Nov/Dec, 2016 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

Nkengne and Bertin

Self Assessment Examination Lambert

DEPARTMENTS HISTORICAL VIGNETTE Eucerin: A Revolutionary Formulation Still Going Strong for Over a Century Anwar and Lowenstein

PERILS OF DERMATOPATHOLOGY Deadly Skin Tags! Singh, John, Lee, Handler, Schwartz, and Lambert

NEW THERAPY UPDATE FINACEA™ (Azelaic Acid) Foam, 15% Gupta, Foley, and Abramovits

The Dermatologic & Aesthetic Surgery International League

African Association for Dermatology

November/December 2016 • Volume 14 • Issue 6

The Dermatologic & Aesthetic Surgery International League

November/December 2016 • Volume 14FILE • Issue 6 THE HEYMANN EDITORIAL Conceptual Confluence: What Is Dry Skin? The Marriage of IgG4-Related Parish, Witkowski, and Lavery Disease and Adult-Onset Asthma With Periocular ORIGINAL CONTRIBUTIONS Xanthogranulomas Can We Predict the Effectiveness of Heymann Intralesional Immunotherapy in Recalcitrant Warts? HISTORY OF DERMATOLOGY Sardana, Goel, Madan, and Garg SOCIETY NEWSLETTER Psoriasis and Upper Wide Morphologic Variability Respiratory Infection of Chromoblastomycosis in Bernhardt the Western Hemisphere Mugleston, Usatine, and Rosen PHOTO CAPSULE Asymptomatic Swelling on the Inner Surface of the Lower Lip REVIEW Aging and Facial Changes— Documenting Clinical Signs, Part 2: Methods of Documentation of Facial Changes

North American Clinical Dermatologic Society

Jha, Prasad, Sinha, Kumar, and Nandan

case studies Simultaneous Occurrence of Papulonecrotic Tuberculid and Erythema Induratum in an Asian Woman

Oon, Chong, Oh, Tan, Lee, Sen, and Tan

Cutaneous Presentation of Angioimmunoblastic T-Cell Lymphoma: A Harbinger of Poor Prognosis?

Wang, Lee, Koh, Busmanis, and Lee

Inflamed Actinic Keratoses After Pemetrexed

Cameron, Suárez, Kris, and Myskowski

Pilomatrix Carcinoma Mimicking a Pigmented Basal Cell Carcinoma Glick, Alapati, and Khachemoune

CORRESPONDENCE Neurofibromatosis Type 1 and Vitiligo, a Rare Association

Prieto Herman Reinehr, Prieto Herman Reinehr, and Cestari

BOOK REVIEW History, Sex and Syphilis Parish

Voriconazole-Induced Subacute Cutaneous Lupus Erythematosus in an Adult With Aspergillosis Ezra, Jourabchi, and Mousdicas

A Yellow Papular Eruption on the Arms, Legs, and Neck: A Rare Masquerader

Chappell, Kozel, Hurley, and Vidal

Multiple Familial Trichoepithelioma Successfully Treated With CO2 Laser and Imiquimod McGee, Suchter, and Milgraum

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Finacea® (azelaic acid) Foam, 15% is indicated for topical treatment of the inflammatory papules and pustules of mild to moderate rosacea.

The first and only prescription foam approved by the FDA for the treatment of rosacea In the art of rosacea therapy...

Proven efficacy has another profile with Finacea Foam ®

IMPORTANT SAFETY INFORMATION Warnings and Precautions Skin Reactions: There have been isolated reports of hypopigmentation after use of azelaic acid. Because azelaic acid has not been well studied in patients with dark complexion, monitor these patients for early signs of hypopigmentation. Eye and Mucous Membranes Irritation: Azelaic acid has been reported to cause irritation of the eyes. Avoid contact with the eyes, mouth and other mucous membranes. If Finacea® Foam does come in contact with the eyes, wash the eyes with large amounts of water and consult a healthcare professional if eye irritation persists. Flammability: The propellant in Finacea® Foam is flammable. Instruct the patient to avoid fire, flame, and smoking during and immediately following application. Do not puncture and/or incinerate the containers. Do not expose containers to heat and/or store at temperatures above 120°F (49°C). Most Common Adverse Reactions In clinical studies, the most frequently observed adverse reactions in ≥ 0.5% of subjects treated with Finacea® Foam included local site pain (6.2%), pruritus (2.5%), dryness (0.7%), and erythema (0.7%). For Topical Use Only Finacea® Foam is not for oral, ophthalmic or intravaginal use. Avoid the use of occlusive dressings or wrappings at the application site. Avoid use of alcoholic cleansers, tinctures and astringents, abrasives and peeling agents. Patients should be reassessed if no improvement is observed upon completing 12 weeks of therapy. You are encouraged to report negative side effects of prescription drugs to the FDA. Visit www.fda.gov/medwatch, or call 1-800-FDA-1088. For important risk and use information, see the full Prescribing Information at www.finaceafoam.com. For important risk and use information, see the Brief Summary on the following page.

Discover The Foamulation www.finaceafoam.com

FINACEAÂŽ

(azelaic acid) Foam, 15% for topical use

For Topical Use Onlyâ&#x20AC;&#x201C;Not for Oral, Ophthalmic or Intravaginal Use Rx only BRIEF SUMMARY CONSULT PACKAGE INSERT FOR FULL PRESCRIBING INFORMATION 1 INDICATIONS AND USAGE Finacea (azelaic acid) Foam, 15% is indicated for topical treatment of the inflammatory papules and pustules of mild to moderate rosacea. 5 WARNINGS AND PRECAUTIONS 5.1 Skin Reactions There have been isolated reports of hypopigmentation after use of azelaic acid. Because azelaic acid has not been well studied in patients with dark complexion, monitor these patients for early signs of hypopigmentation. 5.2 Eye and Mucous Membranes Irritation Azelaic acid has been reported to cause irritation of the eyes. Avoid contact with the eyes, mouth and other mucous membranes. If Finacea Foam does come in contact with the eyes, wash the eyes with large amounts of water and consult a physician if eye irritation persists. 5.3 Flammability The propellant in Finacea Foam is flammable. Instruct the patient to avoid fire, flame, and smoking during and immediately following application. Do not puncture and/or incinerate the containers. Do not expose containers to heat and/or store at temperatures above 120Â°F (49Â°C). 6 ADVERSE REACTIONS The following adverse reactions are described elsewhere in the prescribing information: t )ZQPQJHNFOUBUJPO [see Warnings and Precautions (5.1)]. t Eye and Mucous Membranes Irritation [see Warnings and Precautions (5.2)]. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Finacea Foam was evaluated for the treatment of papulopustular rosacea in two multicenter, randomized, double-blind, vehicle-controlled, 12-week clinical trials involving a total of 1362 (Finacea Foam, 15%: 681; vehicle: 681) subjects. Overall, 95.7% of subjects were White, 73.4% were female, and the mean age was 50.6 years. Table 1: Adverse Reactions Occurring in â&#x2030;Ľ 0.5% of Subjects Treated with Finacea Foam Compared with Subjects Treated with Vehicle System/Organ Class Preferred

Finacea Foam, 15% (N=681) n (%)

Vehicle (N=681) n (%)

General disorders and application site conditions Application site pain* Application site pruritus Application site dryness Application site erythema

42 (6.2%) 17 (2.5%) 5 (0.7%) 5 (0.7%)

10 (1.5%) 2 (0.3%) 5 (0.7%) 6 (0.9%)

* â&#x20AC;&#x153;Application site painâ&#x20AC;? is a term used to describe disagreeable skin sensations, including burning, stinging, paraesthesia and tenderness. 6.2 Post-Marketing Experience )ZQFSTFOTJUJWJUZ SBTI BOE XPSTFOJOH PG BTUINB IBWF CFFO SFQPSUFE GSPN the postmarketing experience of azelaic acid-containing formulations. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Local Tolerability Studies In a 21-day cumulative irritation study under occlusive conditions, mildto-moderate irritation was observed for azelaic acid pre-foam emulsion. In B IVNBO SFQFBU JOTVMU QBUDI UFTU )3*15 TUVEZ OP TFOTJUJ[BUJPO QPUFOUJBM was observed for azelaic acid pre-foam emulsion. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Teratogenic Effects: Pregnancy Category B There are no adequate and well-controlled studies in pregnant women. Therefore, Finacea Foam should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Dermal embryofetal developmental toxicology studies have not been performed with azelaic acid, 15% foam. Oral embryofetal developmental studies were conducted with azelaic acid in rats, rabbits, and cynomolgus monkeys. Azelaic acid was administered during the period of organogenesis in all three animal species. Embryotoxicity was observed in rats, rabbits, and monkeys at oral doses of azelaic acid that generated some maternal toxicity. Embryotoxicity was observed in rats given 2500 mg/kg/day [162 UJNFT UIF NBYJNVN SFDPNNFOEFE IVNBO EPTF .3)% CBTFE PO CPEZ surface area (BSA)], rabbits given 150 or 500 mg/kg/day (19 or 65 times UIF .3)% CBTFE PO #4" BOE DZOPNPMHVT NPOLFZT HJWFO NH LH EBZ UJNFT UIF .3)% CBTFE PO #4" B[FMBJD BDJE /P UFSBUPHFOJD FGGFDUT were observed in the oral embryofetal developmental studies conducted in rats, rabbits and cynomolgus monkeys. An oral peri- and post-natal developmental study was conducted in rats. Azelaic acid was administered from gestational day 15 through day 21 postpartum up to a dose level of 2500 mg/kg/day. Embryotoxicity was PCTFSWFE JO SBUT BU BO PSBM EPTF PG NH LH EBZ UJNFT UIF .3)% based on BSA) that generated some maternal toxicity. In addition, slight disturbances in the post-natal development of fetuses was noted in rats at oral doses that generated some maternal toxicity (500 and 2500 mg/ LH EBZ BOE UJNFT UIF .3)% CBTFE PO #4" /P FGGFDUT PO TFYVBM maturation of the fetuses were noted in this study. 8.3 Nursing Mothers It is not known if azelaic acid is secreted into human milk in vivo /P XFMM controlled studies of topically administered azelaic acid in nursing women BSF BWBJMBCMF /FWFSUIFMFTT UIF EFDJTJPO UP EJTDPOUJOVF OVSTJOH PS UP discontinue the drug should take into account the importance of the drug to the mother. 8.4 Pediatric Use The safety and efficacy of Finacea Foam in children below the age of 18 years have not been established. 8.5 Geriatric Use Of the total number of subjects in clinical studies of Finacea Foam, 18.8 QFSDFOU XFSF BOE PWFS XIJMF QFSDFOU XFSF BOE PWFS /P PWFSBMM differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. 17 PATIENT COUNSELING INFORMATION Inform patients using Finacea Foam of the following information and instructions: t 'PS FYUFSOBM VTF POMZ t $MFBOTF BGGFDUFE BSFB T XJUI B WFSZ NJME TPBQ PS B TPBQMFTT DMFBOTJOH lotion and pat dry with a soft towel. t 4IBLF XFMM CFGPSF VTF t "WPJE VTF PG BMDPIPMJD DMFBOTFST UJODUVSFT BOE BTUSJOHFOUT BCSBTJWFT BOE peeling agents. t "WPJE DPOUBDU XJUI UIF FZFT NPVUI BOE PUIFS NVDPVT NFNCSBOFT *G Finacea Foam does come in contact with the eyes, wash the eyes with large amounts of water and consult your physician if eye irritation persists. t *G BMMFSHJD SFBDUJPOT PDDVS EJTDPOUJOVF VTF BOE DPOTVMU ZPVS QIZTJDJBO t 8BTI IBOET JNNFEJBUFMZ GPMMPXJOH BQQMJDBUJPO PG 'JOBDFB 'PBN t $PTNFUJDT NBZ CF BQQMJFE BGUFS UIF BQQMJDBUJPO PG 'JOBDFB 'PBN IBT ESJFE t "WPJE UIF VTF PG PDDMVTJWF ESFTTJOHT BOE XSBQQJOHT t 5P IFMQ NBOBHF SPTBDFB BWPJE BOZ USJHHFST UIBU NBZ QSPWPLF FSZUIFNB flushing, and blushing. These triggers can include spicy and thermally hot food and drinks such as hot coffee, tea, or alcoholic beverages. t 5IF QSPQFMMBOU JO 'JOBDFB 'PBN JT nBNNBCMF "WPJE mSF nBNF PS smoking during and immediately following application. t %JTDBSE QSPEVDU XFFLT BGUFS PQFOJOH ÂŠ #BZFS )FBMUI$BSF 1IBSNBDFVUJDBMT *OD "MM SJHIUT SFTFSWFE Manufactured for:

#BZFS )FBMUI$BSF 1IBSNBDFVUJDBMT *OD 8IJQQBOZ /+ Manufactured in Switzerland

6798100BS

TABLE OF CONTENTS November/December 2016 • Volume 14 • Issue 6

EDITORIAL

What Is Dry Skin? ...................................................................................................................................... 409

Lawrence Charles Parish, MD, MD (Hon); Joseph A. Witkowski, MD (Dec); Caroline J. Lavery

ORIGINAL CONTRIBUTIONS

Can We Predict the Effectiveness of Intralesional Immunotherapy in Recalcitrant Warts? ........................ 413

Kabir Sardana, MD, DNB, MNAMS; Khushbu Goel, MD; Anjali Madan, MD; Vijay K. Garg, MD

Wide Morphologic Variability of Chromoblastomycosis in the Western Hemisphere .................................. 423

Brian J. Mugleston, MEd; Richard P. Usatine, MD; Ted Rosen, MD

REVIEW

Aging and Facial Changes—Documenting Clinical Signs, Part 2: Methods of Documentation of Facial Changes ..................................................................................................................................... 429

Alex Nkengne, PhD; Christiane Bertin

Self Assessment Examination ................................................................................................................... 436

W. Clark Lambert, MD, PhD

Departments Historical Vignette

Charles Steffen, MD, Section Editor

Eucerin: A Revolutionary Formulation Still Going Strong for Over a Century .............................................. 437

Yusuf Anwar, MD; Eve J. Lowenstein, MD, PhD

Perils of Dermatopathology

W. Clark Lambert, MD, PhD, Section Editor

Deadly Skin Tags! ..................................................................................................................................... 441

Parmvir Singh, BS; Ann M. John, BA; Brian Lee, MD; M. Zac Handler, MD; Robert A. Schwartz, MD, MPH; W. Clark Lambert, MD, PhD

New Therapy Update

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

FINACEA™ (Azelaic Acid) Foam, 15% ....................................................................................................... 445

Aditya K. Gupta, MD, PhD, FRCPC; Kelly A. Foley, PhD; William Abramovits, MD

The Heymann File

Warren R. Heymann, MD, Section Editor

Conceptual Confluence: The Marriage of IgG4-Related Disease and Adult-Onset Asthma With Periocular Xanthogranulomas ........................................................................................................... 449

Warren R. Heymann, MD

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

Psoriasis and Upper Respiratory Infection ................................................................................................ 453

Mark Bernhardt, MD

402

TABLE OF CONTENTS November/December 2016 • Volume 14 • Issue 6

Photo Capsule

Asymptomatic Swelling on the Inner Surface of the Lower Lip................................................................... 455

Abhijeet Kumar Jha, MBBS, MD; Smita Prasad, MBBS, MD; Rajesh Sinha, MBBS, MD; Shashikant Kumar, MBBS, MD; Nishant Nandan, MBBS

case studies

Vesna Petronic-Rosic, MD, MSc, Section Editor

Simultaneous Occurrence of Papulonecrotic Tuberculid and Erythema Induratum in an Asian Woman ...... 457

Hazel H. Oon, MD; Wei-Sheng Chong, MBBS; Choon Chiat Oh, MBBS; Audrey W. Tan, MBBS; Joyce S. Lee, MBBS; Priya Sen, MBBS; Suat Hoon Tan, MBBS

Voriconazole-Induced Subacute Cutaneous Lupus Erythematosus in an Adult With Aspergillosis .............. 461

Navid Ezra, MD; Natanel Jourabchi, MD; Nico Mousdicas, MD

A Yellow Papular Eruption on the Arms, Legs, and Neck: A Rare Masquerader .......................................... 465

Jeaneen Chappell, MD; Jessica Kozel, MD; M. Yadira Hurley, MD; Claudia I. Vidal, MD, PhD

Multiple Familial Trichoepithelioma Successfully Treated With CO2 Laser and Imiquimod ........................ 467

Jean S. McGee, MD, PhD; Mark F. Suchter, MD; Sandy S. Milgraum, MD

Cutaneous Presentation of Angioimmunoblastic T-Cell Lymphoma: A Harbinger of Poor Prognosis? ........ 469

Luokai Wang, MBBS, MRCP; Haur Yueh Lee, MBBS, MRCP; Hong Yi Koh, MBBS, MRCP; Inny Busmanis, MBBS, FRCPA; Yuh Shan Lee, MBBS, MRCP

Inflamed Actinic Keratoses After Pemetrexed ............................................................................................ 473

Michael C. Cameron, BS; Andrea L. Suárez, MD, PhD; Mark G. Kris, MD; Patricia L. Myskowski, MD

Pilomatrix Carcinoma Mimicking a Pigmented Basal Cell Carcinoma ....................................................... 475

Jaimie B. Glick, MD; Usha Alapati, MD; Amor Khachemoune, MD

CORRESPONDENCE

Snejina Vassileva, MD, PhD, Section Editor

Neurofibromatosis Type 1 and Vitiligo, a Rare Association ....................................................................... 478

Clarissa Prieto Herman Reinehr, MD; Vinícius Prieto Herman Reinehr, MD; Tania Cestari, PhD

BOOK REVIEW

Jennifer L. Parish, MD, Section Editor

History, Sex and Syphilis........................................................................................................................... 480

Lawrence Charles Parish, MD, MD (Hon)

403

IMPORTANT SAFETY INFORMATION Contraindications

exposed to Otezla, compared to none in placebo-treated patients (0/506). Suicidal behavior was observed in 0.1% (1/1308) of ◆ Otezla® (apremilast) is contraindicated in patients on Otezla, compared to 0.2% (1/506) patients with a known hypersensitivity to on placebo. One patient treated with Otezla apremilast or to any of the excipients in attempted suicide; one patient on placebo the formulation committed suicide Warnings and Precautions – Carefully weigh the risks and benefits ◆ Depression: Treatment with Otezla is of treatment with Otezla for patients associated with an increase in adverse with a history of depression and/or suicidal reactions of depression. During clinical thoughts/behavior, or in patients who trials, 1.3% (12/920) of patients treated with develop such symptoms while on Otezla. Otezla reported depression compared to Patients, caregivers, and families should 0.4% (2/506) on placebo; 0.1% (1/1308) of be advised of the need to be alert for the Otezla patients discontinued treatment emergence or worsening of depression, due to depression compared with none on suicidal thoughts or other mood changes, placebo (0/506). Depression was reported and they should contact their healthcare provider if such changes occur as serious in 0.1% (1/1308) of patients

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. Body weight loss of ≥10% occurred in 2% (16/784) of patients treated with Otezla compared to 1% (3/382) 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 (eg, rifampin, phenobarbital, carbamazepine, phenytoin) is not recommended ◆

References: 1. Information derived from Symphony Health Solutions PrescriberSource PatientFocus data, Celgene proprietary methodology. April 2014 through December 2015. 2. Otezla [package insert]. Summit, NJ: Celgene Corporation; 2015. 3. Data on file, Celgene Corporation. 4. Papp K, Reich K, Leonardi CL, et al. J Am Acad Dermatol. 2015;73(1):37-49.

◆

Otezla was evaluated in 2 multicenter, double-blind, placebo-controlled 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 titration2,4

◆

Inclusion criteria: Age ≥18 years, BSA involvement ≥10%, sPGA ≥3, PASI score ≥12, candidates for phototherapy or systemic therapy2,4

◆

Results were similar between ESTEEM 1 and ESTEEM 22,3

BSA, body surface area; PASI, Psoriasis Area and Severity Index; ScPGA, Scalp Physician Global Assessment; sPGA, static Physician Global Assessment.

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

a Results were consistent between ESTEEM 1 and ESTEEM 2. b Week 16: secondary endpoint; all other timepoints: exploratory endpoints. c Baseline mean PASI scores: Placebo, 19; Otezla, 19; Total, 19. d During weeks 16 through 32 (maintenance phase), all patients received Otezla. e Causes of patient dropout include adverse events, lack of efficacy, and patient withdrawal. f 95% confidence interval. g FAS; LOCF. h Week 16: Prespecified exploratory endpoint. In the planned hierarchical statistical testing sequence for ESTEEM 1 and ESTEEM 2, efficacy analyses preceding ScPGA were statistically significant, allowing for control of the overall type 1 error rate at 0.05 significance level in analysis of ScPGA. i Baseline ScPGA ≥3.

Get the latest news at otezlapro.com

◆

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.

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 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) Preferred Term

Placebo (N=506) n (%)

OTEZLA 30 mg BID (N=920) n (%)

Diarrhea

32 (6)

160 (17)

Nausea

35 (7)

155 (17)

Upper respiratory tract infection

31 (6)

84 (9)

Tension headache

21 (4)

75 (8)

Headache

19 (4)

55 (6)

Abdominal pain*

11 (2)

39 (4)

Vomiting

8 (2)

35 (4)

Fatigue

9 (2)

29 (3) (continued)

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 (N=506) n (%)

OTEZLA 30 mg BID (N=920) n (%)

Dyspepsia

6 (1)

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)

Preferred Term

*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 ©2015 Celgene Corporation, All Rights Reserved. Based on APRPI.005

OTZ_PsO_HCP_BSv.004 12_2015

November/December 2016

Volume 14 • Issue 6

Editorial

ABOUT OUR JOURNAL SKINmed: Dermatology for the Clinician®, print ISSN 1540-9740, online ISSN 1751-7125, is published bimonthly by Pulse Marketing & Communications, LLC, located at 4 Peninsula Avenue, Sea Bright, NJ 07760. Printed in the USA. Disclaimer: The Publisher, Editors, and Editorial Board cannot be held responsible for errors or any consequences arising from the use of information contained in this journal; the views and opinions expressed herein do not necessarily reflect those of the Publisher, Editors, and Editorial Board, neither does the publication of advertisements constitute any endorsement by the Publisher, Editors, and Editorial Board of the products or services advertised. The Publisher, Editors, Editorial Board, Reviewers, Authors, and Affiliated Agents shall not be held responsible or in any way liable for the continued accuracy of the information or for any errors, inaccuracies, or omissions of any kind in this publication, whether arising from negligence or otherwise, or for any consequences arising thereafter.

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November/December 2016

Volume 14 • Issue 6

EDITOR IN CHIEF

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

DEPUTY EDITORS William Abramovits, MD

Aditya K. Gupta, MD, PhD, FRCPC

W. Clark Lambert, MD, PhD

Vesna Petronic-Rosic, MD, MSc

Dallas, TX

London, Ontario, Canada

Newark, NJ

Chicago, IL

Larry E. Millikan, MD

Marcia Ramos-e-Silva, MD, PhD

Jennifer L. Parish, MD

Meridian, MS

Rio de Janeiro, Brazil

Philadelphia, PA

EDITORIAL BOARD Mohamed Amer, MD Cairo, Egypt

Howard A. Epstein, PhD Philadelphia, PA

Jasna Lipozencic, MD, PhD Zagreb, Croatia

Todd 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 Engelwood, CO Noah Craft, MD, PhD, DTMH Torrance, CA Natalie M. Curcio, MD, MPH Nashville, TN Ncoza C. Dlova, MBChB, FCDerm Durban, South Africa Richard L. Dobson, MD Mt Pleasant, SC William H. Eaglstein, MD Menlo Park, CA

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 Rochester, MN

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

Charles N. Ellis, MD Ann Arbor, MI

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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

November/December 2016

Volume 14 • Issue 6

Editorial

What Is Dry Skin? Lawrence Charles Parish, MD, MD (Hon);1 Joseph A. Witkowski, MD (Dec);2 Caroline J. Lavery3

s so many patients claim that they have dry skin, we decided to explore what dry skin could be. Is it the debris on the face or the scale covering a psoriatic plaque? Is it the keratotic material of an actinic keratosis or exfoliation following sunburn? Definitions There are at least 20 definitions of the word dry, ranging from being unsweet to not being moist and from being thirsty to being overcooked. Perhaps the best definition of dryness, as related to the xerosis, was created over 60 years ago: Asteatosis is a condition of the skin in which there is absolute or relative deficiency of the sebaceous secretion. At present, the term “xerosis” is preferred to “asteatosis,” although the term “xerosis” was formerly used to designate a mild ichthyosis.1

While washclothes have always been the bane of normal skin, many people today further aggravate skin with the use of loofahs. The soaps of Durhing’s time in the late 19th century were often quite irritating, but that cannot be said for the soaps of much of the 20th century. We recall such products as Camay,® Woodbury,® or Sunlight® being advocated for their mildness (Figure). We know that irritation is reduced by limiting soap to the critical areas (hands, face, axillae, and groin) and that keeping a home humidified is also helpful, yet these are not new recommendations. Could the answer rest with the fact that the over-the-counter hydrocortisone 1% cream is so readily available?

Ashy skin

Types

Xerosis The best example of dry skin is xerosis, the winter itch described by Louis A. Duhring (1845–1913) and characterized by unobtrusive scaling. It represents a dehydration of the skin, a true lack of moisture, with the skin both rough in appearance and on palpation, making another synonym, erythema cracklée most appropriate. This problem does not appear so evident as even a few decades ago. We are hard put to give a good explanation for this—if too much washing is responsible, then in pre–World War II America or Ireland, the paucity of bathing, ie, the Saturday night bath, would have been more beneficial than the current mores of showering once or twice a day.

The term ashy skin, frequently used by the African American community, amounts to scale that may be noticeable on the face and arms, becoming prominent due its light color being more evident against pigmented skin. Frequent applications of moisturizing lotions and even various types of petroleum jelly often accentuate the problem. Much of ashy skin reflects normal skin turnover, and washing without scrubbing will eliminate the excess scale, which should not be considered a disease.

Ichthyosis The genetic diseases labeled as ichthyoses, such as ichthyosis vulgaris and lamellar ichthyosis, obviously represent dry and dermatitic disease. The fish-scale, so characteristic of the condition, has true dryness, associated with the scaling debris. While various therapies, ranging from lactic acid lotions to hyperbaric chamber exposures, have done little to ameliorate these genetic disorders, the retinoids have proven useful, although not curative.

From the Department of Dermatology and Cutaneous Biology and the Jefferson Center for International Dermatology, Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, PA;1 Department of Dermatology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA;2 and Queen’s University Belfast, Belfast, Northern Ireland3 Address for Correspondence: Lawrence Charles Parish, MD, MD (Hon), 1845 Walnut Street, Suite 1650, Philadelphia, PA19103 • E-mail: larryderm@yahoo.com

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Atopic dermatitis This entity, as we know with its predilection for the antecubital and popliteal fossae, truly is a reflection of a lack of moisture. Scaling, made synonymous with dryness, is not a major component of this disease. While there is no cure, the lack of moisture that characterizes the condition is often managed by regular, liberal emollient application, with prescription moisturizers notably showing no significant superiority to over-the-counter moisturizers.4 Treatment

What are moisturizers? Moisturizers form the cornerstone of topical therapy for the many conditions characterized by dry skin, with agents generally divided into four groups according to their primary action. While the first group, occlusives, help form a tight, hydrophobic seal to the skin surface,5 this contrasts with humectants, such as urea and glycerol, which, by exerting a primarily hydrophilic action, promote epidermal water acquisition from the dermis.6 Emollients serve primarily an aesthetic and tactile role, perhaps best understood by the somewhat corrupted Latin etymology of the term (“e-” + “mollis,” inferring a sense of “making soft”).7 Lastly, the so-called rejuvenators contain proteins, such as collagen, elastin, and keratin.5 Despite the complexity of the chemical composition of moisturizers, as well as the wealth of products available both over-the-counter and via prescription, surprisingly 80% of the total composition of moisturizers is identical.8 Are moisturizers effective?

Figure 1. A soap advertisement from the early part of twentieth century to keep “your skin active and clear.”

Psoriasis The psoriatic plaque, readily recognized by its thickening, redness, and scale, may be without moisture but is reduced by compresses, soaks, or even bathing in water with plaque-eating “doctor-fish” of Kangal.2,3 Such scale does not reflect the moisture content of the plaque, as if this assumption were valid, then bathing, notwithstanding Dead Sea therapies with the sun, would be more important and might alleviate much of the patient’s plight. SKINmed. 2016;14:409–411

By enriching the stratum corneum with lipids, moisturizers aim to ameliorate the underlying barrier defect, and their efficacy can be determined using both subjective and objective measures, such as the Investigator’s Global Assessment or transepidermal water loss (TEWL), respectively.9 Although the precise mechanism by which moisturizers achieve this remains to be fully elucidated, this current understanding is supported by results of a study evaluating prophylactic Cetaphil® application in 22 neonates at high risk for developing atopic dermatitis, with only five developing atopic dermatitis over the course of the study (mean follow-up of 547 days).10 Unfortunately, studies have so far failed to demonstrate that moisturizers induce sustained improvements in TEWL beyond the initial promise found immediately after application.11 Adverse effects related to moisturizer use are reportedly rare,7 with Cetaphil® Cream, in particular, being advocated in patients with atopic dermatitis as it is petrolatum-based10 but free from lano-

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lin, a component that, when applied to eczematous skin compared with healthy skin, has been reported to be associated with flares.12 Interestingly, although its efficacy has been questioned,13 mustard oil is traditionally used in cultures in South Asia as a moisturizer for neonates; furthermore, aqueous cream BP, containing the irritant emulsifier sodium lauryl sulfate, has been shown to paradoxically increase TEWL,14 suggesting further compromise of the skin barrier. Lipid components of the stratum corneum, primarily free fatty acids, ceramides, and cholesterol, appear central to homeostasis being maintained,15,16 supported by the many conditions, characterized by dry skin, demonstrating a reduction in stratum corneum ceramides.5 Interestingly, one recent study of patients with xerosis examined the efficacy of several moisturizers, each containing different compositions of ceramides, with all resulting in statistically significant enhancements of electrical capacitance (P<.01) and reciprocal decreases in TEWL (P<.05)16; however, it is yet to proven whether the greatly superior efficacy of ceramide-based moisturizers is sufficient to justify their exceptionally high cost.5 Conclusions Dry skin remains a very common umbrella for a plethora of dermatologic conditions and may even be associated with significant psychologic distress; however, the concept appears subjective, with much disparity between the patient’s perception of dry skin and the clinician’s. The next time a patient complains of dry skin, we would argue one should ask: does that patient really have dry skin? For this reason, we suggest that the use of moisturizers be limited to conditions such as xerosis and atopic dermatitis—conditions characterized by true barrier defects. References 1 Lobitz Jr WC. Diseases of the sebaceous glands. In: Ormsby OS, Montgomery H, eds. Diseases of the Skin. 8th ed. Philadelphia, PA: Lea & Febiger; 1954:1346. 2 Özçelik S, Polat HH, Akyol M, et al. Kangal hot spring with fish and psoriais treatment. J Dermatol. 2000;27:386–390.

3 Warwick D, Warwick J. The doctor fish—a cure for psoriasis? Lancet. 1989;334:1093–1094. 4 Wolf R, Parish LC. Barrier-repair prescription moisturizers: do we really need them? Facts and controversies. Clin Dermatol. 2013;31:787–791. 5 Nolan K, Marmur E. Moisturizers: reality and the skin benefits. Dermatol Ther. 2012;25:229–233. 6 Loden M. Effect of moisturizers on epidermal barrier function. Clin Dermatol. 2012;30:286–296. 7 Loden M. Treatments improving skin barrier function. Curr Probl Dermatol. 2016;49:112–122. 8 Draelos ZD. Active agents in common skin care products. Plast Reconstr Surg. 2010;125:719–724. 9 Goad N, Gawkrodger DJ. Ambient humidity and the skin: the impact of air humidity in healthy and diseased states. J Eur Acad Dermatol Venereol. 2016 Jun 15. [Epub ahead of print]. 10 Simpson EL, Berry TM, Brown PA, Hanifin JM. A pilot study of emollient therapy for the primary prevention of atopic dermatitis. J Am Acad Dermatol. 2010;63:587– 593. 11 Danby SG, Chalmers J, Brown K, Williams HC, Cork MJ. A functional mechanistic study of the effect of emollients on the structure and function of the skin barrier. Br J Dermatol. 2016 Apr 21. [Epub ahead of print]. 12 Wolf R, Orion E, Ruocco E, Baroni A, Ruocco V. Contact dermatitis: facts and controversies. Clin Dermatol. 2013;31:467–478. 13 Darmstadt G, Mao-Qiang M, Chi E, et al. Impact of topical oils on the skin barrier: possible implications for neonatal health in developing countries. Acta Paediatr. 2002;91:546–554. 14 Danby SG, Al-Enezi T, Sultan A, et al. The effect of aqueous cream BP on the skin barrier in volunteers with a previous history of atopic dermatitis. Br J Dermatol. 2011;165:329–334. 15 Berkers T, van Dijk L, Absalah S, van Smeden J, Bouwstra JA. Topically applied fatty acids are elongated before incorporation in the stratum corneum lipid matrix in compromised skin. Exp Dermatol. 2016 Jun 16. [Epub ahead of print]. 16 Shim JH, Park JH, Lee JH, et al. Moisturizers are effective in the treatment of xerosis irrespectively from their particular formulation: results from a prospective, randomized, double-blind controlled trial. J Eur Acad Dermatol Venereol. 2016;30:276–281.

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ORIGINAL CONTRIBUTION

Can We Predict the Effectiveness of Intralesional Immunotherapy in Recalcitrant Warts? Kabir Sardana, MD, DNB, MNAMS; Khushbu Goel, MD; Anjali Madan, MD; Vijay K. Garg, MD Abstract Immunotherapy has been used for recalcitrant, large, and multiple warts, although it is difficult to predict which patient will respond. An open interventional cohort trial was conducted in 50 adult patients with recalcitrant multiple, nongenital warts in whom intralesional immunotherapy was given using the Mycobacterium welchii vaccine. The authors determined whether the wart resolution was dependent on the immune response. The response of various types of warts was also compared with the initial immune response. Complete cure was used as a treatment endpoint, which was defined as a lack of recurrence at follow-up of at least 6 months. The majority of patients had palmoplantar warts (54%). A total of 26 patients achieved a clinical cure. The high immune group achieved a higher complete cure rate (60%) as compared with the low immune group (20%) (P=.008; absolute risk reduction=.44; number needed to treat=3) with a fewer number of sessions (P=.004). This difference was most marked in palmoplantar warts (P=.04). Immunotherapy using M welchii is a useful modality in recalcitrant warts in patients who have a test site induration of ≥10 mm, but this does not affect the recurrence rates. (SKINmed. 2016;14:413–421)

arts can be a major source of concern, and although they do resolve spontaneously over several years, most patients seek treatment, because the warts are unsightly, often tender, and can spread, making its therapy an emergent therapeutic necessity. Therapy typically does not present a hazard to the patient, no scarring should result, and side effects should be minimal. It has been suggested that most common warts can be treated effectively, safely, and conveniently with cryosurgery or salicylic acid as first-line therapy.1,2 In resistant cases, combination treatments may be more effective than monotherapy.1,2 For numerous and large warts, immunotherapy by way of intradermal injection of antigens is a useful method of therapy and has been used for both genital and nongenital warts.3–16 It is not necessary to inject all the warts as distant warts are known to respond to the treatment, making it a convenient form of therapy for patients.6,7,10,11 Various antigens have been used with variable results.3–16 Although immunotherapy has been tried for all types of warts, very few have formally studied its use in recalcitrant warts.5,8,11 There is no consistent way to predict the results of immunotherapy in individual patients, which is evident by the variations in response rates (24%–88%).3–16

Our open-labeled interventional cohort study had two primary objectives. First, to determine whether the delayed-type hypersensitivity (DTH) response to the test dose of intralesional immunotherapy (≥10 mm or ≥5 mm to 9 mm) correlates with its therapeutic response, and, second, to assess whether there was a variation in response between common warts, plane warts, and palmoplantar warts. Methods This was a prospective open-labeled study that was approved by the departmental investigational review board based on the previous studies on Mycobacterium welchii (Mw) in warts and as an immunomodulator in other disorders.15,17–21 Patients were recruited from the outpatient dermatology clinic of a medical college hospital between February 2011 and May 2012. To calculate the sample size, we analyzed our yearly data of recalcitrant warts (n=100) and calculated a maximum sample size of 88 patients. Taking into account a 10% attrition rate, 96 patients should have been recruited but only 78 patients were studied. [Margin of error, 0.05; confidence 0.95; power 0.5; response distribution 0.7; z(alpha/2)+z(beta)=1.95; z(alpha)+z(beta)1.64].

From the Department of Dermatology, Maulana Azad Medical College, New Delhi, India Address for Correspondence: Kabir Sardana, MD, DNB, MNAMS, Department of Dermatology, RML Hospital & PGIMER, New Delhi, India • E-mail: kabirijdvl@gmail.com

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Recalcitrant warts were defined as warts, in which two or more topical therapies had been given for 3 months (inclusive of salicylic acid 12%) with partial or no response. The Mw vaccine (IMMUVAC; Cadila Pharmaceuticals, licensed by National Institute of Immunology, New Delhi, India) was administered intradermally at a dose of 0.1 mL using an insulin syringe at the base of the deltoid muscle at baseline. After 48 to 72 hours, the injected sites were examined for immunologic reaction (induration and or ulceration at the site of intradermal injection). Patients in whom the induration (measured as the largest width) was less than 5 mm were excluded from the intervention, while sensitized individuals (≥5 mm) were given the Mw vaccine. The vaccine was injected intralesionally into three to five lesions in a particular area at 2 weekly intervals. All patients received injections into the same warts until complete clearing was achieved or for a maximum of five sessions. Patients were examined initially and at each session with regard to the number and area of warts. Pregnant women, lactating mothers, children (younger than 12 years), patients with a history of hypersensitivity or allergy to vaccines, and those with ulcerated or inflamed warts were excluded. Patients with human immunodeficiency virus type 1, clinical evidence of epidermodysplasia verruciformis, iatrogenic immunosuppression, or primary immunosuppression were also excluded

Results The demographic profile of patients is given in Table I. Of the 78 patients recruited (intention to treat population), 20 were nonreactive after the test dose, five were bothered by the possibility of repeated intralesional injections, and three wanted a single session therapy; thus, the per-protocol population was 50 patients (Figure 1, Table II). Of the 50 patients studied (per protocol), the majority had palmoplantar warts (54%) followed by common (36%) and plane warts (10%). Of the 50 patients who were given the vaccine, 24 patients had a clinical cure (48%) at the end of the treatment sessions. Six patients had a recurrence; thus an overall complete cure of 60% was achieved in the high immune group (≥10 mm induration), which was significantly better than the low immune group (20%; P<.05). The difference in clinical and complete cure between the two immune groups was significant in those with plantar warts (P<.05; Figure 2) but not in those with common and plane warts (Table II). As a group, plane warts (83%) responded best to therapy, while the palmoplantar and common warts in the high immune group had a better response. The number of sittings required for a clinical response was significantly less in the

Clinical cure was defined as lack of thickening, hyperkeratosis, and dilated vasculature with the return of normal skin markings.13 Complete cure was defined as the absence of recurrence in the follow-up period. Partial response was defined as a diminution of size or number by 25% to 99% by the end of the study protocol, while incomplete response was defined as diminution in size and number by <25%. Clinical cure was correlated with the immunologic response of the test dose; thus, two groups were analyzed in each type of wart based on the test dose induration: low immune group (≥5 mm–9 mm) and high immune group (≥10 mm). Patients with partial response or recurrence were offered intralesional bleomycin therapy (1 U/mL; maximum of 2 mL per session). Patients were followed up for 6 months, after which a follow-up based on telephonic inquiry was made at 3 monthly intervals for another 6 months. Cross-classified categorical data (clinical and complete cure with respect to the immune response) were analyzed using Fisher test. The characteristics measured on a continuous scale (ie, age, mean number of sittings) were compared using t test or Wilcoxon rank-sum test. The simultaneous effects of treatment and age on the probability of response were modeled using logistic regression. P values <.05 were considered significant. Online software was used to analyze data (GraphPad Analysis and Wessa, version 1.1.23-r7; La Jolla, CA) SKINmed. 2016;14:413–421

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Table I. Demographic Profile of the Study Group (per Protocol) Age, mean (standard deviation) [range], y

19.4 (4.25) [13–27]

Male/female, No.

42/8

Disease duration (range), mo

15.25 (5.7)

Type of warts, No. Plane warts

Palmoplantar warts

Common warts

Wart site, No. Head/neck

Palms

Soles

Limbs

Trunk

Previous therapy, No. Salicylic acid/lactic acid

Podophyllin 25%

5% 5-Fluorouracil

Imiquimod

Trichloroacetic acid

Electrocautery

Ablative laser

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Figure 1. Flow chart of the study.

high immune group, which was consistent across all types of warts studied (P<.005). Recurrence (6; 12%) was observed at follow-up in patients with plantar and common warts but there was no statistical difference between the high and low immune groups (P=.13). SKINmed. 2016;14:413–421

After comparing the high immune and low immune group, the absolute risk reduction was found to be 44.0% (95% confidence interval [CI], 19.11%–68.89%). The relative risk was 2.25 (95% CI, 1.27–4.34), the risk difference was 0.4 (0.12–0.62).

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Table II. Overview of Published Data on Intralesional Immunotherapy in Warts Author (year) Patients

Vaccine Used

Clinical Cure

Recurrence

Comments

Summary of studies on immunotherapy in warts Meena (2013)3 37 patients Nongenital warts

Mycobacterium w (0.1 mL/ wk/12 wk)

Complete response 33 patients (83%)a 9 sessions

3 of 37 patients (5 mo)

Comparison of the response in various types of wart not mentioned Short follow-up

Eassa (2011)4 40 patients Genital warts

PPD RT23 (20 patients) Saline (20 patients) 0.1 mL/12 wk (Not given in the wart)

Complete response in 19 patients (47%)a after 12 sessions

None at 6 mo

Patients with an induration of 10 to 15 mm had a better response Included total and partial response Short follow-up Pregnant women with genital warts were studied

Nofal (2010)5 85 patients Nongenital warts

Mumps, measles, and rubella (0.1 mL/2 wk/ 5 sessions)

57 patients (81.4%)a (>75% improvement)

None at 6 mo

Duration of warts was not mentioned Follow-up was short Both common and recalcitrant warts were studied

Kim (2010)6 18 patients Nongenital warts

0.3 mL of Candida antigen/3 wk

9 patients (82%) 4 sessions

Horn (2005)7 54 patients Nongenital warts

Mumps (0.3 mL/3 wk/ 5 sessions)

29 patients (54)a (Candida 59%, mumps 51%, Trichophyton 62%) 5.8 sessions

No follow-up

No follow-up Common warts were studied

Kus (2005)8 11 patients Nongenital warts

PPD-RT-23

5 patients (29.4%)a

No follow-up

Recalcitrant warts Relationship of induration with response was studied but both partial and total response was studied

King (2005)9 21 patients Genital warts

Mumps, Candida, Trichophyton

5 patients (24%)

No follow-up

Genital warts were studied

Johnson (2004)10 206 patients Nongenital warts

Candida albicans, mumps, and Trichophyton

146 of 206 patients (70.9%)a 4.7 sessions

No follow-up

Pilot study on immunotherapy with the largest population studied to date

Clifton (2003)11 47 patients Nongenital warts

Mumps or Candida

47% patientsa 3.78 sessions

No follow-up

Recalcitrant warts Children

Signore (2002)12 87 patients Nongenital warts

Candida antigen

44 of 87 patients (51%)a No follow-up 2.3 sessions

Johnson (2001)13 39 patients Nongenital warts

Candida/mumps (0.1 mL/ 3 wk/3 sessions)

Mumps 22 (71%)a Candida 7 (88%)a

12 mo Candida antigen had a better respons 1 (mumps Periungual and palmoplantar warts were vaccine group) studied

Our study 50 patients

Mycobacterium w (0.1 mL/2 wk/5 sessions)

Clinical cure:a 52% Complete cure:b 40%

12 mo 6 recurrence

Recalcitrant warts were studied Patients with a test dose induration >10 mm had a better response Best response was in plane warts

Follow-up 1 mo

Plane warts

An HPV-57 L1-specific immune response was studied

Plantar warts were also studied

Summary of case reports/case series/studies <10 patients Ritter (2003)14 Nongenital warts

Candida (0.1 mL)

2 sessions

Continued SKINmed. 2016;14:413â&#x20AC;&#x201C;421

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Table II. Overview of Published Data on Intralesional Immunotherapy in Warts (Continued) Author (year) Patients

Vaccine Used

Clinical Cure

Recurrence

Comments

Summary of case reports/case series/studies <10 patients (continued) Gupta (2008)15 10 Genital warts

Mycobacterium w (0.1 mL/ wk/10 wk)

8 patients (88.9%)

Follow-up 5 mo

Genital warts

Daniel (2013)16 4

Quadrivalent Human papillomavirus vaccine (1, 2, 6 mo) (Not given in the wart)

All responded

Follow-up 2 y

Case series One patient was taking oral zinc, cimetidine

Clinical cure: complete clearance at the end of the intervention. Complete cure: patients with no recurrence at follow-up.

The number needed to treat (NNT) was three (95% CI, 1.5–5.2). On logistic regression analysis, there was no effect of age, sex, or site of the warts on the therapeutic results. The adverse effects included tender induration at the test site (50 of 50), erythema/swelling at the wart site (38 of 50), ulceration (2 of 50), and regional lymph node enlargement (3 of 50). Discussion Our study has shown that patients with a robust DTH response have a statistically significantly better response (60% vs 20%; P=.008) with a risk difference of 0.44 and an NNT of three. This difference between the two immune groups was marked in palmoplantar warts (Table II). In addition, the number of sittings required was significantly fewer in the high immune response group (1.83 vs 3.75; P=.004). Overall, plane warts responded best to immunotherapy, although there was no statistical difference between the high and the low immune group. A

C Figure 2. (A) A case of extensive plantar warts. The test dose induration was 12 mm (high immune group). (B) Two weeks after the first session, there was approximately a 50% reduction in the lesion with clearance of a few warts. (C) Two weeks after the second session, there was complete clinical cure with return of skin markings. SKINmed. 2016;14:413–421

The success of immunotherapy is based on multiple factors, for which an understanding of the mode of infection of human papillomavirus (HPV) is necessary (Figure 3).22–24 The first step involves the inoculation that is consequent to abrasion or other trauma that exposes the basal cells to the virus. After successful infection of a basal cell (via L1 and L2) the virus may remain latent for years although it expresses E1 and E2 proteins, which are useful for replicating and maintaining the viral DNA as a circular episome. In the second stage, the viral oncogenes E6 and E7 promote cell growth by inactivating the tumor suppressor proteins p53 and pRb, thus leading to viral replication. This is followed by the third phase, wherein the late genes L1 and L2 are transcribed/translated and serve as structural proteins, which encapsulate the amplified viral genomes. The virus is then shed off from the stratum corneum.

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Figure 3. An overview of the phases of the human papillomavirus infection (top). The proposed mechanism of immunotherapy is also displayed (bottom).

Persistent papilloma virus infections are common, which is the result of an elaborate mechanism wherein the virus has evolved to evade immune surveillance.22 First, there is no viremic phase during the life cycle, therefore a systemic immune response is avoided.23 The levels of viral proteins are expressed in the basal cell layer and stratum malpighii are low, which enables them to escape recogniSKINmed. 2016;14:413â&#x20AC;&#x201C;421

tion by Langerhans cells and infiltrating lymphocytes.22,24 Although cell-mediated responses play a role in eliminating the infection, the exact mechanism is unknown. Presumably, a DTH response would help, which is the basis of immunotherapy.3â&#x20AC;&#x201C;16 It must be emphasized, however, that the type of antigen does not eventually make a difference, as none have any genetic overlap with HPV and immu-

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notherapy likely induces a nonspecific immune response that targets the intracellular antigen. This is evident in most studies, which report a sizeable number of patients with partial response (Table III). Our results (clinical cure of 52% and complete cure of 40%) are lower than those reported in other studies (83%, 81.4%, 82%, 70.9%, 77%).3,5,6,10,13 This could be attributable to our study design, which included patients with recalcitrant warts and palmoplantar warts (selection bias). In studies in which recalcitrant warts were assessed, the results are comparable or even lower than those found in our study (54%, 29.4%, 47%).7,8,11 A more relevant comparison can be made by the number of sessions needed to achieve similar clinical results. Using this criterion, our results (40%, 2.79 sessions) compare favorably with the apparently better results achieved in previous studies (83%, 9 sessions; 54%, 5.8 sessions; 70.9%, 4.7 sessions).3,7,13 The definition of cure varies across studies, and recurrence of disease has not been considered previously. In some studies, complete responders included patients with >75% improvement,5 which is not considered a clinical cure. We used the term complete cure, taking into account the lack of recurrence, which makes the results of immunotherapy more relevant. This would make results more relevant as it is believed that immunotherapy leads to long-term immunity (Table III).

Successful use of immunotherapy depends on multiple factors, including study population, duration of the wart, age of the patient, intrinsic innate immunity, type of wart studied, resistance to previous therapy, and vaccine used. It is well established that older patients (>40 years) are less likely to respond to immunotherapy than younger patients,7,11 although we could not demonstrate any association with age. The efficacy of immunotherapy ranges from 24% to 88% depending on the type of vaccine studied, although this is not consistently borne out by clinical studies.3–16 The Mw vaccine is primarily used for immunotherapy of multibacillary leprosy, but its immunomodulatory effects have also been demonstrated in other mycobacterial infections such as pulmonary tuberculosis, human immunodeficiency infection, and malignant neoplasms of the head, neck, bladder, and lung.17–21 It was initially believed that a vaccine with multiple antigens5,10 has superior results (81.4%–70.9%) compared with immunotherapy with a single antigen; however, there have been studies where a favorable response was reported with a single antigen (83%, 82%, 88%).3,6,13 Although researchers13 found that the Candida antigen is more immunogenic (88%) than the mumps antigen (71%), other investigators12 reported a response rate of 51.2% with the Candida antigen. Interestingly, the mumps antigen had a lower response in children (47%),11 which was probably due to a less robust host immune response.

Table III. Overview of Study Data and Analysis Groups

Group I: plane warts

Group II: palmoplantar warts

Group III: common warts

Total

Treatment Modality Used

Patients, No.

Patients With Clinical Cure, No. (%)a

Sessions, Mean No.

Recurrence

Complete Cure, %b

≥10 mm

2 (100)

1.66

100

≥5–9 mm

2 (66.7)

4.15

66.7

P value

.317

.004

–

≥10 mm

10 (71)

2.33

≥5–9 mm

4 (30)

4.88

P value

.0346

.002

.2617

.0461

≥10 mm

6 (66)

1.78

≥5–9 mm

2 (22)

3.8

P value

.0578

.002

.3458

.1312

≥10 mm

18 (72%)

1.83

≥5–9 mm

8 (32)

3.75

P value

.0046

.004

.1335

.0086

Clinical cure: patients with complete clearance at the end of the intervention. Complete cure: patients with no recurrence at follow-up. Bold values indicate significance.

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This premise is unusual, as the mumps antigen is used in children, as they are exposed to the virus and thus would mount a vigorous response to the antigen. The use of purified protein derivative and tuberculin in a population exposed to the infection was also found to have lower cure rates (29.2%, 47%).4,8 This wide variation proves that the antigen used may have a lesser effect on the results and the host immune response and the type of wart studied may account for eventual results. This DTH immune response can be clinically assessed by the induration achieved by test antigen.13 Although two studies4,8 have addressed this aspect, there were no formal statistical tests performed to validate their findings. Both studies grouped total and partial response in the high immune group, which was found to be superior to the low immune group.4,8 Partial response does not qualify as a cure and we did not include this in our statistical calculations (Table II, Figure 1). Another study in children11 did not find any difference based on the initial test induration; however, notably, this study was in a population that had a less robust immune response than adults.11 The few data on the effects of the test dose response is restricted to study populations (pregnant women4/children8), representing low immune groups, which is a confounding factor in assessing the immune response in the population. Our study in a normal population demonstrated that patients in the high immune group had a better response and was statistically significant in patients with palmoplantar warts (Table II). In patients with plane warts, probably due to the reduced viral load, there was no statistical difference in the two immune groups. The response rate associated with plane warts (83.5%) was the highest compared with palmoplantar and common warts (36.3% vs 33%). Interestingly immunotherapy did not affect recurrence rate, which was primarily seen in palmoplantar and common warts. Study Limitations One of the limitations of our study was the lack of a placebocontrolled group. This is paramount, as we studied recalcitrant warts, and because the patients preferred to receive treatment rather than placebo. We did not use saline as a control even though a response (13%–27.5%)5–7 has been reported, as our aim was to assess the immune response of the active immunotherapy. In addition, saline is not a true placebo as it is possible that local and distant responses of warts in patients who receive saline can develop the same mechanism as when an antigen is injected.7 There is a potential bias in our study as we assessed recalcitrant warts, which may account for the lower cure rates. The external validity of our study in groups with differing age, sex, types of warts, severity of disease, comorbid conditions, and SKINmed. 2016;14:413–421

levels of treatment is an inherent problem in therapeutic studies on warts. There are numerous issues that still need to be researched. Significantly, there is no explanation for the lack of response in the nonresponders (18.2%,7 30%13). Moreover, the exact mechanism of action of intralesional immunotherapy in responders is conjectural and is believed to be based on the DTH response consequent to the intralesional injection of the antigen (Figure 3). It is likely mediated by two steps: the first is the sensitization phase, wherein the test dose helps the processed allergen (from the vaccine) be presented to CD4 Th1 cells by antigenpresenting cells in association with class II major histocompatibility complex. T cells are induced to express interleukin 2 receptors and proliferate and differentiate into memory T cells. In the effector phase, the memory T cells, in response to the test dose, release cytokines that attract and activate nonspecific inflammatory macrophages and neutrophils. These cells display increased phagocytic and microbicidal activities and release large quantities of lytic enzymes that cause extensive tissue damage and target the antigen and intracellular organisms such as HPV; thus, the intralesional antigen likely induces a strong nonspeciﬁc inﬂammatory response mediated by cytokines and the Th1 cells (Figure 4). The innate factors that determine response or resistance to therapy is unclear.25–27 Most papillomavirus infections are self-limited, and it is believed that a cellular immune response is required for clearance of infection.24–26 Cell-mediated immunity to L1 or L2 is unlikely to exhibit therapeutic efficacy, as capsid proteins are expressed neither in basal cells that harbor HPV DNA nor in progressed lesions that do not produce virions.24,25 Candida antigens are the E6 and E7 oncoproteins and E1 or E2 proteins, which are required to maintain the viral genome as an episome (Figure 3).26 As none of the existing modes of intralesional immunotherapy can reliably target these, a definite cure for cutaneous warts will remain a focus of research. As patients with partial response and recurrences likely could not mount an adequate immune response, they were offered intralesional bleomycin based on our experience and previous studies on recalcitrant warts.28,29 Conclusions In spite of the large number of data on immunotherapy, each study can be viewed as a contribution to the literature and not as a stand-alone basis for inference and action. We reiterate the earlier observation that in an immune individual13 with multiple (>5) or large (>1 cm) warts, immunotherapy can be a reasonable alternative to other therapies. This is particularly so as distant warts resolve as a result of a generalized immune response. There

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several issues, however, that are important when results of a trial are applied to an individual patient. Although some variation in treatment response between an individual patient and patients in a trial or systematic review is to be expected, the differences tend to be in magnitude rather than direction. Our study may help the clinician to decide which wart to treat by immunotherapy, and, in difficult-to-treat nongenital warts, the test dose induration is perhaps crucial in predicting both the response and the number of sessions required for treatment. References 1 Dall’oglio F, D’Amico V, Nasca MR, Micali G. Treatment of cutaneous warts: an evidence-based review. Am J Clin Dermatol. 2012;13:73–96. 2 Kwok CS, Gibbs S, Bennett C, Holland R, Abbott R. Topical treatments for cutaneous warts. Cochrane Database Syst Rev. 2012;9:CD001781. 3 Meena JK, Malhotra AK, Mathur DK, Mathur DC. Intralesional immunotherapy with Mycobacterium w vaccine in patients with multiple cutaneous warts: uncontrolled open study. JAMA Dermatol. 2013;149:237–239. 4 Eassa BI, Abou-Bakr AA, El-Khalawany MA. Intradermal injection of PPD as a novel approach of immunotherapy in anogenital warts in pregnant women. Dermatol Ther. 2011;24:137–143. 5 Nofal A, Nofal E. Intralesional immunotherapy of common warts: successful treatment with mumps, measles and rubella vaccine. J Eur Acad Dermatol Venereol. 2010;24:1166–1170. 6 Kim KH, Horn TD, Pharis J, et al. Phase 1 clinical trial of intralesional injection of Candida antigen for the treatment of warts. Arch Dermatol. 2010;146:1431– 1433. 7 Horn TD, Johnson SM, Helm RM, Roberson PK. Intralesional immunotherapy of warts with mumps, Candida, and Trichophyton skin test antigens: a single-blinded, randomized, and controlled trial. Arch Dermatol. 2005;141:589–594. 8 Kus S, Ergun T, Gun D, Akin O. Intralesional tuberculin for treatment of refractory warts. J Eur Acad Dermatol Venereol. 2005;19:515–516. 9 King M, Johnson SM, Horn TD. Intralesional immunotherapy for genital warts. Arch Dermatol. 2005;141:1606–1607. 10 Johnson SM, Horn TD. Intralesional immunotherapy for warts using a combination of skin test antigens: a safe and effective therapy. J Drugs Dermatol. 2004;3:263– 265. 11 Clifton MM, Johnson SM, Roberson PK, Kincannon J, Horn TD. Immunotherapy for recalcitrant warts in children using intralesional mumps or Candida antigens. Pediatr Dermatol. 2003;20:268–271. 12 Signore RJ. Candida albicans intralesional injection immunotherapy of warts. Cutis. 2002;70:185–192.

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13 Johnson SM, Roberson PK, Horn TD. Intralesional injection of mumps or Candida skin test antigens: a novel immunotherapy for warts. Arch Dermatol. 2001;137:451– 455. 14 Ritter SE, Meffert J. Successful treatment of flat warts using intralesional Candida antigen. Arch Dermatol. 2003;139:541–542. 15 Gupta S, Malhotra AK, Verma KK, Sharma VK. Intralesional immunotherapy with killed Mycobacterium w vaccine for the treatment of ano-genital warts: an open label pilot study. J Eur Acad Dermatol Venereol. 2008;22:1089–1093. 16 Daniel BS, Murrell DF. Complete resolution of chronic multiple verruca vulgaris treated with quadrivalent human papillomavirus vaccine. JAMA Dermatol. 2013;149:370–372. 17 Sehgal VN, Sardana K. Lepra vaccine: misinterpreted myth. Int J Dermatol. 2006;45:164–167. 18 Patel N, Trapathi SB. Improved cure rates in pulmonary tuberculosis category II (retreatment) with Mycobacterium w. J Indian Med Assoc. 2003;101:680–682. 19 Chaudhuri P, Mukhopadhyay S. Bladder-preserving approach for muscle invasive bladder cancer: role of Mycobacterium w. J Indian Med Assoc. 2003;101:559– 560. 20 Sur PK, Dastidar AG. Role of Mycobacterium w as adjuvant treatment of lung cancer (non-small cell lung cancer). J Indian Med Assoc. 2003;101:118–120. 21 Kharkar R. Immune recovery in HIV with Mycobacterium w. J Indian Med Assoc. 2002;100:578–579. 22 Howley PM, Lowy DR. Papillomaviruses. In: Knipe DM, Howley PM, eds. Fields Virology. 5th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2001:2299–2354. 23 Stanley M, Pinto LA, Trimble C. Human papillomavirus vaccines—immune responses. Vaccine. 201220;30 5:F83–F87. 24 Doorbar J, Quint W, Banks L, et al. The biology and life-cycle of human papillomaviruses. Vaccine. 2012;30:F55–F70. 25 Christensen ND. Emerging human papillomavirus vaccines. Expert Opin Emerg Drugs. 2005;10:5–19. 26 Greenstone HL, Nieland JD, deVisser KE, et al. Chimeric papillomavirus virus-like particles elicit antitumor immunity against the E7 oncoprotein in an HPV16 tumor model. Proc Natl Acad Sci U S A. 1998;95:1800–1805. 27 Stanley MA. Immunobiology of papillomavirus infections. J Reprod Immunol. 2001;52:45–59. 28 Sardana K, Garg V, Relhan V. Complete resolution of recalcitrant periungual/subungual wart with recovery of normal nail following “prick” method of administration of bleomycin 1%. Dermatol Ther. 2010;23:407–410. 29 Munn SE, Higgins E, Marshall M, Clement M. A new method of intralesional bleomycin therapy in the treatment of recalcitrant warts. Br J Dermatol. 1996;135:969–971.

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Wide Morphologic Variability of Chromoblastomycosis in the Western Hemisphere Brian J. Mugleston, MEd;1 Richard P. Usatine, MD;2 Ted Rosen, MD3 Abstract Chromomycosis is an uncommon fungal disease seen in tropical and subtropical regions of the world. The disorder is most likely the result of traumatic percutaneous inoculation of one of several etiologic dematiaceous fungi. Causative organisms have been associated with dead wood, soil, and plants. Chromomycosis may present clinically in a wide variety of manners. We illustrate the characteristic morphologic appearances of mycosis as it was encountered in both Panama and Texas, including verrucous papules and nodules, scaly plaques, exophytic or ulcerative tumor-like masses, and cicatricial plaques of both small and large dimension. As is typical of this disease, all lesions in this series were located on the extremities, and all patients had frequent and intimate exposure to vegetation in hot, humid environments. Chromomycosis characteristically runs an indolent course and is rarely fatal. The patients described herein had experienced cutaneous lesions for many months to several decades prior to diagnosis. This mycosis is often difficult to treat. Successful therapy may involve one or more oral antifungal drugs (such as itraconazole and terbinafine) and/or use of physically ablative modalities (such as laser, photodynamic therapy, and cryosurgery). (SKINmed. 2016;14:423–427)

hromomycosis (or chromoblastomycosis) is a chronic and slowly progressive cutaneous mycosis caused by various species of dematiaceous (brown pigmented) fungi. The primary lesion is thought to develop as a result of percutaneous traumatic inoculation, the etiologic agents being found in the soil, on dead wood or other organic compounds, or as parasites of plants.1–3 Fonsecaea pedrosoi is the main etiologic organism but several other organisms, including Cladosporium carrionii and Phialophora verrucosa, also cause the disease.4,5 Aside from the typically long duration of disease, the other important clinical aspect of this disorder is the striking morphological variation. We report a series of illustrative cases encountered in two locations within the Western Hemisphere that share the typical tropical to semitropical environment. Case Reports

Patient 1 A 70-year-old farmer was admitted to a rural Panamanian hospital with a painless skin lesion on his left leg. The lesion grew

Figure 1. A lower leg lesion with a cicatricial plaque and verrucous border in patient 1 (Panama).

slowly in a concentric and continuous pattern over the next 25 years until it covered his knee. Associated warmth and swelling improved with antibiotics but did not clear the lesion. Physical examination revealed a pink, cicatricial plaque extending from the patella to the malleolus (Figure 1). The lesional edge was exophytic and exudative. The patient’s medical history included pulmonary tuberculosis, smoking, and frequent alcohol consumption. Results from a potassium hydroxide (KOH) preparation demonstrated Medlar bodies.

From the University of Texas Health Science Center School of Medicine, San Antonio, TX;1 the Division of Dermatology and Cutaneous Surgery and the Department of Family Medicine, University of Texas Health Science Center School of Medicine, San Antonio, TX;2 and the Department of Dermatology, Baylor College of Medicine, Houston, TX3 Address for Correspondence: Richard P. Usatine, MD, 7703 Floyd Curl Drive, Mail Code 7730, San Antonio, TX 78229 • E-mail: usatine@uthscsa.edu

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Patient 2 A 52-year-old farmer was admitted to a rural Panamanian hospital with a cicatricial lesion of about 20 yearsâ&#x20AC;&#x2122; duration involving his left leg, which appeared very similar to that of patient 1. There were prominent verrucous nodules present on the toes, the dorsum of the foot, and at the knee (Figure 2). Findings from a KOH preparation obtained from the nodular component demonstrated Medlar bodies.

Patient 3

Figure 2. Prominent verrucous nodules distal to cicatricial tissue in patient 2 (Panama).

A 36-year-old farmer was admitted to an urban Panamanian hospital with a painful, exophyic, and eroded mass extending from the mid-dorsum to the mid-plantar surface of his left foot (Figure 3). Results from a punch biopsy of this presumed skin neoplasm, present for about 5 years, revealed pseudoepitheliomatous hyperplasia, intraepidermal abscesses containing Medlar bodies, and similar fungal elements within a dermal granulomatous infiltrate.

Patient 4 A 45-year-old farmer was seen in the outpatient department of an urban Panamanian hospital for evaluation of gradually expanding painless, erythematous, slightly scaly plaques involving his right knee and areas immediately proximal and distal to the knee (Figure 4). The lesion had been present for at least 10 years. Results from a KOH preparation demonstrated Medlar bodies.

Patient 5 Figure 3. An exophytic and eroded foot mass in patient 3 (Panama).

A 68-year-old retired Caucasian banker with a history of multiple prior nonmelanoma skin cancers (NMSCs) presented to a Houston, Texas, outpatient dermatology department for evaluation of a slowly expanding, painless, scaly plaque located on the dorsum of his right hand (Figure 5). The lesion had been present for about 18 months. Results from biopsy revealed histologic findings compatible with chromomycosis, and a subsequent culture yielded Fonsecaea pedrosoi. The patient was an avid gardener and denied relevant travel history.

Patient 6

Figure 4. Scaly, erythematous plaques on the knee in patient 4 (Panama). SKINmed. 2016;14:423â&#x20AC;&#x201C;427

A 72-year-old Hispanic, professional gardener presented to the same Houston, Texas, outpatient dermatology department for evaluation of a slowly growing, slightly tender, heavily crusted plaque on the dorsal aspect of the distal aspect of his right arm, near the wrist (Figure 6). The lesion had been present for about 9 months. Results from a KOH preparation revealed classic Medlar bodies, and a subsequent culture yielded F pedrosoi. The patient denied recent travel.

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Figure 6. A thickly crusted plaque located on the distal forearm in patient 6 (Texas). Figure 5. A scaly plaque of dorsum of the hand in patient 5 (Texas).

Patient 7 A 65-year-old practicing physician became concerned about an asymptomatic, scaly patch involving the dorsum of his third finger, just proximal to the knuckle on the right hand (Figure 7). He had a history of actinic keratosis and NMSC, and personally did gardening at his recreational lake home. He presented to the same Houston, Texas, outpatient dermatology department where results from a KOH preparation revealed Medlar bodies and a culture of scales grew F pedrosoi. The patient denied foreign travel, except to Europe (where chromomycosis is uncommon).

Patient 8 A 69-year-old retired schoolteacher had been receiving CHOP chemotherapy (cyclophosphamide, doxorubicin, vincristine, and prednisone) for non-Hodgkin lymphoma. She presented to the Houston, Texas, outpatient dermatology department for the rapid development of a mildly tender ulceration on the dorsum of the left arm (Figure 8). The lesion was presumed to be a basal cell carcinoma due to the presence of a rolled, pearly border and an extensive history of NMSC; however, results from biopsy revealed histologic changes characteristic of chromomycosis, and a subsequent culture performed on a tissue specimen obtained from a different area than the biopsy grew F pedrosoi. The patient worked almost daily in her home flower and vegetable gardens, commonly sustaining minor abrasions. She denied any relevant travel history.

Figure 7. A scaly patch on the finger in patient 7 (Texas). Note the black dots (where potassium hydroxide examination should be performed).

Discussion Chromomycosis may present with any combination of morphologies, including verrucous papulonodules, scaly plaques, exophytic or ulcerative tumor-like masses, cicatricial plaques, and rarely lymphatic spread.6 Chromomycosis is mainly encounSKINmed. 2016;14:423â&#x20AC;&#x201C;427

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Figure 8. A shallow ulceration with rolled border proved to be chromomycosis in patient 8 (Texas). Wide Morphologic Variability of Chromoblastomycosis

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tered in the tropics in rural and humid environments, but has also been reported in temperate climates.7 The disease is found mainly in men who are agricultural workers, which appears to correlate with the presumed method of inoculation, but this raises the question of hormonal involvement, because the disease is less common in women.8,9 In the present series, there was a predominance of men and all had frequent and intimate contact with vegetation. As was true in this series, the legs and arms were the most commonly reported sites of lesions.6

Conclusions Chromomycosis is well-known to occur in tropical and subtropical regions of the world, including Central and South America, India, and portions of Asia. In addition, it has been shown to occur in warm, humid portions of the United States, particularly in Texas.17–19 It should be considered under a wide variety of clinical situations, as the morphology is varied. References

In most cases, cutaneous chromomycosis follows an indolent rather than fulminant course. In this series, lesions had been present many months to more than two decades prior to diagnosis. Symptoms from chromoblastomycosis are often minimal, with pruritus and mild pain being most common.5,6

1 Rubin HA, Bruce S, Rosen T, McBride ME. Evidence for percutaneous inoculation as the mode of transmission for chromoblastomycosis. J Am Acad Dermatol. 1991;25:951–954.

The differential diagnosis of chromomycosis is vast and includes burn or other cicatrix, sporotrichosis, cutaneous tuberculosis, coccidioidomycosis, psoriasis, mycetoma, invasive and in-situ squamous cell carcinoma, and leishmaniasis.5,6 The first and easiest method of establishing the diagnosis is a KOH preparation whereby the muriform cells, also known as sclerotic cells, “copper pennies,” or Medlar bodies, may be visualized.10 Biopsy and tissue fungal cultures may facilitate diagnosis, when the KOH preparation is not diagnostic. Histology may show sclerotic bodies, pseudoepitheliomatous hyperplasia, and intraepidermal and/ or subcutaneous microabscesses containing fungal spores. Immunodiagnostic tests (serum enzyme-linked immunosorbent assay, culture subjected to polymerase chain reaction) exist but are neither standardized nor readily available.6,11 Visualization of typical Medlar bodies is sufficient for diagnosis.

3 Tschen JA, Knox JM, McGavran MH, Duncan WC. Chromomycosis. The association of fungal elements and wood splinters. Arch Dermatol. 1984;120:107–108.

The treatment of chromomycosis remains challenging.11,12 While the disease is often refractory to treatment, it is rarely fatal.5,6,11,12 Secondary bacterial infections are common and may lead individuals to seek treatment.13 There is a lack of controlled randomized studies involving the treatment of chromomycosis, and results may vary based on causative species and duration and severity of illness. Accumulation of clinical data suggests that itraconazole and terbinafine, either alone or in combination, may be the best medical treatments.6,12,14 In some regions, 5-flucytosine may offer synergistic benefits.15 Although voriconazole and posaconazole have low in vitro minimum inhibitory concentrations against the typical etiologic fungi, there is a paucity of clinical information supporting their clinical utility, and cost would be prohibitive in some countries.16 Among physical options, excisional surgery, laser ablation, cryosurgery, photodynamic therapy, and thermotherapy may be employed; cryosurgery may be the most effective among these.6,11,12 SKINmed. 2016;14:423–427

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2 Queiroz-Telles F, McGinnis MR, Salkin I, Graybill JR. Subcutaneous mycoses. Infect Dis Clin North Am. 2003;17:59–85.

4 Caligiorne RB, de Resende MA, Dias-Neto E, Oliveira SC, Azevedo V. Dematiaceous fungal pathogens: analysis of ribosomal DNA gene polymorphism by polymerase chain reaction-restriction fragment length polymorphism. Mycoses. 1999;42:609–614. 5 Bonifaz A, Carrasco-Gerard E, Saul A. Chromoblastomycosis: clinical and mycologic experience of 51 cases. Mycoses. 2001;44:1–7. 6 Queiroz-Telles F, Esterre P, Perez-Blanco M, et al. Chromoblastomycosis: an overview of clinical manifestations, diagnosis and treatment. Med Mycol. 2009;47:3– 15 7 Garnica M, Nucci M, Queiroz-Telles F. Difficult mycoses of the skin: advances in the epidemiology and management of eumycetoma, phaeohyphomycosis and chromoblastomycosis. Curr Opin Infect Dis. 2009;22:559– 563. 8 Hernández-Hernández F, De Bievre C, Camacho-Arroyo I, et al. Sex hormone effects on Phialophora verrucosa in vitro and characterization of progesterone receptors. J Med Vet Mycol. 1995;33:235–239. 9 Silva JP, de Souza W, Rozental S. Chromoblastomycosis: a retrospective study of 325 cases on Amazonic Region (Brazil). Mycopathologia. 1998;143:171–175. 10 Zaias N, Rebell G. A simple and accurate diagnostic method in chromoblastomycosis. Arch Dermatol. 1973;108:545–546. 11 Torres-Guerrero E, Isa-Isa R, Isa M, Arenas R. Chromoblastomycosis. Clin Dermatol. 2012;30:403–408. 12 Queiroz-Telles F, Santos DW. Challenges in the therapy of chromoblastomycosis. Mycopathologia. 2013;175:477– 488. 13 Silva CL, Ekizlerian S. Granulomatous reactions induced by lipids extracted from Fonsecaea pedrosoi, Fonsecaea compactum, Cladosporium carrionii and Phialophora verrucosum. J General Microbiol. 1985;131:187–194

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14 Gupta AK, Taborda PR, Sanzovo AD. Alternate week and combination itraconazole and terbinafine therapy for chromoblastomycosis caused by Fonsecaea pedrosoi in Brazil. Med Mycol. 2002;40:529–534. 15 Antonello VS, Appel da Silva MC, Cambruzzi E, et al. Treatment of severe chromoblastomycosis with itraconazole and 5-flucytosine association. Rev Inst Med Trop Sao Paulo. 2010;52:329–331. 16 Negroni R, Tobon A, Bustamante B, et al. Posaconazole treatment of refractory eumycetoma and chromoblas-

tomycosis. Rev Inst Med Trop Sao Paulo. 2005;47:339– 346. 17 Gardner JT, Pace BF, Knox JM, Smith W. Chromoblastomycosis in Texas. Report of four cases. Tex Med. 1964;60:913–917. 18 Batres E, Knox JM, McGavran MH. Chromomycosis in Texas. Tex Med. 1979;75:59–62. 19 Lee MW, Hsu S, Rosen T. Spores and mycelia in cutaneous chromomycosis. J Am Acad Dermatol. 1998;39:850– 852.

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Edward L. Keyes Resident Contest for Outstanding Case Reports 12th World Congress of the International Academy of Cosmetic Dermatology May 4-6, 2017, Bengaluru, India Abstract deadline: January 10, 2017 To be awarded for the best Case Report submitted by a physician in training (resident, fellow, or registrar) for presentation at the 12th World Congress of the International Academy of Cosmetic Dermatology in Bengaluru, India, May 4-6, 2017. 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, or cosmetic (or combined) in nature. The author, whose abstract receives the highest score during the review process, will be awarded a scholarship by the IACD to present the full paper at the 12th World Congress of the International Academy of Cosmetic Dermatology in Bengaluru, India, May 4-6, 2017. The scholarship will provide reasonable travel expenses, lodging for 3 nights, the Congress registration fee, and a basic spending stipend. Abstracts should be submitted via email to vrosic@medicine.bsd.uchicago.edu before noon, CDT, January 10, 2017, and 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-thought-out, 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 31st, 2017. 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 Committeeâ&#x20AC;&#x2122;s decision by February 5, 2017. Vesna Petronic-Rosic, MD, MSc Chair, Resident Contest Committee Associate Professor and Interim Chair The University of Chicago Pritzker School of Medicine Section of Dermatology Tel: +1.773.702.6559 vrosic@medicine.bsd.uchicago.edu

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Aging and Facial Changes—Documenting Clinical Signs, Part 2: Methods of Documentation of Facial Changes Alex Nkengne, PhD; Christiane Bertin Abstract Skin metrology has emerged as a multidisciplinary approach for objectively documenting skin anatophysiologic aspects and transformations. Methods have been proposed to describe age-related changes of facial skin. Some of them capture information describing visible clinical signs of aging such as wrinkles, sagging, and pigmentation. These methods include but are not limited to digital imaging, 3-dimensional imaging, and colorimetry. Other methods focus more on structural or physiologic changes of underlying tissues, among these are reflectance confocal imaging, magnetic resonance imaging, and ultrasound imaging. Finally, a group of methods including corneometry and reviscometry are used to describe changes in skin properties. This contribution describes available methods for documenting age-related changes affecting the shape, texture, and color of the face. (SKINmed. 2016;14:429–435)

uman desire to preserve a youthful appearance and to correct changes that occur with age is a driving factor in the development of techniques to document and understand the aging process. Clinical evaluation of skin parameters that change with age range from simple clinical evaluation to highly sophisticated instrumentation such as in vivo microscopy and 3-dimensional (3D) imagery. We discern changes in the 3D shape of the face that correlate with structural changes in the skeletal elements, muscle weakening, fat redistribution, and skin sagging caused by gravity and loss of elasticity. These changes occur in the millimetric range and can be captured with more or less sophisticated imaging methods. Changes in skin texture involve the appearance of wrinkles, pores, and changes in the microrelief structure. These are in the order of micrometers, and their measurement requires refined imaging methods or microcopy. Skin hydration, which decreases with age, can be assessed with electrical techniques; furthermore, the tone and color of the skin also undergo typical age-related changes, characterized for Caucasian skin type by a yellowish tone, unevenness, and the apparition of brown spots (age spots), which are documented with imagery, spectroscopic methods, and colorimetry.

Documentation of Facial Changes With Age The assessments of age-related facial changes comprise the evaluation of visually noticeable changes as well as measurable biologic parameters that underlie these changes (Table). Skin pigmentation for example can be evaluated by a physician/experimenter relying on the optical impression of the skin, while the assessment of the distribution of skin chromophores that are responsible for the visually perceptible skin color involves instrument measurements. The foremost advantage of clinical evaluations (besides being inexpensive) is the fact that the global appearance, such as overall wrinkling of the face, is taken into account, while instrument approaches predominantly focus on a single dimension, eg, wrinkle volume. Clinical evaluations by nature take into account only what is obvious, and thus what is important to the human eye, and directly correlate with our perception of an individual’s age, whereas instrumental approaches can investigate beyond the visible and contribute to the understanding of the aging process.

See also Nkengne A, Christiane C. Aging and facial changes—documenting clinical signs, part 1: clinical changes of the aging face. SKINmed. 2013;11:281–286 From Johnson & Johnson Santé Beauté France, Issy les Moulineaux, France Address for Correspondence: Alex Nkengne, PhD, Johnson & Johnson Santé Beauté France, 1, rue Camille Desmoulins, 92787 Issy-les-Moulineaux, France • E-mail: ankengne@its.jnj.com

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Table. Overview of Noninvasive Methods to Study Age-Related Facial Changes Changes in facial shape Volume and overall morphology

Experimenter grading (grading scales, visual analogue scales, photographic scales) Digital imaging (polarization imaging) 3-Dimensional laser surface imaging 3-Dimensional imaging with fringe projection Stereophotogrammetry

Bone and soft tissue

Computed tomography scanning

Soft tissue

Magnetic resonance imaging

Skin elasticity and firmness

Twistometry Suction chamber Ballistometry Reviscometry

Changes in facial skin texture Wrinkling

Experimenter grading (grading scales, visual analogue scales, photographic scales) Digital imaging (polarization imaging) High-angle polarization imaging Skin replicas and automated imaging or profilomety 3-Dimensional imaging with fringe projection

Microrelief

Video microscopy (in addition to the above)

Dryness

Experimenter grading (grading scales, visual analogue scales) Video microscopy D-squams Conductance/capacitance Silicone image sensor

Barrier function

Transepidermal water loss

Epidermal proliferation

Fluorescence microscopy

Epidermal/dermal structures

Confocal laser scanning microscopy, multiphoton laser scanning microscopy

Dermal thickness

Ultrasound

Changes in facial skin color Skin tone

Experimenter grading (grading scales) Colorimetry

Skin radiance

Reflectance analysis

Pigmentation/redness

Digital imaging (polarization, UV) Video microscopy Confocal laser scanning microscopy Reflectance spectrophotometry

Clinical grading is usually performed by dermatologists or experts who have been intensively trained to improve their reproducibility and repeatability. They can consistently assess parameters related to the shape, color, or texture of the skin under standardized conditions of lighting and patient positioning. They use both their visual and tactile accuracy by observing the patients under different angles and palpating the skin to assess its firmness and roughness. The use of scales (photographic scales, visual analogous scales, descriptive scales) is intended to minimize observer-dependent subjectivity in the grading of ageSKINmed. 2016;14:429–435

related changes. When photographic grading scales are used, the acquisition of standardized photographs under controlled lightning and patient positioning conditions is a prerequisite. With the help of these scales, facial shape such as brow positioning and lip volume are assessed,1–3 wrinkle scores are attributed to the overall face or to a particular area of interest, eg, crow’s feet, forehead,4–7 and skin dryness,8 skin tone, and pigmentation are assessed.9,10 Observer-dependent variations in clinical assessments are overcome with instrumental approaches, which rely on physical

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principals and provide principal advantages of repeatability and reproducibility. Multiple methods are frequently used in parallel to strengthen the results and to cover more than one aspect of age-related changes. Changes in Facial Shape Morphologic facial changes, such as drooping of the jaw line, deepening of the nasolabial folds, loss of lip volume, development of under eye bags, and changes in facial contours and curvatures, are reliably documented with digital photography when constraints such as standardization of head, camera, and light positioning are met. Changes in facial shape and volume can be measured with the help of 3D imaging techniques that digitize the

facial surface. Among these techniques is 3D laser surface imaging, where the face is scanned with a laser; the displacement of the light is followed with a digital camera and depth information is subsequently calculated.11 In 3D imaging with digital fringe projection, lines of light are projected on the face and distorted by the skin relief and facial contours. This distortion is captured by a camera, measured, and converted into 3D coordinates12 (Figure 1). In stereophotogrammetry, a structured or speckled light pattern is projected on the face and images are recorded simultaneously from different views and combined into a 3D image.13 The anatomic changes of the facial skeleton and soft tissue structures with age can be visualized and measured with the help of the

S01

S02

Figure 1. Patients S01 and S02 were 36 and 65 years old, respectively. The visible image shows differences in terms of skin tone, texture, and sagging of the jawline. The 3-dimensional image has been smoothed out to emphasize the differences related to the curvature of the face. The color code represents the curvature (mean curvature) of each point of the face. S01 has a rounder cheek than S02, with a more uniform cheekbone. S02 has a visible hollow cheek. SKINmed. 2016;14:429â&#x20AC;&#x201C;435

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more advanced 3D imaging techniques. In computed tomography (CT) imaging, a series of 2-dimensional (2D) x-ray images are digitally transformed to create 3D reconstructions of the face with volume rendering and to measure distances and angles between specific facial landmarks. This way, differences in facial anatomy between young and older individuals have been calculated.14–17 Magnetic resonance imaging (MRI), which is a non-ionizing imaging method, is particularly useful for soft tissue imaging. Volumetric measurements obtained from MRI scans can be used to assess changes in facial fat volume.18 Because these methods are invasive (besides being time consuming and costly), they cannot be used in routine assessments of facial changes. Skin elasticity and firmness that diminish with age and give rise to loose and sagging skin are assessed with mechanical methods that are based on deformation of the skin surface in defined directions. In twistometry, application of a rotational force on the skin plane measures skin stiffness.19 By means of vacuum suction in the suction chamber method, skin is deformed vertically and information on skin stiffness, viscoelasticity, and elasticity is derived from the skin’s resistance to the vacuum, the extent of its distortion, and its ability to return to the initial state.20 In ballistometry, repeated indentation of the skin assesses its firmness and elasticity.21 Information on skin stiffness can also be obtained with reviscometry, where the time it takes an acousti-

cal shockwave to travel through the skin from an emitter to a receiver is measured.22 Changes in Facial Skin Texture With high-resolution digital photography, wrinkles or furrows can be accurately documented.23 Polarization filters are added to reduce glare arising from light reflected by the skin surface and to enhance contrast (Figure 2). Polarization imaging with high angles of incidence further enhances surface details.24 The disadvantage of these imaging methods is the lack of the third dimension to evaluate wrinkle depth. Wrinkle volume, length, and depth can be assessed with skin replicas. Silicone rubber is used to generate an imprint of the skin from which 3D images are reconstituted with automated image analysis25 or with laser profilometry.26 With the latter technique, a laser beam scans the surface of the impression material to measure the surface heights and valleys. Noncontact 3D imaging methods performed directly on the skin, such as 3D imaging with digital fringe projection,27,28 are preferable to profilometry for quantitative wrinkle analysis, as the skin texture may be altered by the contact with the impression material, a disadvantage in addition to the time-consuming analysis of the imprints. The skin microrelief structure (the lines that criss-cross the skin surface) is essentially assessed in the same manner as wrinkles; however, specific pa-

Figure 2. Visible (A), parallel polarized (B) and UV (C) images of the face reveal different conditions of the aging skin. The visible image shows the clinical signs that can be detected by a naïve observer, while the parallel polarized image emphasizes wrinkles and the UV image shows pigmented spots. SKINmed. 2016;14:429–435

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rameters describing the microrelief density and orientation are used to describe the ageing process. Video microscopy with high-resolution image analysis is also a valuable way to visualize and quantify microrelief structures.29 A range of noninvasive methods exist that allow the assessment of epidermal and dermal properties that influence skin texture and contribute to skin sagging. Among these is the hydration status of the epidermis. Video microscopy can be employed to document scaling (ie, desquamation, detachment of corneocytes) as an indicator of skin dryness. The use of adhesive discs enables a quantitative approach to assess scaling.30 A disc is briefly pressed against the skin and the number of corneocytes that are removed upon the removal of the disc is quantified visually or with video imaging analysis. As the moisture level of the Stratum corneum influences the flow of electrons, skin hydration can be determined with electrical methods that measure skin capacitance or conductance (the ease of electrons to flow through skin).31 Depending on the instrument used, these measurements target different depths of the epidermis. With the help of silicone imaging sensors, nonoptical imaging of the skin capacitance is provided and discrete focal variations in skin surface hydration are detected, providing “fingerprints” of skin hydration.32–34 The hydration status of the skin influences its properties as a barrier. The integrity of the Stratum corneum skin barrier function is assessed by measuring the transepidermal water loss.35 Epidermal cell proliferation that tends to decrease with age can be assessed with fluorescence spectroscopy.36 Epidermal and dermal structures can be visualized with high-resolution images acquired with confocal laser scanning microscopy (CLSM) in

reflectance mode (reflectance CLSM).37 With this method, horizontal cross sections of the skin from the surface of the epidermis down to the dermis are acquired (Figure 3). Cellular and nuclear structures of the epidermis and the thickness of the epidermis can be analyzed. The age-related loss in dermal papillae density and flattening of the epidermal-dermal junctions can also be assessed with CLSM.38 This method, however, cannot differentiate between collagen and elastin fibers. This can be achieved with multiphoton laser scanning microscopy, which is used to visualize and quantify the collagen network.39 Ultrasound measurements provide cross-sectional images of the skin and are thus a useful approach to quantify dermal thickness40,41 and subcutaneous fat thickness.42 Changes in Facial Skin Color An individual’s skin tone is determined by the concentration and distribution of different chromophores in the skin. The nature of the skin tone can be expressed as visually perceived skin hue using color scales43 or quantified with instrumental approaches. In tristimulus colorimetry, skin color is expressed numerically in analogy to the sensitivity of a human observer. The light reflected from the skin upon illumination is analyzed and a set of 3 coordinates is ascribed (CIELAB system): L*a*b*; L* for brightness, a* for green to red, and b* for blue to yellow.44 The skin tone together with other factors such as skin texture, brightness, luminosity, and microcirculation determines the complexion radiance. A matt skin surface reflects/scatters light in a manner different from a bright surface. Skin radiance can thus be quantified by capturing and analyzing the reflectance of light shone on the skin.45

Figure 3. Confocal image of the skin at different skin depths. (A) In the epidermis, the size and the organization of the cells can be evaluated. (B) The shape of the papilla is particularly well contrasted when the skin is pigmented. (C) A fibrous structure can be seen at the superficial dermis. SKINmed. 2016;14:429–435

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The loss of homogeneity of the facial skin tone, as seen in the appearance of pigmented spots and redness, can be assessed with various imaging approaches mentioned above. Digital photography, preferably with cross polarization filters to reduce glare, provides a noncontact approach for documentation and quantification of pigmentation.46 UV photography enhances the visualization of UVinduced skin damage (Figure 2) such as excess melanin production resulting in freckles or white spots related to melanocyte destruction by UV exposure.23,47 The surface area and intensity of pigmented spots can be measured with high-resolution digital videomicroscopy.23 CLSM is particularly useful in the documentation of pigmented lesions due to the endogenous contrast provided by melanin.48 Analysis and quantification of skin chromophores that contribute to skin color (melanin, oxy-hemoglobin, and deoxy-hemoglobin) can be performed with spectroscopy. In diffuse reflectance spectroscopy, light is delivered to the skin, the reflected light is collected with flexible fiberoptic bundles, and the spectrum of the reemitted light is analyzed with a spectrometer. Since each chromophore has a characteristic reflectance spectrum, the apparent concentration of each chromophore can be calculated.49 Spectrophotometers exist that provide both the reflectance spectrum of the skin as well the L*a*b* coordinates of the skin color.46 The contribution of microcirculation to skin color can be measured with the laser Doppler method.50 Conclusions The evaluation of skin rejuvenation procedures involve a multidisciplinary approach that combines instrumentation and clinical grading. Over the past 20 years, skin metrology has dramatically evolved in terms of both available methods and study designs. For example, the improvement in skin imaging now allows us to explore the skin surface at different resolutions and wavelengths and to dive into the living tissues. All these methods, combined with a well-designed study protocol, allow a better follow-up of the benefits of cosmetic/dermatologic or surgical procedures. Acknowledgment Beate Gerstbrein assisted in editing and reviewing this manuscript. disclosure All the authors are full-time employees of Johnson & Johnson, Santé Beauté, France. References 1 Carruthers A, Carruthers J, Hardas B, et al. A validated brow positioning grading scale. Dermatol Surg. 2008;34 suppl 2:S150–S154.

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2 Carruthers A, Carruthers J, Hardas B, et al. A validated lip fullness grading scale. Dermatol Surg. 2008;34 suppl 2:S161–S166. 3 Rossi AB, Nkengne A, Stamatas G, Bertin C. Development and validation of a photonumeric grading scale for assessing lip volume and thickness. J Eur Acad Dermatol Venereol. 2011;25:523–531. 4 Kappes UP. Skin ageing and wrinkles: clinical and photographic scoring. J Cosmet Dermatol. 2004;3:23–25. 5 Tsukahara K, Takema Y, Kazama H, et al. A photographic scale for the assessment of human facial wrinkles. J Cosm Sci. 2000;51:127–139. 6 Carruthers A, Carruthers J, Hardas B, et al. A validated grading scale for crow’s feet. Dermatol Surg. 2008;34 suppl 2:S173–S178. 7 Carruthers A, Carruthers J, Hardas B, et al. A validated grading scale for forehead lines. Dermatol Surg. 2008;34 suppl 2:S155–S160. 8 Serup J. EEMCO guidance for the assessment of dry skin (xerosis) and ichthyosis: clinical scoring systems. Skin Res Technol. 1995;1:109–114. 9 Taylor S, Westerhof W, Im S, Lim J. Noninvasive techniques for the evaluation of skin color. J Am Acad Dermatol. 2006;54(5 suppl 2):S282–S290. 10 Stamatas GN, Zmudzka BZ, Kollias N, Beer JZ. In vivo measurement of skin erythema and pigmentation: new means of implementation of diffuse reflectance spectroscopy with a commercial instrument. Br J Dermatol. 2008;159:683–690. 11 Hennessy RJ, McLearie S, Kinsella A, Waddington JL. Facial surface analysis by 3D laser scanning and geometric morphometrics in relation to sexual dimorphism in cerebral–craniofacial morphogenesis and cognitive function. J Anat. 2005;207:283–295. 12 Gorthi SS, Rastogi P. Fringe projection techniques: whiter we are? Opt Lasers Eng. 2010;48:133–140. 13 Heike CL, Upson K, Stuhaug E, Weinberg SM. 3D digital stereophotogrammetry: a practical guide to facial image acquisition. Head Face Med. 2010;6:18. 14 Richard MJ, Morris C, Deen BF, Gray L, Woodward JA. Analysis of the anatomic changes of the aging facial skeleton using computer-assisted tomography. Ophthal Plast Reconstr Surg. 2009;25:382–386. 15 Mendelson BC, Hartley W, Scott M, McNab A, Granzow JW. Age-related changes of the orbit and midcheek and the implications for facial rejuvenation. Aesthetic Plast Surg. 2007;31:419–423. 16 Kahn DM, Shaw RB, Jr. Aging of the bony orbit: a threedimensional computed tomographic study. Aesthet Surg J. 2008;28:258–264. 17 Shaw RB, Jr, Kahn DM. Aging of the midface bony elements: a three-dimensional computed tomographic study. Plast Reconstr Surg. 2007;119:675–681; discussion 82–83. 18 Darcy SJ, Miller TA, Goldberg RA, et al. Magnetic resonance imaging characterization of orbital changes with age and associated contributions to lower eyelid prominence. Plast Reconstr Surg. 2008;122:921–929; discussion 30–31.

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19 Agache PG. Twistometry measurement of skin elasticity. In: Serup J, Jemec GBE, editors. Handbook of NonInvasive Methods and the Skin. Boca Raton, FL: CRC Press; 1995:319–334. 20 Jemec GB, Selvaag E, Agren M, Wulf HC. Measurement of the mechanical properties of skin with ballistometer and suction cup. Skin Res Technol. 2001;7:122– 126. 21 Hargens CW. Ballistometry. In: Serup J, Jemec GBE, eds. Handbook of Non-Invasive Methods and the Skin. Boca Raton, FL: CRC Press; 1995:359–364. 22 Paye M, Mac-Mary S, Elkhyat A, et al. Use of the reviscometer for measuring cosmetics-induced skin surface effects. Skin Res Technol. 2007;13:343–349. 23 Callaghan TM, Wilhelm KP. A review of ageing and an examination of clinical methods in the assessment of ageing skin. Part 2: clinical perspectives and clinical methods in the evaluation of ageing skin. Int J Cosmet Sci. 2008;30:323–332. 24 Bargo PR, Kollias N. Measurement of skin texture through polarization imaging. Br J Dermatol. 2010;162:724–731. 25 Nouveau S, Bastien P, Baldo F, de Lacharriere O. Effects of topical DHEA on aging skin: a pilot study. Maturitas. 2008;59:174–181. 26 Efsen J, Hansen HN, Christiansen S, Keiding J. Laser profilometry. In: Serup J, Jemec GBE, eds. Handbook of Non-Invasive Methods and the Skin. Boca Raton, FL: CRC Press; 1995:97–105. 27 Mac-Mary S, Sainthillier JM, Jeudy A, et al. Assessment of cumulative exposure to UVA through the study of asymmetrical facial skin aging. Clin Interv Aging. 2010;5:277–284. 28 Jacobi U, Chen M, Frankowski G, et al. In vivo determination of skin surface topography using an optical 3D device. Skin Res Technol. 2004;10:207–214. 29 Arakawa N, Ohnishi H, Masuda Y. Development of quantitative analysis for the micro-relief of the skin surface using a video microscope and its application to examination of skin surface texture. Int J Cosmet Sci. 2009;31:69–70. 30 Schatz H, Altmeyer PJ, Kligman AM. Dry skin and scaling evaluated by d-squames and image analysis. In: Serup J, Jemec GBE, eds. Handbook of Non-Invasive Methods and the Skin. Boca Raton, FL: CRC Press; 1995:153–157. 31 Barel AO, Clarys B. Measurement of epidermal capacitance. In: Serup J, Jemec GBE, Grove GL, eds. Handbook of Non-Invasive Methods and the Skin. Boca Raton, FL: CRC Press; 2006:337–344. 32 Xhauflaire-Uhoda E, Pierard-Franchimont C, Pierard GE. Skin capacitance mapping of psoriasis. J Eur Acad Dermatol Venereol. 2006;20:1261–1265. 33 Xhauflaire-Uhoda E, Loussouarn G, Haubrechts C, Leger DS, Pierard GE. Skin capacitance imaging and corneosurfametry. A comparative assessment of the impact of surfactants on stratum corneum. Contact Dermatitis. 2006;54:249–253.

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34 Xhauflaire-Uhoda E, Pierard GE. Skin capacitance imaging of acne lesions. Skin Res Technol. 2007;13:9–12. 35 Levin J, Maibach H. The correlation between transepidermal water loss and percutaneous absorption: an overview. J Control Release. 2005;103:291–299. 36 Stamatas GN, Estanislao RB, Suero M, et al. Facial skin fluorescence as a marker of the skin’s response to chronic environmental insults and its dependence on age. Br J Dermatol. 2006;154:125–132. 37 Rajadhyaksha M, Gonzalez S, Zavislan JM, Anderson RR, Webb RH. In vivo confocal scanning laser microscopy of human skin II: advances in instrumentation and comparison with histology. J Invest Dermatol. 1999;113:293–303. 38 Sauermann K, Jaspers S, Koop U, Wenck H. Topically applied vitamin C increases the density of dermal papillae in aged human skin. BMC Dermatol. 2004;4:13. 39 Fischer F, Achterberg V, Marz A, et al. Folic acid and creatine improve the firmness of human skin in vivo. J Cosmet Dermatol. 2011;10:15–23. 40 Agner T. Ultrasound A-mode measurement of skin thickness. In: Serup J, Jemec GBE, eds. Handbook of Non-Invasive Methods and the Skin. Boca Raton, FL: CRC Press; 1995:289–292. 41 Naouri M, Atlan M, Perrodeau E, et al. High-resolution ultrasound imaging to demonstrate and predict efficacy of carbon dioxide fractional resurfacing laser treatment. Dermatol Surg. 2011;37:596–603. 42 Perin F, Pittet JC, Schnebert S, et al. Ultrasonic assessment of variations in thickness of subcutaneous fat during the normal menstrual cycle. Eur J Ultrasound. 2000;11:7–14. 43 Musnier C, Piquemal P, Beau P, Pittet JC. Visual evaluation in vivo of ‘complexion radiance’ using the C.L.B.T. sensory methodology. Skin Res Technol. 2004;10:50–56. 44 Westerhof W. CIE colorimetry. In: Serup J, Jemec GBE, eds. Handbook of Non-Invasive Methods and the Skin. Boca Raton, FL: CRC Press; 1995:385–397. 45 Petitjean A, Sainthillier JM, Mac-Mary S, et al. Skin radiance: how to quantify? Validation of an optical method. Skin Res Technol. 2007;13:2–8. 46 Stamatas GN, Zmudzka BZ, Kollias N, Beer JZ. Noninvasive measurements of skin pigmentation in situ. Pigment Cell Res. 2004;17:618–626. 47 Fulton JE, Jr. Utilizing the ultraviolet (UV detect) camera to enhance the appearance of photodamage and other skin conditions. Dermatol Surg. 1997;23:163– 169. 48 Busam KJ, Charles C, Lohmann CM, et al. Detection of intraepidermal malignant melanoma in vivo by confocal scanning laser microscopy. Melanoma Res. 2002;12:349–355. 49 Kollias N, Stamatas GN. Optical non-invasive approaches to diagnosis of skin diseases. J Investig Dermatol Symp Proc. 2002;7:64–75. 50 Berardesca E, Leveque JL, Masson P. EEMCO guidance for the measurement of skin microcirculation. Skin Pharmacol Appl Skin Physiol. 2002;15:442–456.

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SELF ASSESSMENT EXAMINATION

SELF ASSESSMENT EXAMINATION W. Clark Lambert, MD, PhD Instructions: For each numbered question, choose the one most appropriate lettered response unless otherwise instructed.

4. Facial pigmentation/redness may be measured by. a. Confocal laser scanning microscopy. b. Digital imaging (using polarization and ultraviolet light). c. Reflectance spectrophotometry. d. Video microscopy. e. All of these.

1. The principal reason for using polarized light in digital photographic studies is to: a. Enhance ballistometry. b. Limit interference due to premature reviscometry. c. Limit interference due to Ramon spectroscopy effects. d. Limit interference due to stereophotogammetry. e. Reduce glare.

5. Facial skin wrinkling may be measured by: (Answer as many lettered responses as apply.) a. Digital imaging (polarization imaging). b. Examination of skin replicas using automated imaging or profilometry. c. Experimenter grading (using grading scales, visual analog scales, and/or photographic scales). d. High-angle polarization imaging. e. Three dimensional imaging with fringe projection.

3. The most useful technology for measuring epidermal cell proliferation is: a. Ballistometry. b. Fluorescence microscopy. c. Stereophotogammetry. d. Three dimensional imaging with fringe projection. e. Ultrasound.

ANSWERS TO EXAMINATION: 1. e, 2. e, 3. b, 4. e, 5. a, b, c, d, e

2. The most useful technology for measuring dermal thickness is: a. Ballistometry. b. Fluorescence microscopy. c. Stereophotogammetry. d. Three dimensional imaging with fringe projection. e. Ultrasound.

VINTAGE LABEL

Courtesy of BuyEnlarge, Philadelphia, PA 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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Volume 14 • Issue 6

HISTORICAL VIGNETTE Charles Steffen, MD, Section Editor

Eucerin: A Revolutionary Formulation Still Going Strong for Over a Century Yusuf Anwar, MD; Eve J. Lowenstein, MD, PhD

Eucerit, now more commonly known as Eucerin, was a revolutionary emulsion developed more than 100 years ago that is still popular and in common use today. The initial formulation is still the basis for a relevant global product line that holds significant market share today. The concept for Eucerin was originally developed in Germany by Dr Isaac Lifschütz, who helped develop Eucerin, meaning “beautiful wax,” in 1898. The ointment was very smooth, allowing Eucerin to develop as a stable emulsion. Eucerin was revolutionary and outperformed all of its predecessors in emulsion stability, moisturizing ability, its ability to resist degradation, and its cost-effectiveness.1 (SKINmed. 2016;14:437–439)

r Lifschütz founded Eucerin on the basis of isolating the water-binding component of lanolin (wool wax), which he called Eucerin anhydricum. He observed that its water-binding capacity increased seven-fold.2 He then added mineral fats to create the hydrophilic ointment (the stable emulsion) known as Eucerin. Eucerin’s increased ability to bind water and remain stable was revolutionary for its time. This unique and long-lasting emulsion had enhanced moisturizing effects.1

Vaseline, a competitor product introduced in the United States in 1872, was easily soluble and did not retain water, ultimately reducing its moisturizing properties.1 Eucerin boasted other advantages: it was odorless and not sticky, it could be sterilized and stored permanently, and could be easily rubbed into the skin. Eucerin also had a cooling effect because of the rapid evaporation of water. This is in contrast to calamine lotion, a competitor astringent, which caused constriction of blood vessels. Eucerin proved to be far less irritating as a cooling agent.2 Dr Lifschütz filed for a patent of a new emulsifying agent, Eucerit, which was approved in 19023 (Figure 1). Lifschütz was approached by entrepreneur Oscar Troplowitz and the renowned

dermatologist Paul Gerson Unna4 who represented Beiersdorf (Hamburg, Germany), offering Lifschütz a position to work as a chemist for Beiersdorf.5 Subsequently, he agreed to sell his patent to Beiersdorf in 1911.1 Despite his initial contributions, Lifschütz’s formal influence in the company was limited; he was later denied a seat on the board of Beiersdorf.6 Professor Unna, in The Struggle for a Science of the Skin, advocated Eucerin ointment as “agreeable for the pharmacist due to its stable and smooth consistency, easily prescribed by the doctor and it creates a good feeling for the patient due to its smoothness and cooling effect”7 (Figure 2). Interestingly, it was after this comment that the product began to develop commercially. While Lifschütz is responsible for its scientific development, Unna has often been credited for Eucerin’s initial commercial success.1 In the early 20th century, brand names were not used widely. The initial Eucerin ointments were thus simply known as “Paul Beiersdorf und Co.” Initially, Eucerin was solely used as a medicinal product. Accordingly, Beiersdorf initially only made them available at local pharmacies in Germany because of concern about proper use and misuse by consumers.1 For instance,

Presented at the History of Dermatology Seminar, Miami Beach, FL February 28,2013. From the Department of Dermatology, SUNY Downstate College of Medicine, Brooklyn, NY Address for Correspondence: Yusuf Anwar, MD, Department of Dermatology, SUNY Downstate College of Medicine, 450 Clarkson Avenue, Brooklyn, NY 11203 • E-mail: yusufanwar@gmail.com

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Figure 3. An image from the 1920s of the Eucerin product line when it first began to sell in the United States.9

Figure 1. The patent application for the revolutionary new product, Eucerit,9 in 1902.

out, and this began a trend with doctors starting to recommend Eucerin more regularly. This marked a significant paradigm shift in the use of Eucerin. In 1920, Eucerin products began to sell in the United States (Figure 3). In 1950, Eucerin finally entered the mainstream commercial marketplace as ph5 Eucerin, a product developed with a specific target base, namely those with sensitive skin.9 Additionally, NIVEA Crème, which was developed later and also based on the Eucerin formulation, had a successful career in the nonmedical skin care market.5 In the 1970s, Eucerin products were developed to include items for the entire body.4 Building on its initial successes, Eucerin went global in the 1980s. Eventually, in the mid-1990s, Eucerin entered the heart of the skin care market, namely facial care. Initially, certain products were listed under different brand names (ie, urea-containing products were named Laceran) to distinguish them from the original formula. The use of various names proved difficult commercially, however. In 1998, Laceran became Eucerin, and Eucerin persisted as the global market brand name of Beiersdorf.1 Today, Eucerin is one of the most highly recommended dermatologist skin care brands, still harboring strong ties to the initial formulation and production breakthrough over a century before.9

Figure 2. A photograph of Professor Unna’s book, The Struggle for a Science of the Skin. His advocacy for Eucerin in this book helped contribute to its commercial success.1

consumers are often unaware that Eucerin contains oils and fats, such as shea butter, which are known to irritate acne-prone skin.8 In the medical market, Eucerin was initially used by surgeons to moisturize skin that was affected by excessive washing. Word got SKINmed. 2016;14:437–439

Acknowledgments Supported by a grant from the Alumni Association of SUNY HSCB. This paper was presented at the annual 2013 History of Dermatology Seminar in Miami, Florida.

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References 1 Eucerin History Germany.

Booklet.

Beiersdorf.

Hamburg,

2 Unna PG. The practical use of Eucerin as an ointment basis. Proc R Soc Med. 1912;15:97–98. 3 Beiersdorf. Brand history. http://www.beiersdorf.com/ About_Us/Our_History/Brand_History/Eucerin.html. Accessed January 10, 2013. 4 Jackson D. Eucerin, a new emollient. Arch Dermatol. 2010;146:599. 5 Beiersdorf. NIVEA history: how it all began. http://www.

niveausa.com/Experience/100years#!stories/how-it-allbegan. Accessed July 3, 2013. 6 P. Beiersdorf and Co: A Historical Sketch. The Pharmaceutical Journal: A Weekly Record of Pharmy and Allied Sciences. 1908:749–750. 7 Unna PG. The Struggle for a Science of the Skin. Norwalk, CT: Beiersdorf Inc; 1980. 8 Begoun P. Don’t Go to the Cosmetics Counter Without Me. 9th ed. Tukwila, WA: Beginning Press; 2009. 9 Beiersdorf Inc. Eucerin history. http://www.eucerin. com/about-eucerin/. Accessed January 10, 2013.

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 451) SKINmed. 2016;14:437–439

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November/December 2016

Volume 14 • Issue 6

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

Deadly Skin Tags! Parmvir Singh, BS;1 Ann M. John, BA;1 Brian Lee, MD;2 M. Zac Handler, MD;2 Robert A. Schwartz, MD, MPH;2 W. Clark Lambert, MD, PhD2 “How is it one careless match can start a forest fire, but it takes a whole box to start a campfire?”––Anonymous

crochorda, also known as skin tags, fibroepithelial polyps, or soft fibromas, are among the most common lesions removed by dermatologists.1 They are asymptomatic lesions found in an estimated 46% of the population.2,3 Clinically, they are small (2–6 mm), flesh-colored, smooth, round, pedunculated, and inelastic.3 They most commonly occur in intertriginous areas. The eyelids, neck, axillae, genitalia, and perineum are typical sites.2,3 Acrochorda most commonly affect middle-aged and elderly individuals with equal sex distribution.2 They are widely considered to be benign, clinically insignificant entities, but there are a few reports of basal and squamous cell carcinomas growing within them.1–3 Large variants have been reported.2 This does not, however, represent the full range of diagnostic possibilities. We present one case of toxic epidermal necrolysis (TEN) caused by a necrotic skin tag and another case of eccrine porocarcinoma growing within a skin tag. Pathogenesis The etiology of skin tags is unknown. They have been linked to diabetes mellitus (acanthosis nigricans), Crohn’s disease, aging, obesity, friction, acromegaly, pregnancy, colonic polyps, organ transplantation, and human papilloma virus infection.4 Growing acrochorda have been associated with increased expression of epidermal growth factor receptor in the epidermis.5 In one study, 13% of patients with two or more acrochordons had abnormal glucose tolerance tests, compared with just 9% in the control group.5 The investigators also reported higher total cholesterol, low-density lipoprotein cholesterol, triglycerides, systolic blood pressure, and diastolic blood pressure, and lower high-density lipoprotein cholesterol in the group with acrochorda. These results suggest that acrochorda are associated with the metabolic syndrome. There is a correlation between elevated liver enzymes

and the occurrence of acrochorda.5 There is also a report of a patient with multiple skin tags in a linear pattern caused by friction from repetitive up-down movements of the arms while working in a chicken slaughterhouse.6 Mast cell–induced fibroblast proliferation has been suggested as a possible mechanism.4 Diagnosis and Treatment Skin tags are dermal connective tissue neoplasms.6 Histopathologic examination is usually not performed, as skin tags are almost universally considered benign. Long-term acrochorda may become vascularized, fibrotic, or ischemic.3 Histopathology of such lesions shows thinning of the epidermis, flattening of the basal layer, papillomatosis, irregular acanthosis, loose collagen fibers, and dilated capillaries. The differential diagnosis may include verrucae, neurofibromatosis, and seborrheic keratosis. Cryotherapy, electrocautery, and snip excision are usually curative, while larger lesions may require simple excision.3 Four patients have even been treated with radiofrequency surgical ablation with excellent results.3 Case Reports

Case 1 A 54-year-old man presented with desquamation in sheets over approximately 40% of his body. Although he did not appear acutely ill, a diagnosis of TEN was rendered, requiring admission to the intensive care unit. He was incidentally found to have an acrochordon on his left arm. This acrochordon was strangulated and edematous. The classic histologic pattern of TEN was present: full thickness destruction of the epidermis underlain by partial regeneration of the basal layer (Figures 1 and 2).7 Excision led to rapid resolution of the TEN. No other cause for the TEN was discovered.

From Rutgers-New Jersey Medical School, Newark, NJ;1 and the Departments of Dermatopathology, Dermatology, and Pathology and Laboratory Medicine, Rutgers-New Jersey Medical School, Newark, NJ2 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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Figure 3. Eccrine porocarcinoma occurring in an acrochordon in case 2 (hematoxylin and eosin stain, original magnification ×135).

Figure 1. Strangulated acrochordon with features of toxic epidermal necrolysis (TEN) in the overlying epidermis (arrow) in case 1. Re-epitheliazation has begun beneath the TEN. The dermis shows edema and strangulated vessels (hematoxylin and eosin stain, original magnification ×135).

Figure 4. Eccrine porocarcinoma demonstrating sheets of tumor cells in the same case as Figure 3. Mitoses are present (arrows) (hematoxylin and eosin stain, original magnification ×540).

Case 2

Figure 2. Strangulated acrochordon with features of toxic epidermal necrolysis in the same case as Figure 1 (hematoxylin and eosin stain, original magnification ×270). SKINmed. 2016;14:441–443

A 38-year old Hispanic man underwent a biopsy of a skin tag from his left arm. Histologically, an eccrine porocarcinoma was found within the acrochordon (Figures 3 and 4). When necessary, cytokeratin 7, cytokeratin 19, and Nestin staining can improve diagnostic specificity8; however, these were not needed in this case. The tumor showed moderate mitotic activity (Figure 4), indicating metastatic potential. The patient remained recurrence-free following excision.

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Conclusions Although they are largely benign, acrochorda can be associated with deadly complications. There are reports of nonmelanoma skin cancer occurring within them. We present a case of TEN occurring as a result of strangulation and ischemic necrosis of an acrochordon. Simply focusing on drug reactions could result in death in such a patient. We also present a case of an eccrine porocarcinoma occurring within an acrochordon. This aggressive tumor could have resulted in death if not diagnosed. Skin tags are so common that they are usually thought to be harmless, but they can be fatal. Dermatopathologic evaluation may be critical. References 1 Schwartz RA, Tarlow MM, Lambert WC. Keratoacanthoma-like squamous cell carcinoma within the fibroepithelial polyp. Dermatol Surg. 2004;30:349–350. 2 Ilango N, Jacob J, Gupta AK, Choudhrie L. Acrochordon– –a rare giant variant. Dermatol Surg. 2009;35:1804– 1805.

3 Ghosh SK, Bandyopadhyay D, Chatterjee G, Bar C. Giant skin tags on unusual locations. J Eur Acad Dermatol Venereol. 2009;23:233. 4 Salem SA, Attia EA, Osman WM, El Gendy MA. Skin tags: a link between lesional mast cell count/tryptase expression and obesity and dyslipidemia. Indian J Dermatol. 2013;58:240. 5 Senel E, Salmanoglu M, Solmazgul E, Bercik Inal B. Acrochordons as a cutaneous sign of impaired carbohydrate metabolism, hyperlipidemia, liver enzyme abnormalities and hypertension: a case-control study. J Eur Acad Dermatol Venereol. 2011 Dec 21. [Epub ahead of print] 6 Allegue F, Fachal C, Perez-Perez L. Friction induced skin tags. Dermatol Online J. 2008;14:18. 7 Mockenhaupt M. The current understanding of StevensJohnson syndrome and toxic epidermal necrolysis. Expert Rev Clin Immunol. 2011;7:803–813; quiz 814–815. 8 Song SS, Wu Lee W, Hamman MS, Jiang SI. Mohs micrographic surgery for eccrine porocarcinoma: an update and review of the literature. Dermatol Surg. 2015;41:301–306.

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November/December 2016

Volume 14 • Issue 6

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

FINACEA™ (Azelaic Acid) Foam, 15% Aditya K. Gupta, MD, PhD, FRCPC;1,2 Kelly A. Foley, PhD;2 William Abramovits, MD3,4,5

osacea is a common inflammatory skin condition that typically affects the face and can result in varying degrees of negative psychosocial manifestations.1,2 The main features of rosacea include transient and nontransient erythema, papules and pustules, and telangiectases, all of which may be accompanied with burning, stinging, plaques, dryness, and/or edema.2 Papulopustular rosacea (PPR) is characterized by nontransient facial erythema of the central face region, with transient papules or pustules found in the same areas.2 While the exact pathophysiologic mechanisms behind rosacea are not known, dysregulation of the immune system, specifically increased levels of cathelicidin and kallikrein, has been implicated.1

Azelaic acid (AzA) 15% gel, metronidazole cream and gels, ivermectin 1% cream, brimonidine 0.33% gel, and doxycycline capsules have been approved by the Federal Drug Administration for use as treatments for PPR. Clinical studies show that AzA gel 15% is effective and safe for treatment of rosacea.3 Alternative formulations for topical drug delivery have gained attention in the last 10 years, as an effort is made to increase the efficacy and safety of treatments, and improve ease of application and perhaps patient compliance.4 On July 29, 2015, the Federal Drug Administration approved the use of Finacea (AzA) 15% foam for topical treatment of mild to moderate PPR,5 providing an alternative to current oral and topical therapies. Phase II Clinical Data Two randomized, double-blind, vehicle-controlled phase II clinical trials were conducted to assess the efficacy and safety of AzA foam 15% in treating moderate to severe PPR.6–8 AzA foam 15% and vehicle foam were applied twice daily for 12 weeks. The first trial enrolled 83 male and female participants, with a mean age of 50.5±12.2 years (AzA foam n=41, vehicle n=42).6 The

second trial enrolled 401 male and female participants, with a mean age of 48.5±11.9 years (AzA foam n=198, vehicle n=203).7 Efficacy outcomes measured at 12 weeks included therapeutic success (Investigator’s Global Assessment [IGA] scores of clear or minimal), and change from baseline in inflammatory lesion count of papules and pustules (Table I). Additionally, patient response was designated as responder vs non-responder based on IGA score. A responder was defined as achieving an IGA score of clear, minimal, or mild at end of treatment (Table I). In the larger of the two trials, therapeutic success (P=.017) and change in inflammatory lesion count (P<.001) were significantly higher in participants using AzA foam 15% compared with vehicle foam (Table I).7 Adverse events (AEs) in this trial were reported in 34.3% (68/198) and 23.7% (48/203) participants in the AzA foam 15% and vehicle foam groups, respectively.7 Serious AEs were reported in one participant applying AzA foam 15% and in three participants from the vehicle foam group. Pain (AzA nine vs vehicle four events), pruritus (AzA three vs vehicle zero events), and dryness (AzA zero vs vehicle one event) at the application site were reported. Common AEs included headache (4.6%), general pain (3.5%), nasopharyngitis (3.5%) and pruritus (2.0%) in the AzA foam 15% group and nasopharyngitis (3.0%) in the vehicle foam group.7 Phase III Clinical Data A phase III multicenter, randomized, double-blind, vehicle-controlled clinical trial evaluated AzA foam 15% in the treatment of moderate to severe PPR in 961 men and women 18 years of age and older.9 Moderate to severe PPR was defined as 12–50 papules and/or pustules and persistent erythema with or without telangiectasia. Treatment was applied to the face twice daily for 12 weeks, with clinical evaluations at weeks 4, 8, 12, and 16 (4 week follow-

From the Department of Medicine, University of Toronto School of Medicine, Toronto, Ontario, Canada;1 Mediprobe Research Inc., London, Ontario, Canada;2 Department of Medicine, Baylor University Medical Center;3 Departments of Dermatology and Family Practice, University of Texas Southwestern Medical School;4 and Dermatology Treatment and Research Center, Dallas, TX5 Address for Correspondence: Aditya K. Gupta, MD, 645 Windermere Road, London, Ontario, Canada N5X 2P1 • E-mail: agupta@execulink.com

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Table I. Phase II efficacy outcomes at 12 weeks Study 1a,6

Study 27

Azelaic Acid Foam 15% n=41 Therapeutic success

Vehicle n=42

Azelaic Acid Foam 15% n=198

Vehicle n=203

46.3%

47.6%

43.4%*

32.5%

ILC change

–11.7 (8.53)

–10.8 (7.80)

–13.4 (10.39)***

–9.5 (9.73)

Respondera

73.7%

62.9%

69.2%

57.6%

Treatment success: Investigator’s Global Assessment (IGA) scores of clear or minimal. ILC change: mean (standard deviation) change in inflammatory lesion count (ILC) from baseline. Responder: patients achieving an IGA score of clear, minimal, or mild. a No statistical analysis was provided in the clinicaltrials.gov record. *P<.05. ***P<.001: azelaic acid foam significantly different from vehicle.

up). Efficacy endpoints were treatment success, measured using the IGA scale (clear, minimal, mild, moderate, severe) at week 12, and change in inflammatory lesion count from baseline to week 12. IGA scores of clear or minimal (minimum two-step improvement) constituted success.

Table II. Percentage of patients achieving Investigator’s Global Assessment scores of clear or minimal in Phase III trials9 Azelaic Acid Foam 15% (%)

Vehicle (%)

Treatment week

n=484

n=477

12.0***

5.9

21.1

17.6

32.0**

23.5

Follow-up

n =410

n =393

30.3*

23.3

*P<.05. **P<.01. ***P<.001: azelaic acid foam significantly different from vehicle.

The percentage of participants achieving treatment success over the course of treatment is shown in Table II. At weeks 4 (P<0.001), 12 (P=0.003) and 16 (P=0.025), significantly more participants achieved treatment success with AzA foam 15% versus vehicle.9 At all time points, the mean change in inflammatory lesion count from baseline was significantly greater with AzA foam 15% treatment versus vehicle (Table III). AEs were reported by 30.8% (149/484) and 24.9% (119/477) of participants in the AzA foam and vehicle groups, respectively.9 The percentage of participants experiencing cutaneous treatment-emergent AEs was significantly greater in the AzA foam group compared with the vehicle group at weeks 4 (P<0.001), 12 (P=0.003), and 16 (follow-up, P=0.025).9 The most common (treatment-emergent AEs) were application site reactions: pain (AzA 23 vs vehicle six events), pruritus (AzA seven vs vehicle two events), and dryness (AzA five vs vehicle three events). Treatment-emergent AEs leading to withdrawal occurred for three participants in the AzA foam group (two cutaneous reactions, one burning sensation), with withdrawal due to any AE occurring in 1.2% and 2.5% of participants in the AzA foam and vehicle groups, respectively. Nontreatment-related AEs included nasopharyngitis, headache, upper respiratory tract infection, and influenza in the AzA foam group, and nasopharyngitis and headache in the vehicle group.9

Table III. Phase III mean change (standard deviation) in inflammatory lesion count from baseline9 Week Azelaic acid foam 15% Vehicle

16 (Follow-up)

–9.4 (8.7) ***

–11.8 (9.8) ***

–13.2 (9.5) ***

–12.1 (10.9) *

–6.7 (7.8)

–-9.8 (9.2)

–10.3 (9.8)

–9.9 (11.2)

*P=.003. ***P<.001: azelaic acid foam significantly different from vehicle. SKINmed. 2016;14:445–447

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Conclusions AzA 15% foam has been approved by the Federal Drug Administration for the treatment of mild to moderate PPR. Phase II and III clinical trials have demonstrated the safety and efficacy of twice-daily AzA 15% foam for 12 weeks in patients with moderate to severe PPR of the face. AEs associated with AzA 15% foam were minimal and included application site reactions.6–9 Although AzA 15% gel has been an effective treatment for PPR for many years, the approval of a foam formulation introduces a potentially easier mode of application to sensitive skin that could improve patient compliance and quality of life.1 Head to head studies comparing the foam formulation to the gel and to other products approved for rosacea are lacking and would be valuable. For patients and physicians searching for such an alternative, AzA 15% foam is an effective treatment option for rosacea. References

3 Del Rosso JQ, Kircik LH. Update on the management of rosacea: a status report on the current role and new horizons with topical azelaic acid. J Drugs Dermatol JDD. 2014;13:s101–s107. 4 Zhao Y, Jones SA, Brown MB. Dynamic foams in topical drug delivery. J Pharm Pharmacol. 2010;62:678–684. 5 Bayer Healthcare. Product Insert: Finacea (azelaic acid) 15% foam. 2015. https://www.accessdata.fda.gov/ scripts/cder/drugsatfda/index.cfm?fuseaction=Search. Label_ApprovalHistory#labelinfo. Accessed March 1, 2016. 6 Bayer. NCT00617903 Exploration of safety and efficacy of AzA 15% foam twice a day in rosacea. https://clinicaltrials.gov/ct2/show/NCT00617903?term=azelaic+a cid&rank=15. Accessed March 1, 2016. 7 Bayer. NCT01025635 Safety and efficacy of azelaic acid foam, 15% in papulopustular rosacea. https://clinicaltrials.gov/ct2/show/NCT01025635?term=azelaic+acid &rank=11. Accessed March 1, 2016.

1 Moustafa F, Lewallen RS, Feldman SR. The psychological impact of rosacea and the influence of current management options. J Am Acad Dermatol. 2014;71:973–980.

8 Draelos ZD, Elewski B, Staedtler G, Havlickova B. Azelaic acid foam 15% in the treatment of papulopustular rosacea: a randomized, double-blind, vehicle-controlled study. Cutis. 2013;92:306–317.

2 Two AM, Wu W, Gallo RL, Hata TR. Rosacea: part I. Introduction, categorization, histology, pathogenesis, and risk factors. J Am Acad Dermatol. 2015;72:749–58; quiz 759–760.

9 Draelos ZD, Elewski BE, Harper JC, et al. A phase 3 randomized, double-blind, vehicle-controlled trial of azelaic acid foam 15% in the treatment of papulopustular rosacea. Cutis. 2015;96:54–61.

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November/December 2016

Volume 14 • Issue 6

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

Conceptual Confluence: The Marriage of IgG4-Related Disease and Adult-Onset Asthma With Periocular Xanthogranulomas Warren R. Heymann, MD

s medicine evolves, newly described entities challenge our diagnostic concepts. Two such diseases, IgG4-related disease and adult-onset asthma with perioculuar xanthogranulomas, appear to intertwine. Dermatologists should be familiar with these rare disorders. This commentary will explore the dermatologic manifestations and overlapping features of these diseases. IgG4-Related Disease IgG4-related disease (IgG4-RD) is a chronic fibroinflammatory disorder that may affect virtually every organ system. It characteristically affects middle-aged men, although for lesions of the head and neck, there is an equal gender distribution. Swelling of salivary and lacrimal glands, lymphadenopathy, and type 1 autoimmune pancreatitis are the most common manifestations of the disease. Up to about half of all patients are considered atopic, displaying a mild eosinophilia and/or elevated IgE. The histopathology is characterized by lymphoplasmacytic infiltration, which may lead to significant organ dysfunction (notably in the retroperitoneum, kidney, lung, thyroid, and heart, among others). IgG4+ plasma cells, “storiform”-like fibrosis, and obliterative phlebitis are noted histologically.1 Although there are no widely accepted criteria to diagnose IgG4RD, the presence of IgG4+ plasma cells are required to establish the diagnosis (with an IgG4+/IgG4– ratio >40% and >10% IgG4+ plasma cells per high-power field). This finding, however, is not pathognomonic, as such cells may be seen in other inflammatory conditions.2 While an elevated serum IgG4 level (>1.35 g/L) may help confirm the diagnosis, approximately 30% to 50%

of patients have normal serum concentrations, even in those with characteristic histologic findings. Imaging with 18F-fluorodeoxyglucose positron emission tomography/computerized tomography highlights the extent of disease, although it may not distinguish IgG4-RD from other causes of inflammation or malignancy.1 Dermatologic lesions in IgG4-RD have been classified into seven types: types 1 to 3 are considered primary lesions with massive plasma cell infiltrates, and types 4 to 7 are considered secondary eruptions without mass formation by plasma cells. Type 1 represents cutaneous plasmacytosis, which is characterized by hyperpigmented circular to oval papules, nodules, and plaques. The main differential diagnosis is multicentric Castleman disease. Type 2 may appear as a pseudolymphoma or angiolymphoid hyperplasia with eosinophilia. It should be noted that not all such cases are part of the IgG4-RD spectrum. These lesions are usually noted on the head and periauricular region. They need to be differentiated from B-cell lymphomas or other lymphocytic infiltrates. Type 3 includes Mikulicz disease, which is now considered synonymous with IgG4-related dacryoadenitis and sialadenitis. Clinically, this presents as palpebral swelling, exophthalmos, and the sicca syndrome. This should be differentiated from Sjögren syndrome. Type 4 is considered psoriasiform and should be distinguished from psoriasis vulgaris or syphilis. Type 5 presents as variable erythematous macules and papules, which may mimic drug eruptions or toxic erythemas. Type 6 resembles hyperglobulinemic purpura or urticarial vasculitis, requiring differentiation from leukocytoclastic vasculitis, Henoch-Schönlein purpura, or lupus erythematosus. Type 7 appears as an ischemic digit secondary to severe Raynaud disease, requiring differentiation from systemic sclerosis or the antiphospholipid syndrome.3

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

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The pathophysiology of IgG4-RD is poorly understood. Most cases appear to be related to a Th2 cytokine response, with IgG4 production being upregulated by interleukin (IL)-4, IL-5, and IL-13. This could explain the associated elevated levels of IgE and associated eosinophilia in some cases. In addition, patients with IgG4-RD have upregulated responses of regulatory T cells associated with elevated levels of transforming growth factor-β that induce fibrosis.1,3 The actual role of IgG4 in IgG4-RD remains to be defined. The cornerstone of treatment of IgG4-RD is systemic corticosteroids, although other immunosuppressive therapies (eg, mycophenolate mofetil, azathioprine, methotrexate, cyclosporine, and cyclophosphamide) may be considered as steroid-sparing agents. The use of rituximab is most promising. Bortezomib (a proteasome inhibitor) has been reported to be effective. Surgery and radiation therapy may be necessary in select cases.1 Adult Orbital Xanthogranulomatous Disease The differential diagnosis of periorbital noduloulcerative lesions is broad, and included diverse entities such as sarcoidosis, lupus profundus, Mikulicz disease, Sjögren syndrome, Hansen disease, cutaneous T-cell lymphoma, cutaneous B-cell lymphoma, autoimmune thyroid disease, amyloidosis, pyoderma gangrenosum, infectious diseases such as Hansen disease, and one of the variants of adult orbital xanthogranulomatous disease (AOXD). AOXD consists of four subtypes, which may share overlapping clinical features: (1) adult-onset xanthogranulomas may affect any part of the body, including the periorbital region. This variant is self-limited and is not accompanied by asthma or an increased IgG level. (2) Adult-onset asthma with perioculuar xanthogranulomas (AAPOX) is characterized by yellowish nonulcerating nodules, limited to the periorbital region. Asthma usually precedes the lesions with a time span of months to years. Rarely, AAPOX may be associated with a monoclonal gammopathy or myeloma. (3) Necrobiotic xanthogranuloma presents as noduloulcerative lesions and histologic necrobiosis of collagen and is frequently accompanied by a paraproteinemia. (4) Erdheim-Chester disease, in addition to presenting with diffuse eyelid tumors, has systemic involvement (ie, heart, lungs, bones, gastrointestinal tract), which may prove fatal.4 Adult-Onset Asthma With Perioculuar Xanthogranulomas I first learned of AAPOX from Misha Rosenbach at a Duhring conference of the Perelman School of Medicine at the University of Pennsylvania. The patient was a 55-year-old African AmeriSKINmed. 2016;14:449–451

Figure 1. Infiltrated nodules involving the patient’s eyelids. (Photo courtesy of Misha Rosenbach, MD.)

can man with a 35-year history of periorbital nodules, infiltrating all of his eyelids (Figure 1), accompanied by mild periocular pruritus and asthma (which was noted a year after the onset of the lesions). Findings from histologic examination demonstrated prominent follicular lymphoid hyperplasia and a xanthogranulomatous infiltrate with Touton giant cells. The patient was treated with methotrexate, with softening of the lesions appreciated after 3 months of therapy.5 To date, fewer than 30 cases of AAPOX have been reported. It is a rare disease, affecting adults aged 22 to 74 years, with a male to female ratio of 2:1. Aside from the periocular disease, chronic rhinosinusitis, lymphadenopathy, a mild eosinophilia, and elevated IgE may be appreciated. An evaluation of three cases of AAPOX, utilizing immunohistochemical stains for IgG4 and serum IgG4, demonstrated that all three cases were positive for IgG4 in tissue and serum, strongly suggesting that AAPOX could be part of the IgG4-RD spectrum.6 Conclusions On a “micro-” level, it appears that the rare disease AAPOX falls under the diagnostic umbrella of the ever-expanding presentations of IgG4-RD. On a “macro-” level, it is “conceptual confluence” (colloquially, “connecting the dots”) that makes practicing medical dermatology such an invigorating endeavor.

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References 1 Vasaitis L. IgG4-related disease: a relatively new concept for clinicians. Eur J Intern Med. 2016;27:1–9. 2 Lowe GC, Bogner RR, el-Azhary RA, et al. Cutaneous manifestations of immunoglobulin G4-related disease: what dermatologists need to know. Int J Dermatol. 2015;54:377–382. 3 Tokura Y, Yagi H, Yanaguchi H, et al. IgG4-related skin disease. Br J Dermatol. 2014;171:959–967. 4 Minami-Hori M, Takahashi I, Honma M, Ito Y, et al. Adult

orbital xanthogranulomatous disease: adult-onset xanthogranuloma of the periorbital location. Clin Exp Dermatol. 2011;36:628–631. 5 Agi CU, Gober MD, Ferenczi K, et al. A case of adultonset asthma with periocular xanthogranulomas. Arch Dermatol. 2011;147:1230–1231. 6 London J, Martin A, Soussan M, et al. Adult onset asthma and periocular xanthogranuloma (AAPOX), a rare entity with a strong link to IgG4-related disease. Medicine (Baltimore). 2015;94:e1916.

Historical Diagnosis and treatment

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November/December 2016

Volume 14 • Issue 6

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

Psoriasis and Upper Respiratory Infection Mark Bernhardt, MD

saw a movie last night, doesn’t matter which one. There were all these different story lines, and at some point I started to wonder, “How are they going to tie this up into a satisfying, plausible ending?” The answer was simple. They didn’t. The movie just ended. A blank, black screen. Thanks for spending your time and money with us, now pick up your wrapper trash and leave. I know that a major tenet of postmodernism is that life itself does not consist of tidy little endings, but that’s one reason I escape into art! If I wanted frustratingly unresolved dilemmas I could just stay home. Or go to work.

report of Pneumocystis pneumonia in previously healthy men until the isolation of the virus responsible for HIV/AIDS was a mere 714 days. In July 1976, some attendees at a Philadelphia convention developed a mysterious respiratory illness. Only 6 months later a previously unknown bacterium was shown to be the cause of Legionnaires’ disease. Dr Joseph Goldberger might hold the record for fastest resolution of a medical mystery: Within 48 hours of being assigned to the case, he figured out the cause of grain itch, a disease that had stumped doctors for over 60 years!

In June 1916, James Winfield MD of Brooklyn, NY, first recognized psoriasis following upper respiratory infection.1 When do we get to find out why this happens? I should probably focus on those amazing instances where there was a conclusive resolution to a medical conundrum. Sometimes, the search takes centuries. The first written descriptions of syphilis date to 1494, but it took over 400 years before Schaudinn and Hoffman identified the causative organism, Treponema pallidum. Sometimes, the whole process can be compressed into a remarkably brief time span. I think it’s miraculous that from the first

Sometimes, it seems that the solution has to be close at hand: the single point mutation responsible for sickle cell anemia has been known since 1956, but when will we finally be able to correct that coding error? I just hope that one day I will open a journal and find out exactly why strep throat causes psoriasis. Reference 1 Winfield JM. Psoriasis as a sequel to acute inflammation of the tonsils: a clinical note. J Cutan Dis Syph. 1916;34:441–443.

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SKINmed. 2016;14:453

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November/December 2016

Volume 14 • Issue 6

PHOTO CAPSULE

Asymptomatic Swelling on the Inner Surface of the Lower Lip Abhijeet Kumar Jha, MBBS, MD;1 Smita Prasad, MBBS, MD;1 Rajesh Sinha, MBBS, MD;1 Shashikant Kumar, MBBS, MD;2 Nishant Nandan, MBBS1

12-year-old girl presented with asymptomatic swelling on the mucosal surface of the lower lip for 1-year duration. On clinical examination, swelling measuring roughly 1×1.5 cm was noted on the inner surface of the lower lip. On palpation, the lesion was firm, nontender, and noncompressible. Complete blood cell count was within normal limits. Surgical excision was planned. After infiltrating local anesthesia around the lesion, a chalazion clamp was fixed around the lesion with ring portion of the forceps facing the mucosal surface (Figure 1). The lesion was then excised, the chalazion clamp released, and then the skin sutured with a chromic catgut 3-0. Histopathologic examination showed stratified squamous epithelial lining with the subepithelial area showing dilated lymphatics of varying sizes lined by flattened cuboidal epithelium and presence of lymph admixed with neutrophils and eosinophils. All lymphatics were embedded in fibrous stroma; therefore, a diagnosis of cavernous lymphangioma was made (Figures 2 and 3). The patient is being followed up at 6-month intervals to check for recurrence of the lesion. Discussion Lymphangiomas are hamartomatous, congenital malformations of the lymphatic system derived embryologically from five primitive buds developing from the venous system.1 Histologically, lymphangioma comprises mainly three types, depending on the size of the lymphatic channels: cystic (macrocystic), capillary (super-microcystic), and cavernous (microcystic). The cavernous type is rare. The tumor is seated deep beneath the dermis, but the external skin is not involved. Because it is deep-seated, it forms a bulging, painless mass.2 Ultrasonography, computed tomography, and magnet-

Figure 1. Chalazion clamp fixed around the lesion with ring portion of the forceps facing the mucosal surface.

ic resonance imaging can be used to define the relationship of the lesion with the neighboring structures and to help plan surgical strategies.3 Surgical excision is the primary method of treatment.

From the Department of Dermatology, STD and Leprosy,1 and the Department of Pathology,2 All India Institute of Medical Sciences, Patna, Bihar, India Address for Correspondence: Abhijeet Kumar Jha, MBBS, MD, Department of Dermatology, STD and Leprosy, All India Institute of Medical Sciences, Patna, Bihar, India • E-mail: drabhijeetjha@gmail.com

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Figure 3. Subepithelial area showing dilated lymphatics of varying sizes lined by flattened cuboidal epithelium and presence of lymph admixed with neutrophils and eosinophils. All lymphatics are embedded in fibrous stroma (hematoxylin and eosin stain, original magnification ×40).

Figure 2. Stratified squamous epithelial lining with subepithelial area showing dilated lymphatics of varying sizes (hematoxylin and eosin stain, scanner view).

References 1 Singh S, Baboo ML, Pathak LC. Cystic lymphangioma in children: report of 32 cases including lesions at rare sites. Surgery. 1971;69:947–951. 2 Faul JL, Berry GJ, Colby TV, et al. Thoracic lymphangio-

mas, lymphangiectasis, lymphangiomatosis, and lymphatic dysplasia syndrome. Am J Respir Crit Care Med. 2000;161:1037–1046. 3 Kennedy TL, Whitaker M, Pellitteri P, Wood WE. Cystic hygroma/lymphangioma: a rational approach to management. Laryngoscope. 2001;111:1929–1937.

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Volume 14 • Issue 6

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

Simultaneous Occurrence of Papulonecrotic Tuberculid and Erythema Induratum in an Asian Woman Hazel H. Oon, MD; Wei-Sheng Chong, MBBS; Choon Chiat Oh, MBBS; Audrey W. Tan, MBBS; Joyce S. Lee, MBBS; Priya Sen, MBBS; Suat Hoon Tan, MBBS A 31-year-old Indonesian woman presented with a 2-month history of recurrent painful nodules on the legs. Review of systems did not reveal any respiratory, gastrointestinal, or abdominal findings. She had been to Singapore working as a domestic helper for close to a year. There was no contact history of tuberculosis. (SKINmed. 2016;14:457–459)

linical examination revealed large dusky, erythematous, tender subcutaneous nodules and plaques on the shins and calves (Figure 1). There was a second morphologically different eruption comprised of small papulovesicles, pustules, and centrally ulcerating papules on the thighs and left forearm (Figure 2). Results from a skin biopsy of a nodule from the shin showed features of a lobular panniculitis with a mixed neutrophilic and lymphocytic infiltrate (Figure 3A). There was frank vasculitis of small- and medium-sized vessels within the lower part of the dermis and subcutis, with marked fibrinoid necrosis and leukocytoclasis (Figure 3B). Areas of necrosis with nuclear debris were present within the panniculitic areas. These features were consistent with the acute stage of erythema induratum. Histologic findings of a pustule showed a subcorneal collection of neutrophils in association with an underlying wedge-shaped dermal infiltrate (Figure 4A). There was frank leukocytoclastic vasculitis of dermal vessels, exhibiting prominent fibrinoid necrosis and leukocytoclasis in association with some neutrophils and red cell extravasation (Figure 4B). There were also a mixed lymphohistiocytic infiltrate and vasculitis of the blood vessel of the lower part of the dermis (Figure 4C). Loose aggregates of histiocytes with early granuloma formation were seen within the dermis (Figure 4B). Acid-fast bacilli were not detected on ZiehlNeelsen stain.

The patient’s chest x-ray were normal. Findings from smears and cultures for mycobacteria were negative from laryngeal swabs and urine. A Mantoux skin test was strongly positive at 20 mm, and results from T-SPOT.TB test were reactive. A diagnosis of erythema induratum with concurrent papulonecrotic tuberculid, with predominantly vasculitic pathology, was made on clinicopathologic correlation. She was started on antituberculous therapy but was unfortunately lost to follow-up. Discussion Erythema induratum, papulonecrotic tuberculid, and lichen scrofulosorum are the result of immunologic reactions to hematogenously spread antigenic components of Mycobacterium tuberculosis. They are defined by an occult focus of M tuberculosis, high degree of immunologic sensitivity in the host, negative smear findings and mycobacterial culture of cutaneous lesions, and response to antituberculous therapy. Erythema induratum presents with chronic, relapsing, tender nodules and ulcers on the calves. The shins and thighs may be affected, but less commonly reported are the thighs, feet, and buttocks.1 The histology of erythema induratum is characterized by a predominantly lobular panniculitis with a varying combination of vasculitis, granuloma formation, and/or caseation necrosis. A case series of 31 histologic specimens from patients with erythema induratum showed the presence of vasculitis, granulo-

From the National Skin Centre, Singapore Address for Correspondence: Choon Chiat Oh, MBBS, 1 Mandalay Road, Singapore 308205 • E-mail: oh.choon.chiat@singhealth.com.sg

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CASE STUDY matous infiltrate, and caseation necrosis in 87.1%, 74.2%, and 71.0% of the specimens, respectively.2 Two major histologic subtypes of patients with erythema induratum have been described.3 The first group showed focal septolobular panniculitis in close association with a single muscular artery or small vessel and primary neutrophilic vasculitis. The second group revealed diffuse septolobular panniculitis with neutrophilic vasculitis of either large or smaller vessels. Inflammation and necrosis were more extensive in the second group.

Figure 1. Large, tender erythematous nodules on the calf.

In contrast to erythema induratum, lesions of papulonecrotic tuberculid feature small, recurrent crops of erythematous or

Figure 2. Papulonecrotic tuberculid with erythematous papuloulcerative lesions on the thigh (A). Close-up view showing central necrosis of the papule (B).

Figure 3. Erythema induratum. (A) Lobular panniculitis with a mixed neutrophilic and lymphocytic infiltrate in association with vasculitis of small- and medium-sized vessels within the subcutis (hematoxylin and eosin stain, original magnification ×20). (B) Fibrinoid necrosis with destruction of a medium-sized vessel within the subcutis in association with leukocytoclasis and a mixed neutrophilic-lymphocytic infiltrate around and within its walls. Necrosis with nuclear debris can be seen in the top left-hand corner of the photomicrograph (hematoxylin and eosin stain, original magnification ×200). SKINmed. 2016;14:457–459

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CASE STUDY flesh-colored papules with central ulceration, predominantly on the extensors. Characteristically, they heal with varioliform scarring. Histology is dependent on the age of the lesion, with early lesions showing a leukocytoclastic vasculitis with a wedge-shaped infarct,4 while later lesions display lymphohistiocytic vasculitis and poorly formed granulomas with absence of caseation.5 Tuberculids have been reported sporadically to coexist. The most common combination is erythema induratum and papulonecrotic tuberculid. A review of 10 cases from the literature during a 32-year period showed that the affected individuals were generally women originating from countries with endemic tuberculosis.6 The site of predilection for both erythema induratum and papulonecrotic tuberculid was the legs. Results of Mantoux testing were strongly positive in all patients and response to antituberculous treatment was prompt. A noteworthy finding in the majority of patients, with one patient having scrofuloderma and another of tuberculous peritonitis.

Conclusions The combintion of erythema induratum and papulonecrotic tuberculid has been postulated to represent a continuum of disease, with smaller, more superficial vessels involved in papulonecrotic tuberculid. Progression of the hypersensitivity reaction culminates in the deeper lesions of erythema induratum.6 The coexistence of both erythema induratum and papulonecrotic tuberculid in our patient further confirms the clinical and histologic continuum of tuberculid reactions as a disease entity.

References 1 Yi SW, Kim EH, Kang HY, Kim YC, Lee ES. Erythema nodosum: clinicopathologic correlations and their use in differential diagnosis. Yonsei Med J. 2007;48:601–608. 2 Cho KH, Lee DY, Kim CW. Erythema induratum of Bazin. Int J Dermatol. 1996;35:802–808. 3 Schneider JW, Jordaan HF. The histopathologic spectrum of erythema induratum of Bazin. Am J Dermatopathol. 1997;19:323–333.

C Figure 1. Papulonecrotic tuberculid. (A) A subcorneal pustule with a wedge-shaped dermal infiltrate beneath (hematoxylin and eosin stain, original magnification ×20). (B) Frank leukocytoclastic vasculitis with features of fibrinoid necrosis, leukocytoclasis, red cell extravasation, and presence of neutrophils. Located on the right of the inflamed vessel is a poorly formed granuloma consisting of loose aggregates of histiocytes (hematoxylin and eosin stain, original magnification ×200). (C) There is a vessel within the lower part of the dermis exhibiting fibrin exudation in association with an infiltrate of lymphocytes and histiocytes (hematoxylin and eosin stain, original magnification ×200). SKINmed. 2016;14:457–459

4 Morrison JG, Fourie ED. The papulonecrotic tuberculide. From Arthus reaction to lupus vulgaris. Br J Dermatol. 1974;91:263–270. 5 Jordaan HF, Van Niekerk DJ, Louw M. Papulonecrotic tuberculid. A clinical, histopathological, and immunohistochemical study of 15 patients. Am J Dermatopathol. 1994;16:474–485. 6 Chuang YH, Kuo TT, Wang CM, et al. Simultaneous occurrence of papulonecrotic tuberculide and erythema induratum and the identification of Mycobacterium tuberculosis DNA by polymerase chain reaction. Br J Dermatol. 1997;137:276–281.

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November/December 2016

Volume 14 • Issue 6

CASE STUDY

Voriconazole-Induced Subacute Cutaneous Lupus Erythematosus in an Adult With Aspergillosis Navid Ezra, MD;1 Natanel Jourabchi, MD;2 Nico Mousdicas, MD1

A 59-year-old man was treated with voriconazole for chronic invasive aspergillosis and who subsequently developed subacute cutaneous lupus erythematosus (SCLE). The patient presented with a 6-week history of multiple erythematous papulosquamous lesions on his chest, upper and lower extremities, and back (Figure 1). They were nonpruritic and nonpainful. He was afebrile and otherwise well. He had no history of extensive sun exposure prior to the appearance of the eruption. He had been taking voriconazole for about 3 months prior to the onset of lesions. He denied any family history of connective tissue disease. (SKINmed. 2016;14:461–463)

esults from a punch biopsy of a plaque on the back showed a superficial and deep perivascular and interstitial lymphohistiocytic infiltrate (Figure 2). On higher magnification, vacuolar degeneration was evident along the dermal-epidermal junction. Liquefaction degeneration of the basal layer with dyskeratosis was present with dermal mucin deposition. Subsequent workup revealed a positive antinuclear antibody, including positive anti-Ro and anti-La. Anti-histone was negative. Complement levels were within normal limits. These findings were most consistent with a lupus-like reaction. It was recommended that voriconazole be discontinued and the patient’s aspergillosis be treated with an alternative antifungal agent. The lesions subsequently resolved 2 weeks after stopping voriconazole and treatment with topical triamcinolone 0.025% cream. The patient returned to our clinic 6 months later with a similar dermatitis and was found to have the same reaction with posaconazole. He discontinued this medication, as well, and has been eruption-free for 6 months. Discussion Voriconazole is a relatively new triazole antifungal agent with activity against a wide range of systemic fungal pathogens, including Aspergillus spp. Clinical studies have demonstrated efficacy in acute and chronic invasive aspergillosis and oral and esophageal candidosis and in a number of rarer systemic fungal infections.1

Lupus erythematosus–like lesions, induced by voriconazole in children with chronic granulomatous disease, are a rarely reported side effect of voriconazole,2,3 with no reported cases of a lupus-like reaction in adults taking voriconazole for the management of aspergillosis. Invasive aspergillosis (IA) is a fungal infection caused by Aspergillus spp. usually related to primary immunodeficiencies, transplantation, or the use of immunosuppressive medications.4 It affects mainly the pulmonary tract but can involve any organ or system.5 Voriconazole is a relatively new triazole antifungal agent with activity against a wide range of systemic fungal pathogens, including Aspergillus spp. Drug-induced SCLE (DI-SCLE) was first described in 1985, where hydrochlorothiazide was found to be the causative agent in 5 patients with a photodistributed papulosquamous eruption.6 Additional drugs have since been implicated, including angiotensin-converting enzyme inhibitors, calcium channel blockers, terbinafine, and several chemotherapeutic agents.7–11 These patients may or may not have a history of previous SCLE or systemic lupus erythematosus (SLE). Clinically, the presentation of DI-SCLE is similar to that of non–DI-SCLE, characterized by nonscarring annular or papulosquamous lesions in a photodistributed pattern. Unlike in non– DI-SCLE, cutaneous lesions in DI-SCLE resolve on withdrawal of the causative pharmacologic agent.7 Systemic involvement

From the Department of Dermatology, Indiana University School of Medicine, Indianapolis, IN;1 and the Department of Dermatology, Johns Hopkins University School of Medicine, Baltimore, MD2 Address for Correspondence: Navid Ezra, MD, 545 Barnhill Drive, EH 139, Indianapolis, IN 46202 • E-mail: navid.ezra@gmail.com

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Figure 2. Histopathologic findings of subacute cutaneous lupus erythematosus include superficial, deep dermal, and periadnexal inflammation. Vacuolar interface dermatitis and hyperkeratosis are additionally present. Highpower photomicrograph showing liquefaction degeneration of the basal layer with dyskeratosis. A perivascular and periadnexal lymphocytic infiltrate and dermal mucin deposition are present. Hematoxylin and eosin stain, original magnification ×200.

Figure 1. Clinical presentation of subacute cutaneous lupus erythematosus (SCLE) with multiple erythematous papulosquamous lesions on the chest, back, and upper and lower extremities. Classically, SCLE presents as nonscarring annular or papulosquamous lesions in a photodistributed pattern.

may be seen in non–DI-SCLE, but it is rare in DI-SCLE.9 The lateral aspect of the neck, upper portion of the back, chest, and dorsal surface of the arms are the most common areas involved in both types of SCLE. The legs may also be afflicted, with clinical features mimicking small vessel vasculitis.7 Laboratory findings associated with both forms include positive antinuclear antibody and anti-Ro/SS-A antibody test results.8 Association between IA and SLE has been seldom described in adults5,12–14 and children with juvenile SLE.15,16 In addition, retinoid-like phototoxic reactions to voriconazole, resulting in a photodistributed erythema and cheilitis, have been documented in immunosuppressed patients;17–19 however, a lupus-like reaction (discoid lupus) secondary to voriconazole has only been reported in one other patient, an immunocompetent adult.19 Our patient has been taking voriconazole for 3 months for the treatment of invasive pulmonary aspergillosis. Voriconazole has also been reported to induce photoaging,20 phototoxicity,20 photoSKINmed. 2016;14:461–463

sensitivity,21 pseudoporphyria,22 and mucocutaneous retinoid effects.19 Voriconazole is the current treatment of choice for IA,23,24 with liposomal amphotericin B indicated in cases of drug intolerance or refractory disease.4,25 Alternative treatment options include echinocandins26 and itraconazole.16 Typical histopathologic features of SCLE include liquefaction degeneration of the basal layer, a perivascular and periadnexal lymphocytic infiltrate, and dermal mucin deposition. Eosinophils are usually not seen in SCLE. Although initially it was demonstrated that tissue eosinophilia was predictive of drug-induced cutaneous vasculitis and thought that perhaps their presence in SCLE might also be predictive of DI-SCLE,27 a recent study showed that tissue eosinophilia is not a differentiating histopathologic feature of DI-SCLE.28 Careful review of a patient’s drug history in correlation with clinical findings remains the standard for identifying a drug as an etiologic or exacerbating factor in patients with SCLE.

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Conclusions It is unclear in our patient whether voriconazole alone induced these skin changes or whether the voriconazole exacerbated an underlying predisposition to lupus-like reactions. Another plausible hypothesis, separate to that of a lupus-like reaction, is that voriconazole or one of its metabolites has the ability to elicit a phototoxic reaction. This possibility has not been excluded by the current report and should be investigated. Patients taking voriconazole should be warned accordingly and advised to use sun protection when outdoors, should early signs of an erythematous reaction occur. Long-term follow-up of patients taking voriconazole will help to define further the association of this medication with lupus-like reactions. References 1 Jabado N, Casanova JL, Haddad E, et al. Invasive pulmonary infection due to Scedosporium apiospermum in two children with chronic granulomatous disease. Clin Infect Dis. 1998;27:1437–1441. 2 Gomez-Moyano E, Vera-Casano A, Moreno-Perez D, SanzTrelles A, Crespo-Erchiga V. Lupus erythematosus-like lesions by voriconazole in an infant with chronic granulomatous disease. Pediatr Dermatol. 2010;27:105–106. 3 Geller L, Raciti PM, Mercer SE, Phelps RG. Lupus-like lesions in a 28-month-old boy with chronic granulomatous disease on long-term voriconazole prophylaxis. J Cutan Pathol. 2011;38:677–678. 4 Chai LY, Hsu LY. Recent advances in invasive pulmonary aspergillosis. Curr Opin Pulm Med. 2011;17:160–166. 5 Fantini F, Cimaz R. A fatal case of systemic lupus erythematosus complicated by acute pancreatitis, invasive aspergillosis and features of thrombotic thrombocytopenic purpura. Lupus. 2003;12:418–421. 6 Reed BR, Huff JC, Jones SK, et al. Subacute cutaneous lupus erythematosus associated with hydrochlorothiazide therapy. Ann Intern Med. 1985;103:49–51. 7 Callen JP. Drug-induced subacute cutaneous lupus erythematosus. Lupus. 2010;19:1107–1111. 8 Srivastava M, Rencic A, Diglio G, et al. Drug-induced, Ro/SSA-positive cutaneous lupus erythematosus. Archives of dermatology. 2003;139:45-49. 9 Lowe G, Henderson CL, Grau RH, Hansen CB, Sontheimer RD. A systematic review of drug-induced subacute cutaneous lupus erythematosus. Br J Dermatol. 2011;164:465–472. 10 Callen JP, Hughes AP, Kulp-Shorten C. Subacute cutaneous lupus erythematosus induced or exacerbated by terbinafine: a report of 5 cases. Arch Dermatol. 2001;137:1196–1198. 11 Funke AA, Kulp-Shorten CL, Callen JP. Subacute cutaneous lupus erythematosus exacerbated or induced by chemotherapy. Arch Dermatol. 2010;146:1113–1116. 12 Kim HJ, Park YJ, Kim WU, Park SH, Cho CS. Invasive fungal infections in patients with systemic lupus erythema-

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tosus: experience from affiliated hospitals of Catholic University of Korea. Lupus. 2009;18:661–666. 13 Quadrelli SA, Alvarez C, Arce SC, et al. Pulmonary involvement of systemic lupus erythematosus: analysis of 90 necropsies. Lupus. 2009;18:1053–1060. 14 Chen HS, Tsai WP, Leu HS, Ho HH, Liou LB. Invasive fungal infection in systemic lupus erythematosus: an analysis of 15 cases and a literature review. Rheumatology (Oxford). 2007;46:539–544. 15 Canova EG, Rosa DC, Vallada MG, Silva CA. Invasive aspergillosis in juvenile systemic lupus erythematosus. A clinico-pathologic case. Clin Exp Rheumatol. 2002;20:736. 16 Ciftci E, Yalcinkaya F, Ince E, et al. Pulmonary involvement in childhood-onset systemic lupus erythematosus: a report of five cases. Rheumatology (Oxford). 2004;43:587-591. 17 Rubenstein M, Levy ML, Metry D. Voriconazole-induced retinoid-like photosensitivity in children. Pediatr Dermatol. 2004;21:675–678. 18 Vandecasteele SJ, Van Wijngaerden E, Peetermans WE. Two cases of severe phototoxic reactions related to longterm outpatient treatment with voriconazole. Eur J Clin Microbial Infect Dis. 2004;23:656–657. 19 Denning DW, Griffiths CE. Muco-cutaneous retinoideffects and facial erythema related to the novel triazole antifungal agent voriconazole. Clin Exp Dermatol. 2001;26:648–653. 20 Racette AJ, Roenigk HH Jr, Hansen R, Mendelson D, Park A. Photoaging and phototoxicity from long-term voriconazole treatment in a 15-year-old girl. J Am Acad Dermatol. 2005;52:S81–S85. 21 Auffret N, Janssen F, Chevalier P, et al. [Voriconazole photosensitivity: 7 cases]. Ann Dermatol Venereol. 2006;133:330–332. 22 Dolan CK, Hall MA, Blazes DL, Norwood CW. Pseudoporphyria as a result of voriconazole use: a case report. Int J Dermatol. 2004;43:768–771. 23 Suh CH, Jeong YS, Park HC, et al. Risk factors for infection and role of C-reactive protein in Korean patients with systemic lupus erythematosus. Clin Exp Rheumatol. 2001;19:191–194. 24 Herbrecht R, Denning DW, Patterson TF, et al. Voriconazole versus amphotericin B for primary therapy of invasive aspergillosis. New Engl J Med. 2002;347:408–415. 25 Walsh TJ, Anaissie EJ, Denning DW, et al. Treatment of aspergillosis: clinical practice guidelines of the Infectious Diseases Society of America. Clin Infect Dis. 2008;46:327–360. 26 Chandrasekar P. Management of invasive fungal infections: a role for polyenes. J Antimicrob Chemother. 2011;66:457–465. 27 Bahrami S, Malone JC, Webb KG, Callen JP. Tissue eosinophilia as an indicator of drug-induced cutaneous smallvessel vasculitis. Arch Dermatol. 2006;142:155–161. 28 Hillesheim PB, Bahrami S, Jeffy BG, Callen JP. Tissue eosinophilia: not an indicator of drug-induced subacute cutaneous lupus erythematosus. Arch Dermatol. 2012;148:190–193.

Voriconazole-Induced Subacute Cutaneous Lupus Erythematosus

MEDIA PARTNER

November/December 2016

Volume 14 • Issue 6

CASE STUDY

A Yellow Papular Eruption on the Arms, Legs, and Neck: A Rare Masquerader Jeaneen Chappell, MD; Jessica Kozel, MD; M. Yadira Hurley, MD; Claudia I. Vidal, MD, PhD

A 54-year-old Caucasian woman with a medical history of mitral valve prolapse presented with a 5-year history asymptomatic papules. There was no family history of similar lesions. Physical examination revealed >100, 2- to 4-mm, firm, yellow, dermal papules located on the neck, antecubital and popliteal fossae, flexor surface of both forearms, and inner aspect of the thighs (Figure 1). There was no skin laxity. A 4-mm punch biopsy was obtained from the left thigh for histologic examination. Findings showed a focal increase in the concentration of elastic fibers highlighted by Verhoeff Van Gieson stain (Figure 2). There was no fragmentation, calcification, or phagocytosis of elastic fibers. There was also no evidence of actinic elastosis. A section stained with hematoxylin and eosin appeared relatively unremarkable. These findings were consistent with late-onset focal dermal elastosis. (SKINmed. 2016;14:465–466)

n review of the literature, late-onset focal dermal elastosis has an average age of onset of 56 years and an average age of 65 years at diagnosis. A total of 88% of reported cases have been in women (Table). Clinically, it is characterized by yellow papules, often with a cobblestone appearance, that resembles pseudoxanthoma elasticum (PXE). The lesions may be asymptomatic and affect the neck and axillae, similar to PXE; however, unlike PXE, late-onset focal dermal elastosis also involves the flexural surfaces of the arms and legs,

which is thought to be a result of high elastic fiber turnover in those areas. Focal dermal elastosis is associated with a later onset than PXE and usually lacks a family history. In addition, patients with late-onset dermal elastosis lack the systemic involvement seen in PXE.1–5 The histopathologic differential diagnosis for disorders with increased elastic fibers includes pseudoxanthoma elasticum, elastoderma, linear focal elastosis, elastofibroma, nevus elasticus, and

Figure 1. Antecubital fossa showing firm yellow dermal papules.

Figure 2. Verhoeff Van Gieson showing focal increase in elastic fiber concentration (original magnification ×10).

From the Department of Dermatology, Saint Louis University School of Medicine, St. Louis, MO Address for Correspondence: Jeaneen Chappell, MD, 1402 South Grand Boulevard, Saint Louis University School of Medicine, Department of Dermatology, St. Louis, MO 63104 • E-mail: jchappmd@gmail.com

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Table. Reported Cases of Late-Onset Focal Dermal Elastosis Patient, No.

Sex

Mean Age at Onset, y

Mean Age at Diagnosis, y

Tajima et al1

Men/women

Kossard

Women

Limas3

Women

Camacho et al

Women

Current case

Women

Total

88% women

4,a

First familial case reported.

Buschke–Ollendorff syndrome. These conditions can be readily distinguished from each other based on clinical and histologic findings.

awareness of this entity is important, as it can clinically resemble other processes associated with systemic manifestations that are notably absent in these patients.

Histopathologically, biopsies of late-onset dermal elastosis show a focal increase in normal-appearing elastic fibers, best highlighted by the use of special stains. Tissue will lack evidence of calcification and elastolytic change distinguishing this entity from PXE and elastolytic entities. There is also no evidence of actinic elastosis.3,5

References 1 Tajima S, Shimizu K, Izumi T, et al. Late-onset focal dermal elastosis: clinical and histological features. Br J Dermatol. 1995;133:303–305. 2 Kossard S. Pseudoxanthoma-like late-onset focal dermal elastosis. Australas J Dermatol. 2005;46:47–50.

Although the pathogenesis of the disease is unknown, it has been suggested that it may be related to the aging process, which has a similar dense elastin network. Molecular examination of fibroblasts in lesional skin showed increased production of elastin messenger RNA. Additionally, lesional skin showed increased staining with monoclonal bovine alpha-elastin antibody and had increased isodesmosine content.6 These findings support the presence of mature elastic fibers in the dermis.

3 Limas C. Late onset focal dermal elastosis: a distinct clinicopathologic entity? Am J Dermatopathol. 1999;21:381–383.

Conclusions

6 Tajima S, Tanaka N, Ohnishi Y, et al. Analysis of elastin metabolism in patients with late-onset focal dermal elastosis. Acta Derm Venereol. 1999;79:285– 287.

Late-onset focal dermal elastosis is a rare disorder, with our patient being the eighth reported isolated case. We believe that

4 Camacho D, Machan S, Pielasinski U, et al. Familial acral localized late-onset focal dermal elastosis. Am J Dermatopathol. 2012;34:310–314. 5 Lewis KG, Bercovitch L, Dill SW, et al. Acquired disorders of elastic tissue: part I. Increased elastic tissue and solar elastotic syndromes. J Am Acad Dermatol. 2004;51:1–21.

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A Yellow Papular Eruption

November/December 2016

Volume 14 • Issue 6

CASE STUDY

Multiple Familial Trichoepithelioma Successfully Treated With CO2 Laser and Imiquimod Jean S. McGee, MD, PhD; Mark F. Suchter, MD; Sandy S. Milgraum, MD

A 33-year-old woman presented with more than 100 flesh-colored papules and nodules centrally located on the face (Figure 1). Since their first appearance at the age of 7, the lesions had increased in number and spread laterally from the nasolabial folds. She underwent surgical removal at age 10 with recurrence afterward. Her mother, maternal grandmother, and maternal great aunt have similar lesions on the face. Histopathologic examination confirmed the diagnosis of trichoepitheliomas and multiple familial trichoepithelioma (MFT). (SKINmed. 2016;14:467–468)

nitially, one lesion was selected and anesthetized using 2% lidocaine with 1:100,000 epinephrine. Several passes were performed with continuous wave carbon dioxide (CO2) laser (Ultrapulse 5000C; Lumenis, Yokneam, Israel), using a 2-mm defocused beam at 4 W to 6 W power until the lesion was flush with the surrounding skin. The char was removed with 3% hydrogen peroxide. The lesion recurred after 1 month. At this time, we decided to treat another lesion with the CO2 laser as described above and apply imiquimod 5% cream 5 nights weekly. After 1 month, the lesion remained flat. The patient subsequently underwent CO2 laser treatment on all lesions along with imiquimod application. At 3 months, her improvement continued with no recurrence (Figure 2). Discussion MFT is an autosomal dominant skin disease characterized by numerous trichoepitheliomas centrally located on the face. These lesions are benign tumors of the pilosebaceous unit and result from mutations of the CYLD gene on chromosome 16q12-q13.1 The defect in CYLD was first implicated in familial cylindromatosis and Brooke-Spiegler syndrome, conditions that share similar phenotypic presentations. MFT lesions were initially described more than 100 years ago2; however, there is still not an effective treatment regimen.

Consequently, MFT runs a chronic, relapsing course with extensive facial disfigurement. The pathogenesis of the disease is not well understood, rendering it difficult to develop evidence-based treatment strategies. In the past, it was speculated that defects of tumor suppressors in the region of chromosome 9p21 drive tumorogenesis.3 Recently, mutations in the CYLD gene have been shown to result in tumor necrosis factor–induced nuclear factor κB activation, leading to cell proliferation and inflammation.1 Currently, treatment options are limited and rely heavily on invasive procedures, such as dermabrasion, surgical excision, electrodessication, cryotherapy, electrosurgery, and laser therapy (pulse dye, CO2, and argon).4–6 Although all of these procedures have shown minimal success. Patients typically undergo multiple surgical procedures due to local recurrence. Radiation therapy, though noninvasive, carries an inherent risk of cutaneous cancer development.7 Immunomodulating agents, such as imiquimod and adalimumab, have had variable success.8,9 Recently, a combination of imiquimod and tretinoin has shown some efficacy in preventing recurrence over a 3-year treatment duration.10 We present a case of MFT successfully treated with CO2 laser and imiquimod. Our treatment regimen yielded an excellent

From the Department of Dermatology, Robert Wood Johnson University Hospital, New Brunswick, NJ Address for Correspondence: Jean S. McGee, MD, PhD, Department of Dermatology, Robert Wood Johnson University Hospital, One World’s Fair Drive, Suite 2400, Somerset, NJ 08873 • E-mail: jeanmcgee@gmail.com

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Figure 1. Pretreatment photograph showing the extent of multiple familial trichoepithelioma lesions in a patient.

Figure 2. Photograph taken 3 months after the last carbon dioxide laser treatment in the same patient.

outcome in a short amount of time and should be considered for patients with severe cases of MFT. The CO2 laser therapy provides an immediate effect, while imiquimod is essential in preventing recurrence. It remains unclear whether imiquimod can serve as a viable long-term therapy for recurrence prevention.

3 Harada H, Hashimoto K, Ko MSH. The gene for multiple familial trichoepithelioma maps to chromosome 9p21. J Invest Dermatol. 1996;107:41–43.

Figure 2. Photograph taken 3 months after the last CO2 laser treatment.  Figure 1. Pre‐treatment photograph showing the extent of MFT lesions.

Conclusions To our knowledge, this is the first successful case reported in the literature of MFT showing a dramatic, persistent response to treatment with continuous wave CO2 laser and imiquimod. The regimen may serve as a viable first-line therapy for severe, treatment-resistant cases. References 1 Zhang XJ, Liang YH, He PP, et al. Identification of the cylindromatosis tumor-suppressor gene responsible for multiple familial trichoepithelioma. J Invest Dermatol. 2004;122:658–664. 2 Brook HG. Epithelioma adenoids cysticum. Br J Dermatol. 1892;4:269–287.

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4 Rosenbach A, Alster TS. Multiple trichoepitheliomas successfully treated with a high-energy, pulsed carbon dioxide laser. Dermatol Surg. 1997;23:708–710. 5 Chaffelburg M, Miller R. Treatment of multiple trichoepithelioma with electrosurgery. Dermatol Surg. 1998;24:1154–1156. 6 Duhra P, Paul JC. Cryotherapy for multiple trichoepithelioma. J Dermatol Surg Oncol. 1998;14:1413–1415. 7 Aygun C, Blum JE. Trichoepithelioma 100 years later: a case report supporting the use of radiotherapy. Dermatology. 1993;187:209–212. 8 Alessi SS, Sanches JA, de Oliveira WR, et al. Treatment of cutaneous tumors with topical 5% imiquimod cream. Clinics (Sao Paulo). 2009;64:961–966. 9 Fisher GH, Geronemus RG. Treatment of multiple familial trichoepitheliomas with a combination of aspirin and a neutralizing antibody to tumor necrosis factor alpha: a case report and hypothesis of mechanism. Arch Dermatol. 2006;142:782–783. 10 Urquhart JL, Weston WL. Treatment of multiple trichoepitheliomas with topical imiquimod and tretinoin. Pediatr Dermatol. 2005;22:67–70.

Multiple Familial Trichoepithelioma

November/December 2016

Volume 14 • Issue 6

CASE STUDY

Cutaneous Presentation of Angioimmunoblastic T-Cell Lymphoma: A Harbinger of Poor Prognosis? Luokai Wang, MBBS, MRCP; Haur Yueh Lee, MBBS, MRCP; Hong Yi Koh, MBBS, MRCP; Inny Busmanis, MBBS, FRCPA; Yuh Shan Lee, MBBS, MRCP

A 62-year-old woman presented with a 2-year history of extensive, pruritic dermatosis over her face, trunk, and limbs. She was initially treated for psoriasis with methotrexate 5 mg twice weekly and topical clobetasol cream; however, her condition worsened, and she was admitted for generalized exfoliative dermatitis. Examination showed generalized erythema and scaling affecting her face (Figure 1A), chest (Figure 1B), back, and limbs. There were also cervical, axillary, and inguinal lymphadenopathy. Laboratory studies revealed a high white blood cell count of 125×109/L (reference range: 4–10×109/L), hemoglobin level of 11.9 g/dL (reference range: 12–16 g/dL), and normal platelet level of 396×109/L (reference range: 140–440×109/L). Results from direct Coombs test were negative and lactate dehydrogenase levels were normal. (SKINmed. 2016;14:469–471)

esional skin histology showed a superficial dermal infiltrate (Figure 2A), which was predominantly composed of CD2-, CD3-, and CD5-positive T cells with reduced expression of CD7, CD4, and CD8. There was no epidermotropism (Figure 2A). Results from double immunostaining illustrated the atypical cell population to be CD2 T-cell marker– positive, with approximately 40% of the population also positive with proliferation marker MIB-1 (Figure 2B). Findings from an excisional biopsy of the left cervical lymph node revealed diffuse architectural effacement by extensive lymphocytes with irregular nuclei and pale cytoplasm centered in expanded paracortical regions with numerous high endothelial venules. They were positive for CD2, CD3, and CD5. There was also the presence of CD7/8 T cells as well as restriction of Epstein-Barr virus (EBV)–encoded RNA expression to a minor scattered population of lymphocytes. There was an extensive meshwork of disrupted, CD21 immunoreactive follicular den-

dritic cells. These findings were consistent with angioimmunoblastic T-cell lymphoma (AITL) with cutaneous involvement. The patient was initially started on a cyclophosphamide, doxorubicin, vincristine, prednisolone (CHOP) regimen; however, she experienced multiple episodes of relapses characterized clinically by exfoliative dermatitis and histologically by the persistence of the atypical lymphoid cells despite switching to other chemotherapy regimens such as etoposide, doxorubicin, cyclophosphamide, vincristine (EPOCH), and then parabinostat/velcade. She is currently maintained on prednisolone and cyclosporine for refractory AITL. Discussion AITL is a distinct peripheral T-cell lymphoma and currently accounts for 18% of peripheral T-cell lymphomas globally.1 Common clinical features include generalized lymphadenopathy, B symptoms, hepatosplenomegaly, pleural effusion, ascites, and

From Singapore General Hospital, Singapore Address for Correspondence: Luokai Wang, MBBS, MRCP, Service Registrar, Dermatology Unit, Singapore General Hospital, Outram Road, Singapore 169608 • E-mail: wangluokai@gmail.com

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Figure 2. (A) Diffuse, superficial dermal infiltrate, without any evidence of epidermotropism (hematoxylin and eosin stain, ×4). (B) Findings from double immunostaining illustrating the atypical cell population to be CD2 T-cell marker–positive (brown), with approximately 40% of the population also positive with proliferation marker MIB-1 (red) (hematoxylin and eosin stain, ×20).

single or multiple nodular or interstitial foci of infiltration composed of a mixed composition of T and B cells.4

Figure 1. Erythema and scaling involving the (A) face and (B) chest.

polyarthritis/arthralgia.2 Laboratory features include anemia, positive Coombs test, lymphopenia, hypergammaglobulinemia, hypereosinophilia, elevated serum lactate, and erythrocyte sedimentation rate.3 Bone marrow involvement can appear as small SKINmed. 2016;14:469–471

Lymph node biopsy is the diagnostic gold standard. Histologic findings include prominent vascularization by arborizing venules, expansion of CD21+ follicular dendritic cell networks, and the malignant T-cell population expressing CD4, CD10, BCL6, and CXCL13. Expansion of B cells infected with EBV is common and associated cytogenetic findings include additional X chromosome, aberrations in the short arm of chromosome 1, or trisomy 5.5 Approximately 50% of AITL patients have skin dermatitis, which is predominantly maculopapular at the point of diagnosis and/or at relapse.6 The eruption is often misdiagnosed as viral/

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drug exanthems or other inflammatory dermatoses. Less common features include erythroderma, purpura, urticaria, nodules, or petechiae.7 Common histopathologic features include: (1) dense atypical lymphocytic infiltrate in the papillary and reticular dermis, (2) superficial perivascular lymphocytic and eosinophilic infiltrate with atypia, (3) mild superficial perivascular infiltrate with lymphocytic atypia, and (4) leukocytoclastic vasculitis.6 Common molecular findings include T-cell receptor gene rearrangement and B-cell clonal immunoglobulin heavy chain gene arrangement.7

References

AITL is an aggressive neoplasm and results with conventional chemotherapy are not satisfactory. The median survival is less than 3 years in most studies, even when treated intensively.8 Factors such as age, B symptoms, stage, pruritus, lactate dehydrogenase, hemoglobin, and cytogenetic findings have been reported to affect prognosis.9 In addition, the pathologic prognosis using histologic patterns, morphologic grade, proportion of transformed large cells, presence of CD10, CXCL13, and EBV-encoded RNA positivity and clonality for T-cell receptor and B-cell clonal immunoglobulin heavy chain gene rearrangement were not successful in predicting survival.10 Currently, it is controversial whether cutaneous involvement portends a poor prognosis in AITL. While some studies have shown significantly shorter median survival, others have demonstrated that cutaneous involvement did not affect prognosis.7 Conclusions Our patient exemplifies three important features of AITL: (1) dermatitis as a predominant feature of disease relapse, (2) cutaneous involvement of AITL is common and may mimic a variety of inflammatory skin dermatosis, and (3) the aggressive nature of the disease even with conventional and trial chemotherapy.

1 Rudiger T, Weisenburger DD, Anderson JR, et al. Peripheral T-cell lymphoma (excluding anaplastic large-cell lymphoma): results from the Non-Hodgkin’s Lymphoma Classification Project. Ann Oncol. 2002;13:140–149. 2 de Leval L, Gisselbrecht C, Gaulard P. Advances in the understanding and management of angioimmunoblastic T-cell lymphoma. Br J Hematol. 2010;148:673–689. 3 Alizadeh AA, Advani RH. Evaluation and management of angioimmunoblastic T-cell lymphoma: a review of current approaches and future strategies. Clin Adv Hematol Oncol. 2008;6:899–909. 4 Sakai H, Tanaka H, Katsurada T, et al. Angioimmunoblastic T-cell lymphoma initially presenting with replacement of bone marrow and peripheral plasmacytosis. Intern Med. 2007;46:419–424. 5 Schlegelberger B, Zwingers T, Hohenadel K, et al. Significance of cytogenetic findings for the clinical outcome in patients with T-cell lymphoma of angioimmunoblastic type. J Clin Oncol. 1996;14:593–599. 6 Martel P, Laroche L, Courville P, et al. Cutaneous involvement in patients with angioimmunoblastic lymadenopathy with dysproteinemia: a clinical, immunohistological, and molecular analysis. Arch Dermatol. 2000;136:881– 886. 7 Balaraman B, Conley JA, Sheinbein DM. Evaluation of cutaneous angioimmunoblastic T-cell lymphoma. J Am Acad Dermatol. 2011;65:855–862. 8 Vose J, Armitage J, Weisenburger D. International peripheral T-cell and natural killer/T-cell lymphoma study: pathology findings and clinical outcome. J Clin Oncol. 2008;26:4124–4130. 9 Iannitto E, Ferreri AJ, Minardi V, et al. Angioimmunoblastic T-cell lymphoma. Crit Rev Oncol Hematol. 2008;68:264–271. 10 Tan LH, Tan SY, Tang T, et al. Angioimmunoblastic T-cell lymphoma with hyperplastic germinal centres (pattern 1) shows superior survival to patterns 2 and 3: a metaanalysis of 56 cases. Histopathology. 2012;60:570–585.

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November/December 2016

Volume 14 • Issue 6

CASE STUDY

Inflamed Actinic Keratoses After Pemetrexed Michael C. Cameron, BS;1 Andrea L. Suárez, MD, PhD;2 Mark G. Kris, MD;3 Patricia L. Myskowski, MD4

A 66-year-old man presented with a 1-day history of a mildly pruritic eruption on the face, chest, arms, and upper part of the back. The dermatitis began 3 weeks after receiving an initial infusion of pemetrexed (500 mg/m2) as induction chemotherapy for non-small cell lung cancer. Physical examination revealed numerous erythematous, scaly papules over the face, extensor surface of the arms, hands, and upper aspects of the chest and back, sparing sun-protected areas (Figure). He acknowledged that in the past he frequently went shirtless outdoors and rarely wore sunscreen or sun protective clothing during the many years he worked at construction sites. Results from a biopsy specimen from a typical lesion on the forearm revealed an inflamed actinic keratosis. Systemic chemotherapy was continued, and only emollients and mid-potency topical steroids were used to treat the skin eruption. At 2-week follow-up, the patient’s eruption was greatly diminished with loss of significant erythema and scale, as well as absence of pruritus. (SKINmed. 2016;14:473–474)

ystemic chemotherapy–induced inflammation of actinic keratoses (AKs) was first described in patients receiving systemic 5-flurouracil therapy.1,2 The eruption is limited to sun-exposed areas, typically occurring in patients with preexisting subclinical AKs and a history of sun damage. Because the keratinocytes comprising an AK exhibit increased DNA synthesis, some hypothesize that chemotherapy-induced inflammation of AKs is due to selective targeting of these atypical keratinocytes by the drug.3 Others postulate that it is an idiosyncratic drug hypersensitivity with direct activation of an acute inflammatory reaction strictly localized to previously irradiated skin.4 Pemetrexed is approved by the US Food and Drug Administration for primary unresectable mesothelioma and non-small cell lung cancer. Pemetrexed-related cutaneous adverse reactions are common and are likely related to the drug’s direct cytotoxicity to epidermal and endothelial cells rather than an indirect immune reaction.5 While “rash” was the most common nonhematologic adverse effect of pemetrexed in phase II and III studies, the nature of cutaneous toxicities was not specified. Subsequent reports of cutaneous toxicities range from benign conditions, such as alopecia, to potentially fatal toxic epidermal necrolysis, which would necessitate cessation of the drug.5 To date, there are no reported cases of pemetrexed-associated inflamed AKs.

Figure. Eruption of erythematous, scaly papules following pemetrexed therapy.

Conclusions Systemic chemotherapy can cause inflammation in existing AKs, which typically occurs in patients with preexisting subclinical AKs and a history of sun damage. “Rash” is the most common nonhematologic adverse effect reported with pemetrexed chemotherapy. To date, there are no reports documenting

From the University of South Florida Morsani College of Medicine, Tampa, FL;1 the Department of Dermatology, New YorkPresbyterian Hospital/Weill Cornell Medical College, New York, NY;2 and the Thoracic Oncology Service3 and Dermatology Service,4 Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY Address for Correspondence: Andrea L. Suarez, MD, PhD, Department of Dermatology, Weill Cornell Medical College, 1305 York Avenue, New York, NY 10021 • E-mail: als9123@nyp.org

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pemetrexed-induced inflamed AKs. Our case demonstrates that inflamed actinic lesions may be managed effectively with topical corticosteroids and do not require cessation of the patient’s cancer treatment. References 1 Falkson G, Schulz EJ. Skin changes in patients treated with 5-fluorouracil. Br J Dermatol. 1962;74:229–236. 2 Chambers CJ, Liu H, White CR, White KP, Sharon VR. Eruptive purpuric papules on the arms; a case of

chemotherapy-induced inflammation of actinic keratoses and review of the literature. Dermatol Online J. 2014;20:21246. 3 Pearse AD, Marks R. Actinic keratoses and the epidermis on which they arise. Br J Dermatol. 1977;96:45–50. 4 Hardwick N, Murray A. Inflammation of actinic keratoses induced by cytotoxic drugs. Br J Dermatol. 1986;114:639–640. 5 Pierard-Franchimont C, Quatresooz P, Reginster MA, Pierard GE. Revisiting cutaneous adverse reactions to pemetrexed. Oncol Lett. 2011;2:769–772.

Pogonology

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Volume 14 • Issue 6

CASE STUDY

Pilomatrix Carcinoma Mimicking a Pigmented Basal Cell Carcinoma Jaimie B. Glick, MD; Usha Alapati, MD; Amor Khachemoune, MD

A 76-year-old Caucasian man presented to the dermatology clinic for evaluation of a growing lesion in his right preauricular area. He first noticed the lesion several months prior to presentation but felt it had enlarged significantly in the past month. He denied any pain, pruritus, or bleeding. His medical history was significant for melanoma of the nose treated 47 years ago, hypertension, hyperlipidemia, chronic obstructive pulmonary disease, and chronic back pain. The patient reported having the melanoma treated but was unaware of any other details concerning the lesion. He denied any allergies and his medications included lisinopril, amlodipine, gabapentin, and budesonide. (SKINmed. 2016;14:475–477)

hysical examination demonstrated a 6×5-mm pink to purple papule with rolled borders located in the right preauricular region. There was a small ulceration at the lower anteroinferior region of the papule (Figure 1). No lymphadenopathy was noted. Clinically, the lesion appeared as a pigmented basal cell carcinoma.

ages of 5 and 15 with a female predominance of 1.5:1.2 In contrast, pilomatrix carcinomas are more common in men and typically present in the fifth to seventh decade of life.3–6 Pilomatrix carcinomas have also been reported in children.7 Tumors most often present on the head and neck followed by the trunk and extremities.3,5,6

A tangential biopsy using shave technique was performed and revealed a poorly circumscribed asymmetric, proliferation of basaloid cells with aggregates of eosinophilic ghost cells (Figure 2A and 2B). There was marked cytologic atypia and numerous mitoses consistent with a pilomatrix carcinoma (Figure 3). No perineural or intravascular invasion was noted. The patient underwent Mohs micrographic surgery with one stage to obtain clear margins. He remains disease-free 1 year after surgery and continues to undergo regular skin examinations every 6 months.

Although the pathogenesis of pilomatrix carcinoma has not been fully elucidated, some authors suggest a role for UV radiation and actinic damage given the increased prevalence in older white patients.5 There have been several cases of pilomatrix carcinoma arising in an existing pilomatricoma or a previously excised pilomatricoma,8,9 although most appear de novo. Both pilomatricoma and pilomatrix carcinoma have been associated with mutations in exon 3 of CTNNB1, a gene that encodes beta-catenin, a signal transduction protein in the WNT-signaling pathway.10,11

Discussion Pilomatrix carcinoma, also referred to as a matrichal carcinoma or malignant pilomatrixoma, is a rare malignant variant of pilomatrixoma first described by Lopansri and Mihm in 1980.1 Pilomatrixoma and pilomatrix carcinoma are adnexal neoplasms that differentiate towards the cells of the hair matrix. Pilomatrixomas occur more frequently in young patients between the

Pilomatrix carcinomas are often clinically misdiagnosed and can appear as papules or cyst-like subcutaneous nodules.3,5 The differential diagnosis is broad and includes pilomatrixoma, tricholemmal cyst, and basal cell carcinoma. Our patient’s lesion appeared clinically as a pigmented and ulcerated basal cell carcinoma. In a case series of 13 pilomatrix carcinomas, no tumor was accurately diagnosed clinically, although malignancy was considered

From the Department of Dermatology, Department of Veterans Affairs, New York Harbor Healthcare System, Brooklyn Campus, Brooklyn, NY Address for Correspondence: Jaimie Glick, MD, Department of Dermatology, Department of Veterans Affairs, New York Harbor Healthcare System, Brooklyn Campus, 800 Poly Place, Brooklyn, NY 11209 • E-mail: jaimiebg@gmail.com

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Figure 1. A 6×5-mm ulcerated papule with rolled borders in the right preauricular region initially thought to be a pigmented basal cell carcinoma.

Figure 3. Basaloid cells with cytologic atypia, pleomorphism, and numerous mitotic figures (hematoxylin and eosin stain, original magnification ×40).

in 15% of cases.5 The final diagnosis of pilomatrix carcinoma is usually made with skin biopsy and histopathological confirmation. Pilomatrix carcinomas are poorly circumscribed neoplasms of the dermis that demonstrate an infiltrative growth pattern and are often ulcerated. Tumors are composed of irregular basaloid cells with prominent nucleoli and frequent mitoses. Ghost cells, also referred to as shadow cells, containing pale eosinophilic cytoplasm and degenerated nuclear outlines, are present as in pilomatricomas. Tumor cells may be surrounded by a desmoplastic stroma with foci of necrosis. Histologically, a pilomatrix carcinoma can resemble other adnexal neoplasms and must be distinguished from a pilomatrixoma, basal cell carcinoma with matrichal differentiation, trichoepithelioma, and sebaceous carcinoma.3

Tumors have a high risk of local recurrence, with reports ranging from 23%5 to as high as 60%.12 In a review of 136 pilomatrix carcinomas, metastasis occurred in 17 cases, with tumor recurrence being the greatest risk factor for metastasis.5 Time to metastasis ranged from 1 to 60 months.5 Metastases most commonly occur in the lymph nodes but have also been reported in the lungs, brain, bones, and visceral organs.3,5,6,13,14 B Figure 2. (A) Initial biopsy demonstrating an ulcerated illdefined nodule of basaloid cells adjacent to pink islands (hematoxylin and eosin stain, original magnification ×4). (B) Eosinophilic ghost cells surrounded by aggregates of basaloid cells (hematoxylin and eosin stain, original magnification ×10). SKINmed. 2016;14:475–477

Most authors suggest wide local excision for the treatment of pilomatrix carcinoma3–5; however, due to the high likelihood of recurrence, Mohs micrographic surgery has been considered as an alternative treatment.4–6 In addition to our case, there have been at least two reports of successful treatment of pilomatrix carcinoma with Mohs micrographic surgery in the literature.4,6

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CASE STUDY

Recurrent lesions as well as metastatic lesions can be treated with radiation therapy.3,5,6,15

pilomatrix carcinoma: a case report of successful treatment with Mohs micrographic surgery and review of the literature. Dermatol Surg. 2011;37:1798–1805.

Conclusions

7 Joshi A, Sah SP, Agrawal CS, et al. Pilomatrix carcinoma in a child. Acta Derm Venereol. 1999;79:476–477.

Pilomatrix carcinoma is a rare malignant tumor derived from follicular matrix cells and most commonly occurs in white middle-aged to elderly men. Clinically, lesions can have varied morphology, and histopathology is diagnostic. Dermatologists and dermatopathologists should be aware of the occurrence of pilomatrix carcinomas due to their clinical complexity, likelihood to recur, and potential to metastasize.

8 Sassmannshausen J, Chaffins M. Pilomatrix carcinoma: a report of a case arising from a previously excised pilomatrixoma and a review of the literature. J Am Acad Dermatol. 2001;44:358–361.

References 1 Lopansri S, Mihm MC Jr. Pilomatrix carcinoma or calcifying epitheliocarcinoma of Malherbe: case report and review of literature. Cancer. 1980;45:2368–2373. 2 Julian CG, Bowers PW. A clinical review of 209 pilomatricomas. J Am Acad Dermatol. 1998; 39:191–195. 3 Cornejo KM, Deng A. Pilomatrix carcinoma: a case report and review of the literature. Am J Dermatopathol. 2013;35:389–394. 4 Sable D, Snow SN. Pilomatrix carcinoma of the back treated by mohs micrographic surgery. Dermatol Surg. 2004;30:1174–1176. 5 Herrmann JL, Allan A, Trapp KM, et al. Pilomatrix carcinoma: 13 new cases and review of the literature with emphasis on predictors of metastasis. J Am Acad Dermatol. 2014;71:38–43. 6 Melancon JM, Tom WL, Lee RA, et al. Management of

9 Nishioka M, Tanemura A, Yamanaka T, et al. Pilomatrix carcinoma arising from pilomatricoma after 10-year senescent period: immunohistochemical analysis. J Dermatol. 2010;37:735–739. 10 Lazar AJ, Calonje E, Grayson W, et al. Pilomatrix carcinomas contain mutations in CTNNB1, the gene encoding beta-catenin. J Cutan Pathol. 2005;32:148–157. 11 Hassanein AM, Glanz SM. Beta-catenin expression in benign and malignant pilomatrix neoplasms. Br J Dermatol. 2004;150:511–516. 12 Chen KT, Taylor DR Jr. Pilomatrix carcinoma. J Surg Oncol. 1986;33:112–114. 13 Niedermeyer HP, Peris K, Hofler H. Pilomatrix carcinoma with multiple visceral metastases. Report of a case. Cancer. 1996;77:1311–1314. 14 Autelitano L, Biglioli G, Migliori G, Colletti G. Pilomatrix carcinoma with visceral metastases: case report and review of the literature. J Plast Reconstr Aesthet Surg. 2009;62:574–577. 15 Bhasker S, Bajpai V, Bahl A, et al. Recurrent pilomatrix carcinoma of scalp treated by electron beam radiation therapy. Indian J Cancer. 2010;47:217–219.

“Candidiasis bei Diabetes”, Moulage No. 171, made by Lotte Volger in 1930 in the Clinic for Dermatology Zurich. Museum of Wax Moulages Zurich, www.moulagen.ch Courtesy of Michael Geiges, MD SKINmed. 2016;14:475–477

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Volume 14 • Issue 6

correspondence Snejina Vassileva, MD, PhD, Section Editor

Neurofibromatosis Type 1 and Vitiligo, a Rare Association Clarissa Prieto Herman Reinehr, MD;1 Vinícius Prieto Herman Reinehr, MD;2 Tania Cestari, PhD1 To the Editor: We report the case of a 33-year-old man with neurofibromatosis type 1 (NF1), diagnosed in childhood, that was associated with vitiligo lesions, a rare combination described in only four previous reports.1–4 NF1 is a phakomatosis that has well-established diagnostic criteria,5 occurring with an incidence of 1 per 3000 births. Vitiligo affects 0.5% to 2% of the world population and is characterized by depigmented lesions of multifactorial etiology.6,7 The patient’s family history was negative for NF1. Clinical examination revealed multiple neurofibromas with axillary and inguinal freckling (Figure 1). The patient also had achromic lesions, best seen on Wood’s lamp examination, that were located on the left wrist and on the back of the left hand (Figure 2). He had strabismus in the right eye as a sequela of meningitis in childhood, with no other abnormalities. Blood pressure was

within normal limits. Laboratory test results, including thyroid function and antithyroid antibodies, were normal. Abdominal and thyroid ultrasonographies were unremarkable. DISCUSSION NF1 is an autosomal dominant disease that mainly affects the skin and central nervous system. About 30% to 50% of NF1 cases are the result of a new mutation, which explains the negative family history in the present case.5 The association of NF1 with benign and malignant tumors is well established. The NF1 gene is located on chromosome 17q11.2 and acts as a tumor suppressor in several organs and tissues, including Schwann cells, fibroblasts, and melanocytes.2 Although autoimmunity plays a role in NF1, the product of the NF1 gene, neurofibromin, acts as a negative regulator of the Ras

Figure 1. Patient with multiple neurofibromas on the trunk (A) and axillary freckles (B), typical features of neurofibromatosis type 1.

From the Department of Dermatology, University of Rio Grande do Sul, Hospital de Clinicas de Porto Alegre, Brazil; and Private Practice, Feliz, Rio Grande do Sul, Brazil Address for Correspondence: Clarissa Prieto Herman Reinehr, MD, Jari Street 735/1002, Passo D’Areia, Porto Alegre, RS, Brazil, CEP: 91350-170 • E-mail: cla.reinehr@gmail.com

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Correspondence activity.8 Furthermore, skin areas affected by vitiligo show a Th1 cytokine profile (interferon-γ, tumor necrosis factor-α, and interleukin-8).7 A review of the literature found only four studies describing vitiligo associated with NF1.1–4 Current knowledge does not allow us to state whether this association is only a casual finding or whether it represents a convergence point in the pathogenesis of these dermatoses, as is suspected for other immune-related disorders previously described in patients with vitiligo. The authors report this case due to the rarity of this association and to bring out the need for further studies to clarify this issue.

Figure 2. Achromic lesions on the left wrist and on the back of the left hand.

References

pathway and a regulator of T-cell apoptosis, which, if not regulated, may lead to the development of autoimmune diseases.2 Autoimmune diseases associated with NF1 include alopecia areata, multiple sclerosis, systemic lupus erythematosus, membranous glomerulonephritis, IgA nephropathy, mixed connective tissue disease, juvenile arthritis, autoimmune hemolytic anemia, bullous pemphigoid, myasthenia gravis, autoimmune thyroiditis, and Graves disease.2,4 Vitiligo is a disease characterized by well-circumscribed achromic or hypochromic spots caused by the loss of melanocytes from the basal layer of the epidermis. It is a complex, multifactorial and polygenic disorder.6,7 Several theories have been proposed to explain its pathogenesis, of which the autoimmune hypothesis is the most widely accepted explanation.6 In nonsegmental vitiligo, the occurrence of concomitant autoimmune diseases and a positive response to immunosuppressive therapy, such as phototherapy and corticosteroids, support this theory.8,9 Abnormalities in humoral and cellular immunity and the presence of high titers of antityrosinase IgG antibodies are reported in 5% to 10% of patients with vitiligo and correlate with disease

1 Oiso N, Iba Y, Kawara S, Kawada A. Halo phenomenon in neurofibromas and generalized vitiligo in a patient with neurofibromatosis type 1. Clin Exp Dermatol. 2007;32:207–208. 2 Yalcin B, Yalcçin B, Tamer E, et al. Neurofibromatosis 1/ Noonan syndrome associated with Hashimoto’s thyroiditis and vitiligo. Acta Derm Venereol. 2006;86:80–81. 3 Zampetti M, Filippetti R. Type 1 neurofibromatosis and the vitiligo. G Ital Dermatol Venereol. 2008;143:352. 4 Nanda A. Autoimmune diseases associated with neurofibromatosis type 1. Pediatr Dermatol. 2008;25:392–393. 5 Tsao H, Luo S. Neurofibromatose e Esclerose Tuberosa. In: Bolognia JL, Jorizzo JL, Schaffer JV, eds. Dermatologia. 3rd ed. Rio de Janeiro: Elsevier; 2015:1459–1473. 6 Ortonne J-P, Passeron T. Vitiligo e Outras Desordens de Hipopigmentação. In: Bolognia JL, Jorizzo JL, Schaffer JV, eds. Dermatologia. 3rd ed. Rio de Janeiro: Elsevier; 2015:1613–1625. 7 Tarlé RG, Nascimento LM do, Mira MT, Castro CCS de. Vitiligo. Part 1. An Bras Dermatol. 2014;89:461–470. 8 Colucci R, Dragoni F, Moretti S. Oxidative stress and immune system in vitiligo and thyroid diseases. Oxid Med Cell Longev. 2015;2015:1–7. 9 Mohammed GF, Gomaa AH, Al-Dhubaibi MS. Highlights in pathogenesis of vitiligo. World J Clin Cases. 2015;3:221–230.

VINTAGE LABEL

Courtesy of BuyEnlarge, Philadelphia, PA SKINmed. 2016;14:478–479

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Volume 14 • Issue 6

Book Review Jennifer L. Parish, MD, Section Editor

History, Sex and Syphilis Lawrence Charles Parish, MD, MD (Hon)

hat a fascinating collection of biographical essays of famous syphilitics! (Mroczkowski, T. F., History, Sex and Syphilis: Famous Syphilitics and their Private Lives. Bradenton, FL, BookLocker.com; 2015: 499p. Kindle $7.99, paperback $28.95, hardcover $39.95.) Details are given about the many members of royal households, musical composers, writers, and artists who were afflicted by this treponemal disease, often euphemistically called lues (Latin for the plague). There were other names given to the great imitator, including the French pox, the Neapolitan disease, the big pox, and the disease from Española. Fortuitously, this work does not dwell on whether syphilis was brought by Columbus’ men from the New World or represented the reemergence of an European disease at the end of the 15th century. Such discussions can be found in other sources.1,2 FAMOUS SYPHILITICS With an estimated 20% of the population of Paris having syphilis in the late 19th century, it is no wonder that many impressionist painters suffered with the disease. Paul Gauguin (1848–1903) had tertiary syphilis, as did Vincent van Gogh (1853–1890) and Henri Toulouse-Lautrec (1864–1901), but whether their strange behaviors, as recounted in the book, were entirely attributable to syphilis is open to conjecture. In the case of several poets, Alfred de Musset (1810–1857) seems to have died of an aortic aneurysm due to tertiary syphilis. With Charles Baudelaire (1821–1867), if his death was not due to syphilis, the infection contributed to his eye problems; he had neurosyphilis and cardiovascular syphilis. Oscar Wilde (1856–1900) most likely had a gumma of the inner ear. How much syphilis interfered with the lives of such men will never be known, as most led dissolute lives. Excessive drinking, with consumption of large amounts of absinthe, and the use of laudanum and other habituating drugs to alleviate real and imaginary pain, may, as the author points out, have contributed to the bizarre behavior of many and probably to their eventual demise. These men were usually sexually promiscuous, having innumer-

able partners, if the accounts of the day are accurate. Whether they also suffered from gonorrhea and other sexually transmitted diseases is unknown, but imagine the various treatments, often ineffective, to which they were subjected: mercury ingestion to the point of losing teeth, potassium iodide by mouth, cold water immersion, spa hydrotherapy, and traction treatment. RECOMMENDATION The highly recommended book provides an insight into how syphilis affected so many lives during its 500 plus years of ravaging not only the sexually promiscuous, but also the innocent victims, be they marital partners or the children with congenital disease –syphilis of the innocent. The author, a syphilologist of note, has written extensively on sexually transmitted disease and has been on the professorial faculty of both New Orleans medical institutions, Tulane University and Louisiana State University. Further details and illustrations can be found at: www.historysexandsyphilis.com. References 1 Holcomb RC. Who Gave the World Syphilis? The Haitian Myth. New York, NY: Froben Press; 1937. 2 Dennie CC. A History of Syphilis. Springfield, IL: Charles C Thomas, 1962.

Reviewed by Lawrence Charles Parish, MD, MD (Hon), Clinical Professor of Dermatology and Cutaneous Biology, Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia PA • 1845 Walnut Street, Suite 1650, Philadelphia, PA 19103 • E-mail: larryderm@yahoo.com

SKINmed. 2016;14:480

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