latter form is usually named metastatic Crohn’s disease. In the absence of digestive involvement, the diagnosis is based on clinical and histologic aspects and on the absence of other clinical and paraclinical signs of a specific infection. Because of the scarcity of this topographic form of Crohn’s disease, and in the absence of randomized essay, treatment remains not standardized.1 Multiple treatments have been tried. They include corticosteroids, which can be injected either topically or locally or administered orally. They are often efficient with a frequent corticodependence and multiple side effects, From the Departments of Dermatology1 and Pathology,2 Charles Nicolle Hospital, Tunis, Tunisia Address for Correspondence: Aida Khaled, MD, Boulevard 9 Avril, 1006 Tunis, Tunisia • E-mail: [email protected] SKINmed. 2010;8:240–241 240 © 2010 Pulse Marketing & Communications, LLC July/August 2010 CASE STUDY especially for oral steroids. Sulfasalazine may lead to a partial healing of cutaneous lesions but is more efficient in digestive forms. Immunosuppressive agents such as azathioprine, methotrexate, and cyclosporine are also efficient, but a long-term treatment may expose the patient to severe side effects. Immunosuppressive treatments should be indicated for digestive involvement and may be an ultimate option in resistant forms of vulvoperineal Crohn’s disease.2 Thalidomide also leads to a satisfactory result in refractory vulvar ulcerations associated with Crohn’s disease.3 Recently, investigators stated that infliximab is a good therapeutic option for recalcitrant vulvar Crohn’s disease, but no optimum regimen was provided.4 Only a few small studies have evaluated metronidazole for the treatment of Crohn’s disease with low convincing results. A better activity has been demonstrated in colonic disease and for perianal fistulas.5 Metronidazole seems to be a good therapeutic option since it has led to complete healing of perineal lesions with a persistent result in our patient and in several uncontrolled reports.2,6–9 Its efficiency is due to antibacterial, antiinflammatory, and immunosuppressive action. As demonstrated by researchers, the efficacy of metronidazole is dependent on the dose and duration of the treatment. According to the largest follow-up study, the optimal dose is 20 mg/kg/d and the duration is at least 12 months, with a maximum duration of 36 months.7 The most commonly reported side effects are digestive and hematologic, but also reversible sensory peripheral neuropathy.10 References 1 Moyes LH, Glen P, Pickford IR. Perineal metastatic Crohn’s disease: a case report and review of the literature. Ann R Coll Surg Engl. 2007;89:W1–3. 2 Conscience I, Perceau G, Durlach A, et al. Vulvar involvement in Crohn’s disease: efficacy of metronidazole. Ann Dermatol Venereol. 2006;133:585–587. 3 Kolivras A, De Maubeuge J, André J, et al. Thalidomide in refractory vulvar ulcerations associated with Crohn’s disease. Dermatology. 2003;206:381–383. 4 Preston PW, Hudson N, Lewis FM. Treatment of vulval Crohn’s disease with infliximab. Clin Exp Dermatol. 2006;31:378–380. 5 Rubin DT, Kornblunth A. Role of antibiotics in the management SKINmed. 2010;8:240–241 241 Figure 2. Almost-complete healing of the ulcerations after 6 months of metronidazole treatment. of inflammatory bowel disease: a review. Rev Gastroenterol Disord. 2005;5(suppl 3):S10–S15. 6 Bernstein LH, Frank MS, Brandt LJ, et al. Healing of perineal Crohn’s disease with metronidazole. Gastroenterology. 1980;79:599. 7 Brandt LJ, Bernstein LH, Boley SJ, et al. Metronidazole therapy for perineal Crohn’s disease: a follow-up study. Gastroenterology. 1982;83:383–387. 8 Bourrat E, Faure C, Vignon-Pennamen MD, et al. Anitis, vulvar edema and macrocheilitis disclosing Crohn disease in a child: value of métronidazole. Ann Dermatol Venereol. 1997;124:626–628. 9 Andreani SM, Ratnasingham K, Dang HH, et al. Crohn’s disease of the vulva. Int J Surg. 2010;8:2–5. Epub 2009 Oct 1. 10 Bernstein LH, Frank MS, Brandt LJ, et al. Healing of perineal Crohn’s disease with metronidazole. Gastroenterology. 1980;79:357–365. Vulvoperineal Crohn’s Disease July/August 2010 Volume 8 • Issue 4 CASE STUDY Folliculocentric Lichen Sclerosus et Atrophicus David J. Mann, MD;1 Irene J. Vergilis-Kalner, MD;2 Justin R. Wasserman, MD;3 Vesna Petronic-Rosic, MD, MSc4 A 71-year-old black woman presented to the dermatology clinic with a several-year history of increasing numbers of itchy white spots spreading over the chest, back, elbows, and legs. In 2004, the patient developed clusters of mildly pruritic hypopigmented and depigmented macules on her back and left shoulder along with depigmented flat papules on the lower extremities. The patient’s condition was unresponsive to topical triamcinolone and tacrolimus, after which she was lost to follow-up for 3 years until her entire chest became involved. Her medical history was significant for hypertension and diabetes mellitus and her medications included amlodipine, aspirin, atorvastatin, hydrochlorothiazide, irbesartan, and metformin. Family history, social history, and review of systems were unremarkable. Physical examination revealed multiple shiny white perifollicular macules, some with slight scale, on the trunk (Figure 1) and extremities (Figure 2). On the left shoulder and back were 2 shiny plaques with hypopigmented macules and follicular scale within. Punch biopsies from the abdomen and back showed atrophy of the epidermis, edema and sclerosis of the papillary dermis, and a patchy lichenoid lymphocytic infiltrate (Figure 3). Despite inspecting multiple step sections, we were unable to histopathologically confirm the clinically apparent folliculocentric distribution. Based on the clinical and histological findings, extragenital lichen sclerosus et atrophicus (LSA) was diagnosed and the patient was treated with clobetasol proprionate 0.05% ointment. While being prepared for narrowband UV-B therapy, a serologic screen revealed antinuclear antibodies at 1:640 with a homogeneous pattern. A subsequent rheumatologic evaluation was negative for autoimmune disorders; pertinent negative serologies included anti–double-stranded DNA, smooth muscle, mitochondrial, thyroid, and parietal cell antibodies. L SA is a chronic inflammatory scarring disease, described clinically by Hallopeau in 1887 and histologically by Darier in 1892. The etiology of the disease still remains unknown. While it can be seen in all age groups, LSA affects women more commonly than men, with a bimodal peak of incidence: the first occurs between 8 and 13 years of age and the second between the fifth and sixth decade, both in women with physiologically low estrogen states. LSA has a predilection for the anogenital region, seen in approximately 85% of cases. While 15% to 20% of those have extragenital lesions,1 the folliculocentric distribution of the lesions in our patient is unique and the generalized distribution itself is uncommonly reported and thus less well understood. We report a case of extragenital LSA that had a folliculocentric and generalized clinical presentation in a patient with antinuclear antibodies. Discussion Extragenital LSA without accompanying genital involvement is uncommon and has been reported in 2.5% to 15% of patients.2,3 Extragenital LSA is histologically identical to the more common genital presentation of LSA and is characterized by homogenization of papillary dermal collagen, extensive edema, a band-like lymphocytic infiltrate, and thinning of the overlying epidermis. Clinically, this results in atrophic or sclerotic ivory white papules, which often coalesce into large plaques that, aside from dryness and itching, are generally asymptomatic. The lesions typically occur on the trunk and proximal extremities, often favoring the neck, shoulders, and wrists,2 although the tongue and oral mucosa may also be involved.1,2 Occasionally, microguttate lesions have been reported. Early on, the white sclerotic or atrophic papules are found between hair follicles and then often coalesce into larger plaques. This case is unusual given its folliculocentric clinical appearance and generalized distribution. The cause of LSA remains undetermined but it is believed to be multifactorial, with genetic, hormonal, and infectious influences, including Borrelia burgdorferi infection.4,5 Patients of both sexes with LSA have a high incidence of systemic autoimmune disease, most commonly autoimmune gastritis and Hashimoto’s thyroiditis.6–10 An exuberant immunologic reaction to an as-yet unidentified antigen has been proposed to be responsible for the characteristic disease manifestations. Supportive evidence for this hypothesis includes the occurrence of a lymphocytic vasculitis and a T-lymphocyte–dominant inflammatory infiltrate with monoclonally rearranged g-chain gene of the T-cell receptor detected in skin lesions of lichen sclerosus and occasionally in blood.11–14 From the Department of Medicine, Section of Dermatology, University of Chicago, Chicago, IL Address for Correspondence: Vesna Petronic-Rosic, MD, MSc, Department of Medicine, Section of Dermatology, University of Chicago, 5841 South Maryland Avenue, MC 5067, Chicago, IL 60637 • E-mail: [email protected] SKINmed. 2010;8:242–244 242 © 2010 Pulse Marketing & Communications, LLC July/August 2010 CASE STUDY A 1981 study of 50 women with histologically confirmed LSA showed that 37 (74%) had tissue autoantibodies and 17 (34%) had at least 1 autoimmune disease.15 A second study in 1988 confirmed this finding, as 147 of 350 (42%) women with LSA had tissue autoantibodies, 74 (21.1%) had ≥1 first-degree relatives with an autoimmune disease, and 75 (21.4%) had ≥1 autoimmune diseases (by history).10 No identifiable difference in clinical features was found among women who developed autoimmune related phenomena, nor was it clear whether screening for such diseases was justifiable, as only a small percentage developed autoimmune diseases after the diagnosis of LSA. First-line treatment for LSA includes ultrapotent topical steroids and intralesional triamcinolone injections. Alternative therapies that have been reported include photodynamic therapy with aminolevulinic acid (effective in relieving pruritus) in one study16 and phototherapy for extragenital LSA, with a marked reduction or clearing after treatment with 40 sessions of UV-A1 at 20 J/cm2 in 10 patients with extragenital lichen sclerosus without adverse effects.17 There are other recent case reports of successful therapy using thrice-weekly narrowband UV-B.18 It is believed that both UV-A-1 and narrowband UV-B work by increasing matrix-metalloproteinase levels. Vitamin D and vitamin A derivatives have also been reported in the treatment of LSA. One study demonstrated a marked reduction in the number of hypertrophic plaques in a patient within 3 weeks of beginning treatment with calcipotriol 0.005% ointment applied twice daily under occlusion.19 Systemic vitamin A has shown some success with both oral and parenteral administration.2 This is thought to work by inhibiting transforming growth factor b, which decreases collagen synthesis by fibroblasts. Figure 1. Myriad folliculocentric white macules on the patient’s chest. Figure 2. Multiple folliculocentric lesions of lichen sclerosus et atrophicus on the patient’s proximal legs. Topical testosterone or progesterone is no longer recommended given the conflicting data and possible adverse effects.16 Likewise, earlier studies showed no benefit of using penicillin, other antibiotics, or penicillamine. Additional treatment options reported to be effective include adrenocorticotropic hormone,20 hydroxychloroquine,21 sulfasalazine,22 oral calcitriol,23 and topical retinoids.24 Surgery is typically reserved for symptomatic patients who have failed multiple medical modalities. Recent research has focused on the use of topical tacrolimus for LSA, with one successful report of treating extragenital LSA with 0.1% tacrolimus ointment and psoralen plus UV-A.25 We find this presentation to be of interest due to the unique folliculocentric and generalized clinical presentation. A diagnosis of LSA should be considered in the differential of perifollicular hypopigmentation. SKINmed. 2010;8:242–244 243 Figures 3. Histological findings characteristic of lichen sclerosus et atrophicus. Folliculocentric Lichen Sclerosus et Atrophicus July/August 2010 CASE STUDY References 1 Powell JJ, Wojnarowska 1999;353:1777–1783. F. Lichen sclerosus. Lancet. cytic infiltrate in penile lichen sclerosus: an immunohistochemical and molecular investigation. Histopathology. 2006;48:730–735. 2 Meffert JJ, Davis BM, Grimwood RE. Lichen sclerosus. J Am Acad Dermatol. 1995;32:393–416; quiz 417–398. 15 Harrington CI, Dunsmore IR. An investigation into the incidence of auto-immune disorders in patients with lichen sclerosus and atrophicus. Br J Dermatol. 1981;104:563–566. 3 Corbalan-Velez R, Perez-Ferriols A. Lichen sclerosus et atrophicus affecting the wrists and left ankle and clinically simulating lichen planus. Cutis. 2001;67:417–419. 16 Smith YR, Haefner HK. Vulvar lichen sclerosus: pathophysiology and treatment. Am J Clin Dermatol. 2004;5:105–125. 4 Eberz B, Berghold A, Regauer S. High prevalence of concomitant anogenital lichen sclerosus and extragenital psoriasis in adult women. Obstet Gynecol. 2008;111:1143–1147. 17 Kreuter A, Gambichler T, Avermaete A, et al. Low-dose ultraviolet A1 phototherapy for extragenital lichen sclerosus: results of a preliminary study. J Am Acad Dermatol. 2002;46:251–255. 5 Smith YR, Haefner HK. Vulvar lichen sclerosus: pathophysiology and treatment. Am J Clin Dermatol. 2004;5:105–125. 18 Colbert RL, Chiang MP, Carlin CS, et al. Progressive extragenital lichen sclerosus successfully treated with narrowband UV-B phototherapy. Arch Dermatol. 2007;143:19–20. 6 Goolamali SK, Barnes EW, Irvine WJ, et al. Organ-specific antibodies in patients with lichen sclerosus. BMJ. 1974;4:78–79. 7 Harrington CI, Dunsmore IR. An investigation into the incidence of auto-immune disorders in patients with lichen sclerosus and atrophicus. Br J Dermatol. 1981;104:563–566. 19 Kreuter A, Gambichler T, Sauermann K, et al. Extragenital lichen sclerosus successfully treated with topical calcipotriol: evaluation by in vivo confocal laser scanning microscopy. Br J Dermatol. 2002;146:332–333. 8 Meyrick Thomas RH, Ridley CM, Black MM. The association of lichen sclerosus et atrophicus and autoimmune-related disease in males. Br J Dermatol. 1983;109:661–664. 20 Di Silverio A, Serri F. Generalized bullous and haemorrhagic lichen sclerosus et atrophicus. Marked improvement with ACTH. Br J Dermatol. 1975;93:215–217. 9 Thomas RH, Ridley CM, Black MM. Lichen sclerosus et atrophicus associated with systemic lupus erythematosus. J Am Acad Dermatol. 1985;13(5 pt 1):832–833. 21 Wakelin SH, James MP. Extensive lichen sclerosus et atrophicus with bullae and ulceration–improvement with hydroxychloroquine. Clin Exp Dermatol. 1994;19:332–334. 10 Meyrick Thomas RH, Ridley CM, McGibbon DH, et al. Lichen sclerosus et atrophicus and autoimmunity–a study of 350 women. Br J Dermatol. 1988;118:41–46. 22 Taveira M, Selores M, Costa V, et al. Generalized morphea and lichen sclerosus et atrophicus successfully treated with sulphasalazine. J Eur Acad Dermatol Venereol. 1999;12:283–284. 11 Lukowsky A, Muche JM, Sterry W, et al. Detection of expanded T cell clones in skin biopsy samples of patients with lichen sclerosus et atrophicus by T cell receptor-gamma polymerase chain reaction assays. J Invest Dermatol. 2000;115:254–259. 23 Ronger S, Viallard AM, Meunier-Mure F, et al. Oral calcitriol: a new therapeutic agent in cutaneous lichen sclerosis. J Drugs Dermatol. 2003;2:23–28. 12 Regauer S, Reich O, Beham-Schmid C. Monoclonal gamma-Tcell receptor rearrangement in vulvar lichen sclerosus and squamous cell carcinomas. Am J Pathol. 2002;160:1035–1045. 13 Regauer S. Immune dysregulation in lichen sclerosus. Eur J Cell Biol. 2005;84:273–277. 14 Regauer S, Beham-Schmid C. Detailed analysis of the T-cell lympho- 24 Guerriero C, Manco S, Paradisi A, et al. Extragenital lichen sclerosus and atrophicus treated with topical steroids and retinoids in a child with vitiligo. Int J Immunopathol Pharmacol. 2008;21:757–759. 25 Valdivielso-Ramos M, Bueno C, Hernanz JM. Significant improvement in extensive lichen sclerosus with tacrolimus ointment and PUVA. Am J Clin Dermatol. 2008;9:175–179. HYPERTRICHOSIS Medications reported to cause excessive hair growth Clomid Erbitux Rogaine Soriatane Corticosteroids Loniten Sandimmune Timoptic Dilantin Neoral Simulect Topamax Zyrtec Adapted from Litt, JZ. Curious, Odd, Rare, and Abnormal Reactions to Medications. Fort Lee, NJ: Barricade Books; 2009:162. SKINmed. 2010;8:242–244 244 Folliculocentric Lichen Sclerosus et Atrophicus July/August 2010 Volume 8 • Issue 4 CASE STUDY Poorly Growing Hair in a Child Diana Bolotin, MD, PhD; Bernhard Ortel, MD; Sarah L. Stein, MD A healthy 5-year-old Caucasian girl presented to the pediatric dermatology clinic for poor hair growth. The patient’s father described slow hair growth and finely textured hair since birth. The patient had her first haircut 1 month before presentation. The family denied bald areas on the scalp, significant hair shedding, and sores on the scalp. The child did not scratch at her scalp or pull her hair. She ate a normal diet and had normal growth and development otherwise. She was not taking any medications or over-the-counter supplements. There was no family history of hair disorders. On physical examination, the patient had short, fine, reddish blond hair that was of different lengths (Figure 1). There were no papules, pustules, scale, or crust on her scalp. Lymphadenopathy was absent. She had normal eyelashes and eyebrows. There were no lesions on her oral mucosa. No tooth or nail abnormalities were present. The rest of the physical examination was normal. The hair pull test resulted in 4 easily pulled hairs (3 anagen and 1 telogen). A hair mount was performed (Figure 2). The hair mount analysis revealed anagen hairs with distorted bulbs and ruffled cuticles extending a short distance distally from the bulb, consistent with loose anagen hair (Figure 2). All of the anagen hairs on the pull test demonstrated the above findings. Based on the patient’s clinical presentation and the findings seen on light microscopy of the hair mount preparation, the patient was diagnosed with loose anagen syndrome. L oose anagen syndrome (LAS) is a hair disorder that is primarily diagnosed in childhood. The most frequent complaint on presentation is poor hair growth and thin hair, although other symptoms include unruly lusterless hair.1,2 In most cases, patients tend to be blonde, although a few dark-haired patients have been described. Three different patterns of LAS have been reported, all of which show loose anagen hair (LAH) phenotype on hair pull test.3 Patients with type A phenotype have sparse Figure 1. Reddish brown fine hair of variable lengths was appreciated on the scalp. From the Section of Dermatology, University of Chicago Medical Center, Chicago IL Address for Correspondence: Diana Bolotin, MD, PhD, University of Chicago Medical Center, Section of Dermatology, MC5067 5841, South Maryland Avenue, Chicago IL 60637 • E-mail: [email protected] SKINmed. 2010;8:246–247 246 © 2010 Pulse Marketing & Communications, LLC July/August 2010 CASE STUDY hair with poor growth; patients with type B phenotype present with sparse, dull, and unruly hair; and patients with type C phenotype present with increased hair shedding.3 The pathogenesis of LAS remains largely unclear. One study has found a mutation in a hair keratin K6hf, present in the companion cell layer of the outer root sheath, detected in 3 of 9 families with LAS.4 It is unclear, however, whether other keratins or adhesion molecules in the inner root sheath may also be responsible for this hair disorder. In addition, it remains to be seen whether genetic differences account for the various subtypes of LAS. Diagnosis of LAS is based on the combination of characteristic clinical findings as well as the presence of microscopically defined LAH on hair pull test.1 On light microscopy, LAH hairs show misshapen hair bulbs, absence of root sheaths, and the characteristically ruffled cuticle.1,2,5,6 It is thought that anywhere from 70% to 100% of hairs in patients with LAS demonstrate LAH features.3 It should be noted, however, that up to 10% of cases of LAH have been reported in normal individuals, although it is unclear whether these individuals may have a milder expression of LAS. A biopsy is usually nondiagnostic for this condition, although one characteristic feature is premature keratinization of the Henle and Huxley layers of the inner root sheath.1,5 The clinical severity of LAS tends to improve with age, with some cases leading to complete resolution.1,2 Generally, aggressive treatment is not warranted, and gentle hair care is recommended for these patients. References 1 Tosti A, Piraccini BM. Loose anagen hair syndrome and loose anagen hair. Arch Dermatol. 2002;138:521–522. Figure 2. Trichogram showing anagen hairs with ruffled cuticles. 2 Cheng AS, Bayliss SJ. The genetics of hair shaft disorders. J Am Acad Dermatol. 2008;59:1–22. 3 Olsen EA, Bettencourt MS, Cote NL. The presence of loose anagen hairs obtained by hair pull in the normal population. J Investig Dermatol Symp Proc. 1999;4:258–260. 4 Chapalain V, Winter H, Langbein L, et al. Is the loose anagen hair syndrome a keratin disorder? A clinical and molecular study. Arch Dermatol. 2002;138:501–506. 5 Smith VV, Anderson G, Malone M, et al. Light microscopic examination of scalp hair samples as an aid in the diagnosis of paediatric disorders: retrospective review of more than 300 cases from a single centre. J Clin Pathol. 2005;58:1294–1298. 6 Cantatore-Francis JL, Orlow SJ. Practical guidelines for evaluation of loose anagen hair syndrome. Arch Dermatol. 2009;145:1123–1128. Formulary of Dr George C. Andrews Bleach • #1 Powder o Bismuth oxychloride – 1 part o Sodium perborate – 2 parts o Talc – 7 parts • #2 Solution o Hydrogen peroxide Sig. Use enough #2 to make a thick paste. Submitted by Douglas D. Altchek, MD, New York, NY SKINmed. 2010;8:246–247 247 Poorly Growing Hair in a Child Locoid Lipocream® Cream, 0.1% (hydrocortisone butyrate 0.1% cream) For Topical Use Only Rx Only BRIEF SUMMARY INDICATIONS AND USAGE Locoid Lipocream is a topical corticosteroid indicated for: relief of the inflammatory and pruritic manifestations of corticosteroid-responsive dermatoses in adults and the treatment of mild to moderate atopic dermatitis in patients 3 months to 18 years of age. WARNINGS AND PRECAUTIONS Reversible hypothalamic-pituitary-adrenal (HPA) axis suppression may occur, with the potential for glucocorticosteroid insufficiency. Consider periodic evaluations for HPA axis suppression if Locoid Lipocream is applied to large surface areas or used under occlusion. If HPA axis suppression is noted, reduce the application frequency, discontinue use, or switch to a lower potency corticosteroid. Systemic effects of topical corticosteroids may also include manifestations of Cushing’s syndrome, hyperglycemia, and glucosuria. Pediatric patients may be more susceptible to systemic toxicity due to their larger skin surface-to-body-mass ratios. Initiate appropriate therapy if concomitant skin infections develop. Discontinue use if irritation develops. ADVERSE REACTIONS The most common adverse reactions (>1%) are HPA axis suppression and application site reactions. The following additional local adverse reactions have been reported infrequently with topical corticosteroids, and they may occur more frequently with the use of occlusive dressings and higher potency corticosteroids. These reactions included: irritation, folliculitis, acneiform eruptions, hypopigmentation, perioral dermatitis, allergic contact dermatitis, secondary infection, skin atrophy, striae, miliaria and telangiectasia. USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category C. Corticosteroids have been shown to be teratogenic in laboratory animals when administered systemically at relatively low dosage levels. Some corticosteroids have been shown to be teratogenic after dermal application in laboratory animals.There are no adequate and well-controlled studies in pregnant women. Therefore, Locoid Lipocream should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Please refer to full prescribing information for detailed information regarding systemic embryofetal development studies. Nursing Mothers Systemically administered corticosteroids appear in human milk and could suppress growth, interfere with endogenous corticosteroid production, or cause other untoward effects. It is not known whether topical administration of corticosteroids could result in sufficient systemic absorption to produce detectable quantities in human milk. Because many drugs are excreted in human milk, caution should be exercised when Locoid Lipocream is administered to a nursing woman. Pediatric Use Safety and efficacy in pediatric patients below 3 months of age have not been established. Because of higher skin surface-to-body-mass ratios, pediatric patients are at a greater risk than adults of HPA axis suppression when they are treated with topical corticosteroids. They are therefore also at a greater risk of glucocorticosteroid insufficiency after withdrawal of treatment and of Cushing’s syndrome while on treatment. Eighty-six (86) pediatric subjects (5 months to less than 18 years of age) with moderate to severe atopic dermatitis affecting at least 25% of body surface area (BSA) treated with Locoid Lipocream three times daily for up to 4 weeks were assessed for HPA axis suppression. The disease severity (moderate to severe atopic dermatitis) and the dosing regimen (three times daily) in this HPA axis study were different from the subject population (mild to moderate atopic dermatitis) and the dosing regimen (two times daily) for which Locoid Lipocream is indicated. Five of the 82 evaluable subjects (6.1%) demonstrated laboratory evidence of suppression, where the sole criterion for defining HPA axis suppression was a serum cortisol level of less than or equal to 18 micrograms per deciliter after cosyntropin stimulation. Suppressed subjects ranged in age from 5 months to 16 years and, at the time of enrollment, had 25% to 95% BSA involvement. These subjects did not develop any other signs or symptoms of HPA axis suppression. At the first follow up visit, approximately one month after the conclusion of treatment, cosyntropin stimulation results of all subjects had returned to normal, with the exception of one subject. This last subject recovered adrenal function by the second post treatment visit, 65 days post-treatment. Cushing’s syndrome, linear growth retardation, delayed weight gain, and intracranial hypertension have also been reported in pediatric patients receiving topical corticosteroids. Manifestations of adrenal suppression in pediatric patients include low plasma cortisol levels to an absence of response to ACTH stimulation. Manifestations of intracranial hypertension include bulging fontanelles, headaches, and bilateral papilledema. Geriatric Use Clinical studies of Locoid Lipocream did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Carcinogenesis, Mutagenesis, Impairment of Fertility No studies were conducted to determine the photococarcinogenic or dermal carcinogenic potential of Locoid Lipocream. Hydrocortisone butyrate revealed no evidence of mutagenic or clastogenic potential based on the results of two in vitro genotoxicity tests (Ames test and L5178Y/TK+ mouse lymphoma assay) and one in vivo genotoxicity test (mouse micronucleus assay). No evidence of impairment of fertility or effect on mating performance was observed in a fertility and general reproductive performance study conducted in male and female rats at subcutaneous doses up to and including 1.8 mg/kg/day (0.7X maximum topical human dose [MTHD]). Mild effects on maternal animals, such as reduced food consumption and a subsequent reduction in body weight gain, were seen at doses ≥0.6 mg/kg/day (0.2X MTHD). PATIENT COUNSELING INFORMATION Patients using Locoid Lipocream should receive the following information and instructions: Apply a thin layer to the affected skin two or three times daily for corticosteroidresponsive dermatoses in adults. Consult with your physician to determine if treatment is needed beyond 2 weeks. Apply a thin film to the affected skin areas two times daily for atopic dermatitis in patients 3 months of age and older. Safety of Locoid Lipocream in pediatric patients has not been established beyond 4 weeks of use. Rub in gently. Avoid contact with the eyes. Do not bandage, otherwise cover, or wrap the affected skin area so as to be occlusive unless directed by your physician. Do not use Locoid Lipocream in the diaper area, as diapers or plastic pants may constitute occlusive dressings. Do not use Locoid Lipocream on the face, underarms, or groin areas unless directed by your physician. If no improvement is seen within 2 weeks, contact your physician. Do not use other corticosteroid-containing products while using Locoid Lipocream without first consulting your physician. Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature]. Protect from freezing. Keep out of the reach of children. Manufactured for: Triax Pharmaceuticals, LLC Cranford NJ 07016 By: Ferndale Laboratories, Inc. Ferndale MI 48220 Locoid Lipocream is a registered trademark of Astellas Pharma Europe BV licensed to Triax Pharmaceuticals, LLC. Marketed and Distributed By: Triax Pharmaceuticals, LLC Cranford NJ 07016 www.Locoid.com 131B301 Rev 11/09 Now younger eczema patients have something to smile about Now approved for use in children down to 3 months of age The power of an ointment with the elegance of a cream Locoid Lipocream is indicated for the relief of the inflammatory and pruritic manifestations of corticosteroid-responsive dermatoses, including the treatment of mild to moderate atopic dermatitis in patients 3 months of age and older. Safety and effectiveness in pediatric patients below 3 months of age have not been established. Reversible HPA axis suppression may occur, with the potential for corticosteroid insufficiency. Consider periodic evaluations for HPA axis suppression if applied to large surface areas or used under occlusion. Systemic effects of topical corticosteroids may also include manifestations of Cushing’s syndrome, hyperglycemia, and glucosuria. Pediatric patients may be more susceptible to systemic toxicity due to their large skin surface-to-body-mass ratios. Initiate appropriate therapy if concomitant skin infection develops. Discontinue use if irritation develops. Please see full Prescribing Information on adjacent page. Visit us at www.locoid.com (hydrocortisone butyrate 0.1%) Cream ©2010 Triax Pharmaceuticals, LLC. All rights reserved. Locoid is a registered trademark of Astellas Pharma Europe B.V. licensed to Triax Pharmaceuticals, LLC. LOC-0410-01
