SkinMed: Sep/Oct 2017 by jo-ann kalaka-Adams

Chinese Society of Dermatology

Lebanese Dermatological Society

Belarusian Society of Dermatovenereologists and Cosmetologists

Lebanese Dermatological Society

Belarusian Society of Dermatovenereologists and Cosmetologists

North American Clinical Dermatologic Society

The Dermatologic & Aesthetic Surgery International League

COMMENTARY Management of Cutaneous Cancers in Patients Undergoing Organ Transplantation—Part I: Current Status: Reactive Approach Sharma, Handler, Shah, Weiss, Lambert, Gagna, and Lambert

ORIGINAL CONTRIBUTIONS Oral Lichen Planus: A Cross-Sectional/Descriptive Study of 33 Patients Sehgal, Syed, Aggarwal, and Sehgal

Vitamin D Deficiency in an Alopecia Referral Clinic During a 3-Month Period: The Need to Pursue Systemic Screening Siddiqui, Rashid, and Mirmirani

Angiokeratoma of the Glans Penis Beutler and Cohen

Efficacy and Tolerability of a Twice-Daily, Three-Step Men’s Skincare Regimen in Improving Overall Skin Quality and Reducing Shave-Related Irritation Rodan, Fields, and Falla

Cryosurgery for Facial and Scalp Lesions of Basal Cell Carcinoma: A Study in 29 Elderly Patients Savant, Savant, and Sehgal

The Dermatologic & Aesthetic Surgery International League

African Association for Dermatology

September/October 2017 • Volume 15• Issue 5

September/October 2017REVIEW • Volume 15• Issue 5 EDITORIAL The Third-Party Payers/Withholders: Advanced Management of They Have a License to Steal and Severe Keloids Hagele, Nyanda, Patel, Russell, They Use It Lambert, Hurlock, Espinal-Mariotte, Parish, and Parish

North American Clinical Dermatologic Society

Cohen, and Nelson

Self Assessment Examination Lambert

DEPARTMENTS PERILS OF DERMATOPATHOLOGY Compromising Patient Care: Gross Payment Disparities in Dermatopathology—Part I Patel, Sharma, Sylvester, Salgado, Peters, and Lambert

NEW THERAPY UPDATE Crisaborole 2% Ointment (EucrisaTM)

Kitty Litter Dermatitis from 2-Bromo-2-Nitropropane-1,3-Diol Sullenbarger, Hensley, and Travers

Two Cases of Lepromatous Leprosy from Exposure to Armadillos in Florida

Harb, Pothiawala, Yonkosky, Talley, and Jukic

Primary Malignant Melanoma of the Bladder

Buscarini, Conforti, Incalzi, Falavolti, Taffon, Muto, and Dianzani

BOOK REVIEW A Helpful Addition to the Flap Literature Pyle

Gupta, Versteeg, Abramovits, and Vincent

THE HEYMANN FILE Herpes Zoster, Immunosuppression, and Vaccination: Far from a Blistering Pace Heymann

PHOTO CAPSULE Oral Mucocoele: The Magic of Sclerotherapy George and Loganathan

case studies Perianal Ulcer in an Asian Man Pillai, Oh, Fung, and Wijaya

Hailey-Hailey Disease Presenting as Lichenoid Plaques on the Thigh Ghosh, Das, Kumar, and Sardar

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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 September/October 2017 • Volume 15 • Issue 5

EDITORIAL

The Third-Party Payers/Withholders: They Have a License to Steal and They Use It ................................. 327

W. Clark Lambert, MD, PhD; William Hurlock, JD; José D. Espinal-Mariotte, MD; Jennifer L. Parish, MD; Lawrence Charles Parish, MD, MD(Hon)

COMMENTARy

Management of Cutaneous Cancers in Patients Undergoing Organ Transplantation—Part I: Current Status: Reactive Approach ............................................................................................................ 329

Divya Sharma, BS; Marc Z. Handler, MD; Radhika Shah, PharmD; Amy Weiss, BA; Muriel W. Lambert, PhD; Claude E. Gagna, PhD; W. Clark Lambert, MD, PhD

ORIGINAL CONTRIBUTIONS

Oral Lichen Planus: A Cross-Sectional/Descriptive Study of 33 Patients .................................................. 333

Virendra N. Sehgal, MD, FNASc, FAMS, FRAS (Lond); Nazim Hussain Syed, MD; Ashok Aggarwal, MD; Shruti Sehgal, MDS

Vitamin D Deficiency in an Alopecia Referral Clinic During a 3-Month Period: The Need to Pursue Systemic Screening ...................................................................................................................... 339

Zuhair Siddiqui, MPH; Rashid M. Rashid, MD, PhD; Paradi Mirmirani, MD

Angiokeratoma of the Glans Penis............................................................................................................. 343

Bryce D. Beutler, BS; Philip R. Cohen, MD

Efficacy and Tolerability of a Twice-Daily, Three-Step Men’s Skincare Regimen in Improving Overall Skin Quality and Reducing Shave-Related Irritation....................................................................... 349

Katie Rodan, MD; Kathy Fields, MD; Timothy J. Falla, MD

Cryosurgery for Facial and Scalp Lesions of Basal Cell Carcinoma: A Study in 29 Elderly Patients............ 357

Satish Savant, MD; Sandeep Savant, MD; Virendra N. Sehgal MD

REVIEW

Advanced Management of Severe Keloids ................................................................................................. 365

Thomas Hagele, MD, MBA; Hoka Nyanda, MD; Nishit Patel, MD; Nicole Russell, MD; George Cohen, MD; Christopher Nelson, MD

Self Assessment Examination ................................................................................................................... 371

W. Clark Lambert, MD, PhD

Departments Perils of Dermatopathology

W. Clark Lambert, MD, PhD, Section Editor

Compromising Patient Care: Gross Payment Disparities in Dermatopathology—Part I .............................. 373

Viral M. Patel, BS; Divya Sharma, BS; Michael Sylvester, AB; Fernanda Salgado, BS; Stephen Peters, MD, PhD; W. Clark Lambert, MD, PhD

New Therapy Update

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

Crisaborole 2% Ointment (EucrisaTM) ........................................................................................................ 377

Aditya K. Gupta, MD, PhD, FRCPC; Sarah G. Versteeg, MSc; William Abramovits, MD; Kimberly Dawn Vincent, MD

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TABLE OF CONTENTS September/October 2017 • Volume 15 • Issue 5

The Heymann File

Warren R. Heymann, MD, Section Editor

Herpes Zoster, Immunosuppression, and Vaccination: Far from a Blistering Pace ..................................... 381

Warren R. Heymann, MD

Photo Capsule

Snejina Vassileva, MD, PhD, Section Editor

Oral Mucocoele: The Magic of Sclerotherapy ............................................................................................ 383

Anju George, MBBS, MD; Eswari Loganathan, MBBS, MD

case studies

Vesna Petronic-Rosic, MD, MSc, Section Editor

Perianal Ulcer in an Asian Man ................................................................................................................. 385

Nilanthy Sharon Anthony Pillai, MBBS, MRCP (UK); Choon Chiat Oh, MBBS, MRCP (UK); Michelle Chan Mei Fung, MBBS, FRCPath; Limin Wijaya, MBBS (Melb), MRCP (UK)

Hailey-Hailey Disease Presenting as Lichenoid Plaques on the Thigh ....................................................... 387

Anupama Ghosh, MD; Anupam Das, MD; Piyush Kumar, MD; Swapan Sardar, MD

Kitty Litter Dermatitis from 2-Bromo-2-Nitropropane-1,3-Diol .................................................................. 389

John W. Sullenbarger, MS3; Brooke Hensley, DO; Jeffrey B. Travers, MD, PhD

Two Cases of Lepromatous Leprosy from Exposure to Armadillos in Florida ............................................. 391

Jennifer Harb, MD; Salma Pothiawala, MD, MPH; Donna Yonkosky, MD; James Talley, MD; Drazen Jukic MD, PhD

Primary Malignant Melanoma of the Bladder............................................................................................. 395

Maurizio Buscarini, MD, PhD; Claudio Conforti, MD; Raffaele Antonelli Incalzi, MD; Cristina Falavolti, MD; Chiara Taffon, MD; Giovanni Muto, MD; Caterina Dianzani, MD, PhD

BOOK REVIEW

Jennifer L. Parish, MD, Section Editor

A Helpful Addition to the Flap Literature ................................................................................................... 399

Tia Pyle, MD

323

September/October 2017

Volume 15 • Issue 5

Editorial

ABOUT OUR JOURNAL SKINmed: Dermatology for the Clinician®, print ISSN 1540-9740, online ISSN 1751-7125, is published bimonthly by Pulse Marketing & Communications, LLC, located at 4 Peninsula Avenue, Sea Bright, NJ 07760. Printed in the USA.

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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

Publishing PUBLISHER Art Kalaka

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Chinese Society of Dermatology

Lebanese Dermatological Society

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324

Belarusian Society of Dermatovenereologists and Cosmetologists

North American Clinical Dermatologic Society

African Association for Dermatology

The Dermatologic & Aesthetic Surgery International League

Volume 15 • Issue 5

September/October 2017

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

Larry E. Millikan, MD

Dallas, TX

London, Ontario, Canada

Newark, NJ

Meridian, MS

Jennifer L. Parish, MD

Vesna Petronic-Rosic, MD, MSc

Marcia Ramos-e-Silva, MD, PhD

Philadelphia, PA

Chicago, IL

Rio de Janeiro, Brazil

EDITORIAL BOARD Mohamed Amer, MD Cairo, Egypt

Howard A. Epstein, PhD Philadelphia, PA

Jasna Lipozencic, MD, PhD Zagreb, Croatia

Todd E. Schlesinger, MD Charleston SC

Robert L. Baran, MD Cannes, France

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

Ada Lo Schiavo, MD Naples, Italy

Virendra N. Sehgal, MD Delhi, India

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

Charles Steffen, MD Oceanside, CA

George M. Martin, MD Kihei, HI

Alexander J. Stratigos, MD Athens, Greece

Marc S. Micozzi, MD, PhD Rockport, MA

James S. Studdiford III, MD Philadelphia, PA

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

Robert J. Thomsen, MD Los Alamos, NM

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

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

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

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

Oumeish Youssef Oumeish, MD, FRCP Amman, Jordan

Seung-Kyung Hann, MD, PhD Seoul, Korea Roderick J. Hay, BCh, DM, FRCP, FRCPath London, UK

Joseph L. Pace, MD, FRCP Naxxar, Malta

María Daniela Hermida, MD Buenos Aires, Argentina

Art Papier, MD Rochester, NY

Warren R. Heymann, MD Camden, NJ

Johannes Ring, MD, DPhil Munich, Germany

Tanya R. Humphreys, MD Bala-Cynwyd, PA

Roy S. Rogers III, MD Scottsdale, AZ

Camila K. Janniger, MD Englewood, NJ

Donald Rudikoff, MD New York, NY

Abdul-Ghani Kibbi, MD Beirut, Lebanon

Robert I. Rudolph, MD Wyomissing, PA

Andrew P. Lazar, MD Washington, DC

Noah Scheinfeld, MD, JD New York, NY

SKINmed. 2017;15:325

325

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

September/October 2017

Volume 15 • Issue 5

Editorial

The Third-Party Payers/Withholders: They Have a License to Steal and They Use It W. Clark Lambert, MD, PhD;1 William Hurlock, JD;2 José D. Espinal-Mariotte, MD;3 Jennifer L. Parish, MD;4 Lawrence Charles Parish, MD, MD(Hon)4 “If you are not at the table, you may find yourself on the menu.”—Variously attributed to any of several different politicians in Washington, DC

n the late 20th century, physicians increasingly found that they were no longer being reimbursed directly by patients, but rather by third parties, initially the US Government, but later also private insurance companies, who in doing so imposed themselves as middlemen in the health care system. Physicians had now become providers! In addition, they began to serve as “gatekeepers,” in the Health Maintenance Organization model, thereby limiting patient access to dermatologists altogether.

Alarm bells were sounded, notably by esteemed dermatologists, such as Peyton Weary (1930 to 2009)1 and one of us (LCP),2 but they went largely unheeded. The reasons for this development, which has progressed over decades, are many and varied, but the end result is that, at present, physicians’ offices are often obliged to contact one or more third-party payers before, during, and after rendering care, essentially to ask permission to be able to properly tend to their patient. THE THIRD-PARTY PAYER The third-party payer, usually represented by an individual with far fewer qualifications than the treating physician, is requested to permit the physician to perform the necessary procedure. This insurance company representative is then in a position to simply deny the request or render only partial payment. To place this in perspective, imagine being sued and brought to court, only to find that the judge, and indeed the entire staff of the court, as well as the jury, if a jury decision is called for, are employees of the opposing party. If you think the outcome is unfair to you, you may take your case to an actual court, but the individual “judgments” are not worth the trouble and expense, even though, collectively, the loss to you, and the gain by your

opponent, is quite substantial. Your opponent, in our example being the third-party payer, ends up with a license to steal from both you and your patient, and they use it with impunity. EXAMPLES Examples of abusive practices by such third-party payers are legion and include denying approval, failing to pay even though approval has been granted, insisting on inappropriate treatment to be used before or instead of the correct treatment, limiting treatment options to choices from poor formularies, and underpaying for services rendered by the physician and/or their staff. Not infrequently, third-party payers capriciously demand return of payments already made in past months or even years. Third-party payers also resort to telling outright lies. For example, one of us (JDE-M) was reimbursed for pathology services at a lower rate than normal, based on the claim that this was the average rate for pathologists practicing in his zip code. It turned out that he was the only pathologist practicing in his zip code. This situation is not limited to physicians and their practices. In the Administrative Procedure Act of 1946, the US Congress created “Administrative Law Judges,” who rule on various matters, regarding numerous federal agencies versus US citizens, usually not employees of the agency in question.3 The problem is that these “Administrative Law Judges” are themselves employees of these agencies, so the same scenario holds as for physicians versus third-party payers. In recent years, the numbers of these “judges” has grown exponentially, with US citizens suffering the consequences. The end result is that the US Federal Government is becoming progressively more powerful and less accountable to anyone.

From the Department of Pathology and Laboratory Medicine, and Department of Dermatology, Rutgers – New Jersey Medical School, Newark, NJ;1 Mueller Law, Montclair, NJ;2 the Department of Pathology, Mountainside Hospital, Glen Ridge, NJ;3 and the Department of Dermatology and Cutaneous Biology, Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, PA4 Address for Correspondence: W. Clark Lambert, MD, PhD, Medical Sciences Building Room H576, Department of Dermatology, Rutgers – New Jersey Medical School, 185 South Orange Avenue, Newark, NJ 07103 • E-mail: lamberwc@njms.rutgers.edu

SKINmed. 2017;15:327–328

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EDITORIAL

THE END RESULT

RECOMMENDED SOLUTIONS

The consequences of these trends are likely to be dire, the more so the longer before action is taken to correct them. Medicine may serve as the “canary in the coal mine,” being the first system to fail completely. This is true for several reasons:

As physicians, we have not historically been politically savvy; we have tended to be on the menu rather than at the table. Furthermore, medical societies, which should have been leading efforts to counteract the trends discussed here, have been woefully disinterested in doing so. This must change. These trends are not static; there are reasons why they are progressing, and at present there is little opposition. In dermatology, the American Academy of Dermatology, or failing that, the American Dermatological Association, must make the public aware of these issues and begin to build a consensus to address them. Time is running out!

1. The financial benefits to the third-party payers are more direct than for government agencies. Monies paid to the government are placed in a pot shared by many, whereas monies paid to a third-party payer go directly to that entity. This incentivizes the entity to influence the “judge,” the person answering the telephone when a physician’s office calls, to be even more obstructionist and unreasonable. (Recently, one of us [LCP] was requested to supply date of birth, social security number, NPI number, and tax ID number, before disconnecting.)

References

2. The Affordable Care Act (“Obamacare”) is financially unstable and will require increasing payments by many parties, including state and federal governments plus individuals. This will motivate probes into medical finances, which should bring some of these insurance excesses to light. 3. Medical care involves great sums of money, and fraud and abuse in this area are always newsworthy.4 4. Other issues, such opioid addiction, also interact with medical care and tend to bring attention to news developments in this area, but these avoid the core problems.4

1 Weary PE. Behold, the gatekeeper cometh. Int J Dermatol. 1984;23:33–35. 2 Parish LC, Witkowski JA, Millikan LE. Government intervention in American dermatology. Int J Dermatol. 1984;23:390–391. 3 Shapiro M. Golden anniversary: The Administrative Procedure Act of 1946. A. 19 Regulation 40 1996. http:// scholarship.law.berkeley.edu/facpubs/379. Accessed August 16, 2017. 4 Gever J. Nationwide medical fraud sweep nets dozens of docs, nurses: Charges range from fraudulent opioid prescribing to kickback schemes. July 13, 2017. http://www.medpagetoday.com/publichealthpolicy/ethics/66599. Accessed August 16, 2017.

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September/October 2017

Volume 15 • Issue 5

Commentary

Management of Cutaneous Cancers in Patients Undergoing Organ Transplantation— Part I: Current Status: Reactive Approach Divya Sharma, BS;1 Marc Z. Handler, MD;2 Radhika Shah, PharmD;1 Amy Weiss, BA;1 Muriel W. Lambert, PhD;2,3,4 Claude E. Gagna, PhD;5 W. Clark Lambert, MD, PhD2,3,4

rgan transplantation is among the more challenging procedures performed today. Patients require multidisciplinary care and surveillance for immune transplant rejection. Immunosuppressance therapy has now become a mainstay of transplantation medicine to prevent destruction of the donated organ. Long-term use, however, has been linked to the development of various cancers. Cutaneous neoplasms affect more than 50% of transplant recipients and are the most commonly diagnosed malignancies in this population, comprising almost 40% of all posttransplant malignancies.1,2 These cancers also are known to act more destructively in immunosuppressed individuals, demonstrating rapid growth, increased recurrence, and greater risk of metastasis. NONMELANOMA SKIN CANCER BURDEN IN POSTTRANSPLANT PATIENTS

Squamous cell carcinoma (SCC) and basal cell carcinoma (BCC), together known as nonmelanoma skin cancer (NMSC), account for approximately 95% of skin cancers in posttransplant patients; the vast majority are SCCs.2 Drug-induced immunosuppression in organ transplant patients increases the risk of SCC by 65- to 250-fold, with risk of BCC increased 10- to 16fold. Furthermore, it has been shown that cancer risk is associated with degree of immunosuppression, with increased frequencies of skin cancers being observed in patients on higher dosage regimens. Risk of NMSC varies by type of organ transplant and degree of immunosuppression; cardiac allografts require greater immunosuppression, followed by lung, kidney, and liver. Other reported risk factors for NMSC in posttransplant patients in-

clude history of human papillomavirus infection, actinic keratosis, NMSC, and melanoma,3 in addition to the same risk factors that apply to the general population. PATHOGENESIS Of NMSC Development of SCC is primarily due to cumulative exposure to ultraviolet (UV) radiation. Cutaneous SCC is thought to start as a single transformed keratinocyte, which proliferates to form an actinic keratosis, and progresses to a neoplasm as a result of a gradual buildup of mutations secondary to UV-induced DNA damage. The p53 gene, which functions in cell cycle arrest and initiation of apoptosis, is most commonly affected. BCC arises from the epidermal basal layer and/or skin adnexae and often manifests as a pink or skin-colored papule on the face, with dilated vessels. Although slow-growing, BCCs can be locally aggressive and destroy surrounding tissue. The primary pathogenic factors for the development of BCC are UV radiation and inherited or acquired mutations in the tumor suppressor gene patched-1 (PTCH1). PTCH proteins act as receptors for the hedgehog (HH) protein involved in the sonic HH pathway that guides embryonic organ development in vertebrates. Currently, it is unclear how sonic HH signal overexpression contributes to neoplasm development. ROLE OF IMMUNOSUPPRESSIVE AGENTS IN NMSC DEVELOPMENT There are several proposed mechanisms by which immunosuppressive agents may cause skin cancer. Skin immune sentinels

From Rutgers University – New Jersey Medical School,1 Department of Dermatology,2 Department of Pathology,3 and Department of Laboratory Medicine,4 Rutgers University – New Jersey Medical School, Newark, NJ; and Department of Life Sciences, New York Institute of Technology, Old Westbury, NY5 Address for Correspondence: W. Clark Lambert, MD, PhD, Departments of Dermatology and Pathology and Laboratory Medicine, Room H576 Medical Science Building, Rutgers – New Jersey Medical School, 185 South Orange Avenue, Newark, NJ 07103 • Email: lamberwc@njms.rutgers.edu

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include epidermal Langerhans cells, dermal dendritic cells, macrophages, T cells, and keratinocytes.4 Cyclosporine, a calcineurin inhibitor and frequently used immunosuppressant, is known to interfere with the functions of Langerhans cells, dermal dendritic cells, mast cells, and T cells, and to inhibit interleukin-2 gene expression.5 Decreased immune surveillance is detrimental to these patients because they may already have precancerous skin lesions from preexisting UV radiation (UVR)-induced DNA damage. Additionally, cyclosporine has been reported to reduce the UVB-induced apoptotic response and to diminish DNA repair, as well as to counter p53-dependent senescence.6,7 Cyclosporine also increases activation of the proto-oncogene Akt in keratinocytes and causes decreased expression of PTEN, a negative regulator of Akt.8 Tumor growth can be further promoted by cyclosporine’s proangiogenic effects through increased expression of vascular endothelial growth factor. Additionally, cyclosporine affects the TAK1/TAB1/TAB2, p38, mitogen-activated protein kinase, and nuclear factor κB pathways, which are thought to contribute to carcinogenesis. Nontransformed cells treated with cyclosporine in vitro and ex vivo acquire an invasive phenotype, and, in vivo, tumor growth is promoted by an apparent cell-autonomous mechanism involving cyclosporine-induced transforming growth factor-β secretion. Increased transforming growth factor-β production, secondary to cyclosporine use, enhances epithelial-mesenchymal transition, contributing to aggressive tumor growth.9 Like cyclosporine, tacrolimus alters the mitogen-activated protein kinase and p53 pathways, inhibits T-cell signaling and transcription of the interleukin-2 gene, and promotes expression of transforming growth factor-β in a dose-dependent fashion. Although

sirolimus binds the same protein as the calcineurin inhibitors, it does not ultimately decrease interleukin-2 production; perhaps consequently, its use has been associated with a decreased incidence of new skin cancers in renal transplant recipients. REACTIVE APPROACH: CURRENT MANAGEMENT OF NMSC BURDEN IN POSTTRANSPLANT PATIENTS Treatment of actinic keratosis, the precursor to SCC, includes destruction with cryotherapy and photodynamic therapy, where a porphyrin chemical is used to photosensitize the affected area before exposure to blue light. Topical pharmacologic treatments such as 5-fluorouracil (5-FU) cream, imiquimod cream, and diclofenac gel may also be used. Their efficacy is reviewed in the Table. This approach shows promise but, in our opinion, has not been applied to maximum benefit in this patient population (see Part II of this contribution). Options for the treatment of SCC include electrodessication and curettage, surgery, cryotherapy, Mohs micrographic surgery, radiation therapy, and photodynamic therapy. Mohs micrographic surgery is performed on patients who have skin cancers in anatomic locations where tissue preservation is a priority. The topical pharmacologic treatment options 5-FU and imiquimod have also been recommended for low-risk cutaneous SCC such as Bowen’s disease. 5-FU is an antipyrimidine cytotoxic agent that is recommended for the treatment of numerous or large actinic keratoses that do not resolve with cryotherapy. Although 5-FU has been extensively used, the physiology underlying its inflammatory sensitization against precancerous lesions is still unclear. Pyropto-

Table. Efficacy of Topical Pharmaceutical Therapies in the Management of Actinic Keratoses Drug

Mechanism of Action

Side Effect Profile

Efficacy

Topical 5-fluorouracil

Conversion to a metabolite that interferes with thymine synthesis and inhibits DNA replication

Localized: erythema, localized pain, hyperpigmentation at application site

Complete clearance of lesions in up to 84% of patients at 24 weeks

Topical imiquimod

Activates toll-like receptor 7, which activates the innate immune response

Local: erythema, dryness, ulcerations, localized pain Systemic: nausea, fatigue, muscle pain

Inhibition of cyclooxygenase-1 and cyclooxygenase-2, which prevents the synthesis of prostaglandins

Local: dryness, dermatitis, ulcerations, vesiculobullous dermatitis, contact dermatitis

Stimulation of the innate immune system through cytokine production and neutrophil recruitment

Local: erythema, crusting, ulcerations, pustules

Topical diclofenac gel

Topical ingenol mebutate

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Complete clearance of lesions in up to 57.1% of patients at 24 weeks Complete clearance of lesions in 47% of patients at 24 weeks Complete clearance of lesions in up to 40–54.4% of patients at 8 weeks

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Commentary

sis—cell death in the context of an inflammatory reaction—may explain the observed response, but is itself poorly understood.10 5-FU is efficacious as a short-term or long-term treatment in clearing actinic keratosis lesions that have been present for more than 24 months. Imiquimod is a synthetic Toll-like receptor 7 agonist that can upregulate cytokines which inhibit growth and promote inflammation, consequently inhibiting tumor progression. It is recommended for treating multiple nonhyperkeratotic lesions in immunocompetent patients, and has been found to significantly decrease the number of actinic keratoses from baseline.11 Diclofenac gel is a nonsteroidal anti-inflammatory agent that inhibits the production of prostaglandin E2. It is recommended for treating nonhyperkeratotic actinic keratosis. It has also been demonstrated to be a viable treatment option for the prevention of SCC in organ transplant patients with actinic keratoses. Both 3% diclofenac gel and 5% imiquimod cream have shown efficacy in the treatment of actinic keratosis.12 Ingenol mebutate gel was recently approved for treating actinic keratosis. It acts on mitochondria in abnormal keratinocytes, resulting in apoptosis. It is also indicated for the treatment of multiple nonhyperkeratotic lesions. Current treatment options for BCC include electrodessication and curettage, surgical excision, or radiation therapy if the tumor is inoperable. Less commonly used treatments include photodynamic therapy, topical imiquimod or 5-FU, and cryosurgery. Emerging therapies include intralesional injection of DNAzyme Dz13 and oral administration of the hedgehog pathway inhibitors itraconazole, vismodegib, and sonidegib.13–15 References 1 Zwald FO, Brown M. Skin cancer in solid organ transplant recipients: Advances in therapy and management: Part I. Epidemiology of skin cancer in solid organ transplant recipients. J Am Acad Dermatol. 2011;65:253–261. 2 Euvrard S, Kanitakis J, Claudy A. Skin cancers after organ transplantation. New Engl J Med. 2003;348:1681– 1691. 3 Karagas MR, Nelson HH, Sehr P, et al. Human papillomavirus infection and incidence of squamous cell and

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basal cell carcinomas of the skin. J Natl Cancer Inst. 2006;98:389–395. 4 Nestle FO, Di Meglio P, Qin J-Z, Nickoloff BJ. Skin immune sentinels in health and disease. Nature Rev Immunol. 2009;9:679–691. 5 Abdul M, Charron D, Haziot A. Selective effects of cyclosporine a on Th2-skewed dendritic cells matured with viral-like stimulus by means of toll-like receptors. Transplantation. 2008;86:880–884. 6 Yarosh DB, Pena AV, Nay SL, Canning MT, Brown DA. Calcineurin inhibitors decrease DNA repair and apoptosis in human keratinocytes following ultraviolet B irradiation. J Invest Dermatol. 2005;125:1020–1025. 7 Wu X, Nguyen B-C, Dziunycz P, et al. Opposing roles for calcineurin and ATF3 in squamous skin cancer. Nature. 2010;465:368–372. 8 Han W, Ming M, He T-C, He Y-Y. Immunosuppressive cyclosporin A activates AKT in keratinocytes through PTEN suppression. Implications in skin carcinogenesis. J Biol Chem. 2010;285:11369–11377. 9 Walsh SB, Xu J, Xu H, et al. Cyclosporine A mediates pathogenesis of aggressive cutaneous squamous cell carcinoma by augmenting epithelial-mesenchymal transition: Role of TGFbeta signaling pathway. Mol Carcinogen. 2011;50:516–527. 10 Lambert WC, Lambert MW. Development of effective skin cancer treatment and prevention in xeroderma pigmentosum. Photochem Photobiol. 2015;91:475–483. 11 Strohal R, Kerl H, Schuster L. Treatment of actinic keratoses with 5% topical imiquimod: A multicenter prospective observational study from 93 Austrian office-based dermatologists. J Drugs Dermatol. 2012;11:574–578. 12 Akarsu S, Aktan S, Atahan A, Koc P, Ozkan S. Comparison of topical 3% diclofenac sodium gel and 5% imiquimod cream for the treatment of actinic keratoses. Clin Exper Dermatol. 2011;36:479–484. 13 Cho EA, Moloney FJ, Cai H, et al. Safety and tolerability of an intratumorally injected DNAzyme, Dz13, in patients with nodular basal-cell carcinoma: A phase 1 firstin-human trial. Lancet. 2013;381:1835–1843. 14 Proctor AE, Thompson LA, O’Bryant CL. Vismodegib: An inhibitor of the Hedgehog signaling pathway in the treatment of basal cell carcinoma. Ann Pharmacother. 2014;48:99–106. 15 Migden MR, Guminski A, Gutzmer R, et al. Treatment with two different doses of sonidegib in patients with locally advanced or metastatic basal cell carcinoma (BOLT): A multicentre, randomised, double-blind phase 2 trial. Lancet Oncol. 2015;16:716–728.

Management of Cutaneous Cancers

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September/October 2017

Volume 15 • Issue 5

ORIGINAL CONTRIBUTION

Oral Lichen Planus: A Cross-Sectional/Descriptive Study of 33 Patients Virendra N. Sehgal, MD, FNASc, FAMS, FRAS (Lond);1 Nazim Hussain Syed, MD;2 Ashok Aggarwal, MD;2 Shruti Sehgal, MDS3 Abstract Oral lichen planus (OLP), a well-known entity, is often neglected; however, its assessment is considered essential for evolving future strategies for treatment. Thirty-three patients with OLP from 200 consecutive patients with oral mucosal lesions were studied according to demography. Tobacco chewing, smoking, and alcohol intake were recorded. Examination of the oral cavity, using a head light and tongue depressor, was undertaken to define the morphology of the lesion(s). Colored photographs were an essential part of the process. OLP, a frequently encountered manifestation of oral mucosal lesions, was responsible for 16.50% of the total number of lesions. There was a preponderance of lesions in women aged 40 to 59 years, in contrast to men in the same age group. The duration of the lesions was variable, and tobacco chewing/smoking and amalgam fillings might have exacerbated them. Morphology ranged from a reticular, erythematous pattern to an erosive one. The diagnosis is largely clinical, but it can be confirmed by histopathology. (SKINmed. 2017;15:333–337)

LP is an extraordinary entity, as it can interfere with the biology of the oral cavity,1 resulting in an intractable ailment, one that has largely been neglected. Most work thus far has emanated from faculties other than dermatology;2–4 hence, it is considered significant to distinguish the entity from other oral mucosal lesions.5 PARTICIPANTS AND METHODS Thirty-three patients (16.5%) out of a total of 200 with oral mucosal lesions attending the outpatient department were diagnosed as having OLP. The consensus diagnosis by two or more consultants was arrived at on the basis of morphological characteristics,6 after which each of the patients was asked to complete a questionnaire, after informed consent had been taken. A detailed history of oral complaints such as pain, burning sensations, discoloration, and roughness of the mucous membrane along with drug intake was recorded. Associated cutaneous lesions were also noted, in addition to the patient’s age, and the duration, progression, site, distribution, and morphology of the lesions. A thorough clinical inspection of the oral cavity was performed according to the World Health Organization guidelines.3 As

described above, close visual inspection using a head light and wooden tongue depressor was mandatory. Each of the anatomic regions in the oral cavity was palpated. The sites of involvement were divided into the buccal mucosa, labial mucosa, floor of the mouth, tongue, lip, palate, and gingiva. The labial mucosa and floor of the mouth were grouped together, as were the palate and gingiva. In addition, examination of the skin and skin appendages, as well as the mucous membranes of the genitalia and conjunctiva, was carried out. A general physical examination was performed on each patient. Each of the lesions was recorded using digital photography, using a Sony 14 megapixel digital camera with 5× optical zoom in macro mode on a standard setting. Histopathology was undertaken when the clinical features were not diagnostic. A mucous membrane biopsy was taken from a representative lesion using a 3-mm punch. The folding of the mucous membrane was reduced by stretching it with a toothpick, and the sample was preserved in formalin 10% solution. The section(s) thus prepared were stained with hematoxylin and eosin, and examined microscopically. Immunofluorescence and other procedures, such as Tzanck smear or KOH preparations, were used wherever indicated.

From the DermatoVenereology (Skin/VD) Center, Sehgal Nursing Home, Panchwati, Delhi;1 School of Dermatology, Skin Institute, Greater Kailash, New Delhi;2 and the Department of Conservative Dentistry and Endodontics, Government Dental College, Raipur, India3 Address for Correspondence: Virendra N Sehgal MD, FNASc, FAMS, FRAS (Lond), DermatoVenerology (Skin/VD) Center, Sehgal Nursing Home, A/6 Panchwati, Delhi-110 033, India • E-mail: drsehgal@ndf.vsnl.net.in

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Table I. Oral Lichen Planus: Age Groups by Sex Sex

Age Groups (n, %)

Subtotal

<20

20 to 39

40 to 59

â&#x2030;Ľ60

Men

0 (0.00)

5 (15.15)

3 (9.10)

13 (39.40)

Women

1 (3.03)

4 (12.12)

12 (36.36)

3 (9.10)

20 (60.60)

Total

1 (3.03)

9 (27.27)

17 (51.51)

6 (18.20)

33 (100)

Clinical pattern

Table II. Oral Lichen Planus: Site of Involvement Site

Number

Percentage

Buccal mucosa

54.54

Labial mucosa/floor of mouth

9.10

Tongue

6.06

Lip

0.00

Palate/gingiva

30.30

The lesions conformed to a reticular pattern comprising papular, plaque-like (Figures 1 and 2) and lacy lesions in 20 (60.60%) patients, an erythematous/atrophic pattern in eight (24.20%), and an erosive/ulcerated and bullous pattern in five (15.20%) (Table III). Pain and burning sensations aggravated by eating spicy foods were recorded in 12 (36.36%), patients. The remaining 21 (63.6%) were asymptomatic.

Potential causative factors Ultimately, the proforma recordings were transferred onto an SPSS software worksheet (Package for the Social Sciences, version 10.0; SSPS Inc., Chicago, IL) and subjected to statistical analysis. RESULTS Of the 33 (16.50%) patients with OLP, 20 (60.60%) were women and 13 (39.40%) were men. Their overall mean age at presentation was 44.30 years, with a standard deviation of 13.90 years. Age ranged from 19 to 74 years, the standard deviation being 13.94 years. The mean age of the men was 42 years, with a standard deviation of 14.0 years, and their age ranged from 20 to 74 years. In contrast, the mean age of the women was 45 years, with a standard deviation of 13.60 years, and the age range was 19 to 70 years.

Age groups A comprehensive account of age groups distribution by sex is displayed in Table I.

Site of OLP Buccal mucosa was affected in 18 (54.54%) patients, followed by palate and gingiva in 10 (30.30%), labial mucosa in 3 (9.10%), and tongue in 2 (6.06%) (Table II). The lip was not involved in any of the patients. In a few cases, there was bilateral involvement of the buccal mucosa. SKINmed. 2017;15:333â&#x20AC;&#x201C;337

Several incriminating and/or exacerbating factors were identified, as shown in Table IV. Tobacco, either smoking and/or chewing, and alcohol were the common offenders, followed by dental amalgam. None of the patients gave any significant history related to hepatitis. Six (18.2%) of the 33 patients had associated cutaneous lesions of lichen planus involving the nails, wrists, and ankles. A single patient had widespread mucocutaneous involvement, with oral lesions present over the buccal mucosa bilaterally, and lesions on the ankles, the lower regions of both legs, the arms, and the wrists. There was extensive diffuse hyperkeratotic thickening of the palms and soles, with nail involvement. Basal cell damage and alterations comprising vacuolization and liquefaction degeneration, were cardinal signs. Melanin incontinence was a regular feature. In addition, multiple spherical, eosinophilic hyaline Civatte bodies were seen in or just beneath the epidermis. Bandlike dermal infiltrates of T lymphocytes and a few macrophages were prominent, and were approximating the undersurface of the epidermis. A few cells were found invading the epidermis. The lymphohistiocytic infiltrate did not, however, obscure the interface or extend into the midepidermis. The prominent epidermal changes were compact orthokeratotsis, hyperkeratosis, hypergranulosis, and variable acanthosis giving an anatomical sawtooth appearance (Figure 3). DISCUSSION Lichen planus, a chronic autoimmune disease involving the skin and/or mucous membrane, seems to be related to a type IV hy-

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Table III. Oral Lichen Planus: Clinical Pattern Clinical Form

Number

Percentage

Clinical Manifestations (Number, %)

Reticular (papular, plaque-like, and lacy)

60.60

Yes = 5 (25.00); no = 15 (75.00)

Erythematous (atrophic)

24.20

Yes = 3 (37.50); no = 5 (62.50)

Erosive (ulcerated and bullous)

15.20

Yes = 4 (80.00); no = 1 (20.00)

Total

100.00

Yes = 12 (35.40); no = 21 (63.60)

Figure 1. Depiction of the reticular configuration of oral lichen planus.

Table IV. Oral Lichen Planus: Potential Causative and/or Exacerbating Factors Incriminating factors

Number

Percentage

Tobacco

39.40

Alcohol

21.21

Tobacco + alcohol

15.15

Dental amalgam

24.24

planus. The estimated prevalence of the former is 0.5% to 3%11, whereas the prevalence of latter is fairly high.12 A large majority of patients were in the age group 20 to 60 years, the most commonly affected sex being women, which is the salient feature of the demographic profile seen here and reiterates previously reported data.9,10,13,14

Figure 2. Lichenoid tissue reaction induced by dental amalgam.

persensitivity reaction to various antigens. Its estimated prevalence in the general population is 2%.7 OLP is a unique entity that affects the mucosal lining of the oral cavity.10 It may be either an exclusive condition or a component of cutaneous lichen 7â&#x20AC;&#x201C;9

SKINmed. 2017;15:333â&#x20AC;&#x201C;337

Several exogenous factor(s) are known to trigger OLP.8,15,16 It is therefore worthwhile emphasizing that tobacco chewing, smoking and alcohol intake may aggravate the condition, a striking revelation of this study from the Indian subcontinent. These findings are in contrast to other studies.17,18

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Figure 3. Oral lichen planus/prototype depicting a lichenoid tissue reaction characterized by vacuolization and liquefaction degeneration of the basal cells, with a bandlike lymphocytic infiltrate containing Civatte bodies and melanin pigment (hematoxylin and eosin stain, magnification Ă&#x2014;10).

The triggering factors mentioned above may facilitate malignant transformation. Although the precise mechanism is unknown, it is speculated that the development of cancer in OLP could result from an interaction of the atrophic mucosa with tobacco carcinogens.19 In addition, tobacco could support tissue destruction in OLP through irritation and other well-established mechanisms.20â&#x20AC;&#x201C;23 c-Met receptors have recently been incriminated.24 Dental amalgam, a well-known trigger for lichenoid tissue reactions, may cause or exacerbate the existing OLP.25 Twenty-one (63.6%) patients had no clinical manifestations, while pain and burning sensations aggravated by spicy food were the presenting feature in the rest. Clinical manifestations were explicit in erosive form. Similar results have been reported in previous studies.17,26 The morphological characteristics seen here corresponded to the well-known pattern of OLP.14,17,27,28 The condition was characSKINmed. 2017;15:333â&#x20AC;&#x201C;337

terized by reticular, comprising papular, plaque-like, and lacy, lesions (60.6%), erythematous/atrophic lesions (24.2%), and erosive/ulcerated and bullous lesions (15.2%). Interestingly, buccal mucosa (54.54%) was the most commonly affected site, followed by palate and gingiva (33.30%), labial mucosa (9.10%), and tongue (6.06%). The histopathology is a useful adjunct to confirm the diagnosis. It is may be relevant to bear in mind the characteristic microscopic pathology, comprising an infiltration of inflammatory cells with a predominance of lymphocytes forming a dense band under the epithelium, and features of hydropic degeneration of the basal cell layer with local loss of the distinct epithelialconnective tissue interface. Additionally, pigment incontinence and exocytosis may be seen. Other histopathological findings include hyperorthokeratosis or hyperparakeratosis, acanthosis, and thickening of the spinous layer.

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CONCLUSIONS OLP is one of the major components of mucosal lesions of the oral cavity. Research is needed to establish its clinical pattern, in order to create an awareness among clinicians, encouraging worldwide studies. References

15 Sugerman PB, Savage NW. Oral lichen planus: Causes, diagnosis and management. Aust Dent J. 2002;47:290– 297. 16 Torti DC, Jorizzo JL, McCarty MA. Oral lichen planus: A case series with emphasis on therapy. Arch Dermatol. 2007;143:511–515. 17 Xue JL, Fan MW, Wang SZ, et al. A clinical study of 674 patients with oral lichen planus in China. J Oral Pathol Med. 2005;34:467–472.

1 Sehgal VN, Syed NH, Aggarwal A, Sehgal S. Oral mucosal lesions: oral cavity biology—part 1. SKINmed. 2015;13:297–300.

18 Carbone M, Arduino PG, Carrozzo M, et al. Course of oral lichen planus: A retrospective study of 808 northern Italian patients. Oral Dis. 2009;15:235–243.

2 Mathew AL, Pai KM, Sholapurkar AA, et al. The prevalence of oral mucosal lesions in patients visiting a dental school in Southern India. Indian J Dent Res. 2008;19:99–103.

19 Gonzales-Moles MA, Scully C, Gil-Montoya JA. Oral lichen planus: Controversies surrounding malignant transformation. Oral Dis. 2008;14:229–243.

3 Shulman JD, Beach MM, Rivera-Hidalgo F. The prevalence of oral mucosal lesions in U.S. adults: Data from the Third National Health and Nutrition Examination Survey, 1988–1994. J Am Dent Assoc. 2004;135:1279–1286.

20 Novak MJ. Classification of diseases and conditions affecting the periodontium. In: Newman MG, Takei HH, Klokkevold PR, Carranza FA, editors. Carranza’s Clinical Periodontology. 10th ed. St. Louis, Missouri: Elsevier; 2007. pp. 103–104.

4 Shulman JD, Beach M, Rivera-Hidalgo F. Prevalence of oral mucosal lesions in children and youths in the USA. Int J Paediatr Dent. 2005;15:89–97. 5 Sehgal VN, Syed NH, Sehgal S. Oral mucosal lesions: miscellaneous—part III. Skinmed. 2016;14:193–201. 6 Sehgal VN, Syed NH, Aggarwal A, et al. Oral mucosal lesions: Oral lichen planus and lichenoid tissue reaction/ interface dermatitis—part II. SKINmed. 2015;13:461– 466. 7 Anuradha CH, Reddy BV, Nandan SR, et al. Oral lichen planus. A review. N Y State Dent J. 2008;74:66–68. 8 Ismail SB, Kumar SK, Zain RB. Oral lichen planus and lichenoid reactions: Etiopathogenesis, diagnosis, management and malignant transformation. J Oral Sci. 2007;49:89–106. 9 Mollaoglu N. Oral lichen planus: A review. Br J Oral Maxillofac Surg. 2000;38:370–377. 10 Chan ES, Thornhill M, Zakrzewska J. Interventions for treating oral lichen planus. Cochrane Database Syst Rev. 2000;(2):CD001168. 11 Farhi D, Dupin N. Pathophysiology, etiologic factors, and clinical management of oral lichen planus, part I: Facts and controversies. Clin Dermatol. 2010;28:100–108. 12 Scully C, Carrozzo M. Oral mucosal disease: Lichen planus. Br J Oral Maxillofac Surg. 2008;46:15–21. 13 Axell T, Rundquist L. Oral lichen planus–A demographic study. Community Dent Oral Epidemiol. 1987;15:52–56. 14 Eisen D. The clinical features, malignant potential, and systemic associations of oral lichen planus: A study of 723 patients. J Am Acad Dermatol. 2002;46:207–214.

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21 Regezi JA, Sciubba JJ, Jordan RCK. Oral Pathology. Clinical Pathologic Correlations. 5th ed. San Francisco, California: Saunders Elsevier; 2008. 22 La Rocca G, Anzalone R, Magno F, et al. Cigarette smoke exposure inhibits extracellular MMP-2 (gelatinase A) activity in human lung fibroblasts. Respir Res. 2007;8:23. 23 Kaddah S, Rashed L, Obaia E, et al. A preliminary study: Matrix metalloproteinase expression as an indicator of the hazards of shisha (nargila) smoking. Arch Med Sci. 2009;5:570–576. 24 Klosek SK, Sporny S, Stasikowska-Kanicka O, et al. Cigarette smoking induces overexpression of c-Met receptor in microvessels of oral lichen planus. Arch Med Sci. 2011;7:706–712. 25 Aggarwal V, Jain A, Kabi D. Oral lichenoid reaction associated with tin component of amalgam restorations: A case report. Am J Dermatopathol. 2010;32:46–48. 26 Gorsky M, Raviv M, Moskona D, et al. Clinical characteristics and treatment of patients with oral lichen planus in Israel. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 1996;82:644–649. 27 Hietanen J, Paasonen MR, Kuhlefelt M, et al. A retrospective study of oral lichen planus patients with concurrent or subsequent development of malignancy. Oral Oncol. 1999;35:278–282. 28 Pakfetrat A, Javadzadeh-Bolouri A, Basir-Shabestari S, et al. Oral lichen planus: A retrospective study of 420 Iranian patients. Med Oral Patol Oral Cir Bucal. 2009;14:E315–E318.

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September/October 2017

Volume 15 • Issue 5

ORIGINAL CONTRIBUTION

Vitamin D Deficiency in an Alopecia Referral Clinic During a 3-Month Period: The Need to Pursue Systemic Screening Zuhair Siddiqui, MPH;1 Rashid M. Rashid, MD, PhD;2 Paradi Mirmirani, MD3 Abstract Alopecia is typically viewed as a localized process, and comorbidities are not usually analyzed. The authors examine the prevalence of vitamin D deficiency among patients attending an alopecia clinic during a 3-month period. The data showed that 79% of patients had vitamin D deficiency, and the average value of low vitamin D was 19.1 mg/mL in patients. Vitamin D levels have not been examined extensively in skin disorders, and it is not clear whether vitamin D levels are correlative or causative in alopecia. The co-occurrence of both findings at such a dramatic level suggests the need for evaluation of this laboratory value in the alopecia population. (SKINmed. 2017;15:339–341)

lopecia is traditionally perceived as a cosmetic and/or localized disease process. The role of comorbidities, outside of psychiatric manifestations, is rarely discussed and comorbidities are not regularly screened in most patients with alopecia. Methods In this contribution, we present and discuss our data on vitamin D levels in patients with scarring alopecia. To study this topic, we evaluated the vitamin D level of patients who presented to an alopecia clinic during a 3-month period (March to May). A total of 57 patients were evaluated. The institutional vitamin D level for low values was established as ≤30 mg/mL. Results The data show that 79% of patients had low vitamin D levels. The average value of patients with low vitamin D was 19.1. Of the nonscarring alopecia subgroups, low vitamin D was noted in 100% (6 of 6) of patients with alopecia areata (AA), 87.5% (7 of 8) of female pattern hair loss cases, 71% (19 of 22) of telogen effluvium (TE), 100% of cases in which TE presented as an overlap with another alopecia, and 72% (13 of 18) of patients with androgenetic alopecia. These values are compared with low

vitamin D found in 50% (4 of 8) of all scarring alopecia patients in Figure 1. In the scarring subgroups, low vitamin D was found in 75% (3 of 4) of patients with central centrifugal cicatricial alopecia and 50% (1 of 2) of patients with traction alopecia. In this time period, the clinic had 1 patient with lichen planopolaris who had normal vitamin D levels (0 of 1) (Figure 2). Because of the potential confounding seasonality of sunlight, the charts of patients with alopecia were reviewed from September to November to assess vitamin D levels. In this group, 76% of patients had low vitamin D levels. Patient age ranged from 21 to 69 years, with a mean age of 41 years. No age-associated pattern was noted in the level of vitamin D deficiency. Although some authors have been advocating a decrease in the cutoff for vitamin D level deficiency, we did not include this cutoff in our evaluation. The lower cutoff may increase sensitivity and be more appropriate to identify deficient patients, but we lack the authority to decide on this new standard. This paper only serves as a brief and early glimpse into our clinic’s data. Should a new cutoff be widely incorporated, our data can be reevaluated. Discussion More extensive research in diseases that are historically perceived as “systemic” has shown that patients who are “sick” tend to be sick in more than one parameter. For example, low vitamin D

From the University of Texas at Houston School of Public Health, Houston, TX;1 the Mosaic Clinic: FUE Hair Transplant Center, Houston, TX;2 and the Dermatology Department, Kaiser Permanente Health Network, Vallejo, CA3 Address for Correspondence: Zuhair Siddiqui, MPH, University of Texas at Houston, 6431 Fannin Street, Houston, TX 77030 • E-mail: Zuhair.A.Siddiqui@uth.tmc.edu

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ORIGINAL CONTRIBUTION is difficult to theorize. These patients may be avoiding outdoor activities because of self-esteem issues, or they may be wearing extra sun protective accessories, such as hats, more often. Further studies would be required to evaluate these and other theories. Recently, a single study showed that the vitamin D receptor is not directly associated with AA, although this does not speak of the other parts of the vitamin D pathway.6 The 100% correlation of AA with low vitamin D in our results could be the result of a multifactorial role that includes patients avoiding the outdoors more often because of increased patches of alopecia. AA is also sudden in onset and notable in social situations, causing potential avoidance of outdoor activities. This is in contrast to other alopecias that tend to have a more discrete and slower onset.

Figure 1. Percentage of nonscarring alopecia patients with vitamin D deficiency compared with scarring alopecia patients. Low vitamin D was examined in patients with alopecia areata (AA), female pattern hair loss (FPHL), telogen effluvium (TE), and androgenetic alopecia (AGA). These groups are compared with patients with low vitamin D found in all scarring alopecia (SA) patients. The values above the bar indicate the percentage of patients with vitamin D deficiency.

These data add a potential important screening tool to the alopecia evaluation scenario. Vitamin D has known roles in hair development and early hair cycles.7 It is not clear whether vitamin D level is correlative (as diabetes correlates with hypertension) or causative (as diabetes causes neuropathy) in alopecia. Dermatologic conditions are only starting to be perceived as a correlative systemic disease. For example, psoriatic patients are now viewed to be at increased risk for cardiac disease. Just as a primary care physician would screen an obese or hypertensive patient for diabetes (comorbidities that do not directly cause each other), larger studies may further justify such screenings in a more comprehensive alopecia evaluation. The ability to see the dermatology patient as having more than one “localized” diagnosis will only improve patient care. Regardless of the reason for this co-occurrence of conditions, when such patients present to us, comprehensive evaluation is important. Study Limitations

Figure 2. Percentage of scarring alopecia patients with vitamin D deficiency. Low vitamin D was examined in patients with central centrifugal cicatricial alopecia (CCCA), traction alopecia, and lichen planopolaris (LPP).

levels are noted in patients with heart failure and diabetes.1,2 On national levels, approximately 70% of Germans, 70% to 90% of Canadians, and 30% to 75% of Americans3,4 have low vitamin D levels. Vitamin D levels have not been examined as extensively in skin disorders as they have in systemic disorders. The percentage of vitamin D–deficient cases in skin disorders appears to be on the higher end of national estimates (90% of patients).5 The reason that alopecia patients are on the higher end of the spectrum SKINmed. 2017;15:339–341

Certain limitations of this study must also be taken into account. These include the specialty nature of the clinic, and thus the selection bias of the patient population. Larger studies would greatly benefit from the exploration of this topic. Larger studies could also shed light on many of the questions that remain, such as a possible age-related pattern to vitamin D levels. We did not incorporate or collect ethnicity data. Studies have suggested vitamin D variations by ethnicity, as this may play a role. Conclusions Further studies are required to determine whether vitamin D and alopecia are correlated in severity or response to therapy. The co-occurrence of both findings at such a dramatic level suggests the need for evaluation of this laboratory value in the alopecia population. We hope that this study serves as a platform to fur-

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ther analysis and inquiry into this topic as we strive to better understand and help our hair loss patients. Acknowledgment The Women’s Dermatologic Society and the North American Hair Research Society provided mentorship grants. References 1 Pilz S, Tomaschitz A, Drechsler C, Dekker JM, März W. Vitamin D deficiency and myocardial diseases. Mol Nutr Food Res. 2010;54:1103–1113. 2 Liu E, Meigs JB, Pittas AG, et al. Predicted 25-hydroxyvitamin D score and incident type 2 diabetes in the Framingham Offspring Study. Am J Clin Nutr. 2010;91:1627– 1633. 3 Zittermann A. The estimated benefits of Vitamin D

for Germany. Mol Nutr Food Res. 2010;54:1164– 1171. 4 Ginde AA, Liu MC, Camargo CA Jr. Demographic differences and trends of Vitamin D insufficiency in the US population, 1988-2004. Arch Intern Med. 2009;169:626– 632. 5 Cutillas-Marco E, Morales-Suárez-Varela MM, MarquinaVila A, Grant WB. Serum 25-hydroxyvitamin D levels in patients with cutaneous lupus erythematosus in a Mediterranean region. Lupus. 2010;19:810–814. 6 Akar A, Orkunoglu FE, Tunca M, Tastan HB, Kurumlu Z. Vitamin D receptor gene polymorphisms are not associated with alopecia areata. Int J Dermatol. 2007;46:927– 929. 7 Amor KT, Rashid RM, Mirmirani P. Does D matter? The role of vitamin D in hair disorders and hair follicle cycling. Dermatol Online J. 2010;16:3

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Edward L. Keyes Resident Contest for Outstanding Case Reports 13th World Congress of the International Academy of Cosmetic Dermatology Dubrovnik, Croatia June 28–July 1, 2018 Abstract deadline: March 31, 2018 To be awarded for the best Case Report submitted by a physician in training (resident, fellow, or registrar) for presentation at the 13th World Congress of the International Academy of Cosmetic Dermatology in Dubrovnik, Croatia from June 28–July 1, 2018. We invite you to submit original Case Reports that reflect the presentation of new ideas and original observations to the Academy membership and other attendees of the Congress. The case may be medical, surgical, and cosmetic (or combined) in nature. The author whose abstract obtains the highest score during the review process will receive a scholarship by the IACD to present the full paper at the 13th World Congress of the International Academy of Cosmetic Dermatology in Dubrovnik, Croatia from June 28-July 1, 2018. The scholarship will provide reasonable travel expenses, lodging for 3 nights, the Congress registration fee, and a basic spending stipend. Please submit your case report abstract via email to vrosic@medicine.bsd.uchicago.edu before noon, CDT, March 31, 2018. The abstract should be no longer than 2,500 characters including spacing. Material that was previously presented, published, or submitted for publication should not be offered. Applications will be graded based upon the educational value of the abstract and the extent to which it presents new and significant work. The Review Committee strongly recommends that abstracts have an organized, coherent, well-thoughtout, and complete presentation. Please note that no paper submitted for consideration will be eligible if it has already been, or is in consideration for, publication elsewhere at any time prior to the meeting. The winner(s) agree to publish their outstanding case report(s) in SKINmed: Dermatology for the Clinician, an official publication of the International Academy of Cosmetic Dermatology. By submitting your paper for consideration, you give SKINmed: Dermatology for the Clinician first-rights of refusal for publication through December 31, 2018. The applicant must be in training at the time of the Congress presentation. All applicants will receive e-mail notice of the Resident Case Report Review Committee’s decision by May 1, 2018. Vesna Petronic-Rosic, MD, MSc Chair, Resident Contest Committee Professor and Chief The University of Chicago Pritzker School of Medicine Section of Dermatology Tel: +1.773.702.6559 vrosic@medicine.bsd.uchicago.edu

September/October 2017

Volume 15 • Issue 5

ORIGINAL CONTRIBUTION

Angiokeratoma of the Glans Penis Bryce D. Beutler, BS;1 Philip R. Cohen, MD2 Abstract Angiokeratomas are benign vascular lesions characterized by ectatic blood vessels in the papillary dermis with overlying acanthosis and hyperkeratosis, often occurring as idiopathic scrotal tumor and rarely as penile lesions. Twelve men, including our case of a 58-year-old white man, have been reported with angiokeratomas of the glans penis. The lesions typically present as asymptomatic dome-shaped papules ranging in size from 0.5 to 5 mm and present as red, purple, blue, or black lesions along the penile coronal rim. Histopathologic examination of the lesions reveals dilated, thin-walled vascular structures in the upper portion of the dermis with overlying acanthosis and/or hyperkeratosis. Such angiokeratomas may have a multifactorial etiology with elevations in local venous pressure, degeneration of elastic tissue, and/or capillary injury. Biopsy would exclude a melanocytic lesion, particularly melanoma. Laser surgery is an option for patients presenting with multiple lesions or lesions that coalesce to form a plaque. (SKINmed. 2017;15:343–347)

ngiokeratomas are benign vascular lesions that occur in several clinical settings, commonly arising as idiopathic tumors on either the scrotum1,2 or the vulva.3 Rarely, angiokeratomas can develop as solitary or multiple lesions on the glans penis.4–13 Such lesions are morphologically and histologically identical to angiokeratomas at other sites. They present as red, purple, blue, or black dome-shaped papules that range in size from 0.5 to 5 millimeters in diameter. Histologically, they are characterized by thin-walled dilated blood vessels in the upper portion of the dermis with overlying acanthosis and/or hyperkeratosis. Case Report A 58-year-old Caucasian man presented for evaluation with an asymptomatic lesion on his glans penis that was present for 2 years. He had no known history of sexually transmitted infections, including condylomas or skin cancer. Physical examination revealed a dome-shaped, purple-black papule, measuring 2×1 mm on the right ventral surface of his glans penis (Figure 1). The patient stated that the lesion had failed to respond to previous treatment with cryotherapy. A shave biopsy was performed. Histopathologic examination revealed a well-demarcated dermal lesion with hyperkeratosis

(with focal areas of hemorrhage) and thickening of the overlying epidermis that extended in a collarette fashion closely abutting the dilated vascular structures. The vessels contained erythrocytes and were lined by thin-walled, benign-appearing endothelial cells. In some areas, fibrin was embedded into the vascular wall and present within the lumen (Figures 2–4). Discussion Angiokeratomas are benign vascular lesions that typically present as 0.5 to 5 millimeter dome-shaped papules. They are most commonly observed on the scrotum1,2 and vulva3 but have also been reported on the glans penis, as in our patient, and the clitoris.14 There are four variants of localized angiokeratomas: (1) angiokeratoma circumscriptum, (2) angiokeratoma of Fordyce, (3) angiokeratoma of Mibelli, and (4) solitary angiokeratoma (Table I). While our patient presented with a solitary angiokeratoma, the morphologic features of the lesion were most suggestive of angiokeratoma of Fordyce. Angiokeratomas may also appear in association with Fabry disease, an X-linked lysosomal storage disorder caused by a mutation in the GLA gene and a resultant deficiency of the enzyme

From the University of Nevada Reno School of Medicine, Reno, NV;1 and the Department of Dermatology, University of California San Diego School of Medicine, La Jolla, CA2 Address for Correspondence: Philip R. Cohen, MD, Department of Dermatology, University of California San Diego School of Medicine, 8899 University Center Lane #350, MC0975, San Diego, CA 92122 • E-mail: mitehead@gmail.com

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ORIGINAL CONTRIBUTION alpha-galactosidase A. In the absence or deficiency of alphagalactosidase A, its substrate, the ganglioside globotriaosylceramide, accumulates within cutaneous endothelial cells, which subsequently swell and bulge into the lumen of blood vessels. Consequently, the channels of the vessels narrow, causing weakness of the capillary wall and secondary ectasia.15 Angiokeratomas associated with Fabry disease typically present as dark red, blue, or black papules that range in size from 1 to 10 millimeters in diameter. Lesions first appear in adolescence, most commonly between the lower portion of the abdomen and the knees, and tend to become increasingly keratotic over time. Fabry disease is predominantly found in Caucasian men.

Figure 1. A dome-shaped, purple-black papule measuring 2×1 mm on the right ventral surface of the glans penis of a 58-year-old man.

The glans penis is an uncommon location for angiokeratomas. Angiokeratoma of the glans penis has only been reported in 12 men, including our patient (Table II).4–13 All of the cases, except for our patient, presented with multiple lesions. To the best of our knowledge, our patient is the first man to present with a single angiokeratoma on his glans penis.

(A)

(B)

(C)

Figure 2. Low- (A), intermediate- (B), and high- (C) magnification views of angiokeratoma of the glans penis histology. There is hyperkeratosis, acanthosis, and extension of the epidermis into the underlying dermis to form a collarette that envelops numerous endothelial-lined blood vessels containing erythrocytes in the upper dermis. (Hematoxylin and eosin, original magnification ×4 [A], ×10 [B], and ×20 [C]). SKINmed. 2017;15:343–347

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Table I. Variants of Localized Types of Angiokeratoma Variant

Clinical Presentation

Angiokeratoma circumscriptum

Typically appears as a solitary papule or plaque with irregular borders Varies in size, from 1–3 millimeters to several centimeters in diameter Elevated and hyperkeratotic Dark red, purple, or black Most commonly appears on lower extremities May arise on the tongue

Angiokeratoma of Fordyce

May appear as solitary or multiple dome-shaped papules 1–6 millimeters in diameter Overlying scaling may be present Dark red, blue, or black Most commonly appears on the scrotum Often arises on the genitals (labia majora and shaft of penis)

Angiokeratoma of Mibelli

Typically appear as multiple vascular papules 1–5 millimeters in diameter Slightly hyperkeratotic surface Blue, red, or gray Most commonly appears on bony prominences, especially fingers and toes May be associated with acrocyanosis and chilbains

Solitary angiokeratoma

Presents as a solitary, warty papule 2–10 millimeters in diameter Elevated and keratotic Red, blue, or black May become increasingly keratotic and darker in color over time Most commonly appears on lower extremities

The lesions were asymptomatic and nontender in all 12 men. Minor bleeding was reported in two patients.4,5 Lesions ranged in size from 0.5 to 5 millimeters in diameter and were either red, dark red, purple, blue, or black. Numerous angiokeratomas coalesced to form a violaceous crusted plaque in one case.4 The most common site of the lesions was the corona of the glans penis. Other sites included the dorsal and ventral surfaces of the glans penis, as well as the distal glans penis. Most of the men were Caucasian, with one man of mixed ethnic background (Caucasian and Asian)4 and another described as Turkish.5 All of the lesions had similar pathologic features: ectatic, thinwalled vascular spaces in the papillary dermis with overlying acanthosis and/or hyperkeratosis. In some patients, the blood vessels were thrombosis. An “epidermal collarette”––in which the vascular spaces were surrounded by an extension of the epidermis into the dermis–– could often be identified. Erythrocytes were observed within the lumen of the blood vessels in all 12 men. The clinical differential diagnosis of angiokeratoma of the glans penis is listed in Table III. It includes both localized vascular and nonvascular lesions. In our patient, in addition to a benign vascular tumor, diagnoses of malignant melanoma and pigmented basal cell carcinoma were also considered. The mechanism of pathogenesis for genital angiokeratomas is unknown. Several hypotheses have been proposed. Angiokeratomas might arise as the result of a congenital defect affecting the walls of the venules.16 Another hypothesis suggests that the le-

Table II. Reports of Angiokeratoma of the Glans Penis Case

Age

Location

Size

Color

Treatment

Reference

Distal glans penis

4–5 mm

Dark purple to black

595-nm pulsed-dye laser

10 (at onset)

Corona of glans penis

2–4 mm

Dark red to blue

532-nm neodymium:YAG laser

Ventral and dorsal surfaces of glans penis

2–4 mm

Dark red-purple

None

Corona of glans penis

2–4 mm

Black

Electrocautery excision

Corona of glans penis

0.5–3 mm

Blue-purple

None

Corona of glans penis

2–4 mm

Red-purple

Excisional biopsy

Corona of glans penis

1–2 mm

Dark red to blue

2,940-nm erbium:YAG laser and 532 nm KTP laser

Right side of glans penis

1–2 mm

Purple-black

Excisional biopsy

Current report Continued

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Table II. Reports of Angiokeratoma of the Glans Penis (Continued) Case

Age

Location

Size

Color

Treatment

Reference

Dorsal corona of glans penis

0.5–2 mm

Red

None

Left side of glans penis

2–4 mm

Red-purple

None

Ventral surface of glans penis

1–4 mm

Red-purple

Emollients

Ventral and dorsal surfaces of glans penis

0.5–1 mm

Purple

None

Conclusions

Table III. Clinical Differential Diagnosis of Angiokeratoma of the Glans Penis Vascular lesions

Nonvascular lesions

Capillary aneurysm

Basal cell carcinoma

Cherry hemangioma

Condyloma acuminata

Petechial angioma

Dermatofibroma

Pyogenic granuloma

Kaposi's sarcoma

Spitz/Reed nevus

Melanoma

Angiokeratomas of the glans penis are rare, asymptomatic domeshaped papules that typically range in size from 0.5 to 5 millimeters and appear as red, dark red, blue, purple, or black papules. They most commonly present as multiple lesions along the coronal rim of the glans penis, although lesions may appear on the dorsal or ventral surfaces of the glans penis as well as the tip of the penis.

Seborrheic keratosis

References

Squamous cell carcinoma

1 Majumdar S, Saha SS. Angiokeratoma of the scrotum (Fordyce). Indian J Dermatol Venereol Leprol. 1996;62:52– 54.

Verruca vulgaris

2 Miller C, James WD. Angiokeratoma of fordyce as a cause of red scrotum. Cutis. 2002;69:50–51.

sions develop as a result of capillary injury secondary to trauma or local venous hypertension.17 One patient had an ipsilateral left-sided varicocele; notably, angiokeratomas appeared on the left side of his glans penis. Another had chronic bronchial asthma, which can increase intra-abdominal pressure. In both of these patients, local venous hypertension may have occurred secondary to the respective medical conditions.9 Angiokeratomas on the glans penis are benign and typically asymptomatic, making treatment unnecessary, although several modalities could be utilized for removal, including excision. Excellent cosmetic results have also been achieved with laser surgery. In one patient who presented with numerous lesions coalescing into a violaceous crusted plaque, treatment with a 595-nm pulsed dye laser resulted in complete clinical resolution.4 Other modalities have included a 532-nm neodynium:YAG laser,5 an erbium:YAG laser, and a 532-nm KTP (frequency doubled neodynium:YAG) laser.10 SKINmed. 2017;15:343–347

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3 Cohen PR, Young AW Jr, Tovell HM. Angiokeratoma of the vulva: diagnosis and review of the literature. Obstet Gynecol Surv. 1989;44:339–346. 4 Burnett CT, Kouba DJ. A rare case of congenital angiokeratoma of the glans penis treated using a 595-nm pulsed dye laser. Dermatol Surg. 2012;38:2028–2030. 5 Bechara FG, Huesmann M, Stucker M, Altmeyer P, Jansen T. An exceptional localization of angiokeratoma of fordyce on the glans penis. Dermatology. 2002;205:187– 188. 6 Carrasco L, Izquierdo MJ, Fariña MC, et al. Strawberry glans penis: a rare manifestation of angiokeratomas involving the glans penis. Br J Dermatol. 2000;142:1256– 1257. 7 Dudani S, Maskara M. Multiple angiokeratomas of fordyce: lesions at an unusual site causing a diagnostic dilemma. Indian J Dermatopathol Diagn Dermatol. 2014;1:46–48. 8 Keen MA, Hassan I. Eruptive angiokeratomas on the glans penis. Indian J Dermatol. 2014;59:424. 9 Erkek E, Basar MM, Bagci Y, et al. Fordyce angiokeratomas as clues to local venous hypertension. Arch Dermatol. 2005;141:1325–1326.

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ORIGINAL CONTRIBUTION

10 Bechara FG, Jansen T, Wilmert M, Altmeyer P, Hoffmann K. Angiokeratoma fordyce of the glans penis: combined treatment with erbium: YAG and 532 nm KTP (frequency doubled neodynium: YAG) laser. J Dermatol. 2004;31:943–945. 11 Feramisco JD, Fournier JB, Zedek DC, Venna SS. Eruptive angiokeratomas on the glans penis. Dermatol Online J. 2005;15:14. 12 Leis-Dosil VM, Alijo-Serrano F, Aviles-Izquierdo JA, Lazaro-Ochaita P, Lecona-Echeverria M. Angiokeratoma of the glans penis: clinical, histopathological and dermoscopic correlation. Dermatol Online J. 2007;13:19. 13 Bruce DH. Angiokeratoma circumscriptum and angiokeratoma scroti. Report of a case. Arch Dermatol. 1960;81:388–393.

14 McNeely TB. Angiokeratoma of the clitoris. Arch Pathol Lab Med. 1992;116:880–881. 15 Larralde M, Boggio P, Amartino H, Chamoles N. Fabry disease: a study of 6 hemizygous men and 5 heterozygous women with emphasis on dermatologic manifestations. Arch Dermatol. 2004;140:1440–1446. 16 Patrizi A, Neri I, Trevisi P, Landi C, Bardazzi F. Congenital angiokeratoma of Fordyce. J Eur Acad Dermatol Venereol. 1998;10:195–196. 17 Haidopoulos DA, Rodolakis AJ, Elsheikh AH, Papaspirou I, Diakomanolis E. Vulvar angiokeratoma following radical hysterectomy and radiotherapy. Acta Obstet Gynecol Scand. 2002;81:466–467

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September/October 2017

Volume 15 • Issue 5

ORIGINAL CONTRIBUTION

Efficacy and Tolerability of a Twice-Daily, Three-Step Men’s Skincare Regimen in Improving Overall Skin Quality and Reducing Shave-Related Irritation Katie Rodan, MD; Kathy Fields, MD; Timothy J. Falla, PhD Abstract More men are beginning to take advantage of opportunities to improve the health and appearance of their skin; however, the effectiveness of men’s skincare regimens has not been well studied. The authors investigated the efficacy and tolerance of a twice-daily, three-step men’s skincare regimen in improving skin appearance and reducing shave-related issues. Twenty-nine men who used a wet-shaving method completed a specific, three-step, twice-daily facial regimen—a Shave Cleanser, a Post-Shave Treatment, and Day Protection—in place of their usual routine for 4 weeks. This skincare regimen produced significant improvements in tactile smoothness, clarity, radiance, and pore size at weeks 2 and 4 and in fine lines, razor burn, and photodamage at week 4 (P<.05). Significant improvements were seen in the appearance of nicks/cuts and folliculitis of the face and neck after weeks 2 and 4 (P<.05). Mean change in the moisture content of the stratum corneum was significant at week 4 (P<.05). The majority of men provided positive self-assessments and indicated an interest in continuing this regimen. (SKINmed. 2017;15:349–355)

istorically, skincare has been focused on the specific needs and desires of women. Recently, however, consumer habits have changed, and more men are taking advantage of opportunities to improve the health and appearance of their skin.1–3 This shift is being driven by changes in cultural attitudes and perceptions, stereotypes, male self-image, and social expectations, with the largest skincare markets for men being Asia Pacific, China, Western Europe, South Korea, East China, and the United States.2–4

Men’s and women’s biologic, physiologic, and functional skin differences are well known.1,5–10 Facial skin differs in thickness, sebum levels, pH, sweat production, subcutaneous fat, transdermal water loss, vasodilation, pore size, sensitivity, and susceptibility to infections.1,5,8,9 The primary differentiator is male hair production and beard hair growth, which create additional skincare needs unique to men.1,8,9,11 Of all men’s grooming practices, shaving is the most common, with an estimated 70% of men using a wet-shaving technique

with a razor blade four to five times per week.1,11 It is not surprising that the most frequently mentioned cosmetic complaint from men in the United States and Europe is shave-induced skin irritation, including erythema, nicks/cuts, burning, stinging, tightness, dryness, and itching.1,9,11 Despite these complaints, the majority of men do not use a skincare regimen.3,4,12 Some men feel skincare is not significant, opening up the possibility that product inefficacy (or the perception of product ineffectiveness) may be more important than cultural stereotypes or entrenched habits in underuse of these products.3 Dermatologic research to determine the clinical and aesthetic benefits of a daily skincare regimen in men has been lacking. This study was done to determine the efficacy and tolerance of a twice-daily, three-step, men’s daily skincare regimen in reducing shave-related issues, improving skin appearance, and assessing men’s willingness to incorporate such a regimen into their daily routine.

From Rodan + Fields, San Francisco, CA. Address for Correspondence: Timothy J. Falla, PhD, Rodan + Fields, 60 Spear Street, San Francisco, CA 94105 • E-mail: tfalla@rodanandfields.com

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ORIGINAL CONTRIBUTION neck and the global (entire) face were evaluated individually for certain parameters.

METHODS

Study Population Men were included in this single-center, 4-week, open-label clinical study if they were between age 30 and 55 years, in good health, and used a wet-shaving method at least five times a week. All subjects were evaluated for skin type (Fitzpatrick Skin Classification Scale) to ensure that 80% had skin type I–IV and 20% had skin type V–VI.13 Those with skin type I–IV were further evaluated for the presence of mild to moderate facial fine lines, using the modified Griffiths scale (score 3–6, where 0=none and 9=severe).14 All subjects were evaluated for the presence of folliculitis (razor bumps) and razor burn (defined as red, macular, irritated areas that occur after shaving). Eligibility criteria were structured to include at least 25% of subjects with folliculitis and/or razor burn. Those with facial acne were eligible if their acne was mild to moderate (score 2–3) according to the Global Acne Severity Scale (0=clear and 5=very severe); those with severe acne (score 4–5) were excluded.15

Acne was assessed using the Global Acne Severity scale.15 Cutaneous tolerability and irritation were evaluated on a 4-point scale (0=none, 1=mild, 2=moderate, 3=severe) for erythema, dryness (feel), and scaling (flaking), and by the subjects’ self-assessment of razor sting. Half-points were used for more accurate descriptions of each parameter.

Subjects were also excluded if they had any known allergies to skincare products or had a sunburn, excessively tanned skin, or any dermatologic disease or other condition that might interfere with the study. Subjects could not have used any antiaging, antiwrinkle, or antioxidant treatments within 30 days of entering the study.

At each study visit, subjects completed a questionnaire about their perceptions and opinions of the efficacy, tolerability, and aesthetic attributes of the shaving regimen and study products. Questions required either a “Yes” or “No” response or a rating of “Significant improvement,” “Slight improvement,” “No change,” “Slightly worse,” or “Much worse.”

Study Design

To ensure treatment compliance, subjects were asked to complete daily diaries. All study products were weighed before distribution, then reweighed, and visually inspected at each study visit.

All subjects who met the eligibility criteria were instructed to complete specific morning and evening facial treatment regimens using a Shave Cleanser, a Post-Shave Treatment, and Day Protection as detailed in the Appendix. The key ingredients of the treatment materials included the following: Shave Cleanser: 3% sulfur, glycerin, aloe; Post-Shave Treatment: 0.5% allantoin, 2.9% dimethicone, honey extract, tetrapeptide-16, oligopeptide-10; Day Protection Treatment: 3% avobenzone, 2.5% homosalate, 5% octisalate, 2.7% octocrylene, tetrapeptide-21, resveratrol. Each subject’s face and neck were evaluated for effectiveness of the test materials at baseline and weeks 2 and 4. Evaluations consisted of clinical grading, tolerability assessments, digital imaging, skin hydration, and self-assessment questionnaires. Clinical grading was conducted by trained evaluators using the modified Griffiths scale for several parameters including clarity, fine lines, the appearance of nicks/cuts, overall appearance, overall appearance of photodamage, pore size, radiance, appearance of folliculitis, razor burn, tactile smoothness, and wrinkles.14 The SKINmed. 2017;15:349–355

The hydration state of each subject’s skin was measured using a Corneometer® CM 825 (Courage + Khazaka Electronic GmbH, Koln, Germany) on either the right or left side of the face (according to a predetermined randomization) at the malar eminence. The CM 825 measures moisture content in the stratum corneum by electrical capacitance, has no units, and is proportional to the dielectric constant of the surface layers of the skin, which increases as the skin becomes more hydrated. CM 825 validity and sensitivity to hydration changes in the skin have been widely documented.16,17

All subjects gave their written informed consent prior to the start of the study in accordance with all applicable local and countryspecific regulations. An institutional review board reviewed and approved this study, which was conducted in compliance with the International Conference on Harmonization Good Clinical Practice guidelines and the Declaration of Helsinki.

Statistical Analyses All statistical analyses were completed on the per-protocol population, defined as all subjects who received treatment materials and completed the study in accordance with the protocol. Descriptive statistics were used to evaluate clinical grading, tolerability evaluations, and skin hydration (CM 825) measurements. For each measure, mean change from baseline, percentage mean change from baseline, and percentage of subjects showing improvement or worsening was calculated. The null hypothesis that the mean change from baseline would be zero was tested using

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a Wilcoxon signed-rank test for clinical grading and tolerability evaluations and using a paired t test for CM 825 measurements. The frequency and percentage of all responses to the subjects’ self-reported questionnaires were tabulated. A binomial test (sign test) was performed to test the null hypothesis that the proportion of the designated favorable response options would be the same as the designated unfavorable response options. All statistical tests were two-sided at a significance level α=0.05. RESULTS A total of 30 men met the eligibility criteria and were enrolled, with 29 subjects completing the study (per-protocol population); one subject was lost to follow-up. Of the per-protocol population, the mean age was 45 years (range 34 to 54 years). The majority were of white ethnicity (n=15; 52%), followed by Hispanic/Latino (n=5; 17%), black (n=5; 17%), Asian (n=3; 10%), and multiracial (n=1; 3%). In line with the study design, the majority of subjects had a Fitzpatrick Skin Classification of type I–IV (n=23; 79%), with 6 (21%) having type V–VI. All but one subject reported folliculitis after shaving (n=28; 97%), and 20 (69%) subjects reported experiencing razor burn.

Efficacy After using the skincare regimen daily, men experienced statistically significant improvement from baseline in key parameters including the appearance of nicks/cuts, folliculitis, and overall appearance of the face and neck and razor burn of the face after 2 and 4 weeks of continued use (P<.05; Figure 1). Improvements (percentage mean change) were also observed in tactile smoothness (6% and 13% at weeks 2 and 4, respectively), clarity (4%, 9%), radiance (5%, 10%), and pore size (4%, 7%), which were significant at weeks 2 and 4, and in fine lines (1%, 7%), razor burn of the neck (25%, 29%), and photodamage (0%, 4%), which were significant at week 4 (P<.05). Three (10%) and 6 (21%) subjects reported an improvement in wrinkles at weeks 2 and 4, respectively, with 1 (3%) subject reporting worsening at week 4; none of these results was significant. Acne at baseline was clear/almost clear, with a mean score of 0.19, which remained unchanged at week 2 and increased (worsened) slightly at week 4 to mean 0.24; however, this was not significant and was considered clear/almost clear using the Global Acne Severity Scale.

FIGURE 1.

WEEK 2

% ME AN C HAN GE F RO M B A S E L I N E

WEEK 4

50* 50* 47*

40* 37* 31* 29*

28*

27 25*

25*

19*

12*

13*

11* 9*

10 5*

0 Nicks/Cuts (Face)

Nicks/Cuts (Neck)

Razor Burn (Face)

Razor Burn (Neck)

Folliculitis (Face)

Folliculitis (Neck)

Acne (Face)

Overall Appearance (Face)

Overall Appearance (Neck)

N=29. *P≤0.05 based on mean change versus baseline (Wilcoxon Signed-Rank test).

Figure 1. Percentage mean change from baseline of efficacy parameters in men who used a twice-daily, three-step, facial skincare regimen. SKINmed. 2017;15:349–355

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Figure 2. Improvements in erythema and the appearance of nicks and cuts after twice-daily use of a three-step facial skincare regimen.

Tolerability No statistically significant changes in any of the tolerability parameters (erythema, dryness [feel], scaling/flaking, razor sting) were observed at any time point. Digital images of the subjects illustrate the types of improvement that were visible after 4 weeks of consistent use of the skincare regimen. Figure 2 corroborates the significant reduction in erySKINmed. 2017;15:349â&#x20AC;&#x201C;355

thema and visible nicks/cuts that was captured in clinical grading parameters.

Skin Hydration The majority of subjects (20 [69%]) demonstrated an improvement in the moisture content of the stratum corneum by week 2. Mean change from baseline was statistically significant after 4 weeks of use, with improvement detected in 24 (83%)

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subjects at week 4 (P<.05). A small proportion of subjects had a worsening of moisture content at weeks 2 (9 [31%]) and 4 (5 [17%]), which was not significant.

Subject Self-Assessment The majority of subjects provided favorable responses regarding the efficacy and tolerability of the test products and shave regimen; the majority of the favorable responses were statistically significant compared to the unfavorable responses (P<.001; Figure 3). The majority of subjects responded “Yes” to questions asking if the regimen provided a close shave, if it was soothing, if they were happy with the results, and if they would continue the regimen; these answers were significant compared to the “No” responses (P<.001; Figure 3a). A majority experienced fewer “bad shave days” by week 4 and less irritation at weeks 2 and 4, which were not significant. Only 5 (17%) and 3 (10%) subjects at weeks 2 and 4 reported experiencing unpleasant or uncomfortable sensations while using the study products. These subjects reported that the level of discomfort experienced was mild or moderate, and all subjects reported the sensations as tolerable. The majority of subjects noticed slight to significant improvements in their skin in all self-rated parameters that were statistically significant at both weeks 2 and 4, compared to those who had a “slightly worse” to “much worse” response (P<.001; Figure 3b). Most subjects reported they were “very satisfied” (48%, 59%) and “somewhat satisfied” (35%, 35%) with this shaving regimen at weeks 2 and 4, respectively, and a minority gave a neutral response (10%, 7%), with only 7% reporting they were “somewhat dissatisfied” at week 2. No subjects were “very dissatisfied” at any time point. DISCUSSION The findings from this study showed that, after 4 weeks of consistent use, this twice-daily regimen was effective and statistically significant in reducing key concerns that men frequently encounter while shaving, such as the appearance of nicks/cuts, razor burn, and folliculitis of the face and neck, as well as stinging, burning, and dryness. In addition, significant improvements were seen in the overall appearance of the face and neck and the skin’s smoothness, clarity, pore size, photodamage, appearance of fine lines, moisture content of the stratum corneum, and overall radiance. Tolerability parameters erythema, dryness (feel), scaling/flaking, and razor sting were all graded as none to mild at baseline, and no statistically significant changes were detected—an indication that the skincare regimen did not cause or exacerbate a worsening of these conditions. Full benefits in all the parameters SKINmed. 2017;15:349–355

measured were seen as early as 2 weeks, with additional benefits observed at 4 weeks. Three (10%) and 6 (21%) subjects reported an improvement in wrinkles at weeks 2 and 4, respectively, with only 1 subject reporting a worsening at week 4. These findings were not significant, possibly due to the relatively young age of the study population (mean age 45 years) and moderate mean wrinkle baseline score (4.29). A longer duration of the treatment regimen in an older population is needed in order to draw meaningful conclusions. Research in male hair removal has identified that some shave irritation can be caused by trapped hair below the stratum corneum, particularly in areas of high susceptibility such as the neck.11 It has been determined that a preshave scrub or cleanser significantly releases trapped hair, resulting in a closer shave, less irritation, and an improved shaving experience, findings that are consistent with this clinical trial in which a preshave cleanser was used.11,18,19 Studies that also included a postshave moisturizer demonstrated improvement in the overall condition of the skin.18,19 Similarly, this study provides clinical evidence that restoring the stratum corneum (which can become damaged during shaving) with emollients and hydrating humectants, such as those in the PostShave Treatment, is a critical component of the regimen, resulting in smoother, more hydrated, and less irritated skin. Men are more susceptible to ultraviolet-induced skin diseases and have a higher incidence of skin cancers than women.20,21 The daily use of Day Protection incorporates much-needed sunprotective factor into the shaving regimens of men who do not regularly use it. Limitations of this study include the relatively low number of subjects and short, 4-week duration, making it difficult to detect small changes and potential differences that might be seen with continued, long-term use. The study also did not account for the variability in subject physiology, shaving behaviors, razor types, and shaving techniques. CONCLUSIONS The findings from this study indicate that a twice-daily, threestep skincare regimen can easily be incorporated into men’s daily schedules with little deviation from traditional routines. The findings also indicate this skincare regimen can provide a reduction in nicks/cuts, folliculitis, razor burn, and photodamage, as well as increased skin smoothness, clarity, and radiance, with the added benefit of sun protection.

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FIGURE 3.A YES

100

90*

86*

3 97*

93*

N E U T RA L

3 97*

90*

83*

% S U B J E CTS

0 2

WEEK

Regimen provided a close shave

Regimen was soothing

Experienced fewer “bad shave days”

Experienced less irritation

Happy with results overall

Would continue skincare regimen

N=29. *P≤0.05 yes versus no responses calculated by binomial test. All categories may not equal 100% due to rounding.

FIGURE 3.B

100

IMP RO VEMEN T (S L IGH T T O S IGNIF IC ANT )

80*

79*

83*

86*

79*

76*

% SUBJ ECT S

86*

NO C H ANGE

93*

90* 7

W O R S E NING (S L IGH T T O MU C H )

86*

72*

79*

76*

69* 66*

62*

59*

20 WEEK

Fewer razor bumps

Less razor burn

Reduction in nicks/cuts

Skin looks better

Less visible lines/ wrinkles

Softer skin

Skin looked younger

Pores looked smaller

Skin looked smoother

Skin looked clearer

Less irritation/ redness

N=29. *P<0.001 improvement responses versus worsening responses by binomial test. All categories may not equal 100% due to rounding.

Figure 3. Subjects’ self-assessment responses to parameters regarding the efficacy and tolerability of a twice-daily, three step facial skincare regimen. (Top) Self-assessment Yes/No responses. (Bottom) Self-assessment improvement/ worsening responses. SKINmed. 2017;15:349–355

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APPENDIX

6 Giacomoni PU, Mammone T, Teri M. Gender-linked differences in human skin. J Dermatol Sci. 2009;55:144–149.

Subject instructions on use of test materials

7 Dao H Jr, Kazin RA. Gender differences in skin: a review of the literature. Gend Med. 2007;4:308–328.

Morning Regimen In the morning, immediately after showering, lightly wet the face and apply Shave Cleanser (Step 1) evenly across the facial and neck shaving areas and wait about 30 seconds before shaving. Shave as normal. Rinse the face thoroughly with warm water and pat dry. Apply the Post-Shave Treatment (Step 2) over the entire face and neck, avoiding the eye area. Wait 60 seconds to dry. Do not rinse off. Apply the Day Protection (Step 3) over the entire face and neck. Avoid the eye area. Do not rinse off.

Evening Regimen At night, lightly wet the face and apply the Shave Cleanser (Step 1) evenly across the face. Rinse the face thoroughly with warm water and pat dry. Apply the Post-Shave Treatment (Step 2) over the entire face and neck, avoiding the eye area, and wait 60 seconds to dry. Do not use the Day Protection (Step 3) during the evening regimen. Acknowledgments This study was funded by Rodan + Fields. Medical writing support was provided by Stephanie Eide and was funded by Rodan + Fields. Disclosure All authors are employees of Rodan + Fields. References 1 Elsner P. Overview and trends in male grooming. Br J Dermatol. 2012;166 suppl 1:2–5. 2 Cheng FS, Ooi CS, Ting DH. Factors affecting consumption behavior of metrosexual toward male grooming products. Int Rev Bus Res Pap. 2010;6:574–590. 3 Moungkhem C, Surakiatpinyo JA. Study of Factors Affecting on Men’s Skin Care Products Purchasing, Particularly in Karlstad, Sweden. http://www. diva-portal.org/smash/get/diva2:328065/fulltext01. pdf&usg=AFQjCNFoWdwp3ofP-dqUDsnyfwn4sZ0dLw&b vm=bv.120551593,d.dmo. Accessed April 27, 2016. 4 Rodan K, Fields K, Falla TJ. Men’s skin care: Wake up and smell the lotion. Househ Pers Care Today. 2015;10:52– 55. 5 de Lacerda D, Thioly-Bensoussan D, Burke K. Cosmeceuticals for men. Cutis. 2013;22 suppl:6–12.

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8 Draelos Z. Male Skin Care in the U.S. Market. Skin Care Forum. http://www.zoedraelos.com/articles/skin-care. Accessed April 27, 2016. 9 Oblong JE. Male skin care: shaving and moisturization needs. Dermatol Ther. 2012;25:238–243. 10 Jacobi U, Gautier J, Sterry W, et al. Gender-related differences in the physiology of the stratum corneum. Dermatology. 2005;211:312–317. 11 Cowley K, Vanoosthuyze K. Insights into shaving and its impact on skin. Br J Dermatol. 2012;166 suppl 1:6–12. 12 Euromonitor International. Personal Appearances: Global Consumer Survey Results on Apparel, Beauty and Grooming. http://www.euromonitor.com/personal-appearances-global-consumer-survey-results-on-apparelbeauty-and-grooming/report. Accessed April 27, 2016. 13 Fitzpatrick TB. The validity and practicality of sunreactive skin types I through VI. Arch Dermatol. 1988;124:869–871. 14 Griffiths C, Wang T, Hamilton T, et al. A photonumeric scale for the assessment of cutaneous photodamage. Arch Dermatol. 1992;128:347–351. 15 Cook CH, Centner RL, Michaels SE. An acne grading method using photographic standards. Arch Dermatol. 1979;115:571–575. 16 Clarys P, Clijsen R, Taeymans J, et al. Hydration measurements of the stratum corneum: comparison between the capacitance method (digital version of the corneometer CM 825®) and the impedance method (Skicon-200EX®). Ski Res Technol. 2012;18:316–323. 17 Hashimoto-Kumasaka K, Takahashi K, Tagami H. Electrical measurement of the water content of the stratum corneum in vivo and in vitro under various conditions: Comparison between skin surface hygrometer and corneometer in evaluation of the skin surface hydration state. Acta Derm Venereol. 1993;73:335–339. 18 McMichael AJ. More Advanced Shaving Routine Better for Men’s Skin. Skin Inc. http://www.skininc.com/treatments/facial/men/87112307.html. Accessed April 27, 2016. 19 McDermott A, Warnke D, Boissy Y, et al. The use of a shaving regimen for male facial shaving improves overall skin condition. J Am Acad Dermatol. 2010;62:AB38. 20 Damian DL, Patterson CR, Stapelberg M, et al. UV radiation-induced immunosuppression is greater in men and prevented by topical nicotinamide. J Invest Dermatol. 2008;128:447–454. 21 Edwards BK, Noone AM, Mariotto AB, et al. Annual report to the nation on the status of cancer, 1975–2010. Cancer. 2014;120:1290–1314.

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Volume 15 • Issue 5

ORIGINAL CONTRIBUTION

Cryosurgery for Facial and Scalp Lesions of Basal Cell Carcinoma: A Study in 29 Elderly Patients Satish Savant, MD;1 Sandeep Savant, MD;2 Virendra N. Sehgal MD3 Abstract Basal cell carcinoma (BCC) is one of the pre-eminent tumors of the epidermis, recognized by explicit clinical-pathologic characteristics. It is relatively uncommon in South Asia including India and is amenable to a variety of modalities, including cryosurgery. The outcome of cryosurgery was evaluated in 18 men and 11 women, aged 58 to 83 years, who were treated with two freeze-thaw cycles of liquid nitrogen under local anesthesia, after requisite preparations. Of the 29 patients, 27 had complete clearance of the lesions in the course of 3 years of follow-up, while only 2 had a recurrence, one at 17 months and one at 23 months. Recurrences were treated with a repeat cryosurgery, with a cure rate of 93%. Cryosurgery is a simple, inexpensive, and dermatologist-friendly office procedure with a high cure rates for well-defined facial BCC lesions. (SKINmed. 2017;15:357–364)

CC is one of the most common forms of skin cancer in white-skinned populations.1 Its incidence in South Asia in general, and India in particular, is low.2–4 BCC is a cosmetic anomaly warranting surgical intervention/removal of the lesion. Mohs micrographic surgery is a treatment of choice for high-risk BCC,5 with curettage and cautery or electrodesiccation for low-risk lesions, although the latter is not recommended for recurrent, large facial tumors. Cryosurgery6,7 is a well accepted office procedure for treating small, low-risk, superficial lesions, and is described in the current report. MATERIAL AND METHODS The study participants were 29 patients with newly diagnosed BCC. Their age and sex, as well as the duration of the lesion, were recorded. The diagnosis was made on the basis of waxy nodules, surface telangiectasia with/without central depression, or ulceration, indurated heaped-up borders, brown to black pigmentation, and scaly erythematous plaques with raised borders.2,3 The size of each lesion was measured in centimeters.

The diagnosis was confirmed by histopathology,8 which characteristically showed a thinned ulcerated epidermis, uniform tumor cells with large, hyperchromatic, oval nuclei, little cytoplasm, and a few scattered mitotic figures, nodular tumor aggregates

of varying sizes aligned more densely in a palisade pattern at the periphery of these nests, and cleft formation. The retraction artifact between the BCC nests and stroma was another feature. The presence of increased melanin within the tumor and in the surrounding stroma was a feature of the pigmented type of BCC. Before the procedure, all the patients were given antibiotics. The periphery of each tumor, with a margin of 5 to 10 mm of normal skin, was marked. One percent lignocaine was used as local anesthesia. Field-block around and below the lesion (ballooning effect) was carried out to protect the underlying structures. Lubricant jelly was applied as an interface before freezing the lesion(s).

Cryosurgery technique Cryogenic liquid nitrogen containers and hand-held Cryocan devices (Kailash Gases, New Delhi, India) were used in 19 cases, and table-top Frigitronics model number CS-76 (Cooper Surgical, Trumbull, CT), a liquid nitrogen cryosurgical system, in 10 (Figure 1).6,7,9,10 The open spray technique11,12 was employed in 21 cases, while eight patients were treated using the cryoprobe (contact probe) technique. In the contact probe method, an overlap technique was carried out in all cases as the lesions were larger than the

From the Department of Skin and STD, Nanavati Superspeciality Hospital, Mumbai;1 Shraddha Vihar Hospital, Mumbai;2 and Dermato-Venereology (Skin/VD) Center, Sehgal Nursing Home, Panchwati Delhi,3 India Address for Correspondence: Satish Savant MD, FAMS, DV&D, DDV, Department of Skin and STD, Nanavati Super Speciality Hospital, Mumbai, India • E-mail: drsatishsavant@yahoo.co.in

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ORIGINAL CONTRIBUTION thicker lesions. A paintbrush and either rotatory or spiral spray technique was used for larger lesions. The cryoprobe method needed a longer time than open spraying for similarly sized lesions to achieve the desired ice field, after which the freeze time was similar to the open spray technique. Probes with diameters slightly larger than the size of the BCC lesions were selected. Overlap technique was undertaken with the cryoprobe for lesions larger than probe size. In the open spray technique, the lateral spread of freeze of 5 to 10 mm around the BCC lesion was achieved.

Figure 1. Hand-held Cryocan (Cryojet-Dermtech instruments) and Frigitronics table top unit model no. CS-76.

probe size (8 mm). All interventions using a contact probe involved the Frigitronics unit. For the open spray technique, spot spraying was carried out at a 90° angle to the BCC lesion, at a distance of 1 to 2 cm, until the lesion and surrounding skin up to the peripheral marking was uniformly frozen, the ‘ice field’ consisting of the lesion and lateral spread. Intermittent spray was undertaken to maintain the ice field for the requisite period. The freeze time was calculated in each case. This was 60 to 90 seconds for lesions up to 1.5 cm in diameter; a longer freeze time of 1 to 2 minutes was required for larger or

In a few cases, thermocouple needles were inserted below the base of the tumor to assess that a temperature of –50°C had been reached. In most cases, the depth dose was assessed using a combination of observation, palpation, measurement of freeze time, and lateral spread of the freeze. Once the depth dose had been achieved, all the lesions were allowed to thaw spontaneously, which was confirmed by palpation. Thaw time was 3 to 5 minutes, being at least three times longer than the freeze time in the open spray technique. Thaw time of 3 to 5 minutes was maintained after the cryoprobe technique, and the probe was separated only after thaw cycle was completed. The freeze-thaw cycle was repeated in the same manner for all BCC lesions, two freeze-thaw cycles being carried out for each lesion (Figures 2 and 3).13 After complete healing,14 follow-up was carried out at 6-month intervals for the first 3 years, and then every year for another 3 years to monitor for recurrence. Patients were instructed to immediately report any new growths appearing in the vicinity of the treated area.

(B)

(A)

Figure 2. (A) Waxy, erythematous, nodular lesions of basal cell carcinoma (BCC) over the left cheek. (B) Erythematous scaly lesion of superficial BCC with raised thread-like borders. SKINmed. 2017;15:357–364

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Figure 3. (A) Pigmented nodular type of basal cell carcinoma (BCC) below the right eyelid with an underlying satellite nodular BCC lesion. Also note the similar smaller, discreetly distributed, multiple waxy to translucent nodular-type BCC lesions on the left cheek. (B) Biopsy of the lesion being taken. (C) A 5-mm margin marked around the lesion. (D) Thermocouple needles inserted underneath the lesion.

RESULTS The 18 men and 11 women included in the study were aged 58 to 83 years, and showed variations in the duration of the lesions. The size of the lesions was recorded (Table). Of the 29 patients, 27 showed complete resolution, while 2 had a recurrence at 17 and 23 months, respectively. These patients were subjected to two more freeze-thaw cycles of liquid nitrogen cryotherapy, and were again closely monitored for the signs of recurrence. Both underwent complete recovery (Figures 4–7). Erythema, edema, vesiculation, exudation, necrosis, and sloughing were the constant sequelae.15–17 The wound(s) were dried at 7 to 14 days after freezing, the net outcome of which was an eschar. A total of 4 to 6 weeks was required for complete healing after freezing. Scarring and depigmentation were the usual SKINmed. 2017;15:357–364

complications; two patients showed hyperpigmentation and one developed a secondary infection (Figures 8 and 9). DISCUSSION Liquid nitrogen, with a boiling point of –196°C, is the cryogen6,7 of choice for use in BCC, as it can achieve a temperature below –50°C.9 A margin of 5 to 10 mm of normal tissue surrounding the BCC lesion(s) should be destroyed by freezing it in situ, in the same way, as it would have been excised by conservative local surgical excision.9,10,18 Studies have indicated a relationship between freeze time, lateral spread, and depth,19–22 which may determine an appropriate clinical endpoint for complete destruction of the malignant cells. The suggested freeze time for BCC lesions of up to 1.5 cm is 90 seconds when open spraying is used and longer when using a cryoprobe for a similarly size lesion.18 Thaw time should at least be three times the freeze time,

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Table. Study of Basal Cell Carcinoma (BCC): Patients’ Age and Sex, Duration, Morphologic Type, and Size of the Lesion, and Method of Cryosurgery Patient No.

Age (Years)

Sex

Morphologic Type of Lesion

Site of Lesion

Size of Lesion (cm)

Duration of Lesion (years)

Method of Cryosurgery

Recurrence

Nodular

Face

<1 cm

Open spray

Noduloulcerative

Nose

<1 cm

Open spray

Nodular pigmented

Face

>1 cm

Contact probe

Nodular

Nose

<1 cm

Open spray

Nodular pigmented

Ear

>1 cm

Open spray

Nodular pigmented

Face

<1 cm

Open spray

Nodular

Face

<1 cm

Open spray

Noduloulcerative

Ear

>1 cm

Open spray

Noduloulcerative

Face

>1 cm

Contact probe

Nodular pigmented

Face

<1 cm

Open spray

Nodular

Face

<1 cm

Open spray

Superficial spreading

Face

>1 cm

Contact probe

Noduloulcerative

Face

>1 cm

Contact probe

Nodular

Face

<1 cm

Open spray

Noduloulcerative

Face

>1 cm

Contact probe

Nodular pigmented

Face

>1 cm

Contact probe

Nodular

Face

<1 cm

Open spray

Noduloulcerative

Nose

<1 cm

Open spray

Nodular pigmented

Face

<1 cm

Open spray

Nodular

Nose

<1 cm

Open spray

Superficial spreading

Face

>1 cm

Contact probe

Noduloulcerative

Face

<1 cm

Open spray

Nodular

Face

<1 cm

Open spray

Superficial spreading

Scalp

>1 cm

Contact probe

Nodular

Face

<1 cm

Open spray

Noduloulcerative

Face

<1 cm

Open spray

Nodular

Face

<1 cm

Open spray

Nodular

Scalp

<1 cm

Open spray

Noduloulcerative

Nose

>1 cm

Open spray

or even longer, to ensure adequate tissue destruction. The lateral spread of the freeze should be at least be 5 to 10 mm.18 The tissue should be frozen up to –50°C to ensure complete destrucSKINmed. 2017;15:357–364

after

Treatment

tion of malignant cells.9,23 It is imperative to treat a BCC with two freeze-thaw cycles, because this may reduce the chance of relapse.6,7,10,24

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Figure 4. (A) Cryoprobe in contact with a thermocouple needle with lateral spread up to the marked tumor margins. (B) Treatment of multiple lesions on the other side of the face. (C) Hemorrhagic bulla. (D) Necrosis and slough. Same patient as in Figure 3.

Figure 5. Complete resolution after cryosurgery showing residual scarring with hypopigmentation, depigmentation, and hyperpigmentation. Same patient as in Figure 3. SKINmed. 2017;15:357â&#x20AC;&#x201C;364

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Figure 8. (A) Nodular pigmented-type basal cell carcinoma (BCC) over the ear showing a central depression and ulceration with rolled borders and satellite lesions. (B) Complete resolution after cryosurgery of the BCC lesion, with sparing of the ear cartilage.

Figure 6. (A) Grouped hyperpigmented waxy nodules of pigmented-type basal cell carcinoma (BCC) over the left eyebrow. (B) Complete resolution after cryosurgery of the BCC lesion, with residual scarring and hypopigmentation. Same patient as in Figure 3.

(A)

(B)

(A)

Figure 7. (A) Waxy nodule of nodular basal cell carcinoma (BCC) with a central depression and rolled borders, situated over the tip of the nose. (B) Complete resolution after cryosurgery of the BCC lesion, with favorable cosmetic outcome.

(C)

Figure 9. Cryosurgery for basal cell carcinoma: complications and sequelae. (A) Tissue edema; (B) intense periorbital edema; and (C) scarring and hypopigmentation.

As the current study shows, the open spray and cryoprobe method6,11,12 are both effective. A hand-held unit used for open spray is ideally versatile, because of its easy maneuverability over curved surfaces and irregular lesions.24 Intermittent spraying is required to maintain an ice field of constant size for the required freeze time.10,18 A paintbrush or spiral spray technique11 can be employed for larger lesions. The cryoprobe method takes longer than the spray technique to achieve the desired ice field extending to the predetermined margins around the lesions. The freeze-thaw cycles are the same length for both methods once the desired size of SKINmed. 2017;15:357â&#x20AC;&#x201C;364

(B)

ice field has formed. The depth of the freeze can be greater if the tissue is compressed with the cryoprobe during freezing.18 The lubricant jelly adheres to the underlying BCC lesion during the course of freezing, protecting the underlying structures. Cryosurgery is often preceded by debulking of the lesion, as this may help to reduce the amount of tissue to be frozen, and thus reduce the volume of tissue that will slough, promoting faster healing; however, the overall cure rate is not affected.10 BCC lesions were not debulked in the present study. BCC lesions with well-defined borders show a good response to cryosurgery compared to lesions with ill-defined borders or

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deeply invading lesions. Mohs (micrographic) surgery24 is useful for areas such as the inner canthus of the eye. Well-circumscribed BCC lesions over the nose and ears can be treated successfully with cryosurgery, preserving the underlying cartilage.9,25 Cryosurgery18,26,27 can be attended by host of sequelae and complications.15–17 Pain, erythema, edema, exudation, and vesiculation were the usual outcomes 24 hours after the procedure. Anti-inflammatory agents and a short, tapering course of oral corticosteroids were deemed essential to treat these. Complications of liquid nitrogen cryosurgery26 include headache, infection, hypopigmentation, depigmentation, and hyperpigmentation, cold urticaria, febrile reactions, neuropathies, paresthesia, atrophic and hypertrophic scarring, ectropion, and tissue defects.

or aggressive histologic types, ie, micronodular, morpheaform, and infiltrating lesions. Conclusions Cryosurgery33 can, therefore, be seen to be an easily accessible, inexpensive, and dermatologist-friendly office procedure that produces fairly high cure rates. It is also readily available, requires no special training, and can be performed on elderly or debilitated patients, as well as individuals who are taking anticoagulants or who have a pacemaker.34 References

Transient hyperpigmentation, gradually resolving over time, was seen in five patients in our study. Secondary infection occurred in only one patient. In all our participants, healing was associated with atrophic scarring and hypopigmentation or depigmentation; scarring alopecia was seen in two patients with lesions on the scalp. As the lesion along with 5 to 10 mm of normal surrounding skin has to be completely destroyed, there is bound to be a wound that, when allowed to heal by secondary intention, will leave behind a scar showing hypopigmentation, depigmentation, or hyperpigmentation.27 These pigment changes are more obvious with darker skin tones than lighter ones. Liquid nitrogen cryosurgery used in tumor doses produces an absence of melanosomes in the keratinocytes, causing hypopigmentation.28 Prolonged freezing destroys the hair follicle pilosebaceous unit along with surrounding dermal connective tissue, causing scarring alopecia.29 A singular achievement of the current study was the high cure rate, which was in agreement with rates reported24,27 elsewhere. A cure rate of more than 97% was recorded in one study,30 while other stuies reported a 99% cure rate.24,25 Only 2 of 29 patients in the current study showed recurrence, while the others were free from disease for 5 or more years, equating to a 5-year cure rate of 93.1%. Both recurrences were seen within 2 years. The size of the recurrent lesions in the study was more than 3 cm in diameter; lesions probably recurred because the depth of the freeze achieved was inadequate in certain places. However, the recurrences were successfully treated with another round of cryosurgery. Undoubtedly, Mohs31,32 microscopic surgery continues to be the “gold standard” for high-risk BCC with ill-defined borders and/ SKINmed. 2017;15:357–364

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1 Raasch BA, Buettner PG, Garbe C. Basal cell carcinoma: Histological classification and body-site distribution. Br J Dermatol. 2006;155:401–407. 2 Malhotra P, Singh A, Ramesh V. Basal cell carcinoma in the North Indian population: Clinicopathologic review and immunohistochemical analysis. Indian J Dermatol Venereol Leprol. 2011;77:328–330. 3 Kumar S, Mahajan BB, Kaur S, et al. A study of basal cell carcinoma in South Asians for risk factor and clinicopathological characterization: A hospital based study. J Skin Cancer. 2014;2014:173582. 4 Sehgal VN, Chatterjee K, Pandhi D, et al. Basal cell carcinoma: Pathophysiology. Skinmed. 2014;176–181. 5 Wong CS, Strange RC, Lear JT. Basal cell carcinoma. BMJ. 2003;327:794–798. 6 Zacarian SA, ed. Cryosurgery for Skin Cancer and Cutaneous Disorders. St. Louis: CV Mosby; 1985. 7 Torre D. Cryosurgery of basal cell carcinoma. J Am Acad Dermatol. 1986;15:917–929. 8 Kirkham N. Tumors and cysts of the epidermis. In: Elder DE, ed. Lever’s Histopathology of the Skin. 10th edn. Philadelphia, PA: Wolters Kluwer/Lippincott Williams & Williams; 2008:791–850. 9 Kuflik EG. Cryosurgery updated. J Am Acad Dermatol. 1994;31:925–944. 10 Mallon E, Dawber R. Cryosurgery in the treatment of basal cell carcinoma. Assessment of one and two freezethaw cycle schedules. Dermatol Surg. 1996;22:854–858. 11 Lubritz RR. Cryo corner: Cryosurgical spray patterns. J Dermatol Surg Oncol. 1978;4:138–139. 12 Kuflik EG. Learning the basics #1: Treatment of basal cell carcinoma with the open spray technique. J Dermatol Surg Oncol. 1986;12:125–126. 13 McLean DI, Haynes HA, MacCarthy PL, et al. Cryotherapy of basal cell carcinoma by a simple method of standardized freeze thaw cycles. J Dermatol Surg Oncol. 1978; 4:175–177. 14 American Academy of Dermatology Committee on Guidelines of Care. Guidelines of care for cryosurgery. J Am Acad Dermatol. 1994;31:648–653. 15 Elton RF. The course of events following cryosurgery. J Dermatol Surg Oncol. 1977;3:448–451.

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16 Zacarian S. Cryogenics: The cryolesion and the pathogenesis of cryonecrosis. In: Zacarian SA, ed. Cryosurgery for Skin Cancer and Cutaneous Disorders. St. Louis: Mosby; 1985:1–30.

26 Zacarian SA. Cryogenics: the cryolesion and the pathogenesis of cryonecrosis. In: Cryosurgery for Skin Cancer and Cutaneous Disorders. St. Louis: Mosby; 1985:283– 297.

17 Kuflik EG, Webb W. Effects of systemic corticosteroids on post-cryosurgical edema and other manifestations of the inflammatory response. J Dermatol Surg Oncol. 1985;11:464–468.

27 Elton RF. Complications of cutaneous cryosurgery. J Am Acad Dermatol. 1983;8:513–519.

18 Savant SS. Chemical cauterization. In: Savant SS, ed. Textbook of Dermatosurgery and Cosmetology. 2nd ed. Mumbai: ASCAD; 2008;108–109. 19 Torre D. Depth dose in cryosurgery. J Dermatol Surg Oncol. 1983;9 :219–225. 20 Torre D. Cryosurgical instrumentation and depth dose monitoring. Clin Dermatol. 1990;8:48–60. 21 Torre D. Understanding the relationship between lateral spread of freeze and depth of freeze. J Dermatol Surg Oncol. 1979;5:51–53. 22 Zacarian SA. Cryo corner: Is lateral spread of freeze a valid guide to depth of freeze? J Dermatol Surg Oncol. 1978;4:561–563. 23 Gage AA. What temperature is lethal for cells? J Dermatol Surg Oncol. 1979;5:459–464. 24 Kuflik EG. Cryosurgery for skin cancer: 30-year experience and cure rates. Dermatol Surg. 2004;30:297–300. 25 Jaramillo-Ayerbe F. Cryosurgery in difficult to treat basal cell carcinoma. Int J Dermatol .2000;39:223–229.

28 Burge SM, Bristol M, Millard PR, Dawber RP. Pigment changes in human skin after cryotherapy. Cryobiology. 1986;23:422–432. 29 Burge SM, Dawber RP. Hair follicle destruction and regeneration in guinea pig skin after cutaneous freeze injury. Cryobiology.1990;2:153–63. 30 Zacarian SA. Cryosurgery of cutaneous carcinomas. An 18 year study of 3022 patients with 4228 carcinomas. J Am Acad Dermatol. 1983; 9:947–956. 31 Samarasinghe V, Madan V. Nonmelanoma skin cancer. J Cutan Aesthet Surg. 2012;5:3–10. 32 Rowe DE, Carroll RJ, Day CL Jr. Mohs surgery is the treatment of choice for recurrent (previously treated) basal cell carcinoma. J Dermatol Surg Oncol. 1989;15:424– 431. 33 Bhattacharya N, Gupta S, Sehgal VN. Cryosurgery. In: Sehgal VN, ed. Dermatologic Surgery Made Easy. 2nd ed. New Delhi: Jaypee Brothers Medical Publishers;2012:61–75. 34 Kaur S, Thami GP, Kanwar AJ. Basal cell carcinomatreatment with cryosurgery. Indian J Dermatol Venereol Leprol. 2003;69:188–190.

VINTAGE LABEL

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Volume 15 • Issue 5

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Advanced Management of Severe Keloids Thomas Hagele, MD, MBA;1 Hoka Nyanda, MD;1 Nishit Patel, MD;1 Nicole Russell, MD;1 George Cohen, MD;2 Christopher Nelson, MD1 Abstract Keloids negatively impact the health and quality of life of many affected dermatologic patients. Treating keloids is often difficult, and suboptimal responses are frequent. Fortunately, there are many treatment options available to the clinician that may lead to improved clinical outcomes. We present a review of currently available therapeutic options. Intralesional steroid injection remains the first-line treatment for keloids. Imiquimod, direct interferon therapy, or intralesional 5-flurouracil may alleviate the need for excessive corticosteroid therapy. Radiation and laser therapy are emerging therapeutic options that have demonstrated efficacy in reviewed studies. Given the unsatisfactory outcomes associated with pressure dressings, vitamin E, ablative laser, and surgical excision, these options should be avoided in keloid management. Further research is needed to evaluate the efficacy and recurrence associated with the reviewed therapeutics. (SKINmed. 2017;15:365–370)

decreased apoptosis have all been shown to contribute to keloid formation.3 The propensity for lesions to develop within families suggests a genetic etiologic factor that also contributes to keloid formation.8

eloid formation negatively affects the lives of patients both physically and psychologically. In addition to the physical clinical manifestations of pruritus, pain, and restricted mobility, the psychologic effects associated with visible lesions can be even more devastating.1 There is a high prevalence of keloids, with approximately 5% to 15% of wounds ultimately resulting in abnormal scar formation (Figures 1 and 2).2 Keloids affect men and women equally and can occur in patients of all races, although they are 3 to 18 times more likely to affect black than white individuals.3–5 Keloidal concerns are common complaints in the dermatologist’s office, accounting for 4.1% of all clinic visits for black adults and 2.6% of visits for children.6

Platelet-derived growth factor and transforming growth factor-β1 (TGF-β1) contribute to wound healing. TGF-β1 leads to increased fibroblast collagen, elastin, and fibronectin production.9,10 In normal fibroblasts, TGF-β1 production is downregulated, as the wound healing process is completed.11 Comparatively, keloidal tissue continues to produce TGF-β1, leading to unregulated wound healing.11

Keloids form as a result of abnormal collagen proliferation within the dermis, which ultimately leads to extensive scar formation that expands outside the borders of the initial injury. Common injuries preceding keloid formation include surgery, burns, trauma, inflammation, foreign body reactions, and endocrine dysfunction.7 The expansion of the scar outside of the wound edge serves to differentiate keloids from hypertrophic scars. While the pathogenesis of the unregulated collagen production is yet to be fully understood, abnormal fibroblast activity, increased hyaluronic acid production, abnormal growth factor levels, and

A number of therapeutic products have been used to treat keloids and prevent their formation. Therapeutic options can vary from low-cost pressure dressings to invasive surgical options. Additional available modalities include intralesional corticosteroid injections, cryotherapy, topical vitamin E, onion extract, imiquimod, interferon, anti-tumor necrosis factor-α antibodies, bleomycin, mitomycin, laser therapy, and radiation. Unfortunately, no single therapy to date has been completely successful in keloid management. We review the current literature related to established and emerging therapeutic modalities for keloids.

From the Department of Dermatology and Cutaneous Surgery, University of South Florida, Morsani College of Medicine; Tampa, FL;1 and the Department of Dermatology, University of Florida College of Medicine, Gainesville, FL2 Address for Correspondence: Thomas Hagele MD, MBA, Department of Dermatology and Cutaneous Surgery, University of South Florida, 13330 USF Laurel Drive, 6th Floor, Tampa, FL 33612 • E-mail: thomashagele@gmail.com

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Figure 2. A 27-year-old African-American woman with severely disfiguring keloids on the back.

Figure 1. A 27-year-old African-American woman with severely disfiguring keloids on the face and chest.

keloids and hypertrophic scars that have become refractive to conventional intralesional corticosteroid therapy.

THERAPEUTIC CONSIDERATIONS

Intralesional corticosteroids Intralesional corticosteroids injections are among the most commonly used treatments for the management of keloids, owing to their ability to induce keloid flattening and softening.12,13 Steroids stimulate a reduction in inflammatory mediators and decrease the production of fibroblasts, thereby limiting the cellular growth process.14 Despite these findings, the exact mechanism by which corticosteroids treat keloids and hypertrophic scars is still being elucidated.14 Mid-potency corticosteroids, such as triamcinolone, are typically injected directly into the keloid with consideration made to preventing inappropriate deposition, which could lead to permanent atrophy.13 Complete lesional resolution is difficult, and therefore educating patients is imperative to ensure realistic expectations.13 The efficacy of treatment with intralesional corticosteroids is variable, with rates of response ranging from 50% to 100%.14 Review of the literature suggests that steroid resistance can occur due to their inherent inability to reduce the synthesis of elastin and collagen.14 To maximize therapeutic results, keloids may require repeat injections every 3 to 4 weeks after the initial intralesional corticosteroid injection.13 Although the steroid is administered locally to the keloid, some systemic absorption may occur and could theoretically lead to the side effects seen with systemic corticosteroid use: glaucoma, bone demineralization, elevated glucose levels, cataracts, cushingoid features, and adrenal gland suppression.14 Given these risks, it is important to consider other treatment modalities when managing severe SKINmed. 2017;15:365–370

Cryodestruction Cryodestruction has been described in the literature as a treatment option for keloids. Its use is based on the principle that fast fluctuations in temperature can facilitate the destruction of abnormal tissue.15 The use of extreme temperatures can cause an improved arrangement of collagen deposition.15 Methods of destruction include traditional contact cryosurgery, as well as intralesional cryosurgery. Intralesional cryosurgery is preferred, as it has been shown to reduce the size of keloid scar formation without the side effects of hypopigmentation commonly seen with contact cryosurgery.16

Onion extract Multiple skin care products containing onion extract claim to diminish the appearance of scars. Mederma®, a product comprosed of onion extract, has become one of the most popular over-the-counter agents for wound healing, despite minimal evidence supporting its use. Its active ingredient, Allium cepa, made up of quercetin, is derived from the onion Allium cepa Linn.17 Quercetin is a bioflavonoid with antiproliferative, anti-inflammatory, and most importantly antihistaminic effects.18 Blocking histamine may decrease inflammation and therefore erythema. A study of hypertrophic scars on rabbit ears exhibited an increase in mature collagen in Mederma®-treated scars; however, there was no decrease in scar height or erythema.18 A recent comparative study found that onion extract is more effective than placebo.19 Multiple prospective and randomized studies have reported that

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the onion extract applied topically may produce better results when used in combination with silicone sheeting, intralesional triamcinolone, pentaglycan, or allantoin.20–22

Radiation therapy Radiation therapy for keloids is a highly effective but highly controversial treatment option available to the dermatologist. Although keloids are benign tumors, their effect on a patient’s quality of life can be significant (Figures 3 and 4). The use of radiation therapy after surgical excision of keloid has been shown to be decidedly effective, with success rates ranging from 67% to 98%.23,24 The exact mechanism by which the radiation is delivered can vary and includes electron beam radiation, orthovoltage therapy, superficial x-ray, and brachytherapy.25–28 It is believed that the radiation results in the correction of an imbalance between procollagen synthesis and procollagen degradation by its ability to manipulate gene expression of fibroblasts and other nearby connective tissue stem cells.29 One author has recommended 3 Gy every other day for five courses, or 5 Gy every other day for three courses, immediately after surgery, although the cumulative dose delivered appears to be a more important factor than the frequency of delivery with regards to success rates.30–33 Longterm cure rates of 77% to 80% have been shown at 1.5 and 5 years, respectively, after treatment.34,35 Of note, primary radiation therapy is rarely used, as it is only effective if used in the first 6 months after keloid formation.36 Unfortunately, radiation therapy may place the patient at higher risk for malignancy of the surrounding tissues, and this has often caused many providers not to employ this treatment modality. This risk may be exaggerated, as one group found no cases of malignancy in 378 cases of keloids treated with 15 Gy of radiation within an 18-to 128-month follow-up (24-month mean follow-up).37 Additionally, a survey showed that more than 90% of radiation oncologists responded that they believed radiation therapy was an appropriate treatment option for the management of keloids.38 Employing simple techniques, such as adequately shielding surrounding tissues, limiting the lifetime dose to less than 20 Gy, and using brachytherapy, when appropriate, can help to minimize the risk of secondary malignancy.28,39–41

Surgical excision Surgical excision is an additional treatment modality, but it should only be employed after other treatment options have proven unsuccessful. Surgical excision alone should not be used for the management and treatment of multiple large keloids due to a recurrence rate, ranging from 50% up to 100%.42 As deSKINmed. 2017;15:365–370

Figure 3. A 27-year-old African-American woman with severely disfiguring keloids on the right side of the face.

Figure 4. A 27-year-old African-American woman with severely disfiguring keloids on the left side of the face.

scribed previously, tissue tension appears to play a significant role in keloid formation. If surgical excision of keloids is chosen, it is critical to minimize tension on the subsequent wound by allowing the sites to heal by secondary intention or by minimizing the amount of subcutaneous suture placed. To maximize outcomes, postoperative intralesional therapy or radiotherapy should be used routinely.43 Surgical margins are found to play a role in keloid recurrence. One retrospective study postulated that incomplete peripheral and deep excision margins and infiltrative borders were associated with higher 1-year recurrence rates;44 however, a significant limitation of this study was the failure to disclose the nature of the surgical closure (secondary excision, flap, or primary clo-

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sure), as this may have played a role in the increased recurrence rates that were reported. This suggests that more studies should be completed to evaluate the role of surgical margins on recurrence rates.

Radiation therapy has a reported efficacy of 67% to 98% within 6 months of keloid formation; however, its use remains controversial due to the potential for malignancy, although shielding protocols exist to reduce that risk.23,24,28,39–41

Weight reduction

The roles of topical onion extract and intralesional bleomycin remain questional, until further studies can confirm their use,

Given the clear role of tension in keloidogenesis, some have postulated that weight reduction may be a useful target as a novel therapy for truncal keloids. Few studies are available in the literature that evaluate the benefit of weight loss in the prevention and treatment of keloids. Weight loss, whether by lifestyle management or bariatric surgery, should theoretically assist in reducing skin tension within keloid lesions. This overall reduction in tension would facilitate primary closure techniques after keloid excision. Due to the importance of mechanical forces and tension in keloid formation, we postulate that weight loss would assist in treatment and decrease recurrence; however, with limited published reports, this is an area that requires further investigation to formulate more tangible conclusions on its benefit for the management and treatment of keloids in the future.

Poor outcomes are associated with pressure dressings and vitamin E application, making each of these therapies less desirable treatment options.15 Similarly, ablative laser therapy (CO2 and Er:YAG) and surgical excision often result in high recurrence rates.42,46–51 As a result, these treatments are not indicated. References

CONCLUSIONS Given keloids resistance to therapeutic intervention and frequent recurrence, treatment can be frustrating for both the practitioner and the patient. Unfortunately, there is no single treatment modality that will satisfy all patients. Accordingly, practitioners must weigh the benefits of the aforementioned treatment modalities while considering potential risks and patient preferences. Intralesional corticosteroid remains the preferred initial therapy for isolated keloidal lesions, with 50% to 100% responding to treatment.14 Unfortunately, the potential for unfavorable side effects and treatment resistance limits the prolonged use of this therapy. The addition of imiquimod, direct interferon therapy, or intralesional 5-fluorouracil may alleviate the need for excessive corticosteroid therapy. Patients who are not candidates for corticosteroid therapy or have not experienced improvement may benefit from laser therapy. Laser therapy has emerged as an efficacious addition to the clinician’s therapeutic repertoire given the evidence of favorable outcomes. Pulse Dye Laser therapy has been demonstrated to be efficacious in 57% to 83% of patients, with its ability to interfere with TGF-β and induce fibroblast apoptosis.45 Additionally, 532-nm–frequency Nd:YAG laser treatment has resulted in a 60% cure rate after 3 months of therapy. Intense pulsed light therapy is emerging as an efficacious choice with a favorable side effect panel. Despite these benefits, laser therapy is not without side effects and can be costly to patients. SKINmed. 2017;15:365–370

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1 Bock O, Schmid-Ott G, Malewski P, Mrowietz U. Quality of life of patients with keloid and hypertrophic scarring. Arch Dermatol Res. 2006;297:433–438. 2 Jansen D, Tandon R, Wang A. Keloids. Updated 2012. http://emedicine.medscape.com/article/1298013overview#showall. Accessed April 1, 2012. 3 Shaffer JJ, Taylor SC, Cook-Bolden F. Keloidal scars: A review with a critical look at therapeutic options. J Am Acad Dermatol. 2002;46:S63–S97. 4 Mathangi-Ramakrishnan K. Study of 1000 patients with keloidal scars in South India. Plast Reconstr Surg. 1974;53:276–280. 5 Cosman B. The surgical treatment of keloidal scars. Plast Reconstr Surg. 1961;27:335–358. 6 Child FJ, Fuller LC, Higgins EM, Du Vivier AW. A study of the spectrum of skin disease occurring in a black population in south-east London. Br J Dermatol. 1999;141:512– 517. 7 Mousavi SR, Raaiszadeh M, Aminseresht M, Behjoo S. Evaluating tamoxifen effect in the prevention of hypertrophic scars following surgical incisions. Dermatol Surg. 2010;36:665–669. 8 Bella H, Heise M, Yagi KI, et al. A clinical characterization of familial keloid disease in unique African tribes reveals distinct keloid phenotypes. Plast Reconstr Surg. 2011;127:689–702. 9 Shockman S, Paghdal KV, Cohen G. Medical and surgical management of keloids: A review. J Drugs Dermatol. 2010;9:1249–1257. 10 Liu JM, Davidson JM. The elastogenic effect of recombinant transforming growth factor-beta on porcine aortic smooth muscle cells. Biochem Biophys Res Commun. 1988;154:895–901. 11 Wolfram D, Tzankov A, Pulzl P, Piza-Katzer H. Hypertrophic scars and keloids—a review of their pathophysiology, risk factors, and therapeutic management. Dermatol Surg. 2009;35:171–181. 12 Lutgendorf MA, Adriano EM, Taylor BJ. Prevention and management of keloid scars. Obstet Gynecol. 2011;118:351–356.

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13 Gupta S, Sharma VK. Standard guidelines of care: Keloids and hypertrophic scars. Indian J Dermatol Venereol Leprol. 2011;77:94–100.

28 Guix B, Henriquez I, Andres A, et al. Treatment of keloids by high-dose-rate brachytherapy: A seven-year study. Int J Radiat Oncol Biol Phys. 2001;50:167–172.

14 Jalali M, Bayat A. Current use of steroids in management of abnormal raised skin scars. Surgeon. 2007;5:175– 180.

29 Niessen FB, Spauwen PH, Schalkwijk J, Kon M. On the nature of hypertrophic scars and keloids: A review. Plast Reconstr Surg. 1999;104:1435–1458.

15 Al-Attar A, Mess S, Thomassen JM, Kauffman CL, Davison SP. Keloid pathogenesis and treatment. Plast Reconstr Surg. 2006;117:286–300.

30 Kelly AP. Update on the management of keloids. Semin Cutan Med Surg. 2009;28:71–76.

16 Goldenberg G, Luber AJ. Use of intralesional cryosurgery as an innovative therapy for keloid scars and a review of current treatments. J Clin Aesthet Dermatol. 2013;6:23–26. 17 Chung VQ, Kelley L, Marra D, Jiang SB. Onion extract gel versus petrolatum emollient on new surgical scars: Prospective double-blinded study. Dermatol Surg. 2006;32:193–197. 18 Saulis AS, Mogford JH, Mustoe TA. Effect of Mederma on hypertrophic scarring in the rabbit ear model. Plast Reconstr Surg. 2002;110:177–83; discussion 184–186. 19 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. 20 Hosnuter M, Payasli C, Isikdemir A, Tekerekoglu B. The effects of onion extract on hypertrophic and keloid scars. J Wound Care. 2007;16:251–254. 21 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. 22 Koc E, Arca E, Surucu B, Kurumlu Z. An open, randomized, controlled, comparative study of the combined effect of intralesional triamcinolone acetonide and onion extract gel and intralesional triamcinolone acetonide alone in the treatment of hypertrophic scars and keloids. Dermatol Surg. 2008;34:1507–1514. 23 Norris JE. Superficial x-ray therapy in keloid management: A retrospective study of 24 cases and literature review. Plast Reconstr Surg. 1995;95:1051–1055. 24 Jones K, Fuller CD, Luh JY, et al. Case report and summary of literature: Giant perineal keloids treated with post-excisional radiotherapy. BMC Dermatol. 2006;6:7. 25 Maarouf M, Schleicher U, Schmachtenberg A, Ammon J. Radiotherapy in the management of keloids. Clinical experience with electron beam irradiation and comparison with X-ray therapy. Strahlenther Onkol. 2002;178:330– 335. 26 Ogawa R, Miyashita T, Hyakusoku H, et al. Postoperative radiation protocol for keloids and hypertrophic scars: Statistical analysis of 370 sites followed for over 18 months. Ann Plast Surg. 2007;59:688–691. 27 Fraunholz IB, Gerstenhauer A, Bottcher HD. Results of postoperative (90)sr radiotherapy of keloids in view of patients’ subjective assessment. Strahlenther Onkol. 2005;181:724–729.

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31 Doornbos JF, Stoffel TJ, Hass AC, et al. The role of kilovoltage irradiation in the treatment of keloids. Int J Radiat Oncol Biol Phys. 1990;18:833–839. 32 Kovalic JJ, Perez CA. Radiation therapy following keloidectomy: A 20-year experience. Int J Radiat Oncol Biol Phys. 1989;17:77–80. 33 Sallstrom KO, Larson O, Heden P, et al. Treatment of keloids with surgical excision and postoperative Xray radiation. Scand J Plast Reconstr Surg Hand Surg. 1989;23:211–215. 34 Ogawa R, Mitsuhashi K, Hyakusoku H, Miyashita T. Postoperative electron-beam irradiation therapy for keloids and hypertrophic scars: Retrospective study of 147 cases followed for more than 18 months. Plast Reconstr Surg. 2003;111:547–53; discussion 554–555. 35 Ragoowansi R, Cornes PG, Moss AL, Glees JP. Treatment of keloids by surgical excision and immediate postoperative single-fraction radiotherapy. Plast Reconstr Surg. 2003;111:1853–1859. 36 Panizzon RG. [Dermatologic radiotherapy]. Hautarzt. 2007;58:701–710, quiz 711. 37 Ogawa R, Mitsuhashi K, Hyakusoku H, Miyashita T. Postoperative electron-beam irradiation therapy for keloids and hypertrophic scars: Retrospective study of 147 cases followed for more than 18 months. Plast Reconstr Surg. 2003;111:547–553; discussion 554– 555. 38 Leer JW, van Houtte P, Davelaar J. Indications and treatment schedules for irradiation of benign diseases: A survey. Radiother Oncol. 1998;48:249–257. 39 Ogawa R, Mitsuhashi K, Hyakusoku H, Miyashita T. Postoperative electron-beam irradiation therapy for keloids and hypertrophic scars: Retrospective study of 147 cases followed for more than 18 months. Plast Reconstr Surg. 2003;111:547–553; discussion 554– 555. 40 Ogawa R, Miyashita T, Hyakusoku H, et al. Postoperative radiation protocol for keloids and hypertrophic scars: Statistical analysis of 370 sites followed for over 18 months. Ann Plast Surg. 2007;59:688–691. 41 Chang P, Laubenthal KN, Lewis RW, 2nd, et al. Prospective, randomized study of the efficacy of pressure garment therapy in patients with burns. J Burn Care Rehabil. 1995;16:473–475. 42 Juckett G, Hartman-Adams H. Management of keloids and hypertrophic scars. Am Fam Physician. 2009;80:253–260. 43 Ogawa R, Akaishi S, Huang C, et al. Clinical applications of basic research that shows reducing skin tension could prevent and treat abnormal scarring:

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The importance of fascial/subcutaneous tensile reduction sutures and flap surgery for keloid and hypertrophic scar reconstruction. J Nihon Med Sch. 2011;78:68–76. 44 Tan KT, Shah N, Pritchard SA, McGrouther DA, Bayat A. The influence of surgical excision margins on keloid prognosis. Ann Plast Surg. 2010;64:55–58. 45 Alster TS. Improvement of erythematous and hypertrophic scars by the 585-nm flashlamp-pumped pulsed dye laser. Ann Plast Surg. 1994;32:186–190. 46 Kelly AP. Update on the management of keloids. Semin Cutan Med Surg. 2009;28:71–76. 47 Stern JC, Lucente FE. Carbon dioxide laser excision of earlobe keloids. A prospective study and critical

analysis of existing data. Arch Otolaryngol Head Neck Surg. 1989;115:1107–1111. 48 Norris JE. The effect of carbon dioxide laser surgery on the recurrence of keloids. Plast Reconstr Surg. 1991;87:44–49; discussion 50–53. 49 Lawrence WT. In search of the optimal treatment of keloids: Report of a series and a review of the literature. Ann Plast Surg. 1991;27:164–178. 50 Gold MH. A controlled clinical trial of topical silicone gel sheeting in the treatment of hypertrophic scars and keloids. J Am Acad Dermatol. 1994;30:506–507. 51 Olbricht SM, Stern RS, Arndt RA. CO2 laser and cold steel surgical treatment of keloids give comparable results. Lasers Surg Med. 1988;8:187.

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

(Continued on page 375)

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SELF ASSESSMENT EXAMINATION W. Clark Lambert, MD, PhD Instructions: For each numbered question, select the one most appropriate lettered response. 1. A keloid is best differentiated from a hypertrophic scar as: a. Cicatrix (scar) formation, following injury, that contains broad bands of collagen in a swirled pattern. b. Cicatrix (scar) formation, following injury, that contains distinct patches of lymphoid cells. c. Cicatrix (scar) formation, following injury, that expands beyond the borders of the initial injury. d. Cicatrix (scar) formation, following injury, that is associated with a dermal infiltrate containing mast cells. e. Cicatrix (scar) formation, following injury, that is associated with a dermal infiltrate containing Sezary cells.

3. Mechanisms that have been shown to contribute to keloid formation include: a. Abnormal fibroblast activity. b. Abnormal growth factor levels.

4. a. b. c. d. e.

The first-line treatment for keloids is: Ablative laser treatment. Direct interferon treatment. Intralesional 5-fluoruracil treatment. Intralesional bleomycin treatment. Intralesional steroid injection.

5. Which of the following should be avoided as a firstline treatment for keloids? a. Ablative laser treatment. b. Pressure dressings. c. Surgical excision. d. Vitamin E treatment. e. All of these should be avoided as a first-line treatment for keloids.

ANSWERS TO EXAMINATION: 1. c; 2. b; 3. e; 4. e; 5. e

2. Keloids: a. Affect men more commonly than women (ratio 1.6:1). b. Are more common in Black than in White people. c. Are not known to occur in persons of Icelandic extraction. d. All of the above. e. None of the above.

c. Decreased apoptosis. d. Increased production of hyaluronic acid. e. All of the above mechanisms have been shown to contribute to keloid formation. f. None of the above mechanisms has been shown to contribute to keloid formation.

From the Departments of Pathology and Dermatology, Rutgers University – 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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W W W. T N L A S E R S O C I E T Y. C O M

September/October 2017

Volume 15 • Issue 5

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

Compromising Patient Care: Gross Payment Disparities in Dermatopathology—Part I Viral M. Patel, BS; Divya Sharma, BS; Michael Sylvester, AB; Fernanda Salgado, BS; Stephen Peters, MD, PhD; W. Clark Lambert, MD, PhD “Common sense is as rare as genius.”- Ralph Waldo Emerson

s a physician or health care provider evaluating and treating patients, particularly those with skin and mucous membrane disorders, including neoplastic disease, you not infrequently obtain biopsies or perform excisions of lesions, from which are derived specimens that you submit to a dermatopathology laboratory for analysis. For doing this, you submit a bill, and the laboratory separately submits their bill to the appropriate payer—you do not see their bill nor they yours; you do not concern yourself about their payment issues. In this and the subsequent contribution in this series, we address this issue and attempt to explain why the reimbursement/payment received by the laboratory is of direct concern to you. Very likely, it will have a major impact on the accuracy and completeness of the report you subsequently receive from the laboratory, on which you are likely to base your management plan as well as what you tell your patient. There are several facets to what goes into the reimbursement/ payment received by the laboratory, as follows: • Arbitrary and capricious changes in the reimbursement/ payment received by the laboratory for the services they perform can be, and in fact are, made without notice at any time. As we shall show, these may be severe and occur without warning, with virtually no opportunity for appeal or redress. In addition to the abrupt loss in revenue, the uncertainty itself makes long-term planning difficult. The end result is that pathology services are more expensive, and there is a reduced focus on the proper processing and evaluation of specimens submitted. This topic will be discussed in Part I of this contribution.

• There are arbitrary and capricious differences, or lack of differences, between the reimbursement/payment received by the laboratory for various services that vary widely in complexity, and in the technical and manpower costs borne by the laboratory. Some of these differences can only be detected by a very close reading of the “CPT” codebook issued each year by the American Medical Association. This will be discussed in Part II of this contribution. As we shall see, the end result is that there are enormous economic incentives for the laboratory to cut corners and to do inferior work. Unfortunately, the periodic inspections undergone by such laboratories are unlikely to find that many of these cut corners. Physician/health care providers should understand what these economic incentives are and how they may affect the accuracy and completeness of the dermatopathology reports they will receive. This is the goal of this series of papers. ARBITRARY AND CAPRICIOUS PAYMENT SCALES Beginning January 2013, Medicare payment for the technical component (TC) of Current Procedural Terminology (CPT) code 88305 was reduced by 52% (from $69.78 to $33.70), while reimbursement for the global code was reduced by 33%. This has been described as “a nightmare scenario for pathology laboratories.” CPT code 88305 is the most common code billed by pathology laboratories. Its official description is “Level IVsurgical pathology, gross and microscopic examination,” and it is used to reimburse laboratories for preparing biopsy tissue slides and for examination of those slides by pathologists. The 33% cuts to the Medicare global rate results in an estimated $460 million revenue loss for pathology laboratories per year. Due to

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

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the drastic cuts to 88305, coupled with only small increases in immunohistochemistry and flow cytometry reimbursements, Medicare expenditures on pathology services have been reduced nearly $358 million per year.1–5 This large decrease is concerning, as is the probability that commercial carriers, which often follow of the Centers for Medicare and Medicaid Services (CMS) lead, may use Medicare’s fee schedule as a guideline to price their own allowable rates. The reduction in payment for the 88305-TC does not accurately reflect true practice expenses. Several components contributing to laboratory expenses are not included, such as specimen transportation fees, storage and disposal costs for specimens and chemicals, equipment maintenance costs, laboratory information systems, and software costs. More importantly, CMS called for independent evidence regarding the appropriate number of blocks it assumed to be “typical” for numerous pathology codes, including 88305. When a sample is sent to the laboratory, it is divided into several segments called blocks, and these blocks are further processed to make slides for staining and subsequent analysis by a pathologist. The number of tissue blocks derived from a sample and the number of slides made from each tissue block vary widely depending on the type and size of the tissue sample being tested. Although many tissue biopsies may use an average of two blocks, many biopsies use more than two. As the current value for CPT 88305 is inadequate for a tissue examination with two blocks, it is significantly inadequate for examinations with even more blocks and slides. EXAMPLES Consider the following scenario. Patient A has a skin lesion that is biopsied and sent for analysis. We will assume that it is sectioned for examination to create two blocks, from which two slides (one slide per block) are prepared for microscopic evaluation by a pathologist. The laboratory receives one 88305 payment (and they have created two blocks, and a total of two slides). Now consider patient B, who has a more complex skin lesion that is biopsied and sent for analysis. Because it is more complex, let us assume it is processed to create 40 blocks, from which 40 slides (one slide per block) are prepared for microscopic evaluation. The laboratory still receives one 88305 payment, even though they created 40 blocks and a total of 40 slides (compared to patient A’s two blocks and two slides). This scenario illustrates that, for the 88305 code, laboratory payment is not increased if more blocks and slides are created, even though they may be needed for proper analysis. The laboratory is under an enormous incentive to prepare and process just two blocks anyway, or even one block and chance that the report may be inaccurate or incomplete. SKINmed. 2017;15:373–375

These scenarios illustrate that the current CPT code has important implications for patients, physicians, and pathology laboratories. Patient care may be impacted, as the laboratory has little incentive to process a larger number of blocks and slides, as illustrated above. They are not reimbursed for the extra work they perform or for the materials they use to process the specimens. This may jeopardize the quality of the test results, as the sample may not have been adequately analyzed to provide accurate results. In an effort to control costs, other quality control parameters and qualified personnel may also be impacted. THE ROLE OF THE SUBMITTING PHYSICIAN Physicians are often not aware of how the laboratory prepares the specimens or of their payment structure. It is generally assumed that once a specimen is sent to the laboratory, it is properly analyzed and the results are accurate. Physicians should, however, ask several questions: • Has the specimen been correctly processed by qualified, well-trained personnel? • Have all the margins (if indicated) been assessed? • Do I trust these results, or are they based on clinical suspicion? • Do I suggest further workup? Physicians can assist the laboratories during this process by clearly documenting the need for ordering tests and by following proper protocols for ordering these studies. Unfortunately, laboratories may be denied payments and may be obliged to honor requests for refunds during audits. THE RESULT Laboratories have been greatly impacted by this payment reduction. First, smaller in-office laboratories, operated by physician specialists in dermatopathology, gastroenterology, and urology groups, have been forced to close, as they lack the diversity of specimens needed to absorb deep cuts to 88305. This creates more business for larger hospital-based laboratories, which have a greater diversity of specimens to absorb these cuts. Second, in rural areas, several hospitals may contract with a single pathologist to act as a medical director for their laboratories, partly due to the cost of hiring a dedicated pathologist in areas where attracting qualified health care professionals is challenging. Cuts to 88305 may jeopardize medical director oversight in rural settings and may have direct impact on patient access to health care in these areas, with patients possibly needing to travel greater distances to get proper treatment and avoid delays. Ironically,

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this shift in site of care from rural to urban areas may actually increase costs for the Medicare system due to price differences between these areas.

References

CONCLUSIONS Reduced reimbursement for CPT code 88305 has already significantly affected laboratories and patient care. Smaller laboratories have been forced to close, while larger laboratories are being forced to contain costs. This scenario will likely impact patient care through compromised quality of test results and challenges to health care access for patients. Further cuts may come at any time without warning, compromising the quality of test results, despite the fact that the American Medical Association, the College of American Pathologists, and the US government (CMS) have all been very active in determining these payment scales. As government takes an even greater role in determining such payment scales, this caprice does not bode well for the future of medicine.

1 Klipp J. Medicare slashes CPT 88305-TC by 52%. Laboratory Economics. 2012;7:1â&#x20AC;&#x201C;3. 2 88305 Reimbursement in 2013. Leading Edge. http:// ascnewsletter.absrcm.com/2013/04/02/215/. Accessed June 8, 2016. 3 ASCP Letter to CMS on Physician Fee Schedule 2013. http://www.ASCP.ORG/pdf/ADVOCACY/ascp-LETTERTO-cms-ON-FINAL-pfs-cy-2013.PDF. March 6, 2016. 4 Burns J. Price Cuts, Long Delays in Payment Are Expected. http://www.darkintelligencegroup.com/wp-content/ uploads/The-Dark-Report-Price-Cuts-Long-Delays-revised policies-for-molecularCPT-codes-123112-2.pdf. Accessed April 12, 2016. 5 Comments Concerning Anatomical Pathology Code 88305. CPACDS. http://cpacds.com/wp-content/ uploads/2013/01/CPACDS-CMS-letter-12-31-12.pdf. Accessed April 12, 2016.

Historical Diagnosis and treatment

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September/October 2017

Volume 15 • Issue 5

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

Crisaborole 2% Ointment (EucrisaTM) Aditya K. Gupta, MD, PhD, FRCPC;1,2 Sarah G. Versteeg, MSc;2 William Abramovits, MD;3,4,5,6 Kimberly Dawn Vincent, MD7

topic dermatitis (AD) is a common skin disorder, impacting children (10% to 20%) and adults (1% to 3%) worldwide.1 Typically, AD presents as pruritic, inflamed, eczematous lesions most commonly located in skin folds.1,2 Topical therapies (corticosteroids, calcineurin inhibitors, etc.) are considered first-line therapy for mild to moderate AD, with systemic therapies (cyclosporine, azathioprine, etc.) and ultraviolet phototherapies as additional treatment options.3,4 Negative side effects of long-term corticosteroid use (systemic absorption, skin atrophy, adrenal suppression) and the limited efficacy of available therapies have led to an interest in the development of new treatments such as crisaborole.5 MECHANISM OF ACTION Crisaborole (EucrisaTM; Pfizer, Inc, New York, NY) is a newly approved (Food and Drug Administration) topical therapy for mild to moderate AD.6 It is a boron-based nonsteroidal antiinflammatory that inhibits phosphodiesterase 4 by substituting the carbon of phosphodiesterase 4 with boron.7 This inhibition prevents the degradation of cyclic adenosine monophosphate, an immune response regulator.6–8 Increasing cyclic adenosine monophosphate levels can lead to concomitant activation of protein kinase A, thereby preventing the activation of proinflammatory cytokines involved in AD pathogenesis.4 PHASE I STUDIES Crisaborole can reduce the severity of mild to moderate AD in pediatric patients. In a phase Ib, open-label, maximal-use study, crisaborole was applied twice daily to AD-affected areas for 28 days in 34 pediatric patients.4 By the end of treatment (day 29), 47% (16/34) of patients had achieved treatment success, an Investigator Static Global Assessment (ISGA) score of ≤1 with ≥2-grade improvement from baseline (Table I). The greatest re-

duction in ISGA scores occurred in patients aged 12 to 17 years old, reporting a 76% reduction from baseline. Minimal systemic absorption was found, with 68% (23/34) of patients reporting one or more treatment-emergent adverse events (TEAEs) (Table II). The majority of TEAEs (95%) were mild to moderate, and no serious AEs were reported. Crisaborole is well tolerated in sensitive body regions, as established through a randomized, double-blind, vehicle-controlled, phase I clinical study.2 In this study, healthy volunteers (18 to 55 years old) applied either crisaborole or vehicle to 13 body regions (eg, intertriginous areas, genitals, face/hairline regions) for 21 days. Crisaborole was well tolerated as burning/stinging, erythema, and pruritus were rarely reported (crisaborole 0.2% to 2.2% vs vehicle 2.4% to 7.1%, P value not reported). Approximately 71% (17/24) of crisaborole-treated patients and 63% (5/8) of vehicle-treated patients reported a TEAE. Only one crisaborole-treated patient reported a treatment-related TEAE (mild application-site pain). PHASE II STUDIES Applying crisaborole 2% twice daily is the most effective regimen in adolescent AD patients. In a double-blind, dose-ranging, 4-week phase II study, 86 patients with mild to moderate AD (12 to 17 years old) were randomly assigned to apply crisaborole once daily (n=44) or twice daily (n=42).9 Under both treatment regimens, two target lesions with similar severity were selected, with crisaborole 0.5% applied to one target lesion and crisaborole 2% applied to the other. Improvements in the signs and clinical manifestations of AD were observed in a dose-related fashion across treatment groups (Table I).

From the Department of Medicine, University of Toronto School of Medicine, Toronto, Ontario, Canada;1 Mediprobe Research Inc., London, Ontario, Canada;2 the Department of Medicine, Baylor University Medical Center, Dallas, TX;3 the Department of Dermatology,4 and Department of Family Practice,5 University of Texas Southwestern Medical School, Dallas, TX; and the Dermatology Treatment and Research Center, Dallas, TX;6 and Belle Meade Dermatology, Nashville, TN7 Address for Correspondence: Aditya K. Gupta, MD, PhD, FRCPC, 645 Windermere Road, London, Ontario, Canada N5X 2P1 • E-mail: agupta@execulink.com

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Table I. Efficacy of Crisaborole in Mild to Moderate Atopic Dermatitis (AD)s Study

Average Improvement in AD Signs and Clinical Manifestations

Number of Improved Patients

Number of Patients Achieving Treatment Success

Erythema 65% Excoriation 58% Exudation 64% Lichenification 61% Pruritus 63%

Clear or almost clear (ISGA) Crisaborole 22/34=65%

Crisaborole 16/34=47%

Total clearance (ADSI) Crisaborole 1/25=4% Vehicle 2/25=8% Partial clearance (ADSI) Crisaborole 12/25=48% Vehicle 2/25=8% Total/partial clearance (ADSI) Crisaborole 13/25=52% Vehicle 4/25=16% ≥4-point improvement (ADSI) Crisaborole 18/25=72% Vehicle 9/25=36%

Stein Gold et al10,b,c

Erythema 67% Excoriation 78% Exudation 80% Lichenification 54% Pruritus 79%

Total clearance (ADSI) Crisaborole 7/42=17% Partial clearance (ADSI) Crisaborole 19/42=45% ≥4-point improvement (ADSI) Crisaborole 35/42=83%

Tom et al11,b

Pruritus 1.30±0.73%

Crisaborole 8/23=35

Erythema Crisaborole 41%* Vehicle 20% Exudation Crisaborole 65%* Vehicle 52% Excoriation Crisaborole 52%* Vehicle 34% Induration/papulation Crisaborole 37%** Vehicle 29% Lichenification Crisaborole 42%* Vehicle 29%

Clear or almost clear (ISGA) Crisaborole study 1 262/503=52%** study 2 251/513=49%* Vehicle study 1 105/256=41% study 2 75/250=30%

Crisaborole study 1 166/503=33%*** study 2 159/513=31%* Vehicle study 1 64/256=25% study 2 45/250=18%

Phase I Zane et al4,b

Phase II Murrell et al9,a

Phase III Paller et al12,b

Number of improved patients: by end of treatment (day 28/29) based on Atopic Dermatitis Severity Index (ADSI) or Investigator Static Global Assessment (ISGA) scores. ADSI is the summation of severity scores measured on a 4-point scale. Scores are based on five AD features: pruritus, erythema, lichenification, excoriation, and exudation. Total clearance: ADSI score 0. Partial clearance: ADSI score 0 to 2. Total or partial clearance: ADSI score ≤2. ISGA is the assessment of AD severity using a 5-point scale. Clear or almost clear: ISGA score 0 to 1. Treatment success: ISGA score ≤1 with ≥2-grade improvement from baseline. Average improvement in AD signs and clinical manifestations is compared to baseline, based on a 4-point scale (0=none, 3=severe). NR, not reported. a Endpoint measured at day 28. b Endpoint measured at day 29. c Strongest crisaborole treatment selected. *P<.001 compared to vehicle. **P<0.01 as compared to vehicle. ***P <.05 as compared to vehicle.

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Table II. Efficacy of Crisaborole in Mild to Moderate Atopic Dermatitis (AD)s Study

Number of Patients Reporting ≥1 TEAE

Frequently Reported TEAEs

Frequently Reported Treatment-Related TEAEs

23/34=68% Crisaborole

Application site pain (n=12) Upper respiratory infection (n=3) Atopic dermatitis (n=7) Application site paresthesia (n=2)

Overall 36/63=57%a Application site pain 12/63=19%a Application site paresthesia 2/63=3%a

11/25=44% Crisaborole + Vehicle

Application site reactions (3/25=12%)

Overall 9/29=31%a

Stein Gold et al10

17/86=20% Crisaborole

Application site pain (2/86=2%) Nasopharyngitis (3/86=3%) Viral respiratory tract infection (2/86=2%)

Application site pain 2/86=2% Application site pruritus 2/86=2%

Tom et al11

10/23=43% Crisaborole

Application site pain (3/23=13%) Nasopharyngitis (3/23=13%)

Application site dermatitis 1/19=5%a Application site pain 4/19=21%a Application site discomfort 1/19=5%a

348/1012=34% Crisaborole 149/499=30% Vehicle

Application site pain Crisaborole (45/1012=4%) Vehicle (6/499=1%) Upper respiratory tract infection Crisaborole (30/1012=3%) Vehicle (15/499=3%)

Application site pain Crisaborole 45/1012=4% Vehicle 6/499=1%

Phase I Zane et al4

Phase II Murrell et al9

Phase III Paller et al12

Treatment-related TEAEs included probably/definitely/possibly related to treatment. Most frequently reported TEAE: based on the number of patients (with the exception of Zane et al). a Frequency is based on total number of TEAEs reported.

The greatest improvement in AD severity was found in lesions treated twice daily with crisaborole 2%, as 62% of crisaborole 2%–treated lesions were totally or partially cleared by the end of treatment (Table I). TEAEs were reported in 20% (17/86) of patients, with no serious AEs encountered (Table II). In an additional phase IIa, multicenter, open-label study, 23 patients with mild to moderate AD (12 to 17 years old) applied crisaborole 2% twice daily for 28 days.10 Crisaborole improved the signs and clinical manifestations of AD, with 35% of patients (8/23) achieving treatment success (an ISGA score ≤ 1 with ≥2-grade improvement from baseline) (Table I). Mild to moderate TEAEs were reported in 43% (10/23) of patients, and one patient discontinued treatment due to application site dermatitis (Table II). Crisaborole 2% can also diminish severity of AD in adults with mild to moderate AD. In a randomized, double-blind, multicenter phase IIa study, 25 patients with mild to moderate AD (18 to 75 years old) were treated with crisaborole 2% twice daily for 6 weeks.11 Two target lesions in each patient were selected; one was treated SKINmed. 2017;15:377–380

with crisaborole and the other treated with vehicle. A greater improvement in AD severity scores was found with crisaborole-treated lesions compared to vehicle-treated lesions at day 14, 28 and 42 (P=.027, P=.017, and P=0.027, respectively). A greater improvement in AD severity scores was found in crisaborole-treated lesions compared to baseline at day 14, 28 and 42 (P=.26, P=.001, and P=.036, respectively). In addition, more patients achieved total or partial clearance with crisaborole ointment compared to vehicle (Table I). Mild and moderate AEs were reported in 44% of patients with no severe or serious AEs noted (Table II). PHASE III STUDIES The efficacy and safety of crisaborole 2% has also been investigated in two multicenter, double-blind phase III studies.12 Patients with mild to moderate AD (aged 2 or more years old) were randomized to apply either vehicle or crisaborole twice daily for 28 days. More crisaborole-treated patients achieved treatment success (an ISGA score of ≤1 with ≥2-grade improvement from baseline) compared to vehicle-treated patients (day 29: study 1,

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P=.038; study 2, P<.001) (Table I). Additionally, more crisaborole-treated patients were clear or almost clear by the end of treatment compared to vehicle-treated patients (day 29: study 1, P=.005; study 2, P<.001) (Table I). Similarly, crisaborole-treated patients showed greater improvement in signs and clinical manifestations of AD compared to vehicle-treated patients (Table I). TEAE rates were similar across treatment groups, with only mild to moderate TEAEs reported (Table II). Patient discontinuations due to AEs were present in both the crisaborole and vehicle treatment groups (1.2% and 1.2%, respectively). CONCLUSIONS Crisaborole is a newly approved (Food and Drug Administration) topical therapy for the treatment of mild to moderate AD (in patients 2 or more years old).6 It is theorized that with crisaborole’s unique benzoxaborole chemistry, inhibition of AD pathogenesis can occur.13 Across age groups, crisaborole (2%) was able to totally clear or partially clear mild to moderate AD in 49% to 65% of treated patients,9,10,12 but only 37% of crisaboroletreated patients achieved treatment success (ISGA score of ≤1 with ≥2-grade improvement from baseline).4,10,12 Research evaluating the potential side effects of long-term crisaborole use is still required as most studies used a 28-day treatment regimen.4,10,12 Crisaborole 2% ointment enters a market in which the only competition from Food and Drug Administration–approved topical nonsteroidal products for AD comes from calcineurin inhibitors (tacrolimus 0.1% and 0.03% ointments, pimecrolimus 1% cream) and barrier repair products for the treatment of signs and clinical manifestations of dermatitis. Further research is required as long-term use can cause compliance issues, as seen with other AD treatments (eg, corticosteroids).5,14,15 Head-to-head comparisons between crisaborole 2% ointment, topical calcineurin inhibitors, and topical corticosteroids are required to assess their relative potency and safety, thereby determining their places within the therapeutic selection order. Research into treating psoriasis and other skin inflammatory conditions with crisaborole may be of value, as its mechanism of action suggests possible benefits.12 References 1 Atopic Dermatitis. American Academy of Dermatology. https://www.aad.org/public/diseases/eczema/atopicdermatitis#symptoms. Accessed April 21, 2017. 2 Zane LT, Hughes MH, Shakib S. Tolerability of crisaborole ointment for application on sensitive skin areas: A randomized, double-blind, vehicle-controlled study in healthy volunteers. Am J Clin Dermatol. 2016;17:519–526.

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3 Megna M, Napolitano M, Patruno C, et al. Systemic treatment of adult atopic dermatitis: A review. Dermatol Ther. 2016;7:1–23. 4 Zane LT, Kircik L, Call R, et al. Crisaborole topical ointment, 2% in patients ages 2 to 17 years with atopic dermatitis: A phase 1b, open-label, maximal-use systemic exposure study. Pediatr Dermatol. 2016;33:380–387. 5 Eichenfield LF, Tom WL, Berger TG, et al. Guidelines of care for the management of atopic dermatitis: Section 2. Management and treatment of atopic dermatitis with topical therapies. J Am Acad Dermatol. 2014;71:116– 132. 6 EUCRISATM (crisaborole) ointment, 2%, for topical use. 2016. http://www.accessdata.fda.gov/drugsatfda_ docs/label/2016/207695s000lbl.pdf. Accessed April 21, 2017. 7 Freund YR, Akama T, Alley MRK, et al. Boron-based phosphodiesterase inhibitors show novel binding of boron to PDE4 bimetal center. FEBS Lett. 2012;586:3410–3414. 8 Ciaravino V, Plattner J, Chanda S. An assessment of the genetic toxicology of novel boron-containing therapeutic agents. Environ Mol Mutagen. 2013;54:338–346. 9 Murrell DF, Gebauer K, Spelman L, Zane LT. Crisaborole topical ointment, 2% in adults with atopic dermatitis: A phase 2a, vehicle-controlled, proof-of-concept study. J Drugs Dermatol JDD. 2015;14:1108–1112. 10 Stein Gold LF, Spelman L, Spellman MC, Hughes MH, Zane LT. A phase 2, randomized, controlled, dose-ranging study evaluating crisaborole topical ointment, 0.5% and 2% in adolescents with mild to moderate atopic dermatitis. J Drugs Dermatol JDD. 2015;14:1394–1399. 11 Tom WL, Van Syoc M, Chanda S, Zane LT. Pharmacokinetic profile, safety, and tolerability of crisaborole topical ointment, 2% in adolescents with atopic dermatitis: An open-label phase 2a study. Pediatr Dermatol. 2016;33:150–159. 12 Paller AS, Tom WL, Lebwohl MG, et al. Efficacy and safety of crisaborole ointment, a novel, nonsteroidal phosphodiesterase 4 (PDE4) inhibitor for the topical treatment of atopic dermatitis (AD) in children and adults. J Am Acad Dermatol. 2016;75:494–503.e4. 13 Smith SD, Farrugia LL, Harris V, Lee A, Blaszczynski A, Fischer G. Evaluation of the influence of family and friends, and the Internet on patient perceptions of long-term topical corticosteroid use. J Dermatol Treat. 2017;28:642–646. 14 El Hachem M, Gesualdo F, Ricci G, et al. Topical corticosteroid phobia in parents of pediatric patients with atopic dermatitis: a multicentre survey. Ital J Pediatr. 2017;43:22. 15 Jarnagin K, Chanda S, Coronado D, et al. Crisaborole topical ointment, 2%: a nonsteroidal, topical, anti-inflammatory phosphodiesterase 4 inhibitor in clinical development for the treatment of atopic dermatitis. J Drugs Dermatol JDD. 2016;15:390–396.

Crisaborole 2% Ointment (EucrisaTM)

September/October 2017

Volume 15 • Issue 5

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

Herpes Zoster, Immunosuppression, and Vaccination: Far from a Blistering Pace Warren R. Heymann, MD

o you recognize the name Chris Gueffroy (1968– 1989)? He was the last person shot trying to escape from East Berlin, before the wall came down. I had long promised myself that I would get Zostavax® when I turned 60. The current vaccine provides protection for up to 3 years. Now 61, I am actively procrastinating—I decided to wait for a new, improved varicella zoster virus subunit zoster vaccine that consists of recombinant varicella zoster virus glycoprotein E and a liposome-based ASO1B adjuvant system.1 I am convinced that I will be the last person to get shingles prior to the release of the new vaccine. On the other hand, if I were at high risk, I would have had it already.

rheumatoid arthritis was associated with a statistically significant increase risk of zoster.”3 The authors recommended considering utilizing the varicella zoster vaccine in patients with cutaneous lupus erythematosus or dermatomyositis prior to their receiving immunosuppressive agents. They correctly state that the standard age of immunization for zoster is now 50 years (it is my understanding that most insurers will not pay for it until age 60, making this a further challenge).3

HERPES ZOSTER AND DISEASE-ASSOCIATED IMMUNOSUPPRESSION

HZ AND IATROGENIC IMMUNOSUPPRESSION

The incidence of herpes zoster (HZ) is increased in many autoimmune diseases. A recent study has demonstrated that the age-specific incidence rates of HZ in patients with rheumatoid arthritis and those with systemic lupus erythematosus (SLE) aged 40 years or over were 1.5–2.0 times greater than those observed in older healthy adults (incidence rate 8.5 per 1000 person-years), for whom the vaccine is currently recommended.2 In a retrospective study of 186 patients with cutaneous lupus erythematosus, dermatomyositis, pemphigus vulgaris, and bullous pemphigoid, it was determined that the risk of zoster was highest in patients with dermatomyositis followed by lupus compared with healthy controls.3 Within each disease group, there was no significant difference in the proportion of patients with and without zoster while taking immunosuppressive agents, including corticosteroids. The authors stated, however, that “Prior studies found that patients with [dermatomyositis] on chloroquine had a 6-fold increased risk of zoster compared with those not on chloroquine, and that the use of hydroxychloroquine in

We recently made a similar recommendation after seeing a patient with lupus develop cutaneous lupus erythematosus lesions as a Koebner phenomenon following her zoster episode.4

Aside from the immunologic aberrations of the autoimmune diseases that increase the risk of zoster infection, additional immunosuppression related to therapy must be addressed. This is of vital importance when using biologic drugs (tumor necrosis factor inhibitors, anti-interleukin [IL]-12/23 inhibitors, antiIL-17 inhibitors), as live vaccines should not be administered to individuals taking these agents. A recent study compared 1555 patients with SLE and HZ to a control group of 3049 matched patients with SLE but without HZ. It was concluded that recent immunosuppression is related to HZ in patients with SLE, especially for those on high-dose corticosteroids or multiple immunosuppressive agents, based on the following results: “Medications associated with greater HZ risk in patients with SLE included oral corticosteroids, intravenous methylprednisolone, hydroxychloroquine, oral cyclophosphamide, intravenous cyclophosphamide, azathioprine, methotrexate, and mycophenolate mofetil. Combination immunosuppressive therapy was common in patients with SLE and was associated with greatly increased HZ risk. For oral corticosteroids and hydroxychloroquine, the risk of HZ was strongly dependent on the medication dose.”5

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, Division of Dermatology, Departments of Medicine and Pediatrics, Cooper Medical School of Rowan University, 100 Brick Road, Suite 306, Marlton, NJ 08053 • E-mail: wrheymann@gmail.com

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References

HZ appears when there is a reduction of cell-mediated immunity, whether due to age-related senescence, an autoimmune disease, treatment for that disease, or any combination of the three. If you read the package insert for Zostavax®, immunosuppression is a contraindication to the vaccine. Despite age restrictions and the risk of immune suppression from the disease itself, we need to weigh the risk–benefit ratio of administering the vaccine to those patients who have not yet received their immunosuppressive drugs. In my estimation, the benefits clearly exceed the risks. I completely concur with Oxman and Schmader6 who opine: In view of the very high degree of attenuation of the Oka vaccine strain of [varicella zoster virus], these observations suggest that it may be time to reconsider the use of zoster vaccine in selected populations of immunocompromised patients who are at increased risk of HZ infection and its debilitating complications. Such considerations should not, however, divert attention from the urgent need to increase the woefully inadequate uptake of zoster vaccine by adults ≥60 years of age, for whom it is already recommended.

1 Gagliardi AM, Andriolo BN, Torloni MR, Soares BG. Vaccines for preventing herpes zoster in older adults. Cochrane Database Syst Rev. 2016;3:CD008858. 2 Yun H, Yang S, Chen L, Xie, et al. Risk of herpes zoster in autoimmune and inflammatory diseases: Implications for vaccination. Arthritis Rheumatol. 2016;68:2328– 2337. 3 Robinson ES, Payne AS, Pappas-Taffer L, Feng R, Werth VP. The incidence of herpes zoster in cutaneous lupus erythematosus (CLE), dermatomyositis (DM), pemphigus vulgaris (PV) and bullous pemphigoid (BP). J Am Acad Dermatol. 2016;75:42–48. 4 Anywanu C, Sommer LL, Heymann WR. Discoid lupus following herpes zoster: Potential prophylaxis for the isomorphic response. Cutis. In Press. 5 Hu SC-S, Yen FL, Wang TN, Lin YC. Immunosuppressive medication use and risk of herpes zoster (HZ) in patients with systemic lupus erythematosus (SLE): A nationwide case-control study. J Am Acad Dermatol. 2016;75:49–58. 6 Oxman MN, Schmader KE. Editorial commentary: Zoster vaccine in immunocompromised patients: time to reconsider current recommendations. Clin Infect Dis. 2014;59:920–922.

“Malum perforans”, Moulage No. 104, made by Adolf Fleischmann in 1920 in the Clinic for Dermatology Zurich. Museum of Wax Moulages Zurich, www.moulagen.ch Courtesy of Michael Geiges, MD

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Volume 15 • Issue 5

PHOTO CAPSULE Snejina Vassileva, MD, PhD, Section Editor

Oral Mucocoele: The Magic of Sclerotherapy Anju George, MBBS, MD;1 Eswari Loganathan, MBBS, MD2

28-year-old man presented with an asymptomatic swelling on the left side of his lower lip that had been present for 2 months. The lesion had begun as a tiny bump after an accidental bite and gradually progressed. There was no significant dental or medical history. Examination revealed a single, soft, mobile, well-defined translucent swelling on the inner aspect of the left lower lip. The swelling was fluctuant and nontender, and measured 1 cm × 0.5 cm in size (Figure 1). A clinical diagnosis of oral mucocoele was considered, and further sclerotherapy was planned. A single ampoule of the sclerosant sodium tetradecyl sulfate (STDS), containing 60 mg/2 mL, was diluted with distilled water in a 1:3 ratio, such that 9 mg/mL was obtained. Several volumes of 5 to 8 units of the drug were

injected into the cavity until blanching was visible. Complete shrinkage was observed after 3 weeks, with a tinge of residual pigmentation (Figure 2). Two units of STDS in the same dilution were administered during the second visit. The patient has since been lost to follow-up. DISCUSSION Oral mucocoeles are common, benign, mucus-containing cysts of the minor salivary glands lined by epithelium or covered by granulation tissue. They may be either extravasation cysts occurring due to rupture of salivary gland duct, or mucus retention cysts as a result of salivary gland duct blockade. The common sites affected include the lower lip, tongue, floor of

Figure 1. Soft, fluctuant swelling measuring 1 × 0.5 cm on the left lower lip.

Figure 2. Complete resolution of the swelling with minimal residual pigmentation.

From the Department of Dermatology, Bangalore Baptist Hospital, Hebbal,1 and the Department of Dermatology, Bowring and Lady Curzon Hospital, Bangalore Medical College and Research Institute, Shivaji Nagar,2 Bengaluru, India Address for Correspondence: Anju George, MBBS, MD, #5A, Apurva Arcade, 25, AECS Layout, 5th Cross, Sanjay Nagar 1st Stage, Bengaluru 560094, India • E-mail: dranjugeo@gmail.com

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the mouth (ranula), and buccal mucosa.1 Clinically, they appear as soft, smooth, painless swellings. The diagnosis is usually clinical based on the typical history and findings. Vascular lesions may often mimic a mucocoele, making it important to differentiate between the two before a surgical excision is attempted.2

CONCLUSIONS Sclerotherapy with STDS is a safe and efficacious technique in treating oral mucocoeles, with rapid results being attained in a single sitting. References

Treatment modalities include complete surgical excision, marsupialization of the cyst cavity, cryotherapy, and CO2 laser ablation. Sclerotherapy of mucocoeles with picibanil (OK-432)2,3 or pingyangmycin4 has been used, although there are very few reports quoting the efficacy of intralesional STDS. Other available sclerosants include hypertonic saline, ethanol, tetracycline, cyclophosphamide, morrhuate sodium, and bleomycin. OK-432, which is frequently used in the treatment of ranulas, induces production of interferon gamma, tumor necrosis factor alpha, interleukin-6, and interleukin-8. This is further accompanied by neutrophilic and monocytic infiltration. These cytokines induce strong local inflammatory reactions in the cyst wall, resulting in fluid drainage, shrinkage, and fibrotic adhesion of the cyst.5

1 Senthilkumar B, Mahabob MN. Mucocele: An unusual presentation of the minor salivary gland lesion. J Pharm Bioallied Sci. 2012;4(suppl 2):180–182. 2 Re Cecconi D, Achilli A, Tarozzi M, et al. Mucoceles of the oral cavity: A large case series (1994–2008) and a literature review. Med Oral Pathol Oral Cir Bucal. 2010;15:e551–e556. 3 Rho MH, Kim DW, Kwon JS, et al. OK 432 sclerotherapy of plunging ranula in 21 patients: It can be a substitute for surgery. Am J Neuroradiol. 2006;27:1090–1095. 4 Cai Y, Wang R, Yang SF, Zhao YF, Zhao JH. Sclerotherapy for the mucocoeles of the anterior lingual salivary glands with pingyangmycin. Oral Dis. 2014;20:473–476. 5 Yoshizawa K, Moroi A, Kawashiri S, Ueki K. A case of sublingual ranula that responded successfully to localized injection treatment with OK-432 after healing from drug induced hypersensitivity syndrome. Case Rep Dent. 2016;2016:1–5.

VINTAGE LABEL

Courtesy of BuyEnlarge, Philadelphia, PA SKINmed. 2017;15:383–384

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September/October 2017

Volume 15 • Issue 5

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

Perianal Ulcer in an Asian Man Nilanthy Sharon Anthony Pillai, MBBS, MRCP (UK);1 Choon Chiat Oh, MBBS, MRCP (UK);1 Michelle Chan Mei Fung, MBBS, FRCPath;2 Limin Wijaya, MBBS (Melb), MRCP (UK)3

A 79-year-old Chinese man presented with a 2-month history of pruritic, tender ulceration covering his perianal region. He was initially treated with oral amoxicillin/clavulanic acid and vancyclovir, with no improvement. His history included hypertension. On physical examination, there was a 1.5-cm solitary, pink shallow ulcer with a tender erythematous base on the right side of the buttock cleft (Figure 1). (SKINmed. 2017;15:385–386)

istologic study of the sections from a skin punch biopsy showed multiple granulomas associated with multinucleated giant cells within the dermis (Figure 2). Some of these cells were surrounded by lymphocytes (Figure 3), but no definitive caseation was seen. Special stains for acid-fast bacilli and fungi were negative. A smear of the ulcer for acid-fast bacilli was 1+ positive, and culture of the skin tissue grew Mycobacterium tuberculosis complex. A chest x-ray showed active tuberculosis (TB). The acid-fast bacillus smear of the sputum was negative, but the culture was positive for Mycobacterium tuberculosis complex. A diagnosis of tuberculosis cutis orificialis (TCO) was made, and the patient was started on standard antituberculosis treatment with ethambutol 800 mg once daily, isoniazid 300 mg once daily, pyrazinamide 1.5 g once daily, and rifampicin 600 mg once daily. At the 6-week visit, the ulcer was seen to be filling in (Figure 4). Contact tracing for TB did not reveal TB in other family members. DISCUSSION TCO is an uncommon manifestation of cutaneous TB. Skin manifestations of TB may be approximately 2.1%, with perianal involvement in approximately 0.7% of patients with TB.1 TCO occurs in oral, perianal, or genital mucosae and adjacent skin.2 Clinically, perianal TB has been classified into five subtypes: ulcerative, verrucous, lupoid, miliary, and fissured. The ulcerative

type is the most common and is often secondary to foci in the lungs or gastrointestinal tract.3 TCO is secondary to autoinoculation of the infectious agent from the pulmonary, gastrointestinal, or genitourinary tract.2 On rare occasions, there may be hematogenous or lymphatic dissemination from an active source of TB.2 TCO is characterized by painful ulcers with indurated erythematous borders and a necrotic base in the mucosal orifices of patients with advanced TB, with the tongue commonly being the site.2 The histologic findings include ulceration surrounded by a nonspecific inflammatory infiltrate and extensive caseous necrosis. Granulomas are composed of epitheloid cells and Langerhans type giant cells in the dermis.2 The differential diagnosis is varied and may include Crohn’s disease, herpes progenitalis, actinomycosis, sarcoidosis, hidradenitis, syphilis, herpes zoster, and lymphogranuloma venereum, as well as trauma and malignancies.1,2 Unfortunately, the diagnosis of TB, especially the cutaneous forms, by conventional laboratory methods is unreliable and time-consuming. In one study, polymerase chain reaction produced the best detection rate (79.4%), followed by histopathology (73.5%), various cultures (29 to 47%) and smear examination (5.8%).4 Treatment of TCO uses the standard antituberculosis regimen. If skin lesions do not respond to medication or are accompanied by obstruction or abscess, surgical intervention is the next step.1

From the Department of Dermatology,1 Department of Pathology,2 and Department of Infectious Disease,3 Singapore General Hospital, Singapore Address for Correspondence: Choon Chiat Oh, Department of Dermatology, Academia Level 4, 20 College Rd, Singapore 169856 • E-mail: oh.choon.chiat@sgh.com.sg

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Figure 1. Solitary, shallow ulcer over the right buttock.

Figure 3. Multiple granulomas with multinucleate giant cells and surrounding lymphocytes.

Figure 4. The healing perianal ulcer after 6 weeks of antituberculosis treatment.

Figure 2. A low-power view shows multiple granulomas within the dermis.

References 1 Gupta PJ. Ano-perianal tuberculosis–solving a clinical dilemma. Afr Health Sci. 2005;5:345–347.

CONCLUSIONS Perianal ulcers can be the initial manifestation of TB in otherwise asymptomatic healthy patients. Anoperineal involvement may be associated with pulmonary and abdominal TB, either as an extension of the original lesion or due to spread via the lymphatics. A high index of suspicion and early treatment can lead to a good prognosis. SKINmed. 2017;15:385–386

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2 Choi SR, Kim JK, Kim DH, Yoon MS. A case of tuberculosis cutis orificalis with perianal involvement. Ann Dermatol. 2009;21:443–446. 3 Ibn Majdoub Hassani K, Ait Laalim S, Toughrai I, Mazaz K. Perianal tuberculosis: A case report and a review of the literature. Case Rep Infect Dis. 2012;2012:852763. 4 Negi SS, Basir SF, Gupta S, Pasha ST, Khare S, Lal S. Comparative study of PCR, smear examination and culture for diagnosis of cutaneous TB. J Commun Dis 2005;37:83–92.

Perianal Ulcer in an Asian Man

September/October 2017

Volume 15 • Issue 5

CASE STUDY

Hailey-Hailey Disease Presenting as Lichenoid Plaques on the Thigh Anupama Ghosh, MD;1 Anupam Das, MD;1 Piyush Kumar, MD;2 Swapan Sardar, MD3

A 40-year-old woman presented with multiple itchy violaceous papules and plaques on the medial aspects of both thighs. This was accompanied by a burning sensation on friction and increased itching that interfered with her daily activities, particularly in the summer. The family history was noncontributory. Cutaneous examination showed multiple flat-topped hyperkeratotic violaceous papules and plaques, appearing in linear fashion on the medial aspects of the thighs bilaterally (Figure 1). Histopathologic examination showed acanthosis, widespread suprabasal acantholysis resembling a “dilapidated brick wall,” without any evidence of dyskeratosis. There was a mild dermal perivascular infiltrate (Figure 2). On the basis of the clinical and histologic findings, she was diagnosed as having localized Hailey-Hailey disease. She was treated conservatively with topical corticosteroids and antimicrobials. She was also advised to lose weight, to avoid friction, and to wear loose-fitting cotton garments. There was marked symptomatic relief, and the lesion showed mild improvement over the next 2 months. (SKINmed. 2017;15:387–388)

ailey-Hailey disease, a genodermatosis inherited as autosomal dominant, is characterized by recurrent vesicular and blistering dermatitis of the neck, axillae, and flexural regions.1, 2 The flaccid vesicles soon rupture, giving rise to crusted and macerated erosions, which spread peripherally. Heat, friction, sweating, and the summer season aggravate this condition.

Besides the classic picture, Hailey-Hailey disease can present in many atypical morphologies.2–4 Genital lesions can appear as verrucous papules. One report described six patients with verrucous anogenital lesions of Hailey-Hailey disease, initially diagnosed as warts.5 Our case presented in a similar manner with verrucous papules on the thighs. One clinical clue to HaileyHailey disease is longitudinal leukonychia. This nail marker may

Figure 1. (A) Bilateral hyperkeratotic plaques arranged in linear fashion on the medial aspects of the thighs. (B) Close-up of the lesions.

From the Department of Dermatology, Medical College and Hospital, Kolkata, India;1 the Department of Dermatology, Katihar Medical College and Hospital, Katihar, India;2 and the Department of Dermatology, North Bengal Medical College and Hospital, Darjeeling, India3 Address for Correspondence: Piyush Kumar, MD, Department of Dermatology, Katihar Medical College and Hospital, Karim Bagh, Katihar Pin 854105, Bihar, India • E-mail: docpiyush099@gmail.com

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Figure 2. Focal acanthosis and acantholysis involving the full thickness of the suprabasal epidermis (hematoxylin and eosin stain, magnification [A] ×100; [B] ×400).

antedate other cutaneous manifestations and is noted in multiple fingernails.6 Our patient did not have longitudinal leukonychia. Arrangement of lesions in linear fashion was another interesting finding, and we attributed this linear arrangement of lesions to a Koebner phenomenon. Rarely, the vaginal area,7 the chest wall, and the lateral aspects of the arms8 can be affected, signifying the variable forms of presentation of this disease. Perianal pseudoverrucous papules and nodules can be considered in the differential diagnosis of these cases. This is a rare entity, attributed to chronic irritation from leakage of urine and sometimes of stool.9 CONCLUSIONS Atypical presentations of common conditions are not infrequent and may pose diagnostic dilemmas. Appropriate and timely investigations, including histopathology, are necessary for early diagnosis and management. References 1 Hu Z, Bonifas JM, Beech J, et al. Mutations in ATP2C1, encoding a calcium pump, cause Hailey-Hailey disease. Nat Genet. 2000;24:61–65. 2 Sudbrak R, Brown J, Dobson-Stone C, et al. Hailey-Hailey

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disease is caused by mutations in ATP2C1 encoding a novel Ca2+ pump. Hum Mol Genet. 2000;9:1131–1140. 3 Mayuzumi N, Ikeda S, Kawada H, Fan PS, Ogawa H. Effects of ultraviolet B irradiation, proinflammatory cytokines and raised extracellular calcium concentration on the expression of ATP2A2 and ATP2C1. Br J Dermatol. 2005;152: 697–701. 4 Mayuzumi N, Ikeda S, Kawada H, Ogawa H. Effects of drugs and anticytokine antibodies on expression of ATP2A2 and ATP2C1 in cultured normal human keratinocytes. Br J Dermatol. 2005;152: 920–924. 5 Langenberg A, Berger TG, Cardelli M, et al. Genital benign chronic pemphigus (Hailey-Hailey disease) presenting as condylomas. J Am Acad Dermatol. 1992;2:951– 955. 6 Meawad OB, Assaf HM. Longitudinal white streaks of fingernails: A useful clinical marker in genital verrucoid Hailey-Hailey disease. J Eur Acad Dermatol Venereol. 1995;2:177–180. 7 Vaclavinkova V, Neumann E. Vaginal involvement in familial benign chronic pemphigus (Morbus Hailey-Hailey). Acta Derm Venereol. 1982;62:80–81. 8 Saied NK, Schwartz RA, Hansen RC, Levine N. Atypical familial benign chronic pemphigus. Cutis. 1981;27:666– 669. 9 Dandale A, Dhurat R, Ghate S. Perianal pseudoverrucous papules and nodules. Indian J Sex Transm Dis. 2013;34: 44–46.

Hailey-Hailey Disease

September/October 2017

Volume 15 • Issue 5

CASE STUDY

Kitty Litter Dermatitis from 2-Bromo-2-Nitropropane-1,3-Diol John W. Sullenbarger, MS3;1 Brooke Hensley, DO;1 Jeffrey B. Travers, MD, PhD1,2,3

A 70-year-old white man presented with a 6-week history of an acute pruritic eruption in the axillary vaults, inguinal folds, and central lumbar area. Due to the severity of the pruritus, the patient was evaluated in the emergency department. He was treated with intramuscular triamcinolone, oral fluconazole, clobetasol cream, and miconazole powder, which provided only minimal relief. The patient had presented with brightly erythematous patches in the axillary vaults and inguinal folds with numerous erythematous, scaly, coalescing papules and plaques agminated on the lumbar region (Figure). Due to persistence, despite topical corticosteroids, an allergic contact dermatitis was suspected so patch-testing using the T.R.U.E. Test (SMARTPractice Denmark ApS, Hillerod, Denmark) epicutaneous system was conducted. Results were positive for 5-chloro-2-methyl-4-isothazolinone (panel 2.1, #17), budesonide (panel 3.1, #30), and 2-bromo2-nitropropane-1,3-diol, also known as bronopol (panel 3.1, #36). The patient’s topical medications were adjusted based on these results, and he was advised to avoid any products containing these contactants. (SKINmed. 2017;15:389–390)

t the follow-up visit, the patient’s eruption had diminished in the intertriginous areas, but the lumbar area remained unchanged. After extensive questioning, it was determined that the patient’s cat slept in his recliner every night. The patient was asked to evaluate the kitty litter to see if it contained the antimicrobial agent bronopol, which, based on the unique distribution, was the suspect. After this discovery, the patient switched to a bronopol-free cat litter with near resolution of the eruption.

Bronopol is a common preservative used in cosmetics, shampoos, skin care products, cleaning agents, detergents, humidifiers, and cat litter, as well as many other home and industrial products.4 Additionally, it has antimicrobial activity against yeast, fungi, gram-positive bacteria, and gram-negative bacteria, being especially known for its activity against Pseudomonas aeruginosa. It acts by forming disulfide bonds with thiol-containing enzymes, which inhibit dehydrogenase activity in metabolizing cells, resulting in alterations in membrane structure and cell leakage.5

Discussion

Bronopol is slowly broken down into formaldehyde, a wellknown contact sensitizer. One study has demonstrated that the degradation rate of bronopol into formaldehyde is accelerated by temperature elevations.6 Given this information, presentation of the patient’s eruption on the lumbar region is likely augmented by the chair fabric insulating the patient’s body heat. The elevated ambient temperature would increase the breakdown of bronopol to formaldehyde and promote an allergic reaction.

There are well-documented cases in the literature describing allergic contact dermatitis caused by bronopol, but most of these are due to exposure to creams,1 lubricants,2 and spin finish oils,3 which contain bronopol as preservatives. To the authors’ knowledge, this is the first published report of cat litter containing bronopol as a source for allergic contact dermatitis, especially in this unique location on the body.

From the Department of Dermatology,1 and Department of Pharmacology and Toxicology,2 Wright State University Boonshoft School of Medicine, Beavercreek, OH; and Dayton Veteran’s Affairs Medical Center, Dayton, OH3 Address for Correspondence: John Sullenbarger, MS3, Wright State Physicians Dermatology, 725 University Blvd., Beavercreek, OH 45324 • E-mail: sullenbarger.4@wright.edu

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Volume 15 • Issue 5 case study demonstrates the widespread use and importance in recognizing the possibility of bronopol-induced allergic contact dermatitis with an atypical distribution. References 1 Choudry K, Beck MH, Muston HL. Allergic contact dermatitis from 2-bromo-2-nitropropane-1,3-diol in Metrogel®. Contact Dermatitis. 2002;46:60–61. 2 Wilson CL, Powell SM. An unusual case of allergic contact dermatitis in a veterinary surgeon. Contact Dermatitis. 1990;23:42–43. 3 Podmore P. Occupational allergic contact dermatitis from both 2-bromo-2-nitropropane-1,3-diol and methylchloroisothiazolinone plus methyllisothiazolinone in spin finish. Contact Dermatitis. 2000;43:45. 4 T.R.U.E Test: 2-bromo-2-nitropropane-1,3-diol (Bronopol). https://www.smartpractice.com/dermatologyallergy/pdfs/allergens/Bronopol-Patient-Info.pdf. Accessed November 2, 2017.

Figure. Erythematous papules in the central part of the lumbar region.

5 Bryce DM, Croshaw B, Hall JE, Holland VR, Lessel B. The activity and safety of the antimicrobial agent bronopol (2-bromo-2-nitropropane-1,3-diol). J Soc Cosmet Chem. 1978;29:3–24.

CONCLUSIONS Previous studies, including a case series,7 have established a link between bronopol-containing products and allergic contact dermatitis. Although most studies concentrate on the allergic contact dermatitis caused by cosmetics and skin care products, this

6 Matczuk M, Obarski N, Mojski M. The impact of the various chemical and physical factors on the degradation rate of bronopol. Int J Cosm Sci. 2012;34:451–457. 7 Peters MS, Connolly SM, Schroeter AL. Bronopol allergic contact dermatitis. Contact Dermatitis. 1983;9:397–401.

VINTAGE LABEL

Courtesy of BuyEnlarge, Philadelphia, PA SKINmed. 2017;15:389–390

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Kitty Litter Dermatitis

September/October 2017

Volume 15 • Issue 5

CASE STUDY

Two Cases of Lepromatous Leprosy from Exposure to Armadillos in Florida Jennifer Harb, MD;1 Salma Pothiawala, MD, MPH;2 Donna Yonkosky, MD;3 James Talley, MD;3 Drazen Jukic MD, PhD4

The first patient was a 41-year-old white man who was referred to the dermatology clinic with a 2-year history of numerous erythematous, hypoesthetic, poorly demarcated papules and plaques present on the trunk, buttocks, and bilateral upper and lower extremities (Figures 1 and 2). The lesions had initially begun as localized erythematous plaques on the right flank, and were diagnosed and treated as cellulitis and allergic contact dermatitis by primary care on separate occasions, with no resolution and continued gradual but persistent spread. (SKINmed. 2017;15:391–393)

unch biopsies from lesions on the trunk showed histiocytic and lymphocytic infiltrates, with concentration around neurovascular bundles (Figure 3). Acid-fast bacillus and Fite-Faraco stains revealed numerous acid-fast bacilli in foamy histiocytes (Figure 4). Treponema stains were negative, as were fungal and bacterial cultures of the tissue. Sputum, chest radiograph, and tuberculin skin test showed no evidence of tuberculosis. The patient had had no exposure to leprosy patients and had never traveled to an endemic country. After repeated inquires, he remembered having a “struggle” with an armadillo in his yard a few years before. Biopsies were sent to the National Hansen’s Disease Program (NHDP) in Baton Rouge, LA, which additionally confirmed the diagnosis of lepromatous leprosy. The patient was placed on triple therapy with minocycline 100 mg, rifampin 500 mg, and dapsone 100 mg daily for 24 months. He responded well, with no adverse events or immunologically mediated reactions. The lesions gradually resolved during treatment, with improved dysthesia. The second patient was a 72-year-old man who presented to the infectious disease clinic with a 1-year history of erythematous, slightly pruritic, and hypoesthetic patches and plaques that ini-

tially began as a single, herald-like patch on the left thigh and subsequently spread to the trunk and upper extremities. He denied systemic clinical manifestations such as fevers, chills, arthralgias, or myalgias. Punch biopsies performed from lesions on the thigh and arm showed a superficial and deep perivascular and perieccrine lymphoplasmocytic infiltrate. AFB stains were negative at the time. Rapid plasma reagin (RPR) and Lyme titers were also negative. The patient was postulated to have a spirochetal disease, in particular the southern tick–associated rickettsial illness (STARI), and was treated with doxycycline 100 mg twice a day for 14 days with no improvement. At this point, he was referred to the dermatology clinic. Additional punch biopsies were taken from lesions on the trunk, which now revealed a granulomatous infiltrate on routine hematoxylin-eosin staining. AFB and Fite-Faraco stains revealed numerous acid-fast bacilli in a perivascular, perineurial, and periadnexal distribution. Treponema stains were negative. The patient denied any history of foreign travel. He was born in Minnesota and had lived there until 1970, at which point he had moved to Florida. He had used to work in a plant nursery in Florida, where he had frequently had trouble with invading armadillos over the previous 15 years. He regularly caught armadillos in a

From the Department of Dermatology, University of Florida College of Medicine, Gainesville, FL;1 Department of Dermatology and Cutaneous Surgery, University of South Florida, Morsani College of Medicine, Tampa, FL;2 Department of Dermatology, Orlando VA Medical Center, Orlando, FL;3 and Department of Dermatopathology, James A. Haley Veterans Hospital, Tampa, FL4 Address for Correspondence: Jennifer Harb, MD, Department of Dermatology, 4037 NW 86th Terrace, 4th Floor, Gainesville, FL 32606 • E-mail: Jennifer.Harb@dermatology.med.ufl.edu

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Figure 1. Patient presenting with multiple erythematous, ill-defined papules and plaques on his trunk, plus the fourth and fifth fingers, in a patient with Raynaud’s disease.

Figure 3. Lesional biopsy section showing epithelioid and lymphocytic infiltrates, concentrated around neurovascular bundles (hematoxylin and eosin stain, original magnification ×100).

Figure 2. Similar lesions to those in Figure 1 were also distributed on the buttocks, legs, and arms. Figure 4. Lesional biopsy section showing numerous acid-fast bacilli in foamy histiocytes (Fite-Faraco stain, original magnification ×60).

metal cage and would carry them to a nearby swamp to release them. For this case, too, the specimens were sent to the NHDP, which confirmed the diagnosis of borderline lepromatous leprosy. The patient was started on a 24-month course of daily minocycline 100 mg, rifampin 600 mg, and dapsone 100 mg. Initially, he responded well with excellent improvement of the eruption and dysthesia. At 4-month follow-up, however, he was found to be having a type I reversal reaction, with marked inflammation, erythema, and local tenderness of existing lesions. Prednisone was initiated, with good response. SKINmed. 2017;15:391–393

DISCUSSION Leprosy, also known as Hansen’s disease, is a chronic infectious disease caused by the acid-fast bacillus Mycobacterium leprae.1 The prevalence of leprosy is greatest in tropical and semitropical regions of the world and is relatively rare in the United States, with approximately 200 new cases reported each year.2 In endemic areas, organisms are most likely to spread between humans via nasal droplets.3 The vast majority of these individuals have reported travel to leprosy-endemic areas. Approximately one third,

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however, report no travel history or contact with leprosy-infected individuals, and seem to have contracted the disease locally.1 One proposed mode of transmission is via direct or indirect armadillo exposure. Other than humans, armadillos are the only known natural hosts of M. leprae, and infection can occur naturally among wild armadillo populations.4 Numerous surveys have confirmed the nine-banded armadillo (Dasypus novemcinctus) to be a reservoir for M. leprae in the southern United States, with infection rates among wild armadillos reported to be between 0.5% and 19%.5 Recent evidence has confirmed that armadillos are likely involved in up to 64% of documented human leprosy cases reported each year in the United States,6 making armadillos a significant risk factor for leprosy in the United States.5,7 Zoonotic transmission of leprosy from armadillo exposure has been reported in Texas, Louisiana, Mississippi, and as far east as Alabama. We report here the first two cases of leprosy, in particular lepromatous leprosy, transmitted from exposure to armadillos in the state of Florida. Most lepromatous lesions in documented cases reportedly develop 3 to 4 years after exposure, which is in line with the incubation period of leprosy. Both our patients contracted leprosy from exposure to armadillos, most likely occurring either after direct inoculation with M. leprae from trauma to the skin and exposure to infected blood or indirectly through excretions in soil.8

pattern of leprosy-infected armadillos is in part due to ecologic components that restrict leprosy to these endemic areas. Exact environmental features are unknown, but are suspected to include prevalence of armadillo populations and low-lying, humid soils that allow M. leprae to survive outside a host.1,9 In these circumstances, the entire state of Florida and surrounding regions with comparable ecosystems are at similar risk for spread of infection. CONCLUSIONS This, and other reports, underscores the importance for primary care providers and dermatologists in the southeastern United States to consider leprosy in the differential diagnosis in any patient from a nonendemic region or even in areas with a very low prevalence of leprosy, having a suspicious eruption and corroborating histopathology. Further, a history of exposure to armadillos as a possible source of infection should be ascertained, and asked for with “pointed” questions; in both our cases, patients initially denied any armadillo contact. Such consideration would likely lead to earlier detection and initiation of treatment. References

Leprosy was first reported in wild nine-banded armadillos in 1975 in Louisiana. The nine-banded armadillo migrated from Mexico to Texas approximately 150 years ago, and then subsequently spread to other southern states. Leprosy has been reported among armadillos in the southern United States, with the majority of cases occurring west of the Mississippi River, and only as far east as Alabama.9 The eastern population of armadillos originated from a separate population of armadillos released from captivity in Florida during the 1920s and has only recently merged with the main US population.1 Through correspondence with the laboratory chief of the NHDP, Dr. Richard Truman, we confirmed that while the armadillo population in Florida was thought to be free of M. leprae infection 20 years ago, recent data (not yet published) indicate that it has now emerged among armadillos in the region (personal communication, March 12, 2014). This recent eastward expansion of infected armadillos is in accordance with our reports of the first two cases of leprosy in Florida transmitted by armadillo exposure. Both our patients were residents of central Florida, having encountered armadillos in Tampa and Orlando. It is hypothesized that the geographic

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1 Truman RW, Singh P, Sharma R, et al. Probable zoonotic leprosy in the southern United States. N Engl J Med. 2011;364:1626–1633. 2 Britton WJ, Lockwood 2004;363:1209–1219.

DN.

Leprosy.

Lancet.

3 U.S. Department of Health and Human Services, Health Resources and Services Administration, National Hansen’s Disease Program. A Summary of Hansen’s disease (Leprosy) in the United States—2009. http://www.hrsa. gov/hansensdisease/dataandstatistics.html. Accessed September 12, 2013. 4 Scollard DM, Adams LB, Gillis TP, et al. The continuing challenges of leprosy. Clin Microbiol Rev. 2006;19:338– 381. 5 Lane JE, Walsh DS, Meyers WM, et al. Borderline tuberculolid leprosy in a woman from the state of Georgia with armadillo exposure. J Am Acad Dermatol. 2006;55:714– 716. 6 Balamayooran G, Pena M, Sharma R, Truman RW. The armadillo as an animal model and reservoir host for Mycobacterium leprae. Clin. Dermatol. 2015;33:108–115. 7 Abide JM, Webb RM, Jones HL, et al. Three indigenous cases of leprosy in the Mississippi delta. South Med J. 2008;101:635–638. 8 Chakrabarty AN, Dastidar SG. Is soil an alternative source of leprosy infection? Acta Leprol 2001–2002;12:79–84. 9 Loughry WJ, Truman RW, McDonough CM, et al. Is leprosy spreading among nine-banded armadillos in the southeastern United States? J Wildl Dis. 2009;45:144– 152.

Two Cases of Lepromatous Leprosy

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September/October 2017

Volume 15 • Issue 5

CASE STUDY

Primary Malignant Melanoma of the Bladder Maurizio Buscarini, MD, PhD;1 Claudio Conforti, MD;2 Raffaele Antonelli Incalzi, MD;3 Cristina Falavolti, MD;1 Chiara Taffon, MD;4 Giovanni Muto, MD;1 Caterina Dianzani, MD, PhD2,5

A 81-year-old man was admitted to our university for a second opinion after diagnosis of bladder melanoma in December 2014. His medical history included arterial hypertension, hypothyroidism, peripheral arterial disease treated with a bypass, and corneal transplantation. His medical history was negative for malignant melanoma. He experienced gross hematuria in the absence of any other clinical manifestations, and urine cytology identified atypical cells. The patient underwent transurethral resection of the bladder with diagnosis of melanoma. (SKINmed. 2017;15:395–397)

e performed another endoscopic resection of a 14mm lesion of the anterior bladder wall that was identified on whole-body computed tomography (CT) on January 1, 2015 (Figure 1). The pathology report was positive for MART1 (MLANA), HMB45, and was diagnostic for melanoma. No evidence of primary melanoma at other sites was found. Positron-emission tomography (PET)-CT was negative for metastases. After giving informed consent, the patient underwent radical cystoprostatectomy and ileoconduit. Gross examination showed two ulcerated lesions (2.5 cm and 1 cm, respectively, in diameter), involving the posterior wall (Figures 2 and 3). The lesions showed proliferation of epithelioid-like cells characterized by ample eosinophilic cytoplasm, nuclear irregularity, and pleomorphism with conspicuous nucleoli arranged in solid nests (Figure 4). The tumor involved the bladder wall up to the adipose tissue. Immunohistochemical analysis evidenced positivity for HMB45, MART1, and, focally, S100 protein (Figure 5), which confirmed the diagnosis of malignant melanoma. The patient was followed up at 3 months with PET-CT that showed one adrenal metastasis. DISCUSSION Fewer than 30 cases of primary malignant melanoma of the bladder have been reported in the literature.1 Primary malignant melanoma is uncommon in the genitourinary tract, especially

in the bladder.2 Most commonly, malignant melanomas of the bladder are metastatic lesions. It is often difficult to discern whether a bladder melanoma is primary or metastatic.3 Some authors have proposed the following criteria for designating a bladder melanoma as a primary lesion: (1) no previous history of a cutaneous lesion; (2) no evidence of a regressed cutaneous malignant melanoma; (3) no evidence of other visceral primary melanomas; and (4) atypical melanocytes at the margins of the bladder lesion.4 Our case fulfilled all the proposed criteria. Our evaluations excluded any primary skin, coroid, esophageal, or metastatic diseases. Two nevi were detected and surgically removed; both presented only dysplastic features. Most cases presented hematuria as the initial clinical manifestation,5 and may mimic urothelial carcinoma microscopically. Our patient’s histology examination revealed atypical melanocytes, necrosis, mitotic figures, and epitheloid cells. The immunohistochemical markers are important for the diagnosis,6 and in our case, the tumor was positive for HMB45, MART1, and S100 protein. MART1 positivity is important to differentiate bladder sarcoma or melanosis. In ectopic melanoma, the melanocytes would migrate from the neural crest through the mesenchyme toward the skin and hair follicles, possibly halting in ectopic locations, including a developing bladder. The therapeutic options for primary bladder melanoma include transurethral resection, partial or total cystectomy, chemotherapy, radiation therapy, and immunotherapy with interferon-α.

From the Department of Urology,1 Department of Dermatology,2 Department of Geriatrics,3 Department of Pathology,4 and Department of Plastic Surgery,5 Campus Bio-Medico University, Rome, Italy Address for Correspondence: Caterina Dianzani, MD, PhD, Department of Dermatology, Campus Bio-Medico University, Via Alvaro Del Portillo 200, Rome, Italy • E-mail: c.dianzani@unicampus.it

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Figure 1. Thickening of the anterior bladder wall.

Figure 3. Macroscopic evidence of the tumor.

Figure 2. Gross specimen of the bladder.

Unfortunately, bladder melanoma is less likely to be responsive to targeted therapy. The prognosis depends on tumor extension and invasion depth, and most patients die within 3 years.3,6 Only one patient in the literature had an overall survival of 144 months.7 In our case, postoperative PET-CT showed only a 3-mm adrenal metastasis, and our patient died from cardiovascular comorbidity 4 months after surgery. SKINmed. 2017;15:395â&#x20AC;&#x201C;397

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Figure 4. Medium-power field of a paraffin section from the bladder wall, stained with hematoxylin and eosin. Primary Malignant Melanoma of the Bladder

September/October 2017

CASE STUDY Acknowledgments Ervin Shehu, MD, Annamaria Salerno, MD, and Rocco Papalia, MD, are members of the urologist’s surgical team who visited and monitored the patient during his hospital stay. They contributed to writing the description of the surgical procedure and the patient’s clinical and family history before the surgical procedure, and gave us information on the his postsurgical condition. Author Contributions R.A.I. was the first doctor to visit the patient and suspected bladder cancer. M.B., with the help of G.M. and C.F., carried out the surgical procedure and provided the surgical samples. C.D. examined the patient to rule out the presence of a cutaneous melanoma, operated on the patient, and provided mole samples. C.T. performed the microscopic study of the samples, making the diagnosis of bladder melanoma, and provided the images. M.B., R.A.I., C.F., C.C., G.M., and C.D. contributed to the writing of the paper. C.D. divided up the tasks for authors and edited the paper. References 1 Venyo, AK. Melanoma of the urinary bladder: A review of the literature. Surg Res Pract. 2014;2014:605802. 2 Tainio HM, Kylmälä TM, Haapasalo HK. Primary malignant melanoma of the urinary bladder associated with widespread metastases. Scand J Urol Nephrol. 1999;33:406–407.

Figure 5. Medium-power field of a section from the bladder wall stained with anti-MART1: immunohistochemical analysis evidenced positivity of neoplastic cells for MART1.

3 Lee SH, Chang ED, Lee EJ, et al. Primary malignant melanoma of the urinary bladder: A case report. Korean J Pathol. 2010;44:216–219. 4 Ainsworth AM, Clark WH, Mastrangelo M, Conger KB. Primary malignant melanoma of the urinary bladder. Cancer. 1976;37:1928–1936.

CONCLUSIONS Primary bladder malignant melanoma is a very rare condition with a poor prognosis. Immunohistochemical markers are very important for the differential diagnosis. There is no consensus regarding treatment options because very few cases have been reported, and almost all have been fatal. Genetic analyses are needed to detect possible genetic mutations that may explain the onset of related visceral and skin cancers.

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5 Pacella M, Gallo F, Gastaldi C, Ambruosi C, Carmignani G. Primary malignant melanoma of the bladder. Int J Urol. 2006;13:635–637. 6 Xu X, Chu AY, Pasha TL, Elder DE, Zhang PJ. Immunoprofile of MITF, tyrosinase, melan-A, and MAGE-1 in HMB45negative melanomas. Am J Surg Pathol. 2002;26:82–87. 7 Engelhardt PF, Hohlbrugger G, Riedl CR.. Melanosis of the urinary bladder: A case report with 10 years of follow-up and review of literature. Aktuelle Urol. 2006;37:222–224.

Primary Malignant Melanoma of the Bladder

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September/October 2017

Volume 15 • Issue 5

Book Review Jennifer L. Parish, MD, Section Editor

A Helpful Addition to the Flap Literature Shokrollahi, K., Whitaker, I., and Nahai F. Flaps: Practical Reconstructive Surgery. New York, NY, Thieme Medical Publishers, 2017: 704 pp, $224.96 Mastering the art of surgical technique is a desired ability and often a major source of anxiety for a first-year dermatology resident. Flawless surgical skill is something I can only hope to obtain throughout my career. Currently, I am seeking to build a solid foundation. My intent when reviewing this text was to achieve a basic understanding of defect closures and, in particular, gain an appreciation of how to choose the best flap for a defect. Flaps: Practical Reconstructive Surgery provides a framework for this reconstructive thought process. From the start, I appreciated the concise review of wound healing, facial subunits, and suture techniques, being thorough in its outline of flap evaluation. It provides a helpful, but concise, breakdown of flap types, their definitions, and key features. In addition to reviewing the stages necessary for successfully creating a rhomboid flap, the authors expanded on the teaching by adding the 20-degree rule, a method that allows for one to adjust for expected flaws when executing the rhomboid flap. It highlights how to envision and prepare for clinical scenarios in advance, serving as an example of insightful expert knowledge necessary for surgical mastery. The steps were easy to follow so that I could grasp each concept. This was enhanced by the conversational style that used realistic comments and pointed questions. There are 1401 illustrations with visual guides. Unfortunately, some diagrams required my imagination to decipher point A

from point B. This could be improved by providing additional step-by-step figures, as could the quality of the online reading software. Lastly, I was disappointed by the video tutorials, which ranged from seconds to a few minutes and used cadavers. Perhaps, longer videos with live patients, if possible, would be helpful. Overall, the text enhanced my knowledge and should prove to be a valuable addition to the flap literature.

Reviewed by Tia Pyle, MD, Division of Dermatology, Cooper Medical School of Rowan University, Camden, NJ Address for Correspondence: Tia Pyle, MD, Division of Dermatology, Cooper Medical School of Rowan University, 401 Broadway, Camden, NJ 08103 • E-mail: Pyle-tia@cooperhealth.edu

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