SKINmed -Mar/Apr, 2018 by jo-ann kalaka-Adams

Chinese Society of Dermatology

Lebanese Dermatological Society

Dermatology Insights and Inquiries

Belarusian Society of Dermatovenereologists and Cosmetologists

North American Clinical Dermatologic Society

The Dermatologic & Aesthetic Surgery International League

African Association for Dermatology

March/April 2018 Volume 16 Issue 2

EDITORIAL Fake News, Predatory Journals, Case Reports, Biostatistics, and Other Journalistic Musings—Part 2 Heymann

CASE STUDIES Melanoma of the Nasal Cavity

Zaouak, Hammami, Jouini, Salah, Debbiche, and Fenniche

Chinese Society of Dermatology

Dermatology Insights and Inquiries

ORIGINAL CONTRIBUTIONS Footwear Contact Dermatitis: A Prospective Cross-Sectional Study of 108 Outpatients from Delhi, India Rasool, Sehgal, Srivastava, Aggarwal, and Hassan

Lebanese Dermatological Society

Systemic Lupus Erythematosus Presenting as Livedoid Vasculopathy over the Forearms

Belarusian Society of Dermatovenereologists and Cosmetologists

North American Clinical Dermatologic Society

The Dermatologic & Aesthetic Surgery International League

Yadav, Garg, Sanke, Chander, and Singh

African Association for Dermatology

Rituximab-Treated Pemphigus Foliaceus in a Schizophrenic Patient: A Challenging Exercise in Diagnosis, Management, and Follow-Up Ross, Vega, and Keller

The Prevalence of Malassezia Folliculitis in Patients with Papulopustular/Comedonal Acne, and Their Response to Antifungal Treatment

Zosteriform Lichen Planus Pigmentosus Altering Segmental Vitiligo

REVIEW Basal Cell Carcinoma of the Buttock

CORRESPONDENCE Central Upper Lip Reconstruction Using Combined Advancement Flaps of Skin and Mucosa

Pürnak, Durdu, Tekindal, Güleç, and Seçkin

Cohen

Self Assessment Examination Lambert

Sawatkar, Kumaran, Narang, and Parsad

Matos-Pires, Fernandes, João, and Carvalho

Diagnostic Error Rates in Dermatology Wu and Lowenstein

DEPARTMENTS CORE CURRICULUM Techniques for Optimizing Surgical Scars, Part 3: Erythema, Hyperpigmentation, and Hypopigmentation

Letters from Botswana: Delayed Diagnosis of Necrotic Leg Ulcerations Rodriguez, Mosojane, Sowash, and Williams

Potter, Konda, Ren, Wang, Srinivasan, and Chilukuri

PHOTO CAPSULE Twenty-Nail Dystrophy: Revisited Sehgal, Chatterjee, and Malhotra

VIGNETTES OF DERMATOLOGIC HISTORY Edward Mentor Perdue (1866 to 1944) Bernhardt

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Otezla® (apremilast) is indicated for the treatment of patients with moderate to severe plaque psoriasis who are candidates for phototherapy or systemic therapy.

Otezla was evaluated in 2 multicenter, double-blind, placebocontrolled trials of similar design. Patients with moderate to severe plaque psoriasis (N = 1257) were randomized 2:1 to Otezla 30 mg or placebo twice daily for 16 weeks, after a 5-day titration1,3 ◆ Inclusion criteria: Age ≥18 years, BSA involvement ≥10%, sPGA ≥3, PASI score ≥12, candidates for phototherapy or systemic therapy1,3 ◆ PASI-75 response at week 16 (primary endpoint) – ESTEEM 1: Otezla 33% vs placebo 5% (P < 0.0001)1-3 ◆

– Similar PASI-75 response was achieved in ESTEEM 21,2 BSA, body surface area; PASI, Psoriasis Area and Severity Index; sPGA, static Physician Global Assessment.

INDICATIONS Otezla® (apremilast) is indicated for the treatment of patients with moderate to severe plaque psoriasis who are candidates for phototherapy or systemic therapy. Otezla is indicated for the treatment of adult patients with active psoriatic arthritis.

IMPORTANT SAFETY INFORMATION Contraindications ◆ Otezla® (apremilast) is contraindicated in patients with a known hypersensitivity to apremilast or to any of the excipients in the formulation Warnings and Precautions ◆ Diarrhea, Nausea and Vomiting: Cases of severe diarrhea, nausea, and vomiting have been reported with the use of Otezla. Most events occurred within the first few weeks of treatment. In some cases patients were hospitalized. Patients 65 years of age or older and patients taking medications that can lead to volume depletion or hypotension may be at a higher risk of complications from severe diarrhea, nausea, or vomiting. Monitor patients who are more susceptible to complications of diarrhea or vomiting; advise patients to contact their healthcare provider. Consider Otezla dose reduction or suspension if patients develop severe diarrhea, nausea, or vomiting ◆ Depression: Treatment with Otezla is associated with an increase in depression. During clinical trials 1.3% (12/920) of patients reported depression, compared to 0.4% (2/506) on placebo. Suicidal behavior was observed in 0.1% (1/1308) of patients on Otezla, compared to 0.2% (1/506) on placebo. Carefully weigh the risks and benefits of treatment with Otezla for patients with a history of depression and/or suicidal thoughts/behavior, or in patients who develop such symptoms while on Otezla. Patients, caregivers, and families should be advised of the need to be alert for the emergence or worsening of depression, suicidal

thoughts or other mood changes, and they should contact their healthcare provider if such changes occur ◆ Weight Decrease: Body weight loss of 5-10% occurred in

12% (96/784) of patients treated with Otezla and in 5% (19/382) of patients treated with placebo. Monitor body weight regularly; evaluate unexplained or clinically significant weight loss, and consider discontinuation of Otezla ◆ Drug Interactions: Apremilast exposure was decreased when Otezla was co-administered with rifampin, a strong CYP450 enzyme inducer; loss of Otezla efficacy may occur. Concomitant use of Otezla with CYP450 enzyme inducers (e.g., rifampin, phenobarbital, carbamazepine, phenytoin) is not recommended Adverse Reactions ◆ Adverse reactions reported in ≥5% of patients were (Otezla%, placebo%): diarrhea (17, 6), nausea (17, 7), upper respiratory tract infection (9, 6), tension headache (8, 4), and headache (6, 4) Use in Specific Populations ◆ Pregnancy and Nursing Mothers: Otezla is Pregnancy Category C; it has not been studied in pregnant women. Use during pregnancy only if the potential benefit justifies the potential risk to the fetus. It is not known whether apremilast or its metabolites are present in human milk. Caution should be exercised when Otezla is administered to a nursing woman ◆ Renal Impairment: Otezla dosage should be reduced in patients with severe renal impairment (creatinine clearance less than 30 mL/min); for details, see Dosage and Administration, Section 2, in the Full Prescribing Information Please turn the page for Brief Summary of Full Prescribing Information. References: 1. Otezla [package insert]. Summit, NJ: Celgene Corporation. 2. Data on file, Celgene Corporation. 3. Papp K, Reich K, Leonardi CL, et al. J Am Acad Dermatol. 2015;73(1):37-49. 4. Information derived from Symphony Health Solutions PrescriberSource PatientFocus data, Celgene proprietary methodology. April 2014 through June 2017. * Data includes healthcare professionals (dermatologists, rheumatologists, nurse practitioners, and physician assistants) and their Otezla prescriptions (including refills) from April 2014 through June 2017 for patients with plaque psoriasis or psoriatic arthritis. Source: Data on file, Celgene Corporation.

Get the latest news at otezlapro.com

Rx Only OTEZLA® (apremilast) tablets, for oral use The following is a Brief Summary; refer to Full Prescribing Information for complete product information. INDICATIONS AND USAGE OTEZLA® (apremilast) is indicated for the treatment of patients with moderate to severe plaque psoriasis who are candidates for phototherapy or systemic therapy. CONTRAINDICATIONS OTEZLA is contraindicated in patients with a known hypersensitivity to apremilast or to any of the excipients in the formulation [see Adverse Reactions (6.1)]. WARNINGS AND PRECAUTIONS Diarrhea, Nausea, and Vomiting: There have been postmarketing reports of severe diarrhea, nausea, and vomiting associated with the use of OTEZLA. Most events occurred within the first few weeks of treatment. In some cases patients were hospitalized. Patients 65 years of age or older and patients taking medications that can lead to volume depletion or hypotension may be at a higher risk of complications from severe diarrhea, nausea, or vomiting. Monitor patients who are more susceptible to complications of diarrhea or vomiting. Patients who reduced dosage or discontinued OTEZLA generally improved quickly. Consider OTEZLA dose reduction or suspension if patients develop severe diarrhea, nausea, or vomiting. Depression: Treatment with OTEZLA is associated with an increase in adverse reactions of depression. Before using OTEZLA in patients with a history of depression and/or suicidal thoughts or behavior prescribers should carefully weigh the risks and benefits of treatment with OTEZLA in such patients. Patients, their caregivers, and families should be advised of the need to be alert for the emergence or worsening of depression, suicidal thoughts or other mood changes, and if such changes occur to contact their healthcare provider. Prescribers should carefully evaluate the risks and benefits of continuing treatment with OTEZLA if such events occur. During the 0 to 16 week placebocontrolled period of the 3 controlled clinical trials, 1.3% (12/920) of patients treated with OTEZLA reported depression compared to 0.4% (2/506) treated with placebo. During the clinical trials, 0.1% (1/1308) of patients treated with OTEZLA discontinued treatment due to depression compared with none in placebo-treated patients (0/506). Depression was reported as serious in 0.1% (1/1308) of patients exposed to OTEZLA, compared to none in placebo-treated patients (0/506). Instances of suicidal behavior have been observed in 0.1% (1/1308) of patients while receiving OTEZLA, compared to 0.2% (1/506) in placebo-treated patients. In the clinical trials, one patient treated with OTEZLA attempted suicide while one who received placebo committed suicide. Weight Decrease: During the controlled period of the trials in psoriasis, weight decrease between 5%-10% of body weight occurred in 12% (96/784) of patients treated with OTEZLA compared to 5% (19/382) treated with placebo. Weight decrease of ≥10% of body weight occurred in 2% (16/784) of patients treated with OTEZLA 30 mg twice daily compared to 1% (3/382) patients treated with placebo. Patients treated with OTEZLA should have their weight monitored regularly. If unexplained or clinically significant weight loss occurs, weight loss should be evaluated, and discontinuation of OTEZLA should be considered. Drug Interactions: Co-administration of strong cytochrome P450 enzyme inducer, rifampin, resulted in a reduction of systemic exposure of apremilast, which may result in a loss of efficacy of OTEZLA. Therefore, the use of cytochrome P450 enzyme inducers (e.g., rifampin, phenobarbital, carbamazepine, phenytoin) with OTEZLA is not recommended [see Drug Interactions (7.1) and Clinical Pharmacology (12.3)]. ADVERSE REACTIONS Clinical Trials Experience in Psoriasis: Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trial of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. Diarrhea, nausea, and upper respiratory tract infection were the most commonly reported adverse reactions. The most common adverse reactions leading to discontinuation for patients taking OTEZLA were nausea (1.6%), diarrhea (1.0%), and headache (0.8%). The proportion of patients with psoriasis who discontinued treatment due to any adverse reaction was 6.1% for patients treated with OTEZLA 30 mg twice daily and 4.1% for placebo-treated patients.

Table 3: Adverse Reactions Reported in ≥1% of Patients on OTEZLA and With Greater Frequency Than in Patients on Placebo; up to Day 112 (Week 16) Placebo OTEZLA 30 mg BID Preferred Term (N=506) (N=920) n (%) n (%) Diarrhea 32 (6) 160 (17) (17(17) (17) Nausea 35(6) (7) 155 (17) (7)(7) ((17) Upper respiratory tract infection 31 (6) 84 (9) Tension headache 21(6) (4) 75 (8) Headache 19(4) (4) 55 (6) ((4) Abdominal pain* 11 (2) 39 (4) Vomiting 8(2) (2) 35 (4) Fatigue 9 (2) 29 (3) Decrease appetite 5 (1) 26 (3) Insomnia 4 (1) 21 (2) Back pain 4 (1) 20 (2) Migraine 5 (1) 19 (2) Frequent bowel movements 1 (0) 17 (2) Depression 2 (0) 12 (1) Bronchitis 2 (0) 12 (1) Tooth abscess 0 (0) 10 (1) Folliculitis 0 (0) 9 (1) Sinus headache 0 (0) 9 (1) *Two subjects treated with OTEZLA experienced serious adverse reaction of abdominal pain. Severe worsening of psoriasis (rebound) occurred in 0.3% (4/1184) patients following discontinuation of treatment with OTEZLA (apremilast). DRUG INTERACTIONS Strong CYP 450 Inducers: Apremilast exposure is decreased when OTEZLA is co-administered with strong CYP450 inducers (such as rifampin) and may result in loss of efficacy [see Warnings and Precautions (5.3) and Clinical Pharmacology (12.3)]. USE IN SPECIFIC POPULATIONS Pregnancy: Pregnancy Category C: OTEZLA should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Pregnancy Exposure Registry: There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to OTEZLA during pregnancy. Information about the registry can be obtained by calling 1-877-311-8972. Nursing Mothers: It is not known whether OTEZLA or its metabolites are present in human milk. Because many drugs are present in human milk, caution should be exercised when OTEZLA is administered to a nursing woman. Pediatric use: The safety and effectiveness of OTEZLA in pediatric patients less than 18 years of age have not been established. Geriatric use: Of the 1257 patients who enrolled in two placebo-controlled psoriasis trials (PSOR 1 and PSOR 2), a total of 108 psoriasis patients were 65 years of age and older, including 9 patients who were 75 years of age and older. No overall differences were observed in the efficacy and safety in elderly patients ≥65 years of age and younger adult patients <65 years of age in the clinical trials. Renal Impairment: Apremilast pharmacokinetics were characterized in subjects with mild, moderate, and severe renal impairment as defined by a creatinine clearance of 60-89, 30-59, and less than 30 mL per minute, respectively, by the Cockcroft–Gault equation. While no dose adjustment is needed in patients with mild or moderate renal impairment, the dose of OTEZLA should be reduced to 30 mg once daily in patients with severe renal impairment [see Dosage and Administration (2.2) and Clinical Pharmacology (12.3)]. Hepatic Impairment: Apremilast pharmacokinetics were characterized in patients with moderate (Child Pugh B) and severe (Child Pugh C) hepatic impairment. No dose adjustment is necessary in these patients. OVERDOSAGE In case of overdose, patients should seek immediate medical help. Patients should be managed by symptomatic and supportive care should there be an overdose. Manufactured for: Celgene Corporation, Summit, NJ 07901 OTEZLA® is a registered trademark of Celgene Corporation. Pat. http://www.celgene.com/therapies ©2014-2017 Celgene Corporation, All Rights Reserved. Based on APRPI.006

OTZ_PsO_HCP_BSv.006 06_2017

TABLE OF CONTENTS March/April 2018 • Volume 16 • Issue 2

EDITORIAL

Fake News, Predatory Journals, Case Reports, Biostatistics, and Other Journalistic Musings—Part 2 ...........................................................................................................................88

Warren R. Heymann, MD

ORIGINAL CONTRIBUTIONS

Footwear Contact Dermatitis: A Prospective Cross-Sectional Study of 108 Outpatients from Delhi, India ..........................................................................................................................90

Farhan Rasool, MD; Virendra N. Sehgal, MD, FNASc, FAMS, FRAS (Lond); Govind Srivastava, MD; Ashok Aggarwal, MD; Iffat Hassan, MD

The Prevalence of Malassezia Folliculitis in Patients with Papulopustular/Comedonal Acne, and Their Response to Antifungal Treatment ..................................................................................99

Seda Pürnak, MD; Murat Durdu, MD; Mustafa Agah Tekindal, MD; A. Tülin Güleç, MD; Deniz Seçkin, MD

REVIEW

Basal Cell Carcinoma of the Buttock ............................................................................................105

Philip R. Cohen, MD

Self Assessment Examination ......................................................................................................111

W. Clark Lambert, MD, PhD

DEPARTMENTS Core Curriculum

Virendra N. Sehgal, MD, FNASc, FAMS, Section Editor

Techniques for Optimizing Surgical Scars, Part 3: Erythema, Hyperpigmentation, and Hypopigmentation ...............................................................................................................113

Kathryn Potter, MD; Sailesh Konda, MD;Vicky Zhen Ren, MD; Apphia Lihan Wang, MD; Aditya Srinivasan, MS; Suneel Chilukuri, MD

Photo Capsule

Snejina Vassileva, MD, PhD, Section Editor

Twenty-Nail Dystrophy: Revisited ................................................................................................119

Virendra N. Sehgal, MD, FNASc, FAMS, FRAS (Lond); Kingshuk Chatterjee, DNB, MNAMS; Shalini Malhotra, DNB, MNAMS

Vignettes of Dermatologic History Mark Bernhardt, MD, Section Editor

Edward Mentor Perdue (1866 to 1944) .......................................................................................121

Mark Bernhardt, MD

TABLE OF CONTENTS March/April • Volume 16 16 • Issue 2 2 March/April 2018 • Volume • Issue

CASE STUDIES

Vesna Petronic-Rosic, MD, MSc, Section Editor

Melanoma of the Nasal Cavity .....................................................................................................122

Anissa Zaouak, MD; Houda Hammami, MD; Raja Jouini, MD; Mariem Belhaj Salah, MD; Achraf Debbiche, MD; Samy Fenniche, MD

Systemic Lupus Erythematosus Presenting as Livedoid Vasculopathy over the Forearms ...............125

Pravesh Yadav, MD; Taru Garg, MD; Sarita Sanke, MD; Ram Chander, MD; Divyanshu Singh, MD

Rituximab-Treated Pemphigus Foliaceus in a Schizophrenic Patient: A Challenging Exercise in Diagnosis, Management, and Follow-Up .....................................................................129

Nicholas A. Ross, MD; Miriam L. Vega, MD, MPH; Matthew S. Keller, MD

Zosteriform Lichen Planus Pigmentosus Altering Segmental Vitiligo ..............................................133

Gitesh U. Sawatkar, MD; Muthu Sendhil Kumaran, MD; Tarun Narang, MD; Davinder Parsad, MD

CORRESPONDENCE

Snejina Vassileva, MD, PhD, Section Editor

Central Upper Lip Reconstruction Using Combined Advancement Flaps of Skin and Mucosa ..........137

Eugénia Matos-Pires, MD; Cândida Fernandes, MD; Alexandre João, MD; Rodrigo Carvalho, MD

Diagnostic Error Rates in Dermatology ........................................................................................139

Jianni Wu, BS; Eve J. Lowenstein, MD, PhD

Letters from Botswana: Delayed Diagnosis of Necrotic Leg Ulcerations ........................................141

Olaf Rodriguez, BS; Karen Mosojane, MBBS; Madeleine Sowash, BA; Victoria Williams, MD

March/April 2018

Volume 16 • Issue 2

ABOUT OUR JOURNAL

MANAGING EDITOR Marla Kipp marla@skinmedjournal.com

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.

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COPYEDITOR Carrie Walker

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Printed in the USA. Authors interested in submitting a paper should refer to the instructions located online at: http://www.skinmedjournal.com/author-info.html. Submissions should be e-mailed to the Editor at: larryderm@yahoo.com

COMPOSITION Paul Bennett

Publishing PUBLISHER Art Kalaka

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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Chinese Society of Dermatology

Lebanese Dermatological Society

Belarusian Society of Dermatovenereologists and Cosmetologists

North American Clinical Dermatologic Society

African Association for Dermatology

The Dermatologic & Aesthetic Surgery International League

Dermatology Insights and Inquiries

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Volume 16 • Issue 2

March/April 2018

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, MBA

Dallas, TX

London, Ontario, Canada

Newark, NJ

Chicago, IL

Larry E. Millikan, MD

Marcia Ramos-e-Silva, MD, PhD

Jennifer L. Parish, MD

Cumming, GA

Rio de Janeiro, Brazil

Philadelphia, PA

EDITORIAL BOARD Mohamed Amer, MD Cairo, Egypt Robert L. Baran, MD Cannes, France Anthony V. Benedetto, DO Philadelphia, PA

Jasna Lipozencic, MD, PhD Zagreb, Croatia

Virendra N. Sehgal, MD Delhi, India

Ada Lo Schiavo, MD Naples, Italy

Charles Steffen, MD Oceanside, CA

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

Alexander J. Stratigos, MD Athens, Greece

George M. Martin, MD Kihei, HI

James S. Studdiford III, MD Philadelphia, PA

Marc S. Micozzi, MD, PhD Rockport, MA

Robert J. Thomsen, MD Los Alamos, NM

Seung-Kyung Hann, MD, PhD Seoul, Korea

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

Julian Trevino, MD Dayton, OH

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

Oumeish Youssef Oumeish, MD, FRCP Amman, Jordan

María Daniela Hermida, MD Buenos Aires, Argentina

Joseph L. Pace, MD, FRCP Naxxar, Malta

Warren R. Heymann, MD Camden, NJ

Art Papier, MD Rochester, NY

Tanya R. Humphreys, MD Bala-Cynwyd, PA

Johannes Ring, MD, DPhil Munich, Germany

Camila K. Janniger, MD Englewood, NJ

Roy S. Rogers III, MD Scottsdale, AZ

Ayse Serap Karadag, MD Istanbul, Turkey

Donald Rudikoff, MD New York, NY

Abdul-Ghani Kibbi, MD Beirut, Lebanon

Robert I. Rudolph, MD Wyomissing, PA

Andrew P. Lazar, MD Washington, DC

Todd E. Schlesinger, MD Charleston SC

Ibrahim Hassan Galadari, MD, PhD, FRCP Dubai, United Arab Emirates Anthony A. Gaspari, MD Philadelphia, PA Michael Geiges, MD Zurich, Switzerland

Brian Berman, MD, PhD Miami, FL 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 Greenwood Village, CO Natalie M. Curcio, MD, MPH Nashville, TN Richard L. Dobson, MD Mt Pleasant, SC

Michael H. Gold, MD Nashville, TN Lowell A. Goldsmith, MD, MPH Chapel Hill, NC

William H. Eaglstein, MD Menlo Park, CA Charles N. Ellis, MD Ann Arbor, MI Howard A. Epstein, PhD Philadelphia, PA

SKINmed. 2018;16:86

Maria M. Tsoukas, MD, PhD Chicago, IL 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

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March/April 2018

Volume 16 • Issue 2

EDITORIAL

Fake News, Predatory Journals, Case Reports, Biostatistics, and Other Journalistic Musings—Part 2 Warren R. Heymann, MD

f anyone wants to fool me, throw some statistics my way. My training in biostatistics was reasonable—in the late 1970s— but my ability has gone the way of my hip-hugging bell-bottoms. For example, the following paragraph defines the statistical analysis on a study of filaggrin loss of function and thymic lymphopoietin variation in treating pediatric atopic dermatitis:1

take my recommendation, I will just have to trust (without being able to verify). POLITICAL CORRECTNESS We live in litigious times enveloped in social media. How quaint to think of my youth when girls in my class would keep their innermost thoughts locked in their diaries. Nothing is secret, and we are all just a few clicks from going viral. The Health Insurance Portability and Accountability Act of 1996 should protect us, but safeguards may be inadequate. To avoid litigation, disclosures of patient consent for even the most obscure possibilities are now de rigueur. I was told by a prestigious journal that I either delete a sentence quoting the patient who said, “it feels like gasoline on my skin,” or get consent to use the phrase, because someone might recognize her based on that comment. I’m not kidding. I deleted the sentence.

Demographic and other subject-level data were described as percentages or means as appropriate and presented according to FLG LOF and TSLP variant status. For each variable, differences among genotypes at enrollment were assessed using χ2 or ANOVA as appropriate. Drug usage was described by proportions and displayed graphically. To analyze variation in our outcomes over time, mixed-effects logistic regression were used. We used mixed-effects models to account for intrasubject correlation due to repeated measurements over time. We specified an independence working correlation for these models. While in the past we based our gene variant analyses on additive models, here we chose a genetic model based on grouping FLG wildtype and heterozygous individuals vs homozygotes and compound heterozygotes. Visit number was also included as a covariate in our models. All analyses were conducted using Stata, version 13.1 (StataCorp).

CONCLUSIONS How can the well-meaning clinician know what’s real and important? Follow the advice of Dr. Richard Lehman, the author of the British Medical Journal’s weekly review—enjoy the privilege of being a physician engaged in the medical literature, but be skeptical of what you read. Abide by the Latin phrase “nullius in verba”—don’t take anyone’s word for it.2 Not even mine!

A SABBATICAL I would love to spend a sabbatical with David Margolis, the senior author of this paper, to learn what all this means. I must take it on faith that the right statistical studies were performed to substantiate the authors’ conclusions. I have always advocated that a sentence or two be devoted to explaining the rationale for choosing analyses and defining them (in plain English). As I am unlikely either to do a dermatoepidemiology fellowship, nor will editors

REFERENCES 1 Chang J, Mitra N, Hoffstad O, Margolis DJ. Association of filaggrin loss of function and thymic stromal lymphopoietin variation with treatment use in pediatric atopic dermatitis. JAMA Dermatol. 2017;153:275–281. 2 Lehman RS. Nullius in verba: Don’t take anyone’s word for it. JAMA Intern Med. 2013;173:1049–1450.

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

SKINmed. 2018;16:88

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March/April 2018

Volume 16 • Issue 2

ORIGINAL CONTRIBUTION

Footwear Contact Dermatitis: A Prospective Cross-Sectional Study of 108 Outpatients from Delhi, India Farhan Rasool, MD;1 Virendra N. Sehgal, MD, FNASc, FAMS, FRAS (Lond);2 Govind Srivastava, MD;1 Ashok Aggarwal, MD;1 Iffat Hassan, MD3 ABSTRACT Footwear contact dermatitis is a common problem with multifactorial exogenous, as well as endogenous, etiologies. Patch testing is the gold standard for detection of the possible contactants. A cross-sectional study was conducted in 108 outpatients over a period of 18 months. Demographic data comprising age, sex, and occupation were collected. Details of clinical and laboratory investigations were used to define the incriminating ingredient(s), subsequently confirmed by patch test using Indian standard and footwear series approved by the Contact and Occupational Dermatitis Forum of India. Reading and interpretation were carried out according to the International Contact Dermatitis Research Group (ICDRG) guidelines. Of the 108 patients, 64 were girls or women and 44 boys or men. Although footwear contact dermatitis affected all age groups, most individuals were 21 to 40 years old. The morphology and distribution of the lesions were very specific. Patch testing was helpful, the primary sensitizing agent being mercapto mix, followed by mercaptobenzothiazole, potassium dichromate, and paraphenylenediamine. Footwear contact dermatitis is an extraordinary entity, requiring a high level of expertise (or knowledge) to determine its etiology through history, clinical examination, and patch testing. (SKINmed. 2018;16:90–97)

2009 to October 2010. A total of 108 cases of footwear dermatitis were included, and informed consent was obtained. Demographic data comprising the patient’s age, sex, occupation, and income were recorded in a case file designed for this study. Details of the history of site of origin, onset, progress, duration, and associated symptoms of dermatitis were carefully taken. Criteria for the diagnosis of atopic dermatitis6,7 and palmoplantar hyperhydrosis,8 in addition to seasonal variations, were also recorded. History of topical medication was also obtained.

he terms eczema and dermatitis are used to indicate a polymorphic pattern of inflammation of the skin. Eczema can be exogenous (caused by external factors such as allergens and/or irritants) or endogenous (eg, atopic dermatitis).1 Footwear dermatitis is a time-old entity. It is a form of exogenous contact dermatitis that exclusively affects the feet after they have come into contact with particular footwear or chemicals.2 The chemicals used in the processing of leather and rubber have been shown to be common sources.3 This is a common problem, affecting individuals from all walks of life.3,4 Reports from India are indicative of a higher prevalence of footwear contact dermatitis.5 Changing quality control on footwear warrants periodic assessment of the spectrum of responsible allergens, as this varies from country to country,3 depending on the local footwear traditions and the different substances and chemicals used during manufacture.4

The description of type and composition of the footwear was the main means of determining possible cause through the use of patch testing to identify allergens. On the day of the procedure, patients were advised to have a thorough cleansing bath before their visit, and to bring all types of footwear used. Patch test material (Chemotechnique Diagnostics, marketed in India by Systopic Laboratories Pvt. Ltd.) using the Indian standard battery of patch test allergens approved by the Contact and Occupational Dermatitis Forum of India4 provided the standard battery and shoe series allergens (Table I).

MATERIAL AND METHODS A cross-sectional (descriptive) study was conducted on outpatients at the Skin Institute, Greater Kailash, New Delhi, India, from April

From the Skin Institute and School of Dermatology, Greater Kailash, New Delhi, India,1 the Dermato-Venereology (Skin/VD) Center, Sehgal Nursing Home, Panchwati, Delhi, India,2 and the Department of Dermatology, Government Medical College, Srinagar,3 India Address for Correspondence: Virendra N. Sehgal MD, FNASc, FAMS, FRAS (Lond), Dermato-Venerology (Skin/VD) Center, Sehgal Nursing Home, A/6 Panchwati, Delhi-110 033, India • E-mail: drsehgal@ndf.vsnl.net.in

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ORIGINAL CONTRIBUTION The first reading was taken 30 minutes after removal of the patch, to allow the pressure affect of the disk to wear off, thus preventing falsepositive recordings. The second reading was taken after 96 hours.

Participants were told to leave the patch tests in place for 48 hours, and readings were taken after 48 and 96 hours. When the patches were removed after 48 hours, the grooves were marked and renumbered.

Table I. Footwear Contact Dermatitis: List of Standard Series Allergens S. Number

Compound

Concentration (%)

Vehicle

Petrolatum (control)

100

Pet

Potassium dichromate

0.5

Pet

Neomycin sulfate

Pet

Cobalt chloride

Pet

Benzocaine

Pet

4- Phenylenediamine base (PPD)

Pet

Parabens

Pet

Nickel sulfate

Pet

Colophony

Pet

Gentamycin

Pet

Mercapto mix

Pet

Epoxy resin

Pet

Fragrance mix

Pet

Mercaptobenzothiazole (MBT)

Pet

Nitrofurazone

Pet

Chlorocresol

Pet

Wood alcohols

Pet

Balsam of Peru

Pet

Thiuram mix

Pet

Chinoform

Pet

Black rubber mix

0.6

Pet

p-Tert-butylphenol formaldehyde resin

Pet

Formaldehyde

Aqu

Propylene glycol

Aqu

Quaternium15

Pet

Ethylenediamine dihydrochloride

Pet

Kathon CG

0.67

Aqu

Polyethylene glycol

100

Aqu

Shoe series allergens: (1) 1% Diphenyl guanidine in petrolatum vehicle; (2) 1% Dibutylthiourea in petrolatum vehicle; (3) 2% p-Tert-butylphenol in petrolatum vehicle; (4) 1% Hydroquinone monobenzyl ether in petrolatum vehicle; (5) 1% Disperse orange in petrolatum vehicle; (6) 1% Glutaraldehyde in petrolatum vehicle. SKINmed. 2018;16:90â&#x20AC;&#x201C;97

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The patch test sites were graded according to the criteria laid down by the International Contact Dermatitis Research Group Guidelines.5,6 Skin scraping with a potassium hydroxide (KOH) mount to identify superficial fungal infection was carried out in individuals with asymmetrical or unilateral involvement who had a negative patch test result.

ing and ulceration was present in 9 (8.33%) and 3 (2.78%) participants, respectively.

Duration Sixteen (14.81%) participants had had dermatitis for less than 6 months, 31 (28.70%) for 6 to 12 months, 38 (35.19%) for 12 to 60 months, 20 (18.52 %) for 60 to 120 months, and 3 (2.78%) for more than 120 months. The duration of disease at the time of presentation ranged from 1 week to more than 15 years. A total of 43.52% of the patients had presented within the first year of onset of the disease, and 21.30% had suffered from foot dermatitis for more than 5 years. The mean duration of disease in female participants was 22.85 months (standard deviation [SD] 22.57 months) and in male participants was 39.22 months (SD 39.04 months); however, this difference was not statistically significant (P=.057, Mann-Whitney U test). The overall mean duration of illness was 29.52 months (SD 31.27 months).

RESULTS

Epidemiologic data A total of 943 patients were patch tested during the study period. Of these, 126 had dermatitis of the feet caused by footwear, which was diagnosed on the basis of clinical history, meticulous and thorough physical examination, and distribution of the lesions on the feet. The prevalence of footwear dermatitis was 13.36% among contact dermatitis cases. A total of 115 patients were willing to answer the detailed proforma and to undergo necessary laboratory investigations. Of these 115 patch tested patients, 108 were included, with seven patients excluded because they did not report back for the patch test reading.

Predisposing factors Of the participants, 34 (31.48%) patients had a personal and/or family history of atopy, and the remaining 74 (68.52%) were nonatopic. A history of palmo-plantar hyperhidrosis was elicited in 41(37.96%) patients.

Age and sex distribution Of the 108 patients included, 39 (36.11%) patients were in the age group 31 to 40 years, 33 (30.56%) were 21 to 30 years old, 15 (13.89%) were 41 to 50 years old, 16 (14.81%) were 20 years of age or less, and only 5 (4.63%) were older than 50 years. In total, 87 (80.56%) patients were between 20 and 50 years of age. The youngest and eldest patients were aged 6 and 64 years, respectively, and the mean age was 31.56 years.

Seasonal variations Exacerbation of foot dermatitis during summer was recorded in 44 (40.74%) patients, and during monsoon and winter in 9 (8.33%) and 3 (2.78%) patients, respectively. In total, 52 (48.15%) patients showed no seasonal variation.

There were 64 (59.26%) girls or women and 44 (40.74%) boys or men participants (ratio 1.45:1).

Footwear Fifty-two (48.15%) patients had worn socks. The use of nylon socks was most common among these participants, followed by cotton socks. The distribution of footwear used is displayed in (Table II); rubber slippers were the most common.

Occupational profile Housewives formed the single largest groupâ&#x20AC;&#x201D;32 (29.63%) participantsâ&#x20AC;&#x201D;followed by students (24, 22.22%), service men in the armed forces (20, 18.52%), laborers (11, 10.19%), businessmen (9, 8.33%), and cycle rickshaw (pedicab) pullers (8, 7.41%).

Usage of topical medicaments A total of 68 (62.96%) patients were using some form of topical medication. Topical steroids were used by 23 (21.30%) patients, followed by antifungal creams in 15 (13.89%); 30 (27.78%) patients were applying different types of combined topical preparations.

Clinical data Symptoms and signs Itching was the most common clinical manifestation, seen in 101 (93.52%) patients, with burning sensations in 66 (61.11%), redness in 52 (48.15%), pain in 43 (39.81%), swelling at the site in 22 (20.37%), dyspigmentation in 17 (15.74%), and fluid-filled lesions in 15 (13.89%). Oozing from the lesions was recorded in 13 (12.03%) patients. CrackSKINmed. 2018;16:90â&#x20AC;&#x201C;97

Clinical pattern Site The pattern of the dermatitis over the feet in 95% of the patients corresponded to that of footwear used, and was symmetrical

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Table II. Footwear Contact Dermatitis: Distribution According to Footwear Used Type of shoe

Number

Percentage

Rubber slipper

62.96

Leather shoe/slipper

43.52

Plastic footwear

24.07

Cloth-based shoe

14.81

Sports shoe

9.26

in 90.74%. The dermatitis involved the dorsa of the feet in 103 (95.37%) patients, dorsal surfaces of the toes in 70 (64.81%), web spaces in 36 (33.33%), plantar aspect of the toes in 22 (20.37%), soles (weight bearing) in 17 (15.74%), ankles in 16 (14.81%), insteps in 7 (6.48%), and heels in 3 (2.78%). Footwear dermatitis with/without involvement of other body surface areas was assessed, with documented spread of the disease to the hands in 9 (8.33%), legs in 6 (5.56%), face in 3 (2.78%), and abdomen in 3 (2.78%) patients. Eighty-seven (80.56%) participants had exclusive involvement of the feet.

Figure 1. Erythema, erosions, oozing, and crusting present over the dorsa of the feet.

Morphology Figures 1 and 2 show the typical morphology. Erythema was present in 67 (62.04%), oozing in 24 (22.22%), papulovesicular lesions in 35 (32.41%), and ulceration in 3 (2.78%) patients during the acute phase. The chronic phase was marked by lichenification in 46 (42.59%), hyperpigmentation in 41 (37.96%), fissuring in 13 (12.04%), and scaling in 16 (14.81%) participants. Edema was present in 9 (8.33%), depigmentation in 8 (7.451%), and ulceration in 3 (2.78%) patients.

Etiological profile In all, 66 (61.1%) participants with suspected allergy tested positive to at least one allergen (Table III). Rubber accelerators and antioxidants were the most common allergens. Mercapto mix, mercaptobenzothiazole, potassium dichromate, and paraphenylenediamine (PPD) were the most common allergens (Table IV). The following were also incriminated: thiuram mix, p-tert-butylphenol formaldehyde resin, nickel, cobalt, monobenzyl ether of hydroquinone, epoxy resin, black rubber, neomycin, diphenylguanidine, colophony, formaldehyde, balsam of Peru, and dibutyl thiourea (Table IV). In total, 103 positive tests to different allergens present in standard and shoe series were recorded. Sensitization to a single antiSKINmed. 2018;16:90â&#x20AC;&#x201C;97

Figure 2. Erythema, erosions, and oozing affecting the dorsa of the feet.

gen was observed in 40 (60.61%), to two antigens in 17 (25.76%), to three in 7 (10.61%), and to four antigens in 2 (3.03%) patch testâ&#x20AC;&#x201C;positive patients (Table V). Among the rubber allergen group, 15 patients each were positive to both mercapto mix and mercaptobenzothiazole. Footwear Contact Dermatitis

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DISCUSSION

be more vulnerable. Interestingly, 90 (83.33%) patients were in the 20 to 60 years age group, an observation similar to that from other Indian studies.4,10,12,16,17 This may be because this is the most active stage of life, necessitating frequent use of footwear. A wider range of 3 to 80 years has also been reported,15,18,19 with a mean age of 42.5 years, because of a more active lifestyle.

Footwear dermatitis is a form of contact dermatitis caused by sensitivity to footwear components. Its overall prevalence among cases of contact dermatitis is 1.5% to 25%.9,10 Its diagnosis is based on the history, clinical picture, and positive patch test reaction to chemicals and/or constituents of the footwear. In this study, the prevalence of footwear dermatitis was found to be 13.36% in contact dermatitis patients, a finding in agreement with other Indian studies10–12 and a study from Nigeria (Africa),13 but in contrast to the low prevalence reported from western countries.10,14,15 The higher prevalence among Indian participants may be due to an indiscriminate use of footwear chemical(s), lack of quality control, and a hot and humid climate.

The preponderance of women over the men is a significant finding, conforming to that of earlier reports.4,10,12,16,20 It is compounded by greater cosmetic concern and awareness. Housewives constituted the single largest group, as has been reported elsewhere;4,12,16 this was followed by students, servicemen in the armed forces, laborers, businessmen, and cycle rickshaw (pedicab) pullers. Pressure, friction, and sweating may reign in the foot environment of these individuals, resulting in rapid wear and tear, and increased chances of chemicals leaching out from the footwear. Housewives are exposed

Footwear dermatitis has a tendency to occur in all age groups, but individuals in their third and fourth decades were found to

Table III. Footwear Contact Dermatitis: Allergen Test Results Test Result Allergens

+++

+/−

Number

Percentage

Mercapto mix

34.85

Mercaptobenzothiazole

25.76

Potassium dichromate

19.70

Paraphenylenediamine

15.15

Thiuram mix

12.12

p-Tert-butylphenol formaldehyde resin

7.58

Nickel

7.58

Cobalt

6.06

Monobenzyl ether of hydroquinone

4.55

Epoxy

4.55

Black rubber

4.55

Neomycin

3.03

Diphenylguanidine

3.03

Colophony

3.03

Formaldehyde

1.52

Dibutylthiourea

1.52

Balsam of Peru

1.52

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ORIGINAL CONTRIBUTION

Table IV. Footwear Contact Dermatitis: Causative Group of Allergens

Table V. Footwear Contact Dermatitis: Distribution of Allergens in Patch Test Positivity

Allergen

Number of Antigens

Number

Percentage

Rubber allergens Mercapto mix Mercaptobenzothiazole Thiuram mix Black rubber Diphenylguanidine Dibutylthiourea

23 17 8 3 2 1

34.85 25.76 12.12 4.55 3.03 1.52

Leather allergens Potassium dichromate Formaldehyde

13 1

19.70 1.52

Glues p-Tert-butylphenol Epoxy resins Colophony Balsam of Peru

5 3 2 1

7.58 4.55 3.03 1.52

Dyes p-Phenylenediamine

15.15

Metals Nickel Cobalt

5 4

7.58 6.06

Monobenzyl ether of hydroquinone

4.55

Neomycin

3.03

Percentage

60.61

25.76

10.61

3.03

Total

100.00

first year after onset of the disease. The mean duration was 22.85 months in female, and 39.22 months in male, participants. The overall mean duration was 29.52 months, comparable to earlier studies.11,15,17 A personal and/or family history of atopy was seen in 34 (31.48 %) patients, implying that atopic individuals have a susceptibility to developing footwear contact dermatitis.15,16,23 Palmoplantar hyperhydrosis15,16 is one of the important predisposing factors because sweat facilitates the leaching-out of chemicals (chromate salts) from the shoes, making them available to sensitize the individual, although this was documented purely on subjective grounds. Genetic and climatic10,16 factors may account for this finding.

to water, household detergents, and cleansing agents that may cause dermatitis of the feet, resulting in impaired epidermal barrier function, and eventually leading to a higher frequency of penetration by shoe allergens. Other predisposing occupations may be those requiring the use of closed, tight-fitting shoes for prolonged durations. A high prevalence rate of footwear dermatitis has been reported among military personnel wearing occlusive boots.21 Itching, burning sensation, redness, and pain were frequently reported. Swelling, fluid-filled lesions, oozing, cracking, and ulceration were the prominent signs, similar to previous reports.16 One group has reported several cases of shoe contact dermatitis to monobenzyl ether of hydroquinone and mercaptobenzothiazole that presented as eczematous and vesicular reactions.22 Depigmentation produced by is usually preceded by an eczematous reaction, as hydroquinone also has the potential to cause contact sensitization. The duration of disease in our study ranged from 1 week to more than 15 years, and 47 (43.52%) patients presented during the SKINmed. 2018;16:90â&#x20AC;&#x201C;97

Number of Patients

Erythema, lichenification, hyperpigmentation, papulovesicles, oozing, crusting, scaling, fissuring, edema, depigmentation, and ulceration were the cardinal clinical features, similar to earlier reports.4,10,16,23 The dorsa of the feet and toes, along with interdigital clefts/ web spaces, are the most frequently encountered sitesâ&#x20AC;&#x201D;Indian sandal strap dermatitis.24,25 The clinical pattern may correspond to the site of the offending antigen, which may migrate to different parts of the shoes, masking the clinical presentation; the area involved can be attributed to the large surface area of the feet, thin stratum corneum, and prolonged intimate contact with the shoes uppers.10,11 The plantar aspect of the toes followed by the weight-bearing areas of the soles, ankles, and insteps were the other sites involved. Sparing of the instep has also been reported.15,16,19 The insteps were usually involved due to an extension of dermatitis from the dorsum of the foot and contact with the straps of flip-flop sandals. The heel was involved in only three (2.78%) participants, in contrast to the volar aspect19 of the foot. Accordingly, the lesions on the soles were divided into two patterns, one in which the entire sole

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ORIGINAL CONTRIBUTION

was involved sparing the insteps, and the other in which only the anterior weight-bearing part of the sole was involved.

Adhesives are used to glue the insoles and lining in place, and are important contributors to footwear dermatitis.16 Sensitivity to glues was observed in 11 (16.67%) of the 66 patch test–positive patients—to p-tert-butylphenol formaldehyde resin in 5 (7.58%), epoxy resins in 3 (4.55%), colophony in 2 (3.03%) patients, and balsam of Peru in 1 (1.52%). These observations were in agreement with those from various others studies.10,11,14,16,29

The hands are the most frequent site of secondary dissemination, which reflects a secondary nonspecific response to shoe dermatitis; moreover, the hands may come into contact with the sensitizer while handling the shoes or tying the shoelaces. Dissemination to the hands was seen in nine (8.33%) patients. Calnan and Sarkany26 recorded similar observations, 5 of their 37 patients with no atopic background showing evidence of dissemination of dermatitis to the hands. Dissemination to the legs (22%), fingers (20%), hands (10%), forearms (8%), thighs (6%), and trunk (4%) has also been recorded.10,11

Ten (15.15%) of the patch test–positive patients reacted to PPD, a chemical used for dyeing footwear. These results are comparable to those previously reported.10,20 Another study reported a higher prevalence of reactivity to this allergen, of about 24.8%, among 108 patch test–positive patients.12 The reason cited for the higher prevalence is that PPD can crossreact with certain rubber additives, which may suggest sensitivity to rubber rather than to dye. Two other patients who showed a positive patch test response to PPD gave a history of onset of aggravation of lesions only after using rubber footwear. Fisher reported positive reactions to PPD in patients wearing fabric or plastic shoes, and in patients with dermatitis of the feet caused by re-dyed shoes.30

Patch testing is an important diagnostic tool in establishing the role of various allergens in footwear dermatitis. Rubber and rubber chemicals (accelerators and antioxidants) have been reported as being the most common sensitizers in various studies from India and abroad.4,9,15,19,23,27 A total of 45.45% of patch test–positive patients were found to be sensitive to rubber allergens. The rising incidence of contact sensitivity to rubber might be a reflection of the much greater use of rubber in shoes in rubber-leather and rubber-resin compositions.19 Such shoes are often more affordable, and hence are more commonly worn. Rubber slippers/shoes were the most common type of footwear, used by 68 (62.96%) patients in the current study.

Metals can be used in various parts of the footwear. Positive reactions to nickel and cobalt was seen in 5 (7.58%) and 4 (6.06%) patients, respectively, in our study. The low prevalence of nickel sensitivity is in agreement with one study,4 wherein sensitivity to nickel was reported in only 3 of 44 patch test–positive patients. Other studies14,31 reported nickel sensitivity in 7.5% and 0.5% of patients, respectively, and concluded that nickel is rarely a relevant allergen for foot dermatitis, unless an obvious source of metal buckles is present.

Out of 108 positive cases reported by one group, however, only eight patients were positive for mercaptobenzothiazole, and four for thiuram disulfide.14 The lower incidence of positivity to rubber chemicals was also reported in Greece.28 The lower frequency of rubber sensitivity in these studies could be because rubber chemicals do not leach out as easily as chrome.

Two (3.03%) participants in our study showed a reaction to the topical antibiotic neomycin. Contact sensitivity to topical medication contributing to the pathogenesis of footwear dermatitis has been reported.4,11,16 This sensitivity may develop from exposure to topical medication any time during the course of the disease, and may possibly contribute to the chronicity of the dermatitis.

Two (3.03%) patients who were patch test–positive showed a positive response to diphenylguanidine, a rubber accelerator that is among one of the allergens present in shoe series.27,28 A positive patch test result to diphenylguanidine has been reported in three patients28 and in two patients.27 Leather allergens were the second most common group of allergens causing footwear dermatitis in 14 (21.21%) patch test–positive patients. These included the two most commonly used agents for tanning leather: potassium dichromate, in 13 (19.70%) patients, and formaldehyde, in one (1.51%). This is in accordance with the findings reported from India.10,12 The higher frequency of leather allergy can be attributed to the poor availability and high cost of chrome-free leather in India; moreover, the climatic conditions prevailing in India contribute to the easier leaching-out of chrome from the footwear, resulting in a higher chance of sensitization. SKINmed. 2018;16:90–97

CONCLUSIONS Footwear dermatitis is an excellent illustration of contact dermatitis, the epidemiology of which may show regional variations. Periodic assessment of the pattern of footwear dermatitis is necessary to evolve new strategies for its prevention and treatment. The former envisages foot care and use of state-of-the-art footwear, while the latter requires treatment as for acute, subacute, and chronic dermatitis; this forms the subject matter of another publication.32

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ORIGINAL CONTRIBUTION 16 Rani Z, Hussain I, Haroon TS. Common allergens in shoe dermatitis: Our experience in Lahore, Pakistan. Int J Dermatol. 2003;42:605–607.

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27 Adams RM. Shoe dermatitis. Calif Med. 1972;117:12–16. 28 Varelzides A, Katsambas A, Georgala S, Capetanakis J. Shoe dermatitis in Greece. Dermatologica. 1974;149:236–239.

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29 Andersen K, Liden C, Hansen J, et al. Dose-response testing with nickel sulphate using the TRUE test in nickel-sensitive individuals. Multiple nickel sulphate patch-test reactions do not cause an ‘angry back’. Br J Dermatol. 1993;129:50–56.

11 Bajaj AK, Gupta SC, Chatterjee AK, Singh KG. Shoe dermatitis in India. Contact Dermatitis. 1988;19:372–375. 12 Chowdhuri S, Ghosh S. Epidemio-allergological study in 155 cases of footwear dermatitis. Indian J Dermatol Venereol Leprol. 2007;73:319–322.

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13 Olumide Y. Contact dermatitis in Nigeria. IV. Dermatitis of the feet. Contact Dermatitis. 1987;17:142–145.

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ORIGINAL CONTRIBUTION

The Prevalence of Malassezia Folliculitis in Patients with Papulopustular/Comedonal Acne, and Their Response to Antifungal Treatment Seda Pürnak, MD;1 Murat Durdu, MD;2 Mustafa Agah Tekindal, MD;3 A. Tülin Güleç, MD;1 Deniz Seçkin, MD1 ABSTRACT Because Malassezia folliculitis (MF) may clinically mimic acne vulgaris (AV), patients usually receive unnecessary and prolonged antibiotic treatment. We aimed to determine the prevalence of MF among patients with AV, and to evaluate its response to antifungal treatment. A total of 217 patients with AV underwent cytologic examination for the presence of Malassezia yeasts. Samples were obtained from lesional and nonlesional skin and stained with May-Grünwald-Giemsa. MF was diagnosed if there were more than six spores in one microscopic field (at ×400 magnification). A modified “lesion-counting” method was used to assess the clinical severity of acne. Treatment included oral itraconazole (2×100 mg daily) and topical ketaconazole for 4 weeks. Fifty-five (25.3%) patients were diagnosed with MF; of these, 38 (69.1%) completed the antifungal treatment. The lesions decreased by 50% or more in 26 (68.4%) of the patients who completed the antifungal treatment, which reduced the number of closed comedones/comedolike or molluscoid papules and inflammatory papules. The average number of spores in lesional samples was significantly decreased after treatment (P=<.0005). We observed that MF can present with AV-like lesions, or the two diseases may coexist. Cytology is helpful for making the correct diagnosis and providing proper management of MF. (SKINmed. 2018;16:99–104)

F is a common acneiform eruption and usually presents with pruritic monomorphic, follicular, domeshaped comedolike papules and pustules on the face and upper portion of the trunk in young to middle-aged adults.1,2 As MF is often misdiagnosed as AV, this may lead to mistreatment of the condition and to unnecessary use of antibiotics, which can also cause worsening of MF.3,4

tology Department of Başkent University Hospital in Ankara, Turkey. To assess whether seasonal differences were affecting the frequency of the disease, some of the patients were enrolled in summer (between June 2012 and August 2012), and the rest in winter (between December 2012 and February 2013). This study was approved by Başkent University Institutional Review Board (Project No. KA14/235).

A limited number of studies exist in the literature that report the clinical differences and similarities between MF and AV.2,3,5–7 We aimed to determine the prevalence of MF among patients clinically diagnosed with papulopustular/comedonal acne, and also to evaluate its response to antifungal treatment.

Cytology Samples for Tzanck smear test were obtained from lesional and nonlesional skin (two sites for each patient). A small dermal incision was made with a scalpel (no. 15). Comedolike papules, if they existed, were selected for sampling.5,7 In the absence of those lesions, samples were taken from pustules or inflammatory papules. The samples from nonlesional skin were obtained by dermal scraping of the nonlesional skin areas closest to the lesions that had already been sampled. The obtained materials were stained with May-Grünwald-Giemsa, and the smears were evaluated un-

PATIENTS AND METHODS

Study design This prospective study included patients clinically diagnosed with papulopustular/comedonal acne who attended the Derma-

From the Department of Dermatology, Baskent University Faculty of Medicine, Ankara1 and Adana,2 Turkey; and the Department of Biostatistics, Izmir University Faculty of Medicine, Izmir, Turkey3 Address for Correspondence: Murat Durdu, MD, Department of Dermatology, Baskent University, Faculty of Medicine, Adana Hospital, 01130, Adana, Turkey • E-mail: sivandr@hotmail.com

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ORIGINAL CONTRIBUTION and homogeneous variance groups were compared by Student’s t test, and dependent groups by paired samples t test. According to these test results, parametric test assumptions were not available for some variables; therefore, comparisons of two independent groups were performed using the Mann-Whitney U test, and comparisons of two dependent groups by Wilcoxon test. Categorical data were analyzed using the χ2 test. All statistical analyses were performed with SPSSTM software (version 17.0; SPSS Inc., Chicago, IL). P values <.05 were considered statistically significant.

217 subjects enrolled

RESULTS

Figure 1. Flowchart of the study.

der a light microscope. The total number of spores were counted in one microscopic field (at ×400 magnification) wherever the smears showed the highest number of spores; the presence of more than six spores was accepted as compatible with a diagnosis of MF.7

Clinical grading of the lesions Clinical severity of the acneiform lesions was assessed with a modified “lesion-counting” method.8 The acne lesion-counting method was modified to find out whether there was a different distribution for MF lesions compared to classical AV lesions, as it has been previously reported that the lateral aspects of the face are more frequently affected in patients with MF.5

This study included 217 patients with a clinical diagnosis of papulopustular/comedonal acne. Of these, 112 (51.6%) were examined in summer, and 105 (48.4%) in winter. A total of 55 (25.3%) patients (34 summer and 21 winter patients) were diagnosed with MF. MF was significantly more frequent in the summer season (P=.001). Of those individuals with MF, 42 (76.4%) were women and 13 (23.6%) were men. The patients’ ages ranged from 14 to 44 years (mean 22.8±6.8 years). The duration of the lesions ranged from 1 week to 10 years (mean 20.1±26.3 months). Thirty-eight of the patients (33 women and five men) completed the antifungal treatment (Figure 1). Of those patients, 28 (73.7%) had previously received one or more treatment modalities for acne. The most commonly used drugs were topical (23.7%) and oral (23.7%) antibiotics.

Cytology

The presence of side effects of itraconazole therapy, such as gastrointestinal complaints, and local side effects of ketaconazole cream, such as burning, were sought at the end of the treatment.

Cytology showed oval single-budding spores in patients who completed the antifungal treatment with MF (Figure 2). The number of spores in lesional skin was higher than that in nonlesional skin (P<.05). The average number of spores in lesional (34.1±33.7) and nonlesional samples (3.4±4.9) were significantly decreased after treatment (1.3±1.1 and 0.7±1.4, respectively; P<.05). Before the treatment, cocci and bacilli were noted in the smears of 26 (68.4%) and 16 (42.1%) patients with MF, respectively (Figure 2B). There was no significant difference between the number of cocci and/or bacilli before and after treatment. Nonresponders showed significantly more bacilli before and after treatment, and more cocci after treatment (P<.05).

Statistical analysis

Clinical evaluation before treatment

Results of homogenity (Levene test) and normality (ShapiroWilk test) tests were used to decide the appropriate statistical methods to compare the study groups. Normally distributed

All patients with MF had lesions in more than one region. The most commonly involved areas were the forehead, trunk, and right and left lateral aspects of the cheeks (Table I). The patients

Treatment Patients diagnosed with MF were treated with oral itraconazole (2×100 mg daily) and ketaconazole cream twice daily 4 four weeks. At the end of the treatment, patients in whom total lesion counts decreased more than 50% were designated as responders.9

Side effects

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Figure 2. Malassezia spores (black arrows) (A), and bacilli (red arrows) and spores (black arrows) (B), in a patient with acne vulgaris (May-Grünwald-Giemsa stain, original magnification ×1000).

Table I. Baseline Lesion Counts in Different Body Sites of the Patients with Malassezia Folliculitis Who Completed the Antifungal Treatment Open Comedones (Mean±SD)

Closed Comedones/ Comedolike Papules (Mean±SD)

Inflammatory Papules (Mean±SD)

Pustules (Mean±SD)

Forehead

2.3±2.9

35.1±21

4±3

1.4±2.8

Lateral aspect of right cheek

1.7±2.9

8.7±6.9

3±2.7

1±2.4

Medial aspect of right cheek

0.4±1.3

1.6±2

2±3.5

0.4±0.2

Lateral aspect of left cheek

1.1±1.7

8.7±7.7

3.7±3.8

0.8±1.6

Medial aspect of left cheek

0.3±1

1.8±2.1

2.1±3

0.5±1.4

Chin

1.4±2.6

3.2±3.3

3.1±2.3

0.8±1.8

Nose

—

0.5±2.2

1.1±1.8

0.1±0.5

Trunk

0.5±1.6

12.6±13.8

11±10.1

3.1±5.5

Neck

3.4±7.2

2.5±3.7

0.6±2.1

Abbreviation: SD, standard deviation.

had closed comedolike papules (100%; Figure 3A), inflammatory

Clinical evaluation of the treatment efficacy

papules (100%; Figure 4A), pustules (78%), and open comedones

Thirty-eight patients who completed the antifungal treatment were divided into two groups: responders (68.4%) and nonresponders (31.6%). The mean duration of the disease was lon-

(73%). Twenty-seven (71%) of the patients with MF complained of pruritus. SKINmed. 2018;16:99–104

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Figure 3. Malassezia folliculitis. Dramatic resolution of comedolike/molluscoid papules on the forehead. (A) Before treatment. (B) After treatment.

Figure 4. Malassezia folliculitis. Dramatic resolution of monomorphic follicular erythematous papules on the back. (A) Before treatment. (B) After treatment.

ger in nonresponders (41.5±33.7 months) than in responders (10.1±14.1 months) (P=.000). There was no statistical difference between the two groups in terms of age, sex and presence of pruritus (Table II). Regarding the distributions of baseline lesions, the number of open comedones on the forehead, medial aspect of the right cheek, and lateral aspects of the cheeks; the number of inflammatory papules on the medial aspect of right and left cheeks; and the number of pustules on the forehead and right cheek were significantly higher in nonresponders than responders (all P<.05). The number of comedolike papules was significantly higher on the forehead area in responders than nonresponders (P<.05) (Table III). SKINmed. 2018;16:99–104

After antifungal treatment, the number of closed comedolike papules was dramatically decreased on the forehead (Figure 3B), lateral and medial aspects of the right cheek, lateral and medial aspects of the left cheek, chin, and trunk area (P<.05), but not the nasal area (P=.131), in responders. In nonresponders, the number of comedolike papules was significantly reduced on the forehead, lateral aspects of the right and left cheeks, and trunk area (P<.05). In responders, inflammatory papules were significantly decreased on the forehead, lateral aspects of the right and left cheeks, medial aspect of the left cheek, nose, chin, and trunk (Figure 4B) (P<.05), but not the medial area of the right cheek (P=.632); on the other hand, there was no change in nonresponders. The number of pustules showed a reduction only in the trunk area in responders and nonresponders (P<.05).

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Table II. Baseline Characteristics of the Patients with Malassezia Folliculitis Who Responded or Did Not Respond to Antifungal Treatment Responders (n=26)

Nonresponders (n=12)

P Value

24.9±7

21.5±5.9

0.139

23 (88.5) 3 (11.5)

10 (83.3) 2 (16.7)

0.664

Duration of lesions (months), mean±SD

10.1±14.1

41.5±33.7

0.000*

Pruritus, n (%)

18 (69.2)

9 (75)

0.722

Age (year), mean±SD Sex, n (%) Female Male

Abbreviation: SD, standard deviation. *Statistically significant.

Table III. Baseline Lesion Counts in Different Body Sites of Patients with Malassezia folliculitis Who Responded or Did Not Respond to Antifungal Treatment Open Comedones (Mean±SD)

Closed Comedones/ Comedolike Papules (Mean±SD)

Inflammatory Papules (Mean±SD)

Pustules (Mean±SD)

0.8±1.7

2.9±3.8*

40.1±22.1*

24.4±13.7

3.4±2.4

5.1±3.8

0.8±1.2

2.9±4.2*

Lateral aspect of right cheek

0.5±1

4.5±3.7*

8.6±9.1

9.1±7.8

2.4±2.2

4.2±4

0.9±0.7

1.2±2.2

Medial aspect of right cheek

0.1±0.6

1±2.1*

1.3±1.8

2.1±2.3

1.1±1

4±5.8*

0.1±0.3

1.2±1.9*

Lateral aspect of left cheek

0.3±0.7

2.8±2*

9.5±9.3

7±5.8

3.1±2.9

5±4.6

0.5±0.4

1.4±2.2

Medial aspect of left cheek

0.1±0.5

0.5±1.7

1.8±2.1

1.8±2

1.5±1.3

3.6±4.8*

0.4±1.2

0.8±1.7

Nose

—

0.8±2.6

0.08±0.2

1.1±2

0.9±1.1

0.1±0.5

Chin

1.2±2.8

1.9±2

2.9±2.6

3.8±4.6

2.8±2.2

3.7±2.5

0.8±2

1±1.4

Trunk

0.2±0.9

1.1±2.4

12.3±14.3

13.3±13.2

11.5±10.8

9.8±8.6

2.8±6.3

3.5±3.2

Neck

4±3.2

2±1.8

1.9±1.6

3.6±3.3

0.8±0.7

0.2±0.1

Forehead

Abbreviations: NR, non-responders; R, responders; SD, standard deviation. *P< .05 (responders versus nonresponders).

Side effects Ten patients had gastrointestinal complaints, such as dyspepsia and stomach pain, due to systemic itraconazole therapy; three of these had to discontinue the drug. Skin burning due to ketaconazole cream developed in five patients, one of whom terminated the topical treatment. DISCUSSION To our knowledge, this is the first study to evaluate the efficacy of antifungal treatment with regard to the type and location of the lesions SKINmed. 2018;16:99–104

in patients with MF who had first been clinically diagnosed as having AV. After the cytologic examination, the subjects who received the diagnosis of MF were treated with systemic and topical antifungal agents, which led to a reduction in the number of closed comedolike papules and inflammatory papules. No change was, however, observed in the number of open comedones and pustular lesions, except for pustular lesions on the trunk. İt is not surprising that the open comedones did not improve with antifungal therapy because they are the primary elementary lesions of AV and only benefit from topical comedolytic agents.10 It seems that those patients with MF who had open comedones had AV as a coexisting disease.

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The lesions of MF can be confused with those of other folliculitides, acne, and systemic candidosis. Cytological examination is positive more often than histology.1,11 Malassezia yeasts can be identified in potassium hydroxide preparations or May-Grünwald-Giemsa–stained smears.6 Being superior to potassium hydroxide preparations, May-Grünwald-Giemsa–stained smears can also reveal other microorganisms.6 Compared to responders, nonresponders had more bacilli before and after treatment; hence, we think that a coexistence of bacteria might be responsible for the treatment failure with antifungal medication, and combination therapies of antiacne medications and antifungal agents would probably have better therapeutic efficacy in nonresponders. Two earlier studies support this opinion, reporting that combination therapy with benzoyl peroxide and miconazole was more effective than benzoyl peroxide alone in the treatment of AV.12,13

papules on the face and pustules on the trunk in summertime, and also in those failing to or partially respond to classical acne treatments. The diagnosis of MF would prevent the unnecessary use of antibiotics and allow for proper treatment in these patients. REFERENCES

The most commonly involved sites in MF have been reported to be the chest, face, upper region of the back, and lateral aspects of the arms.1,6,7 In our study, the most affected areas were the forehead, lateral aspects of the cheeks, and trunk. We detected numerous comedolike papules on the forehead of responders, whereas more inflammatory papules and pustules were observed on medial sites on the cheeks in nonresponders at baseline. We also noticed that the medial aspects of the cheeks had lower response rates to antifungal treatment, especially in nonresponders. Nonresponsive lesions located in medial areas of the cheek may point to coexisting AV lesions in this group. The effectiveness of antifungal treatment for pustules on the trunk may indicate that MF commonly presents as pustules at this location. The average duration of MF lesions has been reported to be 10 months, ranging between 2 weeks and 10 years.6 In our study, mean disease duration was 10.1 months in responders, with a longer disease course (mean 41.5 months) observed in nonresponders. One of the limitations of our study was that we could not perform fungal culture due to technical deficiencies; however, as Malassezia yeasts are members of normal skin flora, culture results may frequently be false-positive.6 The diagnostic value of cytology is almost equal to that of fungal cultures in MF.6,14 Because it was not a goal of our study, bacterial cultures were also not performed in patients whose cytology disclosed bacteria. We took only one sample from the most representative lesion of each patient, which may also have led to an underdiagnosis of other types of coexistent folliculitis.

1 Abdel-Razek M, Fadaly G, Abdel-Raheim M, al-Morsy F. Pityrosporum (Malassezia) folliculitis in Saudi Arabia-diagnosis and therapeutic trials. Clin Exp Dermatol. 1995;20:406–409. 2 Hu G, Wei YP, Feng J. Malassezia infection: Is there any chance or necessity in refractory acne? Chin Med J (Engl). 2010;123:628– 632. 3 Ayers K, Sweeney SM, Wiss K. Pityrosporum folliculitis: Diagnosis and management in 6 female adolescents with acne vulgaris. Arch Pediatr Adolesc Med. 2005;159:64–67. 4 Weary PE, Russell CM, Butler HK, Hsu YT. Acneiform eruption resulting from antibiotic administration. Arch Dermatol. 1969;100:179–183. 5 Jacinto-Jamora S, Tamesis J, Katigbak ML. Pityrosporum folliculitis in the Philippines: Diagnosis, prevalence, and management. J Am Acad Dermatol. 1991;24:693–696. 6 Durdu M, Guran M, Ilkit M. Epidemiological characteristics of Malassezia folliculitis and use of the May-Grünwald-Giemsa stain to diagnose the infection. Diagn Microbiol Infect Dis. 2013;76:450–457. 7 Yu HJ, Lee SK, Son SJ, et al. Steroid acne vs. Pityrosporum folliculitis: The incidence of Pityrosporum ovale and the effect of antifungal drugs in steroid acne. Int J Dermatol. 1998;37:772– 777. 8 Lucky AW, Barber BL, Girman CJ, et al. A multirater validation study to assess the reliability of acne lesion counting. J Am Acad Dermatol. 1996;35:559–565. 9 Arowojolu AO, Gallo MF, Lopez LM, Grimes DA. Combined oral contraceptive pills for treatment of acne. Cochrane Database Syst Rev. 2012;7:CD004425. 10 Zaenglein AL, Graber EM, Thiboutot DM, Strauss JS. Acne vulgaris and acneiform eruptions. In: Wolff K, Goldsmith LA, Katz SI, et al, eds. Fitzpatrick’s Dermatology in General Medicine. 7th ed. New York: McGraw Hill; 2008:690–703. 11 Durdu M, Ilkit M. First step in the differential diagnosis of folliculitis: Cytology. Crit Rev Microbiol. 2013;39:9–25. 12 Mesquita-Guimaraes J, Ramos S, Tavares MR, Carvalho MR. A double-blind clinical trial with a lotion containing 5% benzoyl peroxide and 2% miconazole in patients with acne vulgaris. Clin Exp Dermatol. 1989;14:357–360.

CONCLUSIONS

13 Fluckiger R, Furrer HJ, Rufli T. Efficacy and tolerance of a miconazole-benzoyl peroxide cream combination versus a benzoyl peroxide gel in the topical treatment of acne vulgaris. Dermatologica. 1988;177:109–114.

Cytology is a useful method for diagnosing MF, especially in patients presenting with pruritic, inflammatory or comedolike

14 Back O, Faergemann J, Hornqvist R. Pityrosporum folliculitis: A common disease of the young and middle-aged. J Am Acad Dermatol. 1985;12:56–61.

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Basal Cell Carcinoma of the Buttock Philip R. Cohen, MD ABSTRACT Basal cell carcinoma of the buttock is rare, and only 28 patients have been described. An extensive literature search was performed on basal cell carcinoma and buttock using the PubMed database. The literature was evaluated, and the characteristics of individuals with basal cell carcinoma of the buttock were summarized. The calculated prevalence of basal cell carcinoma of the buttock was 0.35%. The majority of patients had no obvious basal cell carcinoma–associated risk factors. Carcinomas were observed 1.2 times more often in women than in men, and more often on the right buttock. They frequently presented as an asymptomatic nodule. The buttock tumor was typically associated with a nodular histologic subtype of basal cell carcinoma. The prognosis for these patients was excellent after complete removal of the tumor. In conclusion, basal cell carcinoma of the buttock is a rare clinical variant of this type of skin cancer that usually presented as an asymptomatic nodule in an individual who did not have any traditional risk factors for this malignancy. The cancer was typically associated with a nonaggressive histologic subtype. Recurrence or metastasis was not observed after treatment of the primary tumor. (SKINmed. 2018;16:105–110)

asal cell carcinoma is the most common skin cancer. Exposure to ultraviolet radiation is the principal risk factor associated with its development. It is not unexpected therefore that basal cell carcinomas typically occur on sun-exposed sites.1–7

Albeit less commonly, basal cell carcinomas also occur on sites that are usually sun-protected. These include the axilla, breast, foot, groin, nipple, penis, scrotum, and vulva.8–12 The buttock and perianal region are sun-protected sites; however, the latter is defined as “within 3 cm of the anal verge.”13 Including the man described in Figures 1 and 2 here, 28 individuals with buttock basal cell carcinomas have been reported.8–10,14–25 HISTORY A retrospective study of basal cell carcinomas showed the usual and unusual sites of occurrence.8 The authors’ dermatopathology laboratory was located in Monroe, MI, and they reviewed 2126 consecutive cases with a histologic diagnosis of basal cell carcinoma; four of the tumors were located on the buttock. These cancers were from a 67-year-old man (and had mimicked an epidermoid cyst) and three women—two were 70 years old (and the lesion diagnosis before biopsy was either Bowen disease or basal cell carcinoma), and one was 78 years old (and her left buttock lesion was clinically suspected to be a basal cell carcinoma).8

The first complete report of a patient with buttock basal cell carcinoma is credited to Morimoto and Gurevitch from the Division of Dermatology at Harbor-UCLA Medical Center in Torrance, CA.14 In 1985, they described a 69-year-old black man who had lived on a farm in Oklahoma where he and his family drank well water; although chronic arsenic exposure was considered, neither he nor his family had any hyperpigmentation, keratoses, or previous history of skin cancer. He presented with a 2-year history of an asymptomatic pedunculated, pigmented 1.0 cm × 1.5 cm soft, rubbery nodule with a lobulated surface on the medial aspect of his right buttock. A shave excision showed a nodular basal cell carcinoma with numerous pigment-containing melanophages reaching the deep margin of the specimen; 1 month later, the lesional site was excised, and no residual tumor was found.14 Within a year, another report of basal cell carcinoma of the buttock was accepted; Ochiai et al, from the Department of Dermatology at the Nihon University School of Medicine in Tokyo, Japan, described a 69-year-old woman with a pleomorphic nodular basal cell carcinoma measuring 33 mm × 19 mm that presented as an enlarging, ulcerated, and bleeding nodule of 5 years’ duration on her right buttock.21 Subsequently, Bang and coauthors in 1987 and Halder and Bang in 1988 published the results of their retrospective study of skin cancer in black Americans that was based on the tumor registry of Howard University Cancer

From the Division of Dermatology, University of California San Diego School of Medicine, San Diego, CA Address for Correspondence: Philip R. Cohen, MD, 10991 Twinleaf Court, San Diego, CA 92131-3643 • E-mail: mitehead@gmail.com

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Figure 2. A postoperative view of the right buttock. The basal cell carcinoma presented as a flesh-colored, 2 mm × 2 mm papule with surrounding erythema (Figure 1). A biopsy, using a shave technique, was performed. Microscopic examination showed nodular aggregates of atypical basaloid epithelium with peripheral palisading and retraction artifact; there were also focal areas of squamous differentiation. The basal cell carcinoma had narrowly been removed during the biopsy. Subsequently, the lesion site, with a conservative margin of normal-appearing skin, was excised; microscopic evaluation of the excision margins was performed at the time of surgery. Healing of the surgical site occurred without any complication. At the time of writing, there had not been any persistence or recurrence of the tumor.

Figure 1. A flesh-colored papule on the right buttock of a 62-year-old, Fitzpatrick skin type 3 Argentinian man who presented for evaluation after an unsuccessful cryotherapy treatment of the lesion. He had initially noted a small asymptomatic bump on his right buttock in February 2014. The lesion slowly increased in size; his primary care physician suspected the lesion to be a verruca and treated the nodule with liquid nitrogen cryotherapy in April 2014. He had had no prior melanoma or nonmelanoma skin cancer. He had had no previous actinic keratoses, and there had been no prior exposure to arsenic, environmental toxins, or ionizing radiation. His personal and family medical history was negative for basal cell carcinoma syndrome, Bazex syndrome, and xeroderma pigmentosa. In August 2013, however, a rectal adenocarcinoma (T2N1, clinically stage III, 9 cm from the anal verge) had been diagnosed, and he had received eight cycles of FOLFOX (folinic acid [leucovorin], 5-fluorouracil, oxaliplatin) from August 2013 to December 2013. In January 2014, he had had a laparoscopic, robotic-assisted anterior sigmoid resection of the cancer; postoperatively, beginning in February 2014, he received four cycles of 5-fluorouracil every 2 weeks.

Center from 1947 to 1959, and patients seen in Howard University Hospital and the offices of dermatology faculty from 1960 to 1985.24,25 Skin cancer was found in 126 of these; of the 39 basal cell carcinomas that were noted, only one was discovered on the buttock, in a black woman.24,25 Additional reports of basal cell carcinoma of the buttock were published as either individual reports or retrospective pathology studies. PREVALENCE More than 70% of the individuals with buttock basal cell carcinoma are reported in studies of patients with basal cell carcinoma in covered or unusual sites.8–10,17,20,22 The remaining eight patients SKINmed. 2018;16:105–110

were described in reports of single individuals14–16,18,21,23–25 Investigators observed the prevalence of buttock basal cell carcinoma, compared to basal cell carcinoma at other body sites, to range from 0.19% (1 in 532 tumors)8 to 0.68% (1 in 148 tumors).22 A calculated prevalence of 0.35% (1 in 286 tumors) for buttock basal cell carcinoma is derived by combining the data of six retrospective pathology-based studies that evaluated the location of basal cell carcinomas (Table).8–10,17,20,22 EPIDEMIOLOGY Buttock basal cell carcinomas were described in nine men and 11 women (men:women = 1:1.2); the sex was not mentioned in eight. Most of the patients ranged from 51 to 82 years of age (median = 69 years) at the time of diagnosis; the age was not provided for eight individuals. The men ranged from 51 to 82 years of age (median = 66 years), and the women ranged from 60 to 78 years of age (median = 70 years). Most of the men were diagnosed during their sixth decade (67% [6/9]) and most of the women were diagnosed during their seventh decade (67% [6/9]).

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Table. Prevalence of Buttock Basal Cell Carcinoma Original Dataa

Percentage

BBCC in TBCCb

Reference

4/2126

0.19

1 in 532

3/ 873

0.34

1 in 291

2/ 520

0.38

1 in 260

3/ 708

0.42

1 in 236

6/1050

0.57

1 in 175

0.68

1 in 148

0.35

1 in 286

1/ 148 19/5425

Abbreviations: BBCC, buttock basal cell carcinomas; TBCC, total basal cell carcinomas. Number of patients with buttock basal cell carcinomas per total number of basal cell carcinomas. b Conversion of original data of buttock basal cell carcinomas into prevalence of a single buttock basal cell carcinoma per total number of basal cell carcinomas. c Calculated prevalence of buttock basal cell carcinoma by adding the totals observed in retrospective pathology studies. a

Race was not provided for most of the patients with buttock basal cell carcinoma; however, three patients were black,14,22,24,25 and individual patients were Argentinian (current report), Asian,21 Japanese,23 or Korean.20 CLINICAL PRESENTATION

Signs The tumor presented as an asymptomatic lesion. Indeed, in several individuals the tumor was large secondary to the patient either being unaware of the lesion or neglecting it.10

Affected buttock The involved buttock was designated for eight individuals with buttock basal cell carcinoma. The tumor was located on the right buttock for five patients (two men [including the current report],4 two women,21,23 and one additional patient18) and the left buttock for three patients (one man16 and two women8,19); hence, basal cell carcinomas were observed more often to be located on the right buttock, and were found equally on the right and left buttock in women.

Tumor duration before diagnosis The presence of the buttock tumor before diagnosis was described in only five patients, and the duration ranged from 2 months (in the current patient) to 5 years,21 with a median of 2 years. The tumor had been present 2 years or less in 80% of patients (4/5), and had been noticed by the patient for 6 months or less in 40% of individuals (2/5); however, in one fifth of the patients (1/5), SKINmed. 2018;16:105–110

the tumor had been present for 5 years before receiving medical attention and establishing the diagnosis.

Morphology Most of the buttock basal cell carcinomas presented as smooth papules or nodules (Figure 1). They were as small as 2 mm × 2 mm (current report) or as large as 1.5 cm × 1.0 cm.14 Some of the lesions were pedunculated,14,16 whereas others appeared as an asymmetrical plaque.15 The color of the tumor was described in nine patients (including the current report).14–16,19,21–25 It was flesh-colored in four individuals, two of whom were black (including the current report);14,22,24,25 however, a pigmented basal cell carcinoma was observed in 56% (5/9) of the buttock basal cell carcinomas;15,16,19,21,23 one of these tumors was from either an Asian21 or a Japanese23 woman. PATHOLOGY The histologic subtype of basal cell carcinoma was described for 12 of the tumors. Three-fourths of the patients (9/12), including the person whose tumor had mixed histology, had a nodular basal cell carcinoma; this also includes the current patient.14,15,17,20,21,23 Two individuals had a superficial basal cell carcinoma.18,20 A fibroepithelioma of Pinkus variant of basal cell carcinoma26 was also observed in an 82-year-old man. His tumor presented as a lightly pigmented, polypoid, pedunculated left gluteal nodule of 1.0 cm in greatest dimension. He had a history of multiple subcu-

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taneous lipomas; his basal cell carcinoma presented as an irritated buttock lesion which was excised at the base.16 In addition to this patient with a fibroepithelioma of Pinkus variant of basal cell carcinoma in a site that was not sun-exposed, this same subtype of basal cell carcinoma has also been described in some of the patients with axillary basal cell carcinoma.11,27,28 Two of the buttock basal cell carcinomas demonstrated a histologic subtype that can be associated with tumors of more aggressive biologic behavior. One patient, a 62-year-old Argentinian man with a 2 mm × 2 mm flesh-colored papule on his right buttock (the current patient), had a nodular basal cell carcinoma with focal areas of squamous differentiation. The other patient had a basal cell carcinoma of mixed histology;29,30 it consisted of a less aggressive variant (nodular) and a more aggressive subtype (infiltrating).17 Two of the individuals with buttock basal cell carcinomas had tumors that demonstrated large pleomorphic neoplastic cells.16,21 One of the patients with a pleomorphic basal cell carcinoma31,32 was the 82-year-old man with a fibroepithelioma of Pinkus variant of the cancer.16 The second patient was a 69-year-old Asian woman with a nodular basal cell carcinoma of 5 years’ duration that presented as a 33 mm × 19 mm black crusted and bleeding tumor with central ulceration on her right buttock.21

Postulated pathogenesis of buttock basal cell carcinoma in patients with tumorrelated risk factors In addition to sun exposure (ultraviolet A and B radiation), risk factors for basal cell carcinoma include other environmental exposures (radiation [ionizing and tanning bed] and toxins [arsenic, coal tar, paraffin]), genodermatoses (basal cell nevus syndrome, Bazex syndrome, epidermolysis bullosa simplex Dowling Meara subtype, oculocutaneous albinism, Rombo syndrome, xeroderma pigmentosa), immunosuppressed individuals (human immunodeficiency virus seropositive and solid-organ transplant recipients), injuries (burns, trauma), and certain physical phenotypic characteristics (burn/tan = always/never, eyes = blue or green, freckles = present, hair = blond or red, and skin color = fair or light).1–7 None of the patients with buttock basal cell carcinomas had a history of extensive sun exposure to that region of their body; however, 23% (5/22) of those with buttock basal cell carcinoma (including the current patient) had another tumor-related risk factor.14,19,20 Arsenic exposure was suspected, but unproven, in one patient and confirmed in another. A 69-year-old black man (and his family) drank well water on their farm in Oklahoma; however, he had no SKINmed. 2018;16:105–110

other cutaneous stigmata of arsenic exposure, and no other family members had a history of skin cancer.14 The second patient was a 56-year-old Korean man with a several-year exposure to herbal medication that contained arsenic; in addition to the buttock basal cell carcinoma, he also had arsenic keratoses on his whole body.20 A girl, initially seen at age 6 years, with basal cell nevus syndrome had multiple basal cell carcinomas including a tumor on her left buttock.19 As in this girl, basal cell carcinomas have also been discovered in other sun-protected sites, such as the axilla and inguinal area, in women with basal cell nevus syndrome.12,33 One patient with buttock basal cell carcinoma had recently received immunosuppressant therapy: this was a 62-year-old Argentinian man who, during his final months of chemotherapy for the treatment of rectal adenocarcinoma, developed a basal cell carcinoma on his right buttock (Figures 1 and 2). Exposure to ionizing radiation may have contributed to the development of basal cell carcinoma of the buttock in one individual. A 78-year-old Korean woman had received radiation therapy for the treatment of cervical cancer 17 years previously.20 Prior exposure to ionizing radiation has also been associated with basal cell carcinoma in other areas not sun-exposed, such as the axilla—a 65-year-old woman had received radiation to the affected axilla to treat hidradenitis suppurativa 20 years earlier,34 and a 68-year-old man had received x-ray treatments to the affected axilla to manage dermatitis 50 years earlier.33

Postulated pathogenesis of buttock basal cell carcinoma in patients without an established tumor-associated risk factor The majority of individuals with buttock basal cell carcinoma had no obvious tumor-associated risk factors. Specific textural changes (such as reduced skin tension and dermal thickness) may enable local factors (such as concave shape, reduced skin tension, and the presence of marked skin folds) to result in the occurrence of basal cell carcinoma. In addition, the development of basal cell carcinoma at sun-protected sites may—in part—be secondary to a local disturbance of cell matrix interactions.35 Local factor–associated textural changes were postulated to account for the observation that nearly 10 times more basal cell carcinomas were found in the less exposed medial quadrant of the orbit than the more exposed lateral quadrant.35 Similarly, some investigators have attributed the development of basal cell carcinoma localized to the axilla, another typically sun-protected location, to these site-specific changes.33 Therefore, local site factors may also contribute to the occurrence of basal cell carcinoma on

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the non–sun-exposed buttocks of affected individuals without other tumor-associated risk factors. Ultraviolet radiation may be associated with the subsequent depression of immune surveillance. This observation has prompted researchers to speculate that the influence of ultraviolet radiation at distant sun-exposed sites may have a role in the tumorigenesis of basal cell carcinomas in sun-protected areas.36 Other investigators have proposed that this concept possibly contributes to the pathogenesis of basal cell carcinomas not only in the typically non–sun-exposed axillae,27,33,37 but also in the covered areas of the perianal and genital regions.38 TREATMENT Most of the reports on buttock basal cell carcinoma do not address treatment of the residual tumor after diagnosis. Excision of the residual tumor is described for four patients: an Argentinian man, using the Mohs technique with microscopic evaluation of the margins at the time of surgery (the current patient; Figure 2), an Asian woman,21 a black man,14 and a Japanese woman.23

ing medications, or ionizing radiation—were only observed in five cases. Hence, the majority of patients with buttock basal cell carcinoma have no obvious tumor-associated risk factors. It has been hypothesized that textural skin changes (resulting from disturbed cell matrix interactions) may serve as a cofactor for the development of basal cell carcinoma in areas of low ultraviolet exposure, such as the buttock. In addition, the development of basal cell carcinoma in locations that were not sun-exposed, such as the buttock, may result from depressed immune surveillance caused by ultraviolet radiation at distant sun-exposed sites. Treatment consisted or an excision of the residual cancer or tumor site. The prognosis for patients with buttock basal cell carcinoma is excellent; neither recurrence nor metastasis has been reported. REFERENCES

PROGNOSIS The prognosis for patients with buttock basal cell carcinoma is presumed to be excellent. Neither recurrence nor metastasis has been reported for any of the individuals described. CONCLUSIONS Buttock basal cell carcinoma is rare; 28 patients have been described, whose median age at presentation was 69 years. The calculated prevalence of basal cell carcinoma of the buttock is 1 in 286 basal cell carcinomas. Buttock basal cell carcinomas are 1.2 times more common in women than in men. In 80% of patients, the tumor had been present for 2 or less years; however, in many individuals, the tumor was large secondary to the patient either being unaware of the neoplasm or neglecting it. The tumor typically presents as an asymptomatic nodule. The tumor appeared more often on the right buttock. The most common histologic subtype of basal cell carcinoma was nodular; less often, the pathology showed either a superficial or fibroepithelioma of Pinkus variant. Only two tumors had a histologic subtype that might be associated with tumors of more aggressive biologic behavior: a nodular basal cell carcinoma with areas of focal squamous differentiation, and a basal cell carcinoma with mixed histology that included infiltrative and nodular components. Risk factors usually associated with basal cell carcinoma—basal cell nevus syndrome and exposure to arsenic, immunosuppressSKINmed. 2018;16:105–110

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1 Kasper M, Jaks V, Hohl D, Toftgard R. Basal cell carcinoma— molecular biology and potential new therapies. J Clin Invest. 2012;122:455–463. 2 Chinem VP, Miot HA. Epidemiology of basal cell carcinoma. An Bras Dermatol. 2011;86:292–305. 3 Rubin AI, Chen EH, Ratner D. Basal cell carcinoma. N Eng J Med. 2005;353:2262–2269. 4 Brooke RCC. Basal cell carcinoma. Clin Med. 2005;5:551–554. 5 Wong CSM, Strange RC, Lear JT. Basal cell carcinoma. Br Med J. 2003;327:794–798. 6 Cohen PR. Basal cell carcinoma. J Gt Houst Dent Soc. 1995;67:20–21. 7 Sehgal VN, Chatterjeek K, Pandhi D, Khurana A. Basal cell carcinoma: Pathophysiology. SKINmed. 2014;12:176–181. 8 Rahbari H, Mehregan AH. Basal cell epitheliomas in usual and unusual sites. J Cutan Pathol. 1979;6:425–431. 9 Betti R, Urbani CE, Lodi A, Crosti C. Unusual sites of basal cell epitheliomas according to anatomical distribution and relative tumour density index. Eur J Dermatol. 1992;2:82–84. 10 Betti R, Bruscagin C, Inselvini E, Crosti C. Basal cell carcinomas of covered and unusual sites of the body. Int J Dermatol. 1997;36:503–505. 11 Cohen PR. Basal cell carcinoma of the axilla: Review of the world literature. Am J Clin Dermatol. 2014;15:95–100. 12 Cohen PR. Axillary basal cell carcinoma in patients with GoltzGorlin syndrome: Report of basal cell carcinoma in both axilla of a woman with basal cell nevus syndrome and literature review. Dermatol Online J. 2014;20:8. 13 Paterson CA, Young-Fadok TM, Dozois RR. Basal cell carcinoma of the perianal region: 20-year experience. Dis Colon Rectum. 1999;42:1200–1202. 14 Morimoto SS, Gurevitch AW. Residents’ corner: Pedunculated pigmented basal-cell carcinoma on the buttock of a black man. J Derm Surg Oncol. 1985;11:115–117. 15 Rothe MJ. Pigmented Basal Cell Carcinoma on Buttocks of a 60-Year-Old Woman. ObGyn.net. Published September 14, 2005. http://www.obgyn.net/articles/pigmented-basal-cell-carcinoma-buttocks-60-year-old-woman. Accessed July 12, 2014.

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16 Repertinger SK, Stevens T, Markin N, Klepacz H, Sarma DP. Fibroepithelioma of Pinkus with pleomorphic epithelial giant cells. Dermatol Online J. 2008;14:13.

28 Hayes AG, Berry AD, III. Basal cell carcinoma arising in a fibroepithelial polyp. J Am Acad Dermatol. 1993;28:493– 495.

17 Abeldano A, Hernandez MI, Demarchi M, et al. Basal cell carcinoma of unusual localization. Dermatol Argent. 2010;16:25–33.

29 Cohen PR, Schulze KE, Nelson BR. Cutaneous carcinoma with mixed histology: A potential etiology for skin cancer recurrence and an indication for Mohs microscopically controlled surgery. South Med J. 2005;98:740–747.

18 Cunliffe T. Basal cell carcinoma: Superficial. PCDS: Primary Care Dermatology Society. Published January 20, 2013. http://www. pcds.org.uk/clinical-guidance/basal-cell-carcinoma-superficial. Accessed July 12, 2014. 19 Samela PC, Tosi V, Cervini AB, et al. Nevoid basal cell carcinoma syndrome: Our experience in a pediatric hospital. Actas Dermosifiliogr. 2013;104:426–433. 20 Roh SG, Park J, Song KH, et al. Clinical and histopathological characteristics of extra-facial basal cell carcinoma: Analysis of 35 patients at the Chonbuk National University Hospital in Korea. Australas J Dermatol. 2014;55:e65–e68. 21 Ochiai T, Suzuki H, Morioka S. Basal cell carcinoma with giant tumor cells: Light and electronic microscopic study. J Cutan Pathol. 1987;14:242–247. 22 Ng KS, Stewart P, Gladman MA. Uncommon site for a common lesion. ANZ J Surg. 2013;83:88–89. 23 Yoshikawa Y, Takahata Y, Ichimiya M, Hamamoto Y, Muto M. A case of multiple unilateral localized basal cell carcinomas. J Dermatol. 2005;32:66–88. 24 Bang KM, Halder RM, White JE, Sampson CC, Wilson J. Skin cancer in black Americans: A review of 126 cases. J Natl Med Assoc. 1987;79:51–58. 25 Halder RM, Bang KM. Skin cancer in Blacks in the United States. Dermatol Clin. 1988;6:397–405.

30 Cohen PR, Schulze KE, Nelson, BR. Basal cell carcinoma with mixed histology: A possible pathogenesis for recurrent skin cancer. Dermatol Surg. 2006;32:542–551. 31 Garcin JA, Cohen PR, Herzberg AJ, Wallis ME, Rapini RP. Pleomorphic basal cell carcinoma. J Am Acad Dermatol. 1995;32:740– 746. 32 Tschen JP, Cohen PR, Schulze KE, Tschen JA, Nelson BR. Pleomorphic basal cell carcinoma: Case reports and review. South Med J. 2006;99:296–302. 33 LeSueur BW, DiCaudo DJ, Connolly SM. Axillary basal cell carcinoma. Dermatol Surg. 2003;29:1105–1108. 34 Susong CR, Ratz JL. Basal-cell carcinoma in an axilla: A case presentation and a review of factors related to tumor development. J Dermatol Surg Oncol. 1985;11:526–530. 35 Heckmann M, Zogelmeier F, Konz B. Frequency of facial basal cell carcinoma does not correlate with site-specific UV exposure. Arch Dermatol. 2002;138:1494–1497. 36 Strickland PT, Creasia D, Kripke ML. Enhancement of two-stage skin carcinogenesis by exposure of distant skin to UV radiation. J Natl Cancer Inst. 1985;74:1129–1134.

26 Cohen PR, Tschen JA. Fibroepithelioma of Pinkus presenting as a sessile thigh nodule. SKINmed. 2003;2:385–387.

37 Lin C-T, Chen S-G, Chen T-M, Chang S-C. Axillary basal cell carcinoma: Case report and literature review. Acta Dermatovenerol Croat. 2011;19:107–109.

27 Betti R, Crosti C, Moneghini L, Crespi E, Menni S. Axillary basal cell carcinoma: Additional 25 patients and considerations. J Eur Acad Dermatol Venereol. 2011;25:858–860.

38 Gibson GE, Ahmed I. Perianal and genital basal cell carcinoma: A clinicopathologic review of 51 cases. J Am Acad Dermatol. 2001;45:68–71.

VINTAGE LABEL

Courtesy of BuyEnlarge, Philadelphia, PA SKINmed. 2018;16:105–110

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SELF ASSESSMENT EXAMINATION W. Clark Lambert, MD, PhD Instructions: For each numbered question, choose the one most appropriate lettered response. 1 a b c d e f g

2 a b c d e f

Genodermatoses that predispose a patient to development of basal cell carcinoma include: Basal cell nevus syndrome (Gorlin syndrome). Bazex syndrome. Epidermolysis bullosa simplex, Dowling-Meara subtype. Oculocutaneous albinism. Rombo syndrome. Xeroderma pigmentosum. Each of the above genodermatoses predisposes a patient to development of basal cell carcinoma. Known risk factors for development of basal cell carcinoma include environmental exposure to: Arsenic. Coal tar. Ionizing radiation. Paraffin. Tanning bed radiation. Each of the above is known to predispose a patient to development of basal cell carcinoma.

b Ultraviolet B radiation exposure at the site where the basal cell carcinoma develops. c Ultraviolet radiation exposure at a site distant from where the basal cell carcinoma develops. d Disturbance of cell–extracellular matrix interactions at the site where the basal cell carcinoma develops. e All of the above. 4 a b c d e

5 a b c d e

Known and/or postulated risk factors for/causes of basal cell carcinomas include: Reduced skin tension. Reduced skin thickness. Concave shape of the skin. Presence of marked skin folds. All of the above. Fibroepithelioma of Pinkus is considered to be a variant of: Basal cell carcinoma. Merkel cell carcinoma. Pyogenic granuloma. Squamous cell carcinoma. None of the above.

ANSWERS TO EXAMINATION: 1. g; 2. f; 3. e; 4. e; 5. a.

Known and/or postulated risk factors for/causes of basal cell carcinomas include: a Ultraviolet A radiation exposure at the site where the basal cell carcinoma develops.

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From the Department of Dermatopathology, Department of Dermatology, and Department of Pathology and Laboratory Medicine, 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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March/April 2018

Volume 16 • Issue 2

CORE CURRICULUM Virendra N. Sehgal, MD, FNASc, FAMS, Section Editor

Techniques for Optimizing Surgical Scars, Part 3: Erythema, Hyperpigmentation, and Hypopigmentation Kathryn Potter, MD;1 Sailesh Konda, MD;1,2 Vicky Zhen Ren, MD;3 Apphia Lihan Wang, MD;4 Aditya Srinivasan, MS;5 Suneel Chilukuri, MD6

Surgical management of benign or malignant cutaneous tumors may result in noticeable scars that are of great concern to patients, regardless of sex, age, or ethnicity. Techniques to optimize surgical scars are discussed in this three-part review. Part 3 focuses on scar revision for erythema, hyperpigmentation, and hypopigmentation. Scar revision options for erythematous scars include moist exposed burn ointment (MEBO), onion extract, silicone, methyl aminolevulinate-photodynamic therapy (MAL-PDT), pulsed dye laser, intense pulsed light (IPL), and nonablative fractional lasers. Hyperpigmented scars may be treated with tyrosinase inhibitors, IPL, and nonablative fractional lasers. Hypopigmented scars may be treated with needle dermabrasion, medical tattoos, autologous cell transplantation, prostaglandin analogues, retinoids, calcineurin inhibitors, excimer laser, and nonablative fractional lasers. (SKINmed. 2018;16:113–117)

his review examines the scar revision outcomes for each technique, discusses potential adverse effects, and highlights the importance of further studies to optimize postsurgical scar revision. ERYTHEMA

MEBO MEBO is a patented formulation containing six different herbal extract with β-sitosterol as the active ingredient, with a vehicle of beeswax and sesame oil.1 MEBO has been shown to significantly improve the appearance of surgical and traumatic scars, with less hyperemia and less postinflammatory hyperpigmentation, along with faster healing. It has been hypothesized that MEBO promotes faster maturation of regenerating keratinocytes.2 The downside of MEBO includes potential dermal hypersensitivity, strong odor, and its greasy formulation.3

Onion extract Onion extract has been shown to decreased erythema when compared to controls. Three studies found a decrease in erythema with application of onion extract gel, while one study failed to find any significant difference when compared to placebo.4–7 An in-depth discussion of the studies can be found in the section on hypertrophic scars and keloids.8

Silicone Silicone gel sheeting reduces erythema and improves pigmentation of surgical scars through increasing hydration and occlusion of wounds. Collagen deposition, extracellular matrix production, hyperemia, and capillary activity are also decreased, improving scar cosmesis.2,9 Activity of mast cells and interleukin-1 levels are decreased with silicone use.9 Silicone gel sheeting can be impractical for larger areas, mobile areas over joints, or exposed areas such

From the Department of Dermatology, University of Florida College of Medicine, Gainesville, FL;1 the Department of Dermatology, Loma Linda University Medical Center, Loma Linda, CA;2 the Department of Dermatology, Baylor College of Medicine, Houston, TX;3 the Department of Dermatology, University of Alabama at Birmingham School of Medicine, Birmingham, AL;4 McGovern Medical School, Houston, TX;5 and Refresh Dermatology, Houston, TX6 Address for Correspondence: Suneel Chilukuri, MD, Refresh Dermatology, 4914 Bissonnet Street, #100A, Houston, TX 77401 • Email: dermsurg@gmail.com

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as the face, although adhesives and tapes can be used to secure silicone gel sheets over larger or mobile areas. Silicone gel sheets are reusable after washing. An alternative to silicone gel sheeting is topical silicone gel, which forms a protective layer over the scar.3

erythema, and hardness.14 IPL can be used to treat skin photoaging such as telangiectasias, fine wrinkles, and pigmentation. No current studies directly investigate the effects of IPL on postsurgical erythema in scars.

Topical MAL-PDT

Nonablative fractional lasers

Topical MAL-PDT over a period of 5 months has been shown not only to decrease erythema, but also to reduce size of a keloid scar refractory to silicone gel sheets, topical steroids, steroid injections, and surgical excision.10 There was a decrease in erythema at the scar margin and overall improvement in the color of the scar, which had a better match to surrounding skin. Further studies are needed with MAL-PDT to determine its efficacy in treating erythema associated with keloids and hypertrophic scars.

Two female patients (Fitzpatrick skin types II and IV) with atrophic acne scarring of their cheeks and postinflammatory erythema present for longer than 1 year were treated with a 1550-nm fractional photothermolysis laser with five or six treatments at 2- to 4-week intervals. Both patients had moderate to marked improvement in atrophic acne scarring and a continued improvement in erythema. The authors postulate that the 1550-nm wavelength may lead to photothermal microvascular destruction of dermal vasculature, resulting in improved erythema. Additionally, microthermal treatment zones in the dermis may result in frequent, random hits to dermal blood vessels.15 Side effects are as described in the section on atrophic scarring.16

Pulsed dye laser Pulsed dye laser selectively destroys blood vessels and impairs microcirculation surrounding the scar, leading to decreased transforming growth factor-beta and impaired proliferation of fibroblasts, which results in scar reduction. Marked reduction of postsurgical erythema and telangiectasias has been shown in one to three sessions spaced 6 to 8 weeks apart. Side effects of pulsed dye laser are minimal, the most common being postoperative purpura that can last up to a week, and edema, which usually resolves in 2 days.11 It is advisable to start treatment with the lowest effective energy density and increase the parameters only if results are inadequate. A stronger than needed fluence may result in oozing, crusting, or scarring of the treated region.11 Subsequent treatment must be delayed until the skin completely heals.

HYPERPIGMENTATION

Tyrosinase inhibitors Topical treatment of postsurgical hyperpigmentation can be challenging. Most of the research on the topical treatment of hyperpigmentation has focused on melasma, and this may be extrapolated to the treatment of postsurgical hyperpigmentation. Tyrosinase, the primary regulatory enzyme in the melanin production pathway, converts dopa to melanin and has become a primary target in the treatment of hyperpigmentation.

IPL produces infrared wavelengths from a full-spectrum broadband light that penetrates and heats deep skin. The efficacy of IPL is mild, while having advantages of low cost and short downtime.12 Polychromatic light with wavelengths of 490 nm to 950 nm is delivered with variable pulse durations and shows selected light absorption with minimal damage to surrounding tissue.13 Glass filters with 515- and 550-nm wavelengths can be applied to target erythematous scars.

Hydroquinone, a topical form of phenol, is a commonly used tyrosinase inhibitor and despite being banned over the counter in 2006 by the Food and Drug Administration because of carcinogenic concerns, it is now classified as a safe agent when used topically.17 There were previous concerns that hydroquinone could be a carcinogen, given that benzene exposure can result in aplastic anemia and leukemia in humans; however, there have been no reports of topical hydroquinone in association with bone marrow toxicity.18 Common acute adverse effects include allergic and irritant contact dermatitis, while chronic adverse effects are more concerning and include ochronosis and nail discoloration.

Successful treatment of inflamed, hypertrophic, and keloidal scars was reported in three patients treated with IPL.13 Additionally, IPL treatments administered at 2- to 4-week intervals were used to treat 109 patients with hypertrophic scars, requiring an average of eight treatments. A majority of the patients (92.5%) showed an improvement in the appearance of scars and reductions in height,

Recently, a study evaluated the efficacy of four tyrosinase inhibitors: hydroquinone, arbutin, kojic acid, and 4-n-butylresorcinol. Topical 4-n-butylresorcinol was proven to be the most efficacious when compared to the other three topical treatments. The other tyrosinase inhibitors in order of decreasing potency were kojic acid, arbutin, and hydroquinone.19 Fifty-two Indian patients with

IPL

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melasma were also treated with 4-n-butylresorcinol 0.3% cream, with a significant decrease in modified Melasma Area Severity Index scores after week 4 and at week 8. While patients in this study did not report any adverse events, there have been rare reports of allergic and irritant contact dermatitis after topical treatment with tyrosinase inhibitors.20

IPL In addition to reducing scar erythema, IPL can be useful in improving scar hyperpigmentation. IPL has been used in the treatment of various skin conditions including Mongolian spots, melasma, and solar lentigines. IPL was used to treat seven patients with aberrant Mongolian spots, and an obvious decrease in the number of melanocytes in the upper and middle dermis was found at 6 months.21 A pilot study to examine the efficacy of IPL in the treatment of burn scar dyschromias included 20 patients. IPL treatments were performed at fluences between 10 and 22 J/cm2 with filters ranging from 560 to 650 nm. Sixteen patients noted mild to moderate improvement, and side effects included pain, hyperpigmentation, and blistering.22 Additionally, modified Kligman cream (hydroquinone, vitamin C, tretinoin, and triamcinolone) with and without IPL was compared in the treatment of post-burn hyperpigmentation. The group treated with modified Kligman cream and IPL had better efficacy and a faster response.23 Further studies are necessary to examine the efficacy of IPL in the treatment of postsurgical hyperpigmentation.

Nonablative fractional lasers Bach and colleagues used a 1550-nm fractional nonablative laser to treat a hyperpigmented burn scar on the arm of a 22-yearold woman (Fitzpatrick skin type IV). After the patient had undergone one test spot treatment and three full treatments at low fluences (13 to 15 mJ), she noticed a marked reduction in hyperpigmentation with no recurrence at her 1-year follow-up. The authors postulate that the decrease in hyperpigmentation is mediated via a “melanin shuttle” mechanism whereby thermally damaged dermal and epidermal components, including melanin, are expelled through the epidermis.24 Nonablative fractional laser may be a viable treatment option in patients that fail to respond to conventional treatments. Until further data become available, it may be best to avoid ablative and fractional ablative lasers in the treatment of postsurgical hyperpigmentation as these treatment modalities may cause additional hyperpigmentation as an adverse effect. Side effects are as described in the previous section under atrophic scarring.16 SKINmed. 2018;16:113–117

HYPOPIGMENTATION

Needle dermabrasion A randomized control trial was conducted to assess the efficacy of needle dermabrasion combined with UVA to correct hypopigmented scarring on the head and neck regions. Twenty patients were randomized to receive treatment with UVA light with or without needle dermabrasion. After 7 months, the needle dermabrasion group showed a significant improvement in the subjective evaluation of their scars, and scar melanin content increased to resemble surrounding skin. The investigators hypothesized that direct injury to the epidermis and dermis combined with UVA exposure stimulated postinflammatory hyperpigmentation. Needle dermabrasion, also known as dry needling or dry tattooing (tattooing without ink), combined with UV light exposure provides a good alternative for treating hypopigmented scars.25

Medical tattoos Dermatography, also termed medical tattooing, employs a microsurgical needle to ink skin-colored tattoos on hypopigmented scars to achieve more uniform pigmentation.26 A retrospective review of 32 depigmented or hairless scars treated with a permanent makeup device system did not show any adverse events. Patients were followed for an average of 14 months and were generally satisfied, with 31% of cases needing a retouch procedure. Even though the pigments used in medical tattoos differ from those used in decorative tattoos, there are still documented adverse effects to medical tattoos, including allergic dermatitis and granulomatous reactions. Additionally, tattooing a scar can be less predictable than tattooing nonscarred areas.27 The use of medical tattooing is gradually gaining traction.

Autologous cell transplantation Recently, autologous cell transplantation has been investigated as a means of repigmenting hypopigmented burn scars. Autologous cell transplantation was originally employed to assist with reepithelization after burn injuries; however, repigmentation was also noted within treated areas. During autologous cell transplantation, a donor split-thickness skin sample with a thickness of 0.2 mm is harvested with a dermatome, and digested with trypsin to release skin cells from the extracellular matrix. After rinsing with a buffer solution, the cells are mechanically removed and the resulting noncultured autologous skin cell suspension is sprayed on the desired treatment area.27 The cells harvested from the dermal-epidermal junction, including keratinocytes and melanocytes, provide rapid would healing and pigmentation.

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Twenty patients with scars from deep second- and third-degree burns were treated with medical needling followed by application of noncultured autologous skin cell suspension; they found improvement in 17 patients, and statistically significant increases in melanin at 1-year follow-up. Alternatively, wound preparation can also be accomplished with ablative lasers or dermabrasion.28 A 35-year-old woman with hypopigmentation secondary to a facial chemical peel was treated with erbium laser resurfacing followed by NCASCS, and up to 90% repigmentation at 3 months was noted on her forehead and right cheek, with sustained results at 7 months.29

Prostaglandin analogues, retinoids, and calcineurin inhibitors Topical bimatoprost, a prostaglandin analogue typically used to decrease intraocular pressure, has been found to induce growth of eyelashes and a dose-dependent periorbital cutaneous hyperpigmentation as side effects of treating glaucoma. This bimatoprost-induced hyperpigmentation may be secondary to increased melanogenesis and increased transfer of melanosomes to keratinocytes. A study evaluated the efficacy of combining fractional laser resurfacing with topical bimatoprost and topical tretinion or pimecrolimus for the treatment of hypopigmented scars. Hypopigmented scars in 14 patients (Fitzpatrick skin types II to IV) were treated with a nonablative fractionated 1550-nm erbium-doped laser followed by treatment with topical bimatoprost 0.03% twice daily for at least 3 months, and either topical tretinion or pimecrolimus as tolerated. Patients were evaluated 4 weeks after the last treatment; five patients had greater than 75% improvement in hypopigmentation, and 12 had greater than 50% improvement. Side effects were a transient posttreatment erythema and edema, and prolonged results were evident at a mean follow-up of 20.1 months.30

Excimer laser The 308-nm excimer laser has a wavelength close to traditional narrow-band UVB light, and is effective in the treatment of psoriasis, vitiligo, and hypopigmented scars. Thirty-one patients with hypopigmented scars or striae albae were randomized to receive or not receive treatment with the 308-nm excimer laser, with site-matched normal control areas. Treatments were performed biweekly until 50% to 75% repigmentation was seen; this was followed by treatments every 2 weeks until a maximum of 10 treatments, a 75% increase in colorimetric measurements, or 100% visual pigment correction had been reached. Mean percentage pigment correction by calorimetric measurements and visual asSKINmed. 2018;16:113–117

sessment relative to controls were achieved after nine treatments; however, these values gradually declined over the 6-month followup.31 Another study evaluated the effectiveness of the 308-nm excimer laser in the treatment of hypopigmented striae in 75 patients receiving an average of 8.4 treatments, and found an improvement in the cosmetic appearance of striae in 80% of patients.32 Advantages include treatment of localized disease by a smaller headpiece, thereby avoiding large areas exposed to narrow-band UVB, and fast repigmentation with treatments two or three times per week. Drawbacks include only transient repigmentation, which may subside after completing treatment.

Nonablative fractional lasers Nonablative fractional lasers have been shown to be effective in improving hypopigmented scars while maintaining the epidermal barrier.33,34 Seven patients (Fitzpatrick skin types I to IV) with hypopigmented scars secondary to acne were treated with 1550-nm nonablative fractional resurfacing with two to four treatments at 4-week intervals. Improvements of 51% to 75% in hypopigmentation were seen in six of seven patients, and the results lasted longer than 3 months.34 Pham and colleagues also conducted a prospective study with 13 patients (Fitzpatrick skin types I to III) with facial scars present for at least 6 months postoperatively. These scars, many of which were hypopigmented, were treated once every 4 weeks for a total of four treatments, and patients noted a statistically significant improvement in the skin color match.33 Side effects were as described in the section under atrophic scarring. CONCLUSIONS Many options are available to improve the cosmesis of postsurgical scars. Although the treatment options discussed in this threepart review are categorized based on scar characteristics, many of these treatments can be combined to treat each patient’s unique scar. For example, a patient may have a scar characterized by both erythema and atrophy, and the physician may consider treating both characteristics with different treatment modalities to optimize scar improvement. Before initiating treatment, the physician should outline a therapeutic plan depending on the scar type, patient’s skin type, and eventual outcome desired by the patient. Reasonable expectations regarding cost, time, and ultimate outcome should be discussed with the patient to maximize patient satisfaction with their postsurgical scar. REFERENCES

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1 Chanprapaph K, Tanrattanakorn S, Wattanakrai P, Wongkitisophon P, Vachiramon V. Effectiveness of onion extract gel on surgical scars in Asians. Dermatol Res Pract. 2012;2012:212945.

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2 Liu A, Moy RL, Ozog DM. Current methods employed in the prevention and minimization of surgical scars. Dermatol Surg. 2011;37:1740–1746. 3 Mustoe TA. Evolution of silicone therapy and mechanism of action in scar management. Aesthetic Plast Surg. 2008;32:82– 92. 4 Perez OA, Viera MH, Patel JK, et al. A comparative study evaluating the tolerability and efficacy of two topical therapies for the treatment of keloids and hypertrophic scars. J Drugs Dermatol. 2010;9:514–518. 5 Campanati A, Savelli A, Sandroni L, et al. Effect of allium cepa-allantoin-pentaglycan gel on skin hypertrophic scars: Clinical and video-capillaroscopic results of an open-label, controlled, nonrandomized clinical trial. Dermatol Surg. 2010;36:1439–1444.

pigmentation. J Eur Acad Dermatol Venereol. 2013;27(suppl 1):19–23. 20 Madan Mohan NT, Gowda A, Jaiswal AK, et al. Assessment of efficacy, safety, and tolerability of 4-n-butylresorcinol 0.3% cream: An Indian multicentric study on melasma. Clin Cosmet Investig Dermatol. 2016;9:21–27. 21 Shirakawa M, Ozawa T, Tateishi C, et al. Intense pulsed light therapy for aberrant Mongolian spots. Osaka City Med J. 2012;58:59–65. 22 Hultman CS, Friedstat JS, Edkins RE. Efficacy of intense pulsed light for the treatment of burn scar dyschromias: A pilot study to assess patient satisfaction, safety, and willingness to pay. Ann Plast Surg. 2015;74(suppl 4):S204–S208.

6 Draelos ZD, Baumann L, Fleischer AB, Jr, et al. A new proprietary onion extract gel improves the appearance of new scars: A randomized, controlled, blinded-investigator study. J Clin Aesthet Dermatol. 2012;5:18–24.

23 Siadat AH, Iraji F, Bahrami R, et al. The comparison between modified kligman formulation versus kligman formulation and intense pulsed light in the treatment of the post-burn hyperpigmentation. Adv Biomed Res. 2016;5:125-9175.186997.eCollection 2016.

7 Chung VQ, Kelley L, Marra D, Jiang SB. Onion extract gel versus petrolatum emollient on new surgical scars: Prospective doubleblinded study. Dermatol Surg. 2006;32:193–197.

24 Bach DQ, Garcia MS, Eisen DB. Hyperpigmented burn scar improved with a fractionated 1550 nm non-ablative laser. Dermatol Online J. 2012;18:12.

8 Potter K, Konda S, Ren VZ, Wang AL, Srinivasan A, Chilukuri S. Techniques for optimizing surgical scars, part 2: hypertrophic scars and keloids. Skinmed. 2017;15:451–456.

25 Brandt MG, Moore CC, Conlin AE, Stein JD, Doyle PC. A pilot randomized control trial of scar repigmentation with UV light and dry tattooing. Otolaryngol Head Neck Surg. 2008;139:769– 774.

9 Bianchi FA, Roccia F, Fiorini P, Berrone S. Use of Patient and Observer Scar Assessment Scale for evaluation of facial scars treated with self-drying silicone gel. J Craniofac Surg. 2010;21:719–723. 10 Nie Z, Bayat A, Behzad F, Rhodes LE. Positive response of a recurrent keloid scar to topical methyl aminolevulinate-photodynamic therapy. Photodermatol Photoimmunol Photomed. 2010;26:330–332. 11 Alster T, Zaulyanov L. Laser scar revision: A review. Dermatol Surg. 2007;33:131–140. 12 Wu EC, Wong BJ. Lasers and optical technologies in facial plastic surgery. Arch Facial Plast Surg. 2008;10:381–390. 13 Cartier H. Use of intense pulsed light in the treatment of scars. J Cosmet Dermatol. 2005;4:34–40. 14 Erol OO, Gurlek A, Agaoglu G, Topcuoglu E, Oz H. Treatment of hypertrophic scars and keloids using intense pulsed light (IPL). Aesthetic Plast Surg. 2008;32:902–909. 15 Glaich AS, Goldberg LH, Friedman RH, Friedman PM. Fractional photothermolysis for the treatment of postinflammatory erythema resulting from acne vulgaris. Dermatol Surg. 2007;33:842–846. 16 Konda S, Potter K, Ren VZ, Wang AL, Srinivasan A, Chilukuri S. Techniques for optimizing surgical scars, part 1: wound healing and depressed/atrophic scars. Skinmed. 2017;15:271–276. 17 U.S. Food and Drug Administration. Hydroquinone Studies Under the National Toxicology Program (NTP). http://www.fda. gov/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/CDER/ucm203112.htm. Accessed June 21, 2013. 18 Nordlund JJ, Grimes PE, Ortonne JP. The safety of hydroquinone. J Eur Acad Dermatol Venereol. 2006;20:781–787. 19 Kolbe L, Mann T, Gerwat W, et al. 4-N-butylresorcinol, a highly effective tyrosinase inhibitor for the topical treatment of hyper-

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26 Chen MA, Davidson TM. Scar management: Prevention and treatment strategies. Curr Opin Otolaryngol Head Neck Surg. 2005;13:242–247. 27 Kim EK, Chang TJ, Hong JP, Koh KS. Use of tattooing to camouflage various scars. Aesthetic Plast Surg. 2011;35:392–395. 28 Busch KH, Bender R, Walezko N, et al. Combination of medical needling and non-cultured autologous skin cell transplantation (ReNovaCell) for repigmentation of hypopigmented burn scars. Burns. 2016;42:1556–1566. 29 Goodman GJ. An automated autologous cell transplantation method for the treatment of hypopigmented scarring. Dermatol Surg. 2008;34:578–581. 30 Massaki AB, Fabi SG, Fitzpatrick R. Repigmentation of hypopigmented scars using an erbium-doped 1,550-nm fractionated laser and topical bimatoprost. Dermatol Surg. 2012;38:995– 1001. 31 Alexiades-Armenakas MR, Bernstein LJ, Friedman PM, Geronemus RG. The safety and efficacy of the 308-nm excimer laser for pigment correction of hypopigmented scars and striae alba. Arch Dermatol. 2004;140:955–960. 32 Goldberg DJ, Sarradet D, Hussain M. 308-nm Excimer laser treatment of mature hypopigmented striae. Dermatol Surg. 2003;29:596–598; discussion 598–599. 33 Pham AM, Greene RM, Woolery-Lloyd H, Kaufman J, Grunebaum LD. 1550-nm nonablative laser resurfacing for facial surgical scars. Arch Facial Plast Surg. 2011;13:203–210. 34 Glaich AS, Rahman Z, Goldberg LH, Friedman PM. Fractional resurfacing for the treatment of hypopigmented scars: A pilot study. Dermatol Surg. 2007;33:289–294; discussion 293– 294.

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March/April 2018

Volume 16 • Issue 2

PHOTO CAPSULE Snejina Vassileva, MD, PhD, Section Editor

Twenty-Nail Dystrophy: Revisited Virendra N. Sehgal, MD, FNASc, FAMS, FRAS (Lond);1 Kingshuk Chatterjee, DNB, MNAMS;2 Shalini Malhotra, DNB, MNAMS1

n 11-year-old-boy presented with asymptomatic, peculiarly dirty, rough, lackluster, brittle fingernails and toenails. The abnormalities had been noted in infancy, but only a few nails had then been involved; subsequently, the condition had spread to eventually affect all the nails. Examination of the nails revealed a lack of resilience, a deficient luster, and pitting, longitudinal ridging, roughing, and splitting. The most obvious characteristic was a muddy, grayish-white, sandblasted appearance to the nails (Figure). No other cutaneous abnormalities were found.

DISCUSSION Twenty-nail dystrophy is a well-known inflammatory disease of the nail unit with unknown etiology that occurs primarily in childhood.1,2 Its histopathology is nonspecific unless there is an associated dermatosis such as lichen planus,3 psoriasis,4 or extensive dermatitis.5 Slight nail abnormalities, evident at birth, may slowly progress over the years to cause changes in the texture of the fingernails and toenails. The nails are characterized by a dirty appearance with a rough, brittle, and distorted appearance. A few nails may show longitudinal ridging, pitting, roughening, and splitting. Nails may lose their usual luster and change to a muddy, grayish-white color, giving a sand-blasted appearance. Universally accepted treatment protocols are lacking for this chronic disorder. Invasive treatments such as injection of triamcinolone acetonide, either once into the proximal nail fold (2.5 to 10 mg/mL) or intramuscularly (0.5 to 1 mg/kg per month), and systemic medications like betamethasone, chloroquine, cyclosporine, and acitretin, have been used with variable success. Topical tazarotene and 5-flurouracil have also been used in cases associated with alopecia areata and psoriasis, without much success.6 REFERENCES 1 Sehgal VN. Twenty nail dystrophy trachyonychia: An overview. J Dermatol. 2007; 34:361–366. 2 Hazelrigg DE, Duncan WC, Jarratt M. Twenty-nail dystrophy of childhood. Arch Dermatol. 1977;113:73–75. 3 Sehgal VN, Sharma S, Khandpur S. Twenty-nail dystrophy originating from lichen planus. SKINmed. 2005;4:58–59. 4 Schissel DJ, Elston DM. Topical 5-fluorouracil treatment for psoriatic trachyonychia. Cutis. 1998;62:27–28. 5 Scher RK, Fischbein R, Ackerman AB. Twenty-nail dystrophy: A variant of lichen planus. Arch Dermatol. 1978;114:612–613. 6 Scheinfeld NS. Trachyonychia: A case report and review of manifestations, associations, and treatments. Cutis. 2003;71:299– 302.

Figure. The muddy, grayish-white, sand-blasted appearance of the affected fingernails and toenails.

From the Dermato Venereology (Skin/VD) Center, Sehgal Nursing Home, Panchwati-Delhi,1 and the Department of Dermatology, Bankura Sammilani Medical Collage, Bankura, West Bengal,2 India Address for Correspondence: Virendra N. Sehgal MD, FNASc, FAMS, FRAS (Lond), Dermato Venerology (Skin/VD) Center, Sehgal Nursing Home, A/6 Panchwati, Delhi 110 033, India • E-mail: drsehgal@ndf.vsnl.net.in or sehgalvn@yahoo.co.in

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VIGNETTES OF DERMATOLOGIC HISTORY Mark Bernhardt, MD, Section Editor

Edward Mentor Perdue (1866 to 1944) Mark Bernhardt, MD “Does it seem reasonable that we are the first ones lucky enough to be born in the perfect generation, the one in which the assumption of a comprehensive science is finally true? Or does it seem more likely that in one hundred years people will look back on us and wonder what it was like to be ignorant of what they know?”—David Eagleman, Incognito

dward Mentor Perdue was eclectic and proud of it. Eclectic medicine was a home-grown American phenomenon that embraced the herbal therapies of Native American Indians. Over time, practitioners of eclecticism adopted other treatment modalities, such as Albert Adams’ electronic therapy, but they always steadfastly opposed the means and methods of the medical establishment. Perdue was a graduate of the Eclectic Medical University, Kansas City, MO. Even then, this institute was widely derided as a diploma mill. (The Eclectic Medical Institute in Cincinnati, OH, was considered more reputable and prestigious.) Perdue completely rejected mainstream medical research in the United States: “It refuses scientific research not originating in Germany … It is committed to the tedious, abstruse, impossible German method.”1 Interestingly, in the same paragraph, Perdue berates American research because, “In animal experimentation ... it ignores the Postulates of Koch.”1 The last time I checked, Robert Koch was German. Perdue’s xenophobia sometimes took on a more racist tone, as when he denounced Dr. Joseph Goldberger, the discoverer of the true cause of pellagra, by referring to “the impossible theories of individuals with long German names.”2 The last time I checked, Goldberger was Hungarian.

The Flexner report on medical education spelled the death knell for Eclectic Medicine as a viable alternative to allopathic medicine. Unwilling to abandon their heterodox teachings and refusing to adopt the changes that Flexner proposed, Eclectic schools progressively withered away. The last bastion of Eclectic teaching, the Eclectic Medical Institute, closed its doors in 1939. QUO VADIS? I’ve been doing this too long to believe that what we now hold as absolute truths might not one day be dismissed as hollow falsehoods. I remember when keratoacanthomas were considered benign lesions unrelated to sun damage. I have seen too many conflicting recommendations regarding sun exposure and sunscreen use to believe that whatever I tell my patients today might not be obsolete in another 10 years. So I guess I should not feel too smug about the decline of eclecticism and the triumph of allopathic medicine. Who knows what the accepted face of medicine will look like in another hundred years? REFERENCES 1 Alessandrini CG. Pellagra. Kansas City, MO: Burton Publishing Co.; 1916:7. 2 Perdue EM. Pellagra. Pacific Med J. 1917; 60:276–277.

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Volume 16 • Issue 2

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

Melanoma of the Nasal Cavity Anissa Zaouak, MD;1 Houda Hammami, MD;1 Raja Jouini, MD;2 Mariem Belhaj Salah, MD;2 Achraf Debbiche, MD;2 Samy Fenniche, MD1

A 78-year-old man presented with complaints of progressive nasal blockage and epistaxis over the previous 2 months. Clinical examination revealed a nodular, polypoid, ulcerated nonpigmented tumor filling the right nasal cavity (Figure 1). A punch biopsy was taken from the mass for histopathologic examination, which revealed many melanocytes in the submucosa. The stroma contained large numbers of spindleshaped cells with hyperchromatic spindleoid nuclei (Figure 2), confirming the diagnosis of malignant melanoma. The tumor cells stained positive for melan-A (Figure 3) and HMB-45. (SKINmed. 2018;16:122–123)

he patient underwent a computed tomography scan, which revealed a soft tissue density mass in the right nasal cavity with extension to the ethmoid cavity and with intraorbital involvement. Further workup, which included computed tomography of the chest and abdomen, revealed no distant metastases. The patient was treated with radiotherapy, but 3 months later there was a reoccurrence. The patient developed lung metastases and died 6 months later. DISCUSSION

Mucosal malignant melanomas of the nose and paranasal sinuses are rare tumors, often occurring in elderly patients. They represent 2% to 9% of melanomas of the head and neck, and 3% to 4% of all nasal tumors.1 The most common site of origin within the nose is the nasal septum, followed by the inferior and middle turbinates. The melanomas usually appear as polypoid brown or black pigmented masses that are often ulcerated; however, they can also be amelanotic, as in our patient. The tumor surface can be homogenous or heterogenous, and may ulcerate; one-third of melanomas are achromic. Most mucosal melanomas occur in occult sites, which, together with early and specific signs, contributes to the late diagnosis and poor prognosis.2 The histopathology of nasal melanoma is variable. The tumor is usually formed by epithelioid, spindle, and plasmacytoid cells arranged in a sheetlike, organoid, alveolar, solid, or desmoplas-

Figure 1. Nodular, polypoid, ulcerated nonpigmented tumor filling the right nasal cavity.

tic configuration. When the tumor cells are melanin-rich, the diagnosis is not difficult;3 however, with an amelanotic lesion, the tumor may be misdiagnosed as being another neoplasm, such as a fibrosarcoma, malignant peripheral nerve sheath tumor, or spindle cell carcinoma. Immunohistochemichal stains are important to distinguish mucosal melanomas from other tumors. Confirmation of the diagnosis is based on immunohis-

From the Department of Dermatology1 and Department of Anatomopathology,2 Habib Thameur Hospital, Research Unit “Genodermatoses and Cancers” LR12SP03, Tunis, Tunisia Address for Correspondence: Anissa Zaouak, MD, 8 Street Ali Ben Ayed, Montfleury 1008, Tunis, Tunisia • E-mail: anissa_zaouak@yahoo.fr

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Figure 2. A large number of spindle-shaped cells with hyperchromatic spindleoid nuclei (hematoxylin and eosin stain, magnification ×100).

Figure 3. Tumor cells stained positive for melan-A.

tochemistry, using a panel of markers: protein S100 and melanocytic markers (HMB45, melan-A). Epithelial cell markers are negative.1,3,4 Melanoma of the nasal cavity is a rare disease with an aggressive natural history and poor long-term prognosis because the tumor tends to recur locally and develop distant metastases. Mucosal melanomas are also characterized by satellite formations and early angiolymphatic invasion, resulting in advanced locoregional stages and spread at a distance with a high mortality rate.

CONCLUSIONS The presence of a nonpigmented lesion in the nasal cavity should raise suspicion of a melanoma to facilitate early diagnosis and treatment. REFERENCES

Despite aggressive treatment, the 5-year survival rate of these patients is very low.1 Surgery remains the treatment of choice for sinonasal melanoma, although complete surgical removal is often limited by the surrounding structures, as in our patient. Early diagnosis of mucosal melanoma of the nasal cavity is an essential prognostic factor.2

1 Mendenhall WM, Amdur RJ, Hinerman RW, et al. Head and neck mucosal melanoma. Am J Clin Oncol. 2005;28:626–630. 2 Gilain L, Houette A, Montalban A, Mom T, Saroul N. Mucosal melanoma of the nasal cavity and paranasal sinuses. Eur Ann Otorhinolaryngol Head Neck Dis. 2014;131:365–369. 3 Benevenuto de Andrade BA, Piña AR, León JE, Paes de Almeida O, Altemani A. Primary nasal mucosal melanoma in Brazil: Clinicopathologic and immunohistochemical study of 12 patients. Ann Diagn Pathol. 2012;16:344–349. 4 Abe T, Ebara T, Miyaura K, et al. Malignant melanoma of the nasal cavity treated with stereotactic radiotherapy using CyberKnife: Report of 2 cases. Am J Otolaryngol. 2015;36:306–309.

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March/April 2018

Volume 16 • Issue 2

CASE STUDY

Systemic Lupus Erythematosus Presenting as Livedoid Vasculopathy over the Forearms Pravesh Yadav, MD; Taru Garg, MD; Sarita Sanke, MD; Ram Chander, MD; Divyanshu Singh, MD

A 38-year-old married woman presented with multiple spontaneous painful ulcers that had involved both forearms for the previous month, along with a single episode of generalized tonic-clonic seizures, with no residual palsy or paresis. She complained of photosensitivity and diffuse hair loss for the past 6 months. She also had had arthralgia for the previous 3 years, which had initially involved the small joints of the fingers (especially the proximal interphalangeal joints) and gradually progressed to involve the larger joints. There was no history of recurrent oral ulcers, psychosis, thromboembolic events, or any other skin lesions. Two years previously, she had taken antitubercular treatment for pulmonary tuberculosis. (SKINmed. 2018;16:125–127)

eneral physical examination was normal, except for pallor. Cutaneous examination revealed multiple punchedout ulcers ranging from 0.5 cm to 1 cm in size and in various stages of healing on both forearms. Porcelain white atrophic scars with stellate borders, mild erythema, and telangiectasia were seen at the margins (Figure 1). A biopsy from an atrophic scar showed hyalinization of blood vessels with fibroblastic proliferation, red blood cell extravasation, and plump endothelial cells, with no evidence of vasculitis or necrosis; this was suggestive of livedoid vasculopathy (LV) (Figure 2). Hematologic examination revealed a low hemoglobin (8.4 g/dL, normal 12 to 14 g/dL), a raised total leukocyte count (13200 cells/ mm3, normal 4000 to 11000 cells/mm3), and a reticulocyte count of 2%. The erythrocyte sedimentation rate was raised (100 mm in the first hour), and C-reactive protein (>6 mg/L) and rheumatoid factor were positive. On immunologic investigation (enzymelinked immunosorbent assay), antinuclear antibody was reported as 2+ (diffuse, mitosis +) and double-stranded DNA as 1+ (140 IU/ml). SS-A antibody (3+) and SS-B antibody (2+) were also positive. Complement levels were normal; however, anticardio-

lipin, antilupus anticoagulant, c- and p-antineutrophil cytoplasmic antibody, direct Coombs test, and LE cell test were negative. The coagulation profile was normal. Viral markers were negative, and a Venereal Disease Research Laboratory test was nonreactive. Liver and renal function tests were normal. Radiographs of small and large joints did not reveal any abnormality. A chest x-ray showed opacities in the right upper zone, suggestive of old healed pulmonary tuberculosis. Cerebrospinal fluid examination showed normal glucose and protein concentrations, and a total leukocyte count of 10 cells/µL, with a differential of 100% lymphocytes. Contrast-enhanced computed tomography of the head was normal. Based on these findings, a diagnosis of LV secondary to systemic lupus erythematosus (SLE) was made. The patient did not fulfill the criteria for Sjögren syndrome.1 The patient was started on oral prednisolone (50 mg) and antitubercular therapy, with a probable diagnosis of tubercular meningitis. Hydroxychloroquine (400 mg) was added in view of photosensitivity and LV lesions. The active ulcers healed within 4 weeks, associated with a fall in double-stranded DNA titers.

From the Department of Dermatology and Sexually Transmitted Diseases, Lady Hardinge Medical College and Suchita Kriplani Hospital, Shaheed Bhagat Singh Marg, Delhi, India. Address for Correspondence: Pravesh Yadav, MD, RZ-97, Phase-III, Prem Nagar, Najafgarh, New Delhi-110043, India • E-mail: rao.pravesh@gmail.com

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One month later, the patient developed multiple erythematous, discrete to coalescent plaques with coarse semiadherent scales over the face, predominantly over the malar areas, earlobes, lateral as-

pect of the neck and V-area of the neck. These were suggestive of subacute cutaneous lupus erythematosus (Figure 3). Subsequently, the patient was lost to follow-up. DISCUSSION LV usually presents as recurrent, painful, deep punched-out ulcers on the lower extremities, which heal with stellate, porcelain white scars, known as atrophie blanche. It is a cutaneous manifestation of several diseases that lead to noninflammatory thrombosis of the dermal vessels. The most common cause is chronic venous disease.2 Autoimmune connective tissue diseases causing LV include SLE, scleroderma, rheumatoid arthritis, and mixed connective tissue disease.1

Figure 1. Porcelain white atrophic scars with stellate borders and mild erythema and telangiectasia at the periphery over the forearms bilaterally. Inset: Close-up view of atrophic scar.

The exact etiology of LV remains unknown, although the disease is now widely believed to have a procoagulant pathogenesis.3 LV has been reported in SLE in association with antiphospholipid antibody syndrome, with positive anticardiolipin/antilupus anti-

Figure 2. (A) Histopathology of an atrophic scar showing hyalinization of blood vessels with fibroblastic proliferation and plump endothelial cells suggestive of livedoid vasculopathy (LV) (hematoxylin and eosin stain, magnification ×10). (B) Hyalinization of blood vessels with fibroblastic proliferation and plump endothelial cells (hematoxylin and eosin stain, magnification ×40). (C) Extravasation of red blood cells (hematoxylin and eosin stain, magnification ×40). (D) Plump endothelial cells (hematoxylin and eosin stain, magnification ×40). SKINmed. 2018;16:125–127

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CASE STUDY Various treatment options that have been successfully used for LV are colchicine, pentoxifylline, prednisolone, aspirin, antiplatelet, anticoagulant and fibrinolytic therapy, and anabolic steroids, such as danazol and stanozolol.2 Antimalarial therapy may be effective in patients with cutaneous lesions of SLE and atrophie blanche–like lesions.8 The LV lesions in our patient responded well and showed marked improvement to a combination of oral steroids and hydroxychloroquine. CONCLUSIONS The presentation in this patient indicated that nonspecific cutaneous lesions of lupus erythematosus can precede the development of systemic symptoms or specific manifestations in SLE, providing an opportunity for early diagnosis. In addition, LV on the arms is an interesting and uncommon presentation: a recent review of 70 patients reported only a single case of LV involving the forearms.8 The response to hydroxychloroquine is also noteworthy.

Figure 3. Multiple erythematous, discrete to coalescent plaques with coarse semiadherent scales over the V-area of the neck.

REFERENCES coagulant antibody.4,5 LV occurring in an SLE patient with recurrent thrombosis but negative anticardiolipin/antilupus antibody has also been reported, characterizing seronegative antiphospholipid syndrome.6 The histopathologic changes of LV depend on the age of the lesion. In the early stage, hyaline thrombus formation is present in the lumen of small vessels in the mid and papillary dermis, along with extravasation of red blood cells. Angiocentric findings, ie, infarction of the papillary dermis, is often present, associated with ulceration. Partially developed lesions show thickening and hyalinization of vessel walls in the papillary dermis, with some endothelial edema and proliferation. Dermal sclerosis and scarring with epidermal atrophy is evident in older lesions. Direct immunofluorescence usually demonstrates deposition of immunoglobulin, fibrin, and complement components on the vessel walls.2 Our patient fulfilled the Systemic Lupus International Collaborating Clinics criteria for SLE;7 however; she did not fulfill the 2010 American College of Rheumatology/European League Against Rheumatism Rheumatoid Arthritis Classification Criteria due to the lack of synovitis in any joint.

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1 Baldini C, Talarico R, Tzioufas AG, Bombardieri S. Classification criteria for Sjogren’s syndrome: A critical review. J Autoimmun. 2012;39:9–14. 2 Criado PR, Rivitti EA, Sotto MN, et al. Livedoid vasculopathy: An intringuing cutaneous disease. An Bras Dermatol. 2011;86:961–977. 3 Hairston BR, Davis MD, Pittelkow MR, Ahmed I. Livedoid vasculopathy: Further evidence for procoagulant pathogenesis. Arch Dermatol. 2006;142:1413–1418. 4 Oh YB, Jun JB, Kim CK, et al. Mixed connective tissue disease associated with skin defects of livedoid vasculitis. Clin Rheumatol. 2000;19:381–384. 5 Chen KR, Toyohara A, Suzuki A, Miyakawa S. Clinical and histopathological spectrum of cutaneous vasculitis in rheumatoid arthritis. Br J Dermatol. 2002;147:905–913. 6 Sopeña B, Pérez-Rodríguez MT, Rivera A, et al. Livedoid vasculopathy and recurrent thrombosis in a patient with lupus: Seronegative antiphospholipid syndrome? Lupus. 2010;19:1340– 1343. 7 Petri M, Orbai AM, Alarcon GS, et al. Derivation and validation of the Systemic Lupus International Collaborating Clinics classification criteria for systemic lupus erythematosus. Arthritis Rheum. 2012;64:2677–2786. 8 Gan EY, Tang MB, Tan SH, Chua SH, Tan AW. A ten-year retrospective study on livedo vasculopathy in Asian patients. Ann Acad Med Singapore. 2012;41:400–406.

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Volume 16 • Issue 2

CASE STUDY

Rituximab-Treated Pemphigus Foliaceus in a Schizophrenic Patient: A Challenging Exercise in Diagnosis, Management, and Follow-Up Nicholas A. Ross, MD;1 Miriam L. Vega, MD, MPH;1 Matthew S. Keller, MD1,2

Dermatology was consulted in the care of a 58-year-old man with a history of paranoid schizophrenia, neuroleptic malignant syndrome, a positive purified protein derivative test, and a lack of bathing for approximately 4 years who had been admitted to the hospital because of thick, crusted lesions over an increasing portion of his body. Admitted involuntarily, he was disinterested in the history, physical examination, and diagnostic testing. Comorbid schizophrenia presented a unique challenge because he was unable to participate in his care effectively. His story was told through caregivers. Although mostly compliant, the patient was reserved and indifferent, and had little to add even with direct questions. (SKINmed. 2018;16:129–131)

xamination revealed diffuse, crusted lesions with minimal visible erythema on the skin of the back, chest, left upper extremity, right upper extremity, and face. Some lesions formed shallow ulcers and superficial erosions over the chest and shoulders. The initial impression was retention hyperkeratosis, although, because of excess crusting and noncompliance with the examination, underlying primary skin disease could not be excluded. Initially, daily showers and emollients to clear the excessive crusting and scale were recommended. Four days later, the team was reconsulted by the psychiatric team because the patient stated, “the shower water burns when it touches my skin;” they added that the lesions appeared to be changing. Reexamination revealed flaccid bullae with surrounding erythema, erosions, and crusting (Figures 1 and 2). Clinically, pemphigus foliaceus was suspected. Confirmatory serologic titers of anti-desmoglein 1 and 3 were ordered. The lesions rapidly evolved to greater than 90% body surface area. Pemphigus foliaceus was diagnosed, and we prescribed oral prednisone and topical fluocinonide 0.05% ointment, both of which he rejected. Paranoid delusions caused the patient to refuse oral and topical medication, citing it as “poison.” Because he did not reject in-

travenous medications, a parenteral therapeutic course was designed. As he was at risk to being lost in follow-up, the goal was to discharge him with the fewest medications possible. Of note, collaboration with case management revealed that he could not return to his psychiatric home with continuing intravenous therapy requirements as tubes posed a safety threat. On the other hand, nearby outpatient medical/infusion centers were uncomfortable treating a patient with profound psychiatric limitations. Initially, the rheumatology team was reluctant to use intravenous immunosuppressive agents because an interferon gamma release assay returned an indeterminate result. Serology showed a negative human immunodeficiency virus enzyme-linked immunosorbent assay result, and hepatitis panel titers demonstrating immunity. During his hospital stay, the patient also had a methicillin-sensitive Staphylococcus aureus bacteremia. With a chest x-ray free of active tuberculous lesions, the patient was started on rifampin 600 mg intravenous daily for 120 days for latent tuberculosis infection treatment. The medical team treated his bacteremia with cefazolin 500 mg intravenous daily for 14 days. As this patient rejected oral prednisone, methylprednisone 60 mg every 12 hours intravenously, tapered slowly, was substi-

From the Department of Dermatology and Cutaneous Biology1 and Psoriasis Center,2 Department of Dermatology and Cutaneous Biology, Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, PA. Address for Correspondence: Matthew Keller, MD, 833 Chestnut Street, Suite 740, Philadelphia PA 19107 • E-mail: Matthew.Keller@jefferson.edu

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Figure 1. Crust, scale, and superficial erosions on the face, ear, scalp, and neck before rituximab infusion.

Figure 3. Face, ear, scalp and neck demonstrating 95% clinical resolution 11 weeks after the first rituximab infusion.

infused on day 1 and day 15 of the month. The only adverse effect was a postinfusion fever that resolved with acetaminophen. Laboratory examination showed initially elevated anti-desmoglein 1 antibodies at 880 U/mL (normal: <14 U/mL) and anti-desmoglein 3 antibodies within normal limits at 2 U/mL (normal: <9 U/mL). Within 12 days of the first (of two) rituximab infusions, the patient’s anti-desmoglein 1 antibodies had decreased to 201 U/mL, and there were early signs of clinical resolution. Trending this value, a decrease to 194 U/mL 5 weeks after infusion and to 168 U/mL 9 weeks after infusion was noted. By 11 weeks, the patient’s lesions showed 95% clinical resolution (Figures 3 and 4). This patient returned home with topical fluocinonide ointment 0.05% as needed. The patient did not present for a follow-up appointment 2 months after discharge. Telephone follow-up 6 and 8 months after treatment suggested no recurrence of the lesions.

Figure 2. Diffuse, thick, crusted lesions with flaccid bullae on the chest and abdomen before rituximab infusion.

tuted. The patient continued to reject topical fluocinonide 0.05% ointment intermittently. After 3 weeks of treatment with rifampin, the infectious disease team cleared the patient to start immunosuppressive therapy. Informed consent was obtained from his mother as the patient was determined to be without capacity. Rituximab 1000 mg was SKINmed. 2018;16:129–131

DISCUSSION The cornerstone in management of pemphigus is corticosteroids. In cases of severe disease, adjuvant immunosuppression therapy proves beneficial.1 Rituximab, a chimeric immunoglobulin G monoclonal antibody, targets premature and mature CD20 B cells.2,3 In such cases, the drug lowers circulating pathogenic an-

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CASE STUDY as a therapeutic option early in the disease course.7,8 This case demonstrate safe and effective use of high-dose rituximab early in the treatment algorithm with intravenous corticosteroids, which served particularly well in the care of this psychiatrically impaired patient who could not tolerate multiple, protracted therapeutic interventions. CONCLUSIONS For this patient, rituximab provided a rapid response and decreased the length of therapy required, thereby maximizing his quality of life as he returned to his psychiatric home without a prolonged medication regimen.9 This case provides a reasonable alternative for those unable to tolerate a standard, comprehensive regimen of oral corticosteroids and immunosuppressive therapy. REFERENCES 1 Ruocco E, Wolf R, Ruocco V, et al. Pemphigus: Associations and management guidelines: Facts and controversies. Clin Dermatol. 2013;31:382–390. 2 Balighi K, Daneshpazhooh M, Khezri S, et al. Adjuvant rituximab in the treatment of pemphigus vulgaris: A phase II clinical trial. Int J Dermatol. 2013;52:862–867.

Figure 4. Chest and abdomen demonstrating 95% clinical resolution 11 weeks after the first rituximab infusion.

3 Fatourechi MM, el-Azhary RA, Gibson LE. Rituximab: Applications in dermatology. Int J Dermatol. 2006;45:1143–1155; quiz 1155.

tibodies via action on the humoral and cell-mediated pathways. This treatment modality served the patient well in that it required a limited number of therapeutic interventions with promise of rapid clearance of widespread disease. More specifically, rituximab is useful in decreasing the steroid dose and length of treatment required.2,4 In addition, it served the role of an immunosuppressant required in a comprehensive treatment regimen for widespread disease, while circumventing our patient’s intolerance of oral immunosuppressant medications such as azathioprine, mycofenolate mofetil, or cyclophosphamide. Importantly, years of research in fields such as rheumatology and oncology have demonstrated its apparent safety in patients with latent tuberculous infection.5,6 Case reports and series in the literature have suggested the utility of rituximab in severe, recalcitrant pemphigus.4 It is now increasingly accepted for treatment of less severe disease, and even

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4 Kolesnik M, Becker E, Reinhold D, et al. Treatment of severe autoimmune blistering skin diseases with combination of protein A immunoadsorption and rituximab: A protocol without initial high dose or pulse steroid medication. J Eur Acad Dermatol Venereol. 2014;28:771–780. 5 Pehlivan Y, Kisacik B, Bosnak VK, Onat AM. Rituximab seems to be a safer alternative in patients with active rheumatoid arthritis with tuberculosis. BMJ Case Rep. 2013;Jan 21;2013. 6 Buch MH, Smolen JS, Betteridge N, et al. Updated consensus statement on the use of rituximab in patients with rheumatoid arthritis. Ann Rheum Dis. 2011;70:909–920. 7 Cho HH, Jin SP, Chung JH. Clinical experiences of different dosing schedules of rituximab in pemphigus with various disease severities. J Eur Acad Dermatol Venereol. 2014;28:186–191. 8 Lunardon L, Tsai KJ, Propert KJ, et al. Adjuvant rituximab therapy of pemphigus: A single-center experience with 31 patients. Arch Dermatol. 2012;148:1031–1036. 9 Paradisi A, Cianchini G, Lupi F, et al. Quality of life in patients with pemphigus receiving adjuvant therapy. Clin Exp Dermatol. 2012;37:626–630.

Rituximab-Treated Pemphigus Foliaceus

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March/April 2018

Volume 16 • Issue 2

CASE STUDY

Zosteriform Lichen Planus Pigmentosus Altering Segmental Vitiligo Gitesh U. Sawatkar, MD; Muthu Sendhil Kumaran, MD; Tarun Narang, MD; Davinder Parsad, MD

A 22-year-old student presented with a 3-year history of hyperpigmented, minimally pruritic skin lesions over his trunk. They had begun as small discrete macules over the left side of the trunk, with some coalescing to form patches. He had had right-sided segmental vitiligo (SV) for the previous 7 to 8 years (Figure 1A), and this had started to cross the midline, covering a margin over the left side of the chest and back. This coincided with the onset and spread of the hyperpigmented patches. He denied any history of drug intake, or history of inflammatory dermatoses at either the vitiliginous or the hyperpigmented sites. (SKINmed. 2018;16:133–135)

linical examination revealed slate-blue to brownish-colored macules and patches, distributed in a zosteriform pattern over the left side of the chest and back (Figure 1B). Depigmented patches were present over the upper right portion of the trunk and back, spreading from the midline to the left side. Histopathology of the hyperpigmented macules revealed vacuolar degeneration of the basal cell layer, apoptotic keratinocytes, and basket-weave hyperkeratosis in the epidermis, in addition to melanin incontinence with a bandlike lymphocytic infiltrate in the dermis, characteristic for lichen planus pigmentosus (LPP) (Figure 2). Based on these findings, a diagnosis of zosteriform LPP was made, which changed the diagnosis of SV to mixed vitiligo. DISCUSSION

LPP is a disease of skin phototype IV, commonly seen in the third to fifth decades of life,1 with an equal sex incidence. Although its pathogenesis is still unclear, several provoking factors, such as mustard oil, gold, hepatitis C virus, or relapse of the nephrotic syndrome, have been incriminated.1 LPP may present in a linear pattern2 along the lines of Blaschko,3 with superficial veins observed4 and involvement of the intertriginous areas.5 To the best of our knowledge, there is only one report of LPP presenting in a zosteri-

form pattern over the left flank;6 however, our patient had zosteriform LPP over the left side of the back and chest. In cutaneous mosaicism, neural and autoinflammatory factors play an important role, and they may not follow Blaschko lines.7 As the pattern is determined by cell migration, it depends on the stage of development at which the mosaicism arises, and also on the cell type affected. This explains the phylloid pattern of vitiligo seen in many pigmentary conditions, as in our case. Additionally, Happle has suggested that mixed vitiligo might represent a superimposed form of segmental mosaicism.8 SV is considered to be different from vitiligo vulgaris in several respects: it predominantly affects younger patients; it stabilizes early in a limited quasi-dermatomal distribution indicating involvement of neural/developmental mechanisms; and it is relatively resistant to medical treatments. The autoimmune hypothesis, largely accepted for generalized vitiligo, is not considered to be pertinent in SV; however, bilateral/plurisegmental lesions of SV, mirror image/sharply segmented lesions in generalized vitiligo, and the recent discovery of “mixed vitiligo” cases all suggest that mosaicism may be a common factor in both. Some studies have also demonstrated lichenoid infiltrates in both SV and generalized vitiligo. Long-standing vitiligo has been hypothesized to al-

From the Department of Dermatology, Venereology and Leprology, Postgraduate Institute of Medical Education and Research, Chandigarh, India Address for Correspondence: Muthu Sendhil Kumaran, MD, Department of Dermatology, Venereology and Leprology, Postgraduate Institute of Medical Education and Research, Sector 12, Chandigarh 160012, India • E-mail: drsen_2000@yahoo.com

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Figure 2. Skin biopsy showing vacuolar degeneration of basal layer, melanin incontinence with lymphocytic infiltrate (H and E Ă&#x2014;10).

ter the exposure of antigens identified by the effector T cells of lichen planus, or to inactivate the suppressor mechanisms responsible for lichen planus.9 Long-standing SV would have produced similar changes in our patient, leading to the onset of LPP. LPP subsequently might have caused cell damage in the surrounding skin, thus inciting an immune reaction and eventually leading to reduced amounts of melanin. This might be one of the causes that changes the course of SV to mixed vitiligo.10 A biopsy from the vitiliginous area was planned, but the patient declined any further intervention and was lost to follow-up.

Figure 1. (A) Well-defined, depigmented patches with an irregular border present over the right side of chest and lower trunk, crossing the midline (red arrows). (B) Slate blue to brownish confluent macules presenting in a zosteriform pattern over the left side of upper back and left side of upper chest (yellow arrows). SKINmed. 2018;16:133â&#x20AC;&#x201C;135

Association of SV with dermatoses such as segmental lichen planus, linear scleroderma, lichen sclerosus, and psoriasis has been reported.11 To the best of our knowledge, there has been no report of zosteriform LPP coexisting with SV with the onset of LPP changing its course. An interrelation between immunity and mosaicism could be the triggering mechanism. CONCLUSIONS Cutaneous mosaicism, in the form of fragile melanocytes susceptible to external and/or autoinflammatory mechanisms, is an

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attractive hypothesis to pursue in relation to the causation and spread of vitiligo. SV and zosteriform LPP coexisting and altering each other’s course is a rare occurrence. This interesting phenomenon should be investigated further to unravel the mysteries of mosaicism and pigmentary disorders. REFERENCES 1 Sehgal VN, Verma P, Bhattacharya SN, Sharma S, Rasool F. Lichen planus pigmentosus. SKINmed. 2013;11:96–103. 2 Seo JK, Lee HJ, Lee D, Choi JH, Sung H-S. A case of linear lichen planus pigmentosus. Ann Dermatol. 2010;22:323–325. 3 Akarsu S, Ilknur T, Özer E, Fetil E. Lichen planus pigmentosus distributed along the lines of Blaschko. Int J Dermatol. 2013;52:253–254. 4 Zhang RZ, Zhu WY. Lichen planus pigmentosus over superficial leg veins. J Dtsch Dermatol Ges. 2011;9:540–541.

5 Gaertner E, Elstein W. Lichen planus pigmentosus-inversus: Case report and review of an unusual entity. Dermatol Online J. 2012;18:11. 6 Cho S, Whang KK. Lichen planus pigmentosus presenting in zosteriform pattern. J Dermatol. 1997;24:193–197. 7 van Geel N, Speeckaert R, Melsens E, et al. The distribution pattern of segmental vitiligo: Clues for somatic mosaicism. Br J Dermatol. 2013; 168:56–64. 8 Happle R. Superimposed segmental manifestation of polygenic skin disorders. J Am Acad Dermatol. 2007; 57:690–699. 9 Anstey A, Marks R. Colocalization of lichen planus and vitiligo. Br J Dermatol. 1993;128:103–104. 10 Baghestani S, Moosavi A, Eftekhari T. Familial colocalization of lichen planus and vitiligo on sun exposed areas. Ann Dermatol. 2013;25:223–225. 11 van Geel N, Mollet I, Brochez L, et al. New insights in segmental vitiligo: Case report and review of theories. Br J Dermatol. 2012;166:240–246.

“Pemphigus vulgaris”, Moulage No. 25, made in the Clinic for Dermatology Zurich. Museum of Wax Moulages Zurich, www.moulagen.ch Courtesy of Michael Geiges, MD SKINmed. 2018;16:133–135

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March/April 2018

Volume 16 • Issue 2

CORRESPONDENCE Snejina Vassileva, MD, PhD, Section Editor

Central Upper Lip Reconstruction Using Combined Advancement Flaps of Skin and Mucosa Eugénia Matos-Pires, MD; Cândida Fernandes, MD; Alexandre João, MD; Rodrigo Carvalho, MD To the Editor: The lips are crucial for facial appearance, facial expression, language, and deglutition; therefore, the principles of an ideal upper lip reconstruction should involve repair of all the subunits to maintain the cosmetic integrity and functions of the lip.1 To repair all the lip subunits, complex cross-lip reconstructive procedures (including the cheek advancement flap, the Abbe flap, and myocutaneous rotation) requiring a second-stage procedure, with risk of facial asymmetry, have been reported for many years and continue to be widely used.1 Basal cell carcinoma is uncommon.2 We report here, in two patients, a single-stage method that allowed efficacious reconstruction of a central upper lip defect (skin and mucosa) after radical excision of a basal cell carcinoma, with good functional and esthetic results (Table). Preoperatively, the clinical extent of the tumor and the 4-mm security margins of healthy tissue, as well as the vermilion border, were marked using a surgical pen (Figure 1). The tumor was removed using a single-stage classic surgery under local anesthesia (2% lidocaine with adrenaline 1:80,000). A combined defect of the skin and mucosa, including no more than one-third of the lip length, with preservation of the adjacent orbicularis oris muscle, was obtained (Figure 2). We designed an A-to-T advancement flap on the skin, to be advanced along with the inner mucosa of the upper lip. The secondary defect created by the A-to-T advancement flap runs perpendicularly and hides the skin defect (Figure 3). The inner mucosa of the vermilion border was undermined at the submu-

cosal level, creating an advancement flap on the mucosa (Figure 3). The skin and mucosal flap edges were brought together to create a new skin-vermilion border. The flap wedges were sutured in place, along with the original skin-vermilion border edges (previously marked), using a simple suture with 5.0 nylon, which was removed 7 days after surgery. Closure of the defect was achieved using a simple single-stage procedure, with no immediate complications (Figure 4). Histopathologic examination confirmed complete excision of the basal cell carcinoma. The 12-month follow-up demonstrated that the function and esthetic appearance of the lip had been preserved, without tumor relapse (Figure 5). Complete surgical excision is the treatment of choice for basal cell carcinoma of the lip.3 The closure of defects that involve various cosmetic subunits still, however, presents a challenge for dermatologic surgeons. CONCLUSIONS In the reported cases, the defects were less than one-third of the lip length, and part of the orbicularis orbis muscle was preserved; thus, we were able to avoid the use of complex techniques. We decided to combine two techniques to repair each cosmetic subunit (vermilion lip and skin). We based the techniques on the principle that advancement of Ato-T flaps is used when there is a higher degree of laxity along the minor axis defect, or when distortion of structures adjacent to the boundary of the defect is undesirable.4 Vermilion advancements are based on the arterial supply of the lip, and therefore are useful for central defects, typically healing well.2 We adapted the versatil-

From the Department of Dermatology and Venereology, Centro Hospitalar de Lisboa Central, Lisbon, Portugal. Address for Correspondence: Eugénia Matos-Pires, MD, Alameda de Santo António dos Capuchos, 1620 – 050 Lisboa, Portugal • E-mail: eugeniampp@gmail.com

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Table. Central Upper Lip Reconstruction with Combined Advance Flaps of the Skin and Mucosa Was Successfully Used in Two Patients with Basal Cell Carcinoma (BCC) of Central Upper Lip Patient

Sex

Age

Pathology

Location

Defect

Follow-up

Female

BCC

Upper lip (center)

1 cm

12 months

Male

BCC

Upper lip (center)

1 cm

12 months

Figure 1. Preoperative view of the tumor. The safety margins of 4 mm were drawn with a surgical pen.

Figure 3. Schematic representation of the surgical technique. Skin and mucosal flap wedges were brought together to create a new vermilion border.

Figure 2. Surgical defect of skin and mucosa after tumor removal by classic surgery. The surgical defect was less than one-third the length of the upper lip. Each cosmetic subunit was repaired: the skin with an A-to-T advancement flap, and the inner mucosa with an advancement flap.

Figure 4. Immediate surgical reconstruction. The flaps were sutured to each other, with preservation of the function and cosmetic appearance of the lip.

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Figure 5. (A, B) Outcome 1 year after surgery, with preservation of lip function and good cosmetic results in our two patients.

ity and the mobility of the A-to-T advancement flap combined with the inner mucosa advancement flap to restore the integrity of all lip subunits.

REFERENCES 1 Martin TJ, Zhang Y, Rhee JS. Options for upper lip reconstruction: A survey-based analysis. Dermatol Surg. 2008;34:1652– 1658.

The combination of the two techniques allowed for a redistribution of skin forces, creating a sustained structure to produce a new vermilion border, while restoring the integrity of all the lip subunits. The combination of techniques meant reconstruction could be achieved in a single-stage procedure, with preservation of motor and sensory function as well as the esthetic appearance of the upper lip.

2 Wetzig T, Woitek M, Eichhorn K, Simon JC, Paasch U. Surgical excision of basal cell carcinoma with complete margin control: Outcome at 5-year follow-up. Dermatology. 2010;22:363–369. 3 Baker SR. Local Flaps in Facial Reconstruction. 2nd ed. Elsevier Mosby; St Louis, MO, 2007. 4 Vaienti L, Zilio D, Di Matteo A, Riccio M, Marchesi A. Central upper lip reconstruction by two vermillion flaps and a rotational skin flap. Dermatology. 2012;224:130–133.

Diagnostic Error Rates in Dermatology Jianni Wu, BS;1,2 Eve J. Lowenstein, MD, PhD1,2 To the Editor:

CHART REVIEW

Diagnostic error is common in medical practice, with a 10% to 15% initial diagnostic error rate cited across specialties.1–5 Interestingly, a lower error rate (2% to 5%) has been found among the specialties of pathology and radiology, implying that visual reliance improves diagnostics.2 In dermatology, data regarding diagnostic error remain limited.6 We designed a study to assess accuracy in predicting dermatologic diagnoses.

An institutional review board–exempt, retrospective review of charts for 230 adult patients at King’s County Hospital Dermatology Clinic was conducted. The charts of 219 consecutive patients biopsied between April 2016 and September 2016 were reviewed. Diagnostic groups included infectious (34), inflammatory/reactive (102), neoplastic (76), and autoimmune (7) etiologies. To increase the autoimmune sample size, 11 additional cases

From the Department of Dermatology, SUNY Health Science Center at Brooklyn,1 and Kings County Hospital Center, Brooklyn,2 New York, NY Address for Correspondence: Eve J. Lowenstein, MD, PhD, Department of Dermatology, SUNY Health Science Center at Brooklyn, Box 46, 450 Clarkson Avenue, Brooklyn, NY 11203 • E-mail: evlow13@yahoo.com

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Figure. Overall rate of consistency between the clinical and the histopathologic diagnosis. Red columns indicate the proportion of clinical differential diagnoses consistent with biopsy results. Blue columns indicate the proportion of clinical differential diagnoses inconsistent with biopsy results.

of autoimmune etiology were added by including charts from March 2015 to December 2016, increasing the total number of autoimmune cases to 18. The study was designed to assess the rate of diagnostic discordance between clinical and histologic diagnoses (our “gold standard”). Although measuring diagnostic error rate is ideal, histopathologic comparators are the surrogate used and are not a true measure of error. A “correct” diagnosis was deemed if any one of the clinical differential diagnoses was consistent with the final histopathologic diagnosis, as read by a board-certified dermatopathologist. Of the discordant diagnoses, we further quantified how many were clinically significant, or required a different treatment approach. INVESTIGATIONS Data review showed that the overall number of discordant cases was 47 out of 230 cases (20%). The Figure shows that, within the four diagnostic classes, inflammatory/reactive and neoplastic diagnoses harbored higher discordance rates than autoimmune and infectious etiologies. Of the 30 discordant inflammatory/ reactive cases, 23 (77%) required consideration of a potentially different treatment. Of the 16 discordant neoplastic cases, only two (12.5%) were clinically significant. One case appeared clinically benign, yet biopsy suggested leiomyosarcoma. Another suspicious for melanoma was confirmed as squamous cell carcinoma in situ on biopsy. SKINmed. 2018;16:137–143

To assess the importance of differential diagnoses, a comparison showed that 103 cases listed one differential diagnosis, whereas 127 cases listed more than one. Interestingly, the rate of discordance was similar between the two groups: 19% (20/103) and 22% (28/127), respectively. These data suggest that having a differential diagnosis does not imply less diagnostic confidence. This study suggests higher diagnostic accuracy for autoimmune (discordance rate of 0%, 0/18) and infectious (discordance rate of 3%, 1/34) dermatoses by clinical assessment alone. Inflammatory/reactive cases showed the greatest discordance rate (29%, 30/102), possibly a consequence of less specificity in clinical presentations. This finding highlights the role of clinical correlation with biopsy in clarifying inflammatory etiologies. Finally, neoplastic cases also showed a significant discordance rate (21%, 16/76); however, these were overwhelmingly trivial as only two cases were clinically significant. The limitations of this study include a small sample size with a high proportion of African American individuals (82%, 189/230), which may elicit visual diagnostic limitations and a representation bias. The reliance on histopathology as an equivalent “gold standard” comparator across all disease etiologies is, furthermore, problematic, because, for example, clinical judgment plays a greater role in diagnosing inflammatory diseases. Moreover, the accuracy of histopathology is limited by how representative biopsies and their reading are. Finally, recorded differentials may not accurately reflect all diagnostic considerations and may vary between physicians.

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CORRESPONDENCE 3 Sonderegger-Iseli K, Burger S, Muntwyler J, et al. Diagnostic errors in three medical eras: A necropsy study. Lancet. 2000;355:2027–2031.

CONCLUSIONS Data examining diagnostic error in dermatology remain limited. Our study identifies some interesting trends, but additional studies are warranted.

4 Institute of Medicine. To Err Is Human: Building a Safer Health System. 1999. http://www.nationalacademies.org/hmd/~/ media/Files/Report%20Files/1999/To-Err-is-Human/To%20 Err%20is%20Human%201999%20%20report%20brief.pdf. Accessed June 2017.

REFERENCES 1 Elstein A. Clinical reasoning in medicine. In: Higgs J, ed. Clinical Reasoning in the Health Professions. Oxford, UK; ButterworthHeinemann; 1995:49–59.

5 Elstein AS. Thinking about diagnostic thinking: A 30-year perspective. Adv Health Sci Educ Theory Pract. 2009;14(suppl 1):7–18.

2 Berner ES, Graber ML. Overconfidence as a cause of diagnostic error in medicine. Am J Med. 2008;121(5 suppl):S2–S23.

6 Cao LY, Taylor JS, Vidimos A. Patient safety in dermatology: A review of the literature. Dermatol Online J. 2010;16:3.

Letters from Botswana: Delayed Diagnosis of Necrotic Leg Ulcerations Olaf Rodriguez, BS;1 Karen Mosojane, MBBS;2 Madeleine Sowash, BA;3 Victoria Williams, MD2,4 To the Editor: A 37-year-old, human immunodeficiency virus–negative man with a history of congestive heart failure and chronic kidney disease was admitted to a hospital in Botswana for a presumed diagnosis of cellulitis. The patient reported developing blisters on his thighs 10 days before admission; these then progressed to large painful sores. He denied any prior history of skin disease, lung disease, sinusitis, blood clots, or drug abuse. At the time of consultation, the patient was being treated with a combination of metronidazole and vancomycin. A review of systems was positive for intermittent fevers and severe leg pain. The past medical history was notable for diabetes and hypertension. The etiology of the congestive heart failure and chronic kidney disease was unknown. He was employed as a nurse assistant and denied any occupational exposure to livestock or animal products. Chronic medications included furosemide and metformin.

After consultation with the cardiology, infectious disease, and general surgery departments, dermatology was consulted to evaluate the patient 2 weeks after initial admission. Examination revealed large, well-demarcated ulcerations with thick necrotic eschars and peripheral gray-violaceous stellate borders on the right thigh extending to the lower leg (Figure, A). Laboratory testing revealed the following: white blood cell count of 20 cells/μL (85% polymorphonuclear cells), hemoglobin 15.1 g/dL with a hematocrit of 43.5%, platelets 95 cells/μL, creatinine 380 µmol/L, urea 1014 mmol/L, aspartate aminotransferase 56 U/L, alanine aminotransferase 46 U/L, and lactic acid dehydrogenase 453 U/L. Additional studies requested after consultation included a coagulation panel, urinalysis, calcium level, phosphate level, rheumatoid factor, and antinuclear, antineutrophil cytoplasmic, and anticardiolipin antibody studies, all of which were negative or normal.

From the Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA;1 the Ministry of Health of Botswana, Gaborone, Botswana;2 the College of Physicians & Surgeons, Columbia University, New York, NY;3 and the Department of Dermatology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA4 Address for Correspondence: Olaf Rodriguez, BS, Perelman School of Medicine, University of Pennsylvania, 3400 Civic Center Boulevard, Building 421, Philadelphia, PA 19104 • E-mail: olaf.rodriguez@uphs.upenn.edu

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CORRESPONDENCE After debridement, the patient was discharged with a 4-week course of oral ciprofloxacin, with close follow-up in dermatology for continued debridement and wound care. Near-complete healing of the lesions was achieved at 12 weeks (Figure, C). DISCUSSION EG is a cutaneous infection classically associated with up to 3% of Pseudomonas bacteremia cases.1 It most commonly occurs in the setting of immunodeficiency or critical illness,2 particularly in patients with neutropenia or on immune-modulating agents. Healthy, immunocompetent patients have, however, been reported to develop EG in the setting of other predisposing factors, such as local trauma, infection, diabetes, and malnutrition.3

Clinically, patients with EG most often present with constitutional signs, such as fever. The lesions are characterized by initially painless red macules on the skin or mucous membranes, which rapidly (within 18 hours) become indurated, with a hemorrhagic center. They subsequently develop into bullae, and finally gangrenous ulcers. The lesions most commonly affect the anogenital and axillary areas.1

A diagnosis of EG can be made based on characteristic lesion morphology in a patient with predisposing risk factors. Blood cultures should be collected to isolate the causative organism and guide antibiotic treatment. Skin biopsy is helpful for routine histology, tissue culture, and potentially special stains to rule out other organisms that may cause similar-appearing necrotic skin lesions.

C Figure. (A) Clinical images demonstrating multiple welldemarcated ulcerations with thick necrotic eschars and grey-violaceous stellate borders on the right thigh extending to the lower leg. (B) Clean ulcerations with sharply demarcated borders on the right thigh and leg after debridement. (C) Nearcomplete healing of ulcerations at 12 weeks after treatment with antibiotics and wound care.

Thoracic x-ray and abdominal ultrasound imaging studies were normal. Blood cultures were negative. An echocardiogram demonstrated an ejection fraction of 45%, with no evidence of blood clots or valvulopathy. A punch biopsy was obtained from the edge of an ulceration on the right leg for histopathology and tissue culture. Histopathology revealed epidermal necrosis with a neutrophilpredominant inflammatory infiltrate of the deep dermis and subcutis. Tissue cultures exhibited growth of Pseudomonas aeruginosa. A diagnosis of ecthyma gangrenosum (EG) was rendered, and the patient was initiated on meropenem, the only antibiotic with pseudomonal coverage available in our hospital. After 7 days on this treatment, the lesions showed some improvement. Debridement was then recommended to remove necrotic eschars and encourage healing (Figure, B). SKINmed. 2018;16:137â&#x20AC;&#x201C;143

Treatment of suspected EG can begin with empiric antipseudomonal coverage, with directed therapy to follow once the causative agent has been identified. As in the case of our patient, surgical debridement may be necessary to aid in the healing process if there is extensive skin necrosis.4 CONCLUSIONS In resource-limited settings, a patientâ&#x20AC;&#x2122;s initial contact with specialist care may be significantly delayed, potentially leading to incorrect diagnoses and initiation of ineffective treatments. In Botswana, dermatology is a scarce skill with only one dermatology specialist to serve the entire public health system. Delays can also occur due to lack of understanding of a dermatologistâ&#x20AC;&#x2122;s role in caring for patients with complex conditions. Despite the availability of a dermatologist and review by multiple other specialist physicians, the correct diagnosis was repeatedly overlooked in this patient. To improve access, our dermatology team has made significant efforts to increase the availability of in-person and remote consultation. By encouraging physician

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CORRESPONDENCE

providers to share clinical photos of challenging cases via the encrypted mobile application Whatsapp, we have improved triage of critically ill patients into dermatology care. In this manner, providers in Botswana can quickly access the skills of a trained dermatologist to interpret examination findings and receive management guidance, resulting in improved patient outcomes.

REFERENCES

It is important for all clinicians to understand the critical role dermatology can play in the multidisciplinary care of complex patients, and also understand the potential that mobile telemedicine has to increase access to critically underrepresented specialties.

1 Sarkar S, Patra AK, Mondal M. Ecthyma gangrenosum in the periorbital region in a previously healthy immunocompetent woman without bacteremia. Indian Dermatol Online J. 2016;7:36–39. 2 Zomorrodi A, Wald ER. Ecthyma gangrenosum: Considerations in a previously healthy child. Pediatr Infect Dis J. 2002;21:1161– 1164. 3 Bettens S, Delaere B, Glupczynski Y, Schoevaerdts D, Swine C. Ecthyma gangrenosum in a non-neutropaenic, elderly patient: case report and review of the literature. Acta Clinica Belgica. 2008;63:394–397. 4 Khalil BA, Baillie CT, Kenny SE, et al. Surgical strategies in the management of ecthyma gangrenosum in paediatric oncology patients. Pediatr Surg Int. 2008;24:79–797.

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Botulinum Toxins:

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Levulan® Kerastick® (aminolevulinic acid HCl) for Topical Solution, 20% Initial U.S. approval: 1999

INDICATIONS AND USAGE The LEVULAN KERASTICK for Topical Solution, a porphyrin precursor, plus blue light illumination using the BLU-U® Blue Light Photodynamic Therapy Illuminator is indicated for the treatment of minimally to moderately thick actinic keratoses of the face or scalp. CONTRAINDICATIONS The LEVULAN KERASTICK for Topical Solution plus blue light illumination using the BLU-U Blue Light Photodynamic Therapy Illuminator is contraindicated in patients with cutaneous photosensitivity at wavelengths of 400-450 nm, porphyria or known allergies to porphyrins, and in patients with known sensitivity to any of the components of the LEVULAN KERASTICK for Topical Solution. WARNINGS AND PRECAUTIONS Photosensitivity During the time period between the application of LEVULAN KERASTICK Topical Solution and exposure to activating light from the BLU-U Blue Light Photodynamic Therapy Illuminator, the treatment site will become photosensitive. After LEVULAN KERASTICK Topical Solution application, patients should avoid exposure of the photosensitive treatment sites to sunlight or bright indoor light (e.g., examination lamps, operating room lamps, tanning beds, or lights at close proximity) during the period prior to blue light treatment. Exposure may result in a stinging and/or burning sensation and may cause erythema and/or edema of the lesions. Before exposure to sunlight, patients should, therefore, protect treated lesions from the sun by wearing a wide-brimmed hat or similar head covering of light-opaque material. Sunscreens will not protect against photosensitivity reactions caused by visible light. It has not been determined if perspiration can spread the LEVULAN KERASTICK Topical Solution outside the treatment site to eye or surrounding skin. Application of LEVULAN KERASTICK Topical Solution to perilesional areas of photodamaged skin of the face or scalp may result in photosensitization. Upon exposure to activating light from the BLU-U Blue Light Photodynamic Therapy Illuminator, such photosensitized skin may produce a stinging and/or burning sensation and may become erythematous and/or edematous in a manner similar to that of actinic keratoses treated with LEVULAN KERASTICK Photodynamic Therapy. Because of the potential for skin to become photosensitized, the LEVULAN KERASTICK should be used by a qualified health professional to apply drug only to actinic keratoses and not perilesional skin. If for any reason the patient cannot return for blue light treatment during the prescribed period after application of LEVULAN KERASTICK Topical Solution (14 to 18 hours), the patient should call the doctor. The patient should also continue to avoid exposure of the photosensitized lesions to sunlight or prolonged or intense light for at least 40 hours. If stinging and/or burning is noted, exposure to light should be reduced. Irritation The LEVULAN KERASTICK Topical Solution contains alcohol and is intended for topical use only. Do not apply to the eyes or to mucous membranes. Excessive irritation may be experienced if this product is applied under occlusion. Coagulation Defects The LEVULAN KERASTICK for Topical Solution has not been tested on patients with inherited or acquired coagulation defects. ADVERSE REACTIONS In Phase 3 studies, no non-cutaneous adverse events were found to be consistently associated with LEVULAN KERASTICK Topical Solution application followed by blue light exposure. Photodynamic Therapy Response: The constellation of transient local symptoms of stinging and/or burning, itching, erythema and edema as a result of LEVULAN KERASTICK Topical Solution plus BLU-U treatment was observed in all clinical studies of LEVULAN KERASTICK for Topical Solution Photodynamic Therapy for actinic

keratoses treatment. Stinging and/or burning subsided between 1 minute and 24 hours after the BLU-U Blue Light Photodynamic Therapy Illuminator was turned off, and appeared qualitatively similar to that perceived by patients with erythropoietic protoporphyria upon exposure to sunlight. There was no clear drug dose or light dose dependent change in the incidence or severity of stinging and/or burning. In two Phase 3 trials, the sensation of stinging and/or burning appeared to reach a plateau at 6 minutes into the treatment. Severe stinging and/or burning at one or more lesions being treated was reported by at least 50% of the patients at some time during treatment. The majority of patients reported that all lesions treated exhibited at least slight stinging and/or burning. Less than 3% of patients discontinued light treatment due to stinging and/or burning. In the Phase 3 trials, the most common changes in lesion appearance after LEVULAN KERASTICK for Topical Solution Photodynamic Therapy were erythema and edema. In 99% of active treatment patients, some or all lesions were erythematous shortly after treatment, while in 79% of vehicle treatment patients, some or all lesions were erythematous. In 35% of active treatment patients, some or all lesions were edematous, while no vehicle-treated patients had edematous lesions. Both erythema and edema resolved to baseline or improved by 4 weeks after therapy. LEVULAN KERASTICK Topical Solution application to photodamaged perilesional skin resulted in photosensitization of photodamaged skin and in a photodynamic response (see Warnings and Precautions). Other Localized Cutaneous Adverse Experiences: Table 1 depicts the incidence and severity of cutaneous adverse events in Phase 3 studies, stratified by anatomic site treated.

•

After LEVULAN KERASTICK Topical Solution is applied to the actinic keratoses in the doctor’s office, the patient will be told to return the next day. During this time the actinic keratoses will become sensitive to light (photosensitive). Care should be taken to keep the treated actinic keratoses dry and out of bright light. After LEVULAN KERASTICK Topical Solution is applied, it is important for the patient to wear light-protective clothing, such as a wide-brimmed hat, when exposed to sunlight or sources of light.

•

Fourteen to eighteen hours after application of LEVULAN KERASTICK Topical Solution the patient will return to the doctor’s office to receive blue light treatment, which is the second and final step in the treatment. Prior to blue light treatment, the actinic keratoses will be rinsed with tap water. The patient will be given goggles to wear as eye protection during the blue light treatment.

•

The blue light is of low intensity and will not heat the skin. However, during the light treatment, which lasts for approximately 17 minutes, the patient will experience sensations of tingling, stinging, prickling or burning of the treated lesions. These feelings of discomfort should improve at the end of the light treatment.

•

Following treatment, the actinic keratoses and, to some degree, the surrounding skin, will redden, and swelling and scaling may also occur. However, these lesion changes are temporary and should completely resolve by 4 weeks after treatment.

LEVULAN, KERASTICK, BLU-U and DUSA are registered trademarks of DUSA Pharmaceuticals, Inc., a Sun Pharma company. Sun Dermatology is a division of Sun Pharmaceutical Industries, Inc. © 2016 Sun Pharmaceutical Industries, Inc. All rights reserved. US

Patents: 5,954,703,

Manufactured for: DUSA Pharmaceuticals, Inc.® 25 Upton Drive, Wilmington, MA 01887 For more information please contact: 1-877-533-3872 or 1-978-657-7500 www.dusapharma.com Adverse Experiences Reported by Body System: In the Phase 3 studies, 7 patients experienced a serious adverse event. All were deemed remotely or not related to treatment. No clinically significant patterns of clinical laboratory changes were observed for standard serum chemical or hematologic parameters in any of the controlled clinical trials. OVERDOSAGE LEVULAN KERASTICK Topical Solution Overdose LEVULAN KERASTICK Topical Solution overdose has not been reported. In the unlikely event that the drug is ingested, monitoring and supportive care are recommended. The patient should be advised to avoid incidental exposure to intense light sources for at least 40 hours after ingestion. The consequences of exceeding the recommended topical dosage are unknown. BLU-U Light Overdose There is no information on overdose of blue light from the BLU-U Blue Light Photodynamic Therapy Illuminator following LEVULAN KERASTICK Topical Solution application. Information for Patients: LEVULAN KERASTICK Photodynamic Therapy for Actinic Keratoses. •

The first step in LEVULAN KERASTICK Photodynamic Therapy (PDT) for actinic keratoses is application of the LEVULAN KERASTICK Topical Solution to actinic keratoses located on the patient’s face or scalp.

LAB-1442AW Rev D

REDISCOVER

FOR MORE INFORMATION CONTACT US AT (877) 533-DUSA Please see full prescribing information on adjacent page. LEVULAN, KERASTICK, BLU-U and DUSA are registered trademarks of DUSA Pharmaceuticals, Inc., a Sun Pharma company. Â©2016 DUSA Pharmaceuticals, Inc. All rights reserved.

MKT-1790AW Rev C