May / June 2013 by jo-ann kalaka-Adams

May/June 2013 • Volume 11 • Issue 3 EDITORIAL Louis A. Duhring, MD (1845–1913): The Centennial of His Death Parish

COMMENTARY Dyslipidemia in Skin Disease: Now We Know More and Should Do More Kroumpouzos

ORIGINAL CONTRIBUTIONS A Clinicoepidemiological Study of Pityriasis Rosea in South India Ganguly

Severity of Acne and Its Impact on Quality of Life

Zaraa, Belghith, Ben Alaya, Trojjet, Mokni, and Ben Osman

REVIEWS Cutaneous Mucormycosis Skiada and Petrikkos

Self Assessment Examination Lambert

case studies Sporadic Progressive Mucinous Histiocytosis in a Mexican Patient Narváez-Rosales, Sáez-de-Ocariz, Toussaint-Caire, Ortiz-Hidalgo, and Espinosa-Rosales

Giant Metastatic Merkel Cell Carcinoma Bognet, Thompson, and Campanelli

Oral Squamous Cell Carcinoma of the Mandibular Region Presenting as Multiple Discharging Sinuses: Imperative of Magnetic Resonance Imaging and Computerized Tomography Sehgal, Sehgal, Oberai, Verma, Sharma, Pahwa, and Dogra

Vesiculobullous Dermatomyositis With Sensory Motor Neuropathy Ayhan, Baykara, Ozekinci, and Aytekin

CORRESPONDENCE Congenital Triangular Alopecia: An Imitator of Alopecia Areata Yaghoobi, Yaghoobi, and Feily

Celecoxib-Induced Bullous Pemphigoid Apap, Boffa, and Cordina

Lichen Planopilaris: Update on Pathogenesis and Treatment Baibergenova and Donovan

DEPARTMENTS perils of dermatopathology Anonymous Dermatopathologists: A Socioeconomic Solution to a Medical Problem Wassef, Lambert, Gagna, Harmon, and Lambert

new to the clinic Sklice (Ivermectin) Lotion for the Treatment of Head Lice Scheinfeld

photo capsule Pancreatic Panniculitis Following Endoscopic Retrograde Cholangiopancreatography Oh, Lee, Chan, and Thirumoorthy

Lebanese Dermatological Society

TABLE OF CONTENTS May/June 2013 • Volume 11 • Issue 3

EDITORIAL

Louis A. Duhring, MD (1845–1913): The Centennial of His Death.............................................................. 134

Lawrence Charles Parish, MD, MD (Hon)

COMMENTARy

Dyslipidemia in Skin Disease: Now We Know More and Should Do More.................................................... 137

George Kroumpouzos, MD, PhD

ORIGINAL CONTRIBUTIONs

A Clinicoepidemiological Study of Pityriasis Rosea in South India............................................................. 141

Satyaki Ganguly, MD, DNB

Severity of Acne and Its Impact on Quality of Life...................................................................................... 148

Inès Zaraa, MD; Ikram Belghith, MD; Nissaf Ben Alaya, MD; Sondes Trojjet, MD; Mourad Mokni, MD; Amel Ben Osman, MD

REVIEWS

Cutaneous Mucormycosis........................................................................................................................... 155

Anna Skiada, MD; George Petrikkos, MD

Self Assessment Examination.................................................................................................................... 159

W. Clark Lambert, MD, PhD

Lichen Planopilaris: Update on Pathogenesis and Treatment .................................................................... 161

Akerke Baibergenova, MD, PhD, MPH; Jeff Donovan, MD, PhD

Departments Perils of Dermatopathlogy W. Clark Lambert, MD, PhD, Section Editor

Anonymous Dermatopathologists: A Socioeconomic Solution to a Medical Problem.................................. 167

Cindy Wassef, BA; Peter C. Lambert, BA, MA; Claude E. Gagna, PhD; Gretchen Harmon, BA; W. Clark Lambert, MD, PhD

New to the Clinic Noah Scheinfeld, MD, JD, Section Editor

Sklice (Ivermectin) Lotion for the Treatment of Head Lice.......................................................................... 171

Noah Scheinfeld, MD, JD

Photo Capsule

Pancreatic Panniculitis Following Endoscopic Retrograde Cholangiopancreatography................................ 173

Choon Chiat Oh, MBBS (Singapore), MRCP (UK); Haur Yueh Lee, MBBS (Singapore), MRCP (UK); Mei Fung Michelle Chan, MBBS (UK), FRCPath (UK); T. Thirumoorthy MBBS (Malaya), FAMS, FRCP (Lond), FRCP (Glasg)

case studies Vesna Petronic-Rosic, MD, MSc, Section Editor

Sporadic Progressive Mucinous Histiocytosis in a Mexican Patient............................................................ 175

Verónica Narváez-Rosales, MD; Marimar Sáez-de-Ocariz, MD; Sonia Toussaint-Caire, MD; Carlos Ortiz-Hidalgo, MD;

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TABLE OF CONTENTS May/June 2013 • Volume 11 • Issue 3

Francisco Espinosa-Rosales, MD

Giant Metastatic Merkel Cell Carcinoma.................................................................................................... 179

Rachel Bognet, MD; Christina Thompson, BBA; Carmen Campanelli, MD

Oral Squamous Cell Carcinoma of the Mandibular Region Presenting as Multiple Discharging Sinuses: Imperative of Magnetic Resonance Imaging and Computerized Tomography ............................... 181

Virendra N. Sehgal, MD; Shruti Sehgal, MDS; Rakesh Oberai, MD; Prashant Verma, MD; Sonal Sharma, MD; Pooja Pahwa, MD; Sunil Dogra, MD

Vesiculobullous Dermatomyositis With Sensory Motor Neuropathy............................................................ 185

Erhan Ayhan, MD; Sule Nergiz Baykara, MD; Selver Ozekinci, MD; Sema Aytekin, MD

correspondence

Congenital Triangular Alopecia: An Imitator of Alopecia Areata................................................................. 189

Reza Yaghoobi. MD; Elena Yaghoobi, MD, GP; Amir Feily, MD

Celecoxib-Induced Bullous Pemphigoid..................................................................................................... 190

Charmaine Apap, MD, MRCP(UK); Michael J. Boffa, MD, FRCP(Lond), FRCP (Edin), MSc(Lond); John Cordina, MD, FRCP (Edin)

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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T A A G



May/June 2013

EDITORIAL BOARD

EDITOR IN CHIEF

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

DEPUTY EDITORS William Abramovits, MD Dallas, TX

W. Clark Lambert, MD, PhD Newark, NJ

Larry E. Millikan, MD Meridian, MS

Vesna Petronic-Rosic, MD, MSc Chicago, IL

Marcia Ramos-e-Silva, MD, PhD Rio de Janeiro, Brazil

Jennifer L. Parish, MD Philadelphia, PA

EDITORIAL BOARD Mohamed Amer, MD Cairo, Egypt

Howard A. Epstein, PhD Philadelphia, PA

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

Virendra N. Sehgal, MD Delhi, India

Robert L. Baran, MD Cannes, France

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

George M. Martin, MD Kihei, HI

Riccarda Serri, MD Milan, Italy

Anthony V. Benedetto, DO Philadelphia, PA

Anthony A. Gaspari, MD Baltimore, MD

Marc S. Micozzi, MD, PhD Rockport, MA

Charles Steffen, MD Oceanside, CA

Brian Berman, MD, PhD Miami, FL

Michael Geiges, MD Zurich, Switzerland

George F. Murphy, MD Boston, MA

Alexander J. Stratigos, MD Athens, Greece

Jack M. Bernstein, MD Dayton, OH

Michael H. Gold, MD Nashville, TN

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

James S. Studdiford III, MD Philadelphia, PA

Sarah Brenner, MD Tel Aviv, Israel Joaquin Calap Calatayud, MD Cadiz, Spain Henry H.L. Chan, MB, MD, PhD, FRCP Hong Kong, China Noah Craft, MD, PhD, DTMH Torrance, CA Ncoza C. Dlova, MBChB, FCDerm Durban, South Africa Richard L. Dobson, MD Mt Pleasant, SC William H. Eaglstein, MD Menlo Park, CA Boni E. Elewski, MD Birmingham, AL Charles N. Ellis, MD Ann Arbor, MI

Orin M. Goldblum, MD Pittsburgh, PA

Oumeish Youssef Oumeish, MD, FRCP Amman, Jordan

Lowell A. Goldsmith, MD, MPH Chapel Hill, NC Aditya K. Gupta, MD, PhD, FRCP(C) London, Ontario, Canada Seung-Kyung Hann, MD, PhD Seoul, Korea Roderick J. Hay, BCh, DM, FRCP, FRCPath London, UK Tanya R. Humphreys, MD Philadelphia, PA

Joseph L. Pace, MD, FRCP Naxxar, Malta Art Papier, MD Rochester, NY Johannes Ring, MD, DPhil Munich, Germany Roy S. Rogers III, MD Rochester, MN Donald Rudikoff, MD New York, NY

Camila K. Janniger, MD Englewood, NJ Abdul-Ghani Kibbi, MD Beirut, Lebanon

Robert I. Rudolph, MD Wyomissing, PA

Andrew P. Lazar, MD Livermore, CA

Vincenzo Ruocco, MD Naples, Italy

Jasna Lipozencic, MD, PhD Zagreb, Croatia

Noah Scheinfeld, MD, JD New York, NY

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Robert J. Thomsen, MD Los Alamos, NM 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 Joseph A. Witkowski, MD Philadelphia, PA Ronni Wolf, MD Rechovot, Israel

July 18 - 20, 2014 SulAmĂŠrica Convention Center Rio de Janeiro Brazil

www.iacdRio2014.com.br

May/June 2013

Volume 11 • Issue 3

EDITORIAL

Louis A. Duhring, MD (1845–1913): The Centennial of His Death Lawrence Charles Parish, MD, MD (Hon), Editor-in-Chief

ne hundred years ago, on Thursday, May 8, 1913, Louis A. Duhring, pathfinder for American dermatology,1 died at the age of 67. He succumbed to intestinal obstruction with resulting peritonitis and accompanying arteriosclerosis, pulmonary tuberculosis, Laennec’s cirrhosis, and myocarditis2 (Figure 1). His passing and funeral 5 days later received considerable attention from the press, being one of Philadelphia’s and the University of Pennsylvania’s most highly regarded personages. Rev Henry Duhring, his first cousin, conducted the funeral. The honorary pallbearers included three well-known dermatologists and students of Duhring’s: Milton B. Hartzell (1854–1927), his successor as Professor and Chairman of Dermatology at the University of Pennsylvania; Henry W. Stelwagon (1853–1919), first Professor of Dermatology at Jefferson Medical College; and Arthur Van Harlingen (1845– 1936), prominent Philadelphia clinician (Figure 2). Accomplishments Duhring’s accomplishments were manifold. He set the tone for the development of American dermatology in the latter part of the 19th century when dermatology, like other areas of medicine, was emerging as a distinct specialty. He is perhaps best remembered for having delineated dermatitis herpetiformis, also known as Duhring’s disease, from the morass of vesicularbullous diseases,3 but he was likewise responsible for describing pruritus hiemalis or winter itch, a common affliction in Victorian Philadelphia, and seborrhea corporis or seborrheic dermatitis, emphasizing its presentation on the body other than on the face and scalp. Additionally, one of his early papers pointed out that alopecia areata does not have a fungal origin.4 His publications are legendary, starting with the Photographic Review of Medicine and Surgery,5 which was one of the pioneer dermatology periodicals, if not the first, to effectively utilize photography. This was followed by the Atlas of Skin Diseases in

Figure 1. Duhring in his later years.

1876,6 A Practical Treatise on Diseases of the Skin,7 which went through several editions (1877, 1881, 1882) plus translations into a number of languages, the Epitome of Diseases of the Skin (1885), and the encyclopedic Cutaneous Medicine,8 of which only two of several projected volumes were published in 1895 and 1898, respectively. He was among the distinguished editors of the wonderful International Atlas of Rare Skin Diseases.9

From the Department of Dermatology and Cutaneous Biology, and the Jefferson Center for International Dermatology, Jefferson Medical College of Thomas Jefferson University, Philadelphia, PA Address for Correspondence: Lawrence Charles Parish, MD, MD (Hon), 1760 Market Street, Suite 301, Philadelphia, PA 19103 • E-mail: larryderm@yahoo.com

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Figure 3. North Laurel Hill Cemetery, Philadelphia, where Duhring is buried next to his sister, Julia.

Figure 2. Philadelphia Evening Telegraph, May 15, 1913.

As a leader, Duhring became the first Professor of Dermatology at the University of Pennsylvania in 1875, gaining emeritus status in 1910. He was one of the founders of the American Dermatological Association, the first national dermatology organization, in 1876, and would serve as its president in 1878 and 1879, as well as vice president on two other occasions. Legacy Although Duhring came from a well-to-do family and could easily afford the niceties of life, he became increasing parsimonious as he grew older. What accounted for his frugality has never been discovered, but he did become more eccentric with the years. This made his last will and testament even more surprising, for his estate was in excess of $1,600,000.00, an enormous sum for the period, and with no income tax at the time (Figure 3). SKINmed. 2013;11:134â&#x20AC;&#x201C;136

Duhring appeared to have created his wealth by investing in several ventures that had been recommended by his patients and friends. For example, he was a stockholder in the traction companies, organized by P.A.B. Widener, which provided trolley service throughout Philadelphia and the burgeoning suburbs. He left $400,000 to his family, that is, his cousins and nephews, as he never married, with the Rev Herman Duhring receiving $100,000. His general books were given to what is now the Free Library of Philadelphia, with the medical volumes going to the Medical Library of the University of Pennsylvania and to the Library of College of Physicians of Philadelphia. Fifty thousand dollars was designated for free beds at the Hospital of the University of Pennsylvania. The largest amount, however, was directed to the Department of Dermatology for the maintenance of the wax model collection (at one time, the dermatology re-

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search building at Penn was called the Duhring Laboratories); to the University of Pennsylvania, which used the funds to build the Duhring Annex to the original Main Library designed by Frank Furness; and to the Library of the College of Physicians of Philadelphia. As a result, the College was once able to subscribe to every dermatology journal but two, and was able to develop a major dermatology collection. Duhring’s portrait continues to hang in one of the main halls of the College. Conclusions The career of Louis A. Duhring has provided an inspiration to many dermatologists. His life and foresight have contributed to making our specialty that much stronger. References 1 Parish LC. Louis A. Duhring, MD, Pathfinder for Dermatology. Springfield, IL: Charles C Thomas; 1967. 2 Autopsy Report 4186-’13-66. Philadelphia, PA: Pathological Laboratory of the University of Pennsylvania; 1913.

3 Jackson R. Duhring on dermatitis herpetiformis. J Cutan Med Surg.1999;3:336–338. 4 Duhring LA. Pathology of alopecia areata. Am J Med Sci. 1870;60:122–126. 5 Maury FF, Duhring LA. Photographic Review of Medicine and Surgery: A Bi-Monthly Illustration of Interesting Cases, Accompanied by Notes. Philadelphia, PA: J.B. Lippincott; 1871. 6 Duhring LA. Atlas of Skin Diseases. Philadelphia, PA: J.B. Lippincott; 1876. 7 Duhring LA. A Practical Treatise on Diseases of the Skin. Philadelphia, PA: J.B. Lippincott; 1877. 8 Duhring LA. Cutaneous Medicine. Philadelphia, PA: J.B. Lippincott; 1895 & 1898. 9 Morris M. Internationaler Atlas seltener Hautkrankheiten = International atlas of rare skin diseases = Atlas international des maladies rares de la peau. Hamburg, London, Paris: Leopold Voss; H.K. Lewis; G. Masson; 1889.

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Volume 11 • Issue 3

COMMENTARY

Dyslipidemia in Skin Disease: Now We Know More and Should Do More George Kroumpouzos, MD, PhD

yslipidemia (DLP) is defined as the presence of one or more of its associated components: elevated total cholesterol (TC), elevated low-density lipoprotein cholesterol (LDL-C), low high-density lipoprotein cholesterol (HDL-C), and elevated serum triglycerides (TGs). In addition to lipidoses that have been traditionally associated with DLP, a number of inflammatory, rheumatic, and granulomatous skin diseases have also been associated with DLP in controlled studies (Table).1-10 In this commentary, data from the past decade that have shed new light on the role of DLP in skin disease are reviewed. Chronic Inflammation and DLP Chronic inflammation in skin diseases with a Th1-associated cytokine profile that includes a high expression of tumor necrosis factor (TNF) a, such as psoriasis, lichen planus (LP), and granuloma annulare (GA), may trigger DLP.1,4,10 Increased levels of oxidized LDL (oxLDL) cholesterol have been shown in psoriasis lesions, and have been associated with the immune-inflammatory events that result in progressive skin damage.11 Interestingly, oxLDL has been shown to increase interleukin 2 receptors in T cells, and interleukin 2 is dramatically increased in granulomatous processes such as GA.10 Furthermore, hypercholesterolemia may promote inflammation and/or microvascular dysfunction, including decreased skin blood flowmotion, thus contributing to the development and/or maintenance of inflammatory skin processes. On the other hand, oxidative stress in diseases with high levels of chronic inflammation, such as systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA), is considered a crucial factor in the development of DLP.6 DLP IN INFLAMMATORY SKIN DISEASE

In a number of hospital- and population-based studies, psoriasis has shown associations with all components of DLP, most commonly an increase in TGs and a decrease in HDL-C.1,3 These lipid abnormalities have been reported even in “low-risk” subsets of psoriasis patients.1 The directionality of the association of psoriasis with DLP, however, has yet to be established. As mentioned above, a common

Th1 cytokine profile between psoriasis and metabolic syndrome (MetS) may predispose psoriasis patients to develop components of MetS such as DLP. Other possible etiologies include lifestyle changes and the effects of medications used to treat psoriasis such as oral retinoids and cyclosporine, which can cause DLP.2 On the other hand, DLP may facilitate and maintain the inflammatory reaction at the skin level, and the level of antibody against oxLDL has been reported to correlate with disease severity.1 Statin therapy may be beneficial in psoriasis because it reduces oxLDL and causes a proinflammatory to anti-inflammatory shift. All components of DLP were more prevalent in LP compared with the control group in 3 case-control studies.4,5 DLP in Rheumatic Skin Disease DLP is a well-recognized comorbidity in SLE6,7 and RA.6,8 Development of DLP in SLE has been partially attributed to oxidative stress secondary to high levels of systemic inflammation.7 Oxidative stress can trigger a broad range of proatherogenic lipid modifications, including the formation of oxLDL. DLP is reported in 55% to 65% of RA patients, and can be diagnosed in patients with early disease.6 The lipid profile in untreated RA is characterized by suppression of both HDL-C and TC levels. As HDL-C levels fall disproportionately more compared with TC levels, an increased atherogenic index (TC:HDL-C ratio) results. Intricate changes in lipid metabolism and high levels of oxidative stress associated with a chronic inflammatory burden have been implicated in the etiology of DLP in RA.6 A significant decrease in TG levels in systemic sclerosis (SSc) has been documented in some studies.6,9 Two small studies showed low HDL-C in primary Sjogren’s syndrome (PSS), with TC being low in one.6 Lipid levels, however, were not associated with markers of inflammation. Primary antiphospholipid syndrome has been preliminarily associated with DLP, but controlled studies are lacking. DLP in Granulomatous Skin Disease GA recently associated with DLP10 shows a T-cell repertoire (CD4T cells)/cytokine pattern (TNF-a, interferon g, and interleukin 2

From the Department of Dermatology, The Alpert Medical School of Brown University, Rhode Island Hospital, Providence, RI Address for Correspondence: George Kroumpouzos, MD, PhD, Department of Dermatology, The Alpert Medical School of Brown University, Rhode Island Hospital, 593 Eddy Street, APC 10, Providence, RI 02903 • E-mail: gk@gkderm.com

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Table. DLP-Associated Skin Disease and Comorbidities Disease

DLP Components

MeTs

Other DLP-Associated Comorbidities

Comments

Psoriasis1-3,14,15

↑ TC, ↑ TG, ↑ LDL-C, ↓ HDL-C

CVD

LP4,5

↑ TC, ↑ TG, ↑ LDL-C, ↓ HDL-C

Hypothyroidism

SLE6,7

↑ TC, ↑ TG, ↑ LDL-C, ↓ HDL-C

CVD

Criteria for MetS are typically HTN and ↓ HDL7

RA6,8

↓ TC, TG ?, LDL-C ?, ↓↓ HDL-C

CVD

Strong association with MetS also in the subset without CVD8

SSc6,9

↑ TG

CVD?

Larger-scale studies needed to assess the impact of ↑ TG on CVD risk

PSS6

↓ TC, ↓ HDL-C

GA10

↑ TC, ↑ TG, ↑ LDL-C

Independent associations with components of MetS,2 directionality of associations to be studied No associations with obesity, HTN or glucose intolerance;5 further studies are needed to assess CVD risk

DLP may be related to low-grade inflammation in PSS; larger-scale studies are needed -

DLP associated with the extent of GA and annular lesion morphology;8 further studies are needed to assess CVD risk

Abbreviations: CVD, cardiovascular disease; DLP, dyslipidemia; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; LP, lichen planus; MetS, metabolic syndrome; PSS, primary Sjogren’s syndrome; RA, rheumatoid arthritis; SLE, systemic lupus erythematosus; SSc, systemic sclerosis; TC, total cholesterol; TG, triglycerides. + = present; - = absent, ↑ = increased levels; ↓ = decreased levels; ? = inadequate data; gray cells = no data.

and 4) similar to that of psoriasis and LP. In a recent case-control study by the author, DLP was more common in generalized than localized/disseminated GA, and the annular lesion morphology was associated with hypercholesterolemia and DLP.10 Sarcoidosis has been associated with hypertriglyceridemia and low HDL-C, which is possibly related to increased serum amyloid A levels; however, controlled studies are lacking. Preliminary associations of necrobiosis lipoidica diabeticorum with lipid abnormalities, and the granulomatous variant of chronic pigmented purpuric dermatosis with hypercholesterolemia also need to be verified by controlled studies. Drug Therapy and DLP Several disease-modifying antirheumatic drugs and TNF-a inhibitors alter the lipid profile, with the most common change seen as an elevation in HDL-C. Treatment of DLP has been associated with clinical improvement in psoriasis, and TNF inhibitors, which are helpful in psoriasis, have been associated with a beneficial increase in HDL-C or decrease in serum TGs.12 TNF-a has been associated with the maintenance stage of granulomatous processes such as GA, and GA has been treated with TNF inhibitors,13 which may be attributed not only to down-regulation of the Th1 cytokine pattern but also improvement of DLP. In addition, hydroxychloroquine, a disease-modifying antirheumatic drug used in the management of SLE, produces a less atherogenic profile by lowering TC, LDL-C, and TGs, and increasing SKINmed. 2013;11:137–139

HDL-C.6 The effects of these drugs on lipid subfractions, levels of oxLDL, and lipid function need to be further investigated.6 MetS in DLP-Associated Skin Disease MetS is the constellation of abdominal obesity, DLP, hypertension (HTN) and insulin resistance, and its presence increases a patient’s risk for cardiovascular disease (CVD), stroke, and type 2 diabetes.2 The DLP component of MetS is defined as the presence of reduced HDL and/or increased TG (National Cholesterol Education Program Adult Treatment Panel III criteria), and/or previous treatment of any of these lipid abnormalities (International Diabetes Federation criteria). MetS has been associated with psoriasis, and the association increases with greater disease severity. The association has not been attributed solely to sharing of the Th1 cytokine pathway but also to lifestyle behaviors (increased cigarette smoking, alcohol consumption, psychological stress, and poor dietary and exercise habits as a result of the effects of the disease on quality of life) that predispose psoriasis patients to components of MetS (obesity, insulin resistance, HTN).2 In support of this view, psoriasis has been independently associated in several hospital-based studies with components of MetS, such as diabetes, obesity, and HTN.2 The association of MetS with SLE is the result of central obesity but of increased prevalence of HTN and low HDL-C.7 MetS is strongly

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associated with RA, even in the subset of RA patients with no overt CVD.8 Two recent case-control studies did not show a difference in the prevalence of MetS between GA or LP groups and the control group.5,10 Larger-scale studies are needed, however. Cardiovascular Risk in DLP-Associated Skin Disease Psoriasis is a risk factor for CVD, which has been attributed to many independent risk factors, including obesity, HTN, smoking, and DLP.2 Some studies have indicated that the CVD risk is higher in chronic severe psoriasis than in mild psoriasis, which may be due to the fact that obesity and diabetes are shown to be more prevalent in severe than mild psoriasis.3 In a prospective, population-based cohort study, the incidences of myocardial infarction per 1000 patient-years for control patients and patients with mild and severe psoriasis were 3.58, 4.04, and 5.13, respectively.14 Both mild and severe psoriasis have been shown to be independent risk factors for stroke (hazard ratios 1.06 and 1.43, respectively).15 The excess risk of stroke attributable to psoriasis in patients with mild and severe disease was 1 in 4115 per year and 1 in 530 per year, respectively.15 Modification of CVD factors is indicated in psoriasis patients. A case-control study revealed that only DLP is a CVD risk factor in LP and not glucose intolerance, abdominal obesity, and HTN.5 Whether LP may be independently associated with CVD needs to be investigated. The association of SLE to CVD is only partially attributable to DLP, since other factors, including inflammation, oxidative stress, and the presence of anti-phospholipid antibodies, have been implicated.6 Antibodies against oxidized cardiolipin confer an increased thrombotic risk in SLE. RA confers a massive CVD risk, with CVD accounting for approximately half of RA deaths.6 This may reflect an impact of systemic inflammation on CVD, since systemic inflammation is an independent risk factor for CVD in the general population.6 The association of PSS and SSc with CVD requires further clarification. DLP has not been associated with atherosclerosis in SSc,9 although SSc shows a 5-fold greater risk of peripheral vascular disease than that of the general population, and endothelial cell dysfunction has been well documented in SSc.6

shown strong associations with CVD, whereas associations of other DLP-associated skin diseases with CVD remain less conclusive and require further investigation. Finally, the close relationship of the aforementioned diseases with DLP may be relevant when defining management options for refractory DLP-associated skin disease. Combined treatment options, including lipid-lowering medications such as statins and/or TNF-a inhibitors, may be beneficial. References

Conclusions During the past decade, a significant amount of new data have shed light on the role of DLP in skin disease. Skin diseases that had been viewed as immunologic are now viewed as immunometabolic, since they are associated with DLP, and can serve as markers of it. The above findings fill some practice gaps: first, lipid levels should be routinely monitored in DLP-associated diseases, especially those that are definitely associated with MetS (psoriasis, SLE, RA). Second, patients should be evaluated for the criteria of MetS and followed up for CVD risk factors. Psoriasis, SLE, and RA have SKINmed. 2013;11:137–139

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1 Dreiher J, Weitzman D, Davidovici B, et al. Psoriasis and dyslipidaemia: a population-based study. Acta Derm Venereol. 2008;88:561–565. 2 Alsufyani MA, Golant KA, Lebwohl M. Psoriasis and the metabolic syndrome. Dermatol Ther. 2010;23:137–143. 3 Shapiro J, Cohen AD, Weitzman D, et al. Psoriasis and cardiovascular risk factors: a case-control study on inpatients comparing psoriasis to dermatitis. J Am Acad Dermatol. 2012;66:252–258. 4 Dreiher J, Shapiro J, Cohen AD. Lichen planus and dyslipidaemia: a case-control study. Br J Dermatol. 2009;161:626–629. 5 Arias-Santiago S, Buendía-Eisman A, Aneiros-Fernández J, et al. Cardiovascular risk factors in patients with lichen planus. Am J Med. 2011;124:543–548. 6 Toms TE, Panoulas VF, Kitas GD. Dyslipidaemia in rheumatological autoimmune diseases. Open Cardiovasc Med J. 2011;5:64–75. 7 Parker B, Ahmad Y, Shelmerdine J, et al. An analysis of the metabolic syndrome phenotype in systemic lupus erythematosus. Lupus. 2011;20:1459–1465. 8 da Cunha VR, Brenol CV, Brenol JC, et al. Metabolic syndrome prevalence is increased in rheumatoid arthritis patients and is associated with disease activity. Scand J Rheumatol. 2012;41:186–191. 9 Hettema ME, Zhang D, de Leeuw K, et al. Early atherosclerosis in systemic sclerosis and its relation to disease or traditional risk factors. Arthritis Res Ther. 2008;10:R49. 10 Wu W, Robinson-Bostom L, Kokkotou E, et al. Dyslipidemia in granuloma annulare: a case-control study. Arch Dermatol. 2012;148:1131–1136. 11 Tekin NS, Tekin IO, Barut F, Sipahi EY. Accumulation of oxidized low-density lipoprotein in psoriatic skin and changes of plasma lipid levels in psoriatic patients. Mediators Inflamm. 2007;78454. 12 Wakkee M, Thio HB, Prens EP, et al. Unfavorable cardiovascular risk profiles in untreated and treated psoriasis patients. Atherosclerosis. 2007;190:1–9. 13 Werchau S, Enk A, Hartmann M. Generalized interstitial granuloma annulare—response to adalimumab. Int J Dermatol. 2010;49:457–460. 14 Gelfand JM, Neimann AL, Shin DB, et al. Risk of myocardial infarction in patients with psoriasis. JAMA 2006;296:1735– 1741. 15 Gelfand JM, Dommasch ED, Shin DB, et al. The risk of stroke in patients with psoriasis. J Invest Dermatol 2009;129:2411– 2418.

Dyslipidemia in Skin Disease

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A Clinicoepidemiological Study of Pityriasis Rosea in South India Satyaki Ganguly, MD, DNB Abstract Pityriasis rosea is an acute self-limiting papulosquamous skin disorder of unknown etiology. Although pityriasis rosea is a common dermatologic disorder, information regarding the epidemiology of the disease in India is limited because of inadequate studies. The incidence and presentation of pityriasis rosea varies from one geographical region to another. The objective was to study the various clinical patterns of the disease and epidemiologic factors influencing its occurrence. A cross-sectional study on the clinicoepidemiologic pattern of pityriasis rosea was conducted. A detailed history of illness regarding onset, evolution, duration, symptoms, systemic features, recurrence, history of contact, and associated factors such as socioeconomic status, history of drug intake, and use of new clothing, along with epidemiologic data, was recorded in the performa. The age of the patients ranged from 3 to 47 (mean 20.32) years. Incidence of pityriasis rosea was highest among patients aged 11 to 20 years followed by those 21 to 30 years. There was a male preponderance. Seasonal variation was not evident. History of using new garments or old garments, unwashed for an extended period was elicited in 23% of cases. The average interval of onset of lesions and presentation to physician was 14.45 days. Pruritus was a common symptom (70%). Of 73 patients, 67 had herald patch. The clinical features of most of the cases were in accordance with the classical pattern of pityriasis rosea. (SKINmed. 2013;11:141–146)

ityriasis rosea (PR) is an acute self-limiting papulosquamous skin disorder of unknown etiology. It occurs all over the world. In different studies the incidence of PR was found to be between 0.39 and 4.80 per 100 dermatology patients.1,2

Researchers found that the incidence of PR has declined in some parts of the world such as Australia and New Zealand, whereas a much higher incidence was reported from Scandinavia. There is wide variation in seasonal incidence.6

Although mostly asymptomatic and self-limiting, the presence of skin eruptions results in considerable anxiety among patients with PR and parents of affected children. The postinflammatory hyperpigmentation may result in significant cosmetic concern.

PR is a common dermatological disorder; however, information regarding the epidemiology of the disease in India is limited because of a lack of suitable studies. South India is a peninsula, bounded on the west by the Arabian Sea, on the east by the Bay of Bengal and on the north by the Vindhya and Satpura ranges. The region has a tropical climate, with monsoons playing a major role. The southwest monsoon accounts for most of the rainfall in the region and much of it falls from about June to October. It has a distinct dry season from about October to May. The days are very hot from March to June, when temperatures can get above 104°.

The exact etiology of PR is not known; however, precipitating factors such as wearing new garments have been identified.3 There is evidence that PR may have an infectious etiology because of recorded clustering of cases of PR.4,5

The incidence and presentation of PR varies from one geographic region to another. Hence, a study was needed to investigate various clinical patterns of the disease and epidemiologic factors influencing its occurrence in South India.

The skin lesions of PR are characterized by erythematous, scaly papules and plaques appearing in crops preceded by a herald patch. The lesions are asymptomatic or associated with mild pruritus. These fade after 3 to 6 weeks with or without postinflammatory pigmentary changes. Many varied clinical presentations are known, other than the classical one.

From the Department of Dermatology, Venereology and Leprosy, Pondicherry Institute of Medical Sciences, Pondicherry, India Address for Correspondence: Satyaki Ganguly MD, DNB, Department of Dermatology, Venereology and Leprosy, Pondicherry Institute of Medical Sciences, Pondicherry, India 605014 • E-mail: satyakiganguly@yahoo.co.in

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Table I. Age and Sex Distribution Among Patients With Pityriasis Rosea Patients, No. Age Group, y

Men

Women

Percentage

0–10

15.06

11–20

41.09

21–30

34.24

31–40

5.47

41–50

4.10

Methods A cross-sectional study on the clinicoepidemiologic pattern of PR was conducted in the department of Dermatology, Venereology and Leprosy, B.L.D.E.A’s Shri.B.M.Patil Medical College Hospital and Research Centre. Seventy-three patients with PR were recruited from the outpatients’ section (OPD) of the department. Informed consents were taken from all patients or their parents. Institutional review board approved the investigation. The study was conducted between November 2006 and May 2008. Patients with clinically diagnosed cases of PR, irrespective of age and sex, were included in the study. Patients who had taken some form of systemic therapy for PR (eg, corticosteroids, erythromycin) before coming to the OPD and those with major systemic illnesses, including renal impairment, were excluded. Patients with a history of intake of drugs known to cause PR-like eruptions during the preceding 3 weeks were also excluded from the study. A detailed history of the illness regarding onset, evolution, duration, symptoms, systemic features, recurrence, history of contact, and associated factors such as socioeconomic status, history of drug intake, and use of new clothing, along with epidemiological data, was recorded in the performa. Complete hemogram and urine analysis were performed for all patients. Skin biopsy for histopathologic examination from the herald patch or secondary eruption was performed with the patient’s consent. Venereal disease research laboratory (VDRL) test was performed in young sexually active adult patients. Results The age of the patients ranged from 3 to 47 (mean 20.32) years. Incidence of PR was highest among patients aged 11 to 20 years, followed by 21 to 30 years. It gradually declined thereafter. There was a male preponderance, with a male (n=42) to female (n=31) ratio of 1.35:1 (Table I). Seasonal variation was not evident, with almost equal incidence in summer (n=30) and winter (n=37). Few cases were recorded SKINmed. 2013;11:141–146

Table II. Distribution of Herald Patches Among Patients With Pityriasis Rosea Area of Involvement

Patients, No.

Percentage

Face

8.82

Neck

13.23

Trunk

38.23

Upper limb

29.41

Lower limb

10.29

in the rainy season (n=6). History of using new or old garments, unwashed for an extended period, was elicited in 23% of cases. History of intake of drugs before the onset of the lesions was obtained in 19% of cases, most commonly nimesulide. The remainder of the patients did not have any predisposing factors. The average interval of onset of lesions and presentation to a physician was 14.45 days. Pruritus was a common symptom (70%). Of 73 patients, 67 (92%) had herald patch. Two herald patches were observed in a single patient, one each on the neck and trunk. The majority (38%) of the herald patches were on the trunk (Table II). Secondary eruptions were more common on the trunk (84%) and upper limbs (70%). Some patients had involvement of multiple sites such as trunk as well as upper and lower limbs (41%). The classic Christmas-tree pattern was present in 22 cases (30%). The time interval between the appearance of herald patch and secondary eruptions ranged from 1 to 20 days (average, 5.65 days). In 47 cases (77%), the secondary lesions appeared within 1 week of the appearance of the herald patch. Sixty-two patients (85%) showed the classical pattern of skin lesions. Six patients had an inverse pattern and 3 patients had a cervicofacial pattern of skin lesions. One case each had papular and unilateral type of disease.

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Figure 3. Extensive secondary eruption with genital involvement.

Figure 1. Herald patch.

Figure 4. Inverse pityriasis rosea.

Figure 2. Christmas-tree pattern.

Figure 5. Neck lesions. SKINmed. 2013;11:141â&#x20AC;&#x201C;146

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Figure 6. Unilateral pityriasis rosea.

Hemography and routine urine analysis results were normal in all cases. Potassium hydroxide preparation results were negative and serological test results for syphilis (VDRL) were nonreactive in all cases. Histopathologic analysis was performed in 39 cases (53%). Skin biopsy was taken from the herald patch in 10 cases (26%) and from secondary lesions in 29 cases (74%). The most common epidermal features were focal parakeratosis and spongiosis. Most of the specimens showed a superficial perivascular lymphocytic infiltration in the dermis. Extravasated erythrocytes (Sabouraud’s sign)7 were present in 44% of biopsy specimens. Apart from hyperkeratosis and acanthosis, there were no differences between histopathologic features of herald patch and secondary lesions. Discussion PR is an acute papulosquamous disorder. It is a self-limiting condition, but the exact etiology is not known. Commonly, only symptomatic treatment is given for PR. The majority of the cases of PR are reported between the ages of 10 to 35 years and it is uncommon in early childhood or older age, although it has been shown to occur in infants and in patients in the ninth decade.8 In the present study, 75% of the cases belonged to the age group between 11 and 30 years. The mean age was 20.32 years, with a range of 6 months to 47 years. In an epidemiologic study conducted in Minnesota, it was observed that more than 75% of the cases were between the ages of 10 and 35 years, with a mean age of 22.7 years (range, 10 months to 78 years).9 Another study showed the average age to be 29.1 years.10 A retrospective study performed in Singapore showed a peak of occurrence between 20 to 29 years (age range, 9 months to 82 years).11 Another study in Eastern Anatolia showed 87% of the cases to be between 10 SKINmed. 2013;11:141–146

Figure 7. Sabouraud’s sign: extravasation of red blood cells.

to 39 years, with a peak in patients from 20 to 29 years.12 In an Indian study, the age of patients with PR ranged from 6 months to 50 years, with 32% of the patients aged 11 to 20 years.13 In the present study, 41% of cases belonged to the same age group. Hence, the results of the present study were similar to previous studies in age of incidence. The results of the present study showed nearly equal sex ratio. Few of the earlier studies showed a female preponderance.9,12 This finding could possibly have been caused by greater cosmetic concern in women. There is likely no real sex predisposition. Conflicting reports are available for seasonal variation in the occurrence of PR. In temperate regions, it is more frequent during winter months. A higher incidence in the winter months was reported by investigators in England, the United States, and Sudan.13,14,15 PR was more common in the rainy season in Lagos, Nigeria.16 A bimodal distribution was reported from Brazil and Singapore.1,17 One Indian study showed that PR was more

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Table III. Comparison Between Indian Studies Regarding Clinical Types Studies

Papular Type

Localized Type

Inverse Type

Unilateral Type

Egwin et al12

Nil

Present study

1.36%

4.1%

8.21%

1.36%

common during rainy season (36%) and less common in winter (10%), but another Indian study showed a higher incidence in winter.10,13 The present study showed almost equal incidence in summer and winter, but a decrease in rainy season. New garments or old garments in storage for long periods are thought to be one of the precipitating factors of PR. In an Indian study, 20% of patients gave a history of using new garments.13 In the present study, 23% of cases gave a similar history. This supports the theory about the transfer of an infectious agent. Presumably the productive infection arises from reactivation, since these patients most likely were infected with both of these viruses previously during childhood. There is also a possibility of interaction between HHV-6 and HHV-7. Most frequently, primary HHV-7 appears to elicit HHV-6 reactivation, although the opposite may also occur. Indian studies showed that in 10% to 16% of cases, PR appeared after the intake of drugs.10,13 The present study showed 19%, a slightly higher percentage of patients with history of drug intake, mostly nimesulide, preceding the appearance of PR. The percentage of patients presenting with pruritus (70%) was less than that found in one study (92%), but similar to that found in another (75%).13,18 The incidence of herald patch varies to a great extent, from 12% to 94% in various studies.1,2,13 The previous Indian studies showed an incidence of 70%.10,13 A high percentage of patients (92%) showed the presence of herald patch in the present study. Two herald patches were observed in a single case, which is a rare occurrence. The herald patch is commonly located on the trunk, in areas covered by clothes. In one study, the trunk was the commonest site of involvement (57%), followed by the extremities (29%).13 The present study showed a similar pattern with presence of herald patch on the trunk in 38% of cases, followed by the upper limb (29%). The secondary eruption is localized mainly to the trunk and adjacent regions of the neck and proximal extremities. The most pronounced lesions extend over the abdomen and anterior surSKINmed. 2013;11:141–146

face of the chest, as well as over the back. Lesions distal to the elbows and knees may occur but are less common. One study showed the trunk to be the commonest site of involvement (94%), followed by trunk and extremities (38%) and trunk, neck, and extremities (30%).13 Another study also showed the trunk to be the commonest site of involvement (84%).10 The findings of the present study were in conformity with the other studies, with involvement of the trunk in 84% of cases, upper limbs in 70% of cases, and trunk and upper and lower limbs in 41% of the cases. Characteristic orientation of the secondary eruption is best described as “along the lines of skin cleavage.” Other descriptions of this orientation are Christmas tree, inverted Christmas tree, fir tree, and parallel to the ribs. This typical pattern was present in 30% of the cases in the present study. The interval between the appearance of the primary plaque and the secondary eruption can range from a few hours to 3 months, but usually within 2 weeks.8 In a previous study, occurrence of secondary eruptions within the first 2 weeks of herald patch was noted in 78% of cases.13 The present study showed a comparatively shorter interval, with a range of 1 to 20 days (mean, 5.65 days). In contrast to the previous study, 77% of the cases developed secondary lesions within 1 week of appearance of the herald patch. The eruption of PR follows a distinctive and remarkably constant pattern and course in 80% of cases (classical pattern). PR may be atypical in morphology or distribution of the lesions. The present study showed similar findings, with 85% of cases with a classical pattern, higher than the previous Indian study (62%)13 (Table III). Conclusions The higher incidence of inverse PR probably reflects a selection bias, as patients are more likely to present to the doctor as lesions are present in exposed parts of the body. A rare case of unilateral PR was recorded in the present study. Mucous membrane involvement is unusual in PR. Oral lesions were not recorded in the present study.

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References 1 de Souza Sittart JA, Tayah M, Soares Z. Incidence pityriasis rosea of Gibert in the Dermatology service of the Hospital do Servidor Publico in the state of Sao Paulo. Med Cutan Ibero Lat Am. 1984;12:336–338. 2 Olumide Y. Pityriasis rosea in Lagos. Int J Dermatol. 1987;26:234–236. 3 Jerome M, Parsons R. Pityriasis rosea update. J Am Acad Dermatol. 1986;15:159–167. 4 Chuh A, Lee A, Molinari N. Case clustering in pityriasis rosea: a multicentre epidemiological study in primary care settings in Hong Kong. Arch Dermatol. 2003;139:489–493. 5 Chuh A, Molinari N, Sciallis G, et al. Temporal case clustering in Pityriasis rosea- a regression analysis on 1379 patients in Minnesota, Kuwait and Diyarbakir, Turkey. Arch Dermatol. 2005;141:767–771. 6 Pettit JHS. Is pityriasis rosea dying? Int J Dermatol. 1983;22:230–231. 7 Prasad D, Mittal RR, Walia RLS, Popli R. Pityriasis rosea: a histopathologic study. Indian J Dermatol Venereol Leprol. 2000;66:244–246. 8 Björnberg A, Tegner E. Pityriasis rosea. In: Freederg IM, Eisen AZ, Woff K, Austen KF, Goldsmith LA, Katz SI, eds. Fitzpatrick’s Dermatology in General Medicine. 6th ed. New York, NY: McGraw-Hill; 2003:445–450. 9 Chuang TY, Ilstrup DM, Perry HO, Kurland LT. Pityriasis ro-

sea in Rochester, Minnesota, 1969 to 1978. J Am Acad Dermatol. 1982;7:80–89. 10 Sharma L, Srivastava K. Clinicoepidemiological study of pityriasis rosea. Indian J Dermatol Venereol Leprol. 2008;74:647–649. 11 Tay YK, Goh CL. One-year review of pityriasis rosea at the National Skin Centre, Singapore. Ann Acad Med Singapore. 1999;28:829–831. 12 Harman M, Aytekin S, Akdeniz S, Inaloz HS. An epidemiological study of pityriasis rosea in the Eastern Anatolia. Eur J Epidemiol. 1998;14:495–497. 13 Egwin AS, Martis J, Bhat RM, Kamath GH, Nanda KB. A clinical study on pityriasis rosea. Indian J Dermatol. 2005;50:136–138. 14 Messenger AG, Knox EG, Summerly R, Muston HL, Ilderton E. Case clustering in pityriasis rosea: support for role of an infective agent. Br Med J. 1982;284:371–373. 15 Ahmed AA. Pityriasis rosea in Sudan. Int J Dermatol. 1986;25:184–185. 16 Jacyk WK. Pityriasis rosea in Nigerians. Int J Dermatol. 1980;19:397–399. 17 Cheong WK, Wong KS. An epidemiological study of pityriasis rosea in Middle Road Hospital. Singapore Med J. 1989;30:60–62. 18 Mandal SB, Datta AK. A clinical study of pityriasis rosea. Indian J Dermatol. 1972;58:100–102.

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Volume 11 • Issue 3

Original contribution

Severity of Acne and Its Impact on Quality of Life Inès Zaraa, MD;1,2 Ikram Belghith, MD;1,2 Nissaf Ben Alaya, MD;2,3 Sondes Trojjet, MD;1,2 Mourad Mokni, MD1,2 Amel Ben Osman, MD1,2 Abstract Acne is a chronic disease that is especially common among adolescents. It can have a considerable psychological and social impact that is not always correlated with clinical severity. The aim of this paper was to evaluate clinical severity and alteration of quality of life in acne patients, and to investigate a possible correlation between the two. A total of 82 patients with juvenile acne were included in this study. The clinical severity of acne was evaluated using the Échelle de Cotation des Lésions d’Acné (ECLA) scale. The Cardiﬀ Acne Disability Index (CADI) was used to assess acne-related quality of life. Acne was mild to moderate in 61% of patients (ECLA ≤12). A considerable alteration of quality of life was present in 51% of cases. There was a positive correlation between overall scores on the ECLA and CADI scales (P=.012) before and after treatment. Additionally, CADI score improved after effective treatment of acne. Acne may have an important impact on teenagers’ psychological and social life. An objective assessment of this impact seems to be necessary. ECLA and CADI scores appear to be objective and simple instruments that may be used in acne management. (SKINmed. 2013;11:148–153)

cne is a chronic multifactorial inflammatory disease of the pilosebaceous unit. It affects >80% of the population at some point in their lives.1 It is, however, more prevalent at puberty and during adolescence, a psychologically labile period in which adolescents develop self-confidence and social abilities. Although it is generally a self-limited disease, it can last for years, mainly affecting sites that are difficult to hide, causing disfiguring scars and thus a profound perceived change in appearance. All of these factors usually lead to negative effects on the psychosocial status of the affected adolescents. Evaluation of the impairment of health-related quality of life (QoL) in patients with acne is therefore an important step for effective therapy, as it improves the physician-patient relationship, reassuring adolescents that their social and emotional problems are considered. As far as we know, there are limited Tunisian data about acne prevalence and especially its effect on psychological distress in adolescents.2 In the present study, we aimed to determine the epidemioclinical profile of acne, with an objective evaluation of its clinical severity. In addition, we investigated the impairment of the psychological and social health caused by this condition, as well as the consistent relationship between clinician rating of acne severity and QoL rating.

Materials and Methods We carried out a prospective cohort study at the dermatology department of La Rabta Hospital of Tunis during a 6-month period (January 2009 to June 2009). Patient selection Our study enrolled newly diagnosed patients with acne vulgaris and/or patients who had not received any treatment for at least 6 months. We included all patients able to give informed consent (in case of minors, consent was given by one of the parents) and who developed acne between the age of 10 and 18 years. Main measures

Epidemioclinical Evaluation Data on epidemiological and clinical features were collected at the first consultation (C1). Outcome was observed after 1 (C2) and 3 months (C3) of follow-up.

Objective Severity Index An objective measure of the clinical severity of acne was defined by the Échelle de Cotation des Lésions d’Acné (ECLA) scale3 (Table I), specifically designed for use by dermatologist practitioners. It is a French semiquantitative grading of acne that has

From the Dermatology Department, La Rabta Hospital;1 Faculté de Médecine de Tunis, Université El Manar;2 and the Observatoire National des Maladies Nouvelles et Émergentes, Belvédère, Tunisia3 Address for Correspondence: Inès Zaraa, MD, Professor Assistant, Dermatology Department, La Rabta, Hospital, Jabbari, Bab Saadoun, Tunis, 1007 Tunisia • E-mail: inesrania@myway.com

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Table I. Echelle de Cotation des Lesions d’acné Scale

Factor 1 (F1): Type and intensity of acne—count on the entire face

Absent=0

Rare=1

Mild=2

Moderate=3

Severe=4

Very severe=5

None

5–9

10–19

20–40

>40

None

5–9

10–19

20–40

>40

None

±5

Comedones

Is Papules and pustules Ip Nodules and cysts Score 1=

Factor 2 (F2): Extension and intensity of acne, away from face

Neck

Number

Absent

Mild

Moderate

Severe

Nodules

Top Bottom

Chest Back

Above scapula Under scapula Arms

Score 2= Factor 3 (F3): scars: absent=0, present=1 Noninflammatory (NI) inflammatory (I) Excoriations (E) Score 3= ECLA=score 1+score 2+score 3 (French validated scale, this is not a valid English translation)

been previously validated. The global score of severity ranges from 1 to 36. Acne was considered as mild for an ECLA score ranging between 1 and11, moderate between 12 and 23, and severe more than 23.

total maximum score of 15; the higher the score, the more the QoL is impaired. The alteration of QoL was considered important when CADI ≥8. It is the only QoL grading system that has been recently translated and validated in the French language.6

Quality of Life

Data analysis

QoL was evaluated in our study using the French version of the Cardiff Acne Disability Index (CADI)4,5 (Table II). This is a 5-item scale with questions 1 and 2 addressing the psychological and social consequences of acne; question 3 concerning the impact of the trunk lesions on the public behavior; question 4 enquiring about the patients’ psychological state; and question 5 about the subjective assessment of the acne severity. Each question has 4 possible answers with a maximum of 3 points and a

Data were collected using Excel and statistical analysis was performed using SPSS 13 (SPSS Inc, Chicago, IL). For qualitative variables, we calculated simple frequencies and relative frequencies (percentages). For quantitative variables, we calculated means, standard deviations, and ranges. The main statistical instruments used were Student t test or Mann-Whitney test (to compare 2 averages), one-way analysis of variance or Kruskall Wallis test (to compare more than 2 averages), Chi-square or

SKINmed. 2013;11:148–153

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Table II. The Cardiff Acne Disability Index As a result of having acne, during the last month have you been aggressive, frustrated, or embarrassed?

(a) (b) (c) (d)

Very much indeed A lot A little Not at all

Do you think that having acne during the last month interfered with your daily social life, social events, or relationships with members of the opposite sex?

(a) (b) (c) (d)

Severely, affecting all activities Moderately, in most activities Occasionally or in only some activities Not at all

During the last month have you avoided public changing facilities or wearing swimming costumes because of your acne?

(a) (b) (c) (d)

All of the time Most of the time Occasionally Not at all

How would you describe your feelings about the appearance of your skin during the last month?

(a) (b) (c) (d)

Very depressed and miserable Usually concerned Occasionally concerned Not bothered

Please indicate how bad you think your acne is now

(a) (b) (c) (d)

The worst it could possibly be A major problem A minor problem Not a problem

The scoring of each answer is as follows: (a) 3; (b) 2; (c) 1; and (d) 0. The Cardiff Acne Disability Index score is calculated by summing the score of each question resulting in a possible maximum of 15 and a minimum of 0. The higher the score, the more the quality of life is impaired.

Fisher test (for percentage comparison), and Pearson coefficient for the measure of correlation. P<.05 was accepted for statistical significance.

cant clinical improvement was noticed, as shown by the decrease in the mean ECLA score (C1=12.37±4.73; C2=10.56±4.06; C3=7.56±2.98).

Results

Quality of Life Using CADI

A total of 82 patients were enrolled during the study period.

About half of our patients reported a high impact of acne on their QoL (CADI ≥8). An important alteration of QoL in patients with acne was also correlated with an early onset of acne (r=–0.236, P=.03), presence of pustule as inaugural lesions (P=.01), with no correlation with sex. We also noted a statistically significant decrease in CADI after treatment.

Epidemiological and Clinical Data Epidemiological, clinical, and therapeutic data are summarized in Table III. On physical examination, we noticed that 85.4% of our patients had skin type 4 according to the Fitzpatrick classification scale.7 Furthermore, 74 patients (90.2%) were overweight (25≤body mass index≤29.9kg/m2). Comedones were the inaugural lesions in most cases (68.3%).

Clinical Severity of Acne Using ECLA Acne was mild to moderate in 61% of patients (ECLA ≤12). We noticed a significant correlation between severity of acne (high ECLA scores) and young age at onset of acne (r=–0.256; P=.02), with no correlation with sex. The clinical severity of acne was determined at each consultation according to the ECLA scale. Through follow-up, a signifiSKINmed. 2013;11:148–153

Correlation Between ECLA and CADI Scales Finally, we found a positive correlation between overall scores on the ECLA and CADI scales. A positive correlation was also observed between overall CADI score and factor F2 (extension and the intensity of acne apart from the face) in the ECLA scale (r=0.262, P=.017). On the other hand, the global ECLA score was significantly correlated with item 2 (social consequences of acne), item 3 (the impact of the trunk lesions on the public behavior), and item 4 (patients’ psychological state) of the CADI questionnaire (r=0.315, P=.004; r=0.245, P=.006; and r=0.25,

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Table III. Epidemiological, Clinical, and Therapeutic Characteristics of the 82 Study Patients Characteristics

Even though acne was mild to moderate in most of our patients, the alteration of QoL was considerable. Using objective scales helped us demonstrate the relationship between clinical severity and psychological distress on acne patients. Our major findings were the presence of a positive correlation between the severity of acne lesions and the alteration of patients’ QoL.

No. (%) or Mean±Standard Deviation

Sex Female

60 (73.2)

Male

22 (26.8)

Mean age at onset, y

14.76±2.55

Mean age at first consultation, y

21.2±4.13

Familial history of acne

50 (61)

Finally, clinical severity and QoL do not change in the same way, as the first gradually declines while the second improves after only 3 months. Few studies evaluate the impact of acne on adolescents’ QoL according to its clinical severity using objective measurement tools. To our knowledge, no such Tunisian study has been published.

Acne lesions Seborrhea

82 (100)

Comedones

82 (100)

Papulo-pustules

78 (95.1)

Nodules

20 (24.4)

Cysts

15 (18.3)

Excoriations

50 (61)

Scars

57 (69.5)

Recently, quantitative and semiquantitative grading based on lesion count and photographs were used in acne. In 1997, Doshi proposed a global acne grading system (GAGS).12 A similar system was proposed by Dreno in 1999 in France, the ECLA scale. This grading has shown excellent reliability in terms of intraobserver and interobserver variability with a short time of fulfillment.3 Being a former France colony, French is the second language used in our country. This is why we chose this scale to assess acne severity, especially since it is the only one validated in French. The ECLA scale was previously used to assess acne severity in a French study among 128 patients. The global score was 8.26±3.32.13 In our study, acne seems to be more severe with a global ECLA score of 12.37±4.7. These findings may be explained by the fact that we chose only patients untreated for at least 6 months and, unlike the French study, which included patients who visited private and hospital dermatologists, all of our patients were consulted in our tertiary department of dermatology.

Extension of acne lesions Face

82 (100)

Neck

52 (63.41)

Higher chest and back

25 (30.48)

Whole trunk

12 (14.63)

Treatment Topical retinoid

71 (86.58)

Benzoyle peroxide

72 (87.8)

Erythromycin

2 (2.43)

Azelaic or fruit acid creams

4 (4.87)

Oral antibiotics (cyclines)

31(37.8)

Oral isotretinoin (0.5 to 1 mg/kg/day)

6 (7.31)

P=.03, respectively). In contrast, there was no correlation between ECLA score and item 5 (representative of patients’ perception of their acne). Furthermore, each factor of the ECLA scale was compared with each item of the CADI; a significant correlation between factor F2 and items 2, 3, and 4 was observed. Those items are correlated with social life, avoidance of public changing facilities, and feelings, respectively. SKINmed. 2013;11:148–153

The face is often involved in acne vulgaris, resulting in the alteration of patient’s perception of body image and social relationships. Even if acne is mild to moderate, in most of adolescents (ECLA ≤12 in 61% of our patients) the impact of this disease on this labile period of life is well recognized. Patients with acne experience depression, anxiety, anger, and even suicidal ideation and suicide itself, with suicidal ideation found in 7.1% of patients with acne in one study.14 Psychosocial problems such as impaired academic performance or increased unemployment rates are also common in acne patients15; however, the perception of the severity of acne can be widely different between the patient and the physician, since measurement tools are proposed to assess the QoL of patients with acne more objectively. First used were global generic scales such as short form-36, which is adaptable to any health problem,16 or Skindex17 and Dermatology Life Quality Index18; however, specific measurements were

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shown to be more sensitive; hence, the emergence of QoL scales specific for acne. The CADI was created in 1991 as a specific questionnaire measuring disability induced by acne. It is a short questionnaire, consisting of only 5 questions, which is convenient for clinical practice. Furthermore, CADI is the only scale for assessing QoL in patients with acne validated in French.6 In a cohort of 200 Scottish adolescents with acne, compared with other scales (the Children’s Dermatology Life Quality Index and CADI], a good correlation was found between the results from the two questionnaires. The overall mean CADI score was 1.9.19 Another investigator used the CADI to evaluate the QoL among Chinese late adolescents with acne in Hong Kong; the mean CADI score was 2.56.20 In another study,13 the global CADI score was 4.8. It seems that acne had a greater impact on our patients’ QoL (mean CADI=7.46), perhaps because we chose only untreated patients, especially that the CADI global score decreased to 4.6 after treatment.

3 months of treatment in our patients. Even though acne is not a life-threatening disease, the assessment of its impact on QoL is primordial. Conclusions Even though acne may seem trivial, the psychosocial consequences can be heavy and severe enough to result in suicide in some cases. The assessment of its impact on patients QoL is important in adolescents and should be associated with a consideration of emotional distress. Objective and valuable measurement tools, such as the CADI scale, are now available to help physicians understand their patients’ distress and should be used in every patient with acne. References

In our study, we noticed a positive correlation between the clinical severity of acne evaluated with the ECLA scale and its psychological impact on CADI scale, before (r=0.276, P=.012) and after treatment (r=0.399, P<10-3). Particularly, a positive correlation was observed between the overall ECLA score and items 2, 3, and 4 of the CADI scores; however, item 5 (the patients’ perception of their acne severity) was not correlated with acne severity. In contrast, past investigators found no correlation between overall scores of the ECLA and CADI scales. This could be explained by sociocultural differences in the perception of acne. Furthermore, the assimilation of each ECLA score factor to the global CADI score showed that scars have the most impact on patients’ QoL (F3). In our study, the extension of acne lesions to the trunk (F2) was the crucial factor.

1 Kilkenny M, Merlin K, Plunkett A, et al. The prevalence of common skin conditions in Australian school students: 3. acne vulgaris. Br J Dermatol. 1998;139:840–845. 2 Mseddi M, Smaoui F, Abdelmaksoud W, et al. Aspect épidémiologiques et cliniques de l’acné en milieu scolaire. Ann Dermatol Venereol. 2007;134:871–872. 3 Dreno B, Bodokh I, Chivot M, et al. ECLA grading: an acne classification for everyday clinical practice. Ann Dermatol Venereol. 1999;126:136–141. 4 Motley RJ, Finlay AY. Practical use of a disability index in the routine management of acne. Clin Exp Dermatol. 1992;17:1–3. 5 Quality of Life. Cardiff University Web site. www.dermatology.org.uk. Accessed March 26, 2013. 6 Dreno B, Finlay AY, Nocera T, et al. The Cardiff Acne Disability Index: Cultural and Linguistic Validation in French. Dermatology. 2004;208:104–108. 7 Fitzpatrick TB. The validity and practicality of sun-reactive skin type I through VI (Editorial). Arch Dermatol. 1988;124:869–871.

In the literature, study results were controversial concerning the correlation between acne severity and alteration of QoL using other scales. Investigators presented a 9-item acne QoL scale that correlated with clinical acne severity.21 While researchers did not find any correlation between clinical acne severity using GAGS scoring system and CADI score in adult female patients with acne.22 In the same way, no correlation was found between GAGS acne severity score and CADI score in the Chinese study.20

8 Poli F, Dreno B, Verschoore M. An epidemiological study of acne in female adults: results of a survey conducted in France. J Eur Acad Dermatol Venereol. 2001;15:541– 545.

Our results show that QoL is impaired in acne, the most significant domains being social consequences of acne, the impact of the trunk lesions on public behavior, and patients’ psychological state. Furthermore, the dimension of self-perception, which seems to be particularly involved in acne, is not significantly linked to the clinical severity of the disorder. CADI sores, as well as ECLA score, decreased significantly after 1 and

11 James KW, Tisserand JB Jr. Treatment of acne vulgaris. GP. 1958;18:131–139.

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9 Smithard A, Glazebrook C, Williams HC. Acne prevalence, knowledge about acne and psychological morbidity in mid-adolescence: a community-based study. Br J Dermatol. 2001;145:274–279. 10 Costa A, Lage D, Abdalla Moisés T. Acne and diet: truth or myth? An Bras Dermatol. 2010;85:346–353.

12 Doshi A, Zaheer A, Stiller MJ. A comparison of current acne grading systems and proposal of a novel system. Int J Dermatol. 1997;36:416–418. 13 Dreno B, Alirezai M, Auffret N, et al. Clinical and psychological correlation in acne: use of the ECLA and CADI scales. Ann Dermatol Venereol. 2007;134:451–455.

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15 Fried RG, Wechsler A. Psychological problems in the acne patient. Dermatol Ther. 2006;19:237–240.

19 Walker N, Lewis-Jones MS. Quality of life and acne in Scottish adolescent schoolchildren: use of the Children’s Dermatology Life Quality Index (CDLQI) and the Cardiff Acne Disability Index (CADI). J Eur Acad Dermatol Venereol. 2006;20:45–50.

16 Al Robaee AA. Assessment of general health and quality of life in patients with acne using a validated generic questionnaire. Acta Dermatovenerol Alp Panonica Adriat. 2009;18:157–164.

20 Law MPM, Chuh AAT, Lee A, Molinari N. Acne prevalence and beyond: acne disability and its predictive factors among Chinese late adolescents in Hong Kong. Clin Exp Dermatol. 2010;35:16–21.

17 Jones-Caballero M, Chren MM, Soler B, Pedrosa E, Peñas PF. Quality of life in mild to moderate acne: relationship to clinical severity and factors influencing change with treatment. J Eur Acad Dermatol Venereol. 2007;21:219– 226.

21 Gupta MA, Johnson AM, Gupta AK. The development of an acne quality of life scale: reliability, validity and relation to subjective acne severity in mild to moderate acne vulgaris. Acta Derm Venereol (Stockh). 1998;78:451– 456.

18 Takahashi N, Suzukamo Y, Nakamura M, et al. Japanese version of the Dermatology Life Quality Index: validity and reliability in patients with acne. Health Qual Life Outcomes. 2006;4:46.

22 Kokandi A. Evaluation of acne quality of life and clinical severity in acne female adults. Dermatol Res Pract. 2010:1–3. doi: 10.1155/2010/410809. Epub 2010 Jul 27.

14 Picardi A, Mazotti E, Pasquini P. Prevalence and correlates of suicidal ideation among patients with skin disease. J Am Acad Dermatol. 2006;54:420–426.

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May/June 2013

Volume 11 • Issue 3

REVIEW

Cutaneous Mucormycosis Anna Skiada, MD;1 George Petrikkos, MD2 Abstract Mucormycosis is an invasive fungal infection caused by fungi of the order Mucorales, mainly affecting immunocompromised patients. Cutaneous mucormycosis is the third most common clinical form of the disease, after pulmonary and rhino-cerebral. The usual factors predisposing to this infection are hematological malignancies and diabetes mellitus, but a significant proportion of patients are immunocompetent. The agents of mucormycosis are ubiquitous in nature and are transmitted to the skin by direct inoculation, as a result of various types of trauma. These include needle sticks, stings and bites by animals, motor vehicle accidents, natural disasters, and burn injuries. The typical presentation of mucormycosis is the necrotic eschar, but it can present with various other signs. The infection can be locally invasive and penetrate into the adjacent fat, muscle, fascia, and bone, or become disseminated. Diagnosis is difficult because of the nonspecific findings of mucormycosis. Biopsy and culture should be performed. The treatment of mucormycosis is multimodal and consists of surgical debridement, use of antifungal drugs (amphotericin B and posaconazole), and reversal of underlying risk factors, when possible. Mortality rates, although lower than in other forms of the disease, are significant, ranging from 4% to 10% when the infection is localized. (SKINmed. 2013;11:155–160)

ucormycosis is an invasive fungal infection, affecting mainly immunocompromised patients. The most common clinical presentations are pulmonary, rhinocerebral, cutaneous and disseminated, but virtually any organ can be affected. The term mucormycosis is used interchangeably with the term zygomycosis by many authors. High-level taxonomy, however, is currently in a state of flux and it seems that the latter may become obsolete.1,2 Until recently, zygomycosis encompassed both mucormycosis and entomophthoramycosis. Mucormycosis refers to infections caused by fungi of the order Mucorales and entomophthoramycosis to infections caused by fungi of the order Entomophthorales. Entomophthoramycosis is a chronic subcutaneous disease that affects immunocompetent patients in tropical and subtropical areas.3 The two fungal diseases have distinct morphologic, epidemiologic, and pathogenic characteristics and should not be described together by the single term zygomycosis. This paper will review the epidemiology, pathogenesis, clinical manifestations, diagnosis, and treatment of cutaneous mucormycosis.

ports, case series, or registries,5,6 but in recent years there have been several publications that indicate an increased incidence.7,8,9 In a review of 929 cases reported from 1940 to 2004, there were 176 cases of cutaneous mucormycosis,5 while in a review from 2005 to 2008, there were 78 cases.10 The increased number of case reports may reflect an increased awareness of the disease as well as publication bias, but it also reflects an actual increase in incidence.

Epidemiology

The most common underlying diseases in patients with cutaneous mucormycosis are hematological malignancy, solid organ transplantation, and diabetes mellitus, but in about 50% of cases the patients are immunocompetent.5 In an older review, diabetes was

Mucormycosis, although rare, is the third most common invasive fungal infection after candidiasis and aspergillosis.3,4 Its prevalence cannot be estimated precisely because most data are from case re-

Mucormycosis has been reported from all around the world. It remains a threat in patients with hematological malignancies or diabetes mellitus in the western world and it is being increasingly recognized in recently developed countries, such as India and China, mainly in patients with uncontrolled diabetes or trauma.8,11 Of particular note, infections with Apophysomyces elegans and Saksenaea vasiformis occur predominantly in tropical and subtropical climates (Australia, India, Mexico, Sri Lanka, Thailand, Saudi Arabia, United States, Central America, South America).12–20 They are both thermophilic fungi that grow at warm incubation temperatures. Infection typically occurs in the extremities after trauma or in the context of prior skin lesions.

From the 1st Department of Propedeutic Medicine, University of Athens, School of Medicine, Laikon General Hospital1 and the 2nd Department of Internal Medicine, University of Athens, School of Medicine, Attikon General Hospital,2 Athens, Greece Anna Skiada, MD, 1st Department of Propedeutic Medicine, Athens University, Laikon General Hospital, Athens, Greece, M. Asias 75, Goudi 11527 • E-mail: askiada@otenet.gr

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present in 26% of cutaneous cases and leukemia and/or neutropenia in 16%.21 In contrast, in a single-center retrospective review from India, where 26 cases of cutaneous mucormycosis were analyzed, diabetes mellitus was the underlying disease in a much larger proportion of patients (46.2%).8 Prior antifungal prophylaxis with voriconazole has been reported in some cases of mucormycosis and may play a role as a risk factor.6 Mode of Transmission: Pathogenesis The agents of mucormycosis are ubiquitous in nature. They are found in soil and in decaying organic matter, as well as in the air, especially near construction sites.3 Spores can be found in wood, cotton, bread, fruits, vegetables, compost piles, and animal excreta. In cutaneous mucormycosis, the most common mode of transmission is direct inoculation of fungi to the skin, as a result of trauma, while in the other forms of the disease the spores are acquired by inhalation or ingestion. Trauma can be minor, such as that produced by insulin injections,22 or massive, occurring in vehicle accidents, or even by natural disasters, such as tsunamis23 or volcano eruptions.24 There are many types of trauma reported as causes of cutaneous mucormycosis. These include stings by spiders,19 scorpions,20 or other arthropods16; scratches or bites by animals, such as dogs25; punctures by lemon tree thorns,26 palm tree thorns,17 cacti18; and various others. In the category of major trauma there are many case reports of car accidents,26,27 crush injuries,28 and falls.21 As already mentioned, natural disasters may be the cause of multiple cases of cutaneous mucormycosis. In the recent tornado in Joplin, Missouri, there were 13 cases of proven cutaneous mucormycosis caused by Apophysomyces trapeziformis. Only two of these patients had diabetes. The other 11 had no underlying disease.29 Burn injuries are also risk factors for mucormycosis. In addition to the breach of the skin, major burns confer immunosuppression of variable duration.30 A significant proportion of injuries leading to mucormycosis are hospital-acquired. Infection can be the result of needle stick exposures occurring at the site of medicine injection,22,31 catheter insertion,32 or even lumbar puncture,33 or the result of the use of adhesive dressings34 or a variety of healthcare-associated procedures or devices, including antifungal prophylaxis, medication patches, and medical instruments.35 In some occasions, outbreaks of cutaneous mucormycosis caused by a common source have been reported. The species most commonly implicated were Rhizopus arrhizus and Rhizopus microspores.35 Depending on the immunity status of the host, the infection may remain localized, spread to contiguous tissues involving underlySKINmed. 2013;11:155â&#x20AC;&#x201C;160

ing fat, muscles, fascia, and bone, or disseminate hematogenously to other organs. The fungal sporangiospores initially invade the dermis at the site of trauma, prior infection, or skin maceration. In normal hosts, phagocytes kill Mucorales by the generation of oxidative metabolites and the cationic peptides defensins.36 If the function of these phagocytes is in any way impaired, the patient is at increased risk of developing mucormycosis. This can occur for example in neutropenia. Other factors that may affect phagocytes are hyperglycemia and acidosis, as well as corticosteroids. The Mucorales are markedly angioinvasive and produce infarctions and tissue necrosis. This angioinvasion is associated with the ability of the organism to hematogenously disseminate from the original site of infection to other target organs.36 Of note, although the dissemination of mucormycosis from the skin to other organs is relatively common, the reverse, ie, spread of the infection to the skin from an internal organ, is very rare. In a review of 176 cases of cutaneous mucormycosis,5 only 3% had this reverse dissemination. Clinical Presentation Cutaneous mucormycosis is the third most common clinical form of the disease (11%â&#x20AC;&#x201C;19%) after rhinocerebral and pulmonary5,6,37; however, it may be the commonest form seen in children.38 The infection may be gradually onset and slowly progressive or, most often, it may be fulminant, leading to necrosis. In the initial phase, mucormycosis may be localized to a small area of the skin. Patients with invasion into muscle, tendon, or bone are classified as having deep extension of infection and patients with cutaneous disease involving another noncontiguous site are defined as having disseminated infection. In one analysis, 96 (56%) infections were localized, 43 (24%) were accompanied by deep extension, and 35 (20%) were disseminated.5 In the literature review from 2005 to 2008, 19 patients (49%) had localized mucormycosis, 14 (36%) had deep extension, and the remaining 5 (13%) had disseminated disease.10 The upper and lower extremities are the more common sites of mucormycosis, but any area of the skin can be affected. The spectrum of signs and symptoms of mucormycosis is wide. The typical sign of this infection is black necrotic eschar, but many other presentations have been described. In the first stages of disease, the eschar may be absent. A relatively common presentation is a painful, indurated, erythematous lesion of several centimeters diameter, which rapidly progresses to tissue necrosis with or without surrounding blisters.21,39 The infection may lead to necrotizing fasciitis and gangrene.31 The lesions may also mimic pyoderma gangrenosum,40 bacterial synergistic gangrene, or other infections.10 When the disease is disseminated, the patient may have general signs and symptoms of sepsis.

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Another clinical presentation that is typical of mucormycosis is a “fuzzy discharge” at the borders of a wound resembling bread mold.41 In contrast, the presentation may be nonspecific. There have been reports of superficial lesions having only slightly elevated circinate and squamous borders resembling tinea corporis42 or targetoid plaques with an outer erythematous rim, described by some authors as a “bull’s eye” cutaneous infarct.43,44 A completely different presentation of cutaneous mucormycosis has been described from several case reports from China.11,45 The authors in one case report a swollen plaque on the root of the nose, 3.5×2.5 cm in diameter, with dry scales on the surface,45 while in another one they describe a confluent, infiltrated, light-red plaque (18×10 cm) with a clear boundary involving her nose, cheeks, eyelids, and glabella, accompanied by punctiform blood crust formation and slight desquamation.11 The lesions affect in most cases the face, and they are noninvasive and progress very slowly, in the range of 7 months to 18 years. The patients are usually immunocompetent and there is no clear history of trauma. They are all caused by Rhizomucor variabilis. Interestingly, two similar cases, caused by the same species, were recently reported from Japan46 and India.47 In the latter case the patient developed a small, hypopigmented, rubbery, elevated lesion over the cheek, at the age of 6 years. The lesion gradually increased in size and 12 years later, the infection caused destruction of the nasal septum and soft and hard palate, leading to collapse of the nose bridge and an ulcerative gaping hole.47 Diagnosis It is important to make the diagnosis of mucormycosis as soon as possible in order to start treatment and improve outcome. This is often difficult, however, because of the nonspecific signs and symptoms of the disease. Mucormycosis should be suspected in any wound that does nott heal or has signs of necrosis or cottonlike material on its surface. Any new skin lesion in a patient who is at high risk for mucormycosis, because of underlying malignancy or diabetes, should be biopsied and cultured. The biopsy specimen should be taken from the center of the lesion and include subcutaneous fat, because molds frequently invade blood vessels of the dermis and subcutis, resulting in an ischemic cone at the skin surface.48 On histology, mucormycosis is characterized by broad, mostly aseptate hyphae, with irregular branching that occasionally occurs at right angles. Occasionally, septae may be noted. It is prudent to obtain more than one biopsy in order to increase the sensitivity of the method. Identification of the fungi at the genus and species levels requires culture studies; however, in about 50% of cases, culture results are negative.5 The most commonly isolated genera from patients with mucormycosis are Rhizopus, Mucor, Rhizomucor, Lichtheimia (formerly Absidia and Mycocladus), Cunninghamella, Apophysomyces, and Saksenae. Over SKINmed. 2013;11:155–160

the past years, molecular methods have significantly aided in the correct diagnosis of mucormycosis. By using several molecular targets and by increasing the number of available DNA sequences in international databases, several studies have shown that accurate molecular identification of the agents of mucormycosis to species level is feasible.49 When the culture results are negative, diagnosis of mucormycosis and species identification can be made directly from tissues, either on unfixed fresh frozen material or on formalin-fixed, paraffin-embedded biopsies.49,50 Treatment Treatment of mucormycosis is multimodal. The cornerstone of treatment of cutaneous mucormycosis is immediate administration of antifungal medications and extensive surgical debridement. In addition, every effort should be made to reverse predisposing factors, if possible. Amphotericin B deoxycholate is the only drug that has been licensed by the Food and Drug Administration for the treatment of mucormycosis. It has been supplanted by lipid forms of amphotericin B, however, which are less toxic and allow the use of higher doses. Most case reports of mucormycosis treatment with lipid formulations of amphotericin B are with liposomal amphotericin B and amphotericin B lipid complex.36 These drugs should be used in a dosage starting at 3 to 5 mg/kg per day, although occasionally higher doses are needed. The duration of antifungal treatment should be determined on an individual basis, but therapy usually continues for at least 6 to 8 weeks. Posaconazole is the only azole with in vitro activity against the agents of mucormycosis. It has been used as salvage therapy, as continuation of treatment with amphotericin B or in combination with amphotericin B. Some clinicians use posaconazole as first-line treatment for cutaneous mucormycosis. Sensitivity testing is performed in some centers and it may aid in the treatment of this infection. Surgical debridement should be repeated as often as necessary. In a series of upper extremities zygomycoses, patients had an average of 10 surgical debridements (range 4–20).51 In some cases, amputation must be performed in order to save the patient’s life.28 In addition to antifungal medications and surgical debridement, some adjunctive treatments may occasionally prove to be useful. These include hyperbaric oxygen and cytokines that enhance phagocytic activity, such as g-interferon and granulocyte-macrophage colony-stimulating factors. Although there have been reports of successful use of these modalities, their role remains uncertain.52,53 Mortality associated with cutaneous mucormycosis is about 30%.5,10 The prognosis is much better when the infection is localized (10% mortality) and dismal when it is disseminated (>80% mortality).5,10

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Conclusions Cutaneous mucormycosis is a potentially fatal disease. A high index of suspicion may lead to earlier diagnosis, prompt treatment with every available modality, and a chance for a better outcome. References 1 Sun H-Y, Singh N. Mucormycosis: its contemporary face and management strategies. Lancet Infect Dis. 2011;11:301–311 2 Hibbett DS, Binder M, Bischoff JF, et al. A higher-level phylogenetic classification of the Fungi. Mycol Res. 2007;111:509–547. 3 Prabhu RM, Patel R. Mucormycosis and entomophthoramycosis: a review of the clinical manifestations, diagnosis and treatment. Clin Microbiol Infect. 2004;10(suppl 1):31–47. 4 Neofytos D, Horn D, Anaissie E, et al. Epidemiology and outcome of invasive fungal infection in adult hematopoietic stem cell transplant recipients: analysis of Multicenter Prospective Antifungal Therapy (PATH) Alliance registry. Clin Infect Dis. 2009;48:265–273. 5 Roden M, Zaoutis T, Buchanan W, et al. Epidemiology and outcome of zygomycosis: a report of 929 reported cases. Clin Infect Dis. 2005;41:634–653. 6 Skiada A, Pagano L, Groll A, et al; for the European Confederation of Medical Mycology Working Group on Zygomycosis. Zygomycosis in Europe. Analysis of 230 cases accrued by the registry of the European Confederation of Medical Mycology (ECMM) Working Group on Zygomycosis between 2005 and 2007. Clin Microbiol Infect. 2011;17:1859–1867. 7 Bitar D, Van Cauteren D, Lanternier F, et al. Increasing incidence of Zygomycosis (mucormycosis), France, 19972006. Emerg Infect Dis. 2009;15:1395–1401. 8 Chakrabarti A, Das A, Mandal J, et al. The rising trend of invasive Mucormycosis in patients with uncontrolled diabetes mellitus. Med Mycol. 2006;44:335–342. 9 Saegeman V, Maertens J, Meersseman W, et al. Increasing incidence of mucormycosis in university hospital, Belgium. Emerg Infect Dis. 2010;16:1456–1458. 10 Skiada A, Petrikkos G. Cutaneous zygomycosis. Clin Microbiol Infect. 2009;suppl 5:41–45. 11 Xue-lian Lu, Ze-hu Liu, Yong-nian Shen, et al. Primary cutaneous zygomycosis caused by Rhizomucor variabilis: a new endemic zygomycosis? A case report and review of 6 cases reported from China. Clin Infect Dis. 2009;49:e39–e43. 12 Gomes MZ, Lewis RE, Kontoyiannis DP. Mucormycosis caused by unusual mucormycetes, non-Rhizopus, -Mucor, and -Lichtheimia species. Clin Microbiol Rev. 2011;24:411–445. 13 Cooter RD, Lim IS, Ellis DH, Leitch IOW. Burn wound zygomycosis caused by Apophysomyces elegans. J Clin Microbiol. 1990;28:2151–2153. 14 Blair JE, Fredrikson LJ, Pockaj BA, Lucaire CS. Locally invasive cutaneous Apophysomyces elegans infection acquired from snapdragon patch test. Mayo Clin Proc. 2002;77:717–720.

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15 Tanphaichitr VS, Chaiprasert A, Suvatte V, Thasnakorn P. Subcutaneous mucormycosis caused Saksenaea vasiformisin a thalassaemic child: first case report in Thailand. Mycoses. 1990;6:303–309. 16 Bearer EA, Nelson PA, Chowers M, Davis CE. Cutaneous zygomycosiscaused by Saksenaea vasiformis in a diabetic patient. J Clin Microbiol. 1994;32:1823–1824. 17 Al-Hedaithy M. Cutaneous zygomycosis due to Saksenaea vasiformis: Case report and literature review. Ann Saudi Med. 1998;18:428–431. 18 Burrell SR, Ostlie DJ, Saubolle M, Dimler M, Barbour SD. Apophysomyces elegans infection associated with cactusspine injury in an immunocompetent pediatric patient. Pediatr Infect Dis J. 1998;17:663–664. 19 Saravia-Flores M, Guaran DM, Argueta V. Invasive cutaneous infection caused by Apophysomyces elegans associated with a spider bite. Mycoses. 2009;53:259– 261. 20 Lechevalier P, Hermoso DG, Carol A, et al. Molecular diagnosis of Saksenaea vasiformis cutaneous infection after scorpion sting in an immunocompetent adolescent. J Clin Microbiol. 2008;3169–3172. 21 Adam RD, Hunter G, DiTomasso J, Comerci G, Jr. Mucormycosis: emerging prominence of cutaneous infections. Clin Infect Dis. 1994;19:67–76. 22 Chambers CJ, Merin MR, Fung MA, Huntley A, Sharon VR. Primary cutaneous mucormycosis at sites of insulin injection. J Am Acad Dermatol. 2011;64:e79–e80. 23 Andresen D, Donaldson A, Choo L, et al. Multifocal cutaneous mucormycosis complicating polymicrobial wound infections in a tsunami survivor from Sri Lanka. Lancet. 2005;365:876–878. 24 Patino JF, Castro D, Valencia A, Morales P. Necrotizing soft tissue lesions after a volcanic cataclysm. World J Surg. 1991;15:240–247. 25 Zachary D, Chapin K, Binns L, Tashima K. Cutaneous mucormycosis complicating a polymicrobial wound infection following a dog bite. Case Rep Infect Dis. 2011;2011:348046. 26 Petrikkos GL, Skiada A, Sambatakou H, et al. Mucormycosis: ten-year experience in a tertiary-care center in Greece. Eur J Clin Microbiol Infect Dis. 2003;22:753–756. 27 Ayala-Gaytan JJ, Petersen-Morfin S, Guajardo-Lara CE, et al. Cutaneous zygomycosis in immunocompetent patients in Mexico. Mycoses. 2010;53:538–540. 28 Arnaiz-Garcia ME, Alonso-Pena D, del Carmen GonzalezVela M, et al. Cutaneous mucormycosis: report of five cases and review of the literature. J Plast Reconstr Aesthet Surg. 2009;62:e434–e441. 29 Lewis RE. Cutaneous mucormycosis in tornado survivors. Curr Fungal Infect Rep. 2011;5:187–189. 30 Ledgard JP, Sebastiaan van Hal, Greenwood JE. Primary cutaneous zygomycosis in a burns patient: a review. J Burn Care Res. 2008;29:286–290. 31 Chander J, Kaur J, Attri A, Mohan H. Primary cutaneous zygomycosis from a tertiary care centre in north-west India. Indian J Med Res. 2010;3:765–770.

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32 Salati SA, Rabah SM. Cutaneous mucormycosis in a leukemic patient. J Coll Physicians Surg Pak. 2011;21:109– 110.

44 Rubin AI, Grossman ME. Bull’s-eye cutaneous infarct of zygomycosis: a bedside diagnosis confirmed by touch preparation. J Am Acad Dermatol. 2004;51:996–1001.

33 Sankar J, Arun S, Sankar MJ, et al. Primary cutaneous mucormycosis during induction chemotherapy in a child with acute lymphoblastic leukemia. Indian J Pediatr. 2009;76:1161–1163.

45 Zhao Y, Zhang Q, Li L, et al. Primary cutaneous mucormycosis caused by Rhizomucor variabilis in an immunocompromised patient. Mycopathologia. 2009;168:243– 247.

34 Lumbang WA, Caufield BA. Vesicular eruption on the arm of an infant. Dermatol Online J. 2010;16:13.

46 Tomita H, Muroi E, Takenaka M, et al. Rhizomucor variabilis infection in human cutaneous mucormycosis. Clin Experiment Dermatol. 2010;36:305–317.

35 Antoniadou A. Outbreaks of zygomycosis in hospitals. Clin Microbiol Infect. 2009;15 (suppl 5):55–59.

47 Hemashettar BM, Patil RN, O’Donnell K, et al. Chronic rhinofacial mucormycosis caused by Mucor irregularis (Rhizomucor variabilis) in India. J Clin Microbiol. 2011;49:2372–2375.

36 Spellberg B, Edwards J, Jr., Ibrahim A. Novel perspectives on mucormycosis: pathophysiology, presentation and management. Clin Microbiol Reviews. 2005;18:556– 569.

48 Kontoyiannis DP, Lewis RE. Invasive zygomycosis: update on pathogenesis, clinical manifestations and management. Infect Dis Clin N Am. 2006;20:581–607.

37 Chakrabarti A, Chatterjee SS, Das A, et al. Invasive zygomycosis in India: experience in a tertiary care hospital. Postgrad Med J. 2009;85:573–581.

49 Dannaoui E. Molecular tools for identification of Zygomycetes and the diagnosis of zygomycosis. Clin Microbiol Infect. 2009;15(suppl 5):66–70.

38 Chakrabarti A. Cutaneous zygomycosis: major concerns. Indian J Med Res. 2010;131:739–741. 39 Song KR, Wong MS, Yeung C. Primary cutaneous zygomycosis in an immunodeficient infant. A case report and review of the literature. Ann Plast Surg. 2008;60:433– 436.

50 Rickerts V, Mousset S, Lambrecht E, et al. Comparison of histopathological analysis, culture, and polymerase chain reaction assays to detect invasive mold infections from biopsy specimens. Clin Infect Dis. 2007;44:1078– 1083.

40 Kerr OA, Bong C, Wallis C, Tidman MJ. Primary cutaneous mucormycosis masquerading as pyoderma gangrenosum. Br J Dermatol. 2004;150:1212–1234.

51 Moran SL, Strickland J, Shin AY. Upper-extremity mucormycosis infections in immunocompetent patients. J Hand Surgery. 2006;31A:1201–1205.

41 Clauss H, Samuel R. Simultaneous mold infections in an orthotopic heart transplant recipient. Transpl Infect Dis. 2008;10:343–345.

52 Shafer MR. Use of hyperbaric oxygen as adjunct therapy to surgical debridement of complicated wounds. Semin Perioper Nurs. 1993;2:256–262.

42 Oliveira-Neto MP, Da Silva M, Monteiro PC, et al. Cutaneous mucormycosis in a young, immunocompetent girl. Med Mycol. 2006;44:567–570.

53 Gil-Lamaignere C, Simitsopoulou M, Roilides E, et al. Interferon-gamma and granulocyte-macrophage colonystimulating factor augment the activity of polymorphonuclear leukocytes against medically important zygomycetes. J Infect Dis. 2005;191:1180–1187.

43 Hansen JP, Kristiansson AK, Stone MS. A neutropenic child with a purple lesion of the thigh. Pediatr Dermatol. 2007;24:560–561.

SELF ASSESSMENT EXAMINATION W. Clark Lambert, MD, PhD Instructions for Questions 1 and 2: For each numbered question, choose the single most appropriate lettered response. 1

Most cases of cutaneous mucormycosis are transmitted by: a. Direct inoculation of fungi. b. Inhalation. c. Ingestion. d. Direct extension from an internal organ. e. Indirect extension from an internal organ.

A significant proportion of patients with mucormycosis have (an) underlying: a. Diabetes mellitus. b. Solid organ transplant. c. Hematological malignancy. d. No known underlying disease. e. All of these are correct.

From the Departments of Dermatology, Medicine, and Pathology and Laboratory Medicine, Rutgers University-New Jersey Medical School, Newark, NJ Address for Correspondence: W. Clark Lambert, MD, PhD, Professor of Dermatology and Pathology, New Jersey Medical School, 185 South Orange Avenue, Newark, NJ 07103 • E-mail: lamberwc@umdnj.edu

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Instructions for Questions 3–5: For each numbered question, choose as many lettered responses as apply. All, some, one, or none of the lettered responses may be appropriate.

4. Factors that may put patients at risk to develop mucormycosis include: a. Percutaneous inoculation. b. Catheter insertion. c. Lumbar puncture. d. Medication patches. e. Antifungal prophylaxis.

5. Which of the following clinical or histopathological signs exclude a diagnosis of mucormycosis? a. A cutaneous infarct resembling a “bulls eye.” b. A “fuzzy discharge” at the edge of a lesion resembling bread mold. c. Invasion of hyphae into blood vessels. d. Branching of hyphae at right angles. e. Septae within hyphae. ANSWERS TO SELF ASSESSMENT EXAMINATION 1.a. 2.e. 3. a, b, c. 4. a, b, c, d, e. 5. None of the answers is correct.

3. The term “zygomcosis” has been widely used to denote: a. Zygomycosis. b. Mucormycosis. c. Entomophthoramycosis. d. Aspergillosis. e. Candidiasis.

Wax Moulage

“Pemphigus vulgaris” (today: bullous Pemphigoid) made by Otto Vogelbacher in Freiburg im Breisgau (Germany) around 1900. This Moulage was also used in the Dermatology Atlas (Fig. 9) edited by Eduard Jacobi, first edition 1903. Museum of Wax Moulages Zurich, www.moulagen.ch. Courtesy of Michael Geiges, MD

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Lichen Planopilaris: Update on Pathogenesis and Treatment Akerke Baibergenova, MD, PhD, MPH;1 Jeff Donovan, MD, PhD1,2 Abstract Lichen planopilaris (LPP) is considered to be a follicular variant of lichen planus. Clinical variants include classic LPP, frontal fibrosing alopecia, and the Graham-Little-Piccardi-Lassueur syndrome. The pathogenesis of LPP remains to be fully elucidated, but like other cicatricial alopecias involves the irreversible destruction of hair follicle stem cells and loss of a hair follicle’s capacity to regenerate itself. In the early stages of LPP, patients may have scalp pruritus, burning, tenderness, and increased hair shedding. A scalp biopsy shows a lymphocytic infiltrate involving the isthmus and infundibulum. Apoptotic cells present in the external root sheath and concentric fibrosis surrounds the hair follicle. Treatment is prescribed with the goal to alleviate patient symptoms and to halt the progression of hair loss. Treatment involves use of potent topical corticosteroids and/or intralesional corticosteroids. Options for systemic treatment include anti-inflammatory agents such as hydroxychloroquine, tetracyclines, pioglitazones, and immunosuppressive medications such as cyclosporine, mycophenolate mofetil, or systemic corticosteroids. Hair transplantation may also be an option if the disease has been in clinical remission. The management of LPP can sometimes be challenging and additional research is needed to improve outcomes for patients. (SKINmed. 2013;11:161–165)

ichen planopilaris (LPP) is considered to be a follicular variant of lichen planus and is classified as one of the causes of primary cicatricial alopecia (PCA). Distinct clinical variants of LPP include classic LPP, frontal fibrosing alopecia (FFA), and the rare LPP syndrome Graham-Little-Piccardi-Lassueur syndrome, which is a combination of scalp LPP, keratosis pilaris of the trunk and extremities, and nonscarring hair loss of the pubis and axillae.1,2 A recently described entity—fibrosing alopecia in a pattern distribution—has overlapping features of both LPP and androgenetic alopecia and may be an additional subtype of LPP.1,3,4 This has not been universally accepted and therefore will not be discussed in this review. Epidemiology

The exact incidence and prevalence of LPP remains to be clarified, but overall it is a rare condition. Pooled data from 4 tertiary hair research centers in the United States estimated that there were 1.15% to 7.59% new patients with biopsy-proven LPP.5 LPP typically affects people in the 5th and 6th decades of life and is more common in women.6,7 Concurrent lichen planus of the skin and mucosae is estimated to occur in 28%6 to 50%7 of patients with LPP.

The incidence of FFA is also unknown, but it is less common than classic LPP. The majority of affected patients are postmenopausal women.8 Pathogenesis The pathogenesis of LPP remains to be fully elucidated. Laboratory research has recently revealed a few of the molecular processes that govern this obscure condition. It is currently accepted that a fundamental process responsible for all PCAs is the irreversible destruction of hair follicle stem cells, which leads to a loss of the hair follicle’s capacity to regenerate itself.9 Epithelial hair follicle stem cells are located in the bulge region of the hair follicle’s outer root sheath. The bulge region is considered to be one of the hair follicle’s “immune privileged” areas providing an immunosuppressive environment that protects hair follicle steam cells from possible autoimmune inflammation and destruction.10 Collapse of this immune privilege, which makes the bulge region vulnerable to potential autoimmune destruction, could be an important factor in the pathogenesis of PCA.11 An abnormality of sebaceous glands may also be involved in the pathogenesis of PCA. All scarring alopecias are characterized by

From the Division of Dermatology, University of Toronto Sunnybrook Health Sciences Centre, Toronto ON Canada;1 and the Cleveland Clinic Canada, Toronto, ON, Canada2 Address for Correspondence: Akerke Baibergenova, MD, PhD, MPH, Division of Dermatology, University of Toronto, Sunnybrook Health Sciences Centre, 2075 Bayview Avenue, M1-700, Toronto ON, M4N 3M5, Canada • E-mail: akerke_b@yahoo.com

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Figure 1. Photograph of the scalp of a patient with advanced lichen planopilaris.

Figure 2. Close-up photograph of typical lichen planopilaris morphology showing perifollicular erythema and scale.

loss of the sebaceous gland and this may occur early in the course of the disease.12 Although the function of sebaceous glands in humans is still unclear, they are thought to facilitate the coordinated breakdown of the inner root sheath during the hair cycle, which is critical for hair follicle regeneration.13 The most recent theory that supports and helps unify theories of autoimmune destruction and sebaceous gland abnormality is a concept of acquired down-regulation of peroxisome proliferator-activated receptor g (PPAR-g). PPAR-g is one of the ligandactivated transcription factors of the nuclear hormone receptor superfamily. Decreased tissue expression of PPAR-g was reported in LPP lesional skin.14 Because it is a transcription factor, PPARg has multiple important functions in the body. Two that would be the most relevant to the pathogenesis of scarring alopecia are: (1) regulation of lipid homeostasis, particularly differentiation and maturation of sebocytes; and (2) potent anti-inflammatory effects through regulation of cytokine production, adhesion molecule expression, and immune cell function.15 Thus, down-regulation of PPAR-g in the skin could lead to multiple pathologic consequences observed in LPP: accumulation of proinflammatory lipids, local tissue inflammation, and eventually destruction of the pilosebaceous unit. Clinical Presentation In the early stages of LPP, patients may have scalp pruritus, burning, tenderness, and increased hair shedding; however, a small proportion may be completely asymptomatic. Later, the main patient concern becomes the expanding areas of scarring alopecia and the challenge in camouflaging the areas of hair loss. ClasSKINmed. 2013;11:161–165

sically, LPP affects the anterior scalp, but other areas of scalp may also be affected. The main morphological element in the acute phase is follicular-based erythematous papules with keratotic plug along with perifollicular erythema and scale (Figure 1 and Figure 2). These tend to locate at the periphery of the scarring alopecia, corresponding to the active margin of expanding areas of alopecia. This differs from discoid lupus where inflammatory elements are located in the center of the area of hair loss. A positive hair “pull test” may occasionally be present when the LPP is clinically active but is neither sensitive nor specific to LPP. Hair tufting, with fusion of 2 or 3 anagen hair follicles, may occur in the lymphocytic scarring alopecias, but does not generally occur to the degree seen in the neutrophilic scarring alopecias. Unlike classic LPP, FFA displays prominent frontal and frontalparietal hairline recession, often with concomitant thinning or complete loss of the eyebrows. Moreover, FFA is frequently associated with peripheral body hair loss, especially of the upper limbs.6 Although eyebrow and upper limb hair loss clinically appears noninflammatory and nonscarring, the histopathologic changes are very similar to those of the scalp. FFA is usually asymptomatic. Investigations At least one deep 4-mm punch biopsy into and including subcutaneous tissue from a clinically active margin should be obtained in all suspected cicatricial alopecia cases.16 Histopathologic evaluation not only confirms the diagnosis of a cicatricial alopecia, but may also help guide treatment based on the type, location, and degree of the inflammatory cellular infiltrate (mild, moderate, or severe inflammation).

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REVIEW dopelade of Brocq. Follicular mucinosis can also appear similar to FFA in some cases. Course of Disease LPP has a less predictable evolution compared with cutaneous lichen planus. Although spontaneous or treatment-induced remission may be achieved within years of onset, some cases continue for many years. These severe cases may lead to total scalp hair loss with inflammation subsiding when the main antigenic culprit—the hair follicle—is destroyed.1 Treatment LPP is managed with two goals: to alleviate patient symptoms such as pruritus, burning, and pain and to halt the progression of hair loss. Although there are many treatment options for LPP, evidence on their effectiveness is derived from case series and small retrospective studies, which in the hierarchy of clinical evidence are considered to be low to very low quality.19 The virtual absence of well-designed randomized clinical trials on LPP treatments could be attributed to several factors: rarity of this disease, preventing recruitment of sufficient number of patients; unpredictable course of disease, which makes it difficult to monitor the efficacy of treatment; and absence of meaningful and objective endpoints to study. The recent work by the UCSF Hair Center tried to overcome some of these issues by introducing a new outcome measurement scale in LPP: the Lichen Planopilaris Activity Index (LPPAI).20,21 This scale has not yet been validated or widely accepted.

Figure 3. Photomicrograph of lichen planopilaris showing perifollicular fibrosis and lymphocytic infiltrate (magnification ×200). (Courtesy of Dr S. Shachar.)

Histopathology In active stages, a biopsy shows a lymphocytic infiltrate involving the isthmus and infundibulum of the hair follicles (Figure 3). Apoptotic cells are typically present in the external root sheath and concentric fibrosis surrounds the hair follicles. The inflammatory infiltrate may involve the interfollicular epidermis in some cases of LPP. Direct immunofluorescence may demonstrate immunoglobulin deposits in a proportion of cases.17 Compared with classic LPP, biopsies from patients with FFA tend to show more prominent apoptosis and less inflammation; however, the histologic changes in the two conditions are very similar.18 Differential Diagnosis In the early stages, LPP might simulate nonscarring inflammatory dermatoses of the scalp such as seborrheic dermatitis or psoriasis. Later, the main differential is other causes of PCA such as discoid lupus, central centrifugal cicatricial alopecia, and pseuSKINmed. 2013;11:161–165

Treatment of LPP usually starts with potent topical corticosteroids and/or intralesional corticosteroids (Table). Depending on the stage and extent of the disease, systemic treatment could be started simultaneously or added later if the first-line treatment fails. Options for systemic treatment include either anti-inflammatory agents such as systemic corticosteroids, hydroxychloroquine, and tetracyclines or immunosuppressive medications such as cyclosporine and mycophenolate mofetil. A relatively new treatment option for LPP is the PPAR-g agonist pioglitazone hydrochloride. It has been used in a limited number of patients.22,23 As discussed above, the rationale for the use of pioglitazone hydrochloride is based on the evidence of downregulation of the PPAR-g receptor in LPP lesions.14 Although retinoids are considered one of the systemic treatment options in lichen planus,24 their benefit in LPP has not been carefully studied.25 Treatment of FFA generally follows the same principals as for treating LPP. The only exception would be the use of the antian-

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Table. Treatment Options for Lichen Planopilaris Treatment

Type of Study

Estimates of Effectiveness From Published Studies (No.)

Potent topical corticosteroids

Case series

1. Resolution of inflammation in 66% and a mild improvement in 20% (N=30).29 2. Good response in 29% and fair response in 54% (N=24).6 3. 70% improvement (N=20).7

Intralesional corticosteroids

Case series

40% of patients had a good response and 50% had a fair response (N=20)6

Tetracyclines

Case series

55% had a good response and 36% had a fair response (N=11)6

Case reports, and retrospective case series

1. Improvement in LPPAI scores in 69% and 83% of patients after 6 and 12 months, respectively (N=40)20 2. Improvement in 22% (N=9)7

Retrospective case series

Greater than 83% of patients were either complete or partial responders (N=12)30

First-line

Plaquenil

Second-line Mycophenolate mofetil Third-line Improvement in 82% (N=11)7 but relapse rate of 80% within a year

Oral corticosteroids Cyclosporine

Case series

Success rate of 83% (N=12)31 but relapse rate of 40% at 6-month follow-up

PPAR-g agonist (pioglitazone hydrochloride)

One case report and case series

Induction of remission in 20% and significant improvement in 50% of patients (N=24)23

Abbreviations: LPPAI, Lichen Planopilaris Activity Index; PPAR-g, peroxisome proliferator-activated receptor g. Good response: stabilization of the disease with greater than minimal response to treatment, greater than minimal regrowth of hair, and a greater than minimal reduction of symptoms.6 Fair response: unstable disease with minimal response to treatment, minimal regrowth of hair, and minimal reduction of symptoms.6

drogens finasteride and dutasteride. Their use was reported to be successful in a proportion of patients with FFA.26–28 The role of this class of antiandrogen drugs in the algorithm of FFA treatment remains to be clarified. To be effective, all of the listed treatments must be continued for a sufficient length of time. Finally, if LPP has been in clinical remission (preferably confirmed by biopsy) for at least 24 months, surgical options such as a hair transplantation, could be pursued. Wigs, hairpieces, and camouflaging options are safe at any time for patients with scarring alopecia.

options, evidence for their effectiveness is exclusively from case series. There is a need for better research studies in the future and joint efforts from both clinical and basic science research are needed to improve management of LPP. References

Conclusions LPP is one of the more common causes of PCA. Early diagnosis and treatment are critical for preventing widespread scalp involvement. Current pathogenetic theories of LPP support the use of anti-inflammatory and immunosuppressive agents for treatment of LPP. Although there is a list of reported treatment SKINmed. 2013;11:161–165

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1 Assouly P, Reygagne P. Lichen planopilaris: update on diagnosis and treatment. Semin Cutan Med Surg. 2009; 28:3–10. 2 Kubba R, Rook A. Graham Little syndrome: follicular keratosis with cicatricial alopecia. Br J Dermatol. 1975;93(suppl 11):53. 3 Zinkernagel MS, Trueb RM. Fibrosing alopecia in a pattern distribution: patterned lichen planopilaris or androgenetic alopecia with a lichenoid tissue reaction pattern? Arch Dermatol. 2000;136: 205–211. 4 Olsen EA. Female pattern hair loss and its relationship to permanent/cicatricial alopecia: a new perspective. J Investig Dermatol Symp Proc. 2005;10:217–221.

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5 Ochoa BE, King LE Jr, Price VH. Lichen planopilaris: annual incidence in four hair referral centers in the United States. J Am Acad Dermatol. 2008;58:352–353.

18 Poblet E, Jiménez F, Pascual A, Piqué E. Frontal fibrosing alopecia versus lichen planopilaris: a clinicopathological study. Int J Dermatol. 2006;45:375–380.

6 Cevasco NC, Bergfeld WF, Remzi BK, et al. A case-series of 29 patients with lichen planopilaris: the Cleveland Clinic Foundation experience on evaluation, diagnosis, and treatment. J Am Acad Dermatol. 2007;57:47–53

19 Atkins D, Best D, Briss PA, et al; GRADE Working Group. Grading quality of evidence and strength of recommendations. BMJ. 2004;328:1490.

7 Mehregan DA, Van Hale HM, Muller SA. Lichen planopilaris: clinical and pathologic study of forty-five patients. J Am Acad Dermatol. 1992;27(6 pt 1):935–942.

20 Chiang C, Sah D, Cho BK, et al. Hydroxychloroquine and lichen planopilaris: efficacy and introduction of Lichen Planopilaris Activity Index scoring system. J Am Acad Dermatol. 2010;62:387–392.

8 Chew AL, Bashir SJ, Wain EM, et al. Expanding the spectrum of frontal fibrosing alopecia: a unifying concept. J Am Acad Dermatol. 2010;63:653–660.

21 Sperling LC, Nguyen JV. Commentary: treatment of lichen planopilaris: some progress, but a long way to go. J Am Acad Dermatol. 2010;62:398–401.

9 Cotsarelis G. Epithelial stem cells: a folliculocentric view. J Invest Dermatol. 2006;126:1459–1468.

22 Mirmirani P, Karnik P. Lichen planopilaris treated with a peroxisome proliferator-activated receptor gamma agonist. Arch Dermatol. 2009;145:1363–1366.

10 Meyer KC, Klatte JE, Dinh HV, et al. Evidence that the bulge region is a site of relative immune privilege in human hair follicles. Br J Dermatol. 2008;159:1077–1085. 11 Harries MJ, Meyer KC, Chaudhry IH, et al. Does collapse of immune privilege in the hair-follicle bulge play a role in the pathogenesis of primary cicatricial alopecia? Clin Exp Dermatol. 2010;35:637–644. 12 Al-Zaid T, Vanderweil S, Zembowicz A, Lyle S. Sebaceous gland loss and inflammation in scarring alopecia: a potential role in pathogenesis. J Am Acad Dermatol. 2011;65:597–603. 13 Stenn KS. Insights from the asebia mouse: a molecular sebaceous gland defect leading to cicatricial alopecia. J Cutan Pathol. 2001;28:445–447. 14 Karnik P, Tekeste Z, McCormick TS, et al. Hair follicle stem cell-specific PPARgamma deletion causes scarring alopecia. J Invest Dermatol. 2009;129:1243–1257. 15 Harries MJ, Paus R. Scarring alopecia and the PPARgamma connection. J Invest Dermatol. 2009;129:1066– 1070. 16 Olsen EA, Bergfeld WF, Cotsarelis G, et al. Summary of the North American Hair Research Society (NAHRS)sponsored workshop on cicatricial alopecia, Duke University Medical Center, February 10 and 11, 2001. J Am Acad Dermatol. 2003;48:103–110. 17 Tandon YK, Somani N, Cevasco NC, Bergfeld WF. A histologic review of 27 patients with lichen planopilaris. J Am Acad Dermatol. 2008;59:91–98.

23 Baibergenova A, Walsh S. Use of pioglitazone in patients with lichen planopilaris. 22nd World Congress of Dermatology. Abstract FP2011-00987 24 Cribier B, Frances C, Chosidow O. Treatment of lichen planus. An evidence-based medicine analysis of efficacy. Arch Dermatol. 1998;134:1521–1530. 25 Harries MJ, Sinclair RD, Macdonald-Hull S, et al. Management of primary cicatricial alopecias: options for treatment. Br J Dermatol. 2008;159:1–22. 26 Tosti A, Piraccini BM, Iorizzo M, et al. Frontal fibrosing alopecia in postmenopausal women. J Am Acad Dermatol. 2005; 52:55–60. 27 Georgala S, Katoulis AC, Befon A, et al. Treatment of postmenopausal frontal fibrosing alopecia with oral dutasteride. J Am Acad Dermatol. 2009;61:157–158. 28 Katoulis A, Georgala, Bozi E, et al. Frontal fibrosing alopecia: treatment with oral dutasteride and topical pimecrolimus. J Eur Acad Dermatol Venereol. 2009;23:580–582. 29 Chieregato C, Zini A, Barba A, et al. Lichen planopilaris: report of 30 cases and review of the literature. Int J Dermatol. 2003;42:342–345. 30 Cho BK, Sah D, Chwalek J, et al. Efficacy and safety of mycophenolate mofetil for lichen planopilaris. J Am Acad Dermatol. 2010;62:393–397. 31 Reygagne P, Assouly P, Matard B, et al. Oral ciclosporin in lichen planopilaris. Dermatology. 2006;213:59

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Discussions in Dermatology December 5-7, 2013

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Proposed Lecture Topics Murad Alam, MD Emily Altman, MD Mimi Cummings, MD Rhett Drugge, MD Carl Thornfeldt, MD Barry Lycka, MD Haines Ely, MD S. Manjula Jegasothy, MD Cory Maas, MD

Save the Date for the 5th Year of Cosmetic Surgery Forum! General Registration: Pre-Conference Pricing (February 15 - May 31, 2013): $500 Regular Pricing (After May 31, 2013): $600 Grants are available to residents and fellows through the process of application and abstract review. Abstract deadline for initial consideration: August 19, 2013. We will accept alternate applications and abstracts until September 23, 2013. Room Rates: $129-$169/night (Rates good while rooms last)

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May/June 2013

Volume 11 • Issue 3

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

Anonymous Dermatopathologists: A Socioeconomic Solution to a Medical Problem Cindy Wassef, BA;1 Peter C. Lambert, BA, MA;2 Claude E. Gagna, PhD;3 Gretchen Harmon, BA;4 W. Clark Lambert, MD, PhD5 Do not be too moral. You may cheat yourself out of much life. So aim above morality. Be not simply good; be good for something. Henry David Thoreau (1817–1862)

he relationships between clinicians and their dermatopathology facility range from intimate to detached. While some allow for consultation and contact with the evaluating dermatopathologists, others are less informative because of location and accessibility factors. This physical and collegiate distance may lead to a decrease in accuracy and confidence in the delivered results, particularly those of controversial cases, exacerbated by lack of knowledge of the procedures of the laboratory. “Do not be too moral. You may cheat yourself out of much life.” The dermatopathology facility chosen is based on many factors. These include geography, cost, and assignment by various insurance providers. These criteria often limit contact with the laboratory and restrict the freedom of clinicians to send specimens to specialists in particular fields. Clinicians may also be unaware of procedures at laboratories and in what manner specimens are handled. Once a specimen leaves the dermatologist’s office, he or she has no control over how it is handled. Such factors make it difficult for a clinician to confidently diagnose patients without having had access to the dermatopathologist for consultation. In addition, assignment to laboratories by insurance carrier may make it difficult for both doctor and patient to gain access to slides, requiring a myriad of phone calls, authorization forms, and slide shipments from storage facilities. Patients often have no choice in the matter. Insurance carriers have signed contracts with facilities that have provided them with the best financial benefit. Whether the expertise and accuracy of the diagnosis

have been taken into account in these contracts is often not addressed. In addition, with the great number of laboratories and insurance carriers available nationwide, it is not feasible for clinicians to investigate every laboratory to which specimens are sent for accuracy and procedural quality. This also becomes difficult because of the lack of standardization of laboratory practices.1 Results of dermatopathology specimens are often accepted blindly unless the clinical presentation warrants further investigation. Dermatologists often do not examine slides themselves to confirm or contest reported diagnoses, which only further leads to poor clinical care. Because of the constant demand for faster service, laboratory technicians are often rushed to quickly process specimens and pathologists to rapidly deliver diagnostic reports, both at the cost of accurate diagnosis and processing. Laboratories are willing to forgo meticulous procedure in exchange for more rapid specimen processing and cost-effective procedures. Companies often use their rapid turnover time as an advertising point irrespective of whether it is necessary for interventional purposes. Often, the rapidness of reporting does not correlate with the seriousness of the diagnosis and may result in less accurate diagnoses.2 Such speed also prevents the serendipitous observation by dermatopathologists that can often lead to the discovery of previously unidentified lesions. A market focused solely on speed and increased productivity severely hinders the opportunity for spontaneous observation. An example of this was experienced by one of our authors (WCL). During a presentation, slides of a decubitus ulcer were shown.

From Rutgers University–New Jersey Medical School, Newark, NJ;1 St. Georges University School of Medicine, Grenada, WI;2 The Department of Life Sciences, New York Institute of Technology, Old Westbury, NY;3 Rowan University-School of Osteopathic Medicine, Stratford, NJ;4 and Departments of Dermatology, Medicine, and Pathology and Laboratory Medicine, Rutgers University-New Jersey Medical School, Newark, NJ.5 Address for Correspondence: W. Clark Lambert, MD, PhD, Professor of Dermatology and Pathology, New Jersey Medical School, 185 South Orange Avenue, Newark, NJ 07103 • E-mail: lamberwc@umdnj.edu

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With ample time available to view the slides, our author realized that what was being viewed was not an ulcer but rather granulation tissue. Further investigation confirmed the presence of granulation tissue in other lesions, which is a major obstacle to healing and cause of ulcer expansion in these patients. This discovery led to an entirely different area of investigation of these lesions, with follow-up studies or possible therapeutic interventions. Such discoveries cannot as frequently be seen when time constraints and a push for increased productivity at the expense of quality are placed on dermatopathologists. The current procedures regarding who examines specimens can also be puzzling. When one receives a histopathological report, as many as 30 names can be listed of various pathologists who work at the facility, with all of their signatures present on reports. Further investigation reveals that not all of these pathologists are necessarily dermatopathologists; more than likely, only one or two of those listed are specifically board-certified in the field of dermatopathology. Such a presentation leads one to wonder who is actually examining the specimens. Are all specimens examined by dermatopathologists? Are only the difficult cases triaged to their specific specialists? Could there be a limit on the number of specimens referred to dermatopathologists in these facilities, possibly based on financial constraints? One may never know, but in high-volume facilities where only one or a few pathologists listed is a dermatopathologist, it is possible that not all specimens are seen by the dermatopathologist. The process of choosing a laboratory can vary greatly depending on whether an institution is private or public. While private institutions have more freedom to choose laboratories based on processing and evaluation quality, public institutions are usually required to allow all companies an equal opportunity to bid for the contract. Laboratory companies are aware of this and are able to alter prices in order to increase their profit margin while not necessarily providing the quality expected by the institution. Public entities may not receive work that is up to the standards that are desired. â&#x20AC;&#x153;So aim above morality. Be not simply good; be good for something.â&#x20AC;? The manner in which specimens are handled can make a great difference in diagnosis. In one case we encountered, an inflammatory lesion was received to be examined for fungi. The top segment of the sample, an area where fungi commonly reside, had been removed as a result of sectioning. While initial examination did not show signs of fungi, further sectioning in our facility revealed the presence of hyphae in the sample. While our facility would routinely re-section and examine such specimens further, the same cannot be said for all facilities, especially those SKINmed. 2013;11:167â&#x20AC;&#x201C;169

that process larger quantities of specimens. If one is not looking in the right place, it is very easy to misdiagnose lesions. In a larger study, 1445 specimens sent to a dermatopathology laboratory during a 3-month period were examined to see whether additional stains or sections had been made. Of these 1445 cases, additional sectioning was requested for 110 samples. In examining these 110 samples, it was found that re-sectioning provided no new information in the diagnosis for 69 cases and a more accurate diagnosis in 26 and aided in making a diagnosis in 15 cases for which a diagnosis could not have been made from the original sections. In this subset of 15 cases, 9 of the re-sections aided in the diagnosis of a benign neoplasm, 4 aided in the diagnosis of a malignant neoplasm and 1 aided in the diagnosis of inflammatory patterns that had not been previously seen in other sections. The results indicated that deeper sections provided additional diagnostic information in 37.3% of cases and that additional sections were able to help support diagnoses in 23.6% of the original sections and form new diagnoses in 3.7%.1 Clearly, there is value in re-sectioning and reexamination of specimens, and familiarizing oneself with the practices of the dermatopathology laboratory is essential to have confidence in the provided results. Striving beyond the required procedures is what distinguishes dermatopathology facilities from one another. It is also important to know the number of dermatopathologists available at each location and how the diagnosis printed on the report has been reached. While some facilities are equipped with 5 or more dermatopathologists who together possess more than a dozen board certifications and can, if need be, view the same specimen simultaneously through a multi-headed microscope,3 such is not the case for all. Such information must be known by the clinician in order to determine whether an outside consultation is warranted. The same can be said for ordering clinicians. Clinicians should do their best to choose a dermatopathology laboratory based on the reputation of the dermatopathologists, the ease of accessibility to dermatopathologists, timeliness in the handling of specimens, and quality of reports. If clinical diagnosis and histopathological diagnosis do not yield the same result, it is the responsibility of the clinician to consult with the dermatopathologist, take a repeat sample, or ask that the slides be sent to another dermatopathologist for a consultation.4 These things are necessary not only to provide a high-quality diagnosis but also to provide accurate details needed for treatment and prognosis. When clinical and histopathological reports do not match, it is the responsibility of the clinician to request slides and view them. All dermatologists have training in dermatopathology as part of their residency and should be able to access the slides. A more accurate diagnosis can be reached with both a clinical and histological picture available. This integration is a critical role of the dermatologist.

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Conclusions

References

Often, a diagnosis is heavily dependent on the outcome of a histopathological sample. It is important to know and be able to contact the dermatopathology facility and consulting dermatopathologist and to be able to review the slides personally. It is also necessary for the referring clinician to know the processing procedures of each facility and how this may affect the diagnoses reached. Close collaboration of the clinical dermatologist and the dermatopathologist are required for optimum diagnosis and patient care.

1 Maingi CP, Helm KF. Utility of deeper sections and special stains for dermatopathology specimens. J Cutan Pathol. 1998;24:171–175. 2 Bhawan J. The apoptosis of dermatopathology? J Cutan Pathol. 2003;30:225–231. 3 Grant-Kels JM. The whys and wherefores of who reads dermatopathology slides. J Am Acad Dermatol. 2005;53:703–704. 4 McNamara D. Expert gives tips on how to get the most from your dermatopathologist. Skin and Allergy News. International Medical News Group. 2005 March; 42.

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2ND ANNUAL CONGRESS

BANGKOK NOVEMBER 6 - 10, 2013

SAVE THE DATE

NOVEMBER 6 - 10, 2013

2013 DASIL CONGRESS The Hilton Millennium Bangkok Hotel

The Dermatologic & Aesthetic Surgery International League For meeting information or to become an industry partner, visit www.theDASIL.org, or contact DASIL headquarters at HQ@theDASIL.org Abstract submissions due by September 1, 2013 and can be submitted to HQ@theDASIL.org

May/June 2013

Volume 11 • Issue 3

New to the Clinic Noah Scheinfeld, MD, JD, Section Editor

Sklice (Ivermectin) Lotion for the Treatment of Head Lice Noah Scheinfeld, MD, JD

ead lice continues to be a public health issue in the United States.1 Ivermectin lotion was approved by the US Food and Drug Administration (FDA) for the treatment of head lice in Feburary of 2012. The FDA approval of Sklice (Sanofi Pasteur Inc, Swiftwater, PA)2,3 was based on 2 phase III trials in which a total of 781 patients aged 6 months and older were treated with 0.5% ivermectin lotion or placebo applied to dry hair and scalp, followed by rinsing after 10 minutes. A nit comb was not used. The primary efficacy endpoint was the proportion of patients who were free of live lice at day 2 and through day 8 to the final evaluation 14 days following a single application. Significantly more patients in the ivermectin lotion group were louse-free compared with those in the placebo group: 76% in study 1 and 71% in study 2. In one phase III study, 765 patients completed therapy. In the intention-to-treat population, significantly more patients receiving ivermectin than patients receiving vehicle control were louse-free on day 2 (94.9% vs 31.3%), day 8 (85.2% vs 20.8%), and day 15 (73.8% vs 17.6%). Fewer than 1% of patients experienced irritation or pruritus from therapy, and ocular irritation did not occur.4 Ivermectin lotion was well-tolerated and the majority of ivermectin lotion–treated patients were lice-free without any nit combing after 2 weeks. The safety of a novel 0.5% ivermectin lotion and potential for ivermectin absorption after application was investigated in an open-label study in young children. Results from human repeat insult patch test and cumulative irritation test were assessed for any potential cumulative dermal irritation and contact sensitization. There were virtually no reactions[AU: EDIT OK?].5 It can work with one application alone.6 Other concentrations have been tested including 0.15%, 0.25%, and 0.5%, but the 0.5% concentration appears to be the most effective.7 Biology The head louse (Pediculus humanus capitis) is an obligate ectoparasite of humans. These lice are wingless insects that spend their entire life on the human scalp and feed exclusively on hu-

man blood. Humans are the only known hosts of this specific parasite, while chimpanzees host a closely related species, Pediculus schaeffi. Other species of lice infest most orders of mammals and all orders of birds. Treatment There are many chemical and pesticide treatments available that aim to kill louse; however, these often do not affect the eggs (nits). Malathion8 0.5% lotion (Ovide; Taro Pharmaceuticals U.S.A., Inc, Hawthorne, NY) in isopropanol is a weaker cholinesterase inhibitor that was most recently approved by the FDA in 1999 for the treatment of head lice and is available in 59-mL bottles. Malathion 0.5% should be applied to dry hair until the hair and scalp appear to be wet. It should be left on for 12 hours, and care should be taken, as it is flammable. Malathion may be useful for resistant infestations and exerts both lousicidal and ovicidal actions. While it is approved in children 6 years and older, malathion is contraindicated in neonates and infants (younger than 2 years), because there is increased absorption of malathion in children younger than 6 months old, as well as in the elderly and anyone weighing less than 110 pounds (50 kg), especially when malthion is applied repeatedly within a short period. Other agents, newer than malathion, have been developed. Natroba (spinosad) Topical Suspension (ParaPRO LLC, Carmel, IN)9 may be used in children 4 years and older. Spinosad contains benzyl alcohol and is not recommended in infants younger than 6 months, in whom there is potential for increased systemic absorption and resulting toxicity. Spinosad binds selectively to certain ion channels in invertebrate nerve and muscle cells, causing neuronal excitation in insects. After periods of hyperexcitation, lice become paralyzed and die. Spinosad is applied once and repeated in 1 week. Older agents exist for treatment of head lice. Permethrin 1% lotion (Nix, INSIGHT Pharmaceuticals, LLC, Trevose, PA10),

From the Department of Dermatology, Weill Cornell Medical College, New York, NY Address for Correspondence: Noah Scheinfeld, MD, JD, Assistant Clinical Professor of Dermatology at Weil Cornell Medical College, 150 West 55th Street, New York, NY 10019 • E-mail: NSS32@columbia.edu

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which is an over-the-counter agent, is also approved for the treatment of head lice down to the age of 2 months. Ulessfia (Shionogi Inc, Florham Park, NJ),11 which is benzyl benzoate( alcohol), is indicated for the treatment of head lice in children 6 months and older. Head lice have become more of a nuisance as resistance to first-line agents, such as permethrin 1% and pyrethrins, has increased; therefore, newer topical products that provide unique mechanisms of action without current signs of resistance are of particular interest.

References

Physical treatment of head lice without medical therapy has been reported for head lice but is not recommended because of treatment failure. Sometimes wet combing can be useful, but persistence is required because of the life cycle of the louse, and it is recommended that combing be performed once every 3 to 7 days. Another nonmedical treatment involves a machine that uses controlled, heated air to dehydrate the lice and their eggs. Applying a blow-dryer may not have a similar effect, as it has a much higher temperature and may cause burns if overused. After treatment, patients are often instructed to wash all bedding and vacuum all areas in which the head may have been in contact with such as car seats, coat hoods, and sofas. Combs and brushes may be deloused by placing them in boiling water or in Lysol or rubbing alcohol for 10 to 20 minutes. Conclusions Ivermectin lotion is an interesting medication for its possible offlabel use for the treatment of rosacea, as oral ivermectin has been suggested for treatment of some variants of rosacea.12 Where ivermectin lotion will fit into the treatment of head lice or rosacea has yet to be defined.

1 Lebwohl M, Clark L, Levitt J. Therapy for head lice based on life cycle, resistance, and safety considerations. Pediatrics. 2007;119:965–974. 2 Sklice Side Effects Center. http://www.rxlist.com/sklicedrug-center.htm. Accessed January 8, 2013. 3 Sklice drug Information. http://www.centerwatch. com/drug-information/fda-approvals/drug-details. aspx?DrugID=1187. Accessed January 8, 2013. 4 Pariser DM, Meinking TL, Bell M, Ryan WG. Topical 0.5% ivermectin lotion for treatment of head lice. N Engl J Med. 2012;367:1687–1693. 5 Hazan L, Berg JE, Bowman JP, et al. Pharmacokinetics and safety of 0.5% ivermectin lotion for head louse infestations. Pediatr Dermatol. 2013;30:323–328. 6 Single application of ivermectin lotion helps get rid of head lice. BMJ. 2012;345:e7472. 7 Meinking TL, Mertz-Rivera K, Villar ME, Bell M. Assessment of the safety and efficacy of three concentrations of topical ivermectin lotion as a treatment for head lice infestation. Int J Dermatol. 2013;52:106–112. 8 Ovide [package insert]. Hawthorne, NY; TaroPharma; July 2005. 9 Scheinfeld NS. Natroba (spinosad) 0.9% suspension topical suspension for head lice. Skinmed. 2011;9:256. 10 Daily Med. Nix (permethrin) shampoo. http://dailymed. nlm.nih.gov/dailymed/drugInfo.cfm?id=9975 Accessed January 8, 2013. 11 Ulesfia [package insert]. Atlanta, GA; Sciele Pharma; April 2009. 12 Allen KJ, Davis CL, Billings SD, Mousdicas N. Recalcitranpapulopustular rosacea in an immunocompetent patient responding to combination therapy with oral ivermectin and topical permethrin. Cutis. 2007;80:149–151.

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photo capsule

Pancreatic Panniculitis Following Endoscopic Retrograde Cholangiopancreatography Choon Chiat Oh, MBBS (Singapore), MRCP (UK);1 Haur Yueh Lee, MBBS (Singapore), MRCP (UK);1 Mei Fung Michelle Chan, MBBS (UK), FRCPath (UK);2 T. Thirumoorthy, MBBS (Malaya), FAMS, FRCP (Lond), FRCP (Glasg)1

63-year-old Indian woman with a history of cadaveric liver transplant for cryptogenic liver cirrhosis was admitted to the hospital for the management of cholestasis secondary to a biliary stricture. Endoscopic retrograde cholangiopancreatography (ERCP) was performed with dilatation of the biliary stricture and insertion of a biliary stent. Four days following the procedure, she developed tender, erythematous, firm nodules over both shins (Figure 1).

Clinically, pancreatic panniculitis presents with ill-defined, tender, edematous, erythematous, or red-brown nodules that may spontaneously ulcerate and drain an oily brown, sterile, and viscous substance that results from liquefaction necrosis of adipocytes. The histopathology of pancreatic panniculitis shows a predominantly lobular panniculitis without vasculitis. Biopsy specimens from fully developed lesions of pancreatic panniculitis show coagulative necrosis of the adipocytes, leading to ‘‘ghost

Histology of the involved skin showed fat necrosis of the subcutis in a lobular distribution (Figure 2, top). There were anucleate ghost adipocytes with basophilic rimming and amorphous eosinophilic material in the center. Foamy histiocytes and lymphocytes were present (Figure 2, bottom). These findings were consistent with pancreatic panniculitis. This patient had developed abdominal pain hours after ERCP and serum amylase was markedly raised at >4000U/L, which was consistent with acute pancreatitis post-procedure. The painful nodules on her shins improved with bed rest and paracetamol analgesics. Discussion Pancreatic panniculitis occurs in 2% to 3% of all patients with pancreatic disease and is most often associated with pancreatic carcinoma or pancreatitis.1 It is a rare complication in the setting of pancreatic disease in which fat necrosis occurs in subcutaneous tissue and elsewhere.2 The pathogenesis of the pancreatic panniculitis is not well understood. It is thought to be partially the result of a large release of pancreatic enzymes such as lipase, amylase, and trypsin. The trypsin may increase the permeability of the cutaneous blood vessels, enabling lipase and/or amylase to enter the subcutaneous tissue and hydrolyze neutral fatty acids into glycerol and freefatty acids leading to fat necrosis.3

Figure 1. Erythematous and firm nodules over bilateral shins.

From the Department sof Dermatology1 and Pathology,2 Singapore General Hospital, Singapore Address for Correspondence: Choon Chiat Oh, Department of Dermatology, Block 6 Level 9, Singapore General Hospital, Outram Road, Singapore 169608, Republic of Singapore • E-mail: oh.choon.chiat@sgh.com.sg

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photo capsule adipocytes,’’ which are cells that have lost their nucleus. These cells have a thick shadowy wall with a fine basophilic granular or homogeneous material within their cytoplasm as a result of calcium deposits from saponification. Conclusions The most common underlying pancreatic disorders associated with pancreatic panniculitis are acute and chronic pancreatitis, as well as complication of pancreatic carcinoma, frequently of acinar cell type.4 If there is involvement of subcutaneous fat other than the lower extremities, persistent disease, frequent relapses, or ulceration, the possibility of an occult underlying carcinoma of the pancreas should be considered. The incidence of post-ERCP pancreatitis is estimated to be around 5%.5 Pancreatic panniculitis following ERCP pancreatitis is very rare, with only a few case reports described to date.6 References 1 Requena L, Sanchez Yus E. Panniculitis. Part II. Mostly lobular panniculitis. J Am Acad Dermatol. 2001;45:325– 361. 2 Garcia-Romero D, Vanaclocha F. Pancreatic panniculitis. Dermatol Clin. 2008;26:465–470. 3 Milena JL. Metabolic panniculitis: alpha-1 antitrypsin deficiency panniculitis and pancreatic panniculitis. Dermatol Ther. 2010;23:368–374. 4 Heykarts B, Anseeuw M, Degreef H. Panniculitis caused by acinous pancreatic carcinoma. Dermatology. 1999:198:182–183. 5 Cotton PB, Garrow DA, Gallagher J, Romagnuolo J. Risk factors for complications after ERCP: a multivariate analysis of 11,497 procedures over 12 years. Gastrointest Endosc. 2009;70:80.

Figure 2. Histology of the involved skin showed fat necrosis of the subcutis in a lobular distribution (hematoxylin and eosin, original magnification ×40) (top). Histology of involved skin showed foamy histiocytes and lymphocytes (hematoxylin and eosin, original magnification ×200) (bottom).

6 Hu JC, Gutierrez MA. Pancreatic panniculitis after endoscopic retrograde cholangiopancreatography. J Am Acad Dermatol. 2011;64:e72-e74.

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Volume 11 • Issue 3

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

Sporadic Progressive Mucinous Histiocytosis in a Mexican Patient Verónica Narváez-Rosales, MD;1 Marimar Sáez-de-Ocariz, MD;1 Sonia Toussaint-Caire, MD;2 Carlos Ortiz-Hidalgo, MD;3 Francisco Espinosa-Rosales, MD4

A 33 year-old woman presented with numerous 3- to 5-mm red-brown and yellow-brown dome-shaped nodules, primarily located on the scalp, dorsal aspects of the forearms, and lower extremities (Figure 1 and Figure 2). Her lesions started to appear 5 years prior to her consultation with increasing number and without spontaneous regression. Findings from a previous biopsy revealed epithelioid dermatofibroma. The remainder of the physical examination was unremarkable. There were no familial cases of this condition (both the mother and two older sisters were examined).

wo skin biopsies, one from the scalp and the other from the forearm, revealed an ovoid and spindle-shaped histiocyte proliferation in the upper and mid-dermis, with large nuclei and abundant eosinophilic cytoplasm. The surrounding stroma showed thick bundles of collagen fibers separated by abundant mucinous material (Figure 3, left). Proliferative cells

did not show evidence of intracytoplasmatic mucin. Marked metachromasia of dermal interstitial mucin was observed with absence of intracytoplasmic mucin (Figure 3, right). Immunohistochemical studies were negative for both S100 protein and CD1a, and CD68 highlighted around 70% to 80% of the histiocytes in this lesion.

Figure 2. Multiple 2- to 3-mm yellow-brown domeshaped nodules on the dorsal aspects of forearms.

Figure 1. Several 3- to 5-mm reddish dome-shaped nodules on the scalp.

From the Department of Dermatology, National Institute of Pediatrics;1 the Department of Dermatology, Hospital General “Dr. Manuel Gea González”;2 the Department of Pathology, ABC Hospital, Mexico City;3 and the Immunodeficiencies Research Unit, National Institute of Pediatrics,4 Mexico City, Mexico Address for Correspondence: Marimar Saez-de-Ocariz, MD, Department of Dermatology, National Institute of Pediatrics, Insurgentes Sur 3700 C, Insurgentes Cuicuilco, 04530, Mexico City, Mexico • E-mail: mariadelmars@prodigy.net.mx

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Figure 3. Forearm biopsy demonstrating ovoid and spindle-shaped histiocyte proliferation in the upper and middermis, with large nuclei and abundant eosinophilic cytoplasm. The surrounding stroma showed thick bundles of collagen fibers separated by abundant mucinous material (right). Marked metachromasia was observed with Alcian blue stain (left).

The diagnosis of progressive mucinous histiocytosis (PMH) was made and the nature of the disease and the lack of effective treatment was explained to the patient. As a test, two lesions were treated with intralesional triamcinolone (40 mg/dL) on 2 occasions with a slight decrease in size. With the patient’s acceptance, thalidomide was offered (with adequate birth control with two contraceptive methods) at a dose of 100 mg/d, which she received for 1 year (until lost for follow-up), noting a decrease in the size of the lesions on the scalp and flattening of the lesions on the arms without further development of new lesions. Hereditary PMH is a benign non–Langerhans cell histiocytosis. It is characterized by few to numerous skin-colored to redbrown papules, mainly located on the face, hands, forearms, and legs without spontaneous regression.1,2 Some sporadic cases have been described. We report an additional sporadic case in a 33 year-old Mexican woman. The term histiocytosis encompasses a heterogeneous group of diseases classified into: class I (or Langerhans cell histiocytoses), class II (or non–Langerhans cell histiocytoses), and class III (or malignant histiocytoses). PMH is included in class II histiocytoses.3–5 Hereditary PMH was first described in 1988 by Bork and Hoede1 in 3 women of the same family in two different generations, suggesting an autosomal-dominant pattern of inheritance. To date, all hereditary PMH cases have been described in women, but there are some sporadic cases6–8 (Table1,2,4,6–11). As 4 (18%) of 22 cases are sporadic, we suggest that PMH may be a preferable designation. SKINmed. 2013;11:175–178

Generally, the onset of the hereditary form of PMH begins during childhood or adolescence, whereas sporadic patients with PMH develop the disease at older ages, with a mean age of 31±17 years at presentation. It is characterized by an unremitting increasing number of red-brown or skin-colored papules, with predilection on the face, hands, forearms, and thighs without spontaneous regression.9 Histopathologic examination reveals epithelioid histiocytic cells aggregated in a storiform pattern located in the upper and middermis, with no epidermal involvement, and numerous mast cells interspersed among the histiocytic cells. Abundant mucin material with marked metachromasia when stained with Alcian blue is evident.9 On electron microscopy, the histiocytes appear to be epithelioid or spindle-shaped, with large, irregular, and sometimes multilobulated nucleus. The abundant cytoplasm contains numerous inclusions of myelin or zebra bodies and dilated granular endoplasmic reticulum with visible vacuoles. Birbeck granules and lipid accumulation are absent.10 PMH belongs to the monocyte/macrophage lineage characterized by the expression of MS1 protein and CD68—which is sometimes negative4—while CD1a and S100 are negative. Some authors consider this entity as part of an overlapping syndrome or as a different phase of a continuous spectrum with other non– Langerhans cell histiocytoses. PMH was initially considered as a lysosomal storage disease, possibly a sphingomyelin disorder, because of the myeloid and zebra bodies found on ultrastructure. Despite positive staining with

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vimentin, a1-antitrypsin, a 1-antichymotrypsin, and lysozyme, the exact classification of the disease remains to be determined.9 Some authors have proposed that the stored material might be a new phospholipid, but a specific enzymatic defect has yet to be reported. Some investigators10 believe PMH has a relationship with dermatofibroma since younger lesions contain epithelioid histiocytes expressing MS1 protein, whereas the older ones may express CD34 as in dermatofibroma. It is interesting to note that in our case, the first diagnosis considered was an epithelioid dermatofibroma. During further development of lesions, MS1 macrophages undergo progressive mucinous degeneration with loss of macrophage-specific antigens as a result of apoptotic mechanisms.10 Investigators8 have demonstrated factor XIIIa positivity. Factor XIIIa is a transglutaminase present in many cells, including dermal dendrocytes, suggesting that PMH could result as a proliferative disorder of factor XIIIa+ dermal dendrocytes. Factor XIIIa and CD34 were not performed in our case. The immunohistochemical stains used to achieve the diagnosis were CD1a, CD20, cytokeratins AE1-AE3, CD3, CD45, and S-100 protein. Diagnoses needed to be considered in the differential include other non–Langerhans cell histiocytoses such as juvenile xanthogranuloma, which classically presents as a solitary small reddish yellow firm papule with surface telangiectasia, but multiple lesions may develop. Systemic involvement has been reported, and spontaneous regression is the norm. Xanthogranuloma’s histol-

ogy usually presents as poorly defined infiltrates of small histiocytes with foreign body giant cells, Touton cells, and foamy cells. Progressive nodular histiocytoma is characterized by slowly progressive development of papules that may reach a diameter of up to 5 cm with central depression and sometimes painful ulceration. Histology may show spindle-shaped histiocytes and cells that tend to lipidize with pleomorphic inclusion bodies. Generalized eruptive histiocytoma presents with a wider distribution and a tendency to resolve spontaneously. Epithelioid histiocytes are found in skin biopsy without mucin deposits. Mucinoses, such as acral persistent papular mucinosis, do not have a histiocytic infiltrate and lack enhanced cellularity. Focal mucinosis or superficial angiomyxomas are usually solitary lesions. Dermatofibromas are larger in size, and multiple lesions are uncommon when located over the upper limbs or hands. In skin biopsy, histiocytes are arranged in an interlacing pattern and mucinosis is not a feature.2,4,6 To date, no effective treatment is available for PMH. Thalidomide is an oral immunomodulatory agent that has been in clinical use for more than 50 years. Experimental studies have identified that thalidomide reduces expression of the cellular inhibitor of apoptosis protein and potentiates proapoptotic processes such as TRAIL/po2L.12 It also reduces nuclear factor k-light-chain-enhancer of activated B cells and I-kB expression, thereby reducing interleukin 6 expression.13 In addition, thalido-

Table. Reported Cases of PMH Author, Year

Number of Reported Patients

Age at Presentation, y

Number of Affected Generations

Iglesias-Diez (referenced by1),a 1987

11 and 12

Bork & Hoede, 1988

8–11

Bork, 1994

38 and 18

Schröder et al,10 1996

20 and 17

Mizushima et al,6 1997

Sporadic

Wong et al, 1999

21 and 23

Sporadic

Antoni-Bach et al, 2000

2 1 mother and 2 sistersa

Young et al,8 2006

43 and 50

Sporadic

Schlegel et al, 2010

25 and 20

Current case, 2011

Sporadic

Sass et al, 2000 2

Published cases including the present total 19; however, when considering the affected mother and two sisters of the patient reported by other investigators,7 the total number of progressive mucinous histiocytosis (PMH) cases is 22. b One of the published patients was a man. a

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mide decreases vascular endothelial growth factor and reduces angiogenesis and vessel density in the marrow of patients with multiple myeloma.14 The lack of a simple mechanism of action has been confusing in the clinical setting because it is unclear which, if any, biomarker is an appropriate correlate of clinical success or toxicity. Nonetheless, efficacy is certainly seen clinically and validated in severe combined immunodeficiency models of human myeloma.15 Recent data point to its clinical efficacy in solid tumors and myelodysplastic syndrome. Apoptosis induction has been previously related with spontaneous regression in generalized eruptive hystiocitosis (another non–Langerhans cell histyocitosis), supporting a thalidomide mechanism of action responsible for the improvement in our patient.16 References

6 Mizushima J, Nogita T, Higaki Y, Kawashima M. Hereditary progressive mucinous histiocytosis. Int J Dermatol. 1997;36:952–960. 7 Antoni-Bach N, Pfister R, Grosshans E, et al. Hereditary progressive mucinous histiocytosis. Ann Dermatol Vénéréol. 2000;127:400–404. 8 Young A, Olivere J, Yoo S, Martins C, Barrett T. Two sporadic cases of adult-onset progressive mucinous histiocytosis. J Cutan Pathol. 2006;33:166–170. 9 Bork K. Hereditary progressive mucinous histiocytosis: immunohistochemical and ultrastructural studies. Arch Dermatol. 1994;130:1300–1304. 10 Schröder K, Hettmannsperger U, Schmuth M, Orfanos C, Goerdet S. Hereditary progressive mucinous histiocytosis. J Am Acad Dermatol. 1996;35:298–303. 11 Schlegel C, Metzler G, Burgdorf W, Schaller M. Hereditary progressive mucinous histiocytosis: first report in a male patient. Acta Derm Venereol. 2010;90:65–67.

1 Bork K, Hoede N. Hereditary progressive mucinous histiocytosis in women. Arch Dermatol. 1988;124:1225– 1229.

12 Mitsiades N, Mitsiades CS, Poulaki V, et al. Apoptotic signaling induced by immunomodulatory thalidomide analogs in human multiple myeloma cells: therapeutic implications. Blood. 2002;99:4525–4530.

2 Sass A, Andrè J, Song M. A sporadic case of progressive mucinous histiocytosis. Br J Dermatol. 2000;142:133– 137.

13 Bartlett JB, Dredge K, Dalgleish AG. The evolution of thalidomide and its IMiD derivatives as anticancer agents. Nat Rev Cancer. 2004;4:314–322.

3 Luz F, Gaspar A, Kalil-Gaspar N, Ramos-e-Silva M. Os histiócitos e as histiocitoses não Langerhans em Dermatología. An Bras Dermatol. 2003:78:99–118.

14 Kumar S, Witzig TE, Dispenzieri A, et al. Effect of thalidomide therapy on bone marrow angiogenesis in multiple myeloma. Leukemia. 2004;18:624–627.

4. Wong D, Killingsworth M, Crosland G, Kossard S. Heredtary progressive mucinous histiocytosis. Br J Dermatol. 1999;141:1101–1105.

15 Yaccoby S, Johnson CL, Mahaffey SC, et al. Antimyeloma efficacy of thalidomide in the SCID-hu model. Blood. 2002;100:4162–4168.

5 Newman B, Hu W, Nigro K, Gillian A. Aggressive histiocytic disorders that can involve the skin. J Am Acad Dermatol. 2007;56:302–316.

16 Tang X, Shen H, Xu A, et al. Spontaneous regression of generalized eruptive histiocytosis: possible involvement of apoptosis? Int J Dermatol. 2007;46:1073–1075.

VINTAGE LABEL

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Volume 11 • Issue 3

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Giant Metastatic Merkel Cell Carcinoma Rachel Bognet, MD; Christina Thompson, BBA; Carmen Campanelli, MD

A 68-year-old man presented with a rapidly growing, asymptomatic mass on his left mid-back for the past 3 months. The patient’s medical history revealed an intentional 60-pound weight loss over the previous 2 years along with smoking approximately 1 pack of cigarettes per day. On physical examination, a fungating, 11-cm red tumor with palpable broader underlying extension (23 cm total) was present on the left mid-back with distinct red dermal nodules in a dermatomal distribution. In close proximity were two ulcerated nodules, proven histologically to be basal cell carcinomas. In the left groin was massive, fixed lymphadenopathy. A punch biopsy of the tumor was performed, which showed a dense infiltrate of small, round hyperchromatic blue cells that stained positive for CD 56 and pancytokeratin in a perinuclear dot pattern. Tumor cells were negative for CK20, TTF, CK7, and LCA.

computed tomographic scan of the chest, abdomen, and pelvis was performed to evaluate for metastatic disease (Figure 3). In the left abdominal wall were two adjacent masses at the mid-lumbar spine level, whose cumulative dimensions measured 20.4×17.8×9.8 cm. There was lymphadenopathy of the retroperitoneal, retrocrural, bilateral iliac crests, and inguinal nodes. Lymphadenopathy was also seen encasing the inferior vena cava and abdominal aorta, constricting the left ureter and causing hydronephrosis. No lymphadenopathy or metastatic disease was noted in the thorax. The patient received chemotherapy with etoposide 200 mg for 2 days prior to requiring hospitalization on the third day. He passed away 3 weeks later.

is very sensitive for primary cutaneous MCC, its negativity does not preclude diagnosis.3 Conclusions MCC is a rapidly growing tumor and carries a poor prognosis. Poor prognosticators include size >2 cm, central location, high mitotic rate, and nodal involvement. Sentinel node biopsy and radiological studies may be employed for accurate staging. Treatment includes wide local excision with pathologic confirmation of clear margins when possible. Adjunctive radiotherapy is essential for lengthening the time to recurrence and preventing lymphatic spread. No standard chemotherapy regimen exists.

Discussion Merkel cell carcinoma (MCC) is a rare, malignant neuroendocrine tumor that most commonly affects the head and neck of fair-skinned, elderly individuals. The average tumor size is 2 cm, but giant variants have been reported.2 Etiological factors include upregulation of the antiapoptotic B-cell lymphoma 2 gene, UV radiation, and immunosuppression.4 In 2008, discovery of the Merkel cell polyomavirus shed light on the role of viral genome integration in clonal expansion of tumor cells.4 Histologically, Merkel cells demonstrate both neuroendocrine and epithelial differentiation with common epidermotropism. The tumor is comprised of small, round-oval blue cells with vesicular nucleoli, scanty cytoplasm, and inconspicuous nucleoli in sheets and/or a trabecular pattern. The tumor cells classically show reactivity for CK20.1 While CK20 perinuclear dot pattern

Figure 1. An 11-cm tumor on the patient’s back.

From the Department of Dermatology, Jefferson Medical College, Sewell, NJ; Department of Dermatology, Perelman School of Medicine, University of Pennsylvania Address for Correspondence: Christina Thompson, BBA, 15 Woodmere Way, Pennington, NJ 08534 • E-mail: christina1516@comcast.net

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Figure 2. Dense infiltrate of small, round hyperchromatic blue cells in a trabecular pattern (hematoxylin and eosin stain, original magnification ×4).

Figure 3. Computed tomography of the abdomen. There are two adjacent abdominal wall masses at the mid-lumbar spine level. The superior mass measures 11.5×9.4×5.8 cm (left). Just inferior is an 8.9×8.4×4.0-cm mass (right).

References 1 Hanly AJ, Elgart GW, Jorda M, Smith J, Nadji M. Analysis of thyroid transcription factor-1 and cytokeratin 20 separates Merkel cell carcinoma from small cell carcinoma of lung. J Cutan Pathol. 2000;27:118–120. 2 Hapcic K, Panchal J, Stewart J, Levine N. Giant merkel cell carcinoma involving the upper extremity. Dermatol Surg. 2001;27:493–494.

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3 Leech SN, Kolar AJ, Barrett PD, Sinclair SA, Leonar N. Merkel cell carcinoma can be distinguished from metastatic small cell carcinoma using antibodies to cytokeratin 20 and thyroid transcription factor-1. J Clin Pathol. 2001;54:727–729. 4 Virve Koljonen. Merkel cell carcinoma: what we know now. Expert Rev Dermatol. 2010;5:345–355.

Giant Metastatic Merkel Cell Carcinoma

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Volume 11 • Issue 3

CASE STUDY

Oral Squamous Cell Carcinoma of the Mandibular Region Presenting as Multiple Discharging Sinuses: Imperative of Magnetic Resonance Imaging and Computerized Tomography Virendra N. Sehgal, MD; Shruti Sehgal, MDS;1 Rakesh Oberai, MD;2 Prashant Verma, MD;3 Sonal Sharma, MD;4 Pooja Pahwa, MD;5 Sunil Dogra, MD6

A 40-year-old woman presented with red swelling of the right mandibular region of the face. She had several painful, progressive, ulcerative, raised serosanguinous discharging sinuses. The presence of granules and bony contents were not reported. She was an habitual tobacco and betel chewer for the past 20 years. There was no history of injury/trauma over the site in the past. Progressive loss of appetite and body weight was prominent. She was nonambulatory and denied treatment.

kin surface examination was marked by well-demarcated, erythematous, and indurated plaque. The plaque was studded with multiple sinuses, exuding serous discharge, free from granules or bony components. The lesions were present over the right mandible, extending to the angle of the mouth (Figure 1). Cervical lymph glands were apparently normal, while submandibular glands were enlarged. The mucous membrane of the oral cavity was erythematous and intensely indurated, involving the cheeks, gums, and floor of the oral cavity. A Bacillus Calmette-Guérin (BCG) vaccination scar on the left deltoid was prominent. Mycobacterium tuberculosis IgM enzymelinked immunosorbent assay performed on peripheral blood was negative. Antibodies/antigen for the human immunodeficiency virus, HIV I and II, were nonreactive. Standard tuberculin purified protein derivative results were negative. Erythrocytic sedimentation rate (Westergren) was 78 mm/1 h, total leukocyte count was 16,400 cub mm (4000–11,000), and differential was P-87, L-10, E-02, M-01. Findings from blood sugar, glycated hemoglobin, xrays of the chest, and ultrasound of the abdomen were normal.

Fine needle aspiration cytology of the smear(s) from the swelling and sinuses revealed clusters of large polygonal cells with glassy cytoplasm, pleomorphic nuclei, and a few keratinized cells, suggestive of squamous cell carcinoma (SCC). Potassium hydroxide mount for fungal infection was negative. Culture on Sabouraud agar did not yield any fungal growth. Hematoxylin-eosin–stained sections prepared from the biopsy of the representative lesions showed skin with foci of ulceration caused by a tumor in the dermis. It was in the form of nests of round, oval to polygonal cells with a moderate amount of eosinophilic cytoplasm and foci of keratinization. The nuclei were pleomorphic, vesicular with prominent nucleoli. The tumor was surrounded by inflammatory infiltrate (Figure 2), conforming to moderately differentiated SCC. Magnetic resonance imaging (MRI) of the oral cavity was performed on a 1.5T MR (Signa, GE Medical systems, Milwaukee, WI) using turbo spin-echo T1-weighted (T1W), T2-weighted (T2W), short-tau inversion recovery (STIR) sequences in axial

From the DermatoVenereology (Skin/VD) Center, Sehgal Nursing Home, Panchwati-Delhi, Department of Conservative Dentistry and Endodontics, Government Dental College, Raipur,1 Ganash Diagnostic and Imaging Centre, Rohini, New Delhi,2 Departments of Dermatology and STD,3 and Department of Pathology,4 University College of Medical Sciences, and associated Guru Teg Bahadur Hospital, Shahdara Delhi, and Department of Dermatology and Venereology,5 All India Institute of Medical Sciences, New Delhi, Depertment of Dermatology Venereology & Leprology, Postgraduate Institute of Medical Education & Research, Chandigarh,6 India Address for Correspondence: Virendra N. Sehgal MD, DermatoVenerology (Skin/VD) Center, Sehgal Nursing Home, A/6 Panchwati, Delhi-110 033 India • E-mail: drsehgal@ndf.vsnl.net.in

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Figure 1. Erythematous, well-defined plaque with multiple ulcers/sinuses. Figure 2. Section showing skin with unremarkable overlying epidermis and nests of tumor cells infiltrating the underlying dermis. The tumor cells show keratinization with keratin pearls formation (inset) (hematoxylin and eosin stain, original magnification Ă&#x2014;100).

Figure 3a. Axial fast spin-echo (FSE) T2-weighted image showing extensive soft tissue lesion of right lower gingiva invading the surrounding structures (buccal space, notched arrow, lower lip-curved arrow, and sublingual space-arrow head) with destruction of body of right mandible (thick arrow). SKINmed. 2013;11:181â&#x20AC;&#x201C;184

Figure 3b. Axial FSE T2-weighted image shows soft tissue lesion of lower gingiva with destruction of right mandibular ramus (thick white arrow), involvement of retromolar trigone (arrow head), masseter muscle (white arrow), and abutting the medial pterygoid muscle (black arrow).

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Figure 3c. Axial FSE T2-weighted image shows soft tissue lesion of right lower gingiva invading the right buccal space (arrow heads) and enlarged right submandibular lymph node (arrow). Figure 4. Axial computed tomography image shows a large soft tissue lesion of lower gingiva (double white arrow) with destruction of right body of the mandible (black arrow).

and coronal planes (Figure 3a and 3b). Noncontrast computerized tomography (CT) of the oral cavity was also performed on LightSpeed volume CT (GE Medical Systems, Milwaukee, WI) and all images were reconstructed with soft tissue and bone algorithm. MRI showed a well-defined extensive, soft tissue mass, arising from right lower gingiva appearing hypo-intense on T1W, and hyper-intense on T2W/STIR images, which spreads laterally to involve right buccal space including buccinator muscle and lower lip. There was an involvement of masseter muscle, and retro-molar trigone and lesion was found abutting the medial pterygoid muscle, which spread medially to involve the sublingual space. Enlarged necrotic right submandibular lymph nodes were also seen (Figure 3c). The involvement of the right mandibular ramus by the mass was confirmed by CT (Figure 4). Oral SCC (OSCC) is an extraordinary entity that affects all age groups.1 Tobacco and alcohol consumption are its typical risk factors. OSCC is characterized by firm papule(s), nodule(s), and/or plaque(s). It is potentially invasive and may involve the adjoining structures of the oral cavity by contiguity. Its prevalence is worldwide, and has a difficult prognosis.2 Occasionally, OSCC may mimic cervico-facial actinomycosis, cutaneous tuberculosis, SKINmed. 2013;11:181â&#x20AC;&#x201C;184

and dento-cutaneous sinus tracts.3 These conditions need to be excluded by appropriate laboratory investigations. OSCC is a clinical challenge and its pretreatment evaluation by MRI and CT is mandatory. The present case emphasizes its unique and special imaging features characterized by well-demarcated, soft tissue mass, marked infiltration of the surrounding structures, and conspicuous absence of inflammation complimented by presence of necrotic lymphadenopathy. In addition, the origin of the tumor and its extent including mandibular invasion were distinctly identified. Furthermore, the absence of intermediate signal intensity of the mass, absence of inflammatory change, and presence of lymphadenopathy despite a large aggressive mass, were helpful in excluding actinomycosis.4 CT and MRI are helpful in determining the extent of tumor and ensuring adequate surgical margins to improve pretreatment staging. Although mucosal spread can be easily assessed with physical examination, deep extension is better evaluated by using crosssectional imaging rather than endoscopy.5,6 CT is an indispensable adjunct for evaluating OSCC and detecting mandibular invasion. It is imperative in OSCC, because tumors that result in saucerization of the mandibular cortex with

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preservation of mandibular cavity are required to be treated with marginal mandiblectomy. Whereas invasion of medullary cavity may necessitate a segmental mandiblectomy instead.7

carcinoma of the oral cavity in patients aged 45 years and under: a descriptive analysis of 116 cases diagnosed in the South East of England from 1990 to 1997. Oral Oncol. 2003;39:106–114.

SCC accounts for approximately 90% of oral cavity and oropharyngeal malignancies. Familiarity with the anatomic subsites and potential routes of spread allows accurate staging of this disease. Hence, the accurate identification and reporting of key imaging findings are required to be clearly recognized to facilitate the appropriate surgical intervention.8

3 Pahwa P, Sharma VK, Chouhan K, et al. Squamous cell carcinoma presenting as multiple discharging sinuses on the chin. Clin Exp Dermatol. 2011;36:641–644. 4 Park JK, Lee HK, Ha HK, et al. Cervicofacial actinomycosis: CT and MR imaging findings in seven patients. AJNR Am J Neuroradiol. 2003;24:331–335.

Conclusions

5 Mukherji SK, Pillsbury HR, Castillo M. Imaging squamous cell carcinomas of the upper aerodigestive tract: what clinicians need to know. Radiology. 1997;205:629– 646.

Both MRI and CT were found beneficial in determining the origin and extent of the lesions in OSCC.

6 Kimura Y, Sumi M, Sumi T, et al. Deep extension from carcinoma arising from the gingiva: CT and MR imaging features. AJNR Am J Neuroradiol. 2002;23:468–472.

References 1 Zygogianni AG, Kyrgias G, Karakitsos P, et al. Oral squamous cell cancer: early detection and the role of alcohol and smoking. Head Neck Oncol. 2011;3:2. 2 Llewellyn CD, Linklater K, Bell J, et al. Squamous cell

7 Mukherji SK, Isaacs DL, Creager A, et al. CT detection of mandibular invasion by squamous cell carcinoma of the oral cavity. AJR Am J Roentgenol. 2001;177:237–243. 8 Trotta BM, Pease CS, Rasamny JJ, et al. Oral cavity and oropharyngeal squamous cell cancer: key imaging findings for staging and treatment planning. Radiographics. 2011;31:339–354.

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.

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Volume 11 • Issue 3

CASE STUDY

Vesiculobullous Dermatomyositis With Sensory Motor Neuropathy Erhan Ayhan, MD;1 Sule Nergiz Baykara, MD;1 Selver Ozekinci, MD;2 Sema Aytekin, MD1 A 74-year-old man presented with muscle weakness in both legs for a duration of 2 months. Physical examination revealed periorbital edema and erythema, erythema on the neck and chest, erythematous papules on the proximal-distal interphalangeal and metocarpophalangeal joints, crusted plaque lesions on the thighs and around the knees, and bullous and ulcerated lesions in the antecubital and popliteal fossae (Figure 1A and 1B). Some bullous lesions were intact and some were ulcerated. There was severe edema especially in the upper extremities. He had a history of 15-kg weight loss for 4 months. Laboratory findings were remarkable for a white blood cell count of 16.0 K/UL (4.60–10.20 K/UL), a C-reactive protein of 6.93 mg/dL (0–0.5 mg/dL), an erythrocyte sedimentation rate of 50 mm/h (8–15 mm/h), an aspartate aminotransferase level of 213 U/L (10–40 U/L), a lactate dehydrogenase of 447 U/L (<225 U/L), and a creatine kinase level of 1733 U/L (29–200 U/L). Results from antinuclear antibody at 1:320 titers and anti-smooth muscle antibody were positive. Results from anti-SS A/SS B antibodies, anti Jo-1 antibody, U1-snRNP antibody, and anti-ds DNA antibody tests were negative. A skin biopsy specimen obtained from the right antecubital fossa showed minimal orthokeratosis and subepidermal detachments. There was marked edema in the dermis and lymphocyte infiltration around the skin appendages (Figure 2). Direct immunofluorescence studies demonstrated scattered staining for C3 and IgM at the basal membrane zone. Results for IgG, IgA, and fibrin staining were negative. Muscle biopsy from left deltoid muscle was performed and some muscle fibers were demonstrated to be atrophied. There was remarkable difference between muscle fiber diameters. With Masson staining, there was increased connective tissue and no inflammation. Electromyography (EMG) showed a myogenic pattern. Nerve conduction studies showed tibial, median, ulnar, peroneal motor neuropathy, and median, ulnar, and sural sensory neuropathy. Based on these findings, diagnosis of vesiculo-bullous dermatomyositis (DM) was made. Further investigation of esophagogastroduodenoscopy with biopsy revealed ulcerated lesions on antrum and corpus and these were assessed as Helicobacter pylori–negative atrophic chronic gastritis. No pathologic findings were described on chest, abdomen, and pelvic tomography. Levels of tumor markers were within normal ranges. Overall, no sign of malignancy was detected. Methyl prednisolone treatment of 1 mg/kg/d was started; however, new bullous lesions erupted while the original lesions were healing.

Discussion DM is an autoimmune inflammatory disease involving the skin and the muscle.1 Gottron’s papules, periorbital heliotrope dermatitis, periungual erythema or nail fold telangiectasia, and poikiloderma are characteristic manifestations of DM.2 Rarely, large, persistent ulceration in flexural areas such as antecubital and popliteal fossa or over pressure points may develop.3 Friction strength, pressure, severe edema, and mucin deposition have been thought to be the most important factors in the development of bullae in lesions of DM.2 The association of DM with internal malignancy has been reported to occur in 10% to 40% of patients.4 Investigators evaluated 15 patients with DM and determined that most patients were of East Asian origin and women. The incidence of malignancy in patients was 10 of 15 (67%). Of the 7 women

with malignancy, 5 had a gynecological cancer, 1 had a mammary carcinoma, and 1 had gastric carcinoma.5 These findings suggest that vesiculo-bullous DM may be associated with a higher risk of malignancy than typical DM, especially gynecological cancers in women, and, hence, a worse prognosis.2 No internal malignancy was detected in this case despite all investigations; however, one patient is still undergoing close follow-up because of the high risk of malignancy. Abnormal EMG findings are between the diagnostic criteria in DM.6 Researchers reviewed EMG findings of 186 patients with DM/polimyositis and demonstrated that myogenic lesions in 177 (95.2%) patients, 37 (19.9%) patients had pure motor involvement and 34 (18.3%) had peripheral neuropathy. Of the 34 patients with peripheral neuropathy, 14 (7.5%) described polyneuropathy. Myogenic combined with neurogenic lesions was found in only 1 patient (0.5%). The prevalence of malignancy

From the Department of Dermatology1 and Pathology,2 Dicle University School of Medicine, Diyarbakır, Turkey Address for correspondence: Erhan Ayhan, MD, Department of Dermatology, Dicle University School of Medicine, Diyarbakır, Turkey • E-mail: nanodunya@hotmail.com

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Figure 2. Atrophic epidermis with increased melanin and vacuolization of basal layer, with mild lichenoid lymphocytic infiltrate and pigment incontinence (hematoxylin and eosin stain Ă&#x2014;400).

Figure 1. (A) Ulcerated bullous lesion on the right antecubital fossa. (B) Complete remission of ulcerated bullous lesion after treatment with 1 mg/kg/d of methyl prednizolon for 6 weeks (arrow) and new bullous lesion formation between folding lines on the right antecubital fossa (star).

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was also found to be significantly higher in DM with peripheral neuropathy.7 Of interest in our patient, associated sensory motor neuropathy and myogenic lesions was described. The association between vesicles-bullae, myogenic lesions, and sensory motor neuropathy in DM might be the first case reported in the literature. DM usually presents with IgM and C3 deposition at the basal membrane zone.8 Although, in vesiculo-bullous DM, direct immunofluorescence findings rarely occur.2,5 In our case, IgM and C3 was deposited as scattered at the basal membrane zone. Other investigators serologically studied 35 patients with DM: 9 patients showed positive results for antinuclear antibody, 1 showed positive results for extractable nuclear antibody, and all 35 showed negative results for anti-Jo-1. Eight patients described other circulating autoantibodies, namely thyroid (3), gastric parietal cell (2), smooth muscle (2), and rheumatoid factor (1).8 In our patient, results for antinuclear and anti-smooth muscle antibodies were positive; however, hepatic or biliary diseases were not observed.

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Conclusions Vesiculo-bullous lesions and peripheral neuropathy such as sensory motor neuropathy may be a sign of malignancy with DM patients. Although, in DM, development of vesicular and bullous lesions is rarely seen; therefore, dermatologists should consider vesiculo-bullous DM in the differential diagnosis of bullous diseases. Early diagnosis of the disease is important because of the high risk of malignancy, and more detailed investigations are required. References 1 Nishigori K, Yamamoto T, Yokozeki H. Vesiculo-bullous dermatomyositis: report of three cases. Dermatol Online J. 2009;15:6. 2 McCollough ML, Cockerell CJ. Vesiculo-bullous dermatomyositis. Am J Dermatopathol. 1998;20:170–174. 3 Maruani A, Armingaud P, Nseir A, et al. Erythroderma

and multiple cutaneous necrosis revealing a dermatomyositis. Ann Dermatol Venereol. 2003;130:353–356. 4 Callen JP. Relation between dermatomyositis and polymyositis and cancer. Lancet. 2001;357:85–86. 5 Tsung-Hua T, Pa-Fan H, Hsin-Yi S, et al. Bullous dermatomyositis associated with gastric carcinoma: a case report. Dermatol Sinica. 2004;22:243–247. 6 Bohan A, Peter JB. Polymyositis and dermatomyositis. N Engl J Med. 1975;292:344–347, 403–407. 7 Wang Y, Cui L, Chen L. Nerve conduction studies in patients with dermatomyositis or polymyositis. Chin Med J (Engl). 2010;123:523–526. 8 Jones SA, Black MM. The value of direct immunofluorescence as a diagnostic aid in dermatomyositis-a study of 35 cases. Clin Exp Dermatol. 1997;22:77–81.

Historical Diagnosis and treatment: eczema varicosum (continued from page 184)

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Please forward your completed application for processing to: Larry Millikan, MD, Secretary-Treasurer General Ms Sandy Silverstein, Executive Secretary 10029 Lynnberry Place Raleigh, NC 27617, USA IACDWorld@yahoo.com

May/June 2013

Volume 11 • Issue 3

correspondence

Congenital Triangular Alopecia: An Imitator of Alopecia Areata Reza Yaghoobi, MD;1 Elena Yaghoobi, MD, GP;1 Amir Feily, MD2,3 To the Editor: A 7-year-old boy born from nonconsanguineous parents presented with normal appearance. They noticed a localized triangular area of hair loss over his bi-temporal region from infancy that remained persistent since its appearance. There was no history of trauma and no family members were similarly affected. No treatment had yet been offered. Physical examination was notable for two 4×2.5cm diameter nonscarring patches of alopecia over his bi-temporal regions with apex toward the vertex. A small island of 6 or 7 terminal dark hairs was observed on each side (Figure 1). The histopathology of a scalp lesion showed a significantly reduced number of hair follicles with some indeterminate ones (Figure 2).

Congenital triangular alopecia (CTA), also called temporal triangular alopecia or Brauer nevus, was first reported by Sabouraud in 1906.1 It is a nonscarring form of alopecia involving the temporal region in almost triangular shape.2 Approximately 52 cases have been currently reported.3 CTA is present at birth but is usually first noticed during infancy.4 It often occurs sporadically; nevertheless, several familial cases have been described.4 CTA usually presents as nonscarring patches of alopecia over bi-temporal regions with sometimes a small island of terminal hairs.1 From a histopathological point of view, usually a normal number of vellus or indeterminate hair follicles is seen in CTA.5 Although androgenetic alopecia may overlap with this condition making diagnosis

Figure 1. Patch of triangular nonscarring alopecia with an island of terminal hairs.

Figure 2. A significantly reduced number of hair follicles and some indeterminate hair follicles (hematoxylin-eosin ×100).

From the Department of Dermatology, Jundishapur University of Medical Sciences, Ahvaz, Iran;1 The Skin and Stem Cell Research Center, Tehran University of Medical Sciences, Tehran, Iran;2 Department of Dermatology, Honari Clinic, Jahrom University of Medical Sciences, Jahrom, Iran3 Address for Correspondence: Amir Feily, MD, Department of Dermatology, Honari Clinic, Motahari Street, Jahrom, Iran • E-mail: Dr.feily@yahoo.com

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of the condition challenging, CTA is the key differential diagnosis of alopecia areata, which is important to consider because inadvertent treatment with steroids can leads to adverse events.3 The cause of congenital triangular temporal alopecia is unknown and, remarkably, there is no specific treatment for this condition.1,4 Accordingly, the aim of this paper is to enlighten our colleagues about this rare case to prevent indiscriminate use of corticosteroids in such cases.

Can Med Assoc J. 1984;131:1253-1254. 2 García-Hernández MJ, Rodríguez-Pichardo A, Camacho F. Congenital triangular alopecia (Brauer nevus). Pediatr Dermatol. 1995;12:301-303. 3 Gupta LK, Khare A, Garg A, Mittal A. Congenital triangular alopecia: a close mimicker of alopecia areata. Int J Trichology. 2011;3:40-41. 4 Happle R. Congenital triangular alopecia may be categorized as a paradominant trait. Eur J Dermatol. 2003;13:346-347. 5 Trakimas C, Sperling LC, Skelton HG, 3rd, Smith KJ, Buker JL. Clinical and histologic findings in temporal triangular alopecia. J Am Acad Dermatol. 1994;31: 205209.

References 1 Happle R. The group of epidermal nevus syndromes 1. Bargman H. Congenital temporal triangular alopecia.

Celecoxib-Induced Bullous Pemphigoid Charmaine Apap, MD, MRCP(UK);1 Michael J. Boffa, MD, FRCP(Lond), FRCP (Edin), MSc(Lond);1 John Cordina, MD, FRCP (Edin)2 To the Editor:

Management

A 67-year-old woman was initially seen in the geriatric clinic with a blistering eruption on the legs. She had been prescribed celecoxib for knee pain a few days earlier; however, she took only 2 tablets as later that same day, she fell, fracturing her right humerus. Within 3 days, small red pruritic macules appeared on both legs, developing into painful blisters the following day. The blisters became confluent in places, particularly on the dorsum of the feet and around the ankles.

A skin biopsy from the dorsum of the left foot was consistent with bullous pemphigoid (BP), showing a subepidermal blister with mainly lymphocytes and scattered eosinophils at the blister base. Direct immunofluorescence staining was negative. Epidermal basal membrane antibodies were not detected in the serum. Results of full blood cell count plus liver and renal function studies were unremarkable. The patient had a history of type 2 diabetes, hypertension, hyperlipidaemia, and osteoarthritis and was taking bendrofluazide, glibenclamide, enalapril, metformin, aspirin, simvastatin, diazepam, and ascorbic acid, all of which she had been taking for several years. She reported being allergic to penicillin.

When first seen at the dermatology department, the signs had been present for about 13 days, with several large and a few small blisters present from the legs to the dorsal surface of the feet. There was also dependent edema but no erythema or blistering elsewhere and no mucosal lesions.

She was admitted and treated with tetracycline 500 mg and nicotinamide 500 mg 3 times daily. Within a few days the blisters became denuded, leaving shallow ulcers (Figure), which healed

From the Department of Dermatology, Sir Paul Boffa Hospital, Floriana, Malta;1 and the Department of Geriatrics, Rehabilitation Hospital Karin Grech, Guardamangia, Malta2 Address for Correspondence: Charmaine Apap, MD, Sir Paul Boffa Hospital, Department of Dermatology, VLT 14, Floriana, Malta • Email: charmaineapap@hotmail.com

SKINmed. 2013;11:189–191

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May/June 2013

CORRESPONDENCE

completely and without scarring within 6 weeks. No new blisters appeared during her admission. Tetracycline and nicotinamide were stopped 3 weeks after being started. Follow-up 6 months post-discharge showed no recurrence of blisters.

triggered by a drug but with a course more consistent with classic, spontaneously occurring disease.3 Our patient followed the first pattern.

Discussion

That celecoxib was the likely cause of BP in this patient is supported by the temporal relation of the appearance of the skin lesions to the time of starting the drug and the fact that no new blisters appeared after the initial crop as well as the quick resolution and nonrecurrence after stopping the medication (using minimal treatment). It is remarkable that blistering occurred after only 2 tablets of the drug. Our report highlights the importance of considering possible drug causes in cases of BP.

BP is the commonest autoimmune blistering disease. It occurs predominantly in the elderly and can cause considerable morbidity. Rarely, BP may be triggered by medications. Although many different drugs, including furosemide, captopril, enalapril, phenacetin, penicillins, sulfasalazine, psoralen with UVA, and neuroleptics have been described to provoke BP, a thorough literature search showed that there has been only one other reported case of celecoxib-induced BP thus far.1 The exact mechanism by which drugs elicit BP remains unclear but several hypotheses have been suggested.2 These include the theory that they may act as a hapten, binding to and thus altering the antigenic properties of the basement membrane.2,3,4 It has also been suggested that they may dysregulate the immune response of B-lymphocytes, leading to the formation of autoantibodies.2,3,4 In addition, as sulphur-containing drugs are the ones most commonly associated with drug-induced BP, it is thought that these drugs may cause a biochemical dermo-epidermal splitting.2,4 Interestingly, celecoxib has a sulphonamide component in its structure.

Conclusions

Acknowledgment Dr F. Casha provided the clinical photographs for this contribution. References

Drug-induced BP has been classified into two types: the first is acute and self-limiting, with rapid resolution after stopping the drug; and the second variant is a more chronic type that seems

1 Yang D, Brownell I, Duvic M. Celecoxib-induced bullous pemphigoid: report of the first case. Internet J Anesthes. 2003;14:2. 2 Lee JJ, Downham T. Furosemide-induced bullous pemphigoid. J Drugs Dermatol. 2006;5:562–564. 3 Baz K, Ikizoglu G, Kaya TI, et al. Furosemide-induced bullous pemphigoid. J Eur Acad Dermatol Venereol. 2002;16:81–82. 4 Ruocco V, Sacerdotti G. Pemphigus and bullous pemphigoid due to drugs. Int J Dermatol. 1991;30:307–312.

Figure. Superficial ulcers and a few residual blisters on the lower limbs of our patient a few days after presentation. SKINmed. 2013;11:189–191

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SORILUX

™

BRIEF SUMMARY Mothers (calcipotriene) Foam, 0.005% Nursing It is not known whether calcipotriene is excreted in human milk. Because

The following is a brief summary only; see full prescribing information for complete product information.

INDICATIONS AND USAGE

SORILUX Foam is indicated for the topical treatment of plaque psoriasis of the scalp and body in patients 18 years and older.

CONTRAINDICATIONS

many drugs are excreted in human milk, caution should be exercised when SORILUX Foam is administered to a nursing woman.

Pediatric Use

Safety and effectiveness of SORILUX Foam in pediatric patients less than 18 years of age have not been established.

Geriatric Use

WARNINGS AND PRECAUTIONS

Clinical trials of SORILUX Foam did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients.

Flammability

Unevaluated Uses

SORILUX Foam should not be used by patients with known hypercalcemia.

The propellant in SORILUX Foam is flammable. Instruct the patient to avoid fire, flame, and smoking during and immediately following application.

Effects on Calcium Metabolism

Transient, rapidly reversible elevation of serum calcium has occurred with use of calcipotriene. If elevation in serum calcium outside the normal range should occur, discontinue treatment until normal calcium levels are restored.

Risk of Ultraviolet Light Exposure

Instruct the patient to avoid excessive exposure of the treated areas to either natural or artificial sunlight, including tanning booths and sun lamps. Physicians may wish to limit or avoid use of phototherapy in patients who use SORILUX Foam. [See Nonclinical Toxicology (13.1).]

ADVERSE REACTIONS Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in 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 clinical practice. SORILUX Foam was studied in four vehicle-controlled trials. A total of 1094 subjects with plaque psoriasis, including 654 exposed to SORILUX Foam, were treated twice daily for 8 weeks. Adverse reactions reported in ≥1% of subjects treated with SORILUX Foam and at a higher incidence than subjects treated with vehicle were application site erythema (2%) and application site pain (3%). The incidence of these adverse reactions was similar between the body and scalp.

DRUG INTERACTIONS

No drug interaction studies were conducted with SORILUX Foam.

USE IN SPECIFIC POPULATIONS Pregnancy

Teratogenic Effects, Pregnancy Category C: There are no adequate and well-controlled trials in pregnant women. Therefore, SORILUX Foam should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Studies of teratogenicity were done by the oral route where bioavailability is expected to be approximately 40-60% of the administered dose. Increased rabbit maternal and fetal toxicity was noted at 12 mcg/kg/day (132 mcg/m2/day). Rabbits administered 36 mcg/kg/day (396 mcg/m2/day) resulted in fetuses with a significant increase in the incidences of incomplete ossification of pubic bones and forelimb phalanges. In a rat study, doses of 54 mcg/kg/day (318 mcg/m2/day) resulted in a significantly higher incidence of skeletal abnormalities consisting primarily of enlarged fontanelles and extra ribs. The enlarged fontanelles are most likely due to calcipotriene’s effect upon calcium metabolism. The maternal and fetal no-effect exposures in the rat (43.2 mcg/m2/day) and rabbit (17.6 mcg/m2/day) studies are approximately equal to the expected human systemic exposure level (18.5 mcg/m2/day) from dermal application.

SORILUX Foam has not been evaluated in patients with erythrodermic, exfoliative, or pustular psoriasis.

OVERDOSAGE

Topically applied calcipotriene can be absorbed in sufficient amounts to produce systemic effects. Elevated serum calcium has been observed with use of topical calcipotriene. [See Warnings and Precautions (5.2).]

NONCLINICAL TOXICOLOGY Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis Calcipotriene topically administered to mice for up to 24 months at dose levels of 3, 10, or 30 mcg /kg/day (corresponding to 9, 30, or 90 mcg /m2/day) showed no significant changes in tumor incidence when compared to controls. In a study in which albino hairless mice were exposed to both UVR and topically applied calcipotriene, a reduction in the time required for UVR to induce the formation of skin tumors was observed (statistically significant in males only), suggesting that calcipotriene may enhance the effect of UVR to induce skin tumors. [See Warnings and Precautions (5.3).]

Mutagenesis The genotoxic potential of calcipotriene was evaluated in an Ames assay, a mouse lymphoma TK locus assay, a human lymphocyte chromosome aberration assay, and a mouse micronucleus assay. All assay results were negative. Impairment of Fertility Studies in rats at doses up to 54 mcg /kg/day (318 mcg /m2/day) of calcipotriene indicated no impairment of fertility or general reproductive performance.

PATIENT COUNSELING INFORMATION

See FDA-approved Patient Labeling (Patient Information) in full Prescribing Information. Inform the patient to adhere to the following instructions: • Avoid excessive exposure of the treated areas to either natural or artificial sunlight, including tanning beds and sun lamps. • Avoid contact with the face and eyes. If SORILUX Foam gets on the face or in or near their eyes, rinse thoroughly with water. • Apply SORILUX Foam to the scalp when the hair is dry. • Talk to your doctor if your skin does not improve after treatment with SORILUX Foam for 8 weeks. • Wash your hands after applying SORILUX Foam unless your hands are the affected site. • Avoid fire, flame, and smoking during and immediately following application since SORILUX Foam is flammable. • Do not place SORILUX Foam in the refrigerator or freezer. SOR:5BRS

INDICATED FOR

My doctor has prescribed SORILUX Foam for my scalp and body plaque psoriasis...

PLAQUE PSORIASIS OF THE SCALP AND BODY IN PATIENTS 18 YEARS AND OLDER

My Life. My Treatment.

The only single-agent vitamin D3 treatment available in a foam formulation for both scalp and body plaque psoriasis in patients 18 years and older VersaFoam® -AEF: Aqueous-based Emulsion Foam Formulation Free of ethanol, preservatives, parabens, and fragrance SORILUX Foam, with VersaFoam technology, penetrates the skin barrier to deliver the molecule into the epidermis and dermis1 The contribution to efficacy of individual components of the vehicle has not been established.

Important Safety Information for SORILUX Foam SORILUX Foam should not be used by patients with known hypercalcemia The propellant in SORILUX Foam is flammable. Instruct the patient to avoid fire, flame, and smoking during and immediately following application Transient, rapidly reversible elevation of serum calcium has occurred with use of calcipotriene. If elevation in serum calcium outside the normal range should occur, discontinue treatment until normal calcium levels are restored Instruct the patient to avoid excessive exposure of the treated areas to either natural or artificial sunlight, including tanning booths and sun lamps. Physicians may wish to limit or avoid use of phototherapy in patients who use SORILUX Foam

Please see Brief Summary of Prescribing Information on the next page.

Adverse reactions reported in ≥1% of subjects treated with SORILUX Foam and at a higher incidence than subjects treated with vehicle were application site erythema (2%) and application site pain (3%). The incidence of these adverse reactions was similar between the body and scalp SORILUX Foam should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus It is not known whether calcipotriene is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when SORILUX Foam is administered to a nursing woman Safety and effectiveness of SORILUX Foam in pediatric patients less than 18 years of age have not been established SORILUX Foam has not been evaluated in patients with erythrodermic, exfoliative, or pustular psoriasis SORILUX Foam is not for oral, ophthalmic, or intravaginal use

Reference: 1. Data on file, Stiefel Laboratories, Inc. SORILUX is a trademark and VersaFoam is a registered trademark of Stiefel Laboratories, Inc. ©2013 Stiefel Laboratories, Inc. All rights reserved. Printed in USA. SLX127R0 April 2013