Page 1

Chinese Society of Dermatology

Chinese Society of Dermatology

Parish, Lee, and Parish

COMMENTARY Gentian Violet: Bench-to-Bedside Research That Lowers Healthcare Costs Arbiser

ORIGINAL CONTRIBUTIONS Correlation Between Severity Index and Quality of Life Index in Patients With Psoriasis Assessed Before and After Phototherapy Couto, Carneiro, Niemeyer-Corbellini, Yoshio, and Ramos-e-Silva

Clinical and Laboratory Characteristics of Patients With Erythema Nodosum

Dogan, Karaduman, and Evans

REVIEW Cyclosporine in Dermatology

Kutlubay, Erdogan, Engin, and Serdaroglu

CORE CURRICULUM Cantharidin in Dermatology Al-Dawsari and Masterpol

DEPARTMENTS PERILS OF DERMATOPATHOLOGY Diagnostic Pitfalls of the “Nothin’ Slide”

Singh, Kim, John, and Lambert

Belarusian Society of Dermatovenereologists and Cosmetologists

Lebanese Dermatological Society

Belarusian Society of Dermatovenereologists and Cosmetologists

EDITORIAL Is There a Cellulitis Epidemic?

Lebanese Dermatological Society

North American Clinical Dermatologic Society

The Dermatologic & Aesthetic Surgery International League

North American Clinical Dermatologic Society

The Dermatologic & Aesthetic Surgery International League

African Association for Dermatology

African Association for Dermatology

March/April 2016 • Volume 14 • Issue 2

March/April 2016 • VolumeUPDATE 14 • Issue 2 NEW THERAPY VALCHLOR (Mechlorethamine) 0.02% Gel Gupta, MacLeod, and Abramovits

THE HEYMANN FILE Carotenemia and Age-Related Macular Degeneration: Seeing Is Believing Heymann

HISTORY OF DERMATOLOGY SOCIETY NEWSLETTER Suture Materials Bernhardt

case studies Lipomembranous Panniculitis Associated With Venous Insufficiency, Morphea, and Psoriasis Aounallah, Zaraa, El Euch, Chelly, Haouet, Mokni, and Ben Osman

Blitz Nevus: A Clinical Simulator of Melanoma

Alonso-Corral, Ruiz-Villaverde, Sánchez-Cano, and Pulido-Fernández

Supravenous Hyperpigmentation in an HIV-Infected Patient

Multisystem Langerhans Cell Histiocytosis in Adults Revealed by Skin Lesions

Atarguine, Hocar, Oussmane, Mouafik, Hamdaoui, Hafiane, Belbaraka, Akhdari, and Amal

Molluscum Contagiosum Infection Involving a Benign Epidermoid Cyst in an Immunocompetent Patient

Husein-ElAhmed, Ruiz-Molina, Cívico-Amat, and Solís-García

Multiple Adult Xanthogranulomas Associated With Cutaneous Lymphoid Hyperplasia and Lupus Erythematosus Hibler, Eastman, Bennett, Swanson, Longley, and Wood

CORRESPONDENCE An Update and Evaluation of Telemedicine and Teledermatology Publications for 2014 Senel and Demir

BOOK REVIEW Hair Loss and Restoration Bernhardt

Gilmour, Bates, Olsen, and Saade

Methotrexate-Induced Nasal Septal Perforation

Kaminska, Sansaricq, and Petronic-Rosic

Primary Cutaneous Coccidioidomycosis Presenting as a Recurrent Preauricular Cyst Rivard and Satter

Dermatological Implications of Coining: An Eastern Medicine Cultural Practice George, Trice, Studdiford, and Trayes

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TABLE OF CONTENTS March/April 2016 • Volume 14 • Issue 2

EDITORIAL

Is There a Cellulitis Epidemic? ................................................................................................................... 89

Lawrence Charles Parish, MD, MD (Hon); Jason B. Lee, MD; Daniel H. Parish, MD, JD

COMMENTARy

Gentian Violet: Bench-to-Bedside Research That Lowers Healthcare Costs ................................................. 91

Jack L. Arbiser, MD, PhD

ORIGINAL CONTRIBUTIONS

Correlation Between Severity Index and Quality of Life Index in Patients With Psoriasis Assessed Before and After Phototherapy .................................................................................................................... 93

Maria Isabel de Noronha Neta Couto, Msc; Sueli Carneiro, MD, PhD; João Paulo Niemeyer-Corbellini, MD, MSc; Jessica Hiromi Yoshio;

Marcia Ramos-e-Silva, MD, PhD

Clinical and Laboratory Characteristics of Patients With Erythema Nodosum ............................................. 99

Sibel Dogan, MD; Aysen Karaduman, MD; Sibel Ersoy Evans, MD

REVIEW

Zekayi Kutlubay, MD; Bigen Çakıl Erdogan, MD; Burhan Engin, MD; Server Serdaroglu, MD B:11”

T:10.75”

Cyclosporine in Dermatology .................................................................................................................... 105

S:10.25”

CORE CURRICULUM Virendra N. Sehgal, MD, Section Editor

Cantharidin in Dermatology ..................................................................................................................... 111

Najla A. Al-Dawsari, MD; Kasia Szyfelbein Masterpol, MD

Departments Perils of Dermatopathology

W. Clark Lambert, MD, PhD, Section Editor

Diagnostic Pitfalls of the “Nothin’ Slide” ................................................................................................. 115

Parmvir Singh, BS; Hee Jin Kim, BS; Ann M. John, BA; W. Clark Lambert, MD, PhD

New Therapy Update

William Abramovits, MD; Aditya K. Gupta, MD, PhD, FRCPC, Section Editors

VALCHLOR (Mechlorethamine) 0.02% Gel ............................................................................................... 120

Aditya K. Gupta, MD, PhD, FRCPC; Melissa A. MacLeod, MSc; William Abramovits, MD

The Heymann File

Warren R. Heymann, MD, Section Editor

Carotenemia and Age-Related Macular Degeneration: Seeing Is Believing ................................................ 123

Warren R. Heymann, MD

History of Dermatology Society Newsletter Eve J. Lowenstein, MD, PhD, Section Editor

Suture Materials ....................................................................................................................................... 125

Mark Bernhardt, MD

81


TABLE OF CONTENTS March/April 2016 2016 •• Volume Volume 14 14 •• Issue Issue 22 March/April

case studies

Vesna Petronic-Rosic, MD, MSc, Section Editor

Lipomembranous Panniculitis Associated With Venous Insufficiency, Morphea, and Psoriasis .................. 127

Amina Aounallah, MD; Inès Zaraa, MD; Dalenda. El Euch, MD; Inès Chelly, MD; Slim Haouet, MD; Mourad. Mokni, MD; Amel Ben Osman, MD

Blitz Nevus: A Clinical Simulator of Melanoma ......................................................................................... 131

M. Jose Alonso-Corral, MD, PhD; Ricardo Ruiz-Villaverde, MD, PhD; Daniel Sánchez-Cano, MD, PhD; Francisco Pulido-Fernández, MD, PhD

Supravenous Hyperpigmentation in an HIV-Infected Patient ...................................................................... 135

Janet Gilmour, MD, FRCPC; Duane Bates, BSc Pharm, ACPR; Genevieve Olsen, BSc Pharm; Allison Saade, BSc Pharm

Methotrexate-Induced Nasal Septal Perforation......................................................................................... 139

Edidiong Ntuen Kaminska, MD; Freda Sansaricq, MS; Vesna Petronic-Rosic, MD, MSc

Primary Cutaneous Coccidioidomycosis Presenting as a Recurrent Preauricular Cyst................................ 142

Shayna C. Rivard, MD; Elizabeth Satter, MD, MPH

Dermatological Implications of Coining: An Eastern Medicine Cultural Practice........................................ 145

Nyasha George, MD; Traci Trice, MD; James S. Studdiford, MD; Kathryn Trayes, MD

Multisystem Langerhans Cell Histiocytosis in Adults Revealed by Skin Lesions......................................... 147

Hanane Atarguine, MD; Ouafa Hocar, MD, PhD; Samia Oussmane, MD; Sara Batoul Mouafik, MD; Abderrachid Hamdaoui, MD; Hanan Hafiane, MD; Rhizlane Belbaraka, MD, PhD; Nadia Akhdari, MD, PhD; Said Amal, MD, PhD

Molluscum Contagiosum Infection Involving a Benign Epidermoid Cyst in an Immunocompetent Patient....................................................................................................................................................... 151

Husein Husein-ElAhmed, MD; Inmaculada Ruiz-Molina, MD; Vicente Cívico-Amat, MD; Eduardo Solís-García, MD

Multiple Adult Xanthogranulomas Associated With Cutaneous Lymphoid Hyperplasia and Lupus Erythematosus................................................................................................................................. 153

Brian P. Hibler, BS; Kristin L. Eastman, MD; Daniel D. Bennett, MD; Andrew M. Swanson, MD; B. Jack Longley, MD; Gary S. Wood, MD

CORRESPONDENCE

Snejina Vassileva, MD, PhD, Section Editor

An Update and Evaluation of Telemedicine and Teledermatology Publications for 2014............................ 157

Engin Senel, MD; Emre Demir, MD

BOOK REVIEW

Jennifer L. Parish, MD, Section Editor

Hair Loss and Restoration.......................................................................................................................... 159

Mark Bernhardt, MD

82


March/April 2016

Volume 14 • Issue 2

Editorial

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. 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.

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Belarusian Society of Dermatovenereologists and Cosmetologists

North American Clinical Dermatologic Society

African Association for Dermatology

The Dermatologic & Aesthetic Surgery International League


March/April 2016

Volume 14 • Issue 2

EDITOR IN CHIEF

Lawrence Charles Parish, MD, MD (Hon) Philadelphia, PA

DEPUTY EDITORS William Abramovits, MD

Aditya K. Gupta, MD, PhD, FRCPC

W. Clark Lambert, MD, PhD

Vesna Petronic-Rosic, MD, MSc

Dallas, TX

London, Ontario, Canada

Newark, NJ

Chicago, IL

Larry E. Millikan, MD

Marcia Ramos-e-Silva, MD, PhD

Jennifer L. Parish, MD

Meridian, MS

Rio de Janeiro, Brazil

Philadelphia, PA

EDITORIAL BOARD Mohamed Amer, MD Cairo, Egypt

Howard A. Epstein, PhD Philadelphia, PA

Jasna Lipozencic, MD, PhD Zagreb, Croatia

Todd Schleslnger, MD Charleston SC

Robert L. Baran, MD Cannes, France

Ibrahim Hassan Galadari, MD, PhD, FRCP Dubai, United Arab Emirates

Ada Lo Schiavo, MD Naples, Italy

Virendra N. Sehgal, MD Delhi, India

Eve J. Lowenstein, MD, PhD New York, NY

Charles Steffen, MD Oceanside, CA

George M. Martin, MD Kihei, HI

Alexander J. Stratigos, MD Athens, Greece

Marc S. Micozzi, MD, PhD Rockport, MA

James S. Studdiford III, MD Philadelphia, PA

Venkataram Mysore, MD, FRCP (Hon, Glasgow) Bangalore, India

Robert J. Thomsen, MD Los Alamos, NM

Anthony V. Benedetto, DO Philadelphia, PA Brian Berman, MD, PhD Miami, FL

Anthony A. Gaspari, MD Baltimore, MD Michael Geiges, MD Zurich, Switzerland

Mark Bernhardt, MD Ft. Lauderdale, FL Jack M. Bernstein, MD Dayton, OH Sarah Brenner, MD Tel Aviv, Israel Henry H.L. Chan, MB, MD, PhD, FRCP Hong Kong, China Joel L. Cohen, MD Engelwood, CO Noah Craft, MD, PhD, DTMH Torrance, CA Natalie M. Curcio, MD, MPH Nashville, TN Ncoza C. Dlova, MBChB, FCDerm Durban, South Africa Richard L. Dobson, MD Mt Pleasant, SC William H. Eaglstein, MD Menlo Park, CA Charles N. Ellis, MD Ann Arbor, MI

Michael H. Gold, MD Nashville, TN Orin M. Goldblum, MD Indianapolis, IN

Oumeish Youssef Oumeish, MD, FRCP Amman, Jordan

Lowell A. Goldsmith, MD, MPH Chapel Hill, NC Seung-Kyung Hann, MD, PhD Seoul, Korea

Joseph L. Pace, MD, FRCP Naxxar, Malta

Roderick J. Hay, BCh, DM, FRCP, FRCPath London, UK

Art Papier, MD Rochester, NY

María Daniela Hermida, MD Buenos Aires, Argentina

Johannes Ring, MD, DPhil Munich, Germany

Warren R. Heymann, MD Camden, NJ

Roy S. Rogers III, MD Rochester, MN

Tanya R. Humphreys, MD Bala-Cynwyd, PA

Donald Rudikoff, MD New York, NY

Camila K. Janniger, MD Englewood, NJ

Robert I. Rudolph, MD Wyomissing, PA

Abdul-Ghani Kibbi, MD Beirut, Lebanon

Noah Scheinfeld, MD, JD New York, NY

SKINmed. 2016;14:85

Julian Trevino, MD Dayton, OH Graham Turner, PhD, CBiol, FSB Port Sunlight, UK Snejina Vassileva, MD, PhD Sofia, Bulgaria Daniel Wallach, MD Paris, France Michael A. Waugh, MB, FRCP Leeds, UK Wm. Philip Werschler, MD Spokane, WA Ronni Wolf, MD Rechovot, Israel Jianzhong Zhang, MD Beijing, China Matthew J. Zirwas, MD Columbus, Ohio

Andrew P. Lazar, MD Washington, DC

85

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Please forward your completed application for processing to: Larry Millikan, MD, Secretary-Treasurer General Ms Anna Gjeci, Executive Secretary 1508 Creswood Road Philadelphia, PA 19115, USA Tel: 215-677-3060 Cell: 267-438-2543 Fax: 215-695-2254 E-mail: IACDworld@yahoo.com Web: www.IACDworld.org SMCOMP_v10_i2_ADS.indd 396 121 SMCOMP_v10_i1_ADS.indd SMCOMP_v9_i5_ADS.indd 60

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A POWERFUL FIRST RESPONDER Prescribe once-daily Enstilar ® for proven efficacy in an elegant vehicle for adult patients with plaque psoriasis1 Eligible* patients may get their prescription for as little as $0. Visit Enstilar.com for details on the Copay Card.

INDICATION AND USAGE Enstilar® (calcipotriene and betamethasone dipropionate) Foam is indicated for the topical treatment of plaque psoriasis in patients 18 years of age and older. Apply Enstilar® to affected areas once daily for up to 4 weeks. Patients should discontinue use when control is achieved. Instruct patients not to use more than 60 g every 4 days. IMPORTANT SAFETY INFORMATION For topical use only. Enstilar® is not for oral, ophthalmic, or intravaginal use. Instruct patients to avoid use on the face, groin, or axillae, or if atrophy is present at the treatment site, and not to use with occlusive dressings, unless directed by a physician. The propellants in Enstilar® are flammable. Instruct patients to avoid fire, flame, or smoking during and immediately after using this product. Hypercalcemia and hypercalciuria have been observed with use of Enstilar®. If hypercalcemia or hypercalciuria develop, patients should discontinue treatment until parameters of calcium metabolism have normalized. Topical corticosteroids can produce reversible hypothalamicpituitary-adrenal (HPA) axis suppression with the potential for glucocorticosteroid insufficiency. Risk factors include use of highpotency topical corticosteroids, use over a large surface area or on areas under occlusion, prolonged use, altered skin barrier, liver failure, and use in pediatric patients. If HPA axis suppression is documented, gradually withdraw the drug, reduce the frequency of Reference: 1. Enstilar® [prescribing information]. Parsippany, NJ: LEO Pharma Inc.; October 2015.

LEO, the LEO Lion Design, and Enstilar are registered trademarks of LEO Pharma A/S. ©2016 LEO Pharma Inc. All rights reserved. March 2016 MAT-02406

application, or substitute with a less potent steroid. Systemic effects of topical corticosteroids may also include Cushing’s syndrome, hyperglycemia, and glucosuria. Use of more than one corticosteroidcontaining product at the same time may increase total systemic corticosteroid exposure. Adverse reactions reported in <1% of subjects treated with Enstilar® in clinical trials included application site irritation, application site pruritus, folliculitis, skin hypopigmentation, hypercalcemia, urticaria, and exacerbation of psoriasis. Patients who apply Enstilar® to exposed skin should avoid excessive exposure to either natural or artificial sunlight, including tanning booths, sun lamps, etc. You may wish to limit or avoid use of phototherapy in patients who use Enstilar®. There are no adequate and well-controlled studies of Enstilar® in pregnant women. Enstilar® should be used during pregnancy only if the potential benefit to the patient justifies the potential risk to the fetus. Because many drugs are excreted in human milk, caution should be exercised when Enstilar® is administered to a nursing woman. Do not use Enstilar® on the breast when nursing. The safety and effectiveness of Enstilar® in pediatric patients have not been studied. Please see Brief Summary on following page. *Must be 18 years of age or older to be eligible. For specific eligibility requirements and program restrictions, visit Enstilar.com or call 1-855-772-7224.


Enstilar ® (calcipotriene and betamethasone dipropionate) Foam, 0.005%/0.064% for topical use Initial U.S. Approval: 2006 BRIEF SUMMARY: Please see package insert for full Prescribing Information. INDICATIONS AND USAGE Enstilar ® (calcipotriene and betamethasone dipropionate) Foam is indicated for the topical treatment of plaque psoriasis in patients 18 years of age and older. CONTRAINDICATIONS None. WARNINGS AND PRECAUTIONS Flammability The propellants in Enstilar ® Foam are flammable. Instruct the patient to avoid fire, flame, and smoking during and immediately following application. Hypercalcemia and Hypercalciuria Hypercalcemia and hypercalciuria have been observed with use of Enstilar ® Foam. If hypercalcemia or hypercalciuria develop, discontinue treatment until parameters of calcium metabolism have normalized. The incidence of hypercalcemia and hypercalciuria following Enstilar ® Foam treatment of more than 4 weeks has not been evaluated. Effects on Endocrine System Systemic absorption of topical corticosteroids can produce reversible hypothalamic-pituitary-adrenal (HPA) axis suppression with the potential for clinical glucocorticosteroid insufficiency. This may occur during treatment or upon withdrawal of the topical corticosteroid. Factors that predispose a patient to HPA axis suppression include the use of high-potency steroids, large treatment surface areas, prolonged use, use of occlusive dressings, altered skin barrier, liver failure, and young age. Evaluation for HPA axis suppression may be done by using the adrenocorticotropic hormone (ACTH) stimulation test. If HPA axis suppression is documented, gradually withdraw the drug, reduce the frequency of application, or substitute with a less potent corticosteroid. Systemic effects of topical corticosteroids may also include 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. Use of more than one corticosteroid-containing product at the same time may increase total systemic corticosteroid exposure. Allergic Contact Dermatitis Allergic contact dermatitis has been observed with topical calcipotriene and topical corticosteroids. Allergic contact dermatitis to a topical corticosteroid is usually diagnosed by observing a failure to heal rather than a clinical exacerbation. Corroborate such an observation with appropriate diagnostic patch testing. Risks of Ultraviolet Light Exposures Patients who apply Enstilar ® Foam to exposed skin should avoid excessive exposure to either natural or artificial sunlight, including tanning booths, sun lamps, etc. Physicians may wish to limit or avoid use of phototherapy in patients who use Enstilar ® Foam. ADVERSE REACTIONS Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The rates of adverse reactions given below were derived from three randomized, multicenter, prospective vehicle and/or active-controlled clinical trials in subjects with plaque psoriasis. Subjects applied study product once daily for 4 weeks, and the median weekly dose of Enstilar ® Foam was 24.8 g. Adverse reactions reported in <1% of subjects treated with Enstilar ® Foam included: application site irritation, application site pruritus, folliculitis, skin hypopigmentation, hypercalcemia, urticaria, and exacerbation of psoriasis. Postmarketing Experience Because adverse reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Postmarketing reports for local adverse reactions to topical steroids include atrophy, striae, telangiectasia, dryness, perioral dermatitis, secondary infection, and miliaria.

USE IN SPECIFIC POPULATIONS Pregnancy Teratogenic Effects: Pregnancy Category C There are no adequate and well-controlled studies in pregnant women. Pregnant women were excluded from the clinical studies conducted with Enstilar ® Foam. Enstilar ® Foam should be used during pregnancy only if the potential benefit to the patient justifies the potential risk to the fetus. Animal reproduction studies have not been conducted with Enstilar ® Foam. Enstilar ® Foam contains calcipotriene that has been shown to be fetotoxic and betamethasone dipropionate that has been shown to be teratogenic in animals when given systemically. Nursing Mothers Systemically administered corticosteroids appear in human milk and can suppress growth, interfere with endogenous corticosteroid production, or cause other untoward effects. It is not known whether topically administered calcipotriene or 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 Enstilar ® Foam is administered to a nursing woman. Instruct the patient not to use Enstilar ® Foam on the breast when nursing. Pediatric Use Safety and effectiveness of the use of Enstilar ® Foam in pediatric patients have not been studied. Because of a higher ratio of skin surface area to body mass, children under the age of 12 years are at particular risk of systemic adverse effects when they are treated with topical corticosteroids. They are, therefore, also at greater risk of HPA axis suppression and adrenal insufficiency with the use of topical corticosteroids. Cushing’s syndrome, linear growth retardation, delayed weight gain, and intracranial hypertension have been reported in pediatric patients treated with topical corticosteroids. Local adverse reactions including striae have been reported with use of topical corticosteroids in pediatric patients. Geriatric Use Of the total number of subjects in the controlled clinical studies of Enstilar ® Foam in plaque psoriasis, 97 were 65 years or older, while 21 were 75 years or older. No overall differences in safety or effectiveness of Enstilar ® Foam were observed between these subjects versus younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. PATIENT COUNSELING INFORMATION [Advise the patient to read the FDA-approved patient labeling (Patient Information and Instructions For Use)] Inform patients of the following: • Instruct patients to shake before use. • Instruct patients not to use more than 60 g every 4 days. • Discontinue therapy when control is achieved unless directed otherwise by the physician. • Avoid use of Enstilar ® Foam on the face, underarms, groin or eyes. If this medicine gets on face or in mouth or eyes, wash area right away. • Wash hands after application. • Do not occlude the treatment area with a bandage or other covering unless directed by the physician. Instruct the patients not to use other products containing calcipotriene or a corticosteroid with Enstilar ® Foam without first talking to the physician. • Instruct patients who use Enstilar ® Foam to avoid excessive exposure to either natural or artificial sunlight (including tanning booths, sun lamps, etc.). Physicians may wish to limit or avoid use of phototherapy in patients who use Enstilar ® Foam. • Enstilar ® Foam is flammable; avoid heat, flame, or smoking when applying this medication. •The foam can be sprayed holding the can in any orientation except horizontally. Manufactured by: Colep Laupheim GmbH & Co. KG Fockestraße 12 88471 Laupheim Germany (DE)

Distributed by: LEO Pharma Inc. 1 Sylvan Way, Parsippany, NJ 07054

LEO, the LEO Lion Design, and Enstilar are registered trademarks of LEO Pharma A/S. ©2015 LEO Pharma Inc. All rights reserved. November 2015 MAT-01533


March/April 2016

Volume 14 • Issue 2

Editorial

Is There a Cellulitis Epidemic? Lawrence Charles Parish, MD, MD (Hon); Jason B. Lee, MD; Daniel H. Parish, MD, JD

C

ellulitis has traditionally been an uncommon diagnosis. The concept is often vague, and the clinical picture, which is not distinctive, may be described as induration extending from the dermis to the subcutaneous tissue, with heat, redness, induration, and tenderness. There may be accompanying fever and chills.1 During the 21st century, the diagnosis has been made so frequently that the medical community and even patients might wonder whether we are in the midst of an epidemic, at least in Philadelphia.2 Considering the Diagnosis T:10.5 in

S:9.75 in

There are many dermatologic conditions that might fall into an umbrella term of cellulitis; however, not every erythematous lesion represents cellulitis nor is every cutaneous inflammatory process indicative of bacterial infection. Take for example, elephantiasis and stasis dermatitis, both of which may be misdiagnosed as cellulitis. Many dermatides are, by definition, red and inflamed. There may be secondary impetigination, so that there are oozing and crusting. Once pustules are seen, the individual lesion can no longer be considered cellulitis. For example, a boil, more properly called a furuncle, represents an erythematous tense lesion with one pustular opening, whereas the proverbial carbuncle contains several pustules. Erysipelas reflects an infection extending deeper into the dermis and may also have vesicles and pustules, which again would distinguish it from cellulitis. Ecthyma is likewise red and tender, but it has a hemorrhagic crust. The uncommon diagnosis of lymphangitis is limited to a red streak without diffuse erythema. Making the Diagnosis Although most bacterial infections are generally confirmed by a positive culture, along with antimicrobial sensitivities, this poses great difficulties in identifying cellulitis. A routine swab

of the skin is unlikely to identify the pathogen. Results from Gram staining will rarely be positive for the material obtained, and recovery through injecting saline into the red induration is infrequently successful in identifying a bacterial infection. The diagnosis of a cellulitis should be based on clinical findings, as results from skin biopsy usually do not reveal highly specific histopathologic findings. The characteristic pattern consists of perivascular and interstitial dermatitis with sparse to a moderate number of neutrophils in an edematous dermis. Types of Cellulitis The dermatologic lexicon is not void of cellulitis, but these are distinct entities. Dissecting cellulitis,3 also known as perifolliculits capitens et suffodiens, is limited to the scalp, where there is oozing, crusting, induration, and often purulent drainage. Pseudocellulitis is a complication of chemotherapy with gemcitabine, while necrotizing fasciitis has also been called necrotizing cellulitis.4 Stage IV of the decubitus ulcer pathway also has red induration, which has been termed cellulitis.5 Why the Diagnosis Is Misappropriated Let’s consider the cases of several patients we have recently encountered. Case 1: An outpatient case of irritant contact dermatitis misdiagnosed as cellulitis. A 71-year-old white woman with a 2-month history of worsening unilateral right shin dermatitis presented to the outpatient dermatology clinic (Figure 1). She was prescribed a 1-week course of cephalexin by her primary care physician, with no success. The patient used a variety of cleansing agents, including hydrogen peroxide, for several weeks. Case 2: An emergency department case of exacerbation of chronic venous stasis dermatitis. A 62-year-old white man with a history of hepatitis C, atrial fibrillation, and leukocytoclastic vasculitis presented to the emergency department with swollen feet and

From the Department of Dermatology and Cutaneous Biology, Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, PA Address for Correspondence: Lawrence Charles Parish, MD, MD (Hon), Clinical Professor of Dermatology and Cutaneous Biology, Sidney Kimmel Medical College at Thomas Jefferson University, 1845 Walnut Street, Suite 1650, Philadelphia, PA 19107 • E-mail: larryderm@yahoo.com

SKINmed. 2016;14:89–90

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March/April 2016

Editorial based on clinical findings and the history of atrial fibrillation, along with significant amount of fluid she had received during the course of the hospital stay. Discussion

Figure 1. Irritant contact dermatitis misdiagnosed as cellulitis.

Figure 2. Chronic venous stasis dermatitis misdiagnosed as cellulitis.

Stasis dermatitis, both the acute and chronic forms, represents the entity most commonly mistaken for cellulitis. Acute stasis dermatitis secondary to iatrogenically induced fluid overload is not an uncommon problem treated as cellulitis in the hospital setting. Exacerbation of chronic venous stasis dermatitis is also a common problem frequently misdiagnosed as cellulitis in the outpatient, emergency department, and inpatient settings. For those patients admitted for cellulitis and for whom a dermatology consultation has been obtained, up to 75% of patients have been misdiagnosed, having a variety of pseudocellulitis that does not require either antimicrobials nor hospitalization.4 Curtailing the misdiagnosis of cellulitis will require a collective effort by dermatologists in educating medical students and primary care residents to recognize mimickers of cellulitis, particularly the frequently present stasis dermatitis. Conclusions Cellulitis is a real entity, even if it is one of exclusion. Exposing every patient who presents with redness and possibly induration to antimicrobial therapy outweighs the concern over infection, including the significant problems with community-acquired methicillin resistant Staphylococcus aureus.6 Not only is hospitalization subjecting the patient to additional medical risks, but there is also the risk of inducing a future drug allergy and even erythema multiforme-like eruptions, preventing the use of the antimicrobial agent, when it is really needed.

Figure 3. Acute stasis dermatitis caused by cardiac complications and fluid overload misdiagnosed as cellulitis.

References 1 Parish LC, Witkowski, JA, Vassileva S. Color Atlas of Cutaneous Infections. Cambridge, MA; Blackwell Scientific; 1995:4. 2 Parish LC, Witkowski JA. Defining cellulitis. SKINmed. 2007;6:261–263.

worsening redness of his lower extremities (Figure 2). The dermatology consult team established an exacerbation of chronic venous stasis dermatitis.

3 Scheinfeld N. Dissecting 2015;13:236–238.

SKINmed.

4 Strazzula L, Cotliar J, Fox LP, et al. Inpatient dermatology consultation aids diagnosis of cellulitis among hospitalized patients: a multi-institutional analysis. J Am Acad Dermatol. 2015;73:70–75.

Case 3: An inpatient case of acute stasis dermatitis caused by cardiac complication and fluid overload. A 77-year-old African American woman who was admitted for pneumonia experienced a new onset of atrial fibrillation during her hospitalization. The patient underwent successful cardioversion, but she was also noted to have swelling of both upper and lower extremities for which she received additional antibiotics (vancomycin and cefepime) for presumed cellulitis (Figure 3). A prompt diagnosis of acute stasis dermatitis was established by the dermatology consult team, SKINmed. 2016;13:89–90

cellulitis.

5 Iori I, Pizzini AM, Arioli D, Favali D, Leone MC. Infected pressure ulcers: evaluation and management. Infez Med. 2009;17 suppl 4:88–94. 6 Yarbrough PM, Kukhareva PV, Spivak ES, Hopkins C, Kawamoto K. Evidence-based care pathway for cellulitis improves process, clinical, and cost outcomes. J Hosp Med. 2015;10:780–786.

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Volume 14 • Issue 2

COMMENTARY

Gentian Violet: Bench-to-Bedside Research That Lowers Healthcare Costs Jack L. Arbiser, MD, PhD

G

entian violet is a coal tar dye that was initially used as crystal violet for Gram staining.1 The Gram stain works in bacteria and fungi that stain positive on Gram staining and form a covalent adduct with gentian violet (crystal violet) that cannot be decolorized with alcohol. Gram-negative bacteria fail to stain because the gentian violet does not pass through the cell wall of the bacteria. It is now known that organisms that stain with gentian violet (Gram-positive bacteria, Candida species, molds, dermatophytes, and intracellular parasites including Leishmania) are sensitive to the killing activity of gentian violet.2 This has direct activity in the clinic, as gentian violet is highly effective against pyodermas, including those caused by methicillin-resistant staphylococcus aureus, superinfected atopic dermatitis, and intertrigo associated with Candida species. It may also be useful in cases of paronychia and onychomycosis. Applications The dystrophic nail can be removed in the clinic and then topical gentian violet applied to the remaining nail and nail bed. The patient is then instructed to repeat the application three times weekly for 1 month. The spongy defective nail takes up aqueous gentian violet by capillary action. After 1 month of application, a reservoir of gentian violet is present in the nail that lasts for up to 6 months. While formal studies of mycologic cure have yet to be performed, in general, patients are satisfied with results, and one can avoid drug interactions that may be problematic for systemic antifungals. A current belief is pervasive in Washington DC that medical research funded by the National Institutes of Health (NIH) leads

to high-priced and relatively ineffective therapies. As “proof ” of this belief, the use of the vascular endothelial growth factor antagonist bevacizumab is used.3 In this paper, I wish to demonstrate how NIH-funded research has led to the expansion of the use of an old and inexpensive drug, gentian violet, into novel human uses that improve patient safety and decrease healthcare expenditure. Optimal use of gentian violet by dermatologists has the potential to dramatically reduce healthcare costs. Our research on gentian violet has determined that it inhibits the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase enzyme complex in mammalian cells. As a consequence of inhibiting this complex, we downregulate the production of angiopoietin-2 (ANG-2), an angiogenic factor associated with leaky blood vessels and inflammation.4 There is an easy way for the clinician to determine whether a skin lesion is producing excess ANG-2, by looking at the color of the lesion. If it is red, it is producing ANG-2. ANG-2 is an essential part of Th2-mediated immunity (atopic dermatitis, contact dermatitis) and Th17-mediated immunity (psoriasis). ANG-2 is also highly expressed in malignant skin disorders, including melanoma. I have found that gentian violet is highly effective against atopic dermatitis by reducing bacterial superinfection as well as decreasing angiogenesis. I routinely use gentian violet for extensive contact dermatitis (poison ivy) and other inflammatory disorders with potentially high levels of ANG-2 (arthropod bites, urticaria, bullous pemphigoid). Gentian violet is also effective against palmoplantar psoriasis, especially when compounded in a lipophilic ointment under occlusion to promote absorption. Finally, I use gentian violet in combination with imiquimod for plantar warts (after paring and/or liquid nitrogen) and for cutaneous metastases of melanoma in a pal-

From the Department of Dermatology, Emory University School of Medicine, Atlanta, GA, and Veterans Affairs Medical Center, Winship Cancer Institute, Atlanta, GA Address for Correspondence: Jack L. Arbiser, MD, PhD, Department of Dermatology, Emory University School of Medicine, WMB 5309, 1639 Pierce Drive, Atlanta, GA 30322 • E-mail: jarbise@emory.edu

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March/April 2016 liative manner. By inhibiting reactive oxygen and ANG-2, the combination of gentian violet and imiquimod may increase antigen presentation and decrease the development of immunosuppressive T-regulatory cells that occur in the presence of solid tumors. A Common Question A common question about gentian violet is its safety. Because gentian violet is a dye, it is reflexively regarded as unsafe. Gentian violet has been in use in humans for almost a century. There is not a single report that links gentian violet to the development of human cancer.5 Our discoveries have extended the use of gentian to multiple cutaneous disorders at a low cost, thus proving that NIH-funded research reduces healthcare costs.

COMMENTARY Disclosures JLA was supported by grant numbers RO1 AR47901 and P30 AR42687 Emory Skin Disease Research Core Center from the National Institutes of Health, a Veterans Administration Hospital Merit Award, as well as funds from the Margolis Foundation, Rabinowitch-Davis Foundation for Melanoma Research, and the Betty Minsk Foundation for Melanoma Research. References 1 Maley AM, Arbiser JL. Gentian violet: a 19th century drug re-emerges in the 21st century. Exp Dermatol. 2013;22:775–780. 2 de Souza Pietra RC, Rodrigues LF, Teixeira E, et al. Triphenylmethane derivatives have high in vitro and in vivo activity against the main causative agents of cutaneous leishmaniasis. PLoS One. 2013;8:e51864.

Finally, we have synthesized novel derivatives of gentian violet for systemic inhibition of NADPH oxidase in vivo. One novel derivative, imipramine blue, blocks the invasion of glioblastoma multiforme into the brain parenchyma and, in combination with conventional chemotherapy (doxorubicin), leads to longterm survival in rats.6

3 Arbiser JL. Reductions in funding for medical research. JAMA. 2013;310:855–856. 4 Perry BN, Govindarajan B, Bhandarkar SS, et al. Pharmacologic blockade of angiopoietin-2 is efficacious against model hemangiomas in mice. J Invest Dermatol. 2006;126:2316–2322. 5 Arbiser JL. Gentian violet is safe. J Am Acad Dermatol. 2009;61:359.

Conclusions

6 Munson JM, Fried L, Rowson SA, et al. Anti-invasive adjuvant therapy with imipramine blue enhances chemotherapeutic efficacy against glioma. Sci Transl Med. 2012;4:127ra136.

Gentian violet and derivatives have the potential to have a tremendous positive impact on human health.

VINTAGE LABEL

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Original contribution

Correlation Between Severity Index and Quality of Life Index in Patients With Psoriasis Assessed Before and After Phototherapy Maria Isabel de Noronha Neta Couto, Msc; Sueli Carneiro, MD, PhD; João Paulo Niemeyer-Corbellini, MD, MSc; Jessica Hiromi Yoshio; Marcia Ramos-e-Silva, MD, PhD Abstract Psoriasis is a common disease whose impact on the life of patients is well documented. The authors investigated the correlation between clinical severity and quality of life in patients with psoriasis before and after phototherapy. Twenty men and women were assessed before and after 32 phototherapy sessions, employing the Dermatology Life Quality Index (DLQI) questionnaire and the Psoriasis Area Severity Index (PASI). A positive and moderate correlation was found between PASI and DLQI after phototherapy (r=0.48, P=.03). This result was not observed before treatment (r=0.13, P=.57). The clinical signs reduction obtained with phototherapy was associated with clinical improvement in patient quality of life. The negative findings for the pretreatment phase suggest a possible acceptance by patients through strategies establishment to improve the handling of the disease, which has a chronic character, and change in the disease’s perception after therapy. (SKINmed. 2016;14:93–97)

P

soriasis is a common disease mediated by the immunologic system that affects approximately 2% to 4% of the world’s population.1,2 Entailed by the clinical complexity of its manifestations, the negative impact on the life of the patients has been observed and is well documented, not only regarding the characteristic cutaneous lesions and articular involvement, but also in relation to psychologic aspects. Such impact could lead to restrictions associated with work and social, leisure, and affective activities.3,4

verse effects compared with other systemic medications.10,11 It has been proposed that PUVA and NB-UVB leads to a positive impact on the quality of life of the patients; however, the association between disease severity and quality of life, as measured by PASI and the questionnaire scores, are still being discussed.4

In order to assess the quality of life of patients with psoriasis, the Dermatology Life Quality Index (DLQI) questionnaire was introduced, specific for dermatology, self-administration, easily understandable, and validated for the Portuguese language.5,6 The Psoriasis Area Severity Index (PASI), commonly utilized in clinical evaluation, was used to quantify treatment response.7

The objective of the present study was to investigate the correlation between the clinical severity of psoriasis, as assessed by PASI, and the quality of life, through the DLQI questionnaire, before and after phototherapy. Methods

Psoralen plus UV-A (PUVA) and narrowband UV-B (NB-UVB) phototherapy are two therapeutic options frequently used to treat psoriasis.8,9 These therapies have been proven to reduce the extension and intensity of plaques and present with fewer ad-

This was an observational study of longitudinal analytical design. The sample included 20 men and women, aged 18 to 64 years, with a clinical and/or histopathologic diagnosis of psoriasis without joint involvement. The patients were observed at the ambulatory for cutaneous/articular diseases of the dermatology service of the University Hospital Clementino Fraga Filho of the Federal University of Rio de Janeiro (HUCFF/UFRJ) in the city of Rio de Janeiro, Brazil.

From the University Hospital and School of Medicine, Federal University of Rio de Janeiro, Brazil Address for Correspondence: Maria Isabel Noronha Neta Couto, Rua Padre Frederico Gióia 266, Niteroi 24355-210 Brazil • E-mail: belnoronha@yahoo.com.br

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ORIGINAL CONTRIBUTION Patients underwent 32 PUVA or NB-UVB phototherapy sessions, twice weekly, following the evaluation protocol of the HUCFF/UFRJ photodermatology ambulatory service. PUVA was indicated in patients with extensive cutaneous involvement, those with thick lesions, and those with skin type III or higher, while UVB was indicated in patients with type I and II skin, according to Fitzpatrick classification, and those with less extensive lesions. Two hours before exposure to UVA radiation, oral 8-methoxypsoralen was administered in a dose of 0.4 mg/kg to 0.6 mg/kg of body weight. The initial UVA and NB-UVB employed in our department is based on the color of the patient’s skin and also according to Fitzpatrick’s skin type classification (Tables I and II). The increase in the irradiated light dose is determined by the intensity of the erythema caused in the previous session.

Table I. Skin Types/Initial NB-UVB Dose Skin Type

Initial Radiation, mJ

I and II

100–130

III to V

130–150

VI

150–200

Abbreviation: NB-UVB, narrowband UV-B.

Table II. Skin Types/Initial PUVA Dose Skin Type

Characteristics

Initial Radiation, Joules/cm2

I

Always burns, never gets tan

0.4

II

Always burns, sometimes gets tan

1.0

III

Sometimes burns, always gets tan

1.5

IV

Never gets burned, always gets tan

2.0

V

Moderately pigmented

2.5

VI

Black

3.0

All patients filled out the DLQI questionnaire and were clinically evaluated by the same investigator using PASI before and after phototherapy. PASI divides the body into four regions (head, trunk, and upper and lower limbs), estimating the affected area in percentage and disease severity by clinical signs (erythema, desquamation, and thickness).12 The ethics committee of the HUCFF/UFRJ approved the study and each participant signed a consent form confirming that they were taking part in the research voluntarily.

Abbreviation: PUVA, psoralen plus UV-A.

Statistical Analysis The Kolmogorov-Smirnov test was used to assess the consistency of all data. Descriptive statistics were carried out for the following variables: age, time of lesion onset (number of years of lesion duration), education (years in school), and average salary in Brazilian reais. Paired t test was used to observe differences in results of PASI and DLQI before and after treatment.

Table III. Social and Economic Profile of the Patients With Psoriasis Variable

Average

Standard Deviation

Age, y

48.9

17.8

Lesion duration, y

12.6

5.2

Education, y in school

7.8

8.2

Average salary (in BRL)

998.00

783.00

Pearson (r) coefficient test was then applied for analysis of the correlation between the results of the DLQI questionnaire and the PASI evaluation before and after treatment. Data analysis was carried out using SPSS version 20.0 (IBM Corp, Armonk, NY) and the level of significance was set at 5%.

Table IV. Comparison of Paired t Test for PASI and DLQI Before and After Treatment Evaluation (n=20)

Before Treatment

After Treatment

PASI

21.34+11

13.1+10.4a

DLQI

10.6+6.2

3.9+6.2a

Results Descriptive data and financial and social profiles are shown in Table III. An average reduction of 8.24 (P<.01) was found in the clinical scores of patients evaluated by PASI. A reduction of 6.7 in the average score (P<.01) and in the scores for quality of life on the DLQI questionnaire were also found. Results of the paired t test between the score differences and DLQI before and after phototherapy are shown in Table IV.

Abbreviations: DLQI, Dermatology Life Quality Index; PASI, Psoriasis Area Severity Index. Values are expressed as averages and standard deviations. aP<.01. SKINmed. 2016;14:93–97

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Table V. Pearson Coefficient Index Between PASI and DLQI Before Treatment (n=20)

After Treatment (n=20)

Before and After Treatment (n=40)

Evaluation

PASI

PASI

PASI

DLQI

r=0.13 P=.57

r=0.48 P=.03a

r=0.37 P=.02a

Abbreviations: DLQI, Dermatology Life Quality Index; PASI, Psoriasis Area Severity Index. aSignificant correlation at level .05.

A positive and moderate correlation was found between PASI and DLQI after phototherapy. There was no correlation between the two variables before treatment. After evaluating the results obtained before and after treatment, a moderate positive correlation was also found, as demonstrated in Table V. Discussion The PASI and DLQI are widely accepted and utilized in psoriasis patients for clinical measurements and quality of life, respectively. The area and severity index for psoriasis was developed in 1978 and, despite receiving criticism for its interobserver reliability (the level of agreement between different persons when applying the scale for the same patient),13 it is still used in clinical media and research to obtain more objective clinical measures. There has been a growing trend in recent years for the evaluation of diseases and treatments, taking into consideration the perception of the patient on the impact of their disease on their health state. The application of such measures or parameters should be encouraged in daily clinical practice.14 The DLQI is frequently used for its subjective character, for being specific for dermatological diseases, for its validity and reliability, and for having been tested and translated in several countries,15 with assessment of the patients’ symptoms, feelings, daily activities, leisure, work, school, personal relations, and collateral effects of the treatments.16 A statistically significant reduction in PASI and DLQI scores of patients after phototherapy shows an improvement in quality of life and reduction of the affected cutaneous area. PUVA and NB-UVB are frequently used options for psoriasis treatment, mainly when a single topic treatment is insufficient for regression of the picture. These therapies have shown welldocumented positive results in the medical literature,17 reporting a reduction in plaques without adverse systemic effects whether from oral immunomodulator, immunosuppressor, or immunobiological medications.8,9 SKINmed. 2016;14:93–97

It would be expected that patients with higher scores on the quality-of-life questionnaire would be those with a higher PASI, ie, the disease severity would be associated with a worse quality of life. This correlation, however, has been frequently studied and has shown conflicting results. The findings of the present study corroborate earlier studies correlating PASI with DLQI after several treatments such as phototherapy,18 infliximab,15,19 and etanercept.20 In a recent article,21 investigators found the same results in 13 reviewed studies, which evaluated 22 treatments with biologics and reported a coefficient index (r) of 0.80. Cutaneous diseases have been shown to cause deleterious effects on patient quality of life. Psoriasis, which is considered a type of psychodermatosis, has a relevant psychosocial aspect. The disease’s negative impact on patients has long been reported and results in significant stress for the patient.22 Patients often feel ashamed and rejected by others and consider themselves unattractive and sexually undesirable,21 strongly disturbing social relationships, self-image, and self-esteem.23 No association was found in the present study between the two study variables before treatment with phototherapy. The studies that did not find a correlation between psoriasis severity and quality of life discuss the chronic character of the disease, which implies a better acceptance by the patient along the years, through the formation of strategies to better cope with the disease and its impact.24 The average duration of the disease was 12.6 years. Another question is how the affected area influences quality of life. The presence of a few lesions on exposed or special areas, such as the face, neck, or genital region, impacts social relations and may compromise work, while extensive lesions on nonvisible areas have lesser impact. Similarly, the PASI score does not reflect the involvement of the nails and genital region, which can also influence quality of life. The way the patient sees the disease is fundamental in the evaluation of quality of life. It should be noted that this study was performed in a tropical country, in a city with an extended beach shoreline, favoring body exposure and greater cultural acceptance of such exposure,

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possibly causing less shame in exposing their extensive lesions. It has been previously demonstrated that patients’ views regarding psoriasis are not associated with the severity of the disease, suggesting that they are responding psychologically to their particular vision of the disease. This may explain why it is not possible to associate the emotional impact with the intensity of the picture or that such a relationship occurs in a less intense manner.19,20,24–26 This study showed a moderate correlation only after treatment, raising the theory that the individual gains a better life perspective with the reduction of the involved area. Investigators27 assessing the correlation between quality of life and clinical improvement in 138 patients who were beginning several types of treatments found a moderate correlation between the two variables and observed the psychological impact caused by the improvement of the clinical picture. Conclusions Despite the small number of patients in this study (n=20), the findings question the pertinence of other studies that address the correlations between clinical and quality-of-life variables in patients treated with phototherapy. These findings show that improvement of treatment can change the manner in which patients cope with the disease. Disclosures Funding was provided by Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) and Fundação de Amparo à Pesquisa do Estado do Rio de Janeiro (FAPERJ). The present study was previously approved by the ethics committee of the University Hospital of the Federal University of Rio de Janeiro. References 1 Dilnawaz M, Sadiq S, Zafar IS, et al. Clinical audit: baseline Psoriasis Area and Severity Index (PASI) and Dermatology Life Quality Index (DLQI) assessment of psoriasis patients. J Pak Assoc Dermatol. 2013;23:407–411. 2 Basavaraj KH, Darshan MS, Shanmugavelu P, et al. Study on the levels of trace elements in mild and severe psoriasis. Clin Chim Acta. 2009;405:66–70. 3 Lago E, Carneiro S, Cuzzi T, et al. Clinical and immunohistochemical assessment of the effect of cyclosporin in keratinocytes and dermal dendrocytes in psoriasis. J Cutan Pathol. 2007;34:15–21. 4 Silva MF, Fortes MR, Miot LD, Marques SA. Psoriasis: correlation between severity index (PASI) and quality of life index (DLQI) in patients before and after systemic treatment. An Bras Dermatol. 2013;88:760–763. 5 Schmitt J, Wozel G, Garzarolli M, Viehweg A, Bauer M, Leopold K. Effectiveness of interdisciplinary vs. derma-

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tological care of moderate-to-severe psoriasis: a pragmatic randomised controlled trial. Acta Derm Venereol. 2014;94:192–197. 6 Martins GA, Arruda L, Mugnaini AS. Validation of life quality questionnaires for psoriasis patients. An Bras Dermatol. 2004;79:521–535. 7 Poulin Y, Sheth P, Gu Y, Teixeira HD. Health-related quality of life worsens disproportionately to objective signs of psoriasis after withdrawal of adalimumab therapy. Dermatol Ther (Heidelb). 2014;4:33–42. 8 Carrascosa JM, Gardeazábal J, Pérez-Ferriols A, et al; Grupo Español de Fotobiología. Documento de consenso sobre fototerapia: terapias PUVA y UVB de banda estrecha. Actas Dermosifiliogr. 2005;96:635–658. 9 Dawe RS, Cameron HM, Yule S, et al. A randomized comparison of methods of selecting narrowband UV-B starting dose to treat chronic psoriasis. Arch Dermatol. 2011;147:168–174. 10 Diffey BL, Farr PM. The challenge of follow-up in narrowband ultraviolet B phototherapy. Br J Dermatol. 2007;157:344–349. 11 Beissert S, Schwarz T. Role of immunomodulation in diseases responsive to phototherapy. Methods. 2002;28:138–144. 12 Mabuchi T, Yamaoka H, Kojima T, et al. Psoriasis affects patient’s quality of life more seriously in female than in male in Japan. Tokai J Exp Clin Med. 2012;37:84–88. 13 Faria JR, Aarão AR, Jimenez LM, Silva OH, Avelleira JC. Inter-rater concordance study of the PASI (Psoriasis Area and Severity Index). An Bras Dermatol. 2010;85:625– 629. 14 Klassen AF, Newton JN, Mallon E. Measuring quality of life in people referred for specialist care of acne: comparing generic and disease-specific measures. J Am Acad Dermatol. 2000;43:229–233. 15 Reich K, Griffiths CE. The relationship between quality of life and skin clearance in moderate-to severe psoriasis: lessons learnt from clinical trials with infliximab. Arch Dermatol Res. 2008;300:537–544. 16 Consenso Brasileiro de Psoríase. Guias de avaliação e tratamento. 2nd ed. Sociedade Brasileira de Dermatologia: Rio de Janeiro; 2012:108. 17 Archier E, Devaux S, Castela E, et al. Efficacy of psoralen UV-A therapy vs. narrowband UV-B therapy in chronic plaque psoriasis: a systematic literature review. J Eur Acad Dermatol Venereol. 2012;26:11–21. 18 Al Robaee AA, Alzolibani AA. Narrowband ultraviolet B phototherapy improvesthe quality of life in patients with psoriasis. Saudi Med J. 2011;32:603–606. 19 Feldman SR, Gordon KB, Bala M, et al. Infliximab treatment results in significant improvement in the quality of life of patients with severe psoriasis: a double-blind placebo-controlled trial. Br J Dermatol. 2005;152:954– 960. 20 Griffiths CE, Sterry W, Brock F, et al. Pattern of response in patients with moderate-to severe psoriasis treated with etanercept. Br J Dermatol. 2015;172:230–238.

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ORIGINAL CONTRIBUTION

21 Mattei PL, Corey KC, Kimball AB. Psoriasis Area Severity Index (PASI) and the Dermatology Life Quality Index (DLQI): the correlation between disease severity and psychological burden in patients treated with biological therapies. J Eur Acad Dermatol Venereol. 2014;28:333– 337. 22 Finlay AY, Kelly SE. Psoriasis: an index of disability. Clin Exp Dermatol. 1987;12:8–11. 23 Arruda LH, Campbell GA, Takahashi MD. Psoríase. An Bras Dermatol. 2001;76:141–165. 24 de Arruda LH, De Moraes AP. The impact of psoriasis on quality of life. Br J Dermatol. 2001;1444:33–36.

25 Touw CR, Hakkaart-Van Roijen L, Verboom P, et al. Quality of life and clinical outcome in psoriasis patients using intermittent cyclosporin. Br J Dermatol. 2001;144:967– 972. 26 Mazzotti E, Picardi A, Sampogna F, et al. Sensitivity of the Dermatology Life Quality Index to clinical change in patients with psoriasis. Br J Dermatol. 2003;149:318– 322. 27 Torres RA, Silva SA, Magalhães RF, Morcillo AM, Velho PE. Comparison of quality of life questionnaires and their correlation with the clinical course of patients with psoriasis. An Bras Dermatol. 2011;86:45–49.

Pogonology

Courtesy of Diana Garrisi, PhD, London, UK

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Volume 14 • Issue 2

Original contribution

Clinical and Laboratory Characteristics of Patients With Erythema Nodosum Sibel Dogan, MD; Aysen Karaduman, MD; Sibel Ersoy Evans, MD Abstract Erythema nodosum (EN) represents an acute, erythematous nodular eruption that is generally found on the lower aspects of the legs. Despite the variety of triggering factors, the clinical findings of EN are classic. It is often hard to determine which patients have an underlying systemic disorder. The aim of this study was to investigate clinical and laboratory parameters in patients with EN, especially those with an underlying systemic disorder. A total of 43 patients diagnosed with EN at an adult and children’s hospital were retrospectively reviewed for triggering factors, any underlying systemic diseases, clinical features, laboratory parameters, treatment modalities, and disease outcome. The mean age of the patients was 40.91±15.57 years (minimum 7 years, maximum 71 years). Patients with an underlying systemic disorder were grouped as complicated EN (CEN), patients without an underlying disorder were grouped as non-complicated EN (NCEN). Patients with EN more frequently presented with more nonpretibial localizations than patients with NCEN (P=.023). Platelet levels in patients with CEN were significantly higher than in patients with NCEN (P=.036). Erythrocyte sedimentation rate, C-reactive protein, and procalcitonin levels did not differ among the two groups (P>.05). Hospitalization shortened the active disease duration (P=.046). EN lesions present on the nonpretibial area, which may be a clue for systemic associations of the disease. The presence of elevated platelet levels may indicate systemic inflammatory and infectious diseases in patients with EN. Procalcitonin, which is a marker for systemic infection, was not helpful in detecting chronic infections such as tuberculosis or systemic fungal infections in patients. (SKINmed. 2016;14:99–103)

E

rythema nodosum (EN), is an acute, erythematous nodular eruption that is generally located on the lower aspects of the legs.1 It is the most common form of panniculitis and may occur as a result of systemic infections, inflammatory diseases, or medication.1–4 Despite a variety of triggering factors, the clinical findings of EN are classic and it is often hard to determine which patients have an underlying systemic disorder.

Materıal and Methods

Patients

The main purpose of this study was to investigate potential triggers, such as infectious-inflammatory diseases and medication in patients with EN, and to determine any relationship between inflammatory acute phase reactants and underlying systemic associations of EN. In the present study, 43 patients diagnosed with EN at our clinic were evaluated for their triggering factors, underlying systemic diseases, clinical features, laboratory parameters, treatment modalities, and disease outcome

Patients diagnosed with EN between January 2005 and December 2012 at our adult and children’s hospital were assesed retrospectively from patient medical records. The diagnosis of EN was made on a clinical basis, and histopathologic examination was available in 16 patients (37.2%). The clinical diagnosis of EN was made if there were acute inflammatory erythematous nodules and plaques on the anterior aspects of the lower extremities. A history of EN was questioned. We recorded the male to female ratio, age at onset, age at first visit, duration of complaints, history of upper airway infection within a month prior to EN, inflammatory disease including Behçet disease (BD), inflammatory bowel disease, rheumatoid arhritis (RA), systemic lupus erythematosus, drug use within a month prior to

From the Department of Dermatology and Venereology, Hacettepe University, Ankara, Turkey Address for Correspondence: Sibel Dogan, MD, Hacettepe University, Faculty of Medicine, Department of Dermatology, Hacettepe Mh. 06230, Ankara, Turkey • E-mail: sibel.dogan@hacettepe.edu.tr

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EN, pregnancy, systemic infectious diseases including tuberculosis (TB), and gastroenteritis other than upper respiratory tract infections.

Table I. Localization of Erythema Nodosum Lesions

Laboratory studies Complete blood cell count, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), anti-streptolysin O antibody (ASO) titer, procalcitonin, liver and renal function tests, urine analysis, chest x-ray, throat culture, and purified protein derivative (PPD) skin test for Mycobacterium tuberculosis were obtained. Interpretation of the findings from PPD test was made at 72 hours after intradermal skin testing was performed.

Treatment and Prognosis Treatment modalities were chosen according to clinical presentation and severity. Follow-up admissions of the patients were investigated from medical charts.

Statistical Evaluation Statistical analyses were performed using SPSS version 17.0.2 (SPSS Inc, Chicago, IL). P<.05 was accepted as statistically significant for all results. To identify prognostic factors, patient and treatment variables were analyzed by means of chi-square test and Fisher exact probability. Background characteristics were compared using chi-square and Mann-Whitney U tests. Results

Demographic data A total of 43 patients diagnosed with EN were evaluated. Biopsies were performed in patients who had atypical presentations, so that the final diagnosis was made according to histopathologic examination. A total of 62.8% of patients (N=27) were diagnosed clinically and the rest were diagnosed by histopathologic examination. Female to male ratio was 6.2 (37:6). The mean age at first visit was 40.91±15.57 years (minimum 7 years, maximam 71 years). The youngest patient was a 7-year-old with streptococcal pharyngitis and the oldest was a 71-year-old man with acute myeloblastic leukemia.

Clinical features Of the 43 patients, 30.2% (N=13) had recurrent EN. Two patients had two episodes, five had three episodes, one had four episodes, one had five episodes, and four had six episodes of EN. On follow-up, three of these patients and two patients with first attack were reported to have a relapse. A total of 38 patients had more than one lesion. The mean lesion number was 5.4±3.8. Although the most common localization of EN was the pretibial SKINmed. 2016;14:99–103

Localization

Number

Percentage

Pretibial lesions

28

65.1

Multiple lesions on lower limbs

4

9.3

Multiple lesions on lower + upper limbs

9

20.9

Multiple lesions on posterior legs

2

4.7

area, there were different sites of localizations in other patients such as multiple lesions limited to the legs, to the legs and arms, and solely to the posterior aspects of the legs (Table I). For comparisons, distribution of EN was grouped as EN with classic localization (N=28) and EN with nonclassic localizations (N=15).

Etiologic factors The most common etiologic factor (46.5%) involved upper respiratory tract infections with accompanying drug intake prior to EN (Table II). Inflammatory diseases (BD, pulmonary sarcoidosis, RA), pregnancy, systemic infections (pulmonary TB, systemic fungal infection), and other systemic diseases (AML, polycythemia vera) were less frequently observed. For comparisons, patients who had systemic associations such as inflammatory diseases (BD, sarcoidosis, RA), systemic infections (TB, systemic fungal infection, salmonella gastroenteritis), or other systemic diseases (AML, polycythemia vera) were grouped as having complicated EN (CEN), and the remaining patients (idiopathic, pregnancy, drugs, upper respiratory tract infection) were considered to have noncomplicated EN (NCEN). A significant difference was found between EN localizations when the patients were compared, depending on whether they were complicated by a serious underlying disease. Patients with CEN more frequently presented with nonclassic EN localizations (P=.023).

Laboratory workup The men in the study had a mean white blood cell count of 12.5±1.2 ×10E3/µL, whereas the women had a mean white blood cell count of 9.4±3.5 ×10E3/µL. The men had a higher level of leucocytes than the women (P=.034). Patients with BD had significantly lower levels of hemoglobin (mean, 10.75±0.63 g/dL) when compared with the remaining patients with EN (mean, 12.54±1.23 g/dL) (P=.047). Platelet levels of patients with CEN (mean, 374±16.1 ×10E3/ µL) were significantly higher than those of NCEN patients

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ORIGINAL CONTRIBUTION Findings from PPD skin testing revealed anergic results in two and positive results in nine patients. These patients received consultations with the pulmonology department. One patient was diagnosed with pulmonary TB. For the remaining patients, results from acid-fast bacilli sputum analysis, sputum culture, polymerase chain reaction (PCR), and culture of bronchoalveolar lavage samples were negative for Mycobacterium tuberculosis.

Table II. Associated Conditions in Erythema Nodosum Associated Condition

Number

Percentage

History of upper respiratory tract infection

20

46.5

Inflammatory diseases

9

20.1

Behçet disease

6

14

Sarcoidosis (lung)

2

4.6

Treatment

Rheumatoid arthritis

1

2.3

Systemic infections

4

9.3

Pulmonary tuberculosis

1

2.3

Systemic fungal infection (pulmonary aspergillosis)

1

2.3

Salmonella gastroenteritis

2

4.6

Other systemic diseases

2

4.6

The mean disease duration was 16.3±11.26 days. Hospitalized patients had significantly shorter disease duration when compared with nonhospitalized patients (P=.046). Systemic corticosteroids and nonsteroidal anti-inflammatory drugs were more frequently used in patients who had a longer disease duration (P=.018). Systemic corticosteroids were also more frequently chosen as a treatment modality in patients with multiple attacks than patients with a single attack (P=.009).

Acute myeloid leukemia

1

2.3

Polycythemia vera

1

2.3

Pregnancy

3

7

Idiopathic

7

16.3

Drugsa

14

32.6

β-Lactam antibiotics

1

2.3

β-Lactam antibiotics + nonsteroidal anti-inflammatory drugs

5

11.6

Nonsteroidal anti-inflammatory drugs

7

25.6

Systemic antifungal drugs

1

2.3

Patients who had elevated ASO titers also had a significantly longer disease duration (P=.043), and they had significantly shorter hospital stays (P=.049). Discussıon EN is the most common form of panniculitis that occurs as a result of complex hypersensitivity reaction caused by several systemic infections, inflammatory diseases, and drugs.1–4 Despite the variety of triggering factors, the clinical findings of EN are generally classic. EN can be triggered by local infections, drugs, or even physiologic conditions, such as pregnancy, whereas serious underlying diseases may also cause EN. There are no supporting data for which patients should be investigated more thoroughly for an underlying disorder; therefore, this study aimed to describe any clinical and/or laboratory parameters that might assist clinicians in differentiating these patients. The study included patients with EN who were admitted to a tertiary medical center; thus, the ratio of patients with serious complicated diseases might be more than expected.

Drug intake was a common condition in many patients (n=14) and all had a coexisting infectious disease such as upper airway tract infection or systemic fungal infection while using the documented drug. a

(mean, 304±76.2 ×10E3/µL) (P=.036). Procalcitonin level was elevated in only one patient who had salmonella gastroenteritis with a concurrent upper respiratory tract infection. CRP was elevated in 25 patients (58.1%). ESR, CRP, and procalcitonin levels did not differ between the two groups. No difference was found in platelet, ESR, CRP, and procalcitonin levels between patients with classic and nonclassic EN localizations (P>.05). Sixteen of the EN patients (37.2%) had elevated ASO titers, and results from throat culture tests were negative in all of them. SKINmed. 2016;14:99–103

EN lesions are classically located on pretibial areas, although involvement of extensor surfaces of the forearms, thigh, and trunk may also occur.2,4 The localization of EN lesions showed various differences among our patients, with 34.9% of the patients’ lesions not pretibial. Different types of panniculitis are known to occur on certain anatomic regions of the body; however, to our knowledge, it was demonstrated for the first time that the lesion localization of EN was important in predicting whether there was an underlying disease.1,2 As a result, different clinical localizations of EN can be a useful clue for the clinician to suspect and assess for underlying diseases.

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ORIGINAL CONTRIBUTION

There are various infectious causes of EN, including bacterial (group A streptococci, mycobacteria, yersinia spp, mycoplasma, chlamydia, salmonella, and campylobacteria), viral (herpes simplex virus, Epstein-Barr virus, and hepatitis B and C), fungal (coccidioidomycosis, histoplasmosis, blastomycosis, and kerion celci).1–4 Streptococcal infections have been reported in up to 16% to 18% of adults and 48% of children with EN.5–7 For the detection of streptococci, investigation of ASO titers and realtime PCR assays are suggested at the time of diagnosis and after 4 weeks of follow-up in patients with EN.4 The most common infectious agent was streptococci in our study, as diagnosed by elevated ASO titer in 37.2% of our patients. One of our patients who presented with EN was diagnosed with active pulmonary TB. Although it is accepted as a historic disease in many developed countries, TB is still a challenging infectious disease in Turkey and an important association of EN.1–4,6,8 Adipose tissue is suggested to act as a reservoir for Mycobacterum tuberculosis.8 Free antigens of bacilli and oxygenated mycolic acids induce type III to IV hypersensitivity reactions and transform macrophages into foam cells.9 Bacillus Calmette-Guerin (BCG) vaccination is suggested to cause EN as well.3,4,7 There are few data about EN presenting in patients without TB but only positive PPD test findings.4,8 Because BCG is within the routine vaccination program in Turkey, positive PPD test results are frequently confronted in daily practice; nevertheless, Mycobacterium tuberculosis is still an epidemic threat, and positive PPD test results are of great importance in indicating further investigations in patients with EN in Turkey. The most common inflammatory disorder accompanying EN was BD, which is a multisystem vasculitis characterized by hyperreactive neutrophils and autoinflammation.10 EN is a clinical feature of BD in approximately 45% of patients, and EN lesions of BD reveal a higher frequency of histopathologic vasculitis.10–11 Although BD patients with EN had significantly lower levels of hemoglobin in the present study, it was considered as anemia of chronic disease. Platelet levels in patients with complicated EN were significantly higher than in patients without a systemic infectious or inflammatory disease. Platelets are known to play an important role in inflammatory processes.12 A systemic response, which induces the bone marrow, stimulates the increase in platelet levels as well as their secretory functions. Increased levels of thromboxane A2, platelet activating factor, interleukin-1β, tumor necrosis factor-α, vascular endothelial growth factor, and platelet-derived growth factor, which are secreted by platelets, are observed in sites of inflammation.12,13 Interleukin-6, interferon-γ, and tumor necrosis factor lead to stimulation of thrombocytopoiesis, which SKINmed. 2016;14:99–103

also contributes to systemic inflammation and inflammation within adipose tissue.12,13 Our results support the notion that elevated platelet level is an important laboratory finding, and, as a sensitive acute phase reactant, it indicates a more detailed investigation for systemic associations in EN patients. Procalcitonin and CRP levels were not correlated with etiologic factors. Procalcitonin is a specific marker of serious infection, and it is elevated in systemic inflammatory response syndrome, sepsis, and multiorgan failure.14 In the present study, only one patient with salmonella and upper respiratory tract infection had an elevated procalcitonin level. The limited number of patients in our study may also have caused an underdetection of procalcitonin’s sensitivity as a marker of infectious diseases, but current data from this study suggest that systemic infections should still be suspected in EN patients with normal procalcitonin levels. CRP is a frequently used laboratory parameter that is efficient in both monitorizing systemic infections and vascular inflammation.15 Although a large percentage of EN patients had elevated CRP levels, it was not statistically significant in differentiating CEN, because many of the patients with previous infections, such as upper respiratory tract infections, had elevated CRP values as well. As a result, elevated CRP is not considered a specific marker for CEN. The most common treatment chosen for EN patients was bed rest, elevation of the affected extremity, cool wet compresses, and nonsteroidal anti-inflammatory drugs. Systemic corticosteroids were more frequently chosen as a treatment modality in patients with multiple attacks and longer disease duration. Hospitalization shortened disease duration, leading us to assume that bed rest significantly decreases the inflammation in panniculus and should be suggested together with conventional anti-inflammatory therapy to all EN patients. Conclusions Our study shows that EN presents in different anatomic regions other than the pretibial area and this can be a clue for systemic associations of the disease. BD was the most common inflammatory disease associated with EN in our study population. Mycobacterium tuberculosis is still an important inciting factor of EN. Platelet levels appear to be a reliable acute phase reactant for suspecting systemic associations of EN, although CRP and procalcitonin levels did not show significant differences as expected. General treatment modalities are safe and effective, with hospitalization significantly shortening the duration of disease.

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References 1 Gilchrist H, Patterson JW. Erythema nodosum and erythema induratum (nodular vasculitis): diagnosis and management. Dermatol Ther. 2010;23:320–327. 2 Requena L, Yus ES. Erythema nodosum. Dermatol Clin. 2008;26:425–438. 3 Requena L, Sánchez Yus E. Erythema nodosum. Semin Cutan Med Surg. 2007;26:114–125. 4 Schwartz RA, Nervi SJ. Erythema nodosum: a sign of systemic disease. Am Fam Physician. 2007;75:695–700.

9 Neyrolles O, Hernández-Pando R, Pietri-Rouxel F, et al. Is adipose tissue a place for Mycobacterium tuberculosis persistence? PLoS One. 2006;1:e43 10 Yazici H, Fresko I, Yurdakul S. Behçet’s syndrome: disease manifestations, management, and advances in treatment. Nat Clin Pract Rheumatol. 2007;3:148–155. 11 Misago N, Tada Y, Koarada S, Narisawa Y. Erythema nodosum-like lesions in Behçet’s disease: a clinicopathological study of 26 cases. Acta Derm Venereol. 2012;92:681–686.

5 Mert A, Kumbasar H, Ozaras R, et al. Erythema nodosum: an evaluation of 100 cases. Clin Exp Rheumatol. 2007;25:563–570.

12 Matowicka-Karna J, Kamocki Z, Polinska B, Osada J, Kemona H. Platelets and inflammatory markers in patients with gastric cancer. Clin Dev Immunol. 2013;2013:401623.

6 Requena L, Yus ES. Panniculitis. Part I. Mostly septal panniculitis. J Am Acad Dermatol. 2001;45:163–183

13 Powner DJ, Hoots WK. Thrombocytosis in the NICU. Neurocrit Care. 2008;8:471–475.

7 Kakourou T, Drosatou P, Psychou F, Aroni K, Nicolaidou P. Erythema nodosum in children: a prospective study. J Am Acad Dermatol. 2001;44:17-21.

14 Lee H. Procalcitonin as a biomarker of infectious diseases. Korean J Intern Med. 2013;28:285–291.

8 Chen S, Chen J, Chen L, et al. Mycobacterium tuberculosis infection is associated with the development of erythema nodosum and nodular vasculitis. PLoS One. 2013;8:e62653.

15 Ilhan N, Ilhan Y, Akbulut H, Kucuksu M. C-reactive protein, procalcitonin, interleukin-6, vascular endothelial growth factor and oxidative metabolites in diagnosis of infection and staging in patients with gastric cancer. World J Gastroenterol. 2004;10:1115–1120.

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䴀愀礀 ㈀ ⴀ㈀㌀Ⰰ ㈀ ㄀㘀   ⴀ   䌀漀攀甀爀 搀ᤠ䄀氀攀渀攀Ⰰ 䤀搀愀栀漀

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刀䔀䜀䤀匀吀䔀刀 一伀圀 戀礀 瘀椀猀椀椀渀最 䄀䴀䐀猀礀洀⸀挀漀洀 


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Cyclosporine in Dermatology Zekayi Kutlubay, MD;1 Bigen Çakıl Erdogan, MD;2 Burhan Engin, MD;1 Server Serdaroglu, MD1 Abstract Cyclosporine, a member of the calcineurin inhibitor family, has immunomodulatory effects on T cells. It blocks the earliest stages of the immune response by binding to cyclophilin, thus inhibiting calcineurin. It was initially used for transplant patients to prevent transplant rejections. The main indication for cyclosporine in dermatology is severe psoriasis. Other dermatologic indications for the use of cyclosporine include atopic dermatitis, chronic idiopathic urticaria, pyoderma gangrenosum, and Behçet’s disease. (SKINmed. 2016;14:105–109)

C

yclosporine, isolated from the soil fungus Tolypocladium inflatum in the early 1970s, was discovered as an antifungal agent, but its immunomodulatory effects were soon realized and the drug was found to be effective in preventing transplant rejection. Due to its immunomodulatory effects, cyclosporine was considered for the management of immunomediated skin diseases. In 1979, the beneficial effects of cyclosporine were first observed for psoriasis; since then, cyclosporine has also been used to treat various immunomediated dermatoses including atopic dermatitis, pyoderma gangrenosum, and chronic idiopathic urticaria.1,2

the activition of T-helper cells, T regulatory cells, natural killer cells, and antigen-presenting cells. Cyclosporine downregulates intercellular adhesion molecule 1 on keratinocytes and endothelial cells and also prevents the recruitment of inflammatory cells into the skin. Cyclosporine also reduces T-helper 17 cells (Th17) pathway genes, decreasing levels of tumor necrosis factor (TNF) and inducible nitric oxide synthase. Th17 cells are a subset of Thelper cells producing IL-17. They are thought to play a key role in autoimmune diseases, such as psoriasis, alopecia areata, vitiligo, and rheumatoid arthritis. Cyclosporine inhibits histamine release from mast cells and keratinocyte hyperproliferation.2–6

Mechanism of Action

Pharmacokinetics

Cyclosporine is a member of the calcineurin inhibitor family and acts on T cells by blocking intracellular signaling pathways. It is a prodrug that becomes active after binding to an intracytoplasmic protein called cyclophilin and inhibits the activity of calcineurin phosphatase. Calcineurin activates the transcription of nuclear factor of activated T cells (NFAT), which regulates the transcription of a number of cytokine genes and the production of crucial proinflammatory cytokines. Cyclosporine inhibits the action of calcineurin, thus preventing the dephosphorylation of NFATs and blocking this pathway to gene transcription.

There are two formulations of cyclosporine––the original and the recent microemulsion forms. The latter formulation is more bioavailable and has less variability in absorption than the conventional form. The microemulsion form allows the achievement of a stable concentration of the active factor. Due to its pharmacokinetics, cyclosporine should be divided into a twicedaily dose in order to achieve more stable effective blood levels and should optimally be taken at the same time each day to minimize intraindividual variation in serum concentration. Cyclosporine emulsion is available in a capsule form (25–100 mg) and a bioequivalent solution (100 mg/5 mL). Cyclosporine is widely distributed in the body due to its lipophilic nature. After absoption, cyclosporine binds to erythrocytes, leukocytes, and lipoproteins. A higher serum concentration is achieved when the

Cyclosporine particularly inhibits interleukin (IL) 2, IL-4, interferon γ, and transforming growth factor (TGF) β production and IL-2 receptor expression. Inhibition of IL-2 production blocks

From the Department of Dermatology, Istanbul University, Cerrahpasa Medical Faculty, Istanbul, Turkey;1 and the Department of Dermatology, Sadi Konuk Research and Training Hospital, Istanbul, Turkey2 Address for Correspondence: Zekayi Kutlubay, MD, Istanbul Universitesi, Cerrahpasa Tıp Fakultesi Dermatoloji Anabilim Dalı, Kocamustafapasa 34098 Fatih Istanbul • E-mail: zekayikutlubay@hotmail.com

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drug is taken before meals. Systemic clearance of cyclosporine is controlled by cytochrome P450 enzymes. Metabolites are excreted primarily in the bile.1,2,6–8 Indications Cyclosporine is approved for the treatment of severe psoriasis and atopic dermatitis but has been succesfully used off-label for several other dermatologic diseases. When choosing the appropriate patient for cyclosporine treatment, the clinician has to consider certain conditions, such as widespread skin involvement, high tendency for recurrences, unsatisfactory response to previous treatments, and psychosocial disability.

Psoriasis Psoriasis is the only dermatologic indication for cyclosporine, approved by the U.S. Food and Drug Administration. Cyclosporine has been used for psoriasis for more than 20 years and is considered to be safe and effective in inducing remission, reducing the severity of disease, and improving quality of life. The assessment of disease severity in psoriasis is based on affected body surface area >10%, psoriasis area and severity index >10, and dermatology life quality index >10. A standard and easily remembered model “the rule of tens” has been developed and is intended to aid in the selection of patients who require systemic therapies.2,5,6,9,10 Severe psoriasis can be treated in four different regimens with cyclosporine: (1) intermittent short course therapy, (2) continuous long-term therapy, (3) crisis intervention, and (4) combination, sequential, and rotational therapy. There is no rule for choosing the pattern of treatment. It is based on the patient’s current condition and the clinician’s experience. Cyclopsorine therapy may be initiated with a dose between 2.5 mg/kg/day to 5 mg/kg/day, preferably 5 mg/kg/day for rapid action in the absence of comorbidities (obesity, older age). In the face of inadequate response with cyclosporine 2.5 mg/kg/ day after 4 weeks of treatment, the dose can be increased gradually by 0.5 mg/kg/day to 1.0 mg/kg/day at 2-week intervals at a maximum of 5 mg/kg/day. After sufficient improvement has been achieved and if the treatment period is planned for longer than 3 months, the dose can be decreased slowly by 0.5 mg/kg/ day to 1 mg/kg/day to the lowest effective dose. When necessary, treatment can be stopped abruptly. Cyclosporine at doses of 2.5 mg/kg/day to 5 mg/kg/day for a period of 12 to 16 weeks produces rapid and significant improvement in psoriasis in 80% to 90% of patients.6 In patients with recalcitrant disease, long-term continuous cyclosporine treatment may be required to maintain disease remisSKINmed. 2016;14:105–109

sion. Cyclosporine dose <3.5 mg/kg/day is sufficient for the majority of patients. Long-term continuous cyclosporine treatment increases nephrotoxicity and hypertension; therefore, continuous use of cyclosporine is limited to 2 years. Cyclosporine can be used in severe forms of psoriasis, including erythrodermic or generalized pustuler psoriasis at a dose of 5 mg/kg/day for a short-term period (4–8 weeks) as rescue therapy. Rapid onset of action of cyclosporine helps in managing acute flares until a maintenance treatment is arranged. Cyclosporine can be used in combination with topical agents including topical steroids or vitamin D3 analogues and also with systemic treatment modalities, such as acitretin, methotrexate, and mycophenolate mofetil. Phototherapy is not recommended due to the incresed risk of squamous cell carcinomas. Acitretin can reduce carcinogenic effects of cyclosporine when used in combination, but this combination can cause hypertriglyceridemia. Combination therapies using cyclosporine tend to minimize toxicity and optimize efficacy. Rotational therapy is a pratical approach to reduce the cumulative toxicity of psoriasis treatments. The rationale of rotational therapy is based on the alternating regimen of drugs with toxic effects on different systems. Rotational therapies can facilitate achievement of long remission periods.1,2,5,7,8,11,12

Atopic Dermatitis Cyclosporine is the only immunosuppressant approved in Europe for the short-term treatment of severe atopic dermatitis that is not reponsive to topical therapies. Cyclosporine treatment is suitable for severe refractory forms of atopic dermatitis only with a strong impact on quality of life and significantly decreases clinical symptom score, reduces disease extent, pruritus, and sleep deprivation, and improves quality of life in patients with atopic dermatitis. Cyclosporine may be started at a higher initial dose (5 mg/kg/day) in order to achieve a rapid response and then, depending on clinical response, the dose can be tapered slowly to a maintenance dose during the subsequent 2 to 3 months. The total duration of treatment is usually at least 6 months. Higher initial doses can have a more rapid improvement at 2 weeks but after 6- to 8-week follow-up with continuous treatment, response rates are similar with a lower initial dose (2.5–3 mg/kg/day). Duration of therapy depends on treatment success and tolerability. Short courses of cyclosporine (8–12 weeks) with drug-free periods can be administered to reduce the cumulative drug exposure. Long-term use of cyclosporine is limited due to the risk of side effects, and treatment should be restricted to less than 1 year. Cyclosporine interacts with a significant number of other medications; therefore, patients should be warned about potential drug interactions.1,2,5,9,12,13

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Pyoderma Gangrenosum Pyoderma gangrenosum is one of the best indications for cyclosporine, which is recommended as first-line treatment at a dose of 5 mg/kg/day or less with or without corticosteroids.The response is rapid, with dramatic improvement achieved within 1 to 3 weeks and complete clearing within 1 to 3 months. For patients who do not remit with treatment of the underlying disease or in idiopathic cases, systemic corticosteroids or cyclosporine alone or in combination are effective treatment options. Relapses can occur during dose tapering or discontinuation and certain patients can require long-term maintenance therapy.1,2,5,7,14

Chronic Idiopathic Urticaria Cyclosporine may be used to treat chronic urticaria as a steroidsparing agent or chronic urticaria that is refractory to corticosteroids. It is suggested that cyclosporine used at a dose less than 5 mg/kg/day could be beneficial in patients with chronic idiopathic urticaria that is unresponsive to conventional therapy. Two thirds of patients with refractory chronic urticaria treated with cyclosporine 3 mg/kg/day for 1 to 3 months achieved a short-term full remission lasting 3 to 6 months. Low-dose (2.5 mg/kg/day) cyclosporine treatment for 4 weeks was shown to be effective in reducing serum levels of certain cytokines such as IL-2R, IL-5, and TNF-α. It is proposed that the most effective cyclosporine treatment regimen for chronic urticaria is to start with a dose of 3 mg/kg/day for 6 weeks, then taper the dose to 2 mg/kg/day and stay at this dose for 3 weeks, and then use for 3 weeks at a dose of 1 mg/kg/day before discontinuing.1,15,16 Cyclosporine can also be used in autoimmune bullous diseases, such as pemphigus vulgaris and epidermolysis bullosa acquisita. It appears to be effective as an adjuvant drug but is not a firstline treatment option. Cyclosporine may be reserved for patients who are unsuitable for other immunosupressants, such as azathioprine.17 Ocular symptoms of Behçet’s disease can be managed by high-dose cyclosporine. It can also be used for mucocutaneous lesions.18 Cyclosporine has a varying degree of efficacy for the treatment of lichen planus, alopecia areata, toxic epidermal necrolysis, prurigo, allergic contact dermatitis, and photodermatoses.1,2,5 Cyclosporine Monitoring Initiation of cyclosporine therapy involves a baseline medical evaulation, including laboratory studies, such as serum creatinine, urea, complete blood cell count, serum magnesium, potassium, uric acid, serum lipids, liver enzymes, and serum bilirubin. Baseline serum creatinine and blood pressure values are obtained with two separate measurements. A complete physical SKINmed. 2016;14:105–109

and dermatologic examination should be performed to evaluate for infection and malignancy. Patients should undergo routine age-appropriate malignancy screening according to standard recommendations. A detailed medical history should also be obtained. History of drug use, malignancy, and tuberculosis should be particularly evaluated.2,6 Appropriate monitoring during cyclosporine therapy is important to prevent adverse effects. Laboratory studies should be obtained every 2 weeks for the first 3 months. Blood pressure should be measured twice weekly for the first 2 months and monthly, thereafter. Serum creatinine should be measured twice weekly for the first 2 months of cyclosporine therapy and monthly, thereafter. Measurement of glomerular filtration rate is mandatory after 1 year of continuous cyclosporine therapy.8,10 Contraindications Cyclosporine has a few absolute contraindications including significant renal impairment, uncontrolled hypertension and infections, relevant malignacies (except basal cell carcinoma), and simultaneous phototherapy. Relative contraindications are significant hepatic impairment, pregnancy (Category C), lactation, epilepsy, diabetes, premalignant conditions, advancing age (>65 years), and the inability to attend for regular monitoring. Patients who have high cumulative dose psoralen–UV-A (PUVA) phototherapy, severe actinic damage, or radiotherapy history should be aware of increased risk for cutaneous carcinogenicity.8–10 Drug Interactions Cyclosporine metobolism may react with several drugs and can delay the metabolism of other drugs. These drugs can be categorized in three major groups. Drugs that inhibit the cytochrome P450 system can lead to higher levels of cyclosporine. The most widely recognized of these drugs are calcium channel blockers, azole antifungal agents, macrolide antibiotics, and oral contraceptives. Grapefruit juice can inhibit the metabolism of cyclosporine. Drugs that stimulate the cytochrome P450 system can lead to lower levels of cyclosporine and poor efficacy. These drugs include anticonvulsants, rifampicin, and metamizole. Drugs that can impair renal function during cyclosporine therapy are nonsteroidal anti-inflammatory drugs, antibiotics, and fibrates.7–9 Side Effects Cyclosporine use in dermatology is typically well tolerated, and the occurrence of significant side effects decreases with careful monitoring. Frequency and severity of side effects often depend

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on dose and duration of therapy and are commonly reversible after discontinuation. The most serious side effects of cyclosporine use are nephrotoxicity and hypertension. Cyclosporine can cause changes in both the vascular and tubular systems of the kidney. These changes can lead to renal dysfunction. Vascular changes result in vasoconstriction of the afferent arterioles and reduction in renal perfusion. Persistant decreased renal perfusion can lead to localized ischemia, glomerular collapse, and finally glomerulosclerosis. Endothelin 1 has been implicated in the vascular dysfunction caused by cyclosporine. Changes in renal tubular structure occur mainly in the proximal tubule, and tubular dysfunction is characterized by decreased magnesium reabsorption, uric acid excretion, and potassium and hydrogen ion secretion.2,7 If there is an elevation in serum creatinine of at least 30% over the baseline value that continues in the two following measurements 2 weeks apart, the dose should be decreased by 25% to 50% for 4 weeks. If serum creatinine levels do not decrease during these 4 weeks, cyclosporine should be decreased another 25% or 50%. If increased serum creatinine values persist, cyclosporine should be discontinued. Cyclosporine nephropathy usually responds rapidly to reduction in dose or cessation of therapy.8,19 Hypertension commonly accompanies renal impairment in cyclosporine therapy. The cyclosporine-induced rise in blood pressure is releated to an increase in vascular resistance in both systemic and renal circulation and can cause renal microvascular and tubulointerstitial damage. Blood pressure should be measured at 2 weekly intervals for the first 2 months. It is important to monitor blood pressure regularly so that cyclosporine-induced hypertension may be discovered earlier. If cyclosporine-induced hypertension appears, it should be remeasured 2 weeks later. In case of sustained hypertension, dose reduction or addition of a suitable antihypertensive agent, such as a calcium channel blocker, should be started. A low-sodium diet is recommended for patients due to its beneficial effects on blood pressure values.7,8,10,20

pores. Psoriatic patients treated with cyclosporine have significantly higher risk of nonmelanoma skin cancers compared with the nonpsoriatic patients; however, this six-fold increased risk is observed in patients who have been previously treated with PUVA. This increased risk was significantly affected by the duration of therapy. The risk of nonmelanoma skin cancers increases in transplant patients with advanced age at transplantation, duration of transplantation, and male sex. Short-term cyclosporine use does not increase the risk of non-skin cancers, and with longterm cyclosporine at a maximum dose of 5 mg/kg/day, there is no evidence of increase in the risk of lymphomas or internal malignancies.2,6,21 Gingival hyperplasia, hypertrichosis, acne, headache, paresthesia, and colic abdominal pain are the other common side effects of cyclosporine.22–25 Conclusions Cyclosporine is an effective and a safe immunosupressant that has been used for the treatment of dermatologic diseases for approximately 20 years. The side effect profile is well known, and careful and intense monitoring of patients can reduce the risk of serious side effects. References

Cyclosporine, which has immunosupressive effects on T cells, also alters mitochondria-dependent cellular functions and blocks the mitochondrial permeability pore opening. This changes the ability of cells to undergo apoptotic cell death. Cyclosporine increases synthesis of growth factors TGF-β, IL-6, and vascular endothelial growth factor in tumor cells, thereby enhancing tumor growth, metastasis, and angiogenesis. Cyclosporine is thought to inhibit DNA repair, thereby accumulating mutations inducing apoptosis in activated T cells and inhibiting apoptosis in other cells by opening the mitochondrial permeability transition SKINmed. 2016;14:105–109

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1 Amor KT, Ryan C, Menter A. The use of cyclosporine in dermatology: part I. J Am Acad Dermatol. 2010;63:925– 946. 2 Madan V, Griffiths CE. Systemic ciclosporin and tacrolimus in dermatology. Dermatol Ther. 2007;20:239–250. 3 Reynolds NJ, Al-Daraji WI. Calcineurin inhibitors and sirolimus: mechanisms of action and applications in dermatology. Clin Exp Dermatol. 2002;27:555–561. 4 Marsland AM, Griffiths CE. The macrolide immunosuppressants in dermatology: mechanisms of action. Eur J Dermatol. 2002;12:618–622. 5 Griffiths CE, Katsambas A, Dijkmans BA, et al. Update on the use of cyclosporine in immune-mediated dermatoses. Br J Dermatol. 2006;155:1–16. 6 Rosmarin DM, Lebwohl M, Elewski BE, Gottlieb AB. Cyclosporine and psoriasis: 2008 national psoriasis foundation consensus conference. J Am Acad Dermatol. 2010;62:838–853. 7 Capella LG, Casa-Alberighi OD, Finzi AF. Therapeutic concepts in clinical dermatology: Cyclosporine A in immunomediated and other dermatoses. Int J Dermatol. 2001;40:551–561. 8 Ryan C, Amor KT, Menter A. The use of cyclosporine in dermatology: part II. J Am Acad Dermatol. 2010;63:949– 972. 9 Cyclosporine in Dermatology Mrowietz U, Klein CE, Reich K, et al. Cyclosporine therapy in dermatology. J Dtsch Dermatol Ges. 2009;7:474–479.

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10 Griffiths CE, Dubertret L, Ellis CN, et al. Ciclosporin in psoriasis clinical practise: an international consensus statement. Br J Dermatol. 2004;150:11–23

18 Alpsoy E, Akman A. Behçet’s disease: an algorithmic approach to its treatment. Arch Dermatol Res. 2009;301:693–702.

11 Paul C, Gallini A, Maza A, et al. Evidence-based recommemdations on conventional systemic treatments in psoriasis: systematic review and expert opinion of a panel of dermatologists. J Eur Acad Dermatol Venereol. 2011;25:2–11.

19 Markham T, Watson A, Rogers S. Adverse effects with long term cyclosporine for severe psoriasis. Clin Exp Dermatol. 2002;27:111–114.

12 Schmitt J, Schmitt N, Meurer M. Cyclosporine in the treatment of patient of patients with atopic eczema––a systemic review and meta-analysis. J Eur Acad Dermatol Venereol. 2007;21:606–619. 13 Schakhavan A, Rudikoff D. Atopic dermatitis: systemic immunosuppressive therapy. Semin Cutan Med Surg. 2008;27:151–155. 14 Wollina U, Haroske G. Pyoderma gangraenosum. Curr Opin Rheumatol. 2011;23:50–56. 15 Inaloz HS, Ozturk S, Akcali C, Kırtak N, Tarakcıoglu M. Low-dose and short-term cyclosporine treatment in patients with chronic idiopathic urticaria: a clinical and immunological evaluation. J Dermatol. 2008;35:276–282. 16 Vena GA, Cassano N, Colombo D, Peruzzi E, Pigatto P, Neo-I-30 study group. Cyclosporine in chronic idiopathic urticaria: a double blind, randomized, placebo-controlled trial. J Am Acad Dermatol. 2006;55:705–709 17 Schiavo AL, Valentina R, Ruocco V, Ruocco E. Adjuvant drugs in autoimmune bullous diseases, efficacy versus safety: facts and controversies. Clin Dermatol. 2010;28:337–343.

20 Magina S, Santos J, Coroas A, et al. Salt sensitivity of blood pressure in patients with psoriasis on ciclosporin therapy. Br J Dermatol. 2005;152:773–776. 21 Xu J, Walsh SB, Verney ZM, et al. Procarcinogenic effects of cyclosporine A are mediated through the activation of TAK1/TAB1 signaling pathway. Biochem Biophys Res Commun. 2011;408:363–368. 22 Weischer M, Röcken M, Berneburg M. Calcineurin inhibitors and rapamycin: cancer protection or promotion? Exp Dermatol. 2007;16:385–393. 23 Vakeva L, Reitamo S, Pukkala E, Sarna S, Ranki A. Long-term follow -up of cancer risk in patients treated with short-term cyclosporine. Acta Derm Venereol. 2008;88:117–120. 24 Naldi L. Malignancy concerns with psoriasis treatments using phototherapy, methotrexate, cyclosporine, and biologics: facts and controversies. Clin Dermatol. 2010;28:88–92. 25 Patel RV, Clark LN, Lebwohl M, Weinberg JM. Treatments for psoriasis and risk of malignancy. J Am Acad Dermatol. 2009;60:1001–1017.

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Volume 14 • Issue 2

Core curriculum Virendra N. Sehgal, MD, Section Editor

Cantharidin in Dermatology Najla A. Al-Dawsari, MD;1 Kasia Szyfelbein Masterpol, MD2,3

Cantharidin is natural toxin produced by the blistering beetle. It has both vesicant and keratolytic features by inducing acanthloysis through targeting the desmosomal dense plaque, leading to detachment of the desmosomes from the tonofilaments. There are two available liquid preparations for dermatologic use, Canthacur (0.7% cantharidin) and Canthacur PS (1% cantharidin 30%/salicylic acid/2% podophylotoxin). The former preparation is indicated for the treatment of common warts, periungual warts, and molluscum contagiosum, while the more potent latter preparation is indicated only for plantar warts. Both preparations provide painless applications with outcomes similar to other treatment modalities for warts and molluscum contagiosum; however, neither is approved by the Food and Drug Administration (FDA). The lack of FDA approval could be related to its toxic effects following oral ingestion, which include ulceration of the gastrointestinal and genitourinary tracts, along with electrolyte and renal function disturbance in humans and animals. The mechanism of action, dermatologic indications, application techniques, and complications of cantharidin preparations are discussed. (SKINmed. 2016;14:111–114)

C

ommon warts and molluscum contagiosum (MC) are commonly encountered in patients presenting to dermatology clinics. Warts are caused by the human papilloma virus, while MC are caused by a pox virus.1,2 Managing warts and MC is a challenge for the dermatologist, as most patients seek rapid resolution and recovery. Treatment is particularly challenging in children as liquid nitrogen and other destructive modalities are a cause of fear and pain. Cantharidin is a topical keratolyic and vesicant that induces blisters if applied on the skin.3 It is present in the Canadian market in liquid preparations with the primary medical ingredients 0.7% cantharidin (Canthacur; Paladin Labs, Montreal, QC, Canada) or 1% cantharidin/30% salicylic acid/2% podophylotoxin (Canthacur PS, Paladin Labs). Both preparations are indicated for the management of common warts, periungual warts, and MC. They are unique for their painlessness and tolerance during application, along with their safety and efficacy if used properly in a dermatology office with appropriate patient counseling.4–9 Mechanism of Action Cantharidin is a natural toxin produced by the blistering beetle, of which there are about 150 species worldwide. The Spanish fly blister beetle is the most common known source of

cantharidin.10 Insects use or produce it as a defense mechanism to protect their eggs from predators.10 In dermatology, cantharidin is used for its vesicant and keratolytic features. Cantharidin induces acanthloysis by targeting the desmosomal dense plaque, leading to detachment of the desmosomes from the tonofilaments. As a consequence of the acantholysis, the wart is exfoliated with the blister. Cantharidin also induces cancer cell death and is currently being studied for its antitumor activity.11,12 Indications Cantharidin is indicated for the treatment of common warts, periungual warts, and MC.4–9 Its efficacy in treating acquired perforating dermatosis and porokeratosis of Mibelli has also been observed.13,14 To date, the use of cantharidin is not approved by the US Food and Drug administration. The two preparations (0.7% cantharidin and 1% cantharidin/30% salicylic acid/2% podophylotoxin) are manufactured in Canada.4,5 In the United States, cantharidin is mainly utilized in private and community clinics. Inaccessibility and lack of FDA approval is likely the cause of its limited use.15 The cantharidin preparation is best utilized for MC and common warts. In one retrospective study of 300 children with

From the Department of Dermatology, John Hopkins Aramco Healthcare, Saudi Arabia1; Dermatology Associates, Winchester, MA2; and the Department of Dermatology, Boston University, Boston, MA3 Address for Correspondence: Najla A. Al-Dawsari, MD, John Hopkins Aramco Healthcare Department of Dermatology, Saudi Arabia, PO Box 2161, Dhahran 31311, Saudi Arabia • E-mail: najla.aldawsari@gmail.com

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MC treated with cantharidin, 90% cleared and 8% showed improvement.6 Cantharidin has also been shown to be successful in the treatment of facial flat warts.9 MC treated with a combination of cantharidin and imiquimod 5% showed greater clearance rates.16 The 1% cantharidin/30% salicylic acid/2% podophylotoxin preparation is preferred for plantar warts and was found to be superior to cryotherapy after five sessions 2 weeks apart.7 This preparation is not recommended for MC given its superior potency and more intense reactions.4,5 Product Utilization Application should be avoided on nevi and in areas of inflamed skin. Patients with diabetes, peripheral neuropathy, and poor circulation should not be treated. The safety of application in pregnant and breast-feeding women was not studied, thus cantharidin use should be avoided in this group. The wooden end of a Q-Tip, an applicator stick, or a 1-mL syringe can be used to apply the liquid and then be disposed of in hazardous waste containers. One layer of cantharidin should be applied on the wart with 1- to 3-mm margins. On the first visit, occluding the treated area is not recommended until the first reaction is observed. On follow-up visits, nonporous plastic adhesive tape can be used if the first reaction was not significant. Curettage of thick lesions can be performed before application. The 1% cantharidin/30% salicylic acid/2% podophylotoxin preparations leave a yellowish white layer on the treated area (Figure 1) while the cantharidin 0.7% preparation is clear after application. Treated areas should be thoroughly washed after 4 to 24 hours (most clinicians apply it for 2–6 hours). The treatment should be repeated weekly every 2 to 3 weeks. Bottles containing cantharidin should be stored at room temperature away from heat, flame, and fire.4,5,17

Figure 1. Yellowish white layer on a treated area with Canthacur PS.

Figure 2. Blistering with erythema surrounding a treated area after 24 hours of application of Canthacur.

Accidental spillage should be wiped off with acetone or alcohol then washed with warm soapy water and rinsed well. If spilled around a mucosal surface, the area should be rinsed for more than 15 minutes and any visualized particles should be removed.4–5 Expected Response After application, mild discomfort around the treated area may be felt in the first 4 hours, followed by blistering typically forming after 24 hours (Figure 2). In 4 days, dryness and crusting develop. Healing occurs with temporary erythema after 1 week. Temporary dyspigmentation may be the end result (Figure 3).4,5 SKINmed. 2016;14:111–114

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Figure 3. Postinflammatory hyperpigmentation following treatment with Canthacur. Cantharidin in Dermatology


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core curriculum ia, Ectromelia, Molluscum Contagiosum). J Exp Med. 1953;98:157–172.

Side Effects Reactions in patients vary in intensity. Fair-skinned people with blue eyes have more intense reactions.4,5 A total of 6% to 37% of patients treated with cantharidin have experienced temporary pain and pruritus after application.6 Soreness that persists after washing can be treated with 15-minute soaks with cold water and repeated as needed. If pain persists, puncture of the blister using a sterile needle is indicated. Nonsteroidal anti-inflammatory agents and paracetamol can help alleviate the pain post treatment.4,5 Rarely, topical application of cantharidin may lead to lymphangitis requiring warm compresses and antibiotics.18 In one case report, the lymphangitis healed with permanent lymphedema.19 Application on large areas should be avoided, particularly if occlusive tape is used, to prevent exaggerated reactions that may lead to secondary infection. Toxic shock syndrome has been reported in one child who had 20 lesions of MC treated then covered with occlusive tape.20

3 Bertaux B, Prost C, Heslan M et al. Cantharide acantholysis: endogenous protease activation leading to desmosomal plaque dissolution. Br J Dermatol. 1988;118:157– 165. 4

Canthacur [package insert]. Montreal, Canada: Paladin Labs Inc.

5 Canthacur PS [package insert]. Montreal, Canada: Paladin Labs Inc. 6 Silverberg NB, Sidbury R, Mancini AJ. Childhood molluscum contagiosum: experience with cantharidin therapy in 300 patients. J Am Acad Dermatol. 2000;43:503–507 7 Kaçar N, Taçlı L, Korkmaz S, et al. Cantharidin-podophylotoxin-salicylic acid versus cryotherapy in the treatment of plantar warts: a randomized prospective study. J Eur Acad Dermatol Venereol. 2012;26:889–893. 8 Becerro de Bengoa Vallejo R, Losa Iglesias ME, GómezMartín B, et al. Application of cantharidin and podophyllotoxin for the treatment of plantar warts. J Am Podiatr Med Assoc. 2008;98:445–450. 9 Kartal Durmazlar SP, Atacan D, Eskioglu F. Cantharidin treatment for recalcitrant facial flat warts: a preliminary study. J Dermatolog Treat. 2009;20:114–119.

Thorough rinsing is essential when cleaning, as application of any ointment-based emollients in areas that are not properly rinsed may lead to spread of the toxin and development of vesicular reactions away from the treated site. This is explained by the lipophilic nature of the toxin.21

10 Moed L, Shwayder TA, Chang MW. Cantharidin revisitedblistering defense of an ancient medicine. Arch Dermatol. 2001;137:1357–1360.

There are no cases reported of accidental ingestion of purified preparations of cantharidin; however, oral ingestion of blister beetles has been shown to cause blistering and ulceration of the gastrointestinal and genitourinary tracts, along with electrolyte and renal function disturbance, in humans and animals.22–24 One ingested beetle can cause symptoms as each beetle produces about 0.2 mg to 0.7 mg of toxin, with 10 mg to 50 mg considered a lethal dose in humans. There is no antidote, and treatment is supportive.22 These systemic side effects could explain the lack of FDA approval.

12 Kim JA, Kim Y, Kwon BM, et al. The natural compound cantharidin induces cancer cell death through inhibition of heat shock protein 70 (HSP70) and Bcl-2-associated athanogene domain 3 (BAG3) expression by blocking heat shock factor 1 (HSF1) binding to promoters. J Biol Chem. 2013;288:28713–28726.

Conclusions Cantharidin is a generally safe and effective treatment for warts and MC if used properly on limited areas by a dermatologist. Its use is particularly helpful in children who cannot tolerate more painful locally destructive methods. References 1 Cubie HA. Diseases associated with human papillomavirus infection. Virology. 2013;445:21–34. 2 Gaylord WH Jr, Melnick JL. Intracellular forms of pox viruses as shown by the electron microscope (Vaccin-

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11 Han W, Wang S, Liang R, et al. Non-ionic surfactant vesicles simultaneously enhance antitumor activity and reduce the toxicity of cantharidin. Int J Nanomedicine. 2013;8:2187–2196.

13 Levitt JO, Keeley BR, Phelps RG. Treatment of porokeratosis of Mibelli with cantharidin. J Am Acad Dermatol. 2013;69:e254–e255. 14 Wong J, Phelps R, Levitt J. Treatment of acquired perforating dermatosis with cantharidin. Arch Dermatol. 2012;148:160–162. 15 Pompei DT, Rezzadeh KS, Viola KV et al. Cantharidin therapy: practice patterns and attitudes of health care providers. J Am Acad Dermatol. 2013;68:1045–1046. 16 Ross GL, Orchard DC. Combination topical treatment of molluscum contagiosum with cantharidin and imiquimod 5% in children: a case series of 16 patients. Australas J Dermatol. 2004;45:100–102. 17 Lao M, Weissler A, Siegfried E. Safe and speedy cantharidin application. J Am Acad Dermatol. 2013;69:e47. 18 Dilaimy M. Lymphangitis caused by cantharidin. Arch Dermatol. 1975;111:1073. 19 Stazzone AM, Borgs P, Witte CL, et al. Lymphangitis and refractory lymphedema after treatment with topical cantharidin. Arch Dermatol.1998;134:104–106.

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20 Langley JM, Soder CM, Schlievert PM, et al. Case report: Molluscum contagiosum. Toxic shock syndrome following cantharidin treatment. Can Fam Physician. 2003;49:887–889. 21 Shah A, Treat J, Yan AC. Spread of cantharidin after petrolatum use resulting in a varicelliform vesicular dermatitis. J Am Acad Dermatol. 2008;59(2 suppl 1):S54–S55. 22 Al-Binali AM, Shabana M, Al-Fifi S, et al. Cantharidin poi-

soning due to blister beetle ingestion in children: two case reports and a review of clinical presentations. Sultan Qaboos Univ Med J. 2010;10:258–261. 23 Helman RG, Edwards WC. Clinical features of blister beetle poisoning in equids: 70 cases (1983–1996). J Am Vet Med Assoc. 1997;211:1018–102 24 Simpson KM, Streeter RN, De Souza P, et al. Cantharidin toxicosis in 2 alpacas. Can Vet J. 2013;54:456–462.

Historical Diagnosis and treatment Diagnosis and treatments have advanced over the past century. This feature depicts conditions from a collection of stereoscopic cards published in 1910 by The Stereoscopic Skin Clinic by, Dr S. I. Rainforth.

(Continued on page 137)

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Volume 14 • Issue 2

Perils of Dermatopathology W. Clark Lambert, MD, PhD, Section Editor

Diagnostic Pitfalls of the “Nothin’ Slide” Parmvir Singh, BS;1 Hee Jin Kim, BS;1 Ann M. John, BA;1 W. Clark Lambert, MD, PhD2 “Beware, so long as you live, of judging men by their outward appearance.”––Jean de La Fontaine

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he late Margaret Gray Wood (1919–2006) was a pioneer in the field of dermatopathology, always challenging her colleagues to be more than just competent. Many others would see a slide with a few extra cells and brush it off as nothing. This is because many dermal proliferations give the appearance of a “busy” dermis. The most common benign proliferation is a dermatofibroma1; however, dermal proliferation offers a unique diagnostic challenge as malignant processes often mimic a busy dermis. Such malignancies include, but are not limited to, epithelioid sarcoma, leukemia cutis, carcinoma cutis including breast cancer metastasis, lymphoma cutis including multiple myeloma, and Kaposi sarcoma.2–5 Dermatofibroma

Dermatofibroma, also known as benign fibrous histiocytoma, is one of the most common benign, cutaneous tumors.2 It has predilection for young women and occurs most commonly in the lower extremities. Multiple dermatofibromas may occur in patients with systemic lupus erythematosus or human immunodeficiency virus infection. Clinically, it presents as a firm, hyperkeratotic, round/ovoid, slow-growing dermal nodule that is less than 1 centimeter in diameter.2 The overlying skin is darkly pigmented and scaly. It often has a central dimple upon lateral squeezing. Trauma, such as insect bites, is a risk factor for the development of dermatofibroma.2 Histopathologically, it contains a mixture of fibroblast-like cells, histiocytes, and blood vessels (Figure 1). It is a poorly circumscribed dermal tumor, with the possibility of deeper extension.2 A grenz zone usually separates the epidermis from tumor cells in the dermis.2 There are many different variants, such as fibrocollagenous, cellular, histiocytic, lipidized, angiomatous, aneurysmal, clear cell, “monster” cell, myxoid, keloidal, palisading, osteoclastic, and epitheloid.1 The triad of dermatofibroma includes hyperkeratosis, acanthosis, and basal layer pigmentation.2

Multiple myeloma Multiple myeloma (MM) is hematologic neoplasm of monoclonal plasma cell proliferation with production of monoclonal antibody.6 MM is associated with a set of cutaneous syndromes including amyloidosis, cryoglobulinemia, POEMS syndrome, normolipemic plane xanthoma, and plasmacytoma.6 In one study, 40% of patients had cutaneous nodules in the setting of advanced disease, while another 40% had them as an early clue to diagnosis.3 The most common cause of cutaneous lesions in MM is direct extension from an underlying bony focus.3,6 Histopathology of cutaneous disease usually shows sheets of atypical cells in the dermis.3 These cells rarely resemble plasma cells; instead, they are often likened to reticulum cells, histiocytes, and lymphoblasts (Figure 2).3 These findings could easily be mislabeled as a “busy” dermis. Cutaneous extramedullary plasmacytoma, although rare, mimics a “nothin’ slide.”6 It forms discrete skin nodules with a grenz zone separating the epidermis from tumor cells in the dermis.6 Kaposi sarcoma Kaposi sarcoma (KS) is a low-grade neoplasm originating from lymphatic endothelium. Cutaneous findings in KS typically progress from patch to plaque to nodule.4,7 Despite its characteristic clinical appearance, KS may histologically mimic many other benign and malignant conditions.7 The latent nuclear antigen stain differentiates KS as a result of its ability to identify the causative human herpes virus 8 infection.7 There are numerous histologic variants of KS.4 The patch stage is most likely to cause confusion in diagnosis.4 The dermis in this stage is defined as “busy” and may mimic mild inflammatory dermatosis (Figure 3).4 New slit-like, jagged vascular spaces form and dissect collagen bundles. Inflammatory cells and hemosiderin-laden macrophages may be present.4 By the plaque stage, the dermis is more diffusely infiltrated by vascular proliferation, often resulting in

From Rutgers – New Jersey Medical School,1 and the Departments of Dermatopathology, Dermatology, and Pathology and Laboratory Medicine,2 Rutgers – New Jersey Medical School, Newark, NJ Address for Correspondence: W. Clark Lambert, MD, PhD, Room H576 Medical Science Building, Rutgers University – New Jersey Medical School, 185 South Orange Avenue, Newark, NJ 07103 • E-mail: lamberwc@njms.rutgers.edu

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Figure 1. Dermatofibroma (hematoxylin and eosin stain, original magnification ×135).

Figure 3. Kaposi sarcoma (hematoxylin and eosin stain, original magnification ×270).

Epithelioid sarcoma Epithelioid sarcoma is known for its tendency to mimic granulomatous processes.8 It may mimic dermatofibroma.5,8 A case report found well-differentiated, ovoid, and spindled cells in a sclerotic collagenous stroma, a quintessential “nothin’ slide.”8 It was not until the deeper portions of the tumor were unearthed that cellular atypia and nuclear pleomorphism were seen.8 Like dermatofibroma, epithelioid sarcoma is also most commonly found on the distal extremities of young adults.8 In contrast to dermatofibroma, epithelioid sarcoma is very aggressive, with recurrences and metastases to lymph nodes and the lungs.8 Carcinoma cutis Figure 2. Multiple myeloma cutis (hematoxylin and eosin stain, original magnification ×540).

subcutaneous extension. In the nodular stage, diagnostic difficulty is rarely encountered. The dermis is expanded with fascicles of neoplastic spindle cells.4 SKINmed. 2016;14:115–118

Carcinoma cutis is most commonly adenocarcinoma, squamous cell carcinoma, or an undifferentiated tumor.9 Cutaneous metastases tend to be much less differentiated than the primary tumor, making primary site and type determination difficult. Gastric cutaneous metastases tend to be mucin-secreting adenocarcinomas with signet ring cells. Metastatic renal cell carcinoma tends to exhibit a glandular arrangement of large, polyhedral cells. Lung

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Figure 4. Carcinoma cutis: primary adenocarcinoma of the breast (hematoxylin and eosin stain, original magnification ×270).

Figure 5. Leukemia cutis: myelogenous leukemia (hematoxylin and eosin stain, original magnification ×270).

cancer metastases are characterized by the following histologic frequencies: squamous cell carcinoma (30%), adenocarcinoma (30%), and undifferentiated (40%). Breast cancer, in particular, may be misinterpreted as a “nothin’ slide” (Figure 4). Inflammatory breast cancer manifests as perivascular infiltrate of lymphocytes and plasma cells. Infiltrative ductal carcinoma may show skin metastases with a bland, uniform histiocytic appearance that is misdiagnosed as xanthoma, xanthelasma, granular cell myoblastoma, or histiocytoma.

lineage. A patchy perivascular infiltrate may create a diagnostic pitfall and lead to confusion with inflammatory skin disorders. Care should be taken to rule out leukemia when a slide with a “busy dermis” is encountered.

Leukemia cutis Skin lesions may be the initial manifestation of leukemia.10 It manifests as papules, plaques, and nodules. Leukemia cutis is typically characterized by a perivascular/periadnexal infiltrate or nodular diffuse infiltrate (Figure 5). Small monomorphic lymphocytes with hyperchromatic nuclei and rare mitoses are seen. Immunophenotypic analysis should be used to reveal cell SKINmed. 2016;14:115–118

Conclusions Nonspecific slides that have a completely benign appearance often turn out to be a malignant process. Some malignancies that are misread as a “nothin’ slide” include multiple myeloma, Kaposi sarcoma, epithelioid sarcoma, carcinoma cutis, and leukemia cutis. Misdiagnosis can have devastating consequences by causing delay in treatment initiation. A large skin biopsy should be taken to avoid misinterpretation. References

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1 Parish LC, Yazdanian S, Lambert WC, et al. Dermatofibroma: a curious tumor. Skinmed. 2012;10:268–270.

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2 Han TY, Chang HS, Lee JH, et al. A clinical and histopathological study of 122 cases of dermatofibroma (benign fibrous histiocytoma). Ann Dermatol. 2011;23:185–192.

7 O’Donnell PJ, Pantanowitz L, Grayson W. Unique histologic variants of cutaneous Kaposi sarcoma. Am J Dermatopathol. 2010;32:244–250.

3 Patterson JW, Parsons JM, White RM, et al. Cutaneous involvement of multiple myeloma and extramedullary plasmacytoma. J Am Acad Dermatol. 1988;19:879–890.

8 Lynch MC, Graber EM, Johnson TS, et al. Epithelioid sarcoma resembling benign fibrous histiocytoma. Cutis. 2015;95:83–86.

4 Grayson W, Pantanowitz L. Histological variants of cutaneous Kaposi sarcoma. Diagn Pathol. 2008;3:31–31. 5 Mirra JM, Kessler S, Bhuta S, et al. The fibroma-like variant of epithelioid sarcoma. Cancer. 1992;69:1382– 1395. 6 Bayer-Garner IB, Smoller BR. The spectrum of cutaneous disease in multiple myeloma. J Am Acad Dermatol. 2003;48:497–507.

9 Schwartz RA. Histopathologic aspects of cutaneous metastatic disease. J Am Acad Dermatol. 1995;33:649– 657. 10 Cerroni L, Zenahlik P, Hofler G, et al. Specific cutaneous infiltrates of B-cell chronic lymphocytic leukemia: a clinicopathologic and prognostic study of 42 patients. Am J Surg Pathol. 1996;20:1000–1010.

“Granuloma anulare”. Made by Lotte Volger in 1919 in the Clinic for Dermatology Zurich. Museum of Wax Moulages Zurich, www.moulagen.ch Courtesy of Michael Geiges, MD

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Volume 14 • Issue 2

New Therapy Update William Abramovits, MD; Aditya K. Gupta, MD, PhD, FRCPC, Section Editors

VALCHLOR (Mechlorethamine) 0.02% Gel Aditya K. Gupta, MD, PhD, FRCPC;1,2 Melissa A. MacLeod, MSc;2 William Abramovits, MD3,4,5

M

ycosis fungoides-type cutaneous T-cell lymphoma (MF-CTCL) is a rare form of non-Hodgkin lymphoma most often diagnosed in patients older than 50 years.1 In the United States, there are approximately 20,000 reported cases of MF-CTCL.2 Mechlorethamine, also known as nitrogen mustard, is an alkylating, cytotoxic chemotherapeutic agent.3 VALCHOR (Actelion Pharmaceuticals Ltd, San Francisco, CA) is the first and only US Food and Drug Administration (FDA)–approved (August 2013) topical mechlorethamine hydrochloride (MCH) gel indicated for the treatment of stage IA and IB MF-CTCL in patients who have received prior skindirected therapy.1,3 Approval was based on a phase II clinical trial comparing it with a pharmacy-compounded MCH ointment. Prior to this, compounded ointments and aqueous-based topical preparations were available, which did not undergo the same rigorous FDA review.1 Compounded MCH formulations have been used since the 1950s and have been shown to be safe and effective in large, uncontrolled case series, and thus are often recommended as a primary treatment for MF-CTCL.4 The gel formulation was compared with an ointment and was reportedly difficult to apply and esthetically unappealing, which may reduce compliance.4 Clinical Trial The phase II, randomized, multicenter, clinical trial that led to FDA approval of MCH gel included 260 patients with stage IA, IB, and IIA MF-CTCL who had received at least one prior skin-directed therapy.4 Prior therapy could have included topical corticosteroids, phototherapy, bexarotene gel, and/or topical MCH. Patients were not required to be refractory or intolerant to prior therapies. Patients were stratified based on stage (IA vs IB and IIA) and randomized 1:1 to receive either 0.02% MCH gel or 0.02% Aquaphor-based MCH ointment (Beiersdorf Inc,

Wilton, CT; n=130 for each group). Treatment was applied topically to the affected areas once daily for 12 months, and dosing was suspended or continued with reduced frequency in the event of adverse reactions, including dermatitis. At the appearance of new lesions, patients were instructed to apply the treatment regionally or to the whole body. Concomitant use of corticosteroids was not permitted. Tumor response was measured using the Composite Assessment of Index Lesion Severity (CAILS) scale and the modified Severity Weighted Assessment Tool (mSWAT) by a blinded observer monthly for the first 6 months and every 2 months for the last 6. The CAILS scale is calculated by adding severity scores for erythema, scaling, plaque, elevation, and surface area for up to five index lesions. A ≥50% reduction in the baseline CAILS value was scored as a response and a 100% reduction was scored as a complete response. Disease was scored as “stable” when there was a <50% reduction in baseline and “progressing” when there was a ≥25% increase in baseline score. The mSWAT as a secondary endpoint assessed each involved area as percentage of total body surface, multiplied by a severity-weighting factor (1 for patch, 2 for plaque, and 3 for tumor or ulcer). Response occurred when there was a ≥50% reduction in baseline mSWAT. mSWAT was used because some patients may have applied treatment regionally or to the whole body rather than to spots only due to the appearance of new lesions during treatment. Noninferiority was tested to show that the gel formulation was statistically and clinically noninferior to a pharmacy-compounded MCH ointment expected to perform similarly. Noninferiority was evident when the lower bound of the 95% confidence interval (CI) of response rates (MCH gel/ointment) was ≥0.75. In the intention-to-treat population, 59% of patients in the MCH gel arm achieved CAILS response compared with 48%

From the Department of Medicine, University of Toronto School of Medicine, Toronto, Ontario, Canada;1 Mediprobe Research Inc, London, Ontario, Canada;2 and the Department of Medicine, Baylor University Medical Center,3 the Departments of Dermatology and Family Practice, University of Texas Southwestern Medical School,4 and the Dermatology Treatment and Research Center,5 Dallas, TX Address for Correspondence: Aditya K. Gupta, MD, 645 Windermere Road, London, Ontario, Canada N5X 2P1 • E-mail: agupta@execulink.com

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in the MCH ointment arm (Figure). Response rates were similar between both strata (stage IA and IB/IIA). Estimated time to 50% response was 16 weeks sooner in the gel vs the ointment groups at 26 weeks (95% CI, 20.7–35.1) vs 42 weeks (95% CI, 29.1–53.0; P<.012). The response rate for both drug arms improved with the length of treatment. Among patients with a response, 86% receiving gel and 82% receiving ointment maintained their response until the end of the trial. MCH gel was found to be noninferior to MCH ointment according to CAILS, with an overall response rate ratio of 1.24 (95% CI, 0.98–1.58). According to mSWAT, 47% of patients receiving MCH gel and 46% receiving MCH ointment achieved response. A 7-month extension study of the phase II trial examined the efficacy and safety of 0.04% MCH gel in patients who did not achieve complete response with 0.02% MCH within 12 months.5 All patients (N=100) applied a thin layer of MCH gel once daily. Response was based on CAILS, with an unconfirmed rate of 40.8% (95% CI, 31.5–50.7). Using baseline data from the initial study, the confirmed response rate was 75.5% (95% CI, 66.3–83.2). By week 88, 84.4% of patients who previously received 0.02% MCH gel and 67.9% who previously received 0.02% MCH ointment achieved response. Overall, six patients achieved complete response. These findings suggest that there is clinical benefit in increasing the dosage of MCH gel to 0.04% for up to 7 months among patients who do not achieve complete response with 0.02% MCH gel within 12 months.

Figure. Percentage of patients in each drug arm who achieved a tumor response based on the Composite Assessment of Index Lesion Severity scale.4

Safety

study, 11% patients reported dermatitis, 10% reported erythema, and 6% reported pruritus. There were no severe drug-related adverse events in either study. In the initial study, 20% of patients receiving MCH gel and 17% receiving MCH ointment discontinued because of adverse events (P=.631), with 90% of withdrawals occurring before 6 months. It is recommended to stop treatment if skin ulcerations, blistering, or moderate to severe dermatitis occurs.3 Treatment can be restarted after improvement of symptoms at a reduced frequency of once every 3 days for at least 1 week, and, if tolerated, increasing to once every other day for another week, then resuming daily.3

In the initial phase II trial, the most common adverse events experienced by those receiving MCH gel were dermatitis (25%), pruritus (20%), and erythema (17%) (Table).4 In the extension

When MCH gel comes in contact with individuals other than patients, it may cause dermatitis, mucosal injury, and secondary cancers.3 In the phase II trial, three patients in the gel arm and

Table. Adverse Events Among Patients Receiving 0.02% MCH Gel Compared With 0.02% MCH Ointment4 Adverse Events

MCH Gel (n=128), No. (%)

MCH Ointment (n=127), No. (%)

Any adverse event

79 (62)

64 (50)

Dermatitisa

32 (25)

18 (14)

Pruritus

25 (20)

20 (16)

Erythema

22 (17)

18 (14)

Contact dermatitis

19 (15)

19 (15)

Skin hyperpigmentation

7 (6)

9 (7)

Folliculitis

7 (6)

5 (4)

P<.05

a

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eight in the ointment arm developed secondary nonmelanoma skin cancers.4

References

In mice, MCH has been shown to increase the incidence of thymic lymphoma and pulmonary adenomas.3 Mutations in the bacterial reverse mutation assay and chromosome aberrations have also been reported.3 MCH may cause fetal harm based on case reports of birth malformations and findings of teratogenicity in animal studies.3 Conclusions MCH gel is effective in treating stage IA and IB MF-CTCL, and is noninferior to pharmacy-compounded 0.02% MCH ointment. FDA approval ensures that the MCH gel manufacturing process is consistent and of standard quality.4 For patients who do not achieve complete response with 0.02% MCH gel within 12 months, the dosage may be safely increased to 0.04% MCH gel to improve response rates. A clinical trial is expected to be completed in 2018 (NCT02296164)6 and is recruiting patients with MF-CTCL to longitudinally examine (up to a maximum of 1 year) demographics, clinical characteristics, treatment patterns, clinical status, MF-CTCL–related healthcare utilization (hospitalizations and emergency department visits), quality-oflife issues, and adverse events associated with the use of MCH gel.

1 Beyer M. Ceptaris receives FDA approval for VALCHLOR (mechlorethamine) gel for the treatment of stage IA and IB mycosis fungoides-type cutaneous T-cell lymphoma in patients who have received prior skin-directed therapy. http://www.businesswire.com/news/ home/20130825005015/en/Ceptaris-Receives-FDAApproval-VALCHLOR%E2%84%A2-mechlorethamineGel. Accessed August 26, 2013. 2 Vij A, Duvic M. Prevalence and severity of pruritus in cutaneous T cell lymphoma. Int J Dermatol. 2012;51:930– 934. 3 Valchlor [package insert]. South San Francisco, CA: Actelion Pharmaceuticals US, Inc.; 2015. 4 Lessin SR, Duvic M, Guitart J, et al. Topical chemotherapy in cutaneous T-cell lymphoma: positive results of a randomized, controlled, multicenter trial testing the efficacy and safety of a novel mechlorethamine, 0.02%, gel in mycosis fungoides. JAMA Dermatol. 2013;149:25–32. 5 Kim YH, Duvic M, Guitart J, Lessin S. Efficacy and safety of mechlorethamine (MCH) 0.04% gel in mycosis fungoides (MF) after treatment with topical MCH 0.02%. Abstract number: 9093. J Clin Oncol. 2014;32:5s. 6 ClinicalTrials.gov [Internet]. Observational US Study Assessing Outcomes, Treatment Patterns, AEs, QOL in MF-CTCL Patients and Treated With Valchlor (PROVe). Identifier: NCT02296164. https://clinicaltrials.gov/ ct2/show/NCT02296164. Accessed October 6, 2015.

VINTAGE LABEL

Courtesy of BuyEnlarge, Philadelphia, PA SKINmed. 2016;14:120–122

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Volume 14 • Issue 2

The Heymann File Warren R. Heymann, MD, Section Editor

Carotenemia and Age-Related Macular Degeneration: Seeing Is Believing Warren R. Heymann, MD

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here had to be a cause. The patient, a 73-year-old man, had been turning yellow for approximately a year. Although he enjoyed fruits and vegetables, his diet had not been any different, as it had been for decades. His medical history was remarkable for rheumatoid arthritis, resolved babesiosis, coronary artery disease, hypertension, hyperlipidemia, leg cramps, nonmelanoma skin cancer, and psoriasis. His medications included prednisone, auranofin, aspirin, topical diclofenac, famotidine, pantoprazole, lisinopril, metoprolol, simvastatin, icosapent ethyl, pregabalin, tramadol, cetirizine, and fluocinolone acetonide cream. Clinical Findings

tends to be grey-blue rather than yellow), it was virtually impossible to consider anything other than carotenemia—he had to be ingesting carotenoids. Upon further inquiry, the patient informed us that he was diagnosed with age-related macular degeneration (AMD) a couple years ago and started taking dietary supplements, including red yeast rice, “Eye Guard” (containing beta-carotene, lutein, Bilberry extract vitamins C and E, and selenium), lutein, zinc, coenzyme Q10, and acidophilus. He also took quinine as necessary for leg cramps. A serum β-carotene level of 337 ug/dL (normal 3–91) confirmed the diagnosis. Age-Related Macular Degeneration

Physical examination demonstrated marked xanthoderma on the palms, soles, forehead, and axillae (Figure). His sclerae appeared normal. The referring dermatologist considered carotenemia; however, he could not find a reason for it. Results from laboratory studies were normal for glucose, liver function, and thyroid function. Findings from a serum protein electrophoresis were normal without evidence of a paraproteinemia. His lipid profile was remarkable only for triglycerides just above normal. A skin biopsy from the axilla was interpreted as “near-normal skin” (some small areas of calcification, possibly of elastic fibers, were noted, raising the possibility of pseudoxanthoma elasticum; this did not correlate with the clinical findings).

AMD is a retinal disease that is the most frequent cause of vision loss in the Western world. The characteristic sign of AMD is drusen, which appear as white to yellow dots on the retina. AMD is considered as early disease when manifested by mild to moderate vision loss or as late-stage disease, characterized by severe vision loss. Late-stage AMD is divided into a dry form, noted by geographic atrophy, and a wet form, manifested by choroidal neovascularization. Although there is controversy as to whether the two forms of late AMD are the same disease entity, it is well established that patients who develop the dry form of AMD can later display the wet form, and vice versa. While the wet form of AMD may be improved by the use of antivascular endothelial growth factor drugs, no proven treatment for dry AMD exists.1

While the clinical differential diagnosis could include other entities, such as plane xanthomas (his lipids were well controlled with no evidence of lipid-laden macrophages on biopsy), hyperbilirubinemia secondary to obstructive liver disease (normal sclerae and bilirubin), carotenemia secondary to systemic diseases (normal glucose and thyroid-stimulating hormone levels ruled out diabetes and hypothyroidism, respectively), or chrysiasis (which

Increasing age is strongly associated with AMD in all ethnic groups. In addition, both environmental and genetic factors contribute to the pathogenesis of AMD. Smoking, hypertension, hypercholesterolemia, and nutrition (dietary fat and obesity) are associated with AMD.2 There is increasing evidence that AMD is closely linked to the alternative pathway of the complement system, involving Factor D (adipsin) as the rate-limiting step in its activation.3

From the Departments of Medicine and Pediatrics, Division of Dermatology, Cooper Medical School of Rowan University, Marlton, NJ Address for Correspondence: Warren R. Heymann, MD, Cooper Medical School of Rowan University, Departments of Medicine and Pediatrics, Division of Dermatology, 100 Brick Road, Suite 306, Marlton, NJ 08053 • E-mail: wrheymann@gmail.com

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Table. Acquired Causes of Carotenemia Ingestion of carotene-rich foods (carrots, green leafy vegetables [spinach, kale], sweet potatoes, squash, green beans, pumpkins, and mangoes) Nutritional supplements (β-carotene, lycopene, lutein, zeaxanthin) Systemic conditions associated with carotenemia (diabetes mellitus, hypothyroidism, anorexia nervosa)

related to zeaxanthin, differing only in the position of the double bonds in the hexenyl ring and position of methyl groups on the long carbon chain. The retina is capable of taking up high concentrations of lutein.1 Figure. Carotenemia manifesting as yellow palms (with the author’s palm in the middle for comparison).

Conclusions

There is substantial evidence that lutein and its isomer zeaxanthin, also known as macular pigment, might prevent the progression of AMD as a result of photooxidative damage, possibly leading to a 4% reduction in the risk of developing early AMD.4 Of more than 600 carotenoids in nature, only lutein and zeaxanthin and their metabolites are present in the foveal region of the human eye where they form the yellow pigment of the macula lutea. These natural blue-light screening antioxidants may play an important physiologic role in the preservation of macular health. While β-carotene was previously recommended as an antioxidant for AMD, it is no longer utilized, because it may augment the risk of lung cancer in smokers.2

As life expectancy increases, it is estimated that the number of AMD patients will triple to 60 to 75 million worldwide in the next several decades.4 Due to the potentially devastating effect on a patient’s vision and the economic cost to society, slowing the progression of AMD with the carotenoids lutein and zeaxanthin appears to be valuable. When seeing an infant with carotenemia, I usually ask if the child enjoys sweet potatoes. Now, when noticing yellow palms in adults, my initial question will be “Do you have macular degeneration?” Acknowledgment Liz Ghazi, MD, assisted in delineating the patient’s medical history and researching the carotenoid nature of lutein. References

Carotenemia Carotenemia is a benign condition of excess cutaneous β-carotene via excessive intake of carotene-rich foods or nutritional supplements or through association with anorexia, liver disease, renal disease, hypothyroidism, or diabetes mellitus (Table). Carotene deposits are most prominent in areas with a thick stratum corneum, such as the palms, soles, and nasolabial folds, as opposed to mucous membranes or conjuctivae. Carotene levels may be tested but are not necessary in securing the diagnosis.5 Familial forms (both autosomal dominant and recessive) of carotenemia associated with vitamin A deficiency have been reported. The mutations cause a partial or complete deficiency of β-carotene 15,15’-dioxygenase, which prevents the intestinal conversion of dietary carotenoids into vitamin A.6 Lutein is a xanthophyll carotenoid, which is found in high concentrations in green leafy vegetables such as spinach or kale, but it is also found in egg yolk and animal fat. Lutein is structurally SKINmed. 2016;14:123–124

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1 Schmidl D, Garhöfer G, Schmetterer L. Nutritional supplements in age-related macular degeneration. Acta Ophthalmol. 2015;93:105–121. 2 Hobbs RP, Bernstein PS. Nutrient supplementation for age-related macular degeneration, cataract, and dry eye. J Ophthalmic Vis Res. 2014;9:487–493. 3 Tian Y, Kijlstra A, Webers CA, Berendschot TT. Lutein and Factor D: two intriguing players in the field of agerelated macular degeneration. Arch Biochem Biophys. 2015;572:49–53. 4 Huang YM, Dou HL, Huang FF, et al. Effect of supplemental lutein and zeaxanthin on serum, macular pigmentation, and visual performance in patients with early age-related macular degeneration. Biomed Res Int. 2015;2015:564738. 5 Silverberg NB, Lee-Wong M. Generalized yellow discoloration of the skin. The diagnosis: carotenemia. Cutis. 2014;93:E11–E12. 6 Karthik SV, Campbell-Davidson D, Isherwood D. Carotenemia in infancy and its association with prevalent feeding practices. Pediatr Dermatol. 2006;23:571–573.

Carotenemia and Age-Related Macular Degeneration


March/April 2016

Volume 14 • Issue 2

HISTORY OF DERMATOLOGY SOCIETY NEWSLETTER Eve J. Lowenstein, MD, PhD, Section Editor

Suture Materials Mark Bernhardt, MD

S

ewing up a wound is hardly a new idea. The oldest medical text, the Edwin Smith Egyptian papyrus (ca 1500 BCE), recommended that a gash in the shoulder be stitched. But with what? If we assume that ancient healers might have used some of the same techniques as “primitive” peoples, the first sutures would have been made from plant fibers (such as linen or cotton) or animal parts (such as kangaroo tendons or even giant ant jaws.) The preeminent Indian physician, Sushruta (ca 800 BCE), specifically recommended horsehair sutures for surgery on the scalp. Other Aryan doctors used horsehair stitches in ocular and anorectal procedures. One of the Tarim mummies (ca 1800 BCE–200 CE) from present-day Xinjiang, China, had evidence of surgery on his neck that was sewn up with horsehair sutures. Horsehair had the advantage of being abundant, inexpensive, and of a fairly uniform diameter. Its greatest drawback was its rigidity especially compared with alternatives such as gut or silk sutures.

importation of silk thread. Southern surgeons realized that soaking the hair in boiling water made it more pliable and easier to knot. In this pre-Listerian world, what they did not realize was that the boiling procedure was the reason their patients had a lower risk of postoperative infections than Northern soldiers who had access to the preferred silk threads. Southerners instead gave credit for this serendipitous result to the horse! The invention by Joseph Lister in 1868 of carbolized catgut, the first absorbable suture, revolutionized surgical technique and materiel. Even so, as late as the 1930s, horsehair sutures were still recommended by many ocular and plastic surgeons. The last medical account I could find of horsehair sutures dates to 1974,1 but visit any number of survivalist and wilderness Web sites and you will still find advocates of horsehair sutures, when things go REALLY wrong. Reference

During the American Civil War, the Confederacy was forced to use horsehair sutures after Union naval blockades prevented the

1 Sinha HN. Evaluation of horse hair as a tendon suturing material an experimental mode. Indian J Orthop. 1974;8:149–156.

A Blaschkolinear Limerick A lady developed a rash so she made an appointment with Blaschko she thought she had tabes but he diagnosed scabies and added a mite to his cash flow. Submitted by Donald Rudikoff, MD New York, NY

Address for Correspondence: Mark Bernhardt, MD, Private Practice, 1601 East Broward Boulevard, Fort Lauderdale, FL 33301 • cheesedb@aol.com

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March/April 2016

Volume 14 • Issue 2

CASE STUDY Vesna Petronic-Rosic, MD, MSc, Section Editor

Lipomembranous Panniculitis Associated With Venous Insufficiency, Morphea, and Psoriasis Amina Aounallah, MD; Inès Zaraa, MD; Dalenda. El Euch, MD; Inès Chelly, MD; Slim Haouet, MD; Mourad. Mokni, MD; Amel Ben Osman, MD

A 45-year-old obese woman diagnosed with morphea on her leg, presented with a 7-year history of cutaneous depressions on her thigh, chest, and back. She recalled that the lesions followed a three-phase course: edema, hardening, and atrophy. Clinical examination revealed a cutaneous indurated depression localized to the thigh, chest, and the back (Figure 1). (SKINmed. 2016;14:127–129)

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istologic examination showed microcysts lined by acellular eosinophilic membranes forming pseudopapillae and highlighted by periodic acid-Schiff staining (Figure 2 and Figure 3). Results from indirect immunofluorescence were negative for autoimmune skin diseases. The patient had an atrophic plaque of morphea on the right thigh confirmed by histologic examination (Figure 4). We noted a psoriatic lesion with erythematous and solid skin plaques with sharply defined borders covered with fine silvery scales on the elbows and knees, associated with palmoplantar keratoderma. In addition, she had venous insufficiency confirmed by Doppler ultrasound examination. Neurologic and bone examinations revealed no abnormalities. the erythrocyte sedimentation rate was 20 mm/h, and serum lipid, glucose, and liver blood tests (alanine transaminase and aspartate transaminase) showed normal values. Serum lipase and amylase levels were normal. Serology for Borrelia burgdorferi was negative. Results from immunologic investigations were negative for antinuclear antibodies (ANAs) and anti-DNA, -Ro, -La, -SM, -RNP, and -Scl 70. A diagnosis of lipomembranous panniculitis (LP) associated with morphea, venous insufficiency, and psoriasis was made. discussion LP is a peculiar manifestation of adipose tissue necrosis with formation of pseudocystic cavities lined by a crenulated membrane. It can occur in combination with a variety of systemic diseases and clinical syndromes, most notably in arterial ischemia and

venous insufficiency.1 Here, we present a case of LP associated with morphea, venous insufficiency, and psoriasis. Membranocystic or lipomembranous fat necrosis is a rare and distinctive degenerative process involving mature adipose tissue.2 It was first described in Nasu-Hakola disease, a genetic disorder characterized by profound membranocystic degeneration of long bones and systemic adipose tissue with associated progressive sudanophilic leukodystrophy of the brain.3 It is known that LP is associated with various diseases. It is typically found with vascular disease in the form of venous insufficiency, arterial ischemia, and varicosity of veins, as seen in our patient.4,5 In a series of 38 cases of LP,5 the mean age of presentation was 57 years (range 32–80 years) and more common in women (89%). Forty of the cases were labelled as “stasis-associated lipomembranous panniculitis.” LP can manifest with different clinical presentations including a sclerotic plaque, subcutaneous nodule, atrophic plaque, ulceration, and purpura. The most common location is the lower aspect of the leg, which was found in 82% of patients.5 Other reported locations include the buttocks, trunk, and arms.5 There are few reports of panniculitis associated with morphea,5,6 with LP associated with morphea in 3 cases (8 %) among the 38 cases reported.5

From the Deom the Dermatology Department, La Rabta Hospital, Jabbari, Bab Saadoun, Tunis, Tunisia. Address for Correspondence: Inès Zaraa, MD, Dermatology Department, La Rabta Hospital, Jabbari, Bab Saadoun, Tunis, 1007 Tunisia • E-mail: inesrania@myway.com

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Figure 3. Lipomembranous changes (hematoxylin and eosin, original magnification ×400). The microcysts are lined by acellular eosinophilic membranes forming pseudopapillae.

Figure 1. Cutaneous induration on the back.

Figure 2. View of lipomembranous panniculitis, characterized by septal fibrosis, sclerosis, and fatty microcysts with foci of membranocystic change. This consists of amorphous eosinophilic material, sometimes with a crenulated appearance, lining microcysts (hematoxylin and eosin original magnification ×60). SKINmed. 2016;14:127–129

Figure 4. Morphea lesions on the right leg with psoriasiform and plantar keratoderma lesions.

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The histologic features of LP are typical. They include microcysts and macrocysts within the subcutaneous adipose tissue, lined by an amorphous, anucleate, eosinophilic membrane, which stains with periodic acid-Schiff.5,6

References

The pathogenesis remains unclear. Some authors believe that the disease is a multisystem genetic disorder of lipid metabolism with an autosomal recessive mode of inheritance.5 Others consider necrotic fat cells to be the anatomic substrate in the formation of pseudomembranes.5 Additional authors propose that microvascular injuries could lead to fragmentation and changes in fat cell membranes. A variety of insults to adipose tissue may cause degeneration of fat cells, such as circulatory disturbances secondary to diabetic microangiopathy, hypertension, arterial thrombosis, and venous thrombosis.2 Conclusions The lipomembranous changes might result from the interaction between residual elements of necrotic fat cells and macrophages, probably as a consequence of inflammatory and ischemic disorders in the fatty tissues.7–8 The lower extremities are the most commonly affected sites, suggesting that antecedent trauma and subsequent interruption of the blood supply are the main causes of the condition.9 LP can be observed in a variety of relatively common inflammatory and noninflammatory diseases. Our patient presented with a simultaneous association of venous insufficiency, psoriasis, and morphea.

1 Niamh L. Panniculitis. Diagn Histopathol. 2005;11:236– 244. 2 Segura S, Pujol R. Lipomembranous fat necrosis of the subcutaneous tissue. Dermatol Clin. 2008;26:509–517. 3 Nasu T, Tsukahara Y, Terayama K. A lipid disease— “membranous lipodystrophy”—an autopsy case demonstrating numerous peculiar membrane-structures composed of compound lipid in bone and bone marrow and various adipose tissues. Acta Pathol Jpn. 1973;23:539– 558. 4 Al Brahim N, Ceballos K, Alowami S. Lipomembranous panniculitis: a report of a case. Ann Diagn Pathol. 2007;11:282–284. 5 Snow JL, Su WP. Lipoàmembranous (membranocystic) fat necrosis. Clinicopathologic correlation of 38 cases. Am J Dermatopathol. 1996;18:151–155. 6 Snow JL, Su WPD, Gibson LE. Lipomembranous (membranocystic) changes associated with morphea: a clinicopathologic review of three cases. J Am Acad Dermatol. 1994;31:246–250. 7 Khoury T, Arayssi T, Kibbi AG, Ghosn S. Extensive fat necrosis with lipomembranous changes and calcification in lupus erythematosus panniculitis is not necessarily associated with systemic lupus erythematosus. Am J Dermatopathol. 2010;32:742–743. 8 Almeida MS, Lima SC, Carvalho LL, et al. Panniculitis— an unusual cutaneous manifestation of systemic sclerosis. J Cutan Pathol. 2010;37:1170–1173. 9 Moreno A, Marcoval J, Peyri J. Traumatic panniculitis. Dermatol Clin. 2008;26:481–483.

Chancre of the eyelid from the collection of George C.Andrews, MD. Submitted by Douglas D. Altchek, MD, New York, NY SKINmed. 2016;14:127–129

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Volume 14 • Issue 2

CASE STUDY

Blitz Nevus: A Clinical Simulator of Melanoma M. Jose Alonso-Corral, MD, PhD;1 Ricardo Ruiz-Villaverde, MD, PhD;2 Daniel Sánchez-Cano, MD, PhD;3 Francisco Pulido-Fernández, MD, PhD4

A 17-year-old adolescent girl attended our clinic for a scheduled review of her nevus lesions. She complained about a lesion on the posterior region of her neck, which she had noticed approximately 2 years before. Even though it had not caused any symptoms, its appearance had changed according to her parents. The patient’s medical history, as well as that of her family’s, was unremarkable. (SKINmed. 2016;14:131–133)

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nevus lesion of 0.7 cm in diameter, with an asymmetric axis, could be observed on the back of the patient’s neck. This lesion presented with an upper area of homogenous blue pigmentation along with a brown lower area. Its limits were regular, but it had no associated ulceration (Figure 1). Other nevus lesions were absent on skin examination. Findings from physical examination were also normal. On dermoscopy, a pigmented tumor could be observed. Its horizontal axis, which was asymmetric, divided the lesion in two well-defined halves. The upper half was of a homogenous blue color, with distinguishable superficial globule aggregates. The lower half lacked a pigmented reticule or an atypical vascular pattern, although it showed brown globule aggregates of homogenous size (Figure 2). Histopathology showed acanthosis and variable hyperkeratosis of the epidermis. Notably, the superficial dermis presented with a proliferation of nested nevus cells, with occasional eosinophilic bodies and fibroplasia foci but without significant features of atypia or mitotic activity (Spitz component; Figure 3). Fusiform cells with variable pigmentation, as well as absence of atypia features, were noticed within deep dermis. These cells were distributed among the collagen bundles of a fibrous dermis in which inflammatory infiltrates were absent (blue component; Figure 4). Combined blue nevus (“blitz” nevus) was then diagnosed. Exci-

sion of the lesion with sufficient surgical margins was performed. The patient was scheduled for regular skin examinations. Combined blue nevus is a condition rarely addressed in the literature. This term designates a usually benign melanocytic proliferation, which combines two well-differentiated types of nevus cells in its histopathology. Thus, its clinical features depend on the majority kind of cells. As such, it is classified as a proliferation of dendritic dermal melanocytes. Furthermore, it could be one of the up to 52 variants of blue nevi described until now, which were examined in a recent dermoscopic analysis in an attempt to approach the different sorts of blue nevi.1 It frequently presents as a well-circumscribed, small, benign lesion, similar to the one found in our patient. The presence of asymmetry and polychromy, however, often leads to its removal upon suspicion of melanoma. In fact, in a recent series,2 combined blue nevus was the presumed clinical diagnosis in only 2.4% of the excised lesions. Combined epithelioid nevi have been classified into three wellcharacterized phenotypic varieties: (1) classic variety or included in Carney complex; (2) combined epithelioid nevi with characteristics overlapping those of deep penetrating blue nevus; and (3) combined epithelioid nevi with histopathologic features of blue nevus and Spitz nevus, hence the term “blitz.”3 In our case,

From the Departments of Dermatology, Complejo Hospitalario Torrecárdenas, Almería,1 and Complejo Hospitalario de Jaen, Jaen;2 the Department of Internal Medicine, Hospital Santa Ana, Motril, Granada;3 and the Department of Anatomía Patológica, Complejo Hospitalario Torrecárdenas, Almería,4 Spain Address for Correspondence: Ricardo Ruiz-Villaverde, MD, PhD, Department of Dermatology, Complejo Hospitalario de Jaen, Carretera Bailen-Motril nº 1, Dermatologia, 1ª planta, 23001, Jaen, Spain • E-mail: ismenios@hotmail.com

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Figure 1. Atypical pigmented lesion on the posterior region of the neck in our patient.

Figure 3. Spitz component. Proliferation of round nevus cell with fibroplasia foci but without significant features of atypia or mitotic activity on papillary dermis (hematoxylin and eosin stain, original magnification x40).

Figure 2. Dermoscopy of homogenous blue-colored superior zone in which superficial globule aggregates can be distinguished, as well as an inferior zone with brown globules of homogenous size.

Figure 4. Blue component. Pigmented spindle cells embedded in a collagenous stroma with no atypical features on reticular dermis (hematoxylin and eosin stain, original magnification x40).

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the clinical, laboratory, and radiologic examinations performed in our patient during her childhood allowed us to rule out Carney complex. In addition, the dermoscopic and histopathologic characteristics of the lesion excluded the second possibility. Dermoscopy, which is a noninvasive diagnostic technique and the authentic link between clinical features and histopathology, may be a tool of paramount importance for an accurate approach to these nevus lesions.4 In fact, the combined blue nevus is included in the brown-blue nevi pattern, in contrast with the penetrating blue nevus, which would be in the polychromatic blue nevi.1 Nevertheless, both share some features as far as pathology, including symmetry in their morphology, absence of atypia, and a mitosis or nevus component in the dermal-epidermal junction, as well as a lack of dermal fibroinflammatory infiltrates. All are benign features, which are helpful for the differential diagnosis with melanoma.5

scopic features, we believe that combined blue nevi should be excised for their accurate identification despite its benign characteristics, since histopathology remains the mainstay of their diagnosis. On the contrary, experts in dermoscopy support a more conservative approach. References

In conclusion, we support the notion that the use of dermoscopy be encouraged in order to achieve a correct diagnosis.4 Even so, because of the lack of new studies regarding clinical and dermo-

1 1 Ferrara G, Soyer HP, Malvehy J, et al. The many faces of blue nevus: a clinicopathologic study. J Cutan Pathol. 2007;34:543–551. 2 Scolyer RA, Zhuang L, Palmer AA, Thompson JF, McCarthy SW. Combined naevus: a benign lesion frequently misdiagnosed both clinically and pathologically as melanoma. Pathology. 2004;36:419. 3 Groben PA, Harvell JD, White WL. Epithelioid blue nevus: neoplasm sui generis or variation on a theme? Am J Dermatopathol. 2000;22:473–488. 4 de Giorgi V, Massi D, Salvini C, et al. Dermoscopic features of combined melanocytic nevi. J Cutan Pathol. 2004;31:600. 5 Arregui MA, Trébol I, Arbide N, et al. Polychromic and indurated lesion in the forearm. Actas Dermosifiliogr. 2007;98:61–62.

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March/April 2016

Volume 14 • Issue 2

CASE STUDY

Supravenous Hyperpigmentation in an HIV-Infected Patient Janet Gilmour, MD, FRCPC;1 Duane Bates, BSc Pharm, ACPR;2 Genevieve Olsen, BSc Pharm;1 Allison Saade, BSc Pharm2

A 47-year-old African American man was seen for routine follow-up for his human immunodeficiency virus (HIV). The patient’s medical history included insomnia, gastroesophageal reflux disease, pulmonary embolism, right shoulder musculoskeletal pain, latent tuberculosis infection, sickle cell trait (hemoglobin S variant), and HIV of 24 years’ duration. (SKINmed. 2016;14:135–137)

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is home medication regimen included ritonavir 100 mg daily, boosted darunavir 800 mg daily, tenofovir 300 mg daily, emtricitabine 200 mg daily, zopiclone 7.5 mg at bedtime as needed, trazodone 50 mg at bedtime, pantoprazole 40 mg daily, and rivaroxaban 20 mg daily. The patient was also receiving intermittent intraarticular triamcinolone and bupivacaine injections for shoulder pain. The patient reported no use of herbal or nonprescription medications. Sixty days prior, his viral load was <40 copies/mL and CD4 count was 0.968×109/L (normal range, 0.499–1.651×109/L), suggesting a good virological response to therapy. The patient noted generalized loss of pigmentation of his skin with the exception of sun-exposed areas (head, neck, hands) and the development of hyperpigmentation on his lower extremities along the course of all the superficial veins (Figure). There had been no erythema, swelling, or pain, and no other changes were noted. There was no history of malignancy, prior cytotoxic drug administration, intravenous drug use, any rheumatologic conditions, or thrombotic phenomenon. Forty-one days later, both the ritonavir 100 mg daily and boosted darunavir 800 mg daily were discontinued and replaced with raltegravir 400 mg twice daily due to a potential drug interaction with rivaroxaban. The tenofovir 300 mg daily and emtricitabine 200 mg daily were continued. At day 147, the rivaroxaban was discontinued, following completion of 6 months of therapy. By

day 177, the bilateral hyperpigmentation of the superficial veins on the lower extremities had resolved. Raltegravir 400 mg twice daily was discontinued on day 182 and replaced with ritonavir 100 mg daily and boosted darunavir 800 mg daily; however, the tenofovir 300 mg daily and emtricitabine 200 mg daily were continued. On day 198, the patient’s viral load was <40 copies/mL and CD4 count 0.910×109/L. Unfortunately, the patient had relocated and upon telephone follow-up (day 237), the patient stated that the hyperpigmentation had returned to his lower extremities for unknown reasons. Discussion Supravenous hyperpigmentation is a rare skin manifestation that presents as a discoloration of the skin, with pigmented linear streaks that typically appear over the superficial venous system. The condition generally affects men nine times more than women and usually occurs in non-Caucasians.1 The reaction is well-documented with the use of antineoplastic chemotherapy agents.1 Supravenous hyperpigmentation has also been reported in patients with collagen vascular diseases, babesiosis infection, and thrombosis in autoimmune hemolytic anemia.2–5 Most commonly, supravenous hyperpigmentation develops around the injection site of the chemotherapeutic agent and is generally limited to the veins of the arms. The reaction may present either upon the first exposure of the antineoplastic agent or

From the Southern Alberta HIV/AIDS Clinic,1 and the Department of Pharmacy, Foothills Medical Centre,2 Alberta Health Services, Calgary, Alberta, Canada Address for Correspondence: Janet Gilmour, MD, FRCPC, Department of Medicine, Foothills Medical Centre, Alberta Health Services, 3330 Hospital Drive NW, Calgary, Alberta, Canada T2N 4N1 • E-mail: gilmourj@ucalgary.ca

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Figure. Presence of supravenous hyperpigmentation on the patient’s right leg.

after repeated administration. To our knowledge, supravenous hyperpigmentation has not been reported with any other class of medications. Patients are usually asymptomatic on presentation without clinical manifestations, including pain, dermatitis, pruritus, venous thrombosis, or soft tissue invasion.1 The hyperpigmentation is known to fade weeks to months after discontinuing the offending agent.6 In rare cases, hyperpigmentation secondary to cytotoxic medications may be permanent.7 A very small number of patients with supravenous hyperpigmentation have had a skin biopsy. In the four patients who have had biopsies, histopathologic study has revealed: (1) increased epidermal melanin content and melanin incontinence extendSKINmed. 2016;14:135–137

An extensive review of the patient’s medications did not suggest an association with serpentine supravenous hyperpigmentation. A literature search in Embase (January 1980 to June 2014), PubMed (January 1980 to June 2014), and Google Scholar (1980 to 2014) using the search terms “supravenous hyperpigmentation” and “human immunodeficiency virus” or “HIV” yielded but one citation. Idiopathic serpentine supravenous hyperpigmentation was found in a case series of three patients who had no history of rheumatologic disease, malignancy, cytotoxic drug administration, or intravenous drug use; two patients were from the Dominican Republic and one patient was African American.6 All patients presented with symmetric, uniform hyperpigmentation of the lower extremities, present for a number of years. Two of the patients had known HIV disease, while the status of the third patient was unknown. Limited information was provided in the case series. Patient one was 55 years old with newly diagnosed advanced HIV disease (CD4=3, viral load=366,000), with Pneumocystis jiroveci and Kaposi’s sarcoma. Patient two had a CD4=3, viral load 58,763, and Candida pneumonia. The authors reviewed home and hospital medications and found that none were associated with supravenous hyperpigmentation. It was not stated whether the supravenous hyperpigmentation resolved. All three cases involved dark-skinned men with symmetric, uniform hyperpigmentation of the supravenous network of the lower extremities, the difference being that our patient did not have advanced HIV disease.

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Conclusions There are only two published cases of supravenous hyperpigmentation in HIV-infected patients with no risk factors. Our patient and the case series noted above suggest that serpentine supravenous hyperpigmentation may be a rare cutaneous manifestation of HIV infection; however, the patients were receiving multiple medications, making it impossible to exclude a drug reaction. An additional limitation in our case was the lack of a full rheumatologic workup, as collagen vascular disease has rarely been associated with supravenous hyperpigmentation. References 1 Geddes ER, Cohen PR. Antineoplastic agent-associated serpentine supravenous hyperpigmentation: superficial venous system hyperpigmentation following intravenous chemotherapy. South Med J. 2010;103:231–235.

2 Jawitz JC, Albert MK, Nigra TP, et al. A new skin manifestation of progressive systemic sclerosis. J Am Acad Dermatol. 1984;11(2 pt 1):265–268. 3 Werth VP, Schumacher HR Jr, Von Feldt JM. Linear hyperpigmentation overlying veins in association with collagen vascular disease. J Am Acad Dermatol. 1993;29:1039–1040. 4 Haapasalo K, Suomalainen P, Sukura A, et al. Fatal babesiosis in man, Finland, 2004. Emerg Infect Dis. 2010;16:1116–1118. 5 Avarbock AB, Lauren CT, Silvers DN, et al. Serpentine supravenous hyperpigmentation secondary to superficial venous thrombosis in autoimmune hemolytic anemia. Int J Dermatol. 2014;53:e96–e97. 6 O’Malley JT, Lieb JL, Weiser JA, et al. Persistent serpentine supravenous hyperpigmentation––a possible cutaneous manifestation of HIV infection or a normal racial variant: a report of 3 cases. Skinmed. 2013;11:93–94. 7 Dereure O. Drug-induced skin pigmentation epidemiology, diagnosis and treatment. Am J Clin Dermatol. 2001;2:253–262.

Historical Diagnosis and treatment: epithelioma

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March/April 2016

Volume 14 • Issue 2

CASE STUDY

Methotrexate-Induced Nasal Septal Perforation Edidiong Ntuen Kaminska, MD;1 Freda Sansaricq, MS;2 Vesna Petronic-Rosic, MD, MSc1

A 58-year-old woman with a 31-year history of Hailey-Hailey (HH) disease that was refractory to treatment with mycophenolate mofetil, cyclosporine, dapsone, sulfasalazine, topical/oral antibiotics, and topical/oral steroids presented for alternative treatment options. Active erythematous, malodorous, eroded, and crusted plaques were present in the axillae, inframammary region, groin, and back (Figure 1). The patient had an undulant course, with acute exacerbations and partial remissions. During a 3-year period, she was prescribed oral methotrexate at a dose of 10 mg to 15 mg per week with daily oral folic acid (1 mg) supplementation, except on the day she took methotrexate. Oral clarithromycin and prednisone were also used intermittently for antibacterial and anti-inflammatory effects. (SKINmed. 2016;14:139–140)

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hile taking methotrexate, the patient was able to achieve marked improvement of her disease, with cumulative doses of 800 mg, 1600 mg, and 2400

mg at 1, 2, and 3 years, respectively. After 2 years she reported sores in her nose that bled intermittently for 1 year. She denied snorting illicit drugs or upper respiratory, pulmonary, and renal symptoms. Laboratory evaluation of a complete blood cell count and a basic metabolic profile was unremarkable. She was referred

to an otorhinolaryngologist and the dose of methotrexate was decreased to 10 mg per week pending further evaluation. Endoscopy confirmed nasal septal perforation (Figure 2) and a perilesional biopsy demonstrated squamous mucosa with ulceration and marked acute and chronic inflammation. At this point, the patient was instructed to discontinue methotrexate. Refractory cases of HH may require systemic therapies, and methotrexate can be effective since patients can tolerate ex-

Figure 1. Hailey-Hailey disease showing eroded malodorous crusted plaques on the patient’s back.

Figure 2. Nasal septal perforation shown on endoscopy of the patient’s nasal septum.

From the University of Chicago Pritzker School of Medicine, Section of Dermatology, Chicago, IL;1 and the University of Chicago Pritzker School of Medicine, Chicago, IL2 Address for Correspondence: Vesna Petronic-Rosic, MD, MSc, University of Chicago Section of Dermatology, 5841 South Maryland Avenue, Chicago, IL 60637 • E-mail: vrosic@medicine.bsd.uchicago.edu

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tended therapy without having systemic steroid side effects. In dermatology, methotrexate is commonly prescribed for psoriasis and most of its side effects are reported in this population. Ulceration is an uncommon toxic adverse effect that may occur with or without other evidence of methotrexate toxicity. Factors that increase toxicity include alteration in the dosage, concomitant use of nonsteroidal anti-inflammatory drugs, renal failure, infection, and a pustular psoriasis flare.1 Two patterns of skin ulceration in psoriasis are type I psoriatic plaques, which erode shortly after starting methotrexate and type II ulcers in nonpsoriatic skin, with a variable relationship to the duration of methotrexate treatment.2 The incidence of skin ulceration with methotrexate is unknown and the dose is widely variable (10 mg to 5000 mg).3 Oral mucosal ulceration is rare, with cumulative doses around 500 mg.4 Two cases of nasal septal perforation caused by methotrexate are reported in the literature; these patients had juvenile rheumatoid arthritis and non-Hodgkin lymphoma.5 The time frame and total dose to toxicity were not reported. Skin and mucosal ulceration may resolve with discontinuation of the drug. When ulceration occurs, a temporal relationship with initiation, increase of the dose, or concomitant therapies must be considered. In the present case, the methotrexate dose was intermittently increased up to 15 mg per week based on the patient’s clinical status. After discontinuing the methotrexate, the patient no longer reported nose bleeds but the nasal septal perforation is permanent.

The antineoplastic properties of methotrexate may hinder the normal physiologic equilibrium of desquamation and regeneration of the nasal epithelium, thereby promoting septal ischemia and predisposing patients to septal perforation.5 Therefore, in addition to oral mucosal lesions, dermatologists should recognize that adverse effects of methotrexate may manifest in the nasal mucosa. Toxicity should be carefully screened, and, if discovered, titration of the dose or cessation may be required. Awareness of methotrexate’s adverse effects and proper patient education may reduce morbidity. References 1 del Pozo J, Martínez W, García-Silva J, et al. Cutaneous ulceration as a sign of methotrexate toxicity. Eur J Dermatol. 2001;11:450–452. 2 Lawrence CM, Dahl MG. Two patterns of skin ulceration induced by methotrexate in patients with psoriasis. J Am Acad Dermatol. 1984;11:1059–1065. 3 Truchuelo T, Alcántara J, Moreno C, Vano-Galván S, Jaén P. Focal skin toxicity related to methotrexate sparing psoriatic plaques. Dermatol Online J. 2010;16:16. 4 Warner J, Brown A, Whitmore SE, Cowan DA. Mucocutaneous ulcerations secondary to methotrexate. Cutis. 2008;81:413–416. 5 Lee SL, Neskey D, Mouzakes J. Potential predisposition for nasal septal perforation with methotrexate use: report of 2 cases and literature review. Ear Nose Throat J. 2009;88:E12–E14.

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March/April 2016

Volume 14 • Issue 2

CASE STUDY

Primary Cutaneous Coccidioidomycosis Presenting as a Recurrent Preauricular Cyst Shayna C. Rivard, MD;1,* Elizabeth Satter, MD, MPH2,*

A 31-year-old Filipino active duty marine presented with a 2-year history of a waxing and waning nodule on his left cheek that had been incised and drained on multiple occasions. The patient had no significant medical history other than a positive purified protein derivative test with negative chest x-ray finding treated with a 9-month course of isoniazid in 2010. He denied cough, fever, chills, night sweats, weight loss, joint/bone pain, or prior trauma to the area. On initial examination, there was a 1×1-cm erythematous indurated nodule associated with an overlying violaceous scar on his left preauricular cheek. Since the lesion was presumed to be an inflamed epidermal cyst, it was initially treated with 0.1 cc of interlesional triamcinolone acetonide (10 mg/cc). At 1-month follow-up, the lesion was slightly less indurated, but an excisional biopsy was performed to remove the residual nodule. The biopsy showed an essentially normal epidermis with focal dermal fibrosis below which were multiple collections of histiocytes and multinucleated giant cells surrounded by a dense lymphoplasmacytic infiltrate with numerous eosinophils (Figure 1). A few multinucleated giant cells contained large thick-walled spherules, some with endospores, consistent with Coccidioides immitis (Figure 2). Serological tests showed positive serum for C immitis IgG antibodies with low levels of complement-fixing antibodies (1:2). IgM antibodies were negative. Findings from chest x-ray and bone scan failed to reveal evidence of systemic disease. Although the infectious disease physician felt that the patient most likely had primary cutaneous coccidioidomycosis (PCC), since the duration of the infection was unknown and the patient was Filipino, thereby increasing his risk of dissemination, he was placed on a daily regimen of 400 mg of oral fluconazole until his complement fixation titers became undetectable. (SKINmed. 2016;14:142–144)

C

occidioidomycosis, also known as Valley Fever, is an increasingly common dimorphic fungal infection endemic to the southwest United States, northern Mexico, and parts of Central and South America. The organism resides in the soil and is transmitted via inhalation of airborne arthroconidia. It has been estimated that 150,000 infections occur annually, with the majority of people having self-limited subclinical pulmonary disease that eventuates in lifetime immunity.1–3 Epidemic outbreaks can occur when an endemic environment is disturbed by earthquakes, drought, and dust storms.1,2,4 People who live in these regions and have prolonged outdoor exposure, such as construction workers, archeologists, and military personnel, have an increased risk of developing primary disease.1,2,4 Approximately 30% to 40% of people develop symptomatic primary pulmonary disease, and, of these, only 0.5% to 2% of patients at low risk subsequently develop disseminated disease.3,5 Extrapulmonary lesions can occur in as many as 30% to 50% of people with altered cell-mediated immunity, however, namely those infected with the human immunodeficiency vi-

rus, organ transplant recipients, patients with hematologic malignancies, patients taking immunosuppressive drugs, and the elderly.1,3–7 Pregnancy, certain ABO blood types, various ethnic groups (Asians, Filipinos, and African Americans), and military members also appear to conifer an increased risk of disseminated disease.1,3–8 The clinical presentation of coccidioidomycosis is protean, with the majority of people having asymptomatic disease; however, extrapulmonary lesions can occur in 0.5% to 50% of infected people depending on underlying risk factors.1,3–7 Frequent sites of dissemination include the skin, meninges, bone, and joints, with cutaneous manifestations most common.1 Skin lesions can be classified as reactive or disease-specific.1,4,5 Reactive eruptions are an immune response to a primary pulmonary infection with no viable organisms located in the tissues. These reactions include, but are not limited to, erythema nodosum, a generalized acute exanthem (toxic erythema), erythema multiforme, Sweet syndrome, and reactive interstitial granulomatous dermatitis.1,4,5

*These authors contributed equally to the work. From the Dermatology Residency Program;1 and the Department of Dermatology and Pathology, Naval Medical Center San Diego, San Diego, CA (retired)2 Address for Correspondence: Elizabeth Satter, MD, MPH • E-mail: esatter@hotmail.com

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A

Figure 1. Multiple collections of histiocytes and multinucleated giant cells surrounded by a lymphoplasmacytic infiltrate with increased eosinophils (hematoxylin-eosin stain, original magnification ×20).

B

Disease-specific lesions, on the other hand, have identifiable organisms within the lesion and can occur as a result of hematogenous dissemination to the skin or, much more rarely, from direct inoculation into the skin.1,4,5,7–10 To date there have been approximately 30 cases of PCC. Because of its rarity, Wilson and colleagues9 devised diagnostic criteria to help differentiate PCC from cutaneous lesion that arose as a result of disseminated disease (Table).9 Although Wilson’s diagnostic criteria provided a basic foundation, these criteria are nonspecific and many have been disputed. A recent review of 30 cases of PCC showed that the clinical presentation is more variable than what was previously described. Lesions can present as ulcers, abscesses, cysts, nodules, and verrucous plaques; can mimic lupus pernio, sporotrichosis, and rosacea; or can even resemble disseminated disease.8 Wilson also required lesions of PCC to spontaneously involute; however, patients with altered immunity often have persistent lesions, and many reported cases of PCC have had excisional biopsies and/or are treated with sys7–10

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Figure 2. (A) Thick-walled spherules with endospores within a multinucleated giant cell (hematoxylin-eosin stain, original magnification ×100; (B) original magnification ×400).

temic antifungal, thus the natural course of these cases remains unknown.7,8,10 Another point of contention is the requirement of a history of direct inoculation, since patients with PCC often cannot endorse a history of trauma.8 Serological studies are also problematic, because, although the coccidioidin test can be useful in population studies, it is not routinely available in the United States, and even when used, it has limited utility since it can show cross-reactivity with other fungi and cannot distinguish acute from prior infection.7,9 Lastly, although the majority of patients with skin lesions from disseminated disease have systemic symptoms and/or positive imaging study findings, there are cases with no evidence of a preceding respiratory illness.1,8,9 In the patient presented herein, it is hypothesized that he may have initially had an epidermal cyst and after one of the episodes of incision and drainage, the open wound was inoculated

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Table. Wilson’s Diagnostic Criteria to Differentiate Primary Cutaneous Coccidioidomycosis From Cutaneous Lesions Caused By Disseminated Disease Primary Cutaneous

Disseminated Disease

History of pulmonary disease

Absent

Present

History of inoculation

Present

Absent

Incubation

1 to 3 weeks from inoculation

1 to 3 months from pulmonary disease

Clinical appearance

Solitary ulcerated nodule resembling a ˚1 chancre

Variable

Regional lymphadenopathy

Present

Absent

Duration

Spontaneous resolution within weeks to months

Lesion persists and may expand beyond 3 months

Intracutaneous coccidioidin test

Rapidly positive

Negative (anergy)

Complement fixation antibody titers

Negative or low (1:2)

High or rising

with the organism during desert training exercises. A diagnosis of PCC is favored based on the fact that there was no evidence of a prior pulmonary infection, the patient was asymptomatic other than a solitary lesion containing scattered organisms, and had low complement fixation titers.

by a military service member or employee of the US Government as part of that person’s official duties.”

In general, PCC has an excellent prognosis, with the majority of cases showing spontaneous involution.7,9 For persistent lesions and for individuals with increased risk factors, however, systemic treatment with an azole antifungal should be considered.1,5,7,8

2 Lee R, Crum-Cianflone N. Increasing incidence and severity of coccidioidomycosis at a naval air station. Mil Med. 2008;173:769–775.

References

Conclusions PCC can present in a myriad of ways and this case demonstrates the importance of maintaining a high index of clinical suspicion especially for patients who live in endemic regions who present with unusual cutaneous lesions. This case also illustrates the need to reevaluate prior proposed criteria used to better differentiate cutaneous lesions caused by PCC from those of disseminated disease. Disclaimer The views expressed in this contribution are those of the authors and do not reflect the official policy or position of the Department of the Navy, Department of Defense, or the United States Government. At the time the paper was drafted, Drs Rivard and Satter were active duty military service members and this work was prepared as part of their official duties. Title 17, USC, § 105 provides that “Copyright protection under this title is not available for any work of the United States Government.” Title 17, USC, § 101 defines a US Government work as a work prepared SKINmed. 2016;14:142–144

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1 Dicaudo DJ. Coccidioidomycosis: a review and update. J Am Acad Dermatol. 2006;55:929–942.

3 Galgiani JN, Ampel NM, Blair JE, et al. Coccidioidomycosis. Clin Infect Dis. 2005;41:1217–1223. 4 Schwartz RA, Lamberts RJ. Isolated nodular cutaneous coccidioidomycosis: the initial manifestation of disseminated disease. J Am Acad Dermatol. 1981;4:38–46. 5 Blair JE. State-of-the-art treatment of coccidioidomycosis: skin and soft-tissue infections. Ann N Y Acad Sci. 2007;1111:411–421. 6 Carpenter JB, Feldman JS, Leyva WH, DiCaudo DJ. Clinical and pathologic characteristics of disseminated cutaneous coccidioidomycosis. J Am Acad Dermatol. 2010;62:831–837. 7 Chang A, Tung RC, McGillis TS, Bergfeld WF, Taylor JS. Primary cutaneous coccidioidomycosis. J Am Acad Dermatol. 2003;49:944–949. 8 Salas-Alanis JC, Ocampo-Candiani J, Cepeda-Valdes R, Gomez-Flores M, Bonifaz A. Primary cutaneous coccidioidomycosis: incidental finding. J Clin Exp Dermatol Res. 2012;3:147. 9 Wilson JW, Smith CE, Plunkett OA. Primary cutaneous coccidioidomycosis: the criteria for diagnosis and a report of a case. Calif Med. 1953;79:233–239. 10 Gildardo JM, Leobardo VA, Nora MO, Jorge OC. Primary cutaneous coccidioidomycosis: case report and review of the literature. Int J Dermatol. 2006;45:121–123.

Primary Cutaneous Coccidioidomycosis


March/April 2016

Volume 14 • Issue 2

CASE STUDY

Dermatological Implications of Coining: An Eastern Medicine Cultural Practice Nyasha George, MD; Traci Trice, MD; James S. Studdiford, MD; Kathryn Trayes, MD

A 36-year-old Chinese man with no significant medical history presented to his clinician’s office for follow-up of results from recent blood work. Upon entering the room, the patient was wearing a mask. After reviewing his lipid panel, he mentioned that he had been “fighting a cold.” He reported 3 days of cough with chest tightness and mild shortness of breath. He denied fever. The patient was using an overthe-counter cough medicine but reported no chronic medication use. On initial inspection, the patient had a vivid purple eruption on his arms. The patient denied pain or itching. After the patient lifted his shirt, the full extent of the discoloration was seen configured in a symmetric fashion over the anterior torso and abdomen (Figure 1). The eruption was purple-red in color and distributed in a linear pattern over the anterior chest contouring the outline of the underlying ribs. Additional vertically arrayed areas of erythematous skin consisting of microecchymoses were appreciated on the anterior abdomen. These appeared to follow an intentional pattern. No other petechiae, palpable purpura, or isolated ecchymoses were seen. When questioned further, our patient readily admitted that he had participated in a common traditional Chinese treatment consisting of “scraping bruises” to relieve his bronchitis. (SKINmed. 2016;14:145–146)

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oining, alternatively known as coin rubbing, “çao gio,” and “cao gío,” is a therapeutic alternative medicine practice that is popular in some parts of China and Vietnam (where it is known as Gua sha). It involves firmly rubbing the edge of a coin (or a porcelain spoon) that has been prepped with hot mentholated oils or balms, along the chest, back, and shoulders. This process is believed to allow for the release of “excess wind” from the body, which is thought to be the cause of minor illnesses such as headaches, fevers, sore throats, and upper respiratory infections. The effectiveness of coining is measured by the result of the characteristic “pine tree” pattern appearance of linear microecchymoses or petechiae (Figure 2). Typically, the dermatosis is transient, resolves within days, and leaves behind no permanent lesions. Minor superficial skin burns are a commonly reported adverse effect of the practice of coining. That there have been scattered case reports of more serious complications associated with cao gío. These include full thickness skin

burns necessitating skin grafting, cerebellar hemorrhage thought to be mediated by the pain-activated sympathetic response to coining, and altered mental status as a result of the systemic absorption of camphor (an ingredient commonly found in balms and oils). The true incidence of these more serious implications is unknown and likely underreported to Western-trained healthcare providers for fear that this cultural practice could be misinterpreted as a form of abuse. Between 2010 and 2013, the net immigration of Asians to the United States exceeded 1 million persons. It is important to recognize that a significant percentage of such immigrants engage in the practice of coining. Given its dramatic skin manifestations, the remote potential for more serious adverse effects, and the risk of misdiagnosis, it is imperative that healthcare providers become familiar with the tradition of cao gío and the characteristic skin findings associated with it.

From the Department of Family and Community Medicine, Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, PA Address for Correspondence: James S. Studdiford, MD, Department of Family and Community Medicine, Sidney Kimmel Medical College at Thomas Jefferson University, 1015 Walnut Street, Suite 401, Philadelphia, PA 19107 • E-mail: James. Studdiford@jefferson.edu

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CASE STUDY References 1 Lilly E, Kundu RV. Dermatoses secondary to Asian cultural practices. Int J Dermatol. 2012;51:372–382. 2 Ponder A, Lehman LB. “Coining” and “coning”: an unusual complication of unconventional medicine. Neurology. 1994;44:774–775. 3 Rampini SK, Schneemann M, Rentsch K, Bächli EB. Camphor intoxication after cao gio (coin rubbing). JAMA. 2002;288:45. 4 Amshel CE, Carusa DM. Vietnamese “coining”: a burn case report and literature review. J Burn Care Rehabil. 2000;21:112–114. 5 Davis R. Cultural health care or child abuse? The Southeast Asian practice of cao gio. J Am Acad Nurse Pract. 2000;12:85–95. 6 Look KM, Look LM. Skin scraping, cupping, and moxibustion that may mimic physical abuse. J Forensic Sci. 1996;42:103–105. 7 United States Census Bureau. Population estimates. Components of resident population change by race and Hispanic origin for the United States: April 1, 2010 to July 1, 2013. https://www.census.gov/popest/data/datasets.html. Accessed August 4, 2014.

Figure 1. Multiple erythematous macular lesions consistent with microecchymoses in a linear pattern located on the anterior chest wall and abdomen.

Figure 2. Linear erythema with petechial appearance located on the volar surface of the left upper extremity.

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March/April 2016

Volume 14 • Issue 2

CASE STUDY

Multisystem Langerhans Cell Histiocytosis in Adults Revealed by Skin Lesions Hanane Atarguine, MD;1,2 Ouafa Hocar, MD, PhD;1,2 Samia Oussmane, MD;1,2 Sara Batoul Mouafik, MD;1,2 Abderrachid Hamdaoui, MD;3 Hanan Hafiane, MD;4 Rhizlane Belbaraka, MD, PhD;2,5 Nadia Akhdari, MD, PhD;1,2 Said Amal, MD, PhD1,2

A 37-year-old woman with no remarkable medical or family history presented with papules and vesicles on an erythematous background involving the neck, sacrum, and folds (postauricular, axillary, inguinal, and under the breasts) (Figure 1). During the previous year, she was treated with local and systemic antifungals without improvement. Her history included a secondary amenorrhea, polydipsia, and polyuria (6 L/d) that started 2 years prior. Physical examination revealed chronic bilateral purulent otorrhea with thick eardrums. Histologic examination of skin biopsy revealed a highly suggestive appearance of multisystem Langerhans cell histiocytosis (LCH) with immunohistochemistry (anti-PS100 and anti-CD1a), which were positive (Figure 2A and 2B). Pituitary magnetic resonance imaging showed a thickening of the pituitary stalk in relation to a location histiocytic (Figure 3). Bone gaps were objectified on two radiographic tibial diaphyseal. Results from computed tomography (CT) scan showed a magma coelio mesenteric, axillary, and inguinal lymph nodes. (SKINmed. 2016;14:147–149)

R

esults from biological tests showed low cortisol to 65.60 ng/mL, low T3 to 1.49, a disturbed gonadal axis with estradiol <0.04 nmol/L, follicle-stimulating hormone <0.10 MIU/mL, and luteinizing hormone <0.10 MIU/mL. Based on these findings we concluded a diagnosis of LCH with cutaneous, otologic, pituitary, bone, and lymph node involvement.

According to the Histiocyte Society’s study in adults,1 the patient received intranasal desmopressin (10 μg twice daily), systemic chemotherapy (vinblastine: weekly 6 mg/m2 intravenous bolus injection), and prednisolone (40 mg/m2/d). After 2 months of treatment, early regression of skin lesions and urine volume decreased to 1.5 L/d to 2 L/d, without major adverse effects. Discussion LCH is a rare proliferative disorder of unknown etiology in which there is an accumulation of pathologic Langerhans cells.2 The incidence of LCH is very low in the whole population and

Figure 1. Papules and vesicles on an erythematous base under the breasts.

From the Department of Dermatology, Hospital Arrazi, CHU Mohamed VI;1 Faculty of Medicine and Pharmacy, Cadi Ayyad University,2 Laboratory “Zohor” of Pathological Anatomy and Cytology;3 the Department of Hematology, CHU Mohamed VI;4 and the Department of Medical Oncology, CHU Mohamed VI,5 Marrakech, Morocco Address for Correspondence: Hanane Atarguine, MD, Hospital Arrazi, Department of Dermatology, CHU Mohamed VI, 40000 Marrakech Maroc • E-mail: hananeatarguine@hotmail.fr

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A

B

Figure 2. (A) Skin biopsy tissue showing granulomatous nodules in the superficial dermis with histiocytic cells and some eosinophils. The histiocytic cells have a nucleus notched with eosinophilic cytoplasm and pagetoid infiltration of the superficial epidermis by these histiocytic cells (hematoxylin and eosin stain, original magnification ×60). (B) Positive immunohistochemical staining for CD1a antigen (CD1a, original magnification ×100).

LCH can affect any organ, with the most common sites being the bone (80%), skin (33%), and pituitary region (25%). Other sites include the liver, spleen, ears, hematopoietic system, lungs (15% each), lymph nodes (5–10%), and central nervous system excluding the pituitary (2–4%).4 Our patient with LCH presented with skin lesions and was subsequently diagnosed with central diabetes insipidus due to pituitary stalk involvement of LCH. The bone lesion was asymptomatic with two other otologic and nodal locations. Cutaneous lesions are very common in LCH. It is usually the first sign of the disease, being reported in 80% of cases, and carries prime diagnostic significance.5 The classical cutaneous lesions of LCH have been described as scaly, erythematous, seborrhea‑like eruptions of brown to red papules involving the face, scalp, and trunk, and are particularly pronounced in the intertriginous zones. Figure 3. Results from magnetic resonance imaging T1 sagittal slice of the pituitary gland revealed a thickened pituitary stalk in relation to a location histiocytic.

it is more common in children aged 1 to 3 years. LCH is considered a pediatric disease but may present at any age from the neonatal period to adult age. In particular, adult-onset LCH is even more rare and its incidence has been reported to be around one to two cases per million people per year.3 SKINmed. 2016;14:147–149

In our case, skin lesions were papules and vesicles on an erythematous base involving the neck, sacrum, and folds. Skin biopsy with immunohistochemical evaluation would have confirmed the diagnosis of LCH. Physical examination and laboratory and radiological investigations are required to find other locations. Unlike LCH in children, therapeutic regimens for adults with LCH have not yet been confirmed.2 The current chemotherapeutic regimen is determined at the physician’s discretion based on case or case series reports of successful treatment.

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Therefore, in 2004, the Histiocyte Society launched the first cooperative international trial for the diagnosis and treatment of LCH in adults.3 This trial, known as the First International Study for Langerhans Cell Histiocytosis in Adults (LCH-A1)s, seeks to define a common treatment strategy for patients with multisystem and pulmonary LCH and to evaluate the efficacy of the standard regimen (vinblastine and prednisone) for multisystem childhood LCH in adult patients with LCH.6

References

Conclusions LCH often presents as a puzzling syndrome and is difficult to diagnose in adults. Because this disease is very rare, only a limited number of large surveys exist in the literature and many aspects of the management of patients remain obscure or controversial. Further fundamental and clinical research is still needed in this field.

1 Aricò M. Langerhans cell histiocytosis in adults: more questions than answers? Eur J Cancer. 2004;40:1467– 1473. 2 Histiocytosis syndromes in children. Writing Group of the Histiocyte Society. Lancet. 1987;1:208–209. 3 Baumgartner I, von Hochstetter A, Baumert B, Luetolf U, Follath F. Langerhans’-cell histiocytosis in adults. Med Pediatr Oncol. 1997;28:9–14. 4 Donadieu J, Chalard F, Jeziorski E. Medical management of langerhans cell histiocytosis from diagnosis to treatment. Expert Opin Pharmacother. 2012;13:1309–1322. 5 Aamir S, Haque A. Langerhan cell histiocytosis—a case report. Int J Pathol. 2005;3:1–4. 6 Girschikofsky M, Arico M, Castillo D, et al. Management of adult patients with Langerhans cell histiocytosis: recommendations from an expert panel on behalf of EuroHistio-Net. Orphanet J Rare Dis. 2013;8:72.

Anthrax. Wax model created by Alfons Kroner. Courtesy of Foundation Deutsches HygieneMuseum in Dresden, Germany, Submitted by Uwe Wollina, MD

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March/April 2016

Volume 14 • Issue 2

CASE STUDY

Molluscum Contagiosum Infection Involving a Benign Epidermoid Cyst in an Immunocompetent Patient Husein Husein-ElAhmed, MD; Inmaculada Ruiz-Molina, MD; Vicente Cívico-Amat, MD; Eduardo Solís-García, MD

A 78-year-old man presented with a round- to oval-shaped nodule on his right eyebrow. The lesion first developed 5 years ago as a small solitary white nodule and subsequently enlarged over the past 2 years. His medical history was unremarkable. Clinical examination revealed a 2-cm round to oval dome-shaped yellowish nodule with a dimple on the top center (Figure 1). No similar lesions were found elsewhere. With a clinical suspicion of sebaceous carcinoma, an excision of the lesion was performed under local anesthesia. The histopathologic analysis showed an epidermal cyst containing molluscum bodies along the keratin inside the cyst (Figure 2). With these findings, the diagnosis of molluscum contagiosum (MC) infection into an epidermoid cyst was made. Neither recurrence nor new similar lesions were observed at follow-up. (SKINmed. 2016;14:151–152)

M

C is a viral infection caused by the molluscum contagiosum virus. This virus belongs to the family of DNA poxviruses, which are particularly well adapted for infecting human skin cells.1 This condition develops characteristic cutaneous lesions consisting of small, firm, dome-shaped, skin-colored papules with a dimple on the center. It mainly occurs in children, but it is also observed in sexually active adults. Immunocompromised individuals, particularly those infected with HIV, have a higher incidence of this infection (up to 33.3%).2 In these patients, infection is usually widespread, involving atypical, nonanogenital areas such as the neck and eyelid.3 MC is rarely associated with other skin diseases, particularly cutaneous neoplasms. Such associations are exceptional and of unknown frequency. In an interesting study published in 2010,4 the analysis of 578 patients with MC showed that only nine cases were associated with epidermal cysts (1.55%). Although this situation may be common in immunocompromised patients, such associations are unlikely in immunocompetent individuals, as in our patient. To rule out a previous medical history of immunocompromised condition, we performed white cell count, HIV status, and plasmatic levels of immunoglobulins to assess the immune system despite his healthy status. Results were normal.

A B Figure 1. (A) A yellowish erythematous nodule involving the supraciliar right area. (B) A closer view of the lesion.

Although several histologic variants of MC have been reported, such as pseudocyst, giant, and pedunculated,4 the clinical appearance of MC is often characteristic and, therefore, the diagnosis is relatively easy to make. In the same way, epidermal cyst is a cutaneous condition that is typically easy to diagnose. When

From the Department of Dermatology and Pathology, Infanta Margarita Hospital, Córdoba, Spain Address for Correspondence: Husein Husein-ElAhmed, MD, University Hospital, Department of Dermatology, Granada, Spain Avd, Madrid S/N, CP, 18012 • E-mail: huseinelahmed@hotmail.com

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B C D Figure 2. (A) Paronamic view of the lesion showing a molluscum contagiosum infection and an underlying epidermal cyst (hematoxilin and eosin x2). (B) Molluscum contagiosum bodies along the keratin fibers (hematoxilin and eosin x4). (C) Some areas in the cyst are spared by molluscum contagiosum bodies. (D) Other areas are infected (hematoxilin and eosin x10).

associated with other lesions, however, MC is frequently clinically misdiagnosed.5 In our patient, the first diagnosis considered was sebaceous carcinoma given the clinical features, the location, and the history of the lesion. Three pathogenic mechanisms have been proposed in the association of MC infection and epidermal cyst6: (1) the inoculation of MC at the time of formation of the cyst; (2) the invasion of a preexisting cyst by the MC virus through the ostium, which connects the cyst with the epidermis above; and (3) from a cyst infected previously by the MC virus, the infection spreads to the epidermis, producing the clinical typical lesions of MC. According to the anamnesis, we think our patient may be included in the second grouping, as he showed a preexisting lesion without changes in size that increased for 2 years. In support of this, histology shows that some areas inside the cyst are infected, while in others, epithelium and keratin were normal. No lesions of MC were observed involving other areas of the skin in our patient; therefore, we think the third pathogenic mechanism may be rationally ruled out.

to date. This highlights the fact that this association is not common, and even less so involving immunocompetent patients, as was the case we present here. References

We performed a PubMed search with the terms “molluscum contagiosum” and “epidermal cyst” with only 16 cases published SKINmed. 2016;14:151–152

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1 Hanson D, Diven DG. Molluscum contagiosum. Dermatol Online J. 2003;9:2. 2 Aldabagh B, Ly MN, Hessel AB, Usmani AS. Molluscum contagiosum involving an epidermoid cyst with xanthogranuloma-like reaction in an HIV-infected patient. J Cutan Pathol. 2010;37:282–286. 3 Massa AF, Borges-Costa J, Soares-Almeida L, Sacramento-Marques M. Molluscum contagiosum eyelid lesions in an HIV-patient. Dermatol Online J. 2013;19:10. 4 Aldabagh B, Ly MN, Hessel AB, Usmani AS. Molluscum contagiosum involving an epidermoid cyst with xanthogranuloma-like reaction in an HIV-infected patient. J Cutan Pathol. 2010;37:282–286 5 Cribier B, Scrivener Y, Grosshans E. Molluscum contagiosum: histologic patterns and associated lesions. A study of 578 cases. Am J Dermatopathol. 2001;23:99–103. 6 Chiu H, Wu C, Chen G, et al. Molluscum contagiosum infestation in an epidermal cyst: still infectious? J Eur Acad Dermatol Venereol. 2010;24:81–83.

Molluscum Contagiosum Infection


March/April 2016

Volume 14 • Issue 2

CASE STUDY

Multiple Adult Xanthogranulomas Associated With Cutaneous Lymphoid Hyperplasia and Lupus Erythematosus Brian P. Hibler, BS; Kristin L. Eastman, MD; Daniel D. Bennett, MD; Andrew M. Swanson, MD; B. Jack Longley, MD; Gary S. Wood, MD

A 50-year-old woman presented to our clinic for evaluation of numerous recurrent, pruritic papules on her upper extremities. She reported a 2- to 3-year history of up to eight unique lesions on the bilateral upper arms that would initially appear as firm papules before gradually softening and flattening out, leaving residual pink macules (Figure 1A). Her medical history was notable for mild hyperlipidemia. On presentation, she had several erythematous papules with overlying telangiectasias scattered throughout her bilateral upper arms. One lesion of concern over the left deltoid had been present for 5 months without signs of regression (Figure 1B). Pathology of this and a similar lesion showed histiocytes forming Touton giant cells with foamy cytoplasm consistent with a xanthogranuloma (AXG). Results from immunoperoxidase stains were negative for factor XIIIa and CD1a, diffusely positive for CD68, and focally positive for S100 (Figure 2). (SKINmed. 2016;14:153–155)

A

pproximately 2 months after her initial presentation, a new violaceous, indurated nodule (Figure 1C) was identified and biopsied. Histologically, this lesion showed a dense mononuclear infiltrate that was strongly CD3 positive with scattered collections of CD20 positive cells (Figure 3). The pathology was consistent with cutaneous lymphoid hyperplasia. This case represents the first report of cutaneous lymphoid hyperplasia in a patient with multiple adult AXG. Comment AXG are a relatively rare, benign proliferative disorder of nonLangerhans cell histiocytes that are typically a disorder of infancy, but have also been reported in adults. Clinically, they appear as yellow-red, firm papules with well-demarcated borders, and may develop surface telangiectasias. Compared with the juvenile form of AXG, the adult type is more often solitary and larger,1 although there is a small number of reports of multiple AXG.2 The differential diagnosis for an adult AXG includes other non-Langerhans cell histiocytoses such as juvenile AXG,

papular xanthoma, xanthoma disseminatum, multicentric reticulohistiocytosis, indeterminate cell histiocytosis, and benign cephalic histiocytosis. Histologically, the adult and juvenile forms are indistinguishable, typically demonstrating foamy histiocytes, Touton giant cells, and inflammatory cells with variable amounts of fibrosis.1,3 Adult AXG are typically factor XIIIa and CD68 positive and S-100 and CD1a negative; however, S-100 positivity and factor XIIIa negativity have been reported.4–9 Although the lesions in our patient had uncommon staining profiles, they were clinically and histologically most consistent with AXG. Discussion There have been 30 reported cases of multiple AXG in the literature, which we defined as five or more AXG in a person 18 years or older. While there are no reports of abnormal laboratory tests associated with AXG, there is an association between the presence of AXG and the development of hematologic malignancies in eight adult cases to date, including monoclonal gammopathy, chronic myelogenous leukemia, essential thrombocytosis, adult

From the Department of Dermatology, University of Wisconsin School of Medicine and Public Health, Madison, WI Address for Correspondence: Kristin Eastman, 1 South Park Street, Madison, WI, 53715 • E-mail: keastman@uwhealth.org

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Figure 3. (A) Histopathology of the lesion shown in Figure 1C revealing cutaneous lymphoid hyperplasia (hematoxylin and eosin stain, original magnification ×40). Immunohistochemistry (B) showing dense CD3 positivity (hematoxylin and eosin stain, original magnification ×100) and (C) scattered CD20 positivity (hematoxylin and eosin stain, original magnification ×40).

Figure 1. (A) Multiple firm, erythematous papules located on the upper extremity that appeared abruptly and flattened over time. (B) Representative lesion appearing as a rubbery, reddish yellow papule. (C) A distinctly different solitary, violaceous nodule on the left elbow.

While the etiology of AXG remains unclear, the association of a hematologic malignancy in 8 of 30 cases of multiple AXG (27%), and now with a cutaneous lymphoproliferative disorder, suggests that individuals with a history of multiple AXG may warrant evaluation for these disease processes with close clinical follow-up. Some cases of cutaneous lymphoid hyperplasia have the potential to progress to overt lymphoma; however, our patient’s lesion clinically resolved with topical clobetasol treatment. She was evaluated thoroughly for an underlying hematologic disorder, and because the workup was unremarkable and she had no concerning signs or symptoms of systemic or ocular involvement, it was decided to observe the patient closely in the clinic.

Figure 2. (A) Histopathology of the lesion shown in Figure 1B revealing a dermal histiocytic infiltration consistent with a xanthogranuloma (hematoxylin and eosin stain, original magnification ×40). (B) Cells positive for S-100 (hematoxylin and eosin stain, original magnification ×100).

T-cell leukemia/lymphoma, large B-cell lymphoma, B-cell acute lymphoblastic leukemia, and follicular lymphoma.10–14 Our case represents the first report of multiple AXG and a cutaneous lymphoproliferative disorder. SKINmed. 2016;14:153–155

One year after our patient’s initial presentation, she was diagnosed with a connective tissue disorder, most consistent with lupus erythematosus. Arthralgias, weakness, facial edema, antinuclear antibody >1:640, and positive anti-dsDNA antibody titers were present, and the symptoms improved on hydroxychloroquine. The literature supports an association between histiocytic disorders and lupus erythematosus.15–18 Furthermore, patients with autoimmune disorders including lupus erythematosus ap-

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pear to be at increased risk for developing lymphoma,19,20 and findings suggestive of lymphocytoma cutis have been observed concomitantly with features characteristic of lupus erythematosus.21

10 Narvaez-Moreno B, Pulpillo-Ruiz A, De Zulueta-Dorado T, Conejo-Mir J. Disseminated juvenile xanthogranuloma associated with follicular lymphoma in an adult: successful treatment with chemotherapy and rituximab. A review of the literature. Actas Dermosifiliogr. 2013;104:242–246.

Conclusions

11 Larson MJ, Bandel C, Eichhorn PJ, Cruz PD Jr. Concurrent development of eruptive xanthogranulomas and hematologic malignancy: two case reports. J Am Acad Dermatol. 2004;50:976–978.

Reporting such cases of the coexistence of these disorders may help reveal associations and the related pathogenesis between each. We hypothesize that some form of systemic immune dysregulation could potentially connect the patient’s lupus erythematosus, histiocytic disorder, and cutaneous lymphoid hyperplasia. References 1 Chang SE, Cho S, Choi JC, et al. Clinicohistopathologic comparison of adult type and juvenile type xanthogranulomas in Korea. J Dermatol. 2001;28:413–418. 2 Saad N, Skowron F, Dalle S, et al. Multiple adult xanthogranuloma: case report and literature review. Dermatology. 2006;212:73–76. 3 Rodriguez J, Ackerman AB. Xanthogranuloma in adults. Arch Dermatol. 1976;112:43–44. 4 Weitzman S, Jaffe R. Uncommon histiocytic disorders: the non-Langerhans cell histiocytoses. Pediatr Blood Cancer. 2005;45:256–264. 5 Zelger B, Cerio R, Orchard G, Wilson-Jones E. Juvenile and adult xanthogranuloma. A histological and immunohistochemical comparison. Am J Surg Pathol. 1994;18:126–135.

12 Pino Gil M, Miquel FJ, Velasco M, et al. Multiple xanthogranulomas in an adult, associated with essential thrombocytosis. Br J Dermatol. 1995;132:1018–1021. 13 Chiou CC, Wang PN, Yang LC, et al. Disseminated xanthogranulomas associated with adult T-cell leukaemia/ lymphoma: a case report and review the association of haematologic malignancies. J Eur Acad Dermatol Venereol. 2007;21:532–535. 14 Shoo BA, Shinkai K, McCalmont TH, Fox LP. Xanthogranulomas associated with hematologic malignancy in adulthood. J Am Acad Dermatol. 2008;59:488–493. 15 Kaur PP, Birbe RC, DeHoratius RJ. Rosai-Dorfman disease in a patient with systemic lupus erythematosus. J Rheumatol. 2005;32:951–953. 16 Grau JM, Aguilar JL, Cid MC, Urbano-Marquez A. Malignant histiocytosis as a fatal complication of systemic lupus erythematosus. Arthritis Rheum. 1991;34:1557– 1559. 17 Dumas G, Prendki V, Haroche J, et al. Kikuchi-Fujimoto disease: retrospective study of 91 cases and review of the literature. Medicine (Baltimore). 2014;93:372–382.

6 Janssen D, Harms D. Juvenile xanthogranuloma in childhood and adolescence: a clinicopathologic study of 129 patients from the kiel pediatric tumor registry. Am J Surg Pathol. 2005;29:21–28.

18 Robak T, Kordek R, Robak E, et al. Langerhans cell histiocytosis in a patient with systemic lupus erythematosus: a clonal disease responding to treatment with cladribine, and cyclophosphamide. Leuk Lymphoma. 2002;43:2041–2046.

7 Tomaszewski MM, Lupton GP. Unusual expression of S-100 protein in histiocytic neoplasms. J Cutan Pathol. 1998;25:129–135.

19 Zintzaras E, Voulgarelis M, Moutsopoulos HM. The risk of lymphoma development in autoimmune diseases: a meta-analysis. Arch Intern Med. 2005;165:2337–2344.

8 Yamamoto Y, Kadota M, Nishimura Y. A case of S100-positive juvenile xanthogranuloma: a longitudinal observation. Pediatr Dermatol. 2009;26:475–476.

20 Goobie GC, Bernatsky S, Ramsey-Goldman R, Clarke AE. Malignancies in systemic lupus erythematosus: a 2015 update. Curr Opin Rheumatol. 2015;27:454–460.

9 Kraus MD, Haley JC, Ruiz R, et al. “Juvenile” xanthogranuloma: an immunophenotypic study with a reappraisal of histogenesis. Am J Dermatopathol. 2001;23:104–111.

21 Magro CM, Crowson AN, Harrist TJ. Atypical lymphoid infiltrates arising in cutaneous lesions of connective tissue disease. Am J Dermatopathol. 1997;19:446–455.

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March/April 2016

Volume 14 • Issue 2

correspondence Snejina Vassileva, MD, PhD, Section Editor

An Update and Evaluation of Telemedicine and Teledermatology Publications for 2014 Engin Senel, MD;1 Emre Demir, MD2

To the Editor: Telemedicine is a technology used to transfer medical information and images via modern communication methods. Teledermatology is a novel and fast-developing application of telemedicine that provides the dermatological evaluation of patients in areas where distance is a critical factor.1 We recently reported a study in which we performed a statistical analysis of studies published in the literature on telemedicine and teledermatology during 1980–2013. We also investigated the correlations between economical productivities, technological advancement levels, humanity index, and publication per-

formances of the countries in both fields.2 We found that the Web of Science database had a total of 9465 publications in the telemedicine field and 572 publications in the teledermatology field from the beginning of 1980 to the end of 2013. A high correlation was detected between the number of telemedicine and teledermatology publications and the 2013 gross domestic product values of the countries. A significant correlation was noted between the number of publications and the human development index of the countries. In our study, we also calculated an estimated publication number for 2014 by using cumulative publication numbers of 1998 and 2013. Our projected publication number was 797 for telemedicine and 48 for teledermatology in 2014.2

Figure. The top 10 countries publishing teledermatology publications by total number of items in 2014.

From the Department of Dermatology1 and the Department of Biostatistics,2 Hitit University Faculty of Medicine, Çorum, Turkey Address for Correspondence: Engin Senel, MD, Hitit University Faculty of Medicine, Department of Dermatology, Çorum, Turkey • E-mail: enginsenel@enginsenel.com

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In 2014, 860 telemedicine and 40 teledermatology publications were indexed in the Web of Science database. The United States ranked first among the countries that produced teledermatology publications in 2014 (Figure), producing 35% of all teledermatology publications that year. The number of telemedicine and teledermatology publications has gradually increased during the past 3 decades. The global distribution of the publications is highly heterogeneous and most of the studies were reported from developed countries. Physicians in developing and unde-

veloped countries should be aware of telemedicine and teledermatology technologies and encouraged to carry out new studies. References 1 Senel E. History of teledermatology: a technique of the future in dermatology. Skinmed. 2010;8:167–170. 2 Senel E, Demir E. A global productivity and bibliometric analysis of telemedicine and teledermatology publication trends during 1980–2013. Dermatol Sin. 2015;33:16–20.

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Volume 14 • Issue 2

Book Review Jennifer L. Parish, MD, Section Editor

Hair Loss and Restoration Mark Bernhardt, MD

T

he first edition of this book was published in 2007 under the sole authorship of Shapiro, a hair expert who currently practices in both Vancouver BC and New York. This second edition (by Jerry Shapiro and Nina Otberg. Second Edition. Boca Raton, FL: CRC Press; 2015. Pages 220. $119.95) must be judged not only on its own merits but in the context of progress in the understanding and treatment of alopecia in the eight intervening years. First to Second The authors have done an admirable job updating the first edition of Hair Loss: Principles of Diagnosis and Management of Alopecia. Although the overall framework of the book and the majority of its illustrations and tables are taken from the first edition, whenever possible, they included the more recent advances from both the laboratory and the clinic. The section on the pathogenesis of alopecia areata is greatly expanded. Male vs female patterns of hair loss are more effectively distinguished, which allows a greater appreciation of the clinical and therapeutic differences between these two frequently conflated conditions. The chapter on scarring alopecias has also been enlarged and provides better distinctions between these extremely diagnostically difficult diseases. The addition of an entirely new chapter on the nonmedical approaches to hair loss is essentially a guide to the various types of camouflage that can be used, when actual hair regrowth is unattainable. Although philosophically the inclusion of a whole chapter on wigs, hairpieces, cosmetics, and tattooing might seem defeatist in a book devoted to hair restoration, it is a sobering and practical recognition that hair regrowth is not always possible. The only significant diagnostic change that has occurred between the first and second editions is the development of optical devices, specifically dermatoscopy, videodermatoscopy, and phototrichograms. Such instrumentation can be very useful in the proper diagnosis of alopecias, as well as in monitoring treatment response. Examples of these technologies and directions for their use are clear and explicit.

If there is one overriding reason for updating a textbook such as this, it would have to be in order to recognize new treatment options. The authors have done their best to include every therapeutic advance for all the different types of hair loss. Sometimes, these options have revolutionized treatment, as illustrated by the follicular unit extraction for the surgical treatment of pattern hair loss. Other modalities are mentioned that will require further investigation and vindication. This, for example, is true for the many options for pattern alopecia that are either unavailable in the United States (ie, topical 17α- and 17β-estradiol for female pattern hair loss) or not currently approved by the Food and Drug Administration for these conditions (ie, dutasteride for male or female pattern hair loss.) The Book on Its Own Overall, this is a comprehensive textbook covering all aspects of hair loss. It can be useful to the novice dermatologist, and there are enough idiosyncratic suggestions to make it of interest even to a jaded clinician. Particularly intriguing is the authors’ recommendation for minoxidil in telogen effluvium and drug-induced alopecia; likewise, the recommendation for ketoconazole shampoo for male pattern alopecia. My complaints are quite minor. They mention over-the-counter 1% ketoconazole shampoo; however, it was withdrawn from the US market even before publication of the first edition. In addition, the claim that a dermatoscope is used in every dermatologic skin examination is untrue. Sometimes, the authors have made contradictory pronouncements; for example, when they state that laboratory tests should be performed in every patient with hair loss, only to state later that laboratory testing is usually unnecessary in patients with male pattern alopecia. Lastly, their recommendation that a thorough inspection of the entire scalp and body is essential for every patient with alopecia areata seems unnecessary. Recommendation For those residents and practicing dermatologist wishing to have a separate, concise, and dedicated resource on hair loss, this volume will satisfy their needs.

Reviewed by Mark Bernhardt, MD, 1601 East Broward Boulevard, Fort Lauderdale, FL 33301 • E-mail: cheesedb@aol.com

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SOOLANTRA®

(ivermectin) Cream, 1% SOOLANTRA Cream is supplied in a child-resistant capped tube.

BRIEF SUMMARY This summary contains important information about SOOLANTRA (soo lan’ trah) Cream. Read this information carefully before you prescribe SOOLANTRA Cream. For full Prescribing Information and Patient Information please see the package insert.

• To open, gently press down on the child resistant cap and twist counterclockwise. To avoid spilling, do not squeeze the tube while opening or closing.

WHAT IS SOOLANTRA CREAM? SOOLANTRA Cream is a topical prescription medicine indicated for the treatment of the inflammatory lesions of rosacea. WHO IS SOOLANTRA CREAM FOR? SOOLANTRA Cream is indicated for people with inflammatory lesions of rosacea. It is not known if SOOLANTRA Cream is safe and effective for children. Advise your patients to not use SOOLANTRA Cream for a condition for which it was not prescribed and remind them to not give SOOLANTRA Cream to other people, even if they have the same symptoms as it may harm them. WHAT SHOULD I ASK MY PATIENTS BEFORE PRESCRIBING SOOLANTRA CREAM? Before you prescribe SOOLANTRA Cream, ask your patients if they: • have any other medical conditions. • are pregnant or planning to become pregnant. It is not known if SOOLANTRA Cream can harm an unborn baby.

• To close, gently press down on the child resistant cap and twist clockwise. WHAT ARE THE INGREDIENTS IN SOOLANTRA CREAM? Active ingredient: ivermectin. Inactive ingredients: carbomer copolymer type B, cetyl alcohol, citric acid monohydrate, dimethicone, edetate disodium, glycerin, isopropyl palmitate, methylparaben, oleyl alcohol, phenoxyethanol, polyoxyl 20 cetostearyl ether, propylene glycol, propylparaben, purified water, sodium hydroxide, sorbitan monostearate, and stearyl alcohol. WHERE SHOULD I GO FOR MORE INFORMATION ABOUT SOOLANTRA CREAM? • This Brief Summary summarizes the most important information about SOOLANTRA Cream. For full Prescribing Information and Patient Information please see the package insert. ®

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• are breastfeeding or plan to breastfeed. It is not known if SOOLANTRA Cream passes into breast milk and if it can harm a baby.

• Go to www.soolantra.com or call 1-866-735-4137

Trademarks are the property of their respective owners.

GALDERMA LABORATORIES, L.P., Fort Worth, Texas 76177 USA Revised: December 2014

WHAT ARE THE MOST COMMON SIDE EFFECTS OF SOOLANTRA CREAM? The most commonly reported side effects when using SOOLANTRA Cream include skin burning sensation and skin irritation. Remind your patients to tell you if they have any side effect that bothers them or that does not go away. These are not all of the possible side effects of SOOLANTRA Cream. For more information, see the full Prescribing Information. You are encouraged to report negative side effects of prescription drugs to the FDA at www.fda.gov/medwatch or call 1-800-FDA-1088. You may also contact GALDERMA LABORATORIES, L.P. AT 1-866-735-4137. HOW SHOULD PATIENTS USE SOOLANTRA CREAM? • SOOLANTRA Cream is for use on the face only and should not be used in the eyes, mouth, or vagina.

References: 1. Stein Gold L, Kircik L, Fowler J, et al; Ivermectin Phase III Study Group. Efficacy and safety of ivermectin 1% cream in treatment of papulopustular rosacea: results of two randomized, double-blind, vehicle-controlled pivotal studies. J Drugs Dermatol. 2014;13(3):316-323. 2. Data on file. Galderma Laboratories, L.P. 3. Taieb A, Ortonne JP, Ruzicka T, et al; Ivermectin Phase III Study Group. Superiority of ivermectin 1% cream over metronidazole 0.75% cream in treating inflammatory lesions of rosacea: a randomized, investigator-blinded trial. Br J Dermatol. In press.

(azelaic acid) Foam,15%

• SOOLANTRA Cream should be applied to the affected areas of the face once a day. APPLYING SOOLANTRA CREAM: • A pea-sized amount of SOOLANTRA Cream should be applied to each area of the face (forehead, chin, nose, each cheek) that is affected. Avoid contact with the lips and eyes.

All trademarks are the property of their respective owners. www.finaceafoam.com ©2015 Galderma Laboratories, L.P. Galderma Laboratories, L.P. 14501 N. Freeway, Fort Worth, TX 76177 IVM-143 Printed in USA 02/15 © 2015 Bayer HealthCare Pharmaceuticals Inc., Whippany, NJ 07981. Bayer, the Bayer Cross, and Finacea are registered trademarks of Bayer. All rights reserved. PP-825-US-0349 September 2015


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